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Áiáëiîòåêà ñòóäåíòà-ìåäèêà Medical Student’s Library GENERAL PHARMACOLOGY

GENERAL PHARMACOLOGY

ОДЕСЬКИЙ МЕДУНІВЕРСИТЕТ

Medical Student’s Library

Initiated in 1999 to mark the Centenary of the Odessa State Medical University (1900 — 2000)

Edited and Published by V. M. ZAPOROZHAN, the State Prize-Winner of Ukraine, Academician of the Academy of Medical Sciences of Ukraine

CHIEF EDITORIAL BOARD

V. M. ZAPOROZHAN, (Chief Editor), Yu. I. BAZHORA, I. S. VITENKO, V. Y. KRESYUN (Vice Chief Editor), O. O. MARDASHKO, V. K. NAPKHANYUK, G. I. KHANDRIKOVA(Senior Secretary), P. M. TCHUYEV

The Odessa State Medical University Dear Reader, When in 1999 the lecturers and researchers of the Odessa State Medi- cal University started issuing a series of books united by the collection entitled “Medical Student’s Library” they had several aims before them. Firstly, they wanted to add new books to the Ukrainian library of medical literature that would be written in Ukrainian, the native language of the country. These books should contain both classical information on medicine and the latest information on the state of the art, as well as reflect extensive experience of our best professionals. Secondly, our lecturers and specialists wanted to write such books which reflected the newest subjects and courses that have recently been introduced into the curricula, and in general there have been no textbooks on these subjects and courses at that time. These two aims have successfully been coped with. Some dozens of textbooks and workbooks published in these years have become a good contribution of their authors and publishers to the development and making of the Ukrainian national educational literature. The next step that we decided to undertake was to issue a unique series of books in foreign languages. The foreign students taking their medical ed- ucation in the Ukraine, our University included, are expecting such books to be published. Other countries are also waiting for them as the Odessa State Medical University is a Fellow Member of the International and European Association of Universities. Our Medical University is over a hundred years old and has long since become a center of various original medical schools and trends. These are headed by well-know medical professionals whose competence is acknowledged not only in this country, but abroad as well.

Valery ZAPOROZHAN, Editor-in-Chief of the Series “Medical Student’s Library” the State Prize-Winner of Ukraine, Academician of the Academy of Medical Sciences of Ukraine

GENERAL PHARMACÎLÎGY COURSE OF LECTURES

Odessa The Odessa State Medical University 2005 UDC 615:378.16=20 BBC 52.81Я93

Authors: V. Y. Kresyun, D. Yu. Andronov, K. F. Shemonaeva, V. V. Godovan, G. G. Vidavska, P. B. Antonenko

Reviewers: Professor V. D. Lukyanchuk, M.D., the Chair of the Pharmacology Department of the Lugansk State Medical University, Ukraine Professor V. I. Mamchur, M.D., the Chair of the Pharmacology Department of the Dnepropetrovsk Medical Academy, Ukraine

The lectures are designed according to pharmacological drug groups due to their effects on particular body systems and intended for the 3rd year students of medical faculty. Information is organized according to the sequence used in many International and Ukrainian pharmacology courses. The textbook is intended for students of higher medical institutions.

Загальна фармакологія: Курс лекцій: Навч. посібник / В. Й. Кресюн, Д. Ю. Андронов, К. Ф. Шемонаєва та ін. — Одеса: Одес. держ. мед. ун-т, 2005. — 215 с. — (Б-ка студента-медика). — Мова англ. ISBN 966-7733-80-7

Курс лекцій для студентів 3-го курсу медичного факультету складається з розділів, упорядкованих за фармакологічними групами ліків згідно з їх ефектами на специфічні системи органів. Матеріал викладено у послідовності, використову- ваній у багатьох міжнародних й українських виданнях з фармакології. Для студентів вищих навчальних медичних закладів. Іл. 30. Табл. 15. Бібліогр.: 37 назв.

ББК 52.81Я93

Рекомендовано до видання Центральною координаційно-методичною радою Одеського державного медичного університету Протокол № 5 від 18.05.2005

6 PREFACE

The lectures are designed to provide a complete, Other lectures within each section emphasize up-to-date and readable pharmacology text for the 3rd therapeutic classes of drugs and prototypical or year students of medical faculty. Planned to be used commonly used individual drugs, those used to treat during the 2 semesters, the text focuses on the major common disorders, and those likely to be encoun- principles of pharmacology with the clinical ap- tered in clinical practice. Lecture’s content is pre- plication of drugs. It also offers special features that sented in a consistent format and includes a descrip- make it useful to practicing clinicians. tion of a condition for which a drug group is used; The content of Lectures is organized in 10 sec- a general description of a drug group, including a tions, primarily by therapeutic drug groups and their small historic review, mechanism(s) of action, indi- effects on particular body systems. This approach cations for use, and contraindications; adverse drug helps the student make logical connections between effects and descriptions of individual drugs, with major drug groups and the conditions for which they recommended dosages and routes of administration. are used. It also provides a foundation for learning The lectures in these sections include drug names, about new drugs, most of which fit into known groups. classifications, prototypes, drug approval process- Information is organized according to the sequence es. Some lectures include initial parts that reviews used in many pharmacology courses: common pharma- the physiology of body systems. The reviews are de- cology; autonomic drugs; neurotropic agents; cardio- signed to facilitate understanding of drug effects on vascular drugs; endocrine and vitamin drugs; anti- a body system. Each section includes examination microbial agents; drugs used to treat diseases of the questions with detailed answers to help students test blood; and special topics. The first lecture contains their knowledge of the covered material. Appendi- knowledge required to understand the main principles ces contain information about main international and rules of medical prescription. Lecture 2 consists pharmacological abbreviations and examples of of common pharmacological information, including: combination drugs. All of this made the Lectures cellular physiology, drug transport, pharmacokinetic book comprehensive but not exhaustive, and accu- processes, the receptor theory of drug action, types of rate — a text that supplies both students and uni- drug interactions, and factors that influence drug ef- versity faculties. fects on body tissues, dosage forms, routes and meth- These lectures are created at the Department of ods of accurate drug administration and general prin- general and clinical pharmacology of the Odessa State ciples of drug therapy. Medical University.

7 MEDICAL PRESCRIPTION

Lecture 1 ument, because it is observed when the correctness of treatment is doubtful. INTRODUCTION TO THE MEDICAL PRESCRIPTION RULES PARTS OF PRESCRIPTION OF PRESCRIPTION WRITING 1. Inscriptio — tells official data about the hospital Prescription is a part of pharmacology. It is divid- (title and address), the physician, who writes prescrip- ed into pharmaceutical prescription, which studies tion (surname, initials), and the patient (surname, ini- rules of drug’s production, and medical prescription tials, age). It is written in national language. that studies rules of prescription writing. 2. Prepositio — consisting of the word recipe, take, Drug substances have different sources. They can or its sign, “Rp.:” be obtained from the plants, animals, minerals, bacte- 3. Designatio materiarum (list of agents) is the main ria, and fungi. Drugs, produced from the plants by sim- part of the prescription, containing the names and ple processing (drying and mixing), are called simple. amounts of the drugs ordered. Each drug substance is They are used seldom. Composite drugs are produced written in own line from a capital letter, in genitive from plant origin by more complex processing. For ex- case, and in Latin. Words can not to be shortened and ample, Galen’s and neo-Galen’s drugs. They are both broken. Doses are written by figures. If ingredient is containing sum of plant’s active substances. Galen’s only one, receipt is simple, if many — complex. drug is obtained by spirit or another kind of extrac- Drug substances are divided according to their im- tion from a plant, e.g. tinctures, extracts; usually it portance. contains ballast or non-active substances. However, a. Remedium cardinale (s.basis) — a drug sub- neo-Galen’s drug is subjected to more composite stance, which carries the main treating effect. processing; it is more pure and can be used parenter- b. Remedium adjuvants are substances with an ad- ally. ditive action. Drug form is a shape that is given to the drug sub- c. Remedium constituents — a shape-making substance. According to their condition drug forms are distance. A constituent is to be indifferent (non-active). vided into solid, (powders, capsules, tablets, dragee, d. Remedium corrigens — substances bettering granules), liquid (infusions, decoctions, mixtures, tinc- taste, smell, type. Corrigens are usually sugar, ether tures, fluid extracts, solutions), and soft (ointments, flu- oils, syrups. id ointments, pasts, suppositories, plasters). Also drug 4. Subscriptio — directions for mixing of the in- forms can be dosed, they usually act after reaching the gredients and designation of the form (pill, powder, bloodstream, and non-dosed, which as a rule act topi- solution, etc.) in which the drug is to be made, e.g. be- cally. Drug substance is a chemical compound that pro- ginning with the word, misce, mix, or its abbreviation, vides drug’s action. Drug is a drug substance, produced M., fiat, make, or its abbreviation, f., and the name of in a concrete drug form. the drug form (pulvis, powder). Also it can include the Pharmacopoeia is a work containing monographs quantity Da (D.), give; tales (t.), such; doses (d.) of therapeutic agents, standards for their production N, number. strength, purity, and their formulations. Pharmacopoe- 5. Signatura — directions to the patient regarding ia includes especial list A (agents with high toxicity, the dose and times of taking the remedy that is preced- poisons, and agents of abuse), list B (potent drugs of ed by the word signa, designate, or its abbreviation, (S.). strict supervision). It is written in national language. Prescription is a written proposition of physician 6. Nomen medici — signature and the own stamp for pharmaceutist to produce and/or to sale a concrete of the physician. drug. It is a written formula for the preparation and Prescription in special cases. It concerns narco- its administration. Also, prescription is a juridical doc- tics and other similar substances. Special blanks for

8 strict calculation are done for this purpose. Those at the factories, that’s why they are prescribed in a blanks have a serial number. They are covered by shortened (brief) form: pink drawing and are proved by stamp of the hospital and a signature of its head. Prescriptions on poi- Rp.: Capsulae Chinini sulfatis 0,2 N 10 sonous substances including spirit are proved by a D.S. By 1 capsule 5 hours before attack. special stamp of the hospital. Prescription for privi- lege using (free of charge for 80%), are proved by Tablet (tabuletta, tab., genitive case — sing., stamp of the hospital also. In emergency prescrip- tabulettae, pl., tabulettarum) is a solid dosage form tion of a drug we write “cito!”, quickly in an upper containing medicinal substances; it may vary in shape, left corner. size, and weight. Tablets may be complex and simple Dose — is a quantity of a drug substance that can according to amount of active substances. They always be expressed in milliliters, grams, and international include nonactive ingredients, but physician doesn’t units. There are following types of doses — moment, consider them. daily, curative, and minimal, medial or maximal therapeutical. A shortened form (for simple prescriptions only): Prescription can indicate a moment dose of an agent (for one time) and its quantity. It is a distribu- Rp.: Tabulettarum Reserpini 0,00025 N 50 tive way of prescribing. Tablets, powders, etc. are pre- D.S. By 1 tablet 3 times a day. scribed in this way. In dividing way we prescribe a summary dose and a patient has to divide it only at A full form (for simple and complex prescriptions): the moment before using, e.g. mixtures, decoctions. Magisterial prescription — prescription that is com- Rp.: Reserpini 0,00025 piled by physician. Officinal prescription — prescrip- D.t.d. N 50 in tabulettis tion of already produced drug substances. S. By 1 tablet 3 times a day. # 1.1. SOLID DOSED Rp.: Acidi acetylsalicylici __ MEDICINAL FORMS Phenacetini aa 0,25 Coffeini natrii-benzoatis 0,1 Powder (pulvis, pulv.) is a homogenous dispersion D.t.d. N 10 in tabulettis of finely divided, relatively dry, particulate matter S. By 1 tablet during headache. consisting of one (simple) or more (complex) substances. Its weight is limited — 0.1–1 g, optimal __ Ana, aa or both means that ingredients have similar weight — 0.3 g. If basis weight is less than 0.1 g, we weight. add a form-making substance — sugar (Saccharum), Patented tablet consists of one or more substances glucose (Glucosum). with fixed (determined) weight. It is written without weight. Patented tablet like a sign, under which one Rp.: Platyphyllini hydrotartratis 0.005 or more active agents are present. Sacchari 0.3 Misce fiat (M.f.) pulvis Rp.: Tabulettarum “Pentalginum” N 10 Da tales doses (D.t.d.) N 6 D.S. By 1 tablet during headache. Signa (S.) By 1 powder 3 times a day. Dragee (dragee, dr.) is a solid dosage form. It is a If basis weight is enough, we don’t add a form- sugarcoated small globular mass of some coherent but making substance. soluble substances, containing a medicinal substance to be swallowed. Consecutive tracing of drug substances Rp.: Amidopyrini 0,3 Simple produces it. Rules of dragee prescription are the same D.t.d. N 6 powder as tablets’. S. By 1 powder during headache. Rp.: Dragee Acidi ascorbinici 0,05 N 10 # — this sign usually separates two prescriptions. D.S. By 1 dragee 3 times a day. Rp.: Amidopyrini 0.3 Coffeini natrii-benzoatis 0.1 Complex M.f. pulv. powder 1.2. LIQUID DOSED MEDICINAL D.t.d. N 6 FORMS S. By 1 powder during headache. Infusion (Inf., in genitive cases — Infusi) is a liquid Capsule (capsula, caps., genitive case — capsulae) form that contains water extract from the plants. It is is a solid dosage form in which the drug is enclosed in produced by steeping of plant origin (leaves — folium, either a hard or soft soluble container or “shell” of a pl. folia, in genitive case — sing., folii, pl., foliorum; suitable form of gelatin. Capsule remove probable grass — herba, in genitive case — herbae) in water and unfavorable taste, smell, prevents irritation of the oral boiling 15 minutes. Decoction (Dec., in genitive case cavity and stomach mucosa, and drug’s inactivation — Decocti) is close to infusion. However, decoction is by the stomach juice. Nowadays capsules are produced prepared from more crude and rough plant origin, e.g.

9 roots — radix, in genitive case — radicis; bark — a moment dose 0.3 each for adult. Take 1 tablespoonful cortex, in genitive case — corticis. That’s why 3 times per day. decoction boiling is longer (about 20–30 minutes) than infusion. Rp.: Natrii bromidi Infusion and decoction are prescribed in a dividing Kalii bromidi ana 3.6 way. It means that a patient obtains a bottle with a total Aquae destillatae 180 ml dose. Then a patient himself selects a moment dose by M.D.S. Take 1 tablespoonful 3 times a day. different spoonfuls. They are a small teaspoonful (for children under 5 years), a teaspoonful (from 6 to 16 Mixture that includes infusions has the next years), and tablespoonful (over 17 years). structure. Prescribe mixture that includes infusion of leaves of Digitalis (a moment dose — 0.05) and 1 small teaspoonful contains 5 ml Themisalum (a moment dose — 0.3). Take 1 table- 1 teaspoonful contains 10 ml spoonful 3 times a day. 1 tablespoonful contains 15 ml Rp.: Infusi foliorum Digitalis 0.6 — 180 ml Both infusion and decoction are unstable; they loose Themisali 3.6 therapeutic action in a few days. Thus, traditionally M.D.S. 1 tablespoonful 3 times a day. they are prescribed for twelve times taking. For prescription of infusion and decoction we have to Syrup (Syrupus, in genitive case — Syrupi) is a multiple a moment dose of a plant origin into 12 highly concentrated aqueous solution of sugar, e.g. (amount of its taking), and we’ll get the total weight sugar syrup (Syrupus simplex). That’s why it improves of plant source. mixture test and prevents bacterial growth. Volume of The water volume for infusion and decoction is to syrup approximately is 20–30% of total mixture be found out as follows: volume. Drops for enteral usage are liquid medicines. Spoon volume · Quantity of intake = Total volume Water, spirit, and vegetable oils are used as solvents. As usually total volume of drops is 10–30 ml. It is 5 ml · 12 = 60 ml (for children under 5 years) known that 1 ml of spirit solution contains 50 drops 10 ml · 12 = 120 ml (for children from 6 to 16 years) and 1 ml of water solution contains 20 drops. For 15 ml· 12 = 180 ml (for patients over 17 years) example, prescribe atropine sulfate (Atropinum sulfas), a moment dose — 0.001. Prescribe 20 drops (1 ml) two For example, prescribe infusion of grass of Adonis times a day during 10 days. vernalis, which moment dose (MD) is 0.5 (5 decigram). Quantity of intakes = quantity of usage during 1 Take 1 tablespoonful three times a day. day · duration of treatment; 2 · 10 = 20. Total weight First of all we have to calculate the total weight of of atropine = moment dose · quantity of intakes; grass and total volume of added water. 0.001 · 20 = 0.02 (g). If it is not mentioned “spirit” Total weight of grass: 0.5 · 12 = 6.0 or “oil” solution, it is water solution. The moment dose Total volume of water: 15 ml · 12 = 180 ml of water is 20 drops or 1 ml. Total volume of water Thus = volume of the moment dose · quantity of intakes; Rp.: Infusi herbae Adonidis vernalis 6.0 — 180 ml 1 ml · 20 = 20 ml. D.S. Take 1 tablespoonful 3 times a day. Rp.: Atropini sulfatis 0.02 Prescription of decoction is similar. For example, Aquae destillatae20 ml prescribe decoction of bark of Frangula, which M.D.S. Take 20 drops 2 times a day. moment dose is 1.5. Take 1 tablespoonful before sleep. More often drops for oral intake are prescribed Rp.: Decocti corticis Frangulae 18.0 — 180 ml in a shortened form. In this case we begin prescription D.S. Take 1 tablespoonful before sleep. from characteristics of a medicinal form — the word “solutionis”; then it should be written the name of the Mixture (Mixtura, in genitive case — Mixturae) is agent, its concentration (%) and the total volume of a liquid medicine that consists of various agents. Water the solution. In general, an expression “1% solution” is a liquid solvent that gives form to mixture. If mixture means that 100 ml of this solution contains 1g of the contains decoction or infusion, water can be present active substance. That’s why, percentage of the in its composition. In the opposite case, water have to solution is a quantity of the active substance (g) in be added separately; it is mentioned Aqua destillata 100 ml of the solution. It can be calculated with the (Aq. destill., in genitive case — Aquae destillatae) on help of the following ratio. For example, we know the last line of the agent’s list. Mixture as well as that it is 0.02 g of atropine sulfate in 20 ml of solution: infusion and decoction are given by spoonfuls, teaspoonfuls, and small teaspoonfuls. Also, mixture is In 20 ml of solution — 0.02 of Atropine sulfate prescribed for twelve intakes and in a dividing way. In 100 ml of solution — X of Atropine sulfate All substances in mixture have to be mixed. That’s why X = 0.02 · 100 / 20 = 0.01 we write Misce (M.), mix after the list of active agents. For example, prescribe mixture that contains Thus, it will be 0.01 (g) of Atropine sulfate in 100 potassium (kalium) and sodium (natrium) bromide, ml of solution; concentration of solution is 0.01%.

10 Rp.: Solutionis Atropini sulfatis 0.1% 20 ml Thick and dry extracts are dosed out in the weight D.S. Take 20 drops 2 times per day. units (gram) and are prescribed in capsules, powders, tablets, and suppositories. If a solvent is spirit or vegetable oil, it must be noted Liquid extract is dosed out in drops and is prescribed spirituosae or oleosae correspondently after the agent’s in the same way as tincture. It means that the total name. volume in milliliters must be the same as the quantity of drops for one intake. Also we have to mark that it is Rp.: Solutionis Nitroglycerini spirituosae 1% 10 ml liquid (fluidum) extract. D.S. Take 2 drops on a peace of sugar under the tongue. Rp.: Extracti Polygoni hydropyperis fluidi 25 ml D.S. Take 25 drops 4 times per day. Tincture (Tinctura, T-ra; in genitive case — Tincturae, T-rae) — is an alcoholic, hydroalcoholic, Solution for injection is a liquid officinal form that or ether-alcoholic extract of raw plant material. A is formed by dissolving of one or more active substances single medical dosage is 20–25 drops of tincture. and is intended for injection using. In general, solution Both infusion and tincture are extracts from the is the incorporation of solid, liquid, or gas in a liquid plant origin. However, infusion is a water extract, resulting in a homogeneous single phase. tincture is an alcoholic extract. Also, tincture is more The solvents are water, spirit, or vegetable oils. stable (during a few years) than infusion. Solution for injection differs from tincture, extract with The rule of tincture writing is following: drop’s higher degree of purity, sterility, and absence of ballast quantity for one intake must be the same as the total substances. Also, solution for injection have such volume of tincture in milliliters. advantages as the higher therapeutic activity, quick Example: onset of action, more exact dosage, portability, possibility of their administration to unconscious Rp.: Tincturae Valerianae 25 ml patients. D.S. Take 25 drops three times per day. A physician begins a prescription from the word solution, sol. (in genitives case — solutionis; in Simple tincture is an alcoholic extract from one nominative case — solutio) and the agent’s name. Then plant origin. Complex tincture is composition of two it must be presented the concentration of the solution or more tinctures. For instance, prescribe composition (in percentage) and volume of one ampoule or bottle. of tincture of Valeriana and tincture of Convallaria in In the next line we have to write Da tales doses, D.t.d., equal volume with addition of tincture of Grataegus, give such doses; amount of ampoules or bottles. volume of which is ј of total composition volume. Solutions for injections are produced in ampoules Prescribe 20 drops 3 times per day. (ampullis) with 1, 2, 5, 10, 20 ml capacity or bottles First of all, if we prescribe 20 drops for one intake, with 5, 10, 50, 200, 400 ml capacity. If they are in the total volume of composition is 20 ml. Then, 1/4 of ampoules, we have to note after figure in ampullis, in total composition volume (20 ml) will be 5 ml. So, the ampull. In case of bottle we don’t write anything after total volume of tinctures of Valeriana and Convallaria amount. is 15 ml. As it mentioned above, tincture of Valeriana and tincture of Convallaria have equal volume. Thus, Rp.: Solutionis Platyphyllini hydrotartratis volume of both tinctures is 7.5 ml. 0.2% 1 ml D.t.d. № 10 in ampullis Rp.: Tincturae Valerianae S. Inject 1 ml 2 times per day Tincturae Convallaria aa 7.5 ml subcutaneously. Tincturae Crataegi 5 ml M.D.S. Take 20 drops 3 times per day. If a solvent is spirit or vegetable oil, it must be noted spirituosae or oleosae correspondingly after the If tincture-including mixture consists of many agent’s name. For aqueous solutions a solvent isn’t ingredients, it is prescribed as a patented officinal indicated. form. For example, “Corvalolum” includes Valerianic acid, phenobarbital, peppermint oil, alcohol, and Rp.: Solutionis Camphorae oleosae 20% 2 ml water. D.t.d. № 10 in ampull S. Inject subcutaneously 2 ml once daily. Rp.: Corvaloli 15 ml # D.S. Take 15 drops in the evening. Rp.: Solutionis Gramicidini spirituosae 2% 5 ml D.t.d. № 10 in ampull. Extract (Extractum, Extr., in genitive case — S. Before use the ampoule’s content is to be Extracti) is a concentrated preparation obtained from diluted of sterile water (500 ml). a plant origin by removing of the constituents with Only for external use. suitable solvents. According to its aggregate condition, extract can be dry (siccum), thick (spissum), and liquid A patented form of solution is prescribed without (fluidum). A dry extract has less than 5% of moister; the word “solution”. For instance, 0.15% solution thick extract has 5–25% of moister; and a liquid of Cytisinum is known as “Cytitonum”. As a rule, extract has over 25% of moister. we can’t write the word “solution” when the

11 concentration is absent. This agent can be prescribed We prescribe it just as solution: in both ways. Rp.: Suspensionis Hydrocortisoni acetatis Rp.: Solutionis Cytisini 0.15% 1 ml 2.5% 5 ml D.t.d. N 10 in ampull. D.t.d. N 6 S. Inject intravenously 1 ml. S. To inject 1,5 ml into the cavity of # the injured joint 1 time per week. Rp.: Cytitoni 1 ml # D.t.d. N 10 in ampull. Rp.: Suspensionis Chlorthiazidi 5% 250 ml S. Inject intravenously 1 ml. D.S. Take orally 10 ml (a teaspoonful) # twice per day. Rp.: Reopolyglucinum 400 ml D.t.d. N 2 Aerosol (Aerosolum; in genitive case — Aerosoli) S. Inject intravenously by drops 200 ml. is liquid or particulate matter dispersed in the air in a form of fine mist for therapeutic purposes. It is Also we don’t write the word “solution” for packaged in bottles under pressure and contains hormones prescription. active ingredients intended for inhalation (mostly) and topical application. For example, prescribe Rp.: Pituitrini 1 ml (5 units) aerosol Salbutamolum, in bottles — 10 ml. One D.t.d. N 6 in ampull. inhalation 4 times per day. S. Inject 1 ml subcutaneous per day. # Rp.: Aerosoli Salbutamoli 10 ml Rp.: Insulini 5 ml (1 ml — 40 units) D.S. One inhalation 4 times per day. D.t.d. N 2 S. 20 units subcutaneous per injection (to inject before half hour of the meal). 1.3. SOFT DOSED MEDICINAL As it was mentioned above, when the substance is FORMS — SUPPOSITORIES produced in a bottle, the word “bottle” isn’t written. Suppository (Suppositorium, Supp., in genitive case Sometimes we prescribe big bottles, which contain — sing. Suppositorii; pl. Suppositoriorum) is a small many units of doses of injection solution. In addition, when bottles are produced in the laboratory of the solid body shaped for ready introduction into one of hospital or drug-store, we have to write instruction for the orifices (opening) of the body other than the oral its purity — Sterilizetur, sterilize. cavity (e.g. rectum, urethra, vagina), made of a substance, which is solid at ordinary temperatures but Rp.: Solutionis Glucosi 5% 400 ml melts at the body temperature. Usually cacao oil Sterilizetur! (Oleum Cacao) is used as form-making substance D.S. For subcutaneous injection. suppository. Rectal and vaginal suppositories are widely spread An agent in the bottle can be produced in a dry in medicine. These suppositories (especially rectal) form. As a rule, it must be dissolved before using. In provide both local therapeutical effect and general signature it have to be marked. The prescription looks absorptive effect thanks to absorptive ability of mucous like the following: membranes. Suppositories are used during treatment of rectum Rp.: Streptomycini sulfatis 1.0 (proctitis, paraproctitis) and vagina (vaginitis) D.t.d. N 6 diseases. The contraceptive agents are prescribed in S. To dissolve the contents of the bottle globules moreover. Administration of drugs into the in 5 ml of 0.25% novocaine solution. rectum has greater importance when the oral using To inject intramuscularly 2.5 ml per of substances is impossible (vomiting, burn of the 12 hours. gullet and others). During some diseases (decom- pensation of heart activity, cirrhosis) the absorption Sometimes the substance is dosed in international from the small intestine is difficult and uncompleted. (biological) units and produced in bottles: Drugs absorbed from suppositories in the lower rectum enter vessels that drain into the inferior vena Rp.: Bicillini — 3,600,000 units cava, thus bypassing the liver. However, partially D.t.d. N 5 drugs achieve superior hemorrhoidal vein that leads S. Inject intramuscularly once a week, to the liver. Also the absorptive ability of the rectum preliminary dissolving the bottle content mucosa is lower than of the small intestine. Thus, in 3 ml of water for injections. dose of active substance is in suppository is higher than the dose for oral use. Suspension (Suspensio, Susp., in genitive case — Rectal suppositories have a conic or a “cigar” Suspensionis) is a class of preparations of finely form with height of 4 cm and weight of 1.1–4.0 g divided, undissolved drugs (e.g. powders for sus- (average is 3.0 g). Vaginal suppositories have a round pension) dispersed in liquid for oral or parenteral or an egg-like form; their weight is 1.5–6.0 (average use. is 4.0).

12 Nowadays, suppositories are prepared mostly in Talc (Talcum) and starch (Amylum) are the form- industrial route. They can be prescribed in a shortened making substances in powders for external usage. form. Powder for external usage can be prescribed in both shortened and complete methods. The shortened Rp.: Suppositoriorum Metronidazoli 0.5 N 10 method is useful for prescription of patented powder D.S. Use 1 suppository into the vagina, or in case when it consists of only one active substance. preliminary taking off packing. When there are two or more compounds in the powder composition, the complete method is used. The The patented suppositories are prescribed as a shortened method is following: ready officinal forms. Rp.: Aspersionis Amycozoli 5% 50.0 Rp.: Suppositoriorum Bethioli N 10 D.S. Apply on the injured surface. D.S. Introduce 1 suppository into the rectum per night. Unlike a shortened variant, the quantity of substances in a full one is expressed in grams: For prescription of suppositories produced in a drug-store we use a full-form. The “basis” (active Rp.: Bismuthi subnitratis substance) is written first of all for the prescription of Zinci oxydi ana 10.0 suppositories. Then the form-making substance Amyli ad 50.0 follows. In subscription we have to write Misce fiat M. f. aspersio suppositorium, M. f. supp. (mix let it be suppository) rectale or vaginale. In signature we indicate how to D.S. Apply on the injured surface. use them. Smallest powders are used for application on the Rp.: Omnoponi 0.24 mucous membranes, e.g. in ophthalmic practice. They Olei Cacao 3.0 are called — pulvis subtilissimus. M.f. supp. rectale D.t.d. N 10 Rp.: Streptocidi subtilissimi 20.0 S. 1 suppository into the rectum per night. D.S. Apply on the injured surface.

Instead of oil cacao quantity it is possible to write Ointment (Unguentum, Ung., in genitive case — quantum satis, q.s., that means — as many as it Unguenti) is a soft non-dosed medicinal form for necessary. external usage. Agents, which are prescribed in ointments, usually have astringent, anti-inflammatory, Rp.: Metronidazoli 0.5 keratolytic (peeling of the skin) or keratoplastic Ol. Cacao q.s. (increasing of keratinization) effects. Vaselin M.f. supp. rectale (Vaselinum) and lanolin (Lanolinum) are used as the D.t.d. N 10 form-making substances in ointments. S. 1 suppository into the vagina The ointment that consists of only one compound, 2 times a day. is prescribed in a shortened way:

Rp.: Unguenti Resorcini 10% 100,0 1.4. NON-DOSED MEDICINAL FORMS D.S. Apply on the injured surface. — POWDERS FOR EXTERNAL USE, Ointment that includes two and more active OINTMENTS, LINIMENTS AND substances is prescribed by a complete method. Unlike SOLUTIONS FOR EXTERNAL USAGE a shortened variant, quantity of substances in a full one Non-dosed medicinal forms are used in external way is expressed in grams. For example, prescribe 50.0 (application, massage, washing). The preparation’s (grams) of ointment that consists of Anaesthesinum (1%) quantity depends on the size of the injured place. The and Xeroforminum (10%). agents that are prescribed in non-dosed forms cause a First of all, we have to convert per cents into grams local action or act in a reflective way. As usually in this with the help of ratio. route we prescribe different disinfectant remedies. According to aggregate condition non-dosed medicinal 100% of ointment — 50.0 (grams) of ointment forms are divided into solid (powder for external use), 1% of anaesthesinum — X (grams) of anaesthesinum liquid (solution for external use), and soft (ointment, X = 50,0 · 1 / 100 = 0.5. pasta). Powder for external usage (Aspersio, Aspers.; in Weight of Xeroforminum: 50 · 10 / 100 = 5.0 genitive case — Aspersionis) is a homogenous dispersion of finely divided, relatively dry, particulate matter Rp.: Anaesthesini 0.5 consisting of one (simple) or more (complex) substances Xeroformini 5.0 for external application on the skin and the mucous Vaselini ad 50.0 membranes. It is used during wetting and maceration Misce fiat unguentum of the skin, pyodermititis, micotic lesion of the skin. D.S. Apply on the injured skin surfaces.

13 Paste (Pasta, in genitive case — Pastae) is a soft The prescription rules are the same as in ointments: semisolid non-dosed medicinal from. It contains more than 25% of solid substances. However, Rp.: Linimenti Synthomycini 10% 20.0 ointment has less than 25% of solid substances. D.S. Apply on the injured surface. Thus, ointment can be transformed into paste by # addition of solid substance (e.g. talc). Paste has the Rp.: Chevroformini same form-making substances as ointment (e.g. Olei Helianthi ana 20.0 Vaseline). M. f. linimentum If paste includes only one active substance, or it is D.S. Apply on the injured surface. produced in a patented form, prescription will have a shortened form: An officinal liniment:

Rp.: Pastae Resorcini 10% 100.0 Rp.: Linimenti Vipratoxi 50,0 D.S. Apply on the injured surface. D.S. Apply on the injured surface.

In other cases the complete method is used. For Solution for external usage is a fluid officinal form, example, prescribe 100,0 (grams) paste with the which is received during dissolution of solid or fluid following composition: Acidum salicylicum (5%), medicinal substance in the solvent. The solutions are Acidum boricum (1%), Zincum oxydum (15%). aqueous, alcoholic, and oil. They are used for The sum of all solid form of this composition is washing, irrigation, rinsing, fomentation in the 21%. It is not enough for paste. We have to add talc, treatment of wounds, ulcers, etc. They are prescribed e.g. 10%. In this case the sum will be 31% that is as already prepared officinal forms: enough. Then we have to express the weight of substances in grams. Rp.: Solutionis Furacilini 0.02% 500 ml D.S. For irrigation of wound. 100% of paste — 100.0 (grams) of paste In addition, concentration can be expressed in the 5% of Acidum salicylicum — X (grams) form of ratio of Acidum salicylicum X = 5 · 100.0 / 100 = 5.0 (grams) Rp.: Solutionis Furacilini 1:5000 — 500 ml D.S. For irrigation of wound. Weight of Acidum boricum = 1 · 100.0 / 100 = 1.0 (grams). In cases of spirit or oil solutions we have to write Weight of Zincum oxydum = 15 · 100.0 / 100 = the word “spirituosae” or “oleosae” correspondingly 15.0. after the agent’s name.

Rp.: Acidi salicylici 5.0 Rp.: Solutionis Iodi spirituosae 5% 50 ml Acidi borici 1.0 D.S. For external application. Zinci oxydi 15.0 # Talci 10.0 Rp.: Solutionis Camphorae oleosae 10% 10 ml Vaselini ad 100.0 D.S. For external using. M. f. pasta D.S. Apply on the injured surface. Usually volume of prescribed solution for irrigation and rinsing of wounds or cavities is about 500 ml, Liniment (Linimentum, Lin., in genitive case — volume for local application is about 50–100 ml, and Linimenti) or fluid ointment is a soft preparation for volume of eye or ear drops is about 10 ml. external application. It is a thick liquid at the room temperature, but melts at the body temperature. Rp.: Solutionis Sulfacili-natrii 30% 10 ml Vegetable oils, e.g. sunflower seed oil (Oleum Helianthi) D.S. Eye drops. Two drops in each eye are used as a form-making substance for liniment. 4 times per day.

14 COMMON PHARMACOLOGY

Lecture 2 entry into the systemic circulation. A drug can be metabolized in the gut wall, but most commonly in the COMMON PHARMACOLOGY liver that is responsible for metabolism before the drug PRINCIPLES reaches the systemic circulation. The hepatic first-pass effect can be avoided to a Pharmacology is the science that studies the inter- great extent by use of sublingual route and by use of action of substances with living systems through chem- rectal suppositories. Sublingual absorption provides ical processes. It concerns drugs, their sources, appear- direct access to systemic — non portal — veins. This ance, chemistry, actions, and uses. route is facile; the onset of action is fast; but the dura- The interactions between the drug and the body are tion of action is short. Drugs absorbed from supposi- conveniently divided into two classes. The actions of tories in the lower rectum enter vessels that drain into the drug on the body are termed pharmacodynamic the inferior vena cava, thus bypassing the liver. How- processes. These properties play the major role in de- ever, partially drugs achieve superior vena cava that ciding whether that group is appropriate therapy for a lead to the liver. In addition the absorptive ability of particular symptom or disease. The actions of the body the rectum mucosa is lower than that one of small in- on the drug are called pharmacokinetic processes. Phar- testine. Thus, only about 50% of a rectal dose can be macokinetic processes govern the absorption, distribu- assumed to bypass the liver. tion, and elimination of drugs. Pharmacotoxicodynam- Injections (1), inhalations (2), and transdermal route ic is a branch of pharmacology that deals with the un- (3) belong to parenteral routes. The first one includes desirable effects of chemicals on living systems, from intracutaneous, intravenous, intramuscular and in- individual cells to complex ecosystems. traarterial infections. The effect appears quickly, especially in case of intravenous injection, and provides precision of dosage. Bioavailability for intravenous PHARMACOKINETIC PROCESSES route is 100%. After intravenous injection the onset of action is quicker, but duration is shorter than during Time, needed for achieving the maximal effect, it’s intramuscular or subcutaneous injection. It is not rec- duration and intensity depend on route of adminis- ommended to use the drugs with strong irritative ac- tration. So it is necessary to consider peculiarities and tion subcutaneously and intramuscularly. It is also principles of different introduction methods, while prohibited to use intravenously insoluble substances choosing. They are divided in to enteral (through the and oily solutions because of embolism risk. Lack of digestive tract) and parenteral (omitting the digestive these routes is tissue damages, necessity of sterility, and tract). risk of non-specific reactions (shock, collapse, cramps). Enteral routes include oral, sublingual, and rectal Gases and aerosols are introduced using inhala- administration. The oral way is the most easy, conven- tions. Therapeutic effect is reached quickly. This route ient, and widely used way of administration. But a lot is predominantly desirable for the treatment of diseas- of factors influence the absorption and bioavailabili- es of air ways. It causes topical action mainly. Lack ty of the drug. Bioavailability is the ratio of the un- of this method is irritation followed by spasm of the changed drug reaching the systemic circulation to the larynx, the bronchi. given dose (in per cent). For an intravenous dose of The oil-solved substances (in the form of ointments the drug, bioavailability is equal to unity (100%). For and liniments) and electrolytes (by electrophoresis) are example, if bioavailability of a drug is 50%, it means introduced through the skin. The transdermal route pro- that 50% of the ingested dose reach the serum. For a vides direct access to systemic — nonportal — veins drug administered orally, bioavailability may be less and prolongs the duration of drug absorption. than 100% for two main reasons — incomplete extent Drug absorption depends on many factors in the di- of absorption and first-pass elimination. The latter gestive tract. Ionized forms of drugs are poorly dis- means that following absorption across the gut wall, solved in lipids and poorly absorbed. Salicylates in the the portal blood delivers the drug to the liver prior to stomach (pH 1.0–1.5) are poorly ionized and absorbed

15 to a great extent in the stomach. Alkaloids are better 2. Filtration or aqueous diffusion appears across ep- absorbed in the intestine (pH in duodenum is ~ 6.6), ithelial membrane through pores that permit the pas- due to poor ionization in alkaline medium. It is neces- sage of small molecules. Filtration depends on the con- sary to consider, that pH in the stomach is the lowest centration gradient of a permeating drug. Small hy- during and just after meals, and the highest — 1 hour drophilic molecules and some ions are transported by before and 1.5–2 hours after meals. So acid substanc- this way. es are necessary to administrate while or just after eat- 3. Active transport is provided by special carrier mol- ing, alkaline substances — 1 hour before and 1.5–2 ecules exist for certain substances that are important for hours after eating. cell function and too large or too insoluble in lipid to Quantity and character of meals, that can change diffuse passively through membranes (e.g., peptides, pH of surrounding, also influence drugs absorption amino acids, glucose). Active transport needs energy, considerably. For example, tetracycline forms stable which occurs due to decomposition of ATP molecule. compounds with calcium, which are not absorbed. 4. Pinocytosis is the process in which the substance That’s why simultaneous using of tetracycline and is engulfed by the cell membrane and carried into the milk that contain calcium can decrease the rate of tet- cell by pinching off the newly formed vesicle inside the racycline absorption. At the same time, lipids increase membrane. This process is responsible for the trans- the absorption of fat-dissolved drugs (vitamins A, D, port of large substances. K, E, etc.). Alkaline promotes ionization of acid sub- There are many biological (blood-histological) stances and impedes their absorption and vice versa. barriers in the organism, except the blood-brain bar- Drugs absorption in the intestine depends consider- rier mentioned above. They are placental, blood-fol- ably on motility of the digestive tract too. Substances licular, blood-testicular, and epithelium of the mam- that decrease motility of the intestine (spasmolytics, mary glands. Blood-histological barrier is the capil- cholinolytics, etc.) promote absorption; substances has- lary wall that consists of endothelium cells, basal mem- tening motility (cholinomimetics) impede absorption. brane, enzymes, and small pores. Lipophilic substanc- The drug’s form has a great meaning during oral es easily pass through cellular membranes, hydrophilic administration. The most common rule is that liquid substances pass through the basal membrane and forms are absorbed better, than powders, absorption pores. The substances with molecular weight smaller of which depends on its dispersion; powders are ab- than 5,000–6,000 DA pass easily through the capil- sorbed better than tablets, dragees and granules. So, lary wall too: blood-brain barrier (BBB) consists of bioavailability of drugs in case of enteral administra- cerebral capillaries and astrocytes (neuroglia cells). It tion depends on many factors, varies greatly and is possesses selective permeability. Ionized molecules can- hardly predicted. not pass trough it. In case of inflammatory process, After parenteral administration drugs absorb into brain BBB becomes more permeable; and the brain is the blood circulation from subcutaneous tissue, mus- subjected to harmful influence of different substances. cles and cavities (depending of injection types), from Placental barrier protects fetus from xenobiotics (non alveoli (during inhalations). A physician can easier endogenous substances). Drugs with molecular weight predict the serum level of the drug and its effective smaller than 400 DA pass easily trough placenta by the dose. However, in the case of bloodstream delay the way of passive diffusion. Permeability of placenta de- absorption after subcutaneous and intramuscular in- pends on many conditions and gradually increases to jections can decrease. 33–35 weeks of pregnancy. Thus, it is necessary to care While choosing the route of administration, it is im- administration of drugs especially in first trimester of portant to consider some basic factors: (1) stability of pregnancy (a period of fetus’ organs appearing). Blood- drug in the digestive tract; (2) possibility of absorption follicular and blood-testicular barrier protect sex cells through the walls of the digestive tract and bioavaila- from action of xenobiotics. They consist of lipoprotein bility; (3) the goal of therapy (in emergency the membranes and pass easily by lipophilic non-ionized parenteral route of administration, especially intrave- molecules (narcotics, alcohol, etc.). So, genetic materi- nous is preferred). al may be damaged (mutagenic effect). The epithelium In the organism drugs permeate through the vari- of the mammary glands is easily passed by lipophilic ous barriers that separate different compartments, e.g., substances. If drugs used by mother are toxic or may the gut, the brain. For a drug given orally to produce cumulate in breast milk, nursing have to be stopped an effect in the central nervous system, these barriers or the drug have to be changed. include the tissues that comprise the wall of the intestine, the walls of the capillaries that perfuse the gut, Distribution of drugs in the organism is done by and the “blood-brain barrier”, the walls of the capil- blood and lymph circulation. There are three fractions laries that perfuse the brain. of substances in the organism: (1) free fraction in serum and tissues; (2) connected with serum proteins; (3) Drug permeation proceeds according to 4 primary fixed in different tissues. mechanisms: These fractions are in dynamic balance and con- 1. Passive or lipid diffusion occurs due to gradient stantly remove from one form to another one. Only free of the substance concentration. Passive diffusion is the fraction is biologically active, because it could trans- most important limiting factor for drug permeation be- form and excrete. So, the high level of free fraction is cause of the large number of lipid barriers that sepa- associated with strong, quick, but short action. The lev- rate the compartments of the body. The lipophilic sub- el of free fraction in blood depends on albumin con- stances are transported by this way. It occurs without tent. In case of low protein levels (diseases of the liv- energy using. er, the kidneys, starvation) concentration of free frac-

16 tion considerably increases, that may cause strength- to yield drug conjugates. For example, histamine and ening of the effect. noradrenaline are methylated; sulfanilamides are Some drugs may deposit in tissues, forming extra- acetylated; morphine and bilirubin bind with glucuron- cellular and cellular depots. It occurs due to connec- ic acid, etc. In general, conjugates are polar molecules tion with proteins and phospholipids. Durability of that are readily excreted and often inactive. Conjugate connection is various. Some drugs (e.g., substances for formation involves high-energy intermediates and spe- narcosis) form not durable complexes with phospholi- cific transfer enzymes (transferases). pids and are quickly deleted from fat depots. Others (sulfanilamides of prolonged action, salts of heavy met- Excretion of drugs occurs basically via kidneys. als) form durable connections with proteins and for a Some drugs are excreted with bile into the lumen of long time remain in tissues. the intestine, via the lungs, the mammary glands, sweat and the sebaceous glands. Drugs excrete in Volume of distribution (Vd) relates the amount of changed (metabolites, conjugates) and unchanged drug in the body to the concentration of drug in blood (non-transformed) forms. Almost all drugs are filtered or plasma. Drugs with very high volume of distribution at the glomerulus. If a drug is in a lipid-soluble form have much higher concentrations in the extravascular during its passage down the renal tubule, a signifi- tissue than in the vascular compartment. Mostly it is cant fraction will be reabsorbed by simple passive dif- preferable for drugs with high selectivity of action. Se- fusion. If the goal is to accelerate excretion of the rum concentration is sum of free and connected with prodrug, it is important to prevent its reabsorption from teins drug fractions. It shows different phases of phar- the tubule. This can often be accomplished by adjust- macokinetic: absorption, distribution and elimination ing urine to make certain that most of the drug is in of the substance. A curve shows the time from the drug the ionized state. As it is mentioned above, acids in acidic medium are poorly ionized and are easily re- administration to appearance of primary effect (latent absorbed. Alkaloids are better reabsorbed from alka- period of action), the time from first appearance to min- line urine. Thus, weak acids are usually excreted in imal therapeutic effect (duration of action). alkaline urine; weak bases are better excreted in acidic urine. Also blood circulation in the kidneys (hypo- Biotransformation (chemical drug conversion) oc- tension diminish glomerular filtration), pathological curs, basically in the liver, and also in the kidneys, processes in the kidneys play an important role in ex- lungs, the wall of the intestines and other organs. The cretion. most part of drugs are biotransformed in an organism, It is necessary to remember that some drugs (e.g., except drugs for narcosis and hydrophilic non-ionized tetracyclines, glycosides), which are excreted with bile, substances that are excreted non-transformed. The re- partially are reabsorbed in the intestine. Some sub- sult of biotransformation is converting of lipid-soluble stances are excreted through the stomach and the in- substances to water-soluble and their excretion. Meta- testine (morphine, salts of heavy metals). bolic products are often less active than the parent drug Drugs excretion into breast milk has a special and may even be inactive. There are two main phases meaning. Most part of the drugs, used by mother, are of biotransformation — metabolism and conjugation. found in breast milk and may cause side effects in infant. If a drug is excreted into milk and is dangerous Metabolism (I phase) occurs due activity of oxidiz- for infant, feeding has to be avoided. er’s systems, basic components of which are cytochrome P-450 and NADP. At this phase reactions usu- Elimination is the process of drug inactivation in ally convert the parent drug to a more polar metabo- result of biotransformation and excretion. It values lite by introducing or unmasking a functional group by half-life of the drug, constant of elimination, and (-OH, -NH2, -SH). Metabolic transformation is done clearance. Half-life (T1/2) is the time required to by oxidation, restoration and hydrolysis. For exam- change the amount of a drug in the body (usually in ple, Imipramine, Ephedrine, and Aminazine are sub- blood) by one-half during elimination time. Constant jected to oxidation; Levomycetin and Nitrazepam are of elimination is the drug quantity (in per cent), that metabolized by restoration; complex ethers (e.g., No- was excreted by the organism during period of time vocain, Atropine) are hydrolyzed. A major part of sub- (usually during 1 day). Total clearance of a drug is stances are metabolized by oxidation for which oxy- the ratio of the rate of elimination by all routes to gen is necessary. So, changes of blood circulation, hy- the concentration of drug in serum. Elimination of poxia sharply lower metabolism of drugs. drug from the body may involve processes occurring An interesting feature of some drugs (e.g., Barbit- in the kidney, the lung, the liver, and other organs. urates, Rifampicin) is their ability, on repeated admin- Dividing the rate of elimination at each organ by the istration, to “induce” cytochrome P-450 by enhancing concentration of drug presented to it yields the respec- the rate of its synthesis or reducing its rate of degra- tive clearance at that organ. dation. Induction results in an acceleration of metabolism and usually in a decrease in the pharmacologic PHARMACODYNAMIC PROCESSES action of the inducer and also of coadministered drugs. However, the other drugs (e.g., Valproic acid, Cimeti- It is a part of pharmacology that studes mechanisms dine) inhibit activity of cytochrome P-450 that can re- of action, pharmacological, therapeutical and side ef- sult in increasing of coadministered drugs action. fects of drugs. Parent drugs or their phase I metabolites that con- The therapeutical and toxic effects of drugs result tain suitable chemical groups often undergo conjuga- from their interactions with molecules in the patient. tion (coupling) reactions with an endogenous substance Most drugs act by associating with specific macromol-

17 ecules in ways that alter the macromolecules’ biochem- Basic action is the main goal of the drug administra- ical or biophysical activities. This idea is embodied in tion, e.g., lowering of blood pressure during adminis- the term receptor. In general, receptor is a structural tration of Octadine. Side action is an additional ef- protein molecule on the cell surface or within the cy- fect to basic action. As a rule, side effect is unfavora- toplasm that binds to a specific factor, such as hor- ble. For example, Octadine can cause dyspeptic dis- mone, antigen, or neurotransmitter. This interaction orders. initiates the chain of biochemical events leading to the Selective action alters function of a certain organ agent observed effects. The receptor’s affinity for bind- and a system. Usually it relates to the action on func- ing a drug determines the concentration of drug re- tionally determined cytoreceptors (e.g., Salbutamol, quired to form a significant number of drug-receptor Pilocarpine). General action is non-specific action in complexes, and the total number of receptors often lim- different organs and tissues (action of narcotic sub- its the maximal effect a drug may produce. Many stances and alcohol). Convertible (reversible) action drugs and endogenous chemical signals, such as me- disappears just after drug elimination. Non-converti- diators, regulate the function of receptor macromole- ble (irreversible) action appears as a result of strong cules as agonists (mimetics); i.e., they change the func- connection of a drug with a receptor (usually covalent) tion of a macromolecule as a more or less direct result that cause irreversible breaking off its functions (e.g., of binding to it. They possess affinity and intrinsic ac- Proserine cause convertible inhibition of acetylcho- tivity. Based on the maximal pharmacologic response linesterase, Phosphacol causes non-convertible inhibi- that occurs when all receptors are occupied, agonists tion of acetylcholinesterase). can be divided into two classes. Partial agonists produce a lower response, at full receptor occupancy, than Factors that influence the drug action. do full agonists. They may be divided into 3 groups: Antagonists (lytics, blockers), however, bind to re- 1. Features of drugs. ceptors without directly altering their function. Thus, 2. Factors related to the whole organism. they prevent the binding of agonist molecules and 3. Environmental factors. block their biologic actions. The two classes of re- The first group includes the drug, its physical and ceptor antagonism are known. In the presence of a chemical features, pharmaceutical form, and doze. fixed concentration of agonist, increasing concentra- Chemical structure of a drug determines its mechanism tions of a competitive antagonist progressively inhibit of action and toxicity. The molecular size, shape, and the agonist response. Conversely, sufficiently high electrical charge of a drug determine whether it will concentrations of agonist can completely surmount bind to a particular receptor among the vast array of the effect of a given concentration of the antagonist. chemically different binding sites available in a cell, Some receptor antagonists bind to the receptor in an an animal, or a patient. Accordingly, changes in the irreversible fashion, i.e., not competitive. The antag- chemical structure of a drug can dramatically increase onist’s affinity for the receptor may be so high that or decrease the new drug affinities for different class- for practical purposes the receptor is unavailable for es of receptors, with resulting alterations in therapeu- binding of agonist. tic and toxic effects. The drug dissociation, solubility Mechanisms of drugs action may be connected with in lipids and water, permeation through biological bar- enzymes inhibition. For example, Proserine, which in- riers and membranes as well as pharmaceutical form hibits acetylcholinesterase, preserves acetylcholine and way of administration determine the drug action from enzymatic decomposition, as a result — tonus of also. Strength and duration of effect, possibility of toxic cholinergic system increases. Mechanism of action of action depends on the doze of the drug. There is di- some drugs is connected with blockade of ionic chan- rect correlation between the doze and the drug level nels in cellular membranes, e.g., antagonists of calci- in serum. um channels. The other drugs cause the exhaustion of As it was said above, the dose is the quantity of a mediator reserves in neural fibers in result of synthe- drug to be taken. It can be expressed in milliliters, sis breach or reverse neuronal seizure (e.g., tricyclic grams, and international unites. There are the moment antidepressants). dose (for one time use), the daily dose (the total amount of a remedy that is to be taken within 24 hours), the Types of the drugs action. There are local, reflec- curative dose (quantity of any substance required to ef- tive, and resorptive action. Under local action one can fect the cure of disease). The minimal (threshold) ther- understand the drug action at the place of administra- apeutical dose is the smallest amount of a drug that tion. It is used seldom. Reflective action appears as a will produce a desired therapeutic effect in an adult; result of irritation of neural fibers that transmitted the maximal therapeutical dose is the largest amount through the CNS or by axon-reflexes. It may appear of a drug that an adult can take with safety; the medi- both: during local and resorptive action (e.g., reflective an therapeutical dose is the dose that produces a de- action of mustard plaster and Cytitone). Resorptive ac- sired therapeutical effect in majority of patients. The tion is observed after the drug reaching the blood. initial (loading) dose is a comparatively large dose There are some types of resorptive action: direct given at the beginning of treatment to get the patient and indirect, basic and side, selective and general, under the influence of the drug; the maintenance dose convertible and non-convertible. Direct action occurs supports the effect of drug therapy. at the place of drug contact with tissues, e.g., cardiot- Therapeutical index is used for evaluation of ac- onic action of cardiac glycosides. Indirect action ap- tivity and safety of drugs. It is a ratio of the dose that pears as a result of function changes, e.g., increased causes death in 50% of laboratory animals to the dose diuresis during administration of cardiac glycosides. that cause a desirable effect in 50% of animals. It can

18 be also expressed as a ratio of the dose, which evokes (enzymopathies). For example, in case of glucose-6- a toxic effect in 50% of patients to the dose which phosphate dehydrogenase of erythrocytes insufficien- evokes a favorable effect in 50% of patients. Another cy sulfanilamides and derivatives of nitrofuran cause data of a drug safety is wideness of therapeutical ac- hemolytic anemia and jaundice. tion — difference between threshold and maximal ther- Pharmacogenetics is also studying mutagenic ef- apeutical doses. That drug is safer, which has large fects of drugs. It has great significance for individual- wideness of therapeutical action. ization of treatment and prognoses efficacy and safe- The factors concerning the whole organism of the ty of pharmacotherapy. patient are age, sex, genetic features, condition of the Factors of environment also have a determined in- patient, and biological rhythms. The age of the patient fluence on the drugs action. They are social conditions influences considerably on the drug action. This fac- that may cause psycho-emotional strain, strong nois- tor is especially important in the children and old pa- es, vibration, radiation, ecological problems, fluctua- tients. Most part of protective mechanisms in a child’s tion of temperature, etc. Prolonged and excessive in- organism is poorly developed. It is necessary to refer fluence of these factors increases the drugs action on possibility of cramps, allergic reactions, slow biotrans- the CNS especially of narcosis substances, soporifics formation and excretion of the drugs, unripeness of bi- and neuroleptics. Some drugs (sulfanilamides) increase ological barriers, high absorptive ability of the skin sensitivity of the skin to sunlight that named as photo- and mucosa coats. In children of first 3 years drugs sensitization. connection with serum proteins is lowered and level of Changes in the drugs action while repeated admin- free fraction is increased. In addition, children possess istration. In many cases drugs are used for prolonged higher sensitiveness to drugs. therapy that can strengthen or weaken their action. Old patients, especially over 75 years are charac- Strengthening of effect may be stipulated by its cumu- terized by higher sensitiveness to drugs, which suppress lation both material and functional. Material cumula- the CNS and lower sensitiveness that cause an oppo- tion is the accumulation of drugs (e.g., digitoxine, site effect. Tonus of the vegetative nervous system, the strychnine) that are slowly excreted from the organ- endocrine gland lowers. Susceptibility to thrombus for- ism. Functional cumulation is the accumulation of the mation increases, and it is dangerous to use coagulants. drugs effect (alcohol, caffeine, etc.). It means that af- Level of serum albumins is lower and level of free frac- ter the drugs excretion their effects are still present. tion is higher. Biotransformation in the liver and ex- As a result, toxic effects may appear. cretion by the kidneys are delayed. So, the dose is smaller and administration is more careful in old pa- Tolerance (accustoming, adaptation) is an ability tients. to endure or be less responsive to the drug, especially It is necessary to consider condition of the patient over a period of continued exposure. Tolerance can be as well. Weakened and exhausted patients need for explained by accelerated biotransformation and excre- lowering the dose. During shock and bleeding the sen- tion, and lowered of receptors sensitiveness. For over- sitiveness for oppressing drugs increases (narcotics, coming the tolerance you need to increase the dose of neuroleptics, etc.). It is necessary to consider the ad- the drug that sometimes cause intoxication. Usually ditive diseases. For example, hepatic disease has been tolerance to one drug is accompanied by developed shown to reduce the clearance and prolong the half- tolerance to pharmacologically similar compounds. life of many drugs. Tachyphylaxis is a rapid appearance of progres- The biological rhythm is alternation activity of sive decrease in response of constantly repeted admin- processes through a determined interval of time. De- istration of pharmacologically or physiologically ac- pendence of the drug action on the biological rhythm tive substances (e.g., while using ephedrine). and the influence on each other are studied by chronopharmacology. Biorhythms may have a season- Dependence (drug abuse, addiction) is character- al, monthly, and daily (circadian) character. Knowl- ized by constant and repeated wish of drug using. Usu- edge of the rhythm is necessary for choosing the drug ally it is indicated by withdrawal symptoms (absti- optimal regimen. For example, it is ascertained that nence) that develop when the use of the substance is maximal production of hormones in adrenal cortex oc- terminated. Psychologic dependence is manifested by curs in the morning and sensitiveness of tissues for those compulsive drug-seeking behavior in which the indi- hormones increases that time too. So, using of corti- vidual uses the drug repeatedly for personal satisfac- costeroids in the morning increases efficacy of thera- tion. Cigarette smoking is an example. Abstinence is py and lowers a risk of complications. characterized by mental depression that includes de- Some effects of drugs concern genetic factors. These pressed or irritable mood, loss of interest in usually problems are studied by pharmacogenetics, part of pleasurable activities, sleep and appetite disturbance, medical genetics. For instance, metabolism of isoni- fatigue, suicidal thoughts, hopelessness, and guilt. azid and apressin occur due to their acetylation in the Physiologic dependence is present when withdrawal of liver. People are divided into “slow acetylators” with the drug produces symptoms and signs that are fre- slow drugs acetylation and “quick acetylators”. One quently the opposite of those sought by the user. It has of genetically determined reactions is idiosyncrasy, been suggested that the body adjusts to a new level of which appears as an abnormal reaction to a drug. It is homeostasis during the period of drug use and reacts characterized by redness, edema of the skin and mu- in the opposite fashion when a new equilibrium is dis- cous, disorders of breathing and blood pressure, fever, turbed. For example, symptoms of opioid withdrawal and other disorders up to shock. Usually these reac- include lacrimation, sweating, weakness, chills, nau- tions are related to congenital insufficiency of enzymes sea and vomiting, muscle aches, hyper- or hypotension.

19 Drugs interaction. Combined therapy is used for the stance (e.g., binding of unithiol with metals). Exam- treatment of majority of diseases. Thus, it is necessary ple of physico-chemical antagonism is neutralization to know more about drugs interaction. There are two of heparin (anticoagulant) by Protamine sulfate, as a types of interaction: pharmaceutical and pharmaco- result of electrostatic interaction. Physical antagonism logical. Pharmaceutical interaction may appear be- is stipulated by physical features of the drug, e.g., ac- tween incompatible drugs while their production, stor- tivated carbon adsorbs molecules of many substances ing or mixing in solution. It can lower components ac- on its own surface. tivity and increase their toxicity. For example, it is not recommended to mix in one-syringe vitamins B1, B6, Types of drug therapy. Basic types of pharmaco- and B12. therapy are prophylactic, etiotropic, pathogenic, and Pharmacological interaction occurs on the level of symptomatic. Prophylactic drug is an agent that acts pharmacodynamic and pharmacokinetic processes. to prevent a disease, e.g., Chloridine for malaria pre- Interaction on the level of pharmacokinetic proc- vention. Etiotropic therapy is directed against the esses can be observed during absorption, transport, bi- cause; etiotropic agent is a remedy that attenuates or otransformation, and excretion of drugs. For example, destroys the causal factor of a disease, e.g., antimicro- activated carbon, which has adsorbent properties, de- bial drugs. Pathogenic therapy is directed on the path- creases the extent of the intestine absorption of the con- ologic, physiologic, or biochemical mechanism result- comitant drug. Competition for binding with serum ing in the development of a disease or morbid process, proteins may develop between drugs, e.g., Salicylates e.g., uses of cardiac glycosides in heart insufficiency. replace Butamide, which decrease the blood glucose Finally, symptomatic therapy is directed on removing concentration, that may cause hypoglycemic coma. of symptoms of a disease (analgesics, stimulators of Drugs interaction on the biotransformation level may breathing, etc.). appear due to inducing or inhibiting effects on microsomal enzymes of the liver. As it is mentioned above Complications of drug therapy. Together with ther- barbiturates increase the enzymes activity that is ac- apeutically action drugs may cause unfavorable side companied by hastened biotransformation of other (adverse) effects. There are different types of side ef- drugs. Cimetidine has an opposite effect. Interaction fects. on the stage of excretion may cause hastening and It may be complications related to the absolute slowing of drugs excretion from the organism. So, al- drug overdose — exceed of the maximal therapeuti- kaline drugs (sodium bicarbonate) hasten excretion of cal dose. A comparative overdose can appear as a the acid substances (salicylates) and on the contrary. result of fast intravenous injection of a drug, in se- This interaction may be used during poisoning, e.g., vere diseases of the liver, kidneys that delay drug administration of sodium bicarbonate during poison- elimination and increase drug concentration in the ing by salicylates and barbiturates. blood. Unfortunately many drugs possess a toxic ac- Drugs interaction on the pharmacodynamic level tion on human’s organs and tissues. For example, appears in the form of synergism or antagonism. Syn- aminoglycosides are ototoxic (vestibular and audi- ergism is a coordinated or correlated action of two tory damage) and nephrotoxic, Chloramphenicol or more agents so that the combined action is greater commonly causes bone marrow depression (anemia, than the effect of each one acting separately. It has leukopenia). two forms: summation (additive) and potentiation. Mutagenic, teratogenic, embryotoxic, and carcino- The former one is a simple sum (addition) of effects, genic effects of the drugs engage prominent place in e.g., combination of agents for narcosis. Potentiation nowadays medicine. Mutagenic effect is a promoting is an interaction between two or more drugs or agents of the changes in the chemistry of a gene that is per- resulting in a pharmacologic response greater than petuated in subsequent divisions of the cell in which it the sum of individual responses to each drug or agent, occurs. It may be a result of the drug action on sex e.g. combination of sedative drugs with alcohol. Syn- cells (e.g., anticancer drugs). Mutagenic action may ergism may be direct, when drugs act on the same lead to congenital diseases like the Daune’s syndrome. substrate, and indirect, when drugs act on different Teratogenic action of the drugs appears after its ad- substrates. ministration during pregnancy. It is characterized by Antagonism is the situation in which the combined the disturbed growth processes of fetus that lead to the effect of two or more agents is smaller than the soli- formation of growth anomalies and malformed ne- tary effect of any of the factors. It can be physiologi- onate. The most dangerous period is the first trimester cal, chemical, physico-chemical and physical. Physi- of pregnancy (2–3 months) during formation of organs ological antagonism appears on the level of a biologi- and systems. That’s why, administration of drugs in cal substrate. It may be direct and indirect. Interac- this period of pregnancy must be especially careful. In tion of cholinomimetic and cholinolytic is an example 60-s years of XX century it was so-called “thalidomide of direct antagonism. Indirect antagonism is stipulat- catastrophe”. Using of thalidomide during pregnancy ed by interaction of drugs with different mechanism of was accompanied by development of numerous congen- action. For example, Pilocarpine narrows the pupil ital defects in fetus. Nowadays, any drug cannot be through the stimulation of M-cholinoreceptors of the proposed for sale and using without observing on ter- pupil’s sphincter; adrenaline widens the pupil due to atogenic features. stimulation of adrenoreceptors of pupil’s radial mus- Negative action on fetus can appear in growth re- cle. Chemical antagonism is a type of chemical reac- tardation as well. If this effect appears during first 12 tion that results in loosing of initial pharmacological weeks of pregnancy, it is named embryotoxic, if later activity of agents and in formation of a non-active sub- — fetotoxic.

20 Allergic reactions are the most spread complica- 7. The body has developed defense mechanisms that tions of pharmacotherapy. They are stipulated by for- reduce the amount of foreign chemicals, such as drugs, mation of antibodies to the drugs that possess antigen that enter the body. One of the more prominent of these features or to their metabolites. Increasing of organ- mechanisms is an efflux transport system that pumps ism’s sensitivity to drugs is named sensitization. Hy- some drugs back into the intestinal lumen following persensitivity can be classified as immediate or delayed absorption into the enterocytes and that is responsible depending on the time required for clinical symptoms for the lack of complete absorption of some drugs. This to become manifest following exposure of the host to efflux transport system is: the sensitizing antigen. The most dangerous is anaphy- (A). Facilitated diffusion. lactic shock. (B). P glycoprotein. (C). Cytochrome P450 3A. (D). Pinocytosis.

EXAMINATION QUESTIONS 8. All of the following statements concerning the 1. Receptors are macromolecules that blood-brain barrier and the passage of drugs from the (A). Are designed to attract drugs. systemic circulation into the cerebrospinal fluid are (B). Are resistant to antagonists. true EXCEPT: (C). Exist as targets for physiological neurotrans- (A). Ionized drugs are more likely to cross into mitters and hormones. the CSF than unionized drugs. (D). Are only on the outer surface of cells. (B). The higher the lipid solubility of a drug, the (E). Are only inside of cells. more likely it will cross into the CSF. (C). Inflammation of the meninges improves the 2. All of the following are capable of initiating a likelihood that drugs will cross the blood- signal transduction process EXCEPT: brain barrier as compared to the uninflamed state (i.e., normal condition). (A). Combination of an agonist with its receptor. (D). P glycoprotein serves to pump drugs back into (B). Combination of an antagonist with its re- the systemic circulation from endothelial cells ceptor. lining the blood-brain barrier. (C). Combination of a neurotransmitter with its receptor. 9. Which of the following organs or tissues is a po- (D). Combination of a hormone with its receptor. tential site for drug accumulation of lead that has been ingested? 3. Which of the following chemical bonds would (A). Eyes. create an irreversible combination of an antagonist (B). Fat. with its receptor? (C). Bone. (A). Ionic bond. (D). Lungs. (B). Hydrogen bond. (E). Blood. (C). Van der Waals bond. (D). Covalent bond. 10. Concerning regulation of CYP-mediated drug metabolism, all of the following statements are true 4. Potency is determined by EXCEPT: (A). Affinity alone. (A). Drugs that competitively inhibit CYP enzymes (B). Efficacy alone. cause a decrease in concentrations of the ob- (C). Affinity and efficacy. ject (original) drug. (D). Affinity and intrinsic activity. (B). Induction of drug-metabolizing enzymes re- (E). Efficacy and intrinsic activity. sults in a decrease in concentrations of the ob- ject (original) drug, thus potentially reducing 5. Following oral administration, a drug is ab- efficacy. sorbed into the body, wherein it can exert its action. (C). Induction of drug-metabolizing enzymes fre- For a drug given orally, the primary site of drug ab- quently requires the synthesis of new enzyme sorption is: protein and thus may not occur immediately (A). The esophagus. upon introduction of the inducing agent. (B). The stomach. (D). Mechanism-based inactivation results in ir- (C). The upper portion of the small intestine. reversible inactivation of the enzyme that lasts (D). The large intestine. for the duration of the enzyme molecule.

6. Patients can exhibit alterations in the rate and 11. Conjugation of a drug with glucuronic acid via extent of drug absorption because of various factors. the glucuronosyl transferases will result in all of the All of the following factors might affect the rate and/ following EXCEPT: or extent of drug absorption EXCEPT: (A). Production of a more water-soluble moiety (A). Gastric emptying time. that is more easily excreted. (B). Intestinal motility. (B). A new compound that may also possess phar- (C). The presence of food. macological activity. (D). The formulation of the drug. (C). A drug molecule that may be more suscepti- (E). A generic form of the drug. ble to biliary elimination. 21 (D). A drug molecule that may undergo enterohe- (A). In general, a drug with a higher degree of patic recirculation and reintroduction into the plasma protein binding will have a lower vol- bloodstream. ume of distribution. (E). A drug with a different pharmacological (B). All drugs distribute to the same degree in all mechanism of action. tissues. (C). The binding of drugs to tissues has no rela- 12. Concerning the renal excretion of drugs: tionship to the distribution of drug in the (A). Drugs that are ionized in the renal tubule are body. more likely to undergo passive reabsorption (D). In general, lipophilic drugs distribute to a than those that are unionized. lesser extent than hydrophilic drugs. (B). Low-molecular-weight drugs are much more likely to be actively secreted than filtered. 18. A clinician must concern the amount of a drug (C). Only drug that is not bound to plasma pro- dose that reaches the systemic circulation, since this teins (i.e., free drug) is filtered by the glomer- will affect the plasma concentration and therapeutic ulus. effects observed. The fraction of a dose reaching the (D). Decreasing renal tubular fluid pH will in- systemic circulation as unchanged drug (i.e., intact) is crease elimination of weakly acidic drugs. defined as: (A). Theoretical dose. 13. Drug presence in breast milk is most likely for: (B). Cmax. (A). Drugs highly bound to plasma proteins. (C). Bioavailability. (B). Lipid-soluble molecules. (D). Ideal dose. (C). Large ionized water-soluble molecules. (D). Acidic compounds. 19. A dental technician begins to display symptoms, including tremor, depression, and insomnia. 14. Frequently it is useful to consider the overall Which of the following chemicals present in the work- exposure of a person to a drug during the dosing in- place may be responsible for the symptoms? terval. Which of the following pharmacokinetic param- (A). Solvents used in dental adhesives. eters defines the exposure of a person to a drug? (B). Fluoride used in oral rinses. (A). C . (C). Mercury used in the preparation of amal- max gams. (B). Tmax. (C). AUC (area under the curve). (D). Lidocaine used as an anesthetic. (D). Half-life. (E). Clearance. 20. A patient has learned recently that she is about 5 weeks pregnant, but as she has been suffering from depression, she asks her physician for a drug to treat 15. Organs such as the liver remove exogenous this problem. Her physician refused to prescribe a drug chemicals, such as drugs, from the body. For drugs such that time because he was concerned that the fetus was as phenytoin, for which the difference between the min- at risk for toxicity from in utero exposure to the drug. imum effective concentration and the minimum toxic What is the most likely adverse outcome if the woman concentration is small, clinicians must calculate the began taking the drug that time? rate at which a given individual removes drug from the (A). The fetus would die. body. The volume of fluid from which drug can be (B). A teratogenic response would occur in the completely removed per unit of time (rate of drug re- fetus. moval) is termed: (C). The growth of the fetus would be retarded. (A). Distribution. (B). Clearance. 21. Exposure to air pollutants can have adverse ef- (C). Metabolism. fects on human health. Which can result of the follow- (D). Excretion. ing conditions an exposure to one such pollutant — carbon monoxide? 16. For a drug such as Piroxicam with a 40-hour (A). Irritation of the deep lungs because of dam- half-life and being dosed once daily (i.e., every 24 age to the epithelium. hours), steady state will be reached shortly following (B). An increased susceptibility to respiratory which DOSE (not which half-life)? infection due to impairment in phagocyte (A). 1st dose. function. (B). 3rd dose. (C). Exacerbation of asthmatic episodes because (C). 5th dose. of bronchoconstriction. (D). 8th dose. (D). Hypoxia due to displacing oxygen from he- (E). 12th dose. moglobin.

17. Volume of distribution (Vd), though not a phys- 22. A 4-year-old boy is taken to the emergency de- iological volume, helps a clinician to estimate drug dis- partment by his parents in the afternoon the first Sat- tribution in the body. Drugs distribute throughout the urday in June. The family is moving into the house. body to differing degrees depending on a number of They found the boy almost unconscious in the corner factors. Which of the following factors is TRUE con- of the garage, having difficulty of breathing. He was cerning drug distribution? surrounded by chemical containers left by the previ-

22 ous owners. The labels had deteriorated and couldn’t sue type, very little drug absorption occurs through the be read. On examination you noted bronchoconstric- esophagus. tion and profuse airway secretion, weakness of the 6. (E). To be approved, generic formulations must ex- muscles, difficulty of breathing, and CNS depression. hibit the same rate and extent of absorption as the trade- Which of the following chemicals do you suspect was mark compound. All of the other choices can affect drug absorption. For example, slowing gastric emptying time involved? may increase the absorption of a drug absorbed in the (A). Compound 1080. stomach. Alterations in gastric motility may affect the (B). Pyrethrin. amount of time a drug spends in the region of the gas- (C). Parathion. trointestinal tract, where it undergoes the most extensive (D). Diquat. absorption. The presence of food may cause decreased absorption through binding to the drug or may increase 23. You are a staff physician at a major chemical absorption through making a better local environment manufacturing company. A worker on the mainte- for absorption of particular drugs. Finally, changes in nance crew has complained of being light-headed and drug formulation can alter absorption by changing dissolution rates. tired occasionally at work and that if it occurs, it 7. (B). P-glycoprotein transporters in the intestinal clears up after he leaves for the day. He was asked to lumen serve as an efflux transporter for many drugs. This write down where he had worked on the days this oc- transporter pumps drugs out of the enterocytes into curred; these are listed below. In which of these are- which they were absorbed and back into the intestinal as is he most likely to have exposures that would lumen, reducing absorption. Facilitated diffusion and cause these symptoms? pinocytosis generally result in drug influx (absorption). (A). Herbicide production area. The cytochrome P450 3A enzymes metabolize drugs; (B). Insecticide packaging area. therefore, even though they may reduce the amount of (C). Label printing area. drug absorbed, the reduction is due to drug metabolism, (D). Kitchen area of the cafeteria. not efflux transport back into the intestinal lumen. 8. (A). Un-ionized drugs cross into the cerebrospinal fluid more readily than ionized drugs. All of the other 24. You have been told there has been a large spill choices are correct. at the chemical company but in the confusion you 9. (C). Lead can substitute for calcium in the bone weren’t told where it occurred. The exposed workers crystal lattice, resulting in bone brittleness. Bone may were agitated and irritable and said to be having dif- become a reservoir for other substances as well. Several ficulty of walking in a coordinated manner. Some feel drugs, such as chlorpromazine, may accumulate in the quite hot as if they are burning up, and one had a sei- eye. Drugs with extremely high lipid-water partition co- zure. Which area do you suspect had the spill? efficients tend to accumulate in fat, while basic amines (A). Herbicide production area. tend to accumulate in the lungs. Many agents bind avid- ly to albumin in the blood. (B). Insecticide packaging area. 10. (A). When one inhibits the action of a drug-me- (C). Label printing area. tabolizing enzyme (A), one would expect an increase in- (D). Kitchen area of the cafeteria. stead of a decrease in drug concentrations, since less is being metabolized. Induction of an enzyme (B) would have the opposite effect, since there would be more enzyme available to metabolize the drug. (C) is correct, ANSWERS since the most common mechanism of enzyme induction is through synthesis of new enzyme protein, which does 1. (C). There are a large number of receptors in the body. Although many drugs are attracted to receptors, the not occur immediately. Finally, mechanism-based inac- receptors are not designed for that purpose. Antagonists tivation (D) is also correct, since this is irreversible, leav- are also attracted to receptors. Some receptors are on the ing the enzyme inactive and eventually it is degraded by cell surface, while others are found inside the cell. the body. 2. (B). An antagonist binds to a receptor and prevents 11. (E). Most glucuronic acid conjugates are less ef- the action of an agonist. Choice (A) is wrong because this fective than the parent drug. The conjugate, however, usu- combination does initiate a signal transduction process. ally maintains the same pharmacological mechanism of (C) and (D) are incorrect because both neuro-transmit- action, although frequently of a lesser magnitude. Con- ters and hormones work through their appropriate re- jugation with glucuronic acid makes a drug molecule ceptor to initiate signal transduction. more water soluble (A), and glucuronic acid conjugates 3. (D). A covalent bond is a strong and stable bond are more likely to be eliminated by secretion into the bile that is essentially irreversibly formed at normal body (C) than are unconjugated compounds. These glucuro- temperature. The other bonds are much weaker. nide conjugates, once secreted into the bile, may be 4. (C). Potency is a useful measure of the comparison cleaved by β-glucuronidases to liberate the parent com- between two or more drugs. It does not equate to thera- pound, which can then be reabsorbed (D). Several glu- peutic superiority but rather is a measure of the size of curonic acid conjugates of drugs (e.g., morphine 6-glu- the dose required to produce a particular level of re- curonide) possess pharmacological activity (B). sponse. 12. (C). Plasma proteins are too large to be filtered 5. (C). The primary site of absorption is the small by the glomerulus, so that any drug molecules bound to intestine. Because of its large surface area and high these plasma proteins will not undergo filtration. A is blood perfusion rate, the small intestine is optimal for not correct: ionized drugs are less likely to undergo rea- absorbing drugs. Some drug absorption occurs in the bsorption, since this is generally thought to be a passive stomach and large intestine, but because of their reduced process. B is also not correct: low-molecular-weight drugs surface area in relative terms and for some drugs less are more likely to be filtered, since they can easily pass than optimal physicochemical conditions, these tissues through the glomerulus filter. Finally, weakly acidic play a lesser role in drug absorption. Because of the tis- drugs will be un-ionized at a low (acidic) pH, hence more 23 likely to undergo reabsorption, thus reducing the net 19. (C). The symptoms are characteristic of a person elimination (D). chronically exposed to vapors released from elemental 13. (B). Lipid-soluble molecules are more likely to be mercury. Since the dental technician may handle elemen- excreted in breast milk because it is primarily a passive tal mercury, including mishandling, the symptoms pre- diffusion process. (A), (C), and (D) are not correct be- sented may occur. While the technician may be exposed cause they are opposite of the typical characteristics of to solvent vapors released from dental adhesives, the drugs excreted into breast milk. symptoms are not characteristic of this type of exposure. 14. (C). The AUC (area under the curve) best describes Fluoride toxicity would not be expected because these the overall exposure of a person to a given drug over the are not symptoms associated with fluoride ingestion, and course of the dosing interval. It describes the concentration the patient and not the technician would be most likely of drug integrated over the period assessed, usually the dos- exposed to quantities high enough to cause any symp- ing interval. (A) (Cmax) is not correct, as Cmax gives the max- toms. The technician has little exposure to lidocaine, and imum concentration achieved but does not reveal how long the symptoms are not typical of lidocaine toxicity. measurable concentrations of the drug were present or how 20. (B). The fetus is particularly vulnerable to tera- long until this concentration was achieved. (B) (Tmax) only togens between days 25 and 40 of gestation, and this refers to the time until the maximum concentration is patient is within this window of time. The fetus is at achieved, again not giving a reference to overall exposure much greater risk for death if exposure occurs during over time. (D) (half-life) simply describes how much time the first 2 weeks of gestation. Growth retardation of is required for the concentration to decrease by one-half. the fetus is the principal outcome if exposure to drugs Finally, clearance (E) is the volume of fluid (usually plas- occurs during the last 6 months of gestation. ma) from which drug can be removed per unit of time and 21. (D). Carbon monoxide can cause hypoxia because as such does not define exposure. it reduces the oxygen carrying capacity of the blood by 15. (B). Clearance is defined as the volume of fluid displacing oxygen from hemoglobin as well as impair- from which drug is completely removed per unit of time ing the erythrocyte’s ability to release oxygen. Particu- and as such is a measure of the body’s ability to remove late air pollutants and reactive air pollutant gases, such drug by whatever manner (e.g., elimination, metabolism, as ozone and nitrogen dioxide, can damage the lungs, excretion). Distribution is the theoretical volume to including increasing susceptibility to respiratory infec- which the drug distributes and metabolism and excretion tion and irritation of the deep lungs, while exposure to are simply methods of clearing drug. sulfur dioxide can exacerbate asthmatic episodes. 16. (D). Approximately five half-lives are required for 22. (C). Bronchoconstriction and secretion and mus- a drug to reach steady-state concentrations. Since Pirox- cular weaknesses occur from acetylcholine accumulation icam has a half-life of 40 hours, it will require approxi- after inhibition of acetylcholinesterase. Parathion is an mately 200 hours before steady state is reached. If given organophosphate insecticide that inhibits acetylcho- every 24 hours, shortly after the 8th dose (192 hours at linesterase, and it is readily available. Poisoning with exactly the 8th dose) steady state will be reached. compound 1080 (fluorocitrate) inhibits mitochondrial 17. (A). Drugs with a higher degree of plasma protein respiration and causes seizures and cardiac arrhythmi- binding in general have a lower volume of distribution, as. Pyrethrin and pyrethroids are generally low in tox- since the plasma proteins (and thus the drug bound to icity and few poisonings have been reported; however, the plasma protein) tend to stay in the plasma and not seizures are a symptom. Diquat causes gastrointestinal distribute to the extravascular tissues. Different drugs can disturbances. have widely disparate volumes of distribution, so (B) is 23. (C). Symptoms that occur during the working day incorrect. Tissue binding of drugs is extremely impor- and clear up after the work are often due to inhalation tant to drug distribution and can override plasma pro- exposure of volatile or aerosol materials. The solvents tein binding, so (C) is incorrect. Finally, (D) is incor- used in printing inks cause light-headedness and seda- rect, since in general the more lipophilic a drug is, the tion. The symptoms are not those of herbicide exposure greater volume of distribution it has. and insecticide exposure. 18. (C). Bioavailability describes the portion of the 24. (B). Spills cause acute high-dose exposures. The drug that reaches the systemic circulation without being symptoms are referable to an acute high exposure to an metabolized or eliminated. Bioavailability is highly de- organochlorine or pyrethroid insecticide. While organ- pendent on the drug and the route of administration. ochlorine pesticides are not used in this country, they Cmax (B) is incorrect, since this is only the maximum con- are manufactured for export. An acute high exposure to centration reached following a dose and gives no meas- herbicide would be primarily irritation of the skin and ure of the amount reaching the circulation. The other mucous membranes. The solvents in printing ink would terms (ideal dose and theoretical dose) are fabricated. cause the CNS depression.

24 DRUGS AFFECTING EFFERENT INNERVATION

The nervous system is divided into two anatomical pressure in the carotid sinus and aortic arch and sign- divisions, the central nervous system (CNS), which is aling the CNS to influence the efferent branch of the composed of the brain and spinal cord, and the periph- system to respond. eral nervous system, which includes neurons located Sympathetic neurons. The efferent autonomic nerv- outside the brain and spinal cord, that is, any nerves ous system is divided into the sympathetic and the par- that enter or leave the CNS (Fig. 1). asympathetic nervous systems. The preganglionic neu- The peripheral nervous system can be further div- ron of the sympathetic system comes from thoracic and ided into the efferent division, whose neurons carry lumbar region of the spinal cord and synapse in two signals away from the brain and spinal cord to the cord-like chains of ganglia that run in parallel on each peripheral tissues, and the afferent division, whose side of the spinal cord. Axons of the postganglionic neurons bring information from the periphery to the neurons extend from these ganglia to the glands and CNS. viscera. [Note: The adrenal medulla, like the sympa- The efferent portion of the peripheral nervous sys- thetic ganglia, receives preganglionic fibers from the tem can be further divided into two major functional sympathetic system. Lacking axons, the adrenal me- subdivisions, the somatic and autonomic systems. The dulla in response to stimulation, influences other or- somatic efferents are involved in voluntarily control- gans by secreting the hormone adrenaline, also known led functions such as contraction of the skeletal mus- as epinephrine (and lesser amounts of noradrenaline) cles in locomotion. The autonomic system functions into the blood.] involuntarily to regulate the everyday needs and re- Parasympathetic neuron. The parasympathetic quirements of the body without the conscious partici- preganglionic fibers arise from the cranial and sacral pation of the mind. It is composed primarily of viscer- areas of the spinal cord and synapse in ganglia near al motor (efferent) neurons that innervate smooth mus- or on the effector organs. In both the sympathetic and cle of the viscera, cardiac muscle, vasculature and the parasympathetic systems, postganglionic fibers extend exocrine glands. from the ganglia to effector organs.

Nervous system ANATOMY OF THE AUTONOMIC NERVOUS SYSTEM Peripheral Central Efferent neurons. The autonomic nervous system nervous system nervous system carries nerve impulses from the CNS to the effector organs by way of two types of efferent neurons. The first nerve cell is called a preganglionic neuron and its cell Efferent Afferent body is located within the CNS. Preganglionic neurons division division emerge from the brain stem or spinal cord and make a synaptic connection in ganglia. These ganglia function as relay stations between the preganglionic neu- Autonomic Somatic ron and the second nerve cell, the postganglionic neu- system system ron. The latter neuron has a cell body originating in the ganglion. It is generally non-myelinated and ter- minates on effector organs such as smooth muscle of Parasympathetic the viscera, cardiac muscle, and the exocrine glands. Afferent neurons. The afferent neurons (fibers) of Sympathetic the autonomic nervous system are important in the reflex regulation of this system, for example, by sensing Fig. 1. Structure of the autonomic nervous system

25 FUNCTIONS OF THE system. Thus, the heart has vagal parasympathetic innervation that slows rate of contraction, and sympa- SYMPATHETIC SYSTEM thetic innervation that speeds contraction. Despite this dual innervation, one system usually predominates in The sympathetic division has the property of ad- controlling the activity of a given organ. E.g., in the justing in response to stressful situations, such as trau- heart, the vagus is the predominant controlling factor ma, fear, hypoglycemia, cold, or exercise (Table 1). for rate. The effect of sympathetic output is to increase heart Organs receiving only sympathetic innervation. rate and blood pressure, to mobilize energy stores, and Although most tissues receive dual innervation, some to increase blood flow to skeletal muscle and heart while effector organs, such as the adrenal medulla, kidney, diverting flow from the skin and internal organs. Sym- pilomotor muscles, and sweat glands, receive innerva- pathetic stimulation also results in dilation of the pu- tion only from the sympathetic system. The control of pils and the bronchioles. The changes experienced by blood pressure is also mainly a sympathetic activity, the body during emergencies have been referred to as with essentially no participation by the parasympa- the “fight or flight” response. These reactions are trig- thetic system. gered both by direct sympathetic activation of the ef- Somatic nervous system. The efferent somatic nerv- fector organs and by stimulation of the adrenal medul- ous system differs from the autonomic system in that a la to release adrenaline which enters the blood stream. single myelinated motor neuron, originating in the The sympathetic nervous system tends to function as a CNS, travels directly to skeletal muscle without the unit and often discharges as a complete system. mediation of ganglia. As noted earlier, the somatic The parasympathetic division maintains essential nervous system is under voluntary control, whereas the bodily functions, such as digestive processes and elim- autonomic is an involuntary system. ination of wastes. It usually acts to oppose or balance Neurotransmitters. Each neuron is a distinct ana- the action of the sympathetic division and is generally tomic unit. Communication between nerve cells — and dominant over the sympathetic system in “rest and di- between nerve cells and effector organs — occurs gest” situation. The parasympathetic system is not a through the release of specific chemical signals, called functional entity as such and never discharges as a neurotransmitters, from the nerve terminals. This re- complete system. If it did, it would produce massive lease depends on processes that are triggered by Ca++ and undesirable symptoms. Instead, discrete parasym- uptake and regulated by phosphorylation of synaptic pathetic fibers are activated separately, and the sys- proteins. The neurotransmitters rapidly diffuse across tem functions to affect specific organs, such as the the synaptic cleft or gap (synapse) between nerve end- stomach or eye. ings and combine with specific receptor on the postsynaptic (target) cell. Membrane receptors. All neurotransmitters (and most hormones and local mediators) are too hy- INNERVATION BY THE drophilic to penetrate the lipid bilayer of cell mem- AUTONOMIC NERVOUS SYSTEM branes; instead, their signal is mediated by binding to specific receptors on the cell surface of target organs. Dual innervation. Most organs in the body are in- [Note: A receptor is defined as a recognition site for a nervated by both divisions of the autonomic nervous substance. It shows a binding specificity and is cou-

Table 1. Action of sympathetic and parasympathetic nervous systems on effector organs Organ Sympathetic Parasympathetic Eye Contraction of iris radial Contraction of iris sphincter muscle muscle (pupil dilates) (pupil contracts) Contraction of ciliary muscle (lens accommodates for near vision) Lacrimal glands Stimulates tears Salivary glands Thick, viscid secretion Copious, water secretion Trachea and bronchioles Dilates Constricts, increases secretions Heart Increased rate and contractility Decreased rate and contractility Blood vessels (skeletal Dilatation muscle, skin, mucus membranes Constriction and splanchnic area) Gastrointestinal Decreased in muscle motility and Increased muscle motility and tone tone; contraction of sphincters Ureters and bladder Relaxes detrusor; contraction of Contraction of detrusor trigone and sphincter Relaxation of trigone and sphincter Genitalia-male Stimulates ejaculation Stimulates erection Genitalia-female Relaxation of uterus

26 pled to processes that eventually evoke a response. Lecture 3 Most receptors are proteins.] Types of neurotransmitters. Although over 50 chem- CHOLINERGIC AGONISTS ical signal molecules in the nervous system have ten- tatively been identified, 6 signal compounds — norepinephrine (and closely related epinephrine), acetyl- Drugs affecting the autonomic nervous system are choline, dopamine, serotonin, histamine, and γ-ami- divided into two subgroups according to the type of no butyric acid — are most commonly involved in the neurons involved in their mechanism of action. The actions of therapeutically useful drugs. Each of these cholinergic drugs act on receptors that are activated chemical signals binds to a specific family of recep- by acetylcholine. The second group — the adrenergic tors. Cholinergic and adrenergic neurotransmitters are drugs — act on receptors that are stimulated by no- the primary chemical signals in the autonomic nerv- radrenaline or adrenaline. Both the cholinergic and ous system, whereas a wide variety of neurotransmit- adrenergic drugs act either by stimulating or blocking ters function in the CNS (Fig. 2). neurons of the autonomic nervous system. Acetylcholine. The autonomic nerve fibers can be classified into two groups based on the chemical nature of the neurotransmitter released. If transmission THE CHOLINERGIC NEURON is mediated by acetylcholine, the neuron is termed cholinergic. Acetylcholine mediates the transmission The preganglionic fibers terminating in the adre- of nerve impulses across autonomic ganglia in both nal medulla, the autonomic ganglia (both parasympa- the sympathetic and parasympathetic nervous sys- thetic and sympathetic), and the postganglionic fibers tems. It is the neurotransmitter at the adrenal me- of the parasympathetic division use acetylcholine as a dulla. neurotransmitter. Cholinergic neurons innervate vol- Transmission from the autonomic postganglionic untary muscles of the somatic system and are also nerves to the effector organs in the parasympathetic found in the CNS. system also involves the release of acetylcholine. In the Neurotransmission at cholinergic neurons. Neu- somatic nervous system, transmission at the neuromus- rotransmission in cholinergic neurons involves six cular junction (that is, between nerve fibers and voluntary muscles) is also cholinergic. steps. The first four, synthesis, storage, release and Noradrenaline and adrenaline. If noradrenaline or binding of acetylcholine to a receptor, are followed adrenaline is the transmitter, the fiber is called by the fifth step, degradation of the neurotransmitter adrenegic (epinephrine being another name for adren- in the synaptic gap, and the sixth step, the recycling aline). In the sympathetic system, noradrenaline me- of choline. diates the transmission of impulses from post-gangli- 1. Synthesis of acetylcholine. Choline is transport- onic nerves to effector organs. A summary of the neu- ed from the extracellular fluid into the cytoplasm of romediators released and the type of receptors within the cholinergic neuron by a carrier system that cotrans- the peripheral nervous system is shown in figure above. ports Na+ and can be inhibited by the drug Hemi- [Note: A few sympathetic fibers, such as those involved cholinium. Choline acetyltransferase (CAT) catalyzes in sweating, are cholinergic; for simplicity, they are the reaction of choline with acetyl CoA to form ace- not shown on the figure.] tylcholine in cytosol.

Autonomic Somatic Sympathetic innervation Sympathetic Parasympathetic of Adrenal medulla

Acetylcholine Acetylcholine Acetylcholine nicotinic nicotinic nicotinic receptor receptor receptor Adrenal medulla Noradrenaline Acetylcholine Acetylcholine Adrenaline released adrenergic muscarinic nicotinic into the blood receptor receptor receptor

Effector organs Striated muscle

Fig. 2. Neurotransmitters of the efferent innervation

27 2. Storage of acetylcholine in vesicles. The acetyl- doses, Pirenzepine does not cause many of the side ef- choline (AC) is packaged into vesicles by an active fects seen with the non-subtype-specific drugs. There- transport process. The mature vesicle not only contains fore, Pirenzepine may be useful in the treatment of gas- AC but also adenosine triphosphate (ATP) and prote- tric and duodenal ulcers. [Note: At present there are oglycan. The function of the latter substances in the no clinically important agents that interact with the M4 nerve terminal is unknown. and M5 receptors.] 3. Release of AC (Acetylcholine). When an action Nicotinic receptors. These receptors, in addition to potential arrives at a nerve ending, voltage-sensitive binding AC, also recognize nicotine but show only a Ca++ channels in the presynaptic membrane open, weak affinity for muscarine. Nicotine initially stimu- causing an increase in the concentration of intracellu- lates and then blocks the receptor. Nicotinic receptors lar Ca++. Elevated Ca++ levels promote the fusion are located in the (1) CNS, (2) adrenal medulla, (3) of synaptic vesicles with the cell membrane and release autonomic ganglia, (4) neuromuscular junctions, and of AC into the synapse. This release is blocked by Bot- (5) in the carotid sinuses. The nicotinic receptors of ulinum toxin. By contrast, black widow spider venom autonomic ganglia differ from those of the neuromus- causes all of the cellular AC stored in synaptic vesi- cular junction. For example, ganglionic receptors are cles to spill into the synaptic gap. selectively blocked by Benzohexonium, whereas neu- 4. Binding to receptor. AC released from the syn- romuscular junction receptors are specifically blocked aptic vesicles diffuses across the synaptic space and by Tubocurarine. binds to either postsynaptic receptors on the target cell or to presynaptic receptors in the membrane of the neuron that released the AC. Binding to the receptor leads DIRECT-ACTING CHOLINERGIC to a biological response within the cell such as the ini- AGONISTS tiation of a nerve impulse in a postganglionic fiber or Cholinergic agonists mimic the effects of acetylcho- activation of specific enzymes in effector cell as medi- line (AC) by binding directly to cholinoreceptors. ated by second messenger molecules. These agents are synthetic esters of choline, such as 5. Degradation of AC. The signal at the postjunc- Carbachol, or naturally occurring alkaloids, such as tional effector site is rapidly terminated. This occurs Pilocarpine. All of the direct acting cholinergic drugs in the synaptic cleft where acetylcholinesterase cleaves have longer duration of action than AC. [Note: Mus- AC to choline and acetate. carinic receptors are located primarily, but not exclu- 6. Recycling of AC. Choline may be recaptured by sively, at the neuroeffector junction of the parasympa- a sodium-coupled high affinity uptake system that thetic nervous system.] However, as a group, the di- transports the molecule back into the neuron, where it rect acting agonists show little specificity in their ac- is acetylated and stored until released by a subsequent tion, which limits their clinical usefulness. action potential. Acetylcholine CHOLINERGIC RECEPTORS Acetylcholine is a quaternary ammonium com- Two families of cholinergic receptors (cholinore- pound that cannot penetrate membranes. Although it ceptors), designated muscarinic and nicotinic recep- is the neurotransmitter of parasympathetic and cholin- tors, can be distinguished from each other on the ba- ergic nerves, it is therapeutically of no importance because of its multiplicity of action and its rapid inacti- sis of their different affinities for agents that mimic the vation by acetylcholinesterase. AC has both muscarin- action of acetylcholine (cholinomimetic agents). ic and nicotinic activity. Its action include: Muscarinic receptors. These receptors, in addition a) decrease in heart rate and cardiac output: The to binding AC, also recognize muscarine, an alkaloid action of AC on the heart mimic the effects of vagal that is present in certain poisonous mushrooms. By con- stimulation. E.g., acetylcholine, if injected intrave- trast, the muscarinic receptors show only a weak af- nously, produces a brief decrease in cardiac rate and finity for nicotine. Using binding studies and specific stroke volume as a result of a reduction in the rate inhibitors, several subclasses of muscarinic receptors of firing at the sinoatrial (SA) node. [ Note: It have been pharmacologically distinguished as M1, M2, should be remembered that normal vagal activity M3, M4, and M5. regulates the heart by the release of AC at the SA Locations of muscarinic receptors. The most impor- node.] tant sites of location of the muscarinic receptors are b) decrease in blood pressure: Although no inner- (1) neuroeffector endings of the parasympathetic sys- vation of vasculature by the parasympathetic system tem. They have been also found (2) sweating glands exists, there are cholinergic receptors on the blood ves- innervated by sympathetic fibers, and (3) in the CNS. sels that respond by causing vasodilation. Vasodila- M1 receptors are found on gastric parietal cells, M2 tion is due to an acetylcholine-induced rise in intra- receptors on cardiac cells and smooth muscle, and M3 cellular Ca++ — caused by the phosphatidylinositol receptors on exocrine glands and smooth muscle. system — that results in the formation of nitric oxide Muscarinic agonists and antagonists. Attempts are (NO) from arginine in endothelial cells. [Note: NO is currently underway to develop muscarinic agonists also known as endothelium-derived relaxing factor and antagonists that are directed against specific re- (EDRF).] In the absence of administered cholinergic ceptor subtypes. For example, pirenzepine, a tricyclic agents, the vascular receptors have no known function, anticholinergic drug, selectively inhibits M1 muscarin- since AC is never released into the blood in any sig- ic receptors, such as in gastric mucosa. At therapeutic nificant quantities. Atropine (see next lecture) blocks

28 these muscarinic receptors and prevents AC from pro- ANTICHOLINESTERASES ducing vasodilation. (REVERSIBLE) c) other actions: In the gastrointestinal tract, AC increases salivary secretion, and stimulates intestinal Acetylcholinesterase is an enzyme that specifically secretion and motility. Bronchiolar secretion is also cleaves acetylcholine (AC) to acetate and choline. It is stimulated. In the urogenital tract, the tone of the uter- located in the nerve terminal, where it is membrane ine detrusor muscle is increased. In the eye, AC is in- bound. Inhibitors of acetylcholinesterase indirectly pro- volved in stimulating ciliary muscle contraction for vide cholinergic action by prolonging the lifetime of AC. near vision and in the constriction of the pupillae This results in accumulation of AC in the synaptic space. sphincter muscle, causing miosis (marked constriction These drugs can thus provoke a response at all cholinor- of the pupil). eceptors in the body, including both muscarinic and nicotinic receptors of the autonomic nervous system as well Carbachol as the neuromuscular junction and the brain. Carbachol has both muscarinic and nicotinic ac- Physostigmine tions. Carbachol is an ester and a poor substrate for acetylcholinesterase. It is biotransformed by other es- Physostigmine is an alkaloid (a nitrogenous com- terases but at a much slow rate. A single administra- pound found in plants) and a tertiary amine. It is a sub- tion can last as long as one hour. strate for acetylcholinesterase, and forms a relatively Actions. Carbachol has a profound influence on stable enzyme-substrate intermediate that reversibly both cardiovascular system and the GI tract because inactivates acetylcholinesterase. The result is potenti- of its ganglion-stimulating activity and may first stim- ation of cholinergic activity throughout the body. ulate and then depress these systems. It can cause re- Action: Physostigmine has a wide range of actions because it stimulates not only muscarinic and nicotin- lease of epinephrine from the adrenal medulla by its ic sites of the autonomic nervous system but also the nicotinic action. Locally instilled into the eye, it mim- nicotinic receptors of the neuromuscular junction. Its ics the effects of AC, causing miosis. duration of action is about 2-4 hours. Physostigmine Therapeutic uses. Because of its high potency and can enter and stimulate the CNS. relatively long duration of action, Carbachol is rare- Therapeutic uses: The drug increases intestinal and ly used therapeutically, except in the eye as a miotic bladder motility, which serve as its therapeutic action agent to cause contraction of the pupil and decrease in atony of either organ. Placed topically in the eye, in intraocular pressure. it produces miosis and spasm of accommodation and Adverse effects. At doses used ophthalmologically, a lowering of intraocular pressure. It is used to treat there are little to no side effects. glaucoma, but Pilocarpine is more effective. Phys- ostigmine is also used in the treatment of overdoses of Pilocarpine drugs with anticholinergic actions such as Atropine, The alkaloid Pilocarpine is a tertiary amine and Phenothiazine, and tricyclic antidepressants. is stable to hydrolysis by acetyl-cholinesterase. Com- Adverse effects: The effects of Physostigmine on the pared with AC and its derivatives, it is far less potent. CNS may lead to convulsions when high doses are Pilocarpine exhibits muscarinic activity and is prima- used. Bradycardia may also occur. Inhibition of ace- rily used in ophthalmology. tylcholinesterase at the skeletal neuromuscular junc- Actions. Applied topically to the cornea, Pilocarpine tion causes the accumulation of AC and ultimately re- produces a rapid miosis and contraction of the ciliary sults in paralysis of skeletal muscle. However, these muscle. The eye undergoes a spasm of accommodation, effects are rarely seen with therapeutic doses. and vision is fixed at some particular distance, making it impossible to focus. Pilocarpine is one of the most po- Neostigmine tent stimulators of secretions such as sweat, tears, and Neostigmine is a synthetic compound that reversibly saliva, but it is not used for this purpose. inhibits acetylcholinesterase as does physostigmine. Un- Therapeutic uses. Pilocarpine is a drug of choice in like Physostigmine, Neostigmine is more polar and there- the emergency lowering of intraocular pressure of both fore does not enter the CNS. Its effect on skeletal muscle narrow-angle (also called closed-angle) and wide-angle is greater than that of Physostigmine, and it can stimu- (also called open-angle) glaucoma. Pilocarpine is ex- late contractility before it paralyzes. Neostigmine has tremely effective in opening the trabecular meshwork a moderate duration of action, usually 2–4 hours. It is around Schlemm’s canal, causing an immediate drop in used to stimulate the bladder and the GI tract, and is intraocular pressure as a result of the increased drain- also used as antidote for Tubocurarine and other com- age of aqueous humor. This action lasts up to 1 day and petitive neuromuscular blocking agents. Neostigmine can be repeated. Cholinesterase inhibitors, such as has found use in symptomatic treatment of myasthenia Phosphacol, have longer duration of action. [Note: Car- gravis, an autoimmune disease caused by antibodies to bonic anhydrase inhibitor Acetazolamide, the β-adren- the nicotinic receptors that bind to the AC receptors of ergic blocker, timolol, and adrenaline are effective in neuromuscular junctions. This causes their degradation, treating glaucoma chronically but are not used for the and thus makes fewer receptors available for interaction emergency lowering of intraocular pressure.] with neurotransmitter. Adverse effects of Neostigmine in- Adverse effects. Pilocarpine can enter the brain and clude the actions of generalized cholinergic stimulation, cause CNS disturbances. It stimulates profuse sweat- such as salivation, flushing, decreased blood pressure, ing and salivation. nausea, abdominal pain, and bronchospasm.

29 Pyridostigmine Lecture 4 Pyridostigmine is another cholinesterase inhibitor CHOLINERGIC ANTAGONISTS that is used in the chronic management of myasthenia gravis. Its duration of action (3–6 hours) is longer than that of Neostigmine. The cholinergic antagonists (also called cholinergic blockers or anticholinergic drugs) bind to cholinoreceptors but do not trigger the usual recep- tormediated intracellular effects. The most useful of ANTICHOLINESTERASES these agents selectively the muscarinic synapses of the (IRREVERSIBLE) parasympathetic nerves. The effects of parasympa- A number of synthetic organophosphate compounds thetic innervation are thus interrupted, and the ac- have the capacity to bind covalently to acetylcho- tions of sympathetic stimulation are left unopposed. linesterase. The result is a long lasting increase in AC A second group of drugs interfere with cholinergic at all sites where it is released. Many of these drugs transmission primary in the CNS and are used in Par- are extremely toxic and were developed by the mili- kinson’s disease. A third group, the ganglionic block- tary as nerve agents. Related compounds such as Par- ers, show a preference for the nicotinic receptors of athion, Chlorophos are insecticides. the sympathetic and parasympathetic ganglia. A fourth family of compounds, the neuromuscular Armine blocking agents, interfere with transmission of efferent impulses to skeletal muscles. Mechanism of action. Armine is an organophosphate that covalently binds to the active site of acetylcholinesterase. Once this occur, the enzyme is permanently inacti- ANTIMUSCARINIC AGENTS vated, and restoration of acetylcholinesterase activity requires the synthesis of new enzyme molecules. Follow- These agents, for example, atropine and scopo- ing covalent modification of acetylcholinesterase, the lamine, block muscarinic receptors causing inhibition phosphorylated enzyme slowly release one of its alkyl of all muscarinic function. In addition, these drugs groups. The loss of an alkyl group, which is called ag- block the few exceptional sympathetic neurons that are ing, makes it impossible for chemical reactivators, such cholinergic, such as those innervating sweat glands. In as Pralidoxime or Dipiroxime (see below), to break the contrast to cholinergic agonists, which have limited bond between the remaining drug and the enzyme. New- usefulness therapeutically, the cholinergic blockers are er nerve agents, available to the military, age in minutes beneficial in a variety of clinical situations. Because or seconds. Armine ages in several hours. they do not block nicotinic receptors, the antimuscarin- Actions: Actions include generalized cholinergic ic drugs have little or no action at skeletal neuromus- stimulation, paralysis of motor function (causing breath- cular junctions or autonomic ganglia. ing difficulties), and convulsions. Armine produces intense miosis and thus has found therapeutic use. Atro- Atropine pine in high dosage can reverse many of the muscarinic Atropine, a belladonna alkaloid, has a high affin- and central effects of organophosphate compounds. ity for muscarinic receptors, where it binds competi- Therapeutic uses: An ophthalmic solution of the tively, preventing acetylcholine (AC) from binding to drug is used topically in the eye for the chronic treat- that site. Atropine is both a central and peripheral mus- ment of open-angle glaucoma. The effect can last for carinic blocker. Its general actions last about 4 hours up to one week after a single administration. except when placed topically in the eye, where the ac- Reactivation of acetylcholinesterase. Dipiroxime, tion may last for days. Pralidoxime (PAM) are synthetic compounds that can Actions: reactivate inhibited acetylcholinesterase. The presence Ophthalmic: Atropine blocks all cholinergic activ- of a charged group allows it to approach an anionic ity on the eye (Fig. 3), resulting in mydriasis (dilation site on the enzyme where it is essentially displaces the of the pupil), unresponsiveness to light and cyclople- organophosphate and regenerates the enzyme. If giv- gia (inability to focus for near vision). In patients with en before aging of the alkylated enzyme occurs, it can glaucoma, intraocular pressure may rise dangerous- reverse the effects of armine except for those for the ly. Locally applied Atropine produces ocular effects CNS. With the newer nerve agents, which produce ag- of considerable duration; accommodation and papil- ing within seconds, reactivators are less effective. lary reflexes may not fully recover for 7 to 12 days. Gastrointestinal (GI): Atropine can be used as an Available forms: antispasmodic to reduce activity of the GI tract. Atro- Aceclidine — in ampoules 0.2% solution 1 and 2 pine and Scopolamine are probably the most potent ml each drugs available that produce that effect. Although gas- Arminum — in bottles 0.01% solution 10 ml each tric motility is reduced, hydrochloric acid production Dipiroxime — in ampoules 15% solution 1 ml each is not significantly affected. Thus, the drug is not ef- Neostigmine — in tablets 0.015 each; in ampoules fective in promoting healing of peptic ulcer. [Note: 0.05% solution 1 ml each Pyrenzipine, an M1-muscarinic antagonist, does re- Physostigmine — in bottles 0.25% solution 5 ml duce gastric acid secretion at doses that do not antag- each onize other systems.] Pilocarpine — in bottles 1% and 2% solution 5 and Urinary system: Atropine is also employed to re- 10 ml each duce hypermotility states of the urinary bladder. It is

30 still occasionally used in enuresis (involuntary void- ing of urine) among children but α-adrenergic agonists may be more effective with fewer side effects. >10.0 mg Hallucination and delirium; coma Cardiovascular: Atropine produces divergent effects on the cardiovascular system, depending on the dose. At low doses the predominant effect is a de- 5.0 mg Rapid heart rate; palpitation; creased cardiac rate (bradycardia). Originally thought marked dryness of mouth; to be due to central activation of vagal efferent out- 2.0 mg dilation of pupil; some blurring of flow, newer data indicate that the effect results from near vision blockade of the M1 receptors on the inhibitory prejunctional neurons, thus permitting increased AC release. 0.5 mg Slight cardiac slowing; With higher doses of Atropine, the cardiac receptors some dryness of the mouth; on the SA node are blocked, and the cardiac rate in- inhibition of sweating creases modestly (tachycardia). This generally requires at least 1 mg of Atropine, which is a higher dose Fig. 3. Dose-dependent effects of Atropine than ordinary given. Arterial blood pressure is unaffected. Secretions: Atropine blocks the salivary glands to Actions: Scopolamine is one of the most effective produce a drying effect on the oral mucous membranes anti-motion sickness drug available. Scopolamine also (xerostomia). The salivary glands are exquisitely sen- has the unusual effect of blocking short-term memory. sitive to atropine. Sweat and lacrimal glands are also In contrast to Atropine, Scopolamine produces sedation, affected. Inhibition of secretions by the former can but at higher doses can instead produce excitement. cause elevated body temperature. Therapeutic uses: Though similar to Atropine, its Therapeutic uses: therapeutic use is limited to prevention of motion sick- Ophthalmic: In the eye, topical Atropine exerts ness (for which Scopolamine is particularly effective) both mydriatic and cycloplegic effects and permits the and blocking of short-term memory. [Note: As with all measurement of refractive errors without interference such drugs used for this condition, it is much more ef- by the accommodative capacity of the eye. Atropine fective prophylactically than for treating motion sick- may induce an attack in individuals with narrow an- ness after it occurs. The amnesic action of Scopolamine gle glaucoma. is sometimes made use of in anesthetic procedures.] Antispasmodic agent: Atropine is used as antispas- Pharmacokinetics and adverse effects. These aspects modic agent to relax the GI tract and bladder. are similar to those of Atropine. As antidote for cholinergic agonists: Atropine is used for the treatment of organophosphate (contained Other compounds in certain insecticides) and some types of mushroom poisoning (certain mushrooms contain cholinergic sub- An alkaloid Platyphylline is a naturally occurring stances). Its ability to enter the CNS is of particular tertiary amine found in plants. Platyphylline is less importance. Atropine blocks the effects of excess ace- potent than Atropine. Its use has been limited chiefly tylcholine (AC) that results from inhibition of acetyl- to gastrointestinal diseases where it is administered as cholinesterase by drugs such as Physostigmine. antispasmodic agent. Anti-secretory agent: The drug is sometimes used Homatropine, a quaternary ammonium compound, to block secretions in the upper and lower respiratory is available in an ophthalmic solution. Applied topi- tracts prior to surgery. cally in the eye, Homatropine produces ocular effects Pharmacokinetics: Atropine is readily absorbed, similar to those of Atropine (pupillary dilation and loss partially metabolized in the liver, and is eliminated of accommodation). Compared with Atropine, its du- primarily in the urine. It has a half-life of about 4 ration of action is shorter (15–20 H). hours. Methacine is a quaternary ammonium derivative Adverse effects: Depending on the dose, Atropine and therefore lacks the central actions. Other pharma- may cause dry mouth, blurred vision, “sandy eyes”, cological properties are similar to those of Atropine. tachycardia, and constipation. Effects on the CNS in- Methacine is used parenterally and enterally. clude restlessness, confusion, hallucination, and delir- Ipratropium bromide, a quaternary derivative of ium, which may progress to depression, collapse of the Atropine, produces effects that are similar to those of circulatory and respiratory systems and death (see Fig. Atropine when each agent is administered parenteral- 3). In older individuals, the use of Atropine to induce ly. These include bronchodilation, tachycardia, and mydriasis and cycloplegia is considered too risky inhibition of salivary secretion. Although Ipratropium since it may exacerbate an attack of glaucoma in some- lacks appreciable effect on the CNS. When Ipratro- one with a latent condition. pium is inhaled, the actions are confined almost exclusively to the airways. Even when administered in Scopolamine amounts many times the recommended dosage, little or no change occurs in heart rate, blood pressure, blad- Scopolamine, another belladonna alkaloid, pro- der function, intraocular pressure, or pupillary diam- duces peripheral effects similar to those of Atropine. eter. This selectively results from the very inefficient However, Scopolamine has greater action on the CNS absorption of the drug from the lungs or the GI tract. and a longer duration of action in comparison to Ipratropium is useful in treating asthma and chronic those of Atropine. It has some special actions indi- obstructive pulmonary disease in patients unable to cated below. take adrenergic agonists. 31 Pyrenzipine hydrochloride is a tricyclic drug, sim- cacious than dopaminergic agonists). Currently avail- ilar in structure to Imipramine. In contrast to the clas- able antiparkinsonian muscarinic antagonists (Cy- sic anticholinergics, Pirenzepine has selectivity for clodolum, Amizylum etc.) qualitatively resemble the M1-receptors and was initially shown to have greater belladonna alkaloids in its pharmacological action gastrointestinal selectivity than other muscarinic an- and side effects. tagonists. Pirenzepine suppresses basal and stimulated gastric acid secretion at doses having a minimal effect on the salivary glands, the heart and the eyes. POISONING BY BELLADONNA ALKALOIDS CENTRALLY ACTING The deliberate or accidental ingestion of bella- ANTIMUSCARINIC DRUGS donna alkaloids or other classes of drugs with atropinic properties is a major cause of poisonings. In- The belladonna alkaloids and related antimus- fants and young children are especially susceptible carinic agents have long been used in the treatment of to the toxic effects of atropinic drugs. Indeed, many Parkinson’s disease. Parkinson’s disease is a progres- cases of intoxication in children have resulted from sive neurologic disorder of muscle movement, charac- conjunctival instillation of atropine eye-drops. Seri- terized by tremor, muscular rigidity, and bradykinesia ous intoxication may occur in children who ingest (slowness in initiating and carrying out voluntary berries or seeds containing belladonna alkaloids. The movements). The disease is correlated with a reduction diagnosis of atropine poisoning is suggested by the in the activity of dopaminergic neurons in the substan- wide-spread paralysis of parasympathetic innervation tia nigra and corpus striatum — parts of the brain ba- — dry mouth, mydriasis, blurred vision, hot dry skin, sal ganglia system that are responsible for motor con- and, in addition, hyperreflexia, excitement, halluci- trol. The substantia nigra, part of the extrapyramidal nations, delirium and later, cerebral depression and system, is the source of dopaminergic neurons that ter- coma. As it was described with characteristic Ameri- minate in the striatum. Dopaminergic system serves as can verbal felicity — “hot as a hare, blind as a bat, a tonic, sustaining influence on motor activity, rather dry as a bone, red as a beet and mad as a hen”. than participating in specific movements. Cells of the The treatment of atropine (and other anticholiner- substantia nigra sends neurons to the striatum, secret- gic drugs) poisoning is on general lines. Measures to ing the inhibitory transmitter dopamine at their termi- limit intestinal absorption should be initiated without ni (Fig. 4). delay if the poison has been taken orally. For sympto- In turn, the striatum is connected to the substan- matic treatment, anticholinesterase drug (physostig- tia nigra by neurons that secrete the inhibitory trans- mine) is the rational therapy. This agent enters the cen- mitter GABA at their termini in the substantia nigra. tral nervous system and reverses both the central and This mutual inhibitory pathway normally maintains peripheral effects. Physostigmine 1–4 mg i.v. or i.m. a degree of the two separate areas. Nerve fibers from is effective, though it may need repeating, as its ac- the cerebral cortex and thalamus secrete acetylcho- tion (1–2 hours) is shorter than that of Atropine. If line (AC) in the neostriatum, causing excitatory ef- marked excitement is present, diazepam is the most suit- fects. In Parkinson’s disease, destruction of cells in able agent for sedation and for control of convulsion. the substantia nigra results in the degeneration of Ice bags and alcohol sponges help to reduce fever, es- neurons responsible for the secreting dopamine in the pecially in children. neostriatum. Consequently, the decrease in dopaminergic activity results in a relative excess of cholinergic influ- AGENTS ACTING ON THE ence. The symptoms of parkinsonism reflect an im- NICOTINIC RECEPTORS balance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory Several drugs have their major action the interrup- dopaminergic neurons. Strategy for the treatment is tion of transmission of the nerve impulses at the skele- aim to restore dopamine in the basal ganglia and an- tal neuromuscular junction and/or autonomic ganglia. tagonizing the excitatory effect of cholinergic neu- These agents can be classified together, since they in- rons, thus reestablishing the correct dopamine/acetyl- teract with a common family of receptors; these recep- choline balance. tors are called nicotinic cholinergic, since they are Anticholinergic drugs play only an adjuvant role stimulated by both the natural transmitter acetylcho- in antiparkinsonian therapy (they are much less effi- line and the alkaloid nicotine. Distinct subtypes of nic-

Substantia nigra Neostriatum DA - ACh +

- GABA

Fig. 4. Relations of synapses of the extrapyramidal system

32 otinic receptors exist at the neuromuscular junction Therapeutic uses: and the ganglia, and two groups of pharmacological Trimethaphan (Arfonad) is a short-acting gangli- agents discriminate between them (ganglionic block- onic blocker that must be given by i.v. infusion. To- ers and neuromuscular blocking agents). day, the drug is used for the emergency lowering of blood pressure, for example, in hypertension caused by pulmonary edema or dissecting aortic aneurysm. GANGLIONIC BLOCKERS Also it is used to produce controlled (moment-to-mo- Ganglionic blockers specifically act on the nico- ment) hypotension in anesthesia. tinic receptors of the autonomic ganglia. These drugs Benzohexonium and Pentamine act longer and are show no selectivity towards the parasympathetic or generally used in the treatment of moderately severe sympathetic ganglia and are not effective as neuromus- to severe hypertension. cular antagonists. Thus, these drugs block the entire Pirilen is useful for the long-term treatment of se- output of the autonomic nervous system at the nicotin- vere hypertension and peripheral vascular disease. ic receptor. The responses observed are complex and Pachycarpine has an additional specific property can be anticipated by knowing which division of the to stimulate myometrium and accelerate parturition. autonomic nervous system exercises dominant control of various organs (Table 2). NEUROMUSCULAR BLOCKING DRUGS Actions: Cardiovascular system: Blockade of sympathetic These drugs block cholinergic transmission be- ganglia interrupts adrenergic control of arterioles and tween motor nerve ending and the nicotinic receptors results in vasodilation, improved peripheral blood flow, on the neuromuscular end-plate of the skeletal mus- and a fall in blood pressure. Venous return decreases cle. These neuromuscular blockers are structural ana- resulting from venous dilation and peripheral pooling logs of acetylcholine and act either as antagonists of blood. In patients with cardiac failure, ganglionic (non-depolarizing type) or agonists (depolarizing blockade results in increased cardiac output due to a type) at the receptors on the end-plate of the neu- reduction in peripheral resistance. Blood flow to the romuscular junction. Neuromuscular blockers are hands and feet may increase and skin temperature in clinically useful during surgery to produce complete the limbs is elevated. muscle relaxation, without having to employ higher Other effects: Generalized ganglionic blockade anesthetic doses to achieve comparable muscular re- may result also in atony of the bladder and the GI laxation. A second group of muscle relaxants, the tract, cycloplegia, xerostomia, diminished perspira- central muscle relaxants, are used to control spastic tion. These changes represent the generally undesira- muscle tone. These drugs include Diazepam (which ble feature, which limits the therapeutic use of the gan- binds at GABA receptors in the CNS), Dantrolene glionic blockers. (which act directly on muscles by interfering with the Pharmacokinetics. Ganglionic blocking agents are release of Ca++ from the sarcoplasmic reticulum), divided chemically into bisquaternary and tertiary and Baclofen (which probably acts at GABA recep- amines. The absorption of quaternary ammonium com- tors in the CNS). pounds from the enteric tract is incomplete and unpredictable (Benzohexonium, Pentamine). Therefore, they are administered parenterally. According to the dura- NONDEPOLARIZING tion of action, ganglionic blockers are classified into: (COMPETITIVE) BLOCKERS — short-acting drugs — 15 to 20 minutes (Trimeth- aphan (Arfonad), Hygronium) The first drug that was found capable of blocking — intermediate-acting drug — up to 6 hours (Ben- the skeletal neuromuscular junction was curare, which zohexonium, Pentamine, Pachycarpine) the native hunters of the Amazon in South America used — long-acting drug — 6 to 12 hours (Pirilen) to paralyze game. The drug Tubocurarine was ultimate-

Table 2. Usual predominance of adrenergic or cholinergic tone at various effector sites, with consequent effects of autonomic ganglionic blockade Site Predominant tone Effect Arterioles Sympathetic (adrenergic) Vasodilation; increased peripheral blood flow; hypotension Veins Sympathetic (adrenergic) Dilation; peripheral pooling of blood; decreased venous return; decreased cardiac output Heart Parasympathetic (cholinergic) Tachycardia Iris Parasympathetic (cholinergic) Mydriasis Ciliary muscle Parasympathetic (cholinergic) Cycloplegia GI tract Parasympathetic (cholinergic) Reduced tone and motility; constipation Urinary bladder Parasympathetic (cholinergic) Urinary retention Salivary glands Parasympathetic (cholinergic) Xerostomia Sweat glands Sympathetic (adrenergic) Anhidrosis

33 ly purified and introduced into clinical practice in the a relatively long time, and providing a constant stim- early 1940s. The neuromuscular blocking agents have ulation of the receptor. The depolarizing agent first significantly increased the safety of anesthesia, since causes the opening of the sodium channel associated less anesthetic is required to produce muscle relaxation. with the nicotinic receptor, which results in depolari- Mechanism of action: Nondepolarizing neuromus- zation (Phase I). This leads to a transient twitching of cular blocking drugs combine with the nicotinic recep- the muscle (fasciculations). The continued binding of tor and prevent the binding of ACh. These drugs pre- the depolarizing agent renders the receptor incapable vent depolarization of the muscle cell membrane and of transmitting further impulses. With time, the con- inhibit muscular contraction. Because these agents tinuous depolarization gives way to gradual repolari- compete with ACh at the receptors, they are called zation as the sodium channel closes or is blocked. This competitive blockers. Their action can be overcome by causes a resistance to depolarization (Phase II) and a increasing the concentration of ACh in the synaptic flaccid paralysis. gap, e.g. by administration of cholinesterase inhibitors Actions. The sequence of paralysis may be slightly such as Neostigmine. Anesthesiologists often employ different, but as is seen with the competitive blockers, this strategy to shorten the duration of the neuromus- the respiratory muscles are paralyzed last. Succinyl- cular blockade. choline initially produces short-lasting muscle fascic- Actions. Not all muscles are equally sensitive to ulations, followed within a few minutes by paralysis. blockade by competitive blockers. Small, rapidly con- Normally, the duration of action of succinylcholine is tracting muscles of the face and eye are most suscepti- extremely short, since this drug is rapidly broken down ble and are paralyzed first, followed by the fingers. by plasma cholinesterase. Thereafter the limbs, neck, and trunk muscles are par- Therapeutic uses. Because of its rapid onset and alyzed, then the intercostal muscles are affected, and short duration of action, Succinylcholine is useful lastly, the diaphragm muscles are paralyzed. when rapid endotracheal intubation is required during Therapeutic uses. These blockers are used therapeu- the induction of anesthesia (a rapid action is essential tically as adjuvant drugs in anes-thesia during surgery if aspiration of gastric contents is to be avoided dur- to relax skeletal muscle. ing intubation). It is also employed during electrocon- Pharmacokinetics. All neuromuscular blocking vulsive shock treatment. agents are injected i.v. since their uptake via oral ab- Pharmacokinetics. Succinylcholine is injected i.v. sorption is minimal. They penetrate membranes very Its brief duration of action (several minutes) results poorly and do not enter cells or cross the blood-brain from rapid hydrolysis by plasma cholinesterase. barrier. Many of the drugs are not metabolized; their Adverse effects: actions are terminated by redistribution. For example, Hyperthermia: When Halothane is used as anesthet- tubocurarine and pancuronium are excreted in the ic, administration of Succinylcholine may occasional- urine unchanged. Atracurium is degraded spontane- ly cause malignant hyperthermia (with muscular rigid- ously in the plasma and by ester hydrolysis. The ami- ity and hyperpyrexia) in genetically susceptible people. nosteroid drug vecuronium is deacetylated in the liv- This is treated by rapid cooling of the patient and by er, and their clearance may be prolonged in patients administration of Dantrolene, which blocks release of with hepatic disease. Ca++ from the sarcoplasmic reticulum of muscle cells, Drug interaction: thus reducing heat production and relaxing muscle tone. a) Cholinesterase inhibitors. Drugs such as Neostig- Apnea: A genetically related deficiency of plasma mine and Physostigmine can over-come the action of non- cholinesterase or presence of an atypical form of the depolarizing neuromuscular blockers, but with increased enzyme can lead to apnea due to paralysis of the dia- dosage, can cause a depolarizing block as a result of el- phragm. evated ACh concentration at the end-plate membrane. b) Halogenated hydrocarbon anesthetics. Drugs Available forms: such as Halothane act to enhance neuromuscular Atropine sulfate — in ampoules 0.1% solution 1 ml blockade by exerting a stabilizing action at the neu- each; in tablets 0.0005 romuscular junction. Benzohexonium — in tablets 0.1 and 0.25 each; in c) Aminoglycoside antibiotics. Drugs like Gen- ampoules 2.5% solution tamicin or Tobramycin inhibit acetylcholine release Diplacini dichloridum — in ampoules 2% solution from cholinergic nerves by competing with calcium 5 ml each ions. They synergize with tubocurarine and other com- Dithylinum — in ampoules 2% solution 5 and petitive blockers, enhancing the blockade. 10 ml each d) Calcium channel blockers. These agents may in- Hygronium — in bottles and ampoules 0.1 each crease the neuromuscular block of competitive block- (to dilute in physiologic solution) ers as well as depolarizing blockers. Ipratropium bromide — in aerosol 15 ml each Pachycarpini hydroiodidum — in tablets 0.1 each; DEPOLARIZING BLOCKERS in ampoules 3% solution 2 ml each Mechanism of action. The depolarizing neuromus- Platyphyllinum — in tablets 0.005 each; in am- cular blocking drug, Succinylcholine (Dithyline), at- poules 0.2% solution 1 ml taches to the nicotinic receptor and acts like ACh to Pyrenzipine — in tablets 0.025 and 0.05 each depolarize the junction. Unlike acetylcholine, which Scopolamine — in ampoules 0.05% solution 1 ml is instantly destroyed by acetylcholinesterase, the de- each polarizing agent persists at high concentrations in the Tubocurarine chloride — in ampoules 1% solution synaptic cleft, remaining attached to the receptor for 1.5 ml each

34 Lecture 5 Synthesis of Noradrenaline. Tyrosine is transported by Na+-linked carrier into the axoplasm of the ADRENERGIC AGONISTS adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. This The adrenergic drugs affect receptors that are stimu- is the rate-limiting step in the formation of Noradrena- lated by Noradrenaline (Norepinephrine) or Adrenaline line. DOPA is decarboxylated to form Dopamine. (Epinephrine). This lecture describes agents that either Storage of Noradrenaline in Vesicles. Dopamine is directly or indirectly stimulate the adrenoreceptors. transported into synaptic vesicles by an amine trans- The adrenergic neuron. Adrenergic neurons release porter system. This carrier system is blocked by Re- Noradrenaline as the neurotransmitter. These neurons serpine. In vesicles, Dopamine is hydroxylated to form are found in the CNS, and also in the sympathetic nerv- Noradrenaline by the enzyme, dopamine β-hydroxy- ous system where they serve as links between ganglia lase. In the adrenal medulla, Noradrenaline is meth- and effector organs. The adrenergic receptors located ylated to yield Adrenaline. On stimulation, the adre- either pre-synaptically on the neuron or postsynapti- nal medulla release about 85% Adrenaline and 15% cally on the effector organ are the sites of action of Noradrenaline. the adrenergic drugs. Release of Noradrenaline. An action potential ar- Neurotransmission at adrenergic neurons. Neuro- riving at the nerve junction triggers an influx of Ca++ transmission in adrenergic neurons closely resembles from the extracellular fluid into the sarcoplasm of the that already described for the cholinergic neurons, ex- neuron. This causes vesicles to fuse with cell membrane cept that Noradrenaline is the neurotransmitter instead and expel their content into the synapse. This release of Acetylcholine. Neurotransmission takes place at nu- is blocked by drugs such as Guanethidine. merous beadlike enlargements called varicosities; the Binding by receptor. Noradrenaline released from process involves five steps: the synthesis, storage, re- the synaptic vesicles diffuses across the synaptic space lease, and receptor binding of the Noradrenaline, fol- and binds to either postsynaptic receptors on the ef- lowed by removal of the neurotransmitter from the syn- fector organ or to presynaptic receptors on the nerve aptic gap (Fig. 5). ending. The recognition of Noradrenaline by the mem-

1. Synthesis of noradrenaline — Hydroxylation of tyrosine is the rate- limiting step

Tyrosine Tyrosine 2. Uptake into storage vesicles — Dopamine enters vesicles and is converted to noradrenaline MAO 5. Removal of — Noradrenaline is protected from degrada- noradrenaline tion in vesicles — Released noradren- — Transport into vesicles is inhibited by re- aline is rapidly taken Dopamine serpine into neuron — Uptake is inhibited by cocaine and imi- Dopamine pramine 3. Release of neurotransmitter — Release blocked by guanethidine Noradrenaline and bretylium

MAO Postsynaptic receptor 6. Metabolism — Noradrenaline is methylated by COMT and oxidized by MAO 4. Binding to receptor — Postsynaptic receptor activated by binding of neurotransmitter COMT Inactive metabolites

Presynaptic receptor Fig. 5. Neurotransmission at adrenergic neurons

35 α brane receptors triggers a cascade of events with in the 1-receptor. A portion of released Noradrenaline “cir- α cell, resulting in the formation of intracellular second cles back” and reacts with the 2-receptors on the pre- α messengers that act as links (transducers) in the com- synaptic membrane. The stimulation of the 2-recep- munication between the neurotransmitter and the ac- tors causes feedback inhibition of the ongoing release tion generated within the effector cell. Adrenergic re- of Noradrenaline from the stimulated neuron. This in- ceptors use both the cyclic adenosine monophosphate hibitory action decreases further output from the adren- (cAMP) second messenger system and the phosphoi- ergic neuron and serves as a local modulating mecha- nositide cycle. nism for reducing sympathetic neuro-mediator output Removal of Noradrenaline. Noradrenaline may (1) when there is high sympathetic activity. diffuse out of the synaptic space and enter the gener- β-Receptors exhibit a set responses different from al circulation, (2) be metabolized to O-methylated de- those of the α-receptors. These are characterized by a rivatives by post-synaptic cell membrane-associated strong response to Isoproterenol, with less sensitivity catechol O-methyltransferase (COMT) in the synap- to Adrenaline and Noradrenaline. For β-receptors, the tic space, or (3) be recaptured by an uptake system rank order of potency is: that pulls the Noradrenaline back into the neuron. The uptake by the neuronal membrane involves a Isoproterenol > Adrenaline > Noradrenaline Na+-K+ activated ATPase that can be inhibited by tricyclic antidepressants such as Imipramine, or by The β receptors can be subdivided into two major β β Cocaine. groups, 1 and 2 based on their affinities for adrener- β Potential fates of recaptured Noradrenaline. Once gic agonists and antagonists. 1 receptors have ap- the Noradrenaline reenters the cytoplasm it may be proximately equal affinities for Adrenaline and No- β taken up into vesicles via the amine transporter sys- radrenaline, whereas 2-receptors have a higher affin- tem and be sequestered for release by another action ity for Adrenaline than for Noradrenaline. Thus, tis- β potential. Alternatively, Noradrenaline can be oxi- sues with a predominance of 2-receptors (such as the dized by monoamine oxidase (MAO) present in neu- vasculature of skeletal muscle) are particularly respon- ronal mitochondria. The inactive products of No- sive to the hormonal effects of circulating Adrenaline radrenaline metabolism are excreted in the urine as released by the adrenal medulla. vanillylmandelic acid (VMA), Metanephrine and Distribution of receptors. Adrenergic innervated Normetanephrine. organs and tissues tend to have a predominance of one Adrenergic receptors. In the sympathetic nervous type of receptor. For example, tissues such as vascu- α β system, several classes of adrenoreceptors can be dis- lature to skeletal muscle have both 1- and 2-recep- β tinguished pharmacologically. Two families of receptors, but 2 receptors predominate. Other tissues may tors, designated ‘α’ and ‘β’, were initially identified have one type of receptors exclusively, with practical- on the basis of their responses to the adrenergic ago- ly no significant numbers of other type of adrenergic nists, Adrenaline, Noradrenaline, and Isoproterenol. receptors. For example, the heart contains predomi- β The use of the specific blocking drugs and the cloning nantly 1-receptors. of genes have revealed the molecular identities of a Characteristic responses mediated by adrenorecep- number of subtypes. Alteration in the primary struc- tors. It is useful to organize the physiologic responses ture of the receptors influence their affinity for vari- according to the receptor type, since many drugs preferentially stimulate or block one type of receptor. As ous agents. α α α a generalization, stimulation of 1-receptors charac- 1- and 2-receptors. The a receptors show a weak response to the synthetic agonist Isoproterenol, but are teristically produces vasoconstriction (particularly in the skin and abdominal viscera) and an increase in to- responsive to the naturally occurring catecholamines, tal peripheral resistance and blood pressure (Table 3). Adrenaline, and Noradrenaline. For a receptors the β Conversely, stimulation of 1-receptors character- rank order of potency is: β istically causes cardiac stimulation, while 2-produces vasodilation (in skeletal vascular beds), and bron- Adrenaline ≥ Noradrenaline >> Isoproterenol chiolar relaxation. The α-adrenoreceptors are subdivided into two α α α groups, 1 and 2 , based on their affinities for -ago- ADRENERGIC AGONISTS α nists and blocking drugs. For example, the 1-recep- Most of adrenergic drugs are derivatives of β-phe- tors have a higher affinity for Phenylephrine than do α nylethylamine. Substitutions on the benzene ring or on the 2-receptors. Conversely, the drug Clonidine selec- α α the ethylamine side chains produce a great variety of tively binds to 2-receptors, and has less effect on 1- compounds with varying abilities to differentiate be- receptors: α β α tween - and -receptors and to penetrate the CNS. a) 1-receptors are present on the postsynaptic Two important structural features of these drugs are membrane of the effector organs and mediate many of α the number and location of OH substitutions on the the classic effects, originally designated as -adrener- benzene ring and the nature of the substituent on the gic, involving constriction of smooth muscle. α amino nitrogen. b) 2-receptors located primarily on presynaptic nerve ending and on other cells, such as the β-cells of HO the pancreas, control adrenergic neuro-mediator and insulin output, respectively. When a sympathetic adrenergic nerve is stimulated, the released Noradren- HO Catechol aline traverses the synaptic cleft and interacts with the

36 Table 3. Effects of adrenoreceptors stimulation Type of receptor α α β β 1 2 1 2 Vasoconstriction Inhibition of Tachycardia Vasodilation Increased peripheral noradrenaline release Increased lipolysis Slightly decreased resistance Inhibition of insulin Increased myocardial peripheral resistance Increased blood pressure release contractility Increased glycogenolysis

Effects Bronchodilation Increased release of glucagon Mydriasis Relaxed uterine smooth muscle Increased closure of internal sphincter of the bladder

Catecholamines. Sympathomimetic amines that and cause the release of Noradrenaline from the cyto- contain the 3,4-dihydrobenzene group (such as, Adren- plasmic pools or vesicles. As with neuronal stimula- aline, Noradrenaline, Isoproterenol, and Dopamine) tion, the Noradrenaline traverses the synapse and binds are called catecholamines. [Note: 1,2-dihydrobenzene to the α or β receptors. is catechol.] These compound share the following prop- Mixed-acting agonists. Some agonists, such as erties: Ephedrine, have the capacity both to direct stimulate High potency. Drugs that are catechol derivatives adrenoreceptors and to release Noradrenaline from the show the highest potency in activation α- or β-recep- adrenergic neuron. tors. Rapid inactivation. Not only the catecholamines are metabolized by COMT postsynaptically and by DIRECT-ACTING AGONISTS MAO intraneuronally, but they are also metabolized Direct-acting agonists bind to adrenoreceptors within other tissues. For example, COMT is in the gut wall out interacting with the presynaptic neuron. The acti- and MAO is in the liver and gut wall. Thus catecho- vated receptor initiates synthesis of second messengers lamines have only a brief period of action when given and subsequent intracellular signals. As a group these parenterally, and are ineffective when administered agents are widely used clinically. orally. Poor penetration into the CNS. Catecholamines are polar and therefore do not readily penetrate into Adrenaline the CNS. Nevertheless, most of these drugs have some Adrenaline is one of five catecholamines — Adren- clinical effects (anxiety, tremor, headaches) that are aline, Noradrenaline, Dopamine, Dobutamine, and attributable to action on the CNS. Isoproterenol — commonly used in therapy. The first Non-catecholamines. Compounds lacking the cat- three catecholamines occur naturally, the latter two are echol hydroxyl groups have longer half-lives, since synthetic compounds. Adrenaline is synthesized in the they are not inactivated by COMT. These include Phe- adrenal medulla and released into the blood stream. nylephrine (Mesaton), Ephedrine, and Amphetamine. Adrenaline interacts with both α- and β-receptors. At Increased lipid solubility of many of the non-catecho- low doses, β-effects (vasodilatation) on the vascular lamines permits greater access to the CNS. These com- system predominate, whereas at high doses, α effects pounds may act indirectly by causing the release of (vasoconstriction) are strongest. stored catecholamines. Actions: Substitution on amine nitrogen. The nature of the Cardiovascular: the major actions of Adrenaline substituent on the amine nitrogen is important in are on the cardiovascular system. Adrenaline determining the β selectivity of the adrenergic agonist. strengthens the contractility of the myocardium (pos- β For example, Adrenaline with a –CH3 substituent is itive inotropic: 1-action) and increases its rate of β β more potent at -receptors than Noradrenaline. contraction (positive chronotropic: 1-action). Car- Similarly, Isoproterenol with an isopropyl substituent diac output therefore increases. With these effects –CH(CH3)2 on the amine nitrogen, is a strong comes increased oxygen demands on the myocar- β-agonist with little α activity. dium. Adrenaline constricts arterioles in the skin, Mechanism of action. mucous membranes, and viscera (α-effects) and di- Direct-acting agonists. These drugs act directly on lates vessels going to the liver and skeletal muscle α β β - or -receptors, producing effects similar to those that ( 2-effects). Renal blood flow is decreased. The cu- occur following stimulation of sympathetic nerves or mulative effect, therefore, is an increase in systolic release of the hormone Adrenaline from the adrenal blood pressure, coupled with a slight decrease in di- medulla. Examples of direct acting agonists include astolic pressure. Adrenaline, Noradrenaline, Isoproterenol, and Phe- Respiratory: Adrenaline causes powerful bron- nylephrine. chodilation by acting directly on bronchial smooth β Indirect-acting agonists. These agents (e.g. Am- muscle ( 2-action). This action relieves all known al- phetamine) are taken up into the presynaptic neuron lergic- or histamine-induced bronchoconstriction. In

37 the case of anaphylactic shock, this can be life-sav- Noradrenaline ing. Hyperglycemia: Adrenaline has a significant hy- Since Noradrenaline is the neuromediator of adrenergic nerves, it should theoretically stimulate all types perglycemic effect because of increased glycogenol- β of adrenergic receptors. In practice, when the drug is ysis in the liver ( 2-effect), increased release of glu- α β given in therapeutic doses, the -receptors are most af- cagon ( 2-effect), and decreased release of insulin α fected. ( 2-effect). Cardiovascular actions: Lipolysis: Adrenaline initiates lipolysis through its β Vasoconstriction: Noradrenaline causes a rise in agonist activity on the -receptors of adipose tissue, peripheral resistance due to intense vasoconstriction of which activate a hormone-sensitive lipase, which hydro- α most vascular beds, including the kidney (an 1-recep- lyzes triacylglycerols to free fatty acids and glycerol. tor effect). Both systolic and diastolic blood pressure Biotransformations. Adrenaline, like other catecho- increase. lamines, is metabolized by two enzymatic pathways: Baroreceptor reflex: In isolated cardiac tissue No- COMT, and MAO. The final metabolites found in the radrenaline stimulates cardiac contractility; how- urine are metanephrine and vanillylmandelic acid. ever, in vivo, little if any cardiac stimulation is noted. [Note: Urine also contains normetanephrine, a prod- This is due to the increased blood pressure that induc- uct of Noradrenaline metabolism.] es the reflex rise in vagal activity by stimulating the Therapeutic uses: baroreceptors. This bradycardia is sufficient to coun- Bronchospasm: Adrenaline is the primary drug teract the local action of Noradrenaline on the heart. used in the emergency treatment or any condition of If atropine (which blocks the transmission of vagal the respiratory tract where the presence of bronchoc- effects) is given before Noradrenaline, Noradrenaline onstriction has resulted in diminished respiratory ex- stimulation of the heart is evident as tachycardia. change. Thus, in the treatment of acute asthma and an- Therapeutic uses. Noradrenaline is used to treat aphylactic shock, Adrenaline is the drug of choice; shock because it increases vascular resistance and, within a few minutes after subcutaneous administra- therefore, increases blood pressure; however, Dopamine tion, greatly improved respiratory exchange is ob- is better, because it does not reduce blood flow to the served. Administration may be repeated after a few kidney as does Noradrenaline. Other actions of No- β hours. However, selective 2-agonists, such as Terbu- radrenaline are not considered clinically significant. taline, are presently favored in the chronic treatment It is never used for asthma. of asthma because of a longer duration of action and minimal cardiac stimulatory effect. Isoproterenol (Isadrinum) Glaucoma: In ophthalmology, a 2% Adrenaline so- Isoproterenol is a direct-acting synthetic catecho- lution may be used topically to reduce intraocular pres- lamine that predominantly stimulates both β and β sure in open-angle glaucoma. It is reduces the produc- 1 2 adrenergic receptors. Its non-selectivity is one of its tion of aqueous humor by vasoconstriction of the cili- drawbacks. Its action on α-receptors is insignificant. ary’s body blood vessels. Actions: Anaphylactic shock: Adrenaline is the drug of Cardiovascular: Isoproterenol produces intense choice for the treatment of Type I hypersensitivity re- stimulation of the heart to increase its rate and force actions in response to allergens. of contraction, causing increased cardiac output. It is In anesthetics: Local anesthetic solutions usually as active as Adrenaline and is therefore useful in the contain 1:100,000 parts of Adrenaline. The effect of treatment of atrioventricular (AV) block or cardiac ar- the drug is to greatly increase the duration of the lo- rest. Isoproterenol also dilates the arterioles of skele- cal anesthesia. It does this by producing vasoconstric- β tal muscle ( 2). Because of its cardiac stimulatory action at the site of injection, thereby allowing the local tion, it may increase systolic blood pressure slightly, anesthetic to persist at the site before being absorbed but it greatly reduces mean arterial and diastolic blood into the circulation and metabolized. Very weak solu- pressure. tions of Adrenaline (1:100,000) can also be used topi- Pulmonary: A profound and rapid bronchodilata- cally to vasoconstriction mucous membranes to con- β tion is produced by the drug ( 2-action). Isoprotere- trol oozing of capillary blood. nol is as active as Adrenaline and rapidly alleviates Pharmacokinetics. Adrenaline has a rapid onset but an acute attack of asthma, when taken by inhalation brief duration of action. In emergency situation Adren- (which is the recommended route). This action lasts aline is given intravenously for the most rapid onset of about one hour and may be repeated by subsequent action; it may also be given subcutaneously, by en- doses. dotracheal tube, by inhalation, or topically to the eye. Therapeutic uses. Isoproterenol is now rarely used Oral administration is ineffective. as a bronchodilator in asthma. It can be employed to Adverse effects. Adrenaline can produce adverse stimulate the heart in emergency situations. CNS effects that include anxiety, fear, tension, head- Pharmacokinetics. Isoproterenol can be absorbed ache, and tremor. The drug may induce cerebral hem- systemically by the sublingual mucosa but is more re- orrhage as a result of a marked elevation of blood pres- liably absorbed when given parenterally or as inhaled sure. Adrenaline can trigger cardiac arrhythmias, par- aerosol. It is a marginal substrate for COMT and is ticularly if the patient is receiving digitalis. Adrena- stable to MAO action. line can induce pulmonary edema in predisposing pa- Adverse effects. Isoproterenole’s adverse effects are tients with left ventricular failure. similar to those of Adrenaline.

38 Dopamine es both systolic and diastolic blood pressures. It has no effect on the heart itself but induces reflex brady- Dopamine, the immediate metabolic precursor of cardia when given parenterally. It is often used topi- Noradrenaline, occurs naturally in the CNS in the ba- cally on the nasal mucous membranes and in ophthal- sal ganglia where it functions as a neurotransmitter as mic solutions for mydriasis. The drug is used to raise well as in the adrenal medulla. Dopamine can activate α β blood pressure and to terminate episodes of supraven- - and -receptors. At higher doses it causes vasocon- tricular tachycardia. Large doses can cause hyper- striction by activating α-receptors, whereas at lower β tensive headache. doses, it stimulates 1 cardiac receptors. In addition, α D1 and D2 dopaminergic receptors, distinct from the Clonidine (Clophelinum) and β adrenergic receptors, occur in the peripheral α mesenteric and renal vascular beds, where binding of Clonidine is an 2-agonist that is used in essen- Dopamine produces vasodilatation. D2 receptors are tial hypertension to lower blood pressure because of also found on presynaptic adrenergic neurons, where its action in the CNS. It can be used to minimize the their activation interferes with Noradrenaline release. symptoms that accompany withdrawal from opiates α Actions: or benzodiazepines. Clonidine acts centrally ( 2) to Cardiovascular: Dopamine exerts a stimulatory ef- produce inhibition of the sympathetic vasomotor β fect on the 1 receptors of the heart, having both ino- centers. tropic and chronotropic effects. At very high doses, dopamine activates α-receptors on the vasculature, re- Metaproterenol (Alupent, Orciprenaline) sulting in vasoconstriction. Renal and visceral: Dopamine dilates renal and Metaproterenol, although chemically similar to splanchnic arterioles by activating dopaminergic re- Isoproterenol, is not a catecholamine and is resistant ceptors, thus increasing blood flow to the kidney and to COMT. It can be administered orally or by inhala- β other viscera. These receptors are not affected by α- tion. The drug acts primarily at 2-receptors, produc- β or β-blocking drugs. Therefore, Dopamine is clinical- ing little effect on the heart ( 1). Metaproterenol is used ly useful in the treatment of shock, in which signifi- to dilate bronchioles and improve airway function. cant increases in sympathetic activity might compro- mise renal function. Terbutaline (Bricanyl) Therapeutic uses. Dopamine is the drug of choice β Terbutaline is a 2-agonist with more selective for shock and is given by continuous infusion. It rais- properties than Metaproterenol and a longer duration β es the blood pressure by stimulating the heart ( 1 ac- of action. Terbutaline can be administered either orally tion). In addition, it enhances perfusion to the kidney or subcutaneously. It is used as a bronchodilator and and splanchnic areas, as described above. An increased to reduce uterine contractions in premature labor. blood flow to the kidney enhances the glomerular filtration rate and causes sodium diuresis. In this regard, Dopamine is far superior to Noradrenaline, which di- INDIRECT-ACTING ADRENERGIC minishes the blood supply to the kidney and may cause AGONISTS kidney shutdown. Adverse effects. An overdose of Dopamine produc- Indirect-acting adrenergic agonists cause No- es the same effects as sympathetic stimulation. radrenaline release from presynaptic terminals. These Dopamine is rapidly metabolized to homovanilic acid, agents do not directly affect postsynaptic receptors. and its adverse effects (nausea, hypertension, arrhyth- For example, the central and peripheral actions of mias) are therefore short-lived. Amphetamine are mediated primarily through the cellular release of stored catecholamines. The actions Dobutamine and uses of Amphetamine are discussed under stimulants of the CNS. Dobutamine is a synthetic, direct-acting catecho- β lamine that is a 1-receptor agonist. The drug increases cardiac output with little change in the heart rate MIXED-ACTING ADRENERGIC and with few vascular effects. It does not significantly AGONISTS elevate oxygen demands of the myocardium — a major advantage over other sympathomimetic drugs. Do- Mixed-action drugs induce the release of No- butamine is used in congestive heart failure. Dob- radrenaline from the presynaptic terminals and acti- utamine should be used with caution in atrial fibrilla- vate adrenergic receptors on the postsynaptic mem- tion, since the drug increases atrioventricular conduc- brane. tion. Other adverse effects are the same as those for Adrenaline. Ephedrine Ephedrine, a plant alkaloid, is now made syntheti- Phenylephrine (Mesatonum) cally. The drug is mixed-action adrenergic agent. It not Phenylephrine is a direct-acting, synthetic adren- only releases stored Noradrenaline from the nerve end- ergic agonist that bind primarily to a receptors and ings but also stimulates both α- and β-receptors. Thus, α α favors 1-receptors over 2-receptors. It is not a cate- a wide variety of adrenergic actions ensue that are sim- chol derivative and therefore not a substrate for ilar to those of Adrenaline, although less potent. Ephe- COMT. Phenylephrine is a vasoconstrictor that rais- drine is not a catechol and is a poor substrate for MAO

39 β β and COMT; thus, the drug has a long duration of ac- blood pressure. [Note: -receptors, including 1-adreno- tion. Ephedrine has excellent absorption orally and pen- receptors on the heart, are not affected by α-blockade]. etrates into the CNS. It is eliminated unchanged in the urine. Ephedrine raises systolic and diastolic blood pres- Phentolamine sures by vasoconstriction and cardiac stimulation. Ephe- α Phentolamine produces a competitive block of 1- drine produces bronchodilatation, but less potent and α more slowly than Adrenaline or Isoproterenol. It is there- and 2-receptors. The drug’s action lasts for approxi- fore sometimes used prophylactically in chronic treat- mately 4 hours after a single administration. α ment of asthma to prevent attacks, rather than to treat Cardiovascular effects: By blocking -receptors, acute attack. Ephedrine enhances contractility and im- Phentolamine prevents vasoconstriction of peripheral proves motor function in myasthenia gravis, particular- blood vessels by endogenous catecholamines. The de- ly when used in conjunction with anti-cholinesterase. creased peripheral resistance provokes a reflex tachy- Ephedrine produces mild stimulation of the CNS. This cardia. Furthermore, the ability to block presynaptic α increases alertness, decreases fatigue, and prevents 2 receptors in the heart can contribute to an increased sleep. It also improves athletic performance. Ephedrine cardiac output. has been used to treat asthma, as a nasal decongestant Adrenaline reversal: All α-adrenergic blockers re- (due to its local vasoconstrictor action), and to raise verse the α-agonist actions of Adrenaline. For exam- blood pressure. [Note: The clinical use of Ephedrine is ple, the vasoconstrictive action of Adrenaline is inter- declining due to the availability of better, more potent rupted, but vasodilatation of other vascular beds agents which cause fewer adverse effects.] caused by stimulation of β-receptors is not blocked. Therefore, the systemic blood pressure decreases in re- Available forms: sponse to Adrenaline given in the presence of Phen- Adrenaline hydrochloride — in bottles 0.1% solu- tolamine. [Note: The action of Noradrenaline is not tion 10 ml each; in ampoules 0.1% solution 1 ml each reversed but diminished, since Noradrenaline lacks sig- Ephedrine — in tablets 0.025 (for adults) and 0.001; nificant β-agonist action on the vasculature.] Phen- 0.002 and 0.003 each; in ampoules 5% solution 1 ml tolamine has no effect on the actions of Isoproterenol, each; in bottles 2% and 3% solution 10 ml each which is a pure β-agonist. Isoproterenol (Isadrinum) — in tablets 0.005 each; Therapeutic uses: Phentolamine is used in the di- in bottles 0.5% and 1% solution 25 ml and 100 ml (for agnosis and treatment of pheochromocytoma, a cate- inhalation) cholamine-secreting tumor of cells derived from the ad- Naphthyzinum — in bottles 0.05% and 0.1% solu- renal medulla. Prior to surgical removal of the tumor, tion 10 ml each patients are treated with Phentolamine to preclude Phenylephrine (Mesatonum) — in ampoules 1% so- hypertensive crisis that can result from manipulation lution 1 ml each on the tissue. This drug also finds use in the chronic Terbutaline (Bricanyl) — in aerosol; in tablets management of these tumors, particularly when the 0.0025 each; in ampoules 0.05% solution 1 ml each Catecholamine cells are diffuse and therefore inoperable. Phentolamine is sometimes effective in treating Raynaud’s disease. Adverse effects: Phentolamine-induces reflex cardiac stimulation and tachycardia are mediated by the Lecture 6 α baroreceptor reflex and by blocking the 2- receptors ADRENERGIC ANTAGONISTS of the cardiac sympathetic nerves. The drug can also trigger arrhythmias and anginal pain and is contraindicated in patients with decreased coronary perfusion. The adrenergic antagonists (also called blockers) It can inhibit ejaculation. bind to adrenoreceptors but do not trigger the usual receptor-mediated intracellular effect. These drugs Prazosin, Terazosin and Doxazosin act by either reversibly or irreversibly attaching to the receptors, thus preventing its activation by endog- Prazosin, Terazosin and Doxazosin are selective α enous catecholamines. Like the agonists, the adren- competitive blockers of 1-receptor. In contrast to ergic antagonists are classified according to their rel- Phentolamine, these drugs are useful in the treatment ative affinity for α- or β-receptors in the peripheral of hypertension. Metabolism leads to inactive products nervous system. [Note: Antagonists that block that are excreted in the urine, except for those of Dox- dopamine receptors are most important in the CNS azosin which appear in the feces. Doxazosin is long- and will be considered in that section.] est acting. Cardiovascular effects: Prazosin and Terazosin decrease peripheral vascular resistance and lower arteri- α-ADRENERGIC BLOCKING AGENTS al blood pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs, unlike Drugs that block α-adrenoreceptors profoundly af- Phentolamine, cause minimal changes in cardiac out- fect blood pressure. Since normal sympathetic control put, renal blood flow, and glomerular filtration rate. of the vasculature occurs in large part through agonist Therapeutic uses: Individuals with elevated blood action on α-receptors, blockade of these receptors re- pressure who have been treated with Prazosin or Ter- duces the sympathetic tone of the blood vessels, result- azosin do not become tolerant to its action. However, ing in decreased peripheral vascular resistance. This in- the first dose of these drugs produces an exaggerated duces a reflex tachycardia resulting from the lowered hypotensive response that can result in syncope (faint-

40 β ing). This action, termed as a “first-dose” effect, may Bronchoconstriction: Blocking 2-receptors in the be minimized by adjusting the first dose to one third lungs of susceptible patients causes contraction of the or one fourth of the normal dose, and by giving the bronchiolar smooth muscle. This can precipitate a res- α drug at bed time. The 1-antagonists have been used piratory crisis in patients with chronic obstructive pul- as an alternative to surgery in patients with sympto- monary disease or asthma. β-blockers are thus con- matic benign prostatic hypertrophy. Blockade of the traindicated in patients with asthma. α-receptors decreases tone in the smooth muscle of the Increased Na+ retention: Reduced blood pressure bladder neck and prostate and improves the urine flow. causes decease in renal perfusion, resulting in an in- [Note: Fenestrate, which inhibits dihydrotestosterone crease in Na+ retention and plasma volume. In some synthesis, has been approved for treatment of benign cases this compensatory response tends to elevate the prostatic hypertrophy, but its effects are not evident for blood pressure. For these patients, β-blockers are of- several weeks.] ten combined with a diuretic to prevent Na+ retention. Adverse effects: Prazosin and terazosin may cause Disturbances in glucose metabolism: β-blockade dizziness, lack of energy, nasal congestion, headache, leads to decreased glyco-genolysis and decreased glu- drowsiness, and orthostatic hypotension (although to cagon secretion. Therefore, if an insulin-dependent di- a lesser degree than that observed with phentolamine). abetic is to be given Propranolol, very careful moni- An additive antihypertensive effect occurs when Pra- toring of blood glucose is essential, since pronounced zosin is given with either a diuretic or a β-blocker, hypoglycemia may occur after Insulin injection. β- thereby necessitating a reduction in its dose. Due to a blockers also attenuate the normal physiologic re- tendency to retain sodium and fluid, Prazosin is fre- sponse to hypoglycemia. quently used along with a diuretic. Male sexual func- Blocks action of Isoproterenol: All β-blockers, in- tion is not as severely affected by these drugs as it is cluding Propranolol, have the ability to block the ac- by Phentolamine. tions of Isoproterenol on the cardiovascular system. Thus, in the presence of β-blocker, Isoproterenol does β not produce either the typical reductions in mean arte- -ADRENERGIC BLOCKING AGENTS rial pressure and diastolic pressure, nor cardiac stimu- β All the clinically available β-blockers are competi- lation. [In the presence of -blocker, Adrenaline no long- β β er lowers diastolic blood pressure nor stimulates the tive antagonists. Nonselective -blockers act at both 1- β β heart, but its vasoconstrictive action (mediated by α-re- and 2-receptors, whereas cardioselective -antagonists primarily block β -receptors. These drugs also differ in ceptors) remains unimpaired. The actions of Noradren- 1 aline on the cardiovascular system are primarily medi- intrinsic sympathomimetic activity, in CNS effects, and α in pharmacokinetics. Although all β-blockers lower ated by -receptors and are, therefore, unaffected.] blood pressure in hypertension, they do not induce pos- Therapeutic uses: tural hypotension because the α-adrenoreceptors remain Hypertension: Propranolol lowers blood pressure in hypertension by decreasing cardiac output. functional; therefore, normal sympathetic control of the β vasculature is maintained. β-blockers are also effective Glaucoma: Propranolol and other -blockers, parin treating angina, cardiac arrhythmias, myocardial in- ticularly Timolol, are effective in diminishing intraoc- farction, and glaucoma, as well as serving in prophy- ular pressure in glaucoma. This occurs by decreasing laxis of migraine headaches. [The names of all β-block- the secretion of aqueous humor by the ciliary body. ers end in “-olol”, except for Labetalol, which has a Many patients with glaucoma have been maintained component of α -blocking action.] with these drugs for years. They neither affect the abil- 1 ity of the eye to focus for near vision, nor change pu- Propranolol pil size, as do the cholinergic drugs. However, in an acute attack of glaucoma, Pilocarpine is still the drug Propranolol is a prototype β-adrenergic antagonist of choice. The β-blockers are only used to treat this β β and blocks both 1- and 2-receptors. disease chronically. Actions: Migraine: Propranolol is also effective in reduc- Cardiovascular: Propranolol diminishes cardiac ing migraine episodes. The value of the β-blockers is output, having both negative inotropic and chronotrop- in the treatment of chronic migraine in which the drug ic effects. It directly depresses sino-auricular and atrio- decreases the incidence and severity of the attacks. ventricular activity. Cardiac output, work, and oxygen The mechanism may depend on the blockade of cate- consumption are decreased; these effects are useful in cholamine-induced vasodilation in the brain vascula- the treatment of angina. The β-blockers are effective in ture. [Note: During an attack, the usual therapy with attenuating supraventricular cardiac arrhythmias but Sumatriptan or other drugs is used.] are generally not effective against ventricular arrhyth- Hyperthyroidism: Propranolol and other β-block- mias (except those induced by exercise). ers are effective in blunting the widespread sympathetic Peripheral vasoconstriction: Blockade of β-receptors stimulation that occurs in hyperthyroidism. In acute β β prevents 2-mediated vasodilatation. The reduction in hyperthyroidism (thyroid storm), -blockers may be cardiac output leads to decreased blood pressure. This lifesaving in protecting against serious cardiac arrhyth- hypotension triggers a reflex peripheral vasoconstric- mias. tion, which is reflected in reduced blood flow to the pe- Angina pectoris: Propranolol decreases the oxygen riphery. On balance, there is a gradual of both systolic requirement of heart muscle and therefore is effective and diastolic blood pressures in hypertensive patients. in reducing the chest pain on exertion that is common α No postural hypotension occurs, since the 1-receptors in angina. Propranolol is therefore useful in the chron- that control vascular resistance are unaffected. ic management of stable angina (not for acute treat-

41 ment). Tolerance to moderate exercise is increased and Atenolol, Metoprolol, Acebutolol and this is noticeable by improvement in the ECG. How- Esmolol ever, treatment with Propranolol does not allow stren- β uous physical exercise, such as tennis. Drugs preferentially block the 1-receptors have Myocardial infarction: Propranolol and other β- been developed to eliminate the unwanted bronchoc- β blockers have a protective effect on the myocardium. onstrictor effect ( 2) of Propranolol seen among asth- β Thus, patients who have had one myocardial infarc- matic patients. Cardioselective -blockers antagonize β tion appear to be protected against a second heart at- 1-receptors at doses 50 to 100 times less than those β tack by prophylactic use of β-blockers. In addition, required to block 2-receptors. This cardioselectivity administration of a β-blocker immediately following is thus most pronounced at low doses and is lost in high a myocardial infarction reduces infarct size and has- drug doses. In contrast to Propranolol, the cardiospe- tens recovery. The mechanisms for these effects may cific blockers have relatively little effect on pulmonary be blocking of the actions of circulating catecho- function, peripheral resistance, and carbohydrate me- lamines, which would increase the oxygen demand in tabolism. Nevertheless, asthmatics must be carefully an already ischemic heart muscle. Propranolol also re- monitored to make certain that respiratory activity is duces the incidence of sudden arrhythmic death after not compromised. Esmolol has a very short lifetime. It myocardial infarction. is only given i.v. if required during surgery.

Adverse effects: Pindolol and Acebutolol: Antagonists Bronchoconstriction: Propranolol has a serious with Partial Agonist Activity and potentially lethal side effect when administered to Acebutolol and Pindolol are not pure blockers; in- an asthmatic. An immediate contraction of the bron- stead they have the ability to weakly stimulate both chiolar smooth muscle prevents air from entering the β β 1- and 2-receptors and are said to have intrinsic sym- lungs. Death by asphyxiation have been reported for pathomimetic activity (ISA). These partial agonists asthmatics who were inadvertently administered the stimulate the β-receptor to which they are bound, yet drug. Therefore, Propranolol must never be used in they inhibit stimulation by the more potent endogenous treating any individual with obstructive pulmonary dis- catecholamines, Adrenaline and Noradrenaline. The ease. β result of these opposing actions is a much diminished Arrhythmias: Treatment with -blockers must nev- effect on cardiac rate and cardiac output, compared er be stopped quickly because of the risk of precipitat- β β to -blockers without ISA. Blockers with ISA minimize ing cardiac arrhythmias, which may be severe. The - the disturbances of lipid and carbohydrate metabolism blockers must be tapered off gradually for a week. seen with other β-blockers. Long-term treatment with a β-antagonist leads to up- β β -Blockers with ISA are used in hypertensive pa- regulation of the -receptor. On suspension of thera- tients with moderate bradycardia, since a further de- py, the increased receptors can worsen angina or hy- crease in heart rate is less pronounced with these drugs. pertension. Carbohydrate metabolism is less affected with Acebu- Sexual impairment: Since sexual function in the α β tolol and Pindolol, making them valuable in the treat- male occurs through -adrenergic activation, -block- ment of diabetics. ers do not affect normal ejaculation nor the internal bladder sphincter function. On the other hand, some α β men do complain of impaired sexual activity. The rea- Labetalol: an - and -Blocker sons for this are not clear and may be independent of Actions: Labetalol is a β-blocker with concurrent β α -receptor blockade. 1-blocking actions that produce peripheral vasodila- Disturbances in metabolism: β-Blockade leads to tion, thereby reducing blood pressure. Labetalol thus decreased glycogenolysis and decreased glucagon se- contrasts with the other β-blockers that produce periph- cretion. Fasting hypoglycemia may occur. [Note: Car- eral vasoconstriction. Labetalol does not alter serum dioselective β-blockers are preferred in treating Insu- lipid or blood glucose levels. lin-dependent asthmatics.] Drug interactions: Drugs that interfere with the metabolism of Propranolol, such as Cimetidine, Furosem- Table 4. Uses of β-adrenoblockers ide, and Chlorpromazine, may potentiate its anti-hypotensive effects. Conversely, those that stimulate its me- Hypertension tabolism, such as barbiturates, Phenytoin and Ri- Glaucoma fampin, can mitigate its effects. Propranolol β , β Migraine 1 2 Hyperthyroidism Timolol and Nadolol: Nonselective Angina pectoris β-Antagonists Myocardial infarction β β Timolol β , β Glaucoma Timolol and Nadolol also block 1- and 2-recep- 1 2 Hypertension tors and are more potent than Propranolol. Nadolol Atenolol has a very long duration of action. Timolol reduces β the production of aqueous humor in the eye and is used Metoprolol 1 Hypertension topically in the treatment of chronic open-angle glau- Acebutolol β β coma, and occasionally for systemic treatment of hy- Pindolol 1, 2 Hypertension pertension (Table 4). α β β Labetalol 1, 1, 2 Hypertension

42 Therapeutic uses in hypertension: Labetalol is use- 2. Which drug does not induce mydriasis? ful for treating the elderly or black patients in whom (A). Phenylephrine. increased peripheral resistance is undesirable. [Note: (B). Cocaine. In general black hypertensive patients are not well con- (C). Phentolamine. trolled with β-blockers.] Labetalol may be employed (D). Norepinephrine. as an alternative to Hydralazine in the treatment of (E). Ephedrine. pregnancy-induced hypertension (PIH). 3. Epinephrine given in small therapeutic doses β (A). Increases systolic blood pressure through 2- SYMPATHOLYTICS receptor stimulation in the left ventricle. (B). Decreases heart rate reflexively. Sympatholytic drugs do not act directly on the (C). Decreases peripheral resistance through stim- β adrenoreceptors. Instead, they exert their effects by ei- ulation of 2-receptors on the vascular smooth ther interfere in neurotransmitter release or alter the up- muscle cells. β take of the neurotransmitter into the adrenergic nerve. (D). Decreases peripheral resistance through 2- adrenoceptor stimulation predominantly in Reserpine skeletal muscle vascular beds. Reserpine, a plant alkaloid, blocks the transport 4. The pressor response to amphetamine is of biogenic amines Noradrenaline, Dopamine, and (A). Decreased in the presence of a monoamine Serotonin from the cytoplasm into storage vesicles in oxidase (MAO) inhibitor. the adrenergic nerves of all body tissues. This cause (B). Potentiated by a reuptake inhibitor, such as an ultimate depletion of Noradrenaline levels in the cocaine. adrenergic neuron, since monoamine oxidase (MAO) (C). Associated with marked tolerance (tachyph- degrade the Noradrenaline in cytoplasm. Sympathet- ylaxis). ic function, in general, is impaired because of de- (D). Potentiated by pretreatment with Reserpine. creased release of Noradrenaline. Hypertensive patients taking the drug show a gradual decline in blood 5. Which of the following actions of epinephrine pressure with a concomitant slowing in the cardiac would be antagonized by prazosin but not by pro- rate. The drug has a slow onset of action. When one pranolol? stops taking the drug, the action persists for many (A). Increase in heart rate. days. (B). Mydriasis. (C). Release of renin. Guanethidine (Octadinum) (D). Bronchiolar dilation. Guanethidine acts by blocking the release of stored (E). Glycogenolysis. Noradrenaline. Guanethidine also displaces Noradren- aline from storage vesicles. This leads to depletion of 6. Which of the following adrenoceptor antagonists the neurotransmitter in nerve endings except those in will reduce responses mediated by both α- and β-re- the CNS. Guanethidine is now rarely used in the treat- ceptors? ment of hypertension. (A). Propranolol. (B). Prazosin. Available forms: (C). Phenoxybenzamine. Atenolol — in tablets 0.1 each (D). Labetalol. Guanethidine (Octadinum) — in tablets 0.025 each (E). Metoprolol. Phentolamine — in tablets 0.025 each 7. A young patient is being treated for myasthenia Pindolol — in tablets 0.005; 0.01 and 0.015 each; gravis, which requires frequent adjustment of the opti- in ampoules 0.004% solution 2 ml each mal dose of neostigmine. The patient is challenged Prazosin — in tablets 0.001 and 0.005 each with edrophonium to evaluate the effectiveness of the Propranolol (Anaprilinum) — in tablets 0.01 and cholinesterase inhibition. Optimal dosing will be in- 0.04 each dicated by (A). An increase in muscle strength. (B). A decrease in muscle strength. EXAMINATION QUESTIONS (C). No change in muscle strength. β 1. Selective 2-agonists, such as terbutaline 8. A young man broke his leg in a skiing accident, (A). Have shorter durations of action than cate- causing severe muscular spasm that necessitated relax- cholamines when taken orally. ation of the muscle with a competitive nicotinic recep- (B). Have stronger cardiac stimulant effects than tor antagonist before the fracture could be set. At the Epinephrine. end of the orthopaedic procedure, the doctor restored (C). Can be taken orally because these agents are neuromuscular transmission by administering: not degraded by COMT. (A). Succinylcholine. (D). Are definitely no better than methylxan- (B). Carbachol. thines for asthmatic patients who are hyper- (C). Physostigmine. tensive. (D). Neostigmine.

43 9. A patient has developed glaucoma that is refrac- 15. In which of the following conditions would at- tory to noncholinergic therapies. You decide to pre- ropine be the least likely to increase blood pressure? scribe eyedrops containing Pilocarpine, but you are (A). A healthy young medical student. concerned about the patient’s ability to self-adminis- (B). A patient being treated with an AChE inhibi- ter the drops. The most sensitive indicator of excessive tor. administration of pilocarpine is (C). A patient being treated with Bethanechol. (A). An increased heart rate. (B). A decreased heart rate. 16. A patient has come to you complaining of feel- (C). Mental confusion. ing drowsy and finding it hard to concentrate. The pa- (D). Constriction of the pupil. tient tells you that he is taking a medication, but he cannot remember the name of the medication. You pro- 10. An 80-year-old man is increasingly forgetful, ceed to ask questions that might provide a clue to the and his wife is afraid he is developing Alzheimer’s source of his problems. Which of the following ques- disease. You are considering prescribing an anti- tions would be least likely to be helpful? AChE drug to see if this will decrease his forgetful- (A). Has the patient had problems with hay fever ness. Before making this prescription, you want to be and stuffiness? sure that these drugs are suitable given the patient’s (B). Is the patient being treated for glaucoma? medical history. Of the possible preexisting condi- (C). Has the patient had back spasms? tions listed below, you should be least concerned (D). Is the patient being treated for mood disor- about ders? (A). Asthma. (B). Weak atrioventricular conduction. 17. During a laboratory demonstration to depict (C). Glaucoma. the complexity of neurotransmission in autonomic (D). Obstruction of the GI tract. ganglia, Professor Smith sets up an anesthetized mammalian preparation in which she is recording 11. The choice of route of administration plays an postsynaptic events following the electrical stimula- important role in the actions of directly acting choli- tion of preganglionic sympathetic nerves. This dem- nomimetics. An adverse effect of choline esters that onstrates a complex action potential that consists of may be avoided by selection of an appropriate route a fast EPSP followed by a slow IPSP followed by a of administration is slow EPSP and finally by a late very slow EPSP. L (A). Bradycardia. In Professor Smith’s demonstration, the mediator of (B). Hypotension. the fast EPSP is (C). Delirium. (A). Dopamine. (D). Sweating. (B). Neuropeptide Y. (C). Serotonin. 12. Which of the responses to atropine listed be- (D). Angiotensin. low is most likely to be different in an elderly versus a (E). Acetylcholine. young patient? (A). Inhibition of sweating. 18. In Professor Smith’s demonstration, the slow (B). Tachycardia. EPSP and slow IPSP can both be blocked by prior ad- (C). Mydriasis. ministration of (D). Drowsiness. (A). Prazosin. (B). Sumatriptan. 13. You have successfully prescribed Neostig- (C). Atropine. mine to a young patient with myasthenia gravis, and (D). Losartan. her muscle strength has improved markedly. How- (E). Chlorpromazine. ever, she also exhibits cardiovascular and gastrointestinal signs of excessive vagal tone, which you 19. In Professor Smith’s demonstration, the recep- would like to block with atropine. Which of the fol- tor most likely mediating the slow EPSP is lowing risk factors in prescribing Atropine is most (A). Nicotinic cholinergic. important to you? (B). Muscarinic cholinergic. (A). Dry mouth. (C). α-Adrenergic. (B). Ocular disturbances. (D). P2X Purinergic. (C). Paralysis of the respiratory muscles. (E). β-Adrenergic. (D). Tachycardia. 20. A patient you are treating in the hospital has a 14. Antimuscarinic mydriatics, such as tropica- hypertensive emergency, with blood pressure of 210/ mide, are useful in ophthalmological examinations. 140 mm Hg. Of the following drugs, which would be Prior to administering tropicamide, it would be most most effective intravenously? important to know (A). Hydralazine. (A). If the patient has angle-closure glaucoma. (B). Hydrochlorothiazide. (B). If the patient has open-angle glaucoma. (C). Trimethaphan. (C). If the patient is taking a cholinomimetic mi- (D). Methyldopa. otic drug. (E). Spironolactone.

44 21. Ganglionic blocking agents are rarely used be- very transiently increase the strength of the muscle, after cause of the numerous side effects they may produce. which it will produce a depolarizing block. Carbachol One such side effect is is a nonselective cholinoreceptor agonist that will stim- (A). Increased stimulation of the genital tract. ulate nicotinic and muscarinic receptors without thera- (B). Urinary hesitation or urgency. peutic benefit. Physostigmine will increase the strength of the muscle by the same mechanism as Neostigmine, but (C). Vasoconstriction. it will also enter the CNS, producing undesirable side (D). Increased cardiac output. effects. (E). Mydriasis. 9. (A). Excessive administration of pilocarpine can cause it to enter the circulatory system, activate endothelial muscarinic receptors, and produce a fall in blood pressure. This will activate sympathetic reflexes that in- ANSWERS crease the heart rate. Higher levels of pilocarpine would be required to stimulate muscarinic receptors on the heart 1. (C). Structural modification by placing the hy- that can decrease the heart rate. Although pilocarpine can droxy groups at positions 3 and 5 of the phenyl ring enter the CNS and produce confusion in older patients, has resulted in compounds that are not substrates for this also requires higher doses. Pilocarpine will constrict COMT, resulting in lower rates of metabolism and en- the pupil at therapeutically appropriate doses. hanced oral bioavailability compared to catecholamines. α 10. (C). Glaucoma as a preexisting condition does not 2. (C). -Adrenoceptors mediate contraction of the ra- contraindicate an AChE inhibitor. The other preexisting dial muscle of the iris. The shortening of the radial mus- α conditions preclude the administration of AChE inhibi- cle cells opens the pupil. Phentolamine blocks -adreno- tors. Potentiation of parasympathetic stimulation can ceptors, allowing parasympathetic nerves innervating the constrict airway smooth muscle and aggravate asthma, sphincter muscle to take over. This leads to a less op- further weaken A-V conduction, and risk perforation of posed contraction of the sphincter muscle induced by the bowel if an obstruction is present. transmitter acetylcholine and a constriction of the pupil 11. (B). Hypotension, which can be life threatening, or miosis. can be avoided by preventing the entry of directly acting 3. (D). A small dose of Epinephrine (0.1 mcg/kg) given cholinomimetics into the circulatory system. Bradycar- by intravenous route may cause the blood pressure to dia and sweating are also avoided by the same precau- fall, decreasing peripheral resistance. The depressor ef- tion, but they are less significant. Delirium is not an is- fect of small doses is due to greater sensitivity to epine- β sue for choline esters, since they do not enter the CNS. phrine of vasodilator 2-adrenoceptors than of constric- α β 12. (B). The resting level of vagal stimulation of the tor -adrenoceptors and a dominant action on 2-adren- heart decreases with age, which is typically accompanied oceptors of vessels in skeletal muscle. Consequently, di- by a gradual increase in heart rate with age. Therefore, astolic blood pressure usually falls. The mean blood pres- the tachycardia produced by atropine is greater in young sure in general, however, is not greatly elevated. The com- patients with strong vagal tone, and the response decreas- pensatory baroreceptor reflexes do not appreciably anes with age in parallel with the decrease in vagal tone. tagonize the direct cardiac actions. 13. (C). Atropine will not directly paralyze the respi- 4. (C). Amphetamine is an indirectly acting adrenomi- ratory muscles. However, it can prevent the detection of metic amine that depends on the release of norepine- early signs of an overdose of neostigmine, which can phrine from noradrenergic nerves for its action. Thus, its quickly progress to a depolarizing block of skeletal mus- effect depends on neuronal uptake (blocked by cocaine) cle and paralysis of the respiratory muscles. Dry mouth, to displace norepinephrine from the vesicles and the avail- ocular disturbances, and tachycardia are common side ability of norepinephrine (depleted by reserpine). The effects of atropine given alone, but these effects are less substitution on the α-carbon atom blocks oxidation by likely to occur with competition between atropine and monoamine oxidase. With no substitution on its benzene the increase in the synaptic ACh produced by inhibition ring, amphetamine resists metabolism by COMT. of AChE by neostigmine. 5. (B). The adrenoceptors that epinephrine acts on to 14. (A). Application of tropicamide to the eye of a pa- affect heart rate, renin release, bronchiolar tone, and gly- tient with narrow-angle (angle-closure) glaucoma is a cogenolysis are β-receptors. Prazosin is an β-antagonist very serious risk, because the peripheral movement of the so would not antagonize epinephrine at those receptors. relaxed iris can block the outflow of fluid and trigger a The radial smooth muscle in the iris has α-receptors that rapid rise in intraocular pressure. Open-angle glaucoma when activated, contract the radial muscle which dilates does not present the same risk for the application of a the pupil. This action is antagonized by prazosin. short-acting mydriatic such as Tropicamide. If the patient 6. (D). Propranolol and metoprolol are selective for is taking a cholinomimetic miotic for open-angle glau- β-receptors, whereas Prazosin and Phenoxybenzamine are coma, there is even less risk of applying tropicamide, al- selective for α-receptors. Labetalol is the only antago- though potential competition between the miotic and the nist in this list that has the ability to reduce responses antagonist may have to be considered. mediated by both α- and β-receptors. 15. (A). Atropine has little effect on blood pressure in 7. (C). At an optimal dose of neostigmine, there the absence of a circulating muscarinic agonist because should be no change in muscle strength with adminis- the muscarinic receptors on endothelial cells do not re- tration of Edrophonium. If Edrophonium increases muscle ceive synaptic input. Therefore, the blood pressure of a strength, the inhibition of AChE is insufficient and the healthy patient will not change with treatment with at- maximum therapeutic benefit is not being achieved. If ropine. In contrast, patients being treated with an AChE edrophonium decreases muscle strength, the dose of ne- inhibitor may have slightly elevated plasma ACh levels, ostigmine is too high, bordering on the production of a and patients being treated with bethanechol may be hypo- depolarizing block of neuromuscular transmission. tensive because of its direct actions on the muscarinic re- 8. (D). Neostigmine will inhibit AChE and increase the ceptors on endothelial cells. ACh available to compete with the antagonist at the neu- 16. (B). The symptoms are suggestive of central an- romuscular junction, overcoming the block of neurotrans- timuscarinic effects of a drug. Glaucoma is treated with mission. Succinylcholine, a nicotinic agonist, will only muscarinic agonists or noncholinergic drugs. Although

45 the entry of pilocarpine into the CNS can disturb CNS promazine is a Dopamine antagonist. Only atropine would function, it is not as likely as an antimuscarinic drug to block both the slow EPSP and the slow IPSP. produce drowsiness and loss of concentration. The oth- 19. (B). The receptor contributing to the slow EPSP is er questions would all be useful. A patient who has hay a muscarinic-cholinergic receptor and is activated by ACh. fever or stuffiness may be taking an antihistamine. A pa- The nicotinic-cholinergic receptor mediates the fast EPSP, α tient with back spasms may be taking a muscle relaxant, an -receptor may mediate the slow IPSP, and a P2X re- such as cyclobenzaprine. One who is being treated for ceptor and a β-adrenergic receptor do not appear to be mood disorders may be taking antipsychotic medication. involved in the complex action potentials seen at auto- All of these treatments can produce significant central nomic ganglia. antimuscarinic side effects. 20. (C). Trimethaphan is a ganglionic blocking agent 17. (E). The principal neurotransmitter released from that will lower blood pressure very rapidly. Hydralazine preganglionic nerve terminals in all autonomic ganglia is a vasodilator; hydrochlorothiazide and spironolactone is acetylcholine. It acts on the postganglionic cell body are diuretics; and methyldopa is a sympatholytic acting to activate a nicotinic-cholinergic receptor resulting in a in the central nervous system. All of these drugs are used fast EPSP. Dopamine or Norepinephrine or both are the me- clinically as antihypertensive agents. None works as rap- diators released from SIF cells or interneurons. Neu- idly as Trimethaphan. Clinically, however, either nitro- ropeptide Y is a peptide neurotransmitter. Angiotensin prusside or clonidine is used much more commonly than and serotonin are modulatory mediators. These last three trimethaphan in this situation. contribute to the late very slow EPSP. 21. (E). The effect of ganglionic blockade depends 18. (C). The slow EPSP results from activation of mus- upon the predominant autonomic tone exerted within carinic-cholinergic receptors on SIF cells or interneurons, various organ systems. Since the activity of the parasym- which release norepinephrine or dopamine from their ter- pathetic nervous system predominates in the eye, the ef- minals. These catecholamines then cause a slow IPSP in fect of ganglionic blockade is mydriasis, not miosis. Sim- the ganglionic cell body. Therefore, both the slow EPSP ilarly, stimulation of the genital tract and urinary reten- and subsequent slow IPSP would be prevented by the mus- tion would be decreased. Since sympathetic nervous sys- carinic antagonist atropine. Prazosin is an ar adrenergic tem activity predominates in blood vessels and the ven- antagonist; Sumatriptan is a serotonin 5HT1D agonist; losa- tricles, vasodilation and a decreased cardiac output would rtan is an angiotensin receptor antagonist; and Chlor- follow ganglionic blockade.

46 DRUGS AFFECTING AFFERENT INNERVATION

Lecture 7 ing sensation on the skin and is mildly anesthetic relieves itching. It is added in liniments and pain balms. DRUGS THAT IRRITATE Taken internally small doses produce a warm and RECEPTORS comforting sensation in epigastria; large doses are Irritants stimulate sensory nerve endings at the emetic. Systemically it produces excitement and convulsions (specially in children). Menthol from mint site of application and induce local and reflex re- or prepared synthetically, has cooling and soothing sponses. Depending on their nature, concentration action. It is added to pain balms, throat paints and and sensitiveness of the site, they produce cooling inhalers for relief of nasal congestion. Menthol is in- sensation or warmth, pricking and tingling, hyper- cluded in Validol — tablets used sublingually in anaesthesia or numbness and local hyperemia. Local gina pectoris. vasodilation improves blood circulation and tissue Mustard seeds contain a glycoside Sinirgin and en- nutrition. zyme Myrosin. When ground seeds are soaked in wa- Certain irritants also produce a remote effect which ter, Myrosin hydrolyses Sinirgin to release Allyl iso- tends to relief pain and inflammation in deeper organs thiocyanate which is strong irritant. Mustard plasters — called counter-irritants. Cutaneous sensations are has been used as counter-irritant. As a suspension in precisely localized. Deeper sensations from muscles, water 4–8 g, it is emetic. joints and viscera are perceived more diffusely. A spinal segment receives afferent impulses from the surface as well as from deeper organs. According to a spinal CAUSTICS AND ESCHAROTICS segment, a determined region of the skin corresponds a determined internal organ (called Zakharin-Ged’s Caustic means corrosive and escharotic means cau- zones). Irritation of afferent nerve endings from the terize. These chemicals cause local tissue destruction surface modulates pain impulses coming from deeper and sloughing. An escharotic, in addition, precipitates organs. This, through segmental association of affer- proteins that exude to form a scarb. They are used to ents, results in decrease of pain afferentation, vasodi- remove moles, warts, condylomata, papillomas and on lation in the corresponding deeper organ. Increased keratotic lesions. Care is needed in their application blood supply helps to fight the cause of pain and in- to avoid ulceration. It is believed that all microorgan- flammation in the deeper organ. isms are killed during cauterization, but it is not al- Counter-irritants are generally massaged to relieve ways so. headache, muscular pain, joint pain, colica etc. The Podophyllum resin as 10–25% alcoholic solution drugs are: or suspension in mineral water; — Volatile oils: Turpentine oil, Eucalyptus oil Silver nitrate as toughened silver nitrate sticks or — Stearoptenes: Camphor, Thymol, Menthol pencils; — Mustard seeds Phenol as 80% solution; — Capsicum Trichloracetic acid as crystals or 10–20% solution. — Ammonia etc. Volatile oils (essential oils) are terpene hydrocarbons KERATOLYTICS of plant origin having a characteristic odor. They have variable properties, but all are irritants. Stearoptenes Keratolytics dissolve the intracellular substance in are solid volatile oils. the horny layer of the skin. The epidermal cells swell, Turpentine oil obtained by distilling Pinus oleores- soften and then desquamate. They are used on hyper- in; used as counterirritant in the form of liniment. keratotic lesions like corns, warts, psoriasis, chronic Eucalyptus oil used in pain balms. dermatitis, ring warm, athletes foot. Camphor obtained from bark of Cinnamomum Salicylic acid as 10–20% solution in alcohol or camphora or produced synthetically. Produces cool- propylene glycol for dissolving corns;

47 Benzoic acid is antifungal with mild keratolytic ac- O tion. CH2 Bitters, emetic drugs, purgatives, and bile-drive H N — — C — O — CH — N drugs are described in lecture “Drugs used in gastroin- 2 2 CH testinal diseases”. 2 Procaine Available forms: Menthol — in bottles 1% and 2% spirit solution 10 ml each СН2 O Validolum — in bottles 10 ml each; in capsules CH2 0.05 and 0.1 each — NH — C — CH — N Camphor — ointment (Unguentum Camphoratum) 2

10% 100.0 CH2 CH2 Salicylic acid — in bottles 1% and 2% spirit solution Lidocaine

The nature of this bond determines certain of the pharmacological properties of these agents. The es- Lecture 8 ter link is important because this bond is readily hy- DRUGS THAT PROTECT drolyzed during metabolic degradation in the body. RECEPTORS According to the chemical structure LAs are classified into: — Ester linked LAs Procaine, Tetracaine, Anaes- LOCAL ANESTHETICS thesin (paraaminobenzoic acid derivatives), and Co- caine. Local anesthetics (LAs) are drugs which upon top- — Amide linked LAs Lidocaine, Trimecaine, Bupi- ical application or local injection cause reversible loss vacaine (xylidine derivatives). They differ from the es- of sensory perception, specially of pain, in a restrict- ter linked LAs in that they are not hydrolyzed by plas- ed area of the body. They block generation and con- ma esterases; are generally longer acting and less fre- duction of nerve impulse at all parts of the neuron where quently produce hypersensitivity reactions; no cross they came in contact, without causing any structural sensitivity with ester linked LAs. damage. Thus, not only sensory but also motor impuls- Mechanism of action: The LAs block the nerve con- es are interrupted when a LA is applied to a mixed duction by decreasing the entry of Na+ ions during up- nerve, resulting in muscular paralysis and loss of au- stroke of action potential. The LAs directly interact tonomic control as well. with voltage-sensitive Na+ channels. As the anaesthetic The first local anesthetic to be discovered was Co- action progressively develops in a nerve, the threshold caine, an alkaloid contained in the leaves of Erythrox- for electrical excitability gradually increases, the rate ylon coca, a shrub growing in the Andes Mountains. of rise of the action potential declines, impulse con- The pure alkaloid was first isolated in 1860 by Nie- duction slows and fails. As a general rule, small nerve mann. A russian scientist Von Anrep in 1880 observed fibers seem to be more susceptible to the action of LAs that the skin became insensitive to the prick of a pin than are large fibers. This may explain why the LAs when Cocaine was infiltrated subcutaneously. He rec- affect the functions of a nerve in predictable order. Au- ommended the alkaloid to be used clinically as a lo- tonomic fibers are generally more susceptible than so- cal anesthetic. A chemical search for synthetic substi- matic fibers. Among the somatic afferents order of tutes for Cocaine started in 1892 with the work of Ein- blockade is: pain — temperature sense — touch — deep horn. This resulted in 1905 in the synthesis of procaine pressure sense. which became the prototype for local anesthetic drugs In clinical practice the preparation of LA often con- for half a century. The most widely used agents today tains a vasoconstrictor, usually Adrenaline (1: 50,000 are Lidocaine, Bupivacaine, and Tetracaine. to 1: 200,000). The vasoconstrictor decreases the rate Properties Desirable in LA. A Good LA should of absorption of a LA into the circulation. This per- combine several properties. It should not be irritating forms a dual service: (1) prolongs duration of action to the tissue to which it is applied, nor should it cause of a LA, and (2) reduces systemic toxicity of a LA. any permanent damage to nerve structure. Its system- Actions: The danger of such adverse reactions is ic toxicity should be low because it eventually ab- proportional to the concentration of LA in the circu- sorbed from its site of application. The ideal LA must lation. be effective regardless of whether it is injected or ap- CNS: Following absorption, LAs may cause stim- plied locally to mucous membranes. It is usually im- ulation of the CNS, producing restlessness and tremor portant that the time required for the onset of anesthe- that may proceed to clonic convulsions followed by de- sia should be as short as possible. Furthermore, the pression with respiratory failure. action must last long enough. CVS (usually seen after high systemic concentra- Chemistry. The clinically useful LAs are weak bases tions): The primary site of action is the myocardium, with amphiphilic property. A hydrophilic secondary or where decreases in electrical excitability, conduction tertiary amine on one side and a lipophilic aromatic rate, and force of contraction occur. In addition, most residue on the other are joined by an alkyl chain LAs cause arteriolar dilation. Lidocaine has little ef- through an ester or amide linkage. fect on contractility and atrioventricular conductivi- 48 ty; it may serve as an antiarrhythmic. Procaine is not travel. The LA injected in this space acts primarily on used as antiarrhythmic, but its amide derivative Pro- nerve roots (in the epidural as well as subarachnoid cainamide is a classical antiarrhythmic. spaces to which it diffuses). It is a popular form of re- Pharmacokinetics: Surface anesthetics are rapidly gional anaesthesia. absorbed from mucous membranes, but absorption from intact skin is poor. Procaine does not significantly penetrate mucous membranes. Rate of absorption depends ASTRINGENTS on the blood flow to the area of application or injec- Astringents are substances that precipitate proteins, tion. Esters linked LAs (procaine etc.) are rapidly hy- but do not penetrate cells, thus affecting the superfi- drolyzed by plasma pseudocholinesterase and the re- cial layer only. They toughen the surface making it maining by esterases in the liver. Amide linked LAs mechanically stronger and decrease exudation and in- (lidocaine etc.) are metabolized only in the liver mi- flammation. crosomes. Adverse effects: Systemic toxicity is related to the These drugs are divided into: intrinsic anesthetic potency of the LA. However, — Organic: Tannins, Tanalbine, Decoctions of toxicity is influenced by relative rates of absorption bark of Oak-Tree, Camomile, etc. and metabolism. CNS effects are mental confusion, — Non-organic: weak solutions of zinc, aluminum, tremors and finally convulsions and respiratory ar- cooper and bismuth salts. They form tough albuminates rest. CVS toxicity is manifested as bradycardia, hy- on the surface, thus serve as protective coat potension, cardiac arrhythmias and vascular col- Astringents are used for the treatment of skin dis- lapse. Hypersensitivity reactions like rashes, derma- eases, inflammatory diseases of oral, nasal cavities. titis, asthma, and rarely anaphylaxis occur. These Tannic acid and Tannin are used in alkaloid poison- are more common with ester type LAs and cross re- ings — precipitate ingested alkaloids (morphine, at- activity is frequent among them, but not with amide ropine, etc.) as tannates. linked LAs. Therapeutic uses: Local anesthesia is the loss of sensation without the loss of consciousness. The choice of COATING DEMULCENTS a LA and the technique of its use are the determinants They are, in general, high molecule weight sub- of the properties and toxicity of the LA. stances and are applied as thick colloidal solutions in Surface anesthesia: It is produced by topical ap- water. They form viscous film over the sooth inflamed plication of surface anaesthetics to mucous membranes mucosa, preventing contact with irritants in the sur- (nose, mouth, throat, tracheobronchial tree, esophagus, roundings. urogenital tract) and abraded skin. Tetracaine (2%), Lidocaine (2 to10%), and Cocaine (1 to 4%) are most often used. Procaine and other more polar LAs ADSORBENTS are clinically unsatisfactory; they penetrate mucous membranes too poorly. Cocaine has the unique advan- Adsorbents are finely powdered, inert and insolu- tage of producing vasoconstriction as well as anaes- ble solids with great adsorptive surface (activated char- thesia. coal, starch, kaolin). They are capable to bind to their Infiltration anaesthesia: Dilute solution of LA is in- surface noxious and irritant substances, preventing jected under the skin in the area of operation — blocks mucosa from irritation and absorption from mucous sensory nerve endings. It is used for minor operations. membrane. These agents are used in case of poison- The LAs most frequently used for infiltration anaes- ing, inflammatory disease of GIT, meteorism, etc. thesia are Lidocaine (0.5 to 1.0%), Procaine (0.25 to 1.0%), and Bupivacaine (0.125 to 0.25%). Conduction block: The LA is injected around nerve EMOLLIENTS trunks so that area distal to injection is anesthetized Emollients are brand oily substances which sooth and paralyzed. It is frequently used for tooth extrac- and soften the skin and mucosa. They form an occlu- tion, operation on eye, limbs, abdominal wall, frac- sive film over the skin, preventing evaporation, thus re- ture setting etc. storing elasticity of cracked and dry skin. They are also Spinal anesthesia: The LA is injected into the lum- used as vehicles for topically applied medicaments. They bar subarachnoid space between LII-III or LIII-IV be- are (1) vegetable oils (Olive oil, Cocoa butter, Linseed low the lower end of spinal cord. The primary site of oil); (2) animal products (Wool fat (Lanolin), Sper- action is the nerve root in the cauda eqina rather than maceti (from the head of sperm whale), Bees wax); (3) the spinal cord. Lower abdomen and lower limbs are petroleum products (Soft and hard paraffin, Liquid par- anesthetized and paralyzed. Spinal anesthesia is used affin). Cocoa butter, wool fat and paraffin are common- for operations on the lower abdomen, pelvis, lower ly employed as ointment bases. Bees wax and sperma- limbs, prostatectomy, obstetric procedures, caesari- ceti are used to harden ointment bases. Wool fat may an section etc. Its advantage over general anesthesia cause allergy in some patients. are — (1) it is safer; (2) produces good analgesia and muscle relaxation without loss of consciousness; (3) cardiac, pulmonary, renal disease and diabetes pose ANTACIDS less problem. Epidural anesthesia: The spinal epidural space is Antacids are described in lecture “Drugs used in filled with semiliquid fat through which nerve roots gastrointestinal diseases”.

49 Available forms: 5. A 25-year-old woman visits your office with red Tetracaine — in bottles 0.5% and 1% solution 10 and itchy eczematoid dermatitis. She had a dental pro- ml each cedure earlier in the day, and the dentist administered Novocain (Procaine) — in ampoules 0.25%; 0.5%; a local anesthetic. There were no other findings, al- 1% and 2% solution 1; 2; 5 and 10 ml each though she indicated that she had a history of allergic Anaesthesinum — in tablets 0.3 each; 5% ointment reactions. Which of the following drugs is most likely Lidocaine hydrochloride (Propoxycaine) — in am- involved? poules 1% solution 10 ml each; in ampoules 2% solu- (A). Cocaine. tion 2 and 10 ml each (B). Procaine. (C). Lidocaine. (D). Bupivacaine. (E). Etidocaine. EXAMINATION QUESTIONS

1. With the movement of which ion as a fundamen- ANSWERS tal basis for their action do the local anesthetics interfere? 1. (B) Inhibition of inward migration of Na+ can re- (A). Calcium. sult in complete block of conduction and therefore abo- (B). Sodium. lition of pain transmission. This block of conduction is (C). Potassium. not a feature of alteration of any of the other ions. (D). Hydrogen. 2. (C) A block at this level will affect only the sympa- (E). Oxygen. thetic nerves, not parasympathetic activity. Application to the nerve cell ending would result only in topical anesthe- 2. Sympathetic block is one use of local anaesthet- sia, and blockade of the neuromuscular junction could produce respiratory failure. Administration to the spinal ics. What is the best location to apply the local anes- cord is too general an answer. The injection must be near thetic? a nerve or nerve plexus proximal to the surgical site. (A). Nerve cell ending. 3. (D) Epinephrine is by far the most commonly em- (B). Neuromuscular junction. ployed vasoconstrictor. Phenylephrine is occasionally (C). Sympathetic ganglia. used with procaine for dental procedures. Levonordefrin (D). Spinal cord. is also used rarely in dental procedures. Dopamine has no vasoconstrictor activity. Cocaine is itself a local an- 3. Frequently vasoconstrictors are combined with esthetic with some vasoconstrictor properties. However, local anesthetics to delay absorption of the anesthetic cocaine, because of its abuse potential and toxicity, is seldom used. Its only use is topical. from its injection site. What is the most widely em- 4. (C) Lidocaine is well tolerated and has a rapid on- ployed agent? set and an adequate duration of action for most proce- (A). Dopamine. dures. Bupivacaine has a particularly long duration of (B). Phenylephrine. action. This may be advantageous in certain procedures, (C). Levonordefrin. but not in most. Procaine has a relatively slow onset of (D). Epinephrine. action as well as a short duration of action. Etidocaine (E). Cocaine. shows a preference for motor rather than sensory block; this limits its effectiveness in obstetrics. 4. What is the most commonly used local anes- 5. (B) Allergic reactions occur only to the ester type of local anesthetics. This is because the metabolism of thetic? all ester-linked local anesthetics leads to the formation (A). Bupivacaine. of PABA, which is known to be allergenic to some indi- (B). Procaine. viduals. Both Cocaine and Procaine are esters. However, (C). Lidocaine. cocaine is not employed in dental procedures. Therefore, (D). Etidocaine. the best choice is Procaine.

50 DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM

Introduction to the CNS. Most drugs that affect the itate intubation and suppress muscle tone to the degree central nervous system (CNS) act by altering some step required for surgery. Potent general anaesthetics are dein the neurotransmission process. Drugs may act pres- livered via inhalation or intravenous injection. With the ynaptically by influencing the production, storage, or exception of nitrous oxide, modern inhaled anaesthet- termination of action of neurotransmitters. Other ics are all volatile, halogenated hydrocarbons that de- agents may activate or block postsynaptic receptors. rive early research and clinical experience with Diethyl In many ways, the basic functioning of neurons in ether and Chloroform. On the other hand, intravenous the CNS is similar to that of the autonomic nervous general anaesthetics consist of a number of chemically system. E.g. transmission of information in the CNS unrelated drug types that are commonly used for the and in the periphery both involve the release of neuro- rapid induction of anaesthesia. transmitters that diffuse across the synaptic space to Concominant use of drugs. Quite often, surgical bind to specific receptors on the postsynaptic neuron. patients receive one or more of the following prean- In both systems, the recognition of the transmitter by aesthetic medications: benzodiazepines (e.g. Di- the membrane receptor of the postsynaptic neuron trig- azepam) to relieve anxiety and facilitate amnesia; bar- gers intracellular changes. Several major differences biturates (e.g. Pentobarbital) for sedation; antihista- exist between neurons in the peripheral autonomic nerv- mines for prevention of allergic reactions (e.g. Dime- ous system and those of the CNS. The circuitry of the drol); antiemetics (e.g. Droperidol); opioids (e.g. Fen- CNS is much more complex than the autonomic nerv- tanyl) for analgesia; anticholinergics (e.g. Scopo- ous system, and the number of synapses in the CNS is lamine) to prevent bradycardia and secretion of fluids far greater. The CNS, unlike the peripheral nervous into the respiratory tract. These agents facilitate system, contain powerful networks of inhibitory neu- smooth induction of anaesthesia, and lower the dose rons that are constantly active in modulating the rate of anaesthetic required to maintain the desired level of of neuronal transmission. In addition, the CNS com- surgical (Stage III) anaesthesia. municates through the use of more than 50 different Induction, maintenance and recovery. Anaesthesia neurotransmitters. In contrast, the autonomic system can be divided into three stages: induction, mainte- uses only two primary neurotransmitters, acetylcholine nance, and recovery. Induction is defined as the peri- and noradrenaline. od of time from onset of administration of the anaesthetic to the development of effective surgical anaesthesia in the patient. Maintenance provides a sustained surgical anaesthesia. Recovery is the time from discontinuation of administration of anaesthesia until Lecture 9 consciousness is regained. Induction of anaesthesia GENERAL ANAESTHETICS depends on how fast effective concentration of anaesthetic drug reach the brain; recovery is the reverse of induction and depends on how fast the anaesthetic drug General anaesthesia is essential to surgical practice is removed from the brain. because it renders patients (1) analgesics, (2) amnesic, Depth of anaesthesia. The depth of anaesthesia can and (3) unconscious while causing (4) muscle relaxation be divided into a series of four sequential stages; each and (5) suppression of undesirable reflexes. No single is characterized by increased CNS depression that is drug is capable of achieving these effects rapidly and caused by accumulation of the anaesthetic drug in the safely. Rather, several different categories of drugs are brain. With ether, which produce a slow onset of an- utilized to produce “balanced anaesthesia”. E.g. ad- aesthesia, all the stages are discernible. However, with juncts to anaesthesia consist of preanaesthetic medica- Halothane and many other commonly used anaesthet- tion and skeletal muscle relaxants. Preanaesthetic med- ics, the stages are difficult to clearly characterize be- ication serves to calm the patient, relieve pain, and pro- cause of the rapidity of onset of anaesthesia. tect against undesirable effects of the subsequently ad- Stage I — analgesia: Loss of pain sensation results ministered anaesthetic. Skeletal muscle relaxants facil- from interference with sensory transmission in the spi-

51 nothalamic tract. The patient is conscious and conver- (Fig. 6). The MAC values are useful in comparing phar- sational. A reduced awareness of pain occurs as Stage macologic effects of different anaesthetics. The more li- II approaches. pid-soluble an anaesthetic, the lower the concentration Stage II — excitement: The patient experiences de- of anaesthetic needed to produce anaesthesia. lirium and violent combative behaviour. There is a rise Uptake and Distribution. The partial of an anaes- and irregularity in blood pressure. The respiratory thetic gas at the origin of the respiratory pathway is rate may be increased. To avoid this stage of anaes- the driving force that moves the anaesthetic into the thesia, a short acting barbiturate, such as sodium thi- alveolar space and hence into the blood, which deliv- opental, is given i.v. before inhalation anaesthesia is ers the drug to the brain and various other body com- administered. partments. Since gases move from one compartment to Stage III — surgical anaesthesia: Regular respi- another within the body according to partial pressure ration and relaxation of the skeletal muscle occur in gradients, a steady state is achieved when the partial this stage. Eye reflexes decrease progressively, until pressure in each of these compartments is equivalent the eye movements cease and the pupil is fixed. Sur- to that in the inspired mixture. The time course for at- gery may proceed during this stage. taining this steady state is determined by the follow- Stage IV — medullary paralysis: Severe depression ing three factors: of the respiratory center and vasomotor center occur 1. Alveolar wash in: This term refers to the replace- during this stage. Death can rapidly occur. ment of the normal lung gases with the inspired anaesthetic mixture. The time required for this process is directly proportional to the functional residual capacity INHALATION ANAESTHETICS of the lung, and inversely proportional to the ventila- Inhaled gases are the mainstay of anaesthesia and tory rate; it is independent to the physical properties are primarily used for the maintenance of anaesthesia of the gas. Once the partial pressure builds within the after administration of an intravenous agent. Inhala- lung, anaesthetic uptake from the lung begins. tion anaesthetics have a benefit that is not available 2. Solubility in the blood: The first compartment that with intravenous agents, since the depth of anaesthe- the anaesthetic gas encounters the blood. Solubility in sia can be rapidly altered by changing the concentra- blood is determined by a physical property of the an- tion of the inhaled anaesthetic. Because most of these aesthetic molecule called the blood/gas portion coeffi- agents are rapidly eliminated from the body, they do cient, which is the ratio of the total amount of gas in not cause postoperative respiratory depression. the blood relative to the gas equilibrium phase. Drugs Common features of inhaled anaesthetics. Modern with low versus high solubility in blood differ in their inhalation anaesthetics are non-explosive agents that speed of induction of anaesthesia. E.g. when an anaes- include the gas nitrous oxide as well as a number of thetic gas with low blood solubility, such as Nitrous ox- volatile halogenated hydrocarbons. As a group, these ide, diffuses from the alveoli into the circulation, little agents decrease cerebrovascular resistance, resulting of the anaesthetic dissolves in the blood. Therefore, the in increased perfusion of the brain. They cause bron- equilibrium between the inhaled anaesthetic and arteri- chodilation and decrease minute ventilation. Their clin- al blood occur rapidly, and relative few additional mol- ical potency cannot be predicted by their chemical ecules of anaesthetic are required to raise arterial ten- structure, but potency does correlate with their solu- sion (that is, steady state is rapidly achieved). In con- bility in lipid. The movement of these agents from the trast, an anaesthetic gas with high blood solubility, such lungs to the different body compartments depends upon as Halothane, dissolves more completely in the blood, their solubility in blood and various tissues. Recovery and greater amount of the anaesthetic and longer peri- from their effects is due to their redistribution from the ods of time are required to raise arterial tension. This brain. results in increased time of induction and recovery, and Potency. The potency of inhaled anaesthetics is de- slower changes in the depth of anaesthesia in response fined quantitatively as the minimum alveolar concen- to changes in the concentration of the inhaled drug. tration (MAC), which is the concentration of anaesthet- 3. Tissue uptake: The arterial circulation distributes ic gas needed to eliminate movement among 50% of the anaesthetic to various tissues, and the pressure gra- patients challenged by standardized skin incision. The dient drives free anaesthetic gas into tissues. The time MAC is usually expressed as the per cent of gas in a required for a particular tissue to achieve a steady-state mixture required to achieve the effect. Numerically, is is inversely proportional to the blood flow to that tissue small for potent anaesthetics, such as Halothane, and (faster flow results in a more rapidly achieved steady- large for less potent agents, such as Nitrous oxide state), and directly proportional to the capacity to store

Halothane Isoflurane MAC for anaesthetic Enflurane gases Ether Nitrous oxide 0 1 2 100 % (MAC)

Fig. 6. Comparative potency of inhalation anaesthetics

52 anaesthetic (larger capacity results in a longer time to Enflurane achieve steady-state). Capacity, in turn, is directly proportional to the tissue’s volume, and the tissue/blood sol- This gas is less potent than Halothane but it produc- ubility coefficient of the anaesthetic. On the basis of es rapid induction and recovery. About 2% of the agent these considerations, four major compartments deter- is metabolized to fluoride ion, which is excreted by the mine the time course of anaesthetic uptake: kidney. Therefore, Enflurane is contraindicated in pa- a) Brain, heart, liver, kidney, endocrine glands: tients with kidney failure. Enflurane anaesthesia exhib- These highly perfused tissues rapidly attain a steady- its the following differences from Halothane: fewer ar- state with the partial pressure of the anaesthetic in rhythmias, less sensitization of the heart catecho- blood. lamines, and greater potentiation of muscle relaxants. b) Skeletal muscles: These are poorly perfused dur- A disadvantage of Enflurane is that it causes CNS exci- ing anaesthesia. This fact prolongs the time required tation at twice the MAC and at lower doses if hyper- to achieve steady-state. ventilation reduces the PCO2. c) Fat: This tissue is also poorly perfused. Howev- er, potent general anaesthetics are very lipid soluble. Isoflurane Therefore, fat has a large capacity to store anaesthet- This is a newer halogenated anaesthetic that has low ic. This combination of slow delivery to a high capac- biotransformation and low organ toxicity. Unlike the ity prolongs the time required to achieve steady state. other halogenated anaesthetic gases, Isoflurane does not d) Bone, ligaments, and cartilage: These are poor- induce cardiac arrhythmias and does not sensitize the ly perfused and have a relatively low capacity to store heart to the action of catecholamines. Isoflurane is a very anaesthetic. Therefore, these tissues have only a slight stable molecule that undergoes little metabolism, as a impact on the time course of anaesthetic distribution result of which, less fluoride is produced. Isoflurane is in the body. not currently believed to be tissue toxic. 4. Washout. When the administration of an inhalation anaesthetic is discontinued, the body now becomes Methoxyflurane the “source” that drives the anaesthetic into the alveolar space. The same factors that influence attainment The agent is the most potent inhalation anaesthet- of steady-state with an inspired anaesthetic determine ic because of its high solubility in lipid. Prolonged ad- the time course of clearance of the drug from the body. ministration of Methoxyflurane is associated with met- Specific inhalation anaesthetics. Each of the halo- abolic release of fluoride, which is toxic to the kidneys. genated gases has characteristics beneficial for select- Therefore, Methoxyflurane is rarely used outside ob- ed clinical applications. No one anaesthetic is superior stetric practice. It finds use in child-birth because it to another under all circumstances. [Note: In a very does not relax the uterus when briefly inhaled. small population of patients, all of the halogenated hydrocarbon anaesthetics have the potential to induce ma- Nitrous oxide lignant hyperthermia. While the etiology of this condi- Whereas Nitrous oxide (N2O or “laughing gas”) tion is unknown, it appears to be inherited. Should a is a potent analgesic, it is a weak general anaesthetic. patient exhibit the hyperthermia and muscle rigidity Thus, it is frequently combined with other more potent characteristic to malignant hyperthermia, Dantrolene is agents. Because it moves very rapidly into and out of given as the anaesthetic mixture is withdrawn.] the body, Nitrous oxide can increase the volume (pneu- mothorax) or pressure (sinuses) within closed body Halothane (Ftorotan) compartments. Furthermore, its speed of movement al- This agent is the prototype to which newer agents lows Nitrous oxide to retard oxygen uptake during re- in this series of anaesthetics are compared. While Ha- covery, thus causing diffusion hypoxia. This anaesthet- lothane is a potent anaesthetic, it is a relatively weak ic does not depress respiration nor does it produce mus- analgesic. Thus, Halothane is usually co-administered cle relaxation. It also has the least effect on cardio- with Nitrous oxide, opioids, or local anaesthetics. Like vascular system and on increasing cerebral blood flow, other halogenated hydrocarbons, Halothane is vagomi- and is the least hepatotoxic of the inhalation anaes- metic and will cause atropine-sensitive bradycardia. In thetics. It is therefore probably the safest of these an- addition, Halothane has the undesirable property of aesthetics, provided that at least 20% of oxygen is al- causing cardiac arrhythmias. Halothane is oxidatively ways administered at the same time. [Note: Nitrous metabolized in the body to tissue-toxic hydrocarbons oxide at 80% (without other adjunct agents) cannot (e.g. trifluoroethanol) and bromide ion. These substanc- produce surgical anaesthesia.] Nitrous oxide is often es may be responsible for the toxic reactions that some employed of 30% in combination with oxygen for an- patients (especially females) develop after Halothane algesia, particularly in dental surgery. anaesthesia. This reaction begins as fever, anorexia, nausea, and vomiting, and patients may exhibit signs INTRAVENOUS ANAESTHETICS of hepatitis. Although the incidence of this reaction is low — approximately 1 in 10,000 individuals — 50% Intravenous anaesthetics are often used for the rap- of such patients will die of hepatic necrosis. [Note: Ha- id induction of anaesthesia, which is then maintained lothane is not hepatotoxic in pediatric patients and that, with an appropriate inhalation agent. They rapidly in- combined with its pleasant odor, make it the agent of duce anaesthesia, and must therefore be injected slow- choice in children.] Halothane anaesthesia is not rely. Recovery from intravenous anaesthetics is due to peated at intervals less than 2 to 3 weeks. redistribution from sites in the CNS.

53 BARBITURATES of the heart and increases blood pressure and cardiac output. Ketamine is therefore used when circulatory Thiopental is a potent anaesthetic and a weak an- depression is undesirable. On the other hand, these ef- algesic. It is the most widely used intravenously ad- fects mitigate against the use of Ketamine in hyperten- ministered general anaesthetic. It is an ultra-short-act- sive or stroke patients. The drug is lipophilic and ening barbiturate and has a high lipid solubility. When ters the brain very quickly, but like the barbiturates, Thiopental is administered intravenously, it quickly it can redistribute to other organs and tissues. It is me- enters the CNS and depresses function, often in less tabolized in the liver. Ketamine is employed mainly than 1 minute. However, diffusion out of the brain can in children and young adults for short procedures. It occur very rapidly as well, because of redistribution is not widely used because it increases cerebral blood of the drug to other body tissues, including skeletal flow and induces postoperative hallucinations (night- muscle and ultimately adipose tissue. This latter site mares). serves as a reservoir of drug from which the agent slowly leaks out and is metabolized and excreted. The Propanidid short duration of action is due to the decrease of its Propanidid (Sombrevin) is an ultra-short-acting concentration in the brain. Thus, metabolism of Thio- intravenous anaesthetic. Onset is smooth and occurs pental is much slower than tissue redistribution. The within about 40 seconds of administration. The emer- barbiturates are not significantly analgesic and require gence from anaesthesia from Propanidid is more rap- some type of supplementary analgesic administration id than that from Thiopental and is characterized by during anaesthesia. Thiopental has minor effects on the minimal postoperative confusion. cardiovascular system, but it may contribute to severe hypotension in hypovolemic or shock patients. All barbiturates can cause apnea, coughing, chest wall spasm, Sodium oxybutyrate laryngospasm, and bronchospasm. Barbiturates are Sodium oxybutyrate is a derivative of γ-ami- contraindicated in patients with acute intermittent or nobutyric acid (GABA). GABA is an inhibitory neu- variegate porphyria. rotransmitter in the CNS. In contrast to GABA, So- dium oxybutyrate readily crosses the blood-brain barrier and produces sedative, hypnotic, anaesthet- BENZODIAZEPINES ic, anticonvulsive, and antihypoxic effects. Howev- er, Sodium oxybutyrate is not good analgesic. The Although Diazepam is the prototype benzodi- onset of action is slow (in 30–40 minutes after i.v. azepine, Lorazepam and Midazolam are more potent. injection). It must be used with other anaesthetics All three facilitate amnesia while causing sedation. for surgical anaesthesia. Midazolam has become popular because of its combination of water solubility, rapid onset and short dura- Available forms: tion of action. It produces amnesia with few side ef- Thiopental-sodium — in bottles 0.5; 1.0 each (to fects. Mental function returns to normal within 4 dilute in 20 ml of physiological solution) hours, making it popular choice for ambulatory sur- Midazolam — in ampoules 0.5% solution 3 ml gery and during regional anaesthesia.

OPIOIDS Because of their analgesic property, opioids are fre- Lecture 10 quently used together with other anaesthetics; e.g. the ETHYL ALCOHOL (ETHANOL) combination of Morphine and Nitrous oxide provide good anaesthesia for cardiac surgery. However, opioids are not good amnesiacs and they can cause hypo- Pharmacology of alcohol is important for its pres- tension, respiratory depression, and muscle rigidity as ence in beverages (which have been used since record- well as post-anaesthetic nausea and vomiting. Fenta- ed history) and for alcohol intoxication, rather than nyl is more frequently used than Morphine. as a drug. Alcohol is manufactured by fermentation of The combination of Droperidol and Fentanyl is a sugar: fixed ration preparation called Thalamonal (Inno- var®). Since Droperidol is a neuroleptic substance, C6H12O6 2CO2 + 2C2H5OH Thalamonal is said to produce neurolept analgesia. A neuroleptic has adrenergic blocking as well as seda- Fermentation proceeds till alcohol content reach- tive, antiemetic properties. es 15%. Then reaction is inhibited by alcohol itself. Local action. Rubbed on skin Ethanol dissolves fat, precipitate surface proteins and harden skin. By pre- OTHER ANAESTHETICS cipitation bacterial proteins it acts as an antiseptic. The antiseptic action increases with concentration Ketamine, a short-acting nonbarbiturate anaesthet- from 20 to 70%, remains constant from 70 to 90% and ic, induces a dissociated state in which the patient ap- decreases above that. 100% Ethanol is more dehydrat- pears awake but is unconscious and does not feel pain. ing but poorer antiseptic than 90% Ethanol. Applied This dissociative anaesthesia provides sedation, amne- to delicate skin or mucous membrane Ethanol produc- sia, and immobility. Ketamine stimulates the central es irritation and burning sensation. Injected s.c. it caus- sympathetic outflow, which in turn, causes stimulation es intense pain, inflammation and necrosis followed by 54 fibrosis. Injected round a nerve it produces permanent Lecture 11 damage. Resorptive action. Ethanol is a neuronal depres- HYPNOTIC DRUGS sant. However, as highest areas are most sensitive to alcohol (these are primarily inhibitory), — excitation and euphoria are experienced at lower plasma concen- Sleep is an active, circadian, physiological depres- trations (30-100 mg/dl). Caution, self criticism and re- sion of consciousness. It is characterized by cyclical straint are lost first. With the increasing concentration electroencephalographic (EEG) and eye movement (100–150 mg/dl) mental clouding, disorganization of changes. Normal sleep (categorized by eye movement) thought and drowsiness occur. At 150–200 mg/dl the is of two kinds: person is sloppy, ataxic and drunk; 200–300 mg/dl NREM (non-rapid eye movement), orthodox, fore- results in stupor and above this unconsciousness pre- brain or slow-wave EEG sleep. Heart rate, blood pres- vails, medullary centers are paralyzed and death may sure and respiration are steady or decline and muscles occur. Though, Ethanol can produce anaesthesia, are relaxed; growth hormone secretion is maximal. margin of safety is narrow. Effects of alcohol are REM (rapid eye movement), paradoxical, hind- more marked when the concentration is rising than brain of fast-wave EEG sleep; awakened subjects state when it is falling. they were ‘dreaming’. Heart rate, blood pressure and Small doses of alcohol produce cutaneous and gas- respiration are increased, skeletal muscles are pro- tric vasodilation, a sense of warmth, but heat lost is foundly relaxed. increased in cold surroundings. Cycles of NREM sleep (about 90 min) alternate Alcoholic beverages have variable effect on gastric with REM sleep (about 20 min). Thus, normal sleep secretion depending on beverage itself and whether the contains 4–6 cycles (NREM+REM). individual likes it. Dilute alcohol (optimum 10%) is a strong stimulant of gastric secretion. Higher concen- Classification of insomnias (sleep disorders): trations (above 20%) inhibit gastric secretion. 1. Difficulty in getting to sleep, onset insomnia; this Regular intake of small amounts of alcohol has was associated with neurotic personality disorder. Peo- been found to raise high density lipids and diminish ple who lie awake in bed for hours unable to relax, low density lipids levels in plasma. This may be re- and then sleep well. sponsible for the somewhat lower incidence of coronary 2. Difficulty in staying asleep, repeated awaken- artery disease. ings. Pharmacokinetics. Rate of alcohol absorption from 3. Early waking in which sleep is shorter. the stomach is dependant on its concentration, pres- In general, a short-acting hypnotic drug is pre- ence of food, and other factors. Absorption from the scribed for patients who have prolonged sleep latency intestines is very fast. Thus, gastric emptying deter- but who sleep well once sleep ensues; and a drug with mines rate of absorption. Alcohol distributes widely in a longer duration of action for those who awaken ear- the body, crosses blood-brain barrier (concentration in ly and have difficulty in returning to sleep. Insomnia the brain is very near to blood concentration); it also has many causes, and an accurate differential diagno- crosses placenta freely. It is oxidized in the liver. sis is required before treatment should be considered. Prescription of a hypnotic without regard to the un- Aldehyde- Acetaldehyde derlying disturbance subjects the patient to the risk of dehydro- dehydro abuse, may mask the signs and symptoms of a perni- genase genase cious disease etc.

Alcohol- Ethanol Acetate CO2 + H2O BARBITURATES Metabolism of alcohol follows zero order kinetics, i.e. a constant amount is degraded in unit time, irre- Barbital was introduced in 1903 and Phenobarbi- spective to blood concentration (8-10 ml of absolute tal in 1912. The barbiturates were formerly the main- alcohol/hour). Small amounts are excreted through stay of treatment used to sedate the patient or to in- kidney and lungs. duce and maintain sleep. Today, they have been large- Acute Alcoholic Intoxication. Nausea, vomiting, ly replaced by the benzodiazepines, mainly because hypotension, hypoglycemia, collapse, respiratory de- barbiturates induce tolerance, drug-metabolizing en- pression, coma and death. zymes, physical dependence, and very severe with- Treatment. Gastric lavage, maintain patent airway drawal symptoms. Foremost is their ability to cause and aspiration of vomitus. Most patients will recover coma in toxic doses. Certain barbiturates, such as the with supportive treatment and maintenance of fluid and very short-acting Thiopental, are still used to induce electrolyte balance. Insulin+Fructose has been found anaesthesia. to accelerate alcohol metabolism. Mechanism of action. Barbiturates are thought to Disulfiram (Teturamum) has found some use in the interfere with Na+ and K+ transport across cell mem- patients seriously desiring to stop alcohol ingestion. brane. This leads to inhibition of the mesencephalic The drug blocks the oxidation of acetaldehyde to ace- reticular activation system. Polysynaptic transmission tic acid by inhibiting aldehyde dehydrogenase. This is inhibited in all areas of the CNS. Barbiturates also results in accumulation of acetaldehyde in the blood, potentiate GABA action on chloride entry into the neu- causing flushing, tachycardia, hyperventilation, and ron, although they do not bind at the benzodiazepine nausea. receptor.

55 Actions. awakes. This drug hangover leads to impaired ability Depression of the CNS: The barbiturates can pro- to function normally for many hours after waking. duce all degrees of depression of the CNS. Low doses Addiction: Abrupt withdrawal from barbiturates produce sedation (calming effect, reducing excite- may cause tremor, anxiety, weakness, restlessness, ment). At high doses, the drugs cause hypnosis, fol- nausea and vomiting, seizures, delirium, and cardiac lowed by anaesthesia (loss of feeling or sensation), and arrest. Withdrawal is much more severe than that as- finally coma and death. Thus, any degree of depres- sociated with opiates and can result in death. sion of the CNS is possible, depending on the dose. Precautions: As noted previously, barbiturates in- Barbiturates do not raise the pain threshold and have duce the P-450 system and therefore may decrease the no analgesic properties. They may even exacerbate effect of drugs that are metabolized by these hepatic pain. enzymes. Barbiturates increase porphyrin synthesis, Respiratory depression: Barbiturates suppress the and are contraindicated in patients with acute inter- hypoxic and chemoreceptor response to CO2, and over- mittent porphyria. dosage is followed by respiratory depression and Poisoning. Barbiturate poisoning has been a lead- death. ing cause of death among drug overdoses for many Enzyme induction: Barbiturates induce P-450 mi- decades. Severe depression of respiration is coupled crosomal enzymes in the liver. Therefore, chronic with central cardiovascular depression, and results in barbiturate administration diminishes the action of a shock-like condition with shallow, infrequent many drugs that are dependant on P-450 metabolism breathing. Treatment includes artificial respiration (including barbiturates themselves). and purging the stomach of its contents if the drug has been recently taken. Hemodialysis may be nec- Barbiturates are classified according to their du- essary if large quantities have been taken. Alkalini- ration of action: zation of the urine often aids in the elimination of 1. Long-acting (Phenobarbital, Barbital, Barbital- Phenobarbital. Analeptics (Bemegride, Corazole) sodium), which have a duration of action greater than may be useful if respiration is not depressed com- a day; Phenobarbital is useful in the treatment of sei- pletely to restore breathing. zures. 2. Intermediate-acting (Pentobarbital, Cyclobarbi- tal, Secobarbital), which are effective as sedative and hypnotic (but not antianxiety) agents. BENZODIAZEPINES 3. Short-acting (Hexobarbital). Chlordiazepoxide was synthesized in 1957 by 4. Ultra short-acting (Thiopental, Hexenal), which Sternbach. Randall discovered its unique pattern of act within seconds and have a duration of action of actions. With its introduction into clinical medicine in about 30 min, are used in the intravenous induction of 1961, more than 3,000 benzodiazepines have been syn- anaesthesia. thesized, over 120 have been tested for biological ac- Therapeutic uses: tivity, and about 35 are in clinical use in various parts Anaesthesia: Selection of a barbiturate is strongly of the world. They have largely replaced barbiturates influenced by the desired duration of action. The ul- and Meprobamate as sedative-hypnotic agents main- tra-short-acting barbiturates, such as Thiopental, are ly because of remarkably low capacity to produce fa- used intravenously to induce anaesthesia. tal CNS depression. Anticonvulsant: Phenobarbital is used in long- Although the benzodiazepines exert qualitatively term management of tonic-clonic seizures, status ep- similar effects, important quantitative differences in ilepticus, and eclampsia. Phenobarbital has been re- their pharmacodynamic spectra and pharmacokinetic garded as the drug of choice for treatment of young properties have led to varying patterns of therapeutic children with recurrent febrile seizures. However, application. Benzodiazepines vary in the degrees of Phenobarbital can depress cognitive performance in sedative-hypnotic, muscle relaxant, anxiolytic, and children, and the drug should be used cautiously. anticonvulsant effects. Phenobarbital has specific anticonvulsant activity Mechanism of action. Binding of GABA to its re- that is distinguished from the nonspecific CNS de- ceptor on the cell membrane triggers an opening of a pression. chloride channel, which leads to an increase in chlo- Sedation-hypnosis: Barbiturates have been used as ride conductance (Fig. 7). mild sedative to relieve nervous tension, and insomnia. The influx of chloride ions causes a small hyper- Most have been replaced by benzodiazepines. polarization that moves the postsynaptic potential Pharmacokinetics. Barbiturates are absorbed oral- away from its firing threshold and thus inhibits the for- ly and distributed widely throughout the body. All bar- mation of action potentials. Benzodiazepines bind to biturates redistribute from the brain to the splanchnic specific, high affinity sites on the cell membrane, areas, to skeletal muscle, adipose tissue. This move- which are separate from but adjacent to the receptor ment is important in causing the short duration of ac- of GABA. The benzodiazepine receptors are found tion of thiopental. Barbiturates are metabolized in the only in the CNS, and their location parallels that of liver, and inactive metabolites are excreted in the urine. GABA neurons. The binding of benzodiazepines en- Adverse effects: hances the affinity of GABA receptors for its neuro- CNS: Barbiturates cause drowsiness, impaired con- transmitter, resulting in a more frequent opening of centration, and mental and physical slugginess. adjacent chloride channels. This in turn results in en- Drug hangover: Hypnotic doses of barbiturates hanced hyperpolarization and further inhibition of produces feeling of tiredness well after the patient neuronal firing.

56 Benzodiazepine GABA Cl-

– – – – –⇓ ⇓ – – –

cell membrane

+ + + + + + +

Cl-

Benzodiazepine GABA Chloride ion receptor receptor channel

Fig. 7. Mode of action of benzodiazepines

Actions. The benzodiazepines are not general neu- who have difficulty in going to sleep. Tolerance fre- ronal depressants, as are the barbiturates. All the ben- quently develops within a few days, and withdrawal of zodiazepines have quite similar pharmacological pro- the drug often results in rebound insomnia, leading the files. The most prominent of these effects are sedation, patient to demand another prescription. Therefore, this hypnosis, decreased anxiety, muscle relaxation, anter- drug is best used intermittently rather than daily. In ograde amnesia, and anticonvulsant activity. Never- general, hypnotics should be given for only a limited theless, the drugs differ in selectivity, and the clinical time, usually less than 2 to 4 weeks. usefulness of individual benzodiazepines varies con- Pharmacokinetics. The benzodiazepines are li- siderably. pophilic and are rapidly and completely absorbed af- Uses in sleep disorders. This lecture describes the ter oral administration and are distributed throughout benzodiazepines used primarily as hypnotic and anti- the body. The half-lives of the benzodiazepines are convulsant agents. Other applications will be discussed very important clinically, since the duration of action in details in a following lecture (see tranquilizers). Not may determine the therapeutic usefulness. The benzo- all of the benzodiazepines are useful as hypnotic diazepines can be roughly divided into short-, inter- agents, although all have sedative or calming effects. mediate- and long-acting groups. The long-acting The three most commonly prescribed benzodiazepines agents form active metabolites with long half-lives. for sleep disorders are long-acting Flurazepam, inter- Most benzodiazepines, including Chlordiazepoxide mediate-acting Temazepam, and short-acting Tria- and Diazepam, are metabolized by the hepatic micro- zolam. The principal factors that determine selection somal metabolizing system to compounds that are also are pharmacokinetics. active. For these benzodiazepines, the apparent half- life of the drug represents the combined actions of the Flurazepam parent drug and its metabolites. The benzodiazepines are excreted in urine as glucuronides or oxidized me- This long-acting benzodiazepine significantly re- tabolites. duces both sleep-induction time and the number of Dependence. Psychological and physical depend- awakening, and increases the duration of sleep. With ence on benzodiazepines can develop if high doses of continued use, the drug has been shown to maintain the drug are given over a prolonged period. Abrupt dis- its effectiveness for up to 4 weeks. Flurazepam has a continuation of the benzodiazepines results in with- half-life of approximately 85 hours, which may result drawal symptoms, including confusion, anxiety, agi- in daytime sedation and accumulation of drug. tation, restlessness, insomnia, and tension. Because of the long half-lives of some of the benzodiazepines, Temazepam withdrawal symptoms may not occur until a number This drug is useful in patients who experience fre- of days after discontinuation. Benzodiazepines with a quent awakening. However, the peak sedative effect short elimination half-life, such as Triazolam, induce occurs two to three hours after an oral dose, and there- more abrupt and severe withdrawal reactions. fore it may be given several hours before bedtime. Adverse Effects. Drowsiness and confusion are the two most common side effect of the benzo-di- Triazolam azepines. Ataxia occurs at high doses and precludes activities that require motor coordination, such as This benzodiazepine has a relatively short dura- driving an automobile. Cognitive impairment (de- tion of action and is therefore used to induce sleep in creased long-term recall and acquisition of new patients with recurring insomnia. Whereas Temazepam knowledge) can occur. Triazolam, the benzodi- is useful for insomnia caused by the inability to stay azepine with most rapid elimination, often show a asleep, Triazolam is effective in treating individuals rapid development of tolerance, early morning in- 57 somnia and daytime anxiety, along with amnesia Etiology. The neuronal discharge in epilepsy re- and confusion. Benzodiazepines potentiate alcohol sults from the firing of a small population of neurons and other CNS depressants. However, they are con- in some specific area of the brain, referred to as the siderably less dangerous than other anxiolytic and primary focus. These focal areas may be triggered into hypnotic drugs. As a result, a drug overdose is sel- activity by changes in any of a variety of environmen- dom lethal, unless other central depressants, such as tal factors, including alteration in blood gases, pH, alcohol, are taken concurrently. electrolytes, or glucose availability. Benzodiazepine antagonists. Flumazenil is a GABA receptor antagonist that can rapidly reverse the Classification of epilepsy: effects of benzodiazepines. The drug is available by Primary epilepsy: When no specific anatomic cause i.v. administration only. Onset is rapid but duration for the seizure, such as trauma or neoplasm, is evident is short, with a half-life of about one hour. Frequent the syndrome called primary epilepsy. These seizures administration may be necessary to maintain reversal may be produced by an inherited abnormality in the of benzodiazepines. CNS. Patients are treated chronically with antiepileptic drugs, often for life. Secondary epilepsy: A number of reversible distur- OTHER HYPNOTIC AGENTS bances, such as tumors, head injury, hypoglycemia, Although the hypnotic Zopiclone (Imovan) is not meningeal infection, or rapid withdrawal of alcohol a benzodiazepine, it acts on a subset of the benzodi- can precipitate seizures. Antiepileptic drugs are given azepine receptor family. Zopiclone has no anticonvul- until the primary cause can be corrected. sive or muscle relaxing properties. It shows no with- Seizures have been classified into two broad drawal effects, exhibits minimal rebound insomnia and groups, partial (or focal), and generalized (Fig. 8). little or no tolerance occurs with prolonged use. Zopi- Choice of drug treatment is based on the classification. clone has a rapid onset of action and short elimina- Partial: The symptoms of each seizure type depend tion. Although zopiclone potentially has advantage on the site of neuronal discharge and on the extent to over the benzodiazepines, clinical experience with the which the electrical activity spreads to other neurons drug is still limited. in brain. Partial seizures may progress, becoming gen- Chloral hydrate is a trichlorinated derivative of eralized tonic-clonic seizures. acetaldehyde that is converted to trichloroethanol in Simple partial. These seizures are caused by a the body. The drug is an effective sedative and hyp- group of hyperactive neurons and are confined to a sin- notic that induces sleep in about 30 minutes and lasts gle locus in the brain; the abnormal activity does not about 6 hours. Chloral hydrate is irritating to the gas- spread. The patient does not lose consciousness and trointestinal tract and causes epigastric distress. It also often exhibits abnormal activity of a single limb or produces an unusual, unpleasant taste sensation. muscle group that is controlled by the region the brain experiencing the disturbance. The patient may also Available forms: show sensory distortions. Simple partial seizures may Thiopental-sodium — in bottles 0.5; 1.0 each (to occur at any age. dilute in 20 ml of physiological solution) Complex partial. These seizures exhibit complex Midazolam — in ampoules 0.5% solution 3 ml sensory hallucinations, mental distortion, and loss of consciousness. Motor dysfunction may involve chewing movements, diarrhea, urination. Most (80%) of individuals experience their initial seizures before 20 years of age. Lecture 12 Generalized: These seizures begin locally, but they rapidly spread, producing abnormal electrical dis- ANTICONVULSANTS charge throughout both hemispheres of the brain. Gen- eralized seizures may be convulsive or nonconvulsive; ANTIEPILEPTIC DRUGS the patient usually has an immediate loss of consciousness. Epilepsy is widespread among the general popula- Tonic-clonic (grand mal). This is the most com- tion. Epilepsy is not a single entity; it is a family of monly encountered and the most dramatic form of ep- different recurrent seizure disorders that have in com- ilepsy. Seizures result in loss of consciousness, fol- mon the sudden and excessive discharge of cerebral lowed by tonic, then clonic phases. The seizure is fol- neurons. This results in abnormal movements or per- ceptions that are of short duration but that tend to recur. The site of electrical discharge determines the  symptoms that are produced. E.g. epileptic seizures Partial Simple Tonic-clonic may cause convulsions if the motor cortex is involved. (focal) Complex (grand mal) The seizures may include visual, auditory, or olfacto- Absence (petit mal) ry hallucinations if the parietal or occipital cortex Generalized plays a role. Drug therapy is the most widely effective  Myoclonic mode of treatment for epilepsy. Seizures can be con- Febrile seizures trolled completely in approximately 50% of epileptic in children patients, and meaningful improvement may be achi-  Status Epilepticus eved in at least one half of the remaining patients. Fig. 8. Classification of epilepsy

58 lowed by a postictal period of confusion and exhaus- Actions. Diphenin is not a generalized CNS de- tion. pressant like the barbiturates, but it does produce some Absence (petit mal). These seizures involve a degree of drowsiness and lethargy. Diphenin reduces brief, abrupt, and self-limiting loss of consciousness. the propagation of abnormal impulses in the brain. The onset occurs in patients at the age of 3 to 5 Therapeutic uses. Diphenin is highly effective for all years and lasts until puberty. The patient stares and partial seizures (simple and complex), for tonic-clon- exhibits rapid eye blinking, which lasts for 3 to 5 ic seizures, and in status epilepticus. Diphenin is not seconds. effective for absence seizures, which often may wors- Myoclonic. These seizures consist of short episodes en if such a patient is treated with this drug. of muscle contractions that may reoccur for several minutes. Myoclonic seizures are rare, occur at any Carbamazepine age, and are often a result of hypoxia, uremia, encephalitis, or drug poisoning. Action. Carbamazepine reduces the propagation of Febrile seizures. Young children (3 month to 5 years abnormal impulses in the brain by blocking sodium of age) frequently develop seizures with illness accom- channels, thereby inhibiting the generation of repeti- panied by high fever. The febrile consist of general- tive action potentials in the epileptic focus. ized tonic-clonic convulsions of short duration. Al- Therapeutic uses. Carbamazepine is highly effective though febrile seizures may be frighten-ing, they are for all partial seizures and is often the drug of first benign and do not cause death, neurologic damage, choice. In addition the drug is highly effective for ton- injury, or learning disorders, and they rarely require ic-clonic seizures and is used to treat trigeminal neuralgia. It has occasionally been used in manic-depres- medication. sive patients to ameliorate the symptoms. Status Epilepticus. Seizures are rapidly recurrent. Mechanism of action. Drugs that are effective in seizure reduction can either block the initiation of the Phenobarbital electrical discharge from the focal area or, more com- Phenobarbital provides a 50% favorable response monly, prevent the spread of the abnormal electrical rate for simple partial seizures, but it is not very effec- discharge to adjacent brain areas. tive for complex partial seizures. The drug has been Initial drug treatment is based on the specific type regarded as the first choice in treating recurrent sei- of seizures (Fig. 9). Thus, tonic-clonic (grand mal) seizures in children, including febrile seizures. The drug zures are treated differently than absence (petit mal). is also used to treat tonic-clonic seizures, especially Several drugs may be equally effective, and the toxici- in patients who do not respond to Diazepam plus ty of the agent is often a major consideration in drug Diphenin. Doses required for antiepileptic action are selection. lower than those that cause pronounced CNS depres- Diphenin (Phenytoin) is effective in suppressing sion. Phenobarbital is also used as a mild sedative to tonic-clonic and partial seizures, and is a drug of relieve anxiety, nervous tension and insomnia, al- choice for initial therapy, particularly in treating though benzodiazepines are superior. adults. Hexamidine (Primidone) is structurally related to Mechanism of action. Diphenin stabilizes neuron- phenobarbital, and resembles Phenobarbital in its anal membranes to depolarization by decreasing the flux ticonvulsive activity. Hexamidine is an alternative of sodium ions in neurons in the resting state or dur- choice in partial seizures and tonic-clonic seizures. ing depolarization and suppresses repetitive firing of Much of Hexamidin’s efficacy comes from its metab- neurons. olites Phenobarbital and Phenylethylmalonamide.

Partial Anticonvulsant agent

simple Diphenin Carbamazepine Phenobarbital Hexamidine complex Diphenin Carbamazepine Hexamidine

Generalized tonic-clonic Diphenin Carbamazepine Phenobarbital Hexamidine Valproic acid absence Ethosuximide Clonazepam Valproic acid myoclonic Valproic acid Clonazepam febrile seizures in children Phenobarbital Hexamidine status epilepticus Diphenin Diazepam Phenobarbital

Key: Preferred drug Alternative drug

Fig. 9. Choice of antiepileptic drug

59 Valproic acid is the most effective agent available vascular lesions. Drugs such as Phenothiazines and for treatment myoclonic seizures. The drug diminish- Haloperidol, whose major pharmacologic action is es absence seizures but is a second choice because of blockade of dopamine receptors in the brain, may also its hepatotoxic potential. Valproic acid also reduces produce parkinsonian symptoms. These drugs should the incidence and severity of tonic-clonic seizures. not be used in parkinsonian patients. Ethosuximide reduces propagation of abnormal Strategy of treatment. In addition to an abundance electrical activity in the brain, and is the first choice of inhibitory dopaminergic neurons, the neostriatum is in absence seizures. also rich in excitatory cholinergic neurons that oppose Several of the benzodiazepines show antiepilep- the action of Dopamine. Many of the symptoms reflect tic activity. Clonazepam and Сlorazepate are used for an imbalance between the excitatory cholinergic neu- chronic treatment, whereas Diazepam is the drug of rons and the greatly diminished number of inhibitory choice in the acute treatment of status epilepticus. Of dopaminergic neurons. Therapy is aimed at restoring all the anti-epileptics, the benzodiazepines are the Dopamine in the basal ganglia and antagonizing the safest. excitatory effect of cholinergic neurons, thus reestablishing the correct Dopamine/Acetylcholine balance. Currently available drugs offer temporary relief DRUGS USED IN PARKINSON’S from the symptoms of the disorder, but do not arrest DISEASE or reverse the neuronal degeneration caused by the disease. Parkinsonism is a progressive neurologic disorder of muscle movement, characterized by tremors, muscular rigidity, and bradykinesia (slowness in initiat- Levodopa ing and carrying out voluntary movements). Parkin- Levodopa is a metabolic precursor of Dopamine. It son’s disease is the fourth most common neurologic dis- restores dopamine level in the extrapyramidal centers order among the elderly. Most cases involve people (substantia nigra) that atrophy in parkinsonism. In pa- over the age of 65 among whom the incidence is about tients with early disease, the number of residual 1:100 individuals. dopaminergic neurons (about 20% of normal) is ade- Etiology. The cause of Parkinson’s disease is un- quate for conversion of Levodopa to Dopamine. Levo- known for most patients. The disease is correlated with dopa decreases the rigidity, tremor, and other symptoms a reduction in the activity of inhibitory dopaminergic of parkinsonism. Unfortunately, with time the number neurons in the substantia nigra and corpus striatum — of neurons decreases and the drug effects “wear off”. parts of the brain’s basal ganglia system that are re- Dopamine itself does not cross the blood-brain sponsible for motor control. Genetic factors do not barrier, but its immediate precursor Levodopa is play a dominant role in the etiology. readily transported into the CNS and is converted to Substantia nigra. The substantia nigra, part of the Dopamine in the brain. Large doses of Levodopa are extrapyramidal system, is the source of dopaminergic required because much of the drug is decarboxylated neurons that terminate in the striatum. Each neuron to Dopamine in the periphery, resulting in peripher- makes thousands synaptic contacts within the striatum al side effects (nausea, vomiting, cardiac arrhythmi- and modulates the activity of a large number of cells. as, hypotension). These dopaminergic projections from the substantia The effects of Levodopa on the CNS can be great- nigra fire tonically, rather than in response to specific ly enhanced by coadministration Carbidopa, a muscular movements or sensory input. Thus, dopamin- Dopamine decarboxylase inhibitor that does not cross ergic system appears to serve as a tonic, sustaining in- the blood-brain barrier. Carbidopa diminishes the me- fluence on motor activity, rather than participating on tabolism of Levodopa in the GI tract and peripheral tissues. The addition of Carbidopa lowers the dose of specific movements. Levodopa needed by 4- to 5-fold and, consequently, Striatum. Normally, the striatum is connected to decreases the severity of the side effects of peripheral- the substantia nigra by neurons that secrete the inhib- ly formed dopamine. itory transmitter GABA at their termini in the substantia nigra. In turn, cells of the substantia nigra sends neurons back to the striatum secreting the inhibitory Bromocriptine transmitter dopamine. This mutual inhibitory pathway Bromocriptine, en ergotamine (an alkaloid with va- normally maintains a degree of inhibition of the two soconstrictor action) derivative, is a dopamine receptor separate areas. Nerve fibers from the cerebral cortex agonist. The drug produces little response in patients and thalamus secrete acetylcholine in the neostriatum, who does not react to Levodopa, but it is often used with causing excitatory effects that initiate and regulate Levodopa in patients responding to drug therapy. gross intentional movements of the body. In Parkin- It was accidentally discovered that the antiviral son’s disease, destruction of cells in the substantia ni- drug, Amantadine, effective in the treatment of influ- gra results in the degeneration of neurons responsible enza, has Antiparkinsonian action. It appears to en- for secreting dopamine in the neostriatum. Thus the hance the synthesis, release, or reuptake of Dopamine normal modulating inhibitory influence of dopamine from the surviving neurons. Amantadine is less effica- on the neostriatum is significantly diminished, result- cious than Levodopa, but it has fewer side effects. The ing in the parkinsonian degeneration of the control of drug has little effect on tremor but is more effective than muscle movement. the Anticholinergics against rigidity and bradykinesia. Secondary parkinsonism. Parkinsonian symptoms The antimuscarinic agents (Cyclodol, Noracin etc.) infrequently follow viral encephalitis or multiple small are much less efficacious than Levodopa and play only

60 adjuvant role in the antiparkinsonian therapy. Block- for tissue repair. However, inflammation is sometimes age of the cholinergic transmission produces similar inappropriately triggered by an innocuous agent, such to augmentation of dopaminergic transmission (again, as pollen, or by an autoimmune response, as in asth- because of the creation of an imbalance in the ma or rheumatoid arthritis. In such cases, the defense Dopamine/Acetylcholine ratio). All these drugs can in- reactions themselves may cause injury, and anti-induce mood changes and produce xerostomia (dryness flammatory drugs may be required to modulate the of the mouth) and visual problems, as do all muscarinic inflammatory process. Inflammation is triggered by blockers. They interfere with gastrointestinal peristal- the release of chemical mediators from injured tissues tic, may cause urinary retention and increase in in- and migrating cells. The specific mediators vary with traocular pressure. the type of inflammation and include amines, such as histamine and 5-hydroxytryptamine; lipids, such as Available forms: prostaglandins; small peptides, such as bradykinin; Phenobarbital — powder; tablets 0.005 each (for and larger peptides, such as interleukin-1. Discovery children) and 0.05; 0.1 (for adults) of the wide variation among chemical mediators has Phenytoin (Dipheninum) — in patented tablets clarified the apparent paradox that an anti-inflam- Carbamazepine — in tablets 0.2 each matory drugs may interfere with the action of a par- Valproate sodium (Acediprolum) — in tablets 0.3 ticular mediator important in one type of inflamma- each tion but be without effect in process not involving the Clonazepam — in tablets 0.001 each drug’s target mediator. Diazepam (Sibazonum) — in tablets 0.005 (for Prostaglandins. Many of the NSAIDs act by inhib- adult) and 0.001 (for children) each; in ampoules 0.5% iting the synthesis of prostaglandins. Thus, an under- solution 2 ml each standing of NSAIDs requires a comprehension of the Baclofen — in tablets 0.01 or 0.025 each actions and biosynthesis of prostaglandins — unsatu- Levodopa — in tablets and capsules 0.25; 0.5 each rated fatty acid derivatives containing 20 carbons that Nakom (composition of Levodopa with Carbidopa) include a cyclic ring structure. [Note: These com- — in patented tablets pounds are sometimes referred to as eicosanoids; “ei- Cyclodolum — in tablets 0.001; 0.002 or 0.005 each cosa” refers to the 20 carbon atoms.] Role of prostaglandins. Prostaglandins and related compounds are produced in minute quantities by virtually all tissues. They generally act locally on the tissues in which they are synthesized, and are rapid- Lecture 13 ly metabolized to inactive products. Therefore, the NONSTEROIDAL ANTI- prostaglandins do not circulate in the blood in significant concentration. Thromboxanes, leukotrienes, INFLAMMATORY DRUGS and the hydroperoxyeicosateraenoic and hydroxyeicosatetraenoic acids (HPETEs and HETEs) are related lipid, synthesized from the same precursors as In this lecture drugs that are anti-inflammatory, are the prostaglandins, using interrelated pathways. analgesics, and antipyretics will be considered; their Synthesis of prostaglandins. Arachidonic acid, a mechanism of action differ from those of the anti-in- 20-carbon fatty acid, is the primary precursor of the flammatory steroids and opioid analgesics. The anti- prostaglandins. Arachidonic acid is present as a com- inflammatory, analgesic, and antipyretic drugs are a ponent of the phospholipids of cell membranes. Free heterogeneous group of compounds, often chemically arachidonic acid is released from tissue phospholipids unrelated (although most of them are organic acids), by the action of phospholipase A2. There are two ma- which share certain therapeutic actions and side ef- jor pathways in the synthesis of the eicosanoids from fects. The prototype is aspirin; hence these compounds arachidonic acid (Fig. 10). are often referred to as aspirin-like drugs. They are Cyclooxygenase pathway. All eicosanoids with also frequently designated as nonsteroidal anti-inflam- ring structures, that is, the prostaglandins, thrombox- matory drugs (NSAIDs). anes, and prostacyclins, are synthesized via the cy- The medicinal effect of the bark of willow has been clooxygenase pathway. Two cyclooxygenases have known to several cultures for centuries. The active in- been identified: COX-1 and COX-2. The former is ubiq- gredient in the willow bark (called salicin) was first iso- uitous and constitutive, whereas the latter is induced lated in a pure form in 1829 by Leroux. The latter com- in response to inflammatory stimuli. pound can be converted into salicylic acid. Sodium Lipoxygenase pathway. Alternatively, several salicylate was first used for the treatment of rheuma- lipoxygenases can act on arachidonic acid to form toid fever and as an antipyretic in 1875. The enormous 5-HPETE, 12-HPETE and 15-HPETE, which are success of this drug prompted Hoffman, a chemist em- unstable peroxidated derivatives that are converted ployed by Bayer, to prepare acetylsalicylic acid. This to the corresponding hydroxylated derivatives compound was introduced into medicine in 1899 by (HEPEs), or to leukotrienes or lipoxins, depending Dresser under the name of Aspirin. on the tissue. Inflammation. Inflammation is a normal, protective Function in the body. Prostaglandins act as local response to tissue injury caused by physical trauma, signals that fine-tune the response of a specific cell noxious chemicals, or microbiologic agents. Inflam- type. Their functions vary widely depending on the tis- mation is the body’s effort to inactivate or destroy in- sue. For example, the release of TXA2 from platelets vading organisms, remove irritants, and set the stage triggers the recruitment of new platelets for aggrega-

61 Phospholipids (forms cell membrane) Corticosteroids + bradykinin –  angiotensin

Phospholipase A2

Arachidonic acid Cyclooxygenase – NSAIDs

5-Lipoxygenase PGG2

Prostacyclin (PGI2) Hydroperoxidase

5-HPETE PGE2 PGH2 PGF2α – Thromboxane A2 Leukotrienes Dipyridamole

Fig. 10. Mechanism of action of nonsteroidal anti-inflammatory drugs tion (the first step in clot formation). However, in oth- Mechanism of action. The antipyretic and anti-in- er tissues, elevated levels of TXA2 convey a different flammatory effects of the salicylates are due primarily signals; e.g. in certain smooth muscle, this compound to the blockade of prostaglandin synthesis at the ther- induces contraction. Prostaglandins are one of the moregulatory centers in the hypothalamus and at the chemical mediators that are released in allergic and peripheral target sites. By decreasing prostaglandin syn- inflammatory processes. thesis, the salicylates also prevent the sensitization of pain receptors to both mechanical and chemical stimuli. Aspirin may also depress pain stimuli at subcortical NONSTEROIDAL ANTI- sites (that is, the thalamus and hypothalamus). INFLAMMATORY DRUGS Actions. The NSAIDs have three major therapeutic actions, namely they reduce inflammation (anti-in- NSAIDs are group of chemically dissimilar agents flammatory), pain (analgesia), and fever (antipyresis). that differ in their antipyretic, analgesic and anti-in- However, not all of the NSAIDs are equally potent in flammatory activities. They act primarily by inhibit- each of these actions. ing the cyclooxygenase enzymes but not the lipoxyge- Anti-inflammatory action: Aspirin modulates those nase enzymes. Aspirin is the prototype of this group; aspects of inflammation in which prostaglandins act it is the most commonly used and the drug to which all as mediators. Aspirin inhibits inflammation in arthri- other anti-inflammatory agents are compared. Some of tis, but it neither arrest the progress of the disease nor the newer NSAIDs are marginally superior to aspirin does it induce remission. in certain patients, because they have greater anti-in- Analgesic action: Prostaglandin E is thought to flammatory activity and/or cause less gastric irritation, 2 sensitize nerve endings to the action of bradykinin, his- or can be taken less frequently. However, the newer tamine, and other chemicals mediators released local- NSAIDs are considerably more expensive than aspi- ly by the inflammatory process. Thus, by decreasing rin, and some have proved to be more toxic in other PGE synthesis, aspirin and other NSAIDs repress the ways. 2 sensation of pain. The salicylates are used mainly for the management of pain of low to moderate intensity ASPIRIN AND OTHER SALICYLATES arising from integumental structures rather than that arising from the viscera. NSAIDs are superior to opi- Aspirin is a weak organic acid that is unique among oids in the management of pain in which inflamma- the NSAIDs in irreversibly acetylating (and thus inac- tion is involved; combination of opioids and NSAIDs tivating) cyclooxygenase. The other NSAIDs, includ- are effective in treating pain in malignancy. ing salicylate, are all reversible inhibitors of cycloox- Antipyretic action: Fever occurs when the set-point ygenase. Aspirin is rapidly deacetylated by esterases of the anterior hypothalamic thermoregulatory center in the body, producing salicylate, which has anti-in- is elevated. This can be caused by PGE2 synthesis, stim- flammatory, antipyretic, and analgesic effects. ulated when an endogenous fever-producing agents 62 (pyrogen) such as a cytokine is released from white Therapeutic uses: cells that are activated by infection, hypersensitivity, Antipyretics and analgesics: Sodium salicylate and malignancy, or inflammation. The salicylates lower aspirin are used as antipyretics and analgesics in the body temperature in patients with fever by impeding treatment of gout, rheumatic fever, and rheumatoid ar- PGE2 synthesis. Aspirin resets the “thermostat” to- thritis. Commonly treated conditions requiring anal- wards normal and lowers the body temperature by in- gesia include headache, arthralgia, and myalgia. creasing heat dissipation as a result of peripheral va- External applications: Salicylic acid is used topi- sodilation and sweating. Aspirin has no effect on nor- cally to treat corns, calluses, and epidermophytosis mal body temperature. (eruption caused by fungi). Methyl salicylate is used Gastrointestinal effects: Normally, prostacyclin externally as a cutaneous counterirritant in liniments. (PGI2) inhibits gastric acid secretion, whereas PGE2 Cardiovascular applications: Aspirin inhibits plate- and PGF2α stimulate synthesis of protective mucus in let aggregation. Low doses are used prophylactically both the stomach and small intestine. In presence of to decrease the incidence of transient ischemic attack Aspirin, these prostanoids are not formed, resulting and unstable angina as well as that of coronary artery in increased gastric acid secretion and diminished mu- thrombosis. cous protection. This may cause epigastric distress, Colon cancer: There is evidence that chronic use ulceration, and/or hemorrhage. At ordinary aspirin of Aspirin reduces the incidence of colorectal cancer. doses, as much as 3 to 8 ml of blood may be lost in Pharmacokinetics. Salicylates, especially methyl feces per day. [Note: Buffered and enteric-coated salicylate, are absorbed through intact skin. After oral preparations are only marginally helpful in dealing administration, the unionized salicylates are passive- with this problem. The PGE1 derivative, Misopros- ly absorbed from the stomach and small intestine. Rec- tol, is used in the treatment of gastric damage induced tal absorption is slow and unreliable, but it is a useful by NSAIDs.] route to vomiting children. Salicylates cross both the Effect on platelets: TXA2 enhances platelet aggre- blood-brain barrier and placenta. gation, whereas PGI2 decreases it. Low doses (60 to The salicylates exhibit analgesic activity at low 80 mg daily) of Aspirin can irreversibly inhibit throm- doses (Fig. 11); only at higher doses these drugs show boxane production platelets without markedly affect- anti-inflammatory activity. E.g. two 300 mg Aspirin ing PGI2 production in the endothelial cells of the tablets administered 4 times a day produce analgesia, blood vessel. [Note: The acetylation of cyclooxygen- whereas 12 to 20 tablets per day produce both analge- ase is irreversible. Because platelets lack nuclei, they sic and anti-inflammatory activity. Low doses of As- cannot synthesize new enzyme, and the lack of throm- pirin (160 mg every other day) have been shown to re- boxane persist for the lifetime of the platelet (3 to 7 duce the incidence of recurrent myocardial infarction days). This contrasts with endothelial cells, which have and to reduce mortality in postmyocardial infarction nuclei and therefore can produce new cyclooxygenase.] patients. Further, Aspirin 160 to 325 mg/day appears Action on the kidney: Cyclooxygenase inhibitors to be beneficial in the prevention of a first myocardial prevent the synthesis of PGE2 and PGI2 — prostag- infarction, at least in men over the age of 50 years. landins that are responsible for maintaining renal Thus, prophylactic Aspirin therapy is advocated in pa- blood flow. Decreased synthesis of prostaglandins can tients with clinical manifestations of coronary disease result in intrarenal vasoconstriction, retention of sodi- if no specific contraindications are present. um and water in some patients. Interstitial nephritis At normal low doses (600 mg/day), aspirin is hy- can also occur with all of the NSAIDs except Aspirin. drolyzed to salicylate and acetic acid by esterases

Vasomotor collapse Coma 150 lethal Dehydration  severe  intoxication 100 mild 

Tinnitus 50  Central hyper-ventilation  anti-inflammatory  10  analgesic, antipyretic Gastric bleeding Plasma concentration of salicylate (mg/dL)  Impaired blood clotting 0  antiplatelet

Fig. 11. Dose-dependent effects of Aspirin

63 present in tissues and blood. Salicylate is converted by elimination of salicylates. In serious cases, mandato- the liver to water-soluble conjugates that are rapidly ry measures include the intravenous administration of cleared by the kidney, resulting in elimination with fluid, dialysis, and correction of acid-base and elec- first-order kinetics and a serum half-life of 3.5 hours. trolyte balances. At anti-inflammatory dosages (>4 g/day), the hepatic metabolic pathway becomes saturated, and zero-order kinetics are observed, with the drug having a half-life PROPIONIC ACID DERIVATIVES of 15 hours or more. Saturation of the hepatic enzymes requires treatment for several days to 1 week. Being Ibuprofen was first in this class of agents to become an organic acid, salicylate is secreted into the urine available. It has been joined by Naproxen, Ketopro- and can affect uric acid secretion. At low doses of as- fen, Flurbiprofen, and others. All of these drugs pos- pirin, uric acid secretion is decreased; at high doses, it sess anti-inflammatory, analgesic and antipyretic ac- is increased. [Note: Alkalinization of the urine pro- tivity and have gained wide acceptance in the chronic motes excretion.] treatment of rheumatoid and osteoarthritis because Adverse effects: their GI effects are generally less intense than that of GI. The most common GI effects of the salicylates Aspirin. These drugs are reversible inhibitors of the are epigastric distress, nausea, and vomiting. Micro- cyclooxygenase and thus, like Aspirin, inhibit the syn- scopic GI bleeding is almost universal in patients thesis of prostaglandins but not that of leukotrienes. treated with salicylates. [Note: Aspirin is an acid. At All are well absorbed on oral administration and are stomach pH, Aspirin is uncharged; consequently it almost totally bound to serum albumin. They undergo readily crosses into the mucosal cells where it ioniz- hepatic metabolism and are excreted by the kidney. es and becomes trapped. Aspirin should be taken with The most common adverse effect is gastrointestinal, food and large volumes of fluids to diminish GI dis- ranging from dyspepsia to bleeding. Side effects involv- turbances. Alternatively, Misoprostol may be taken ing the CNS, such as headache, tinnitus and dizziness, concurrently. have also been reported. Blood. The irreversible acetylation of platelet cyclooxygenase reduces the level of platelet TXA2, resulting in inhibition of platelet aggregation and pro- INDOLEACETIC ACIDS longed bleeding time. For this reason Aspirin should not be taken at least 1 week prior to surgery. This group includes Indomethacin, Sulindac and Respiration. In toxic doses, salicylates cause res- Etodolac. All have anti-inflammatory, analgesic and piratory depression and a combination of uncompen- antipyretic activity. They act by reversibly inhibiting sated respiratory and metabolic acidosis. cyclooxygenase. They are generally not used to lower Metabolic processes. Large doses of salicylates un- fever. couple oxidative phosphorylation. The energy normal- Indomethacin. This NSAID is more potent than ly used for the production of ATP is dissipated as heat, Aspirin as an anti-inflammatory agent, but it is infe- which explains the hyperthermia caused by salicylates rior to the salicylates at doses tolerated by rheuma- when taken in toxic quantities. toid arthritic patients. In certain instances (acute Hypersensitivity. Approximately 15% of patients gouty arthritis, ankylosing spondylitis, and osteoar- taking Aspirin experience hypersensitivity reactions. thritis of the hip) Indomethacin is more effective than Symptoms of true allergy include urticaria, bronchoc- Aspirin is or any of the other NSAIDs. It is also ef- onstriction, or angioneurotic edema. Fatal anaphylac- fective in treating patent ductus arteriosus. Like As- tic shock is rare. pirin, Indomethacin can delay labor by suppressing Reye’s syndrome. Aspirin given during viral infec- uterine contractions. Indomethacin’s toxicity limits tions has been associated with an increased incidence its use. Adverse effects occur in up to 50% of patients; of Reye’s syndrome, an often fatal, fulminating hepa- approximately 20% find the adverse effects to be in- titis with cerebral edema. This is especially encoun- tolerable and discontinue use of the drug. Most ad- tered in children, who therefore should be given Para- verse effects are dose-related. GI complaints consist cetamol instead of Aspirin. of nausea, vomiting, anorexia, diarrhea, and abdom- Salicylate intoxication may be mild or severe. The inal pain. Ulceration of the upper GI tract can oc- mild form is called salicylism and is characterized by cur, sometimes with perforation and hemorrhage. The nausea, vomiting, marked hyperventilation, headache, most severe and frequent CNS effect is frontal head- mental confusion, dizziness, and tinnitus (ringing or ache, which occurs in 25 to 50% of patients who roaring in the ears). When large doses are adminis- chronically use Indomethacin. Other CNS effects are tered, severe salicylate intoxication may result. The dizziness, vertigo, and mental confusion. Concurrent symptoms listed above are followed by restlessness, de- administration of Indomethacin may decrease the an- lirium, hallucinations, convulsions, coma, respiratory tihypertensive effects of Furosemide, the thiazide di- and metabolic acidosis, and death from respiratory uretics, β-blockers and ACE inhibitors. failure. Children are particularly prone to salicylate Sulindac. This inactive pro-drug is closely related intoxication. Ingestion of as little as 10 g of Aspirin to Indomethacin. Metabolism of hepatic microsomal can cause death in children. Treatment of salicylism enzymes produces the active form (a sulfide) of the should include measurement of serum salicylate con- drug, which has a long duration of action. Although centrations and of pH to determine the best form of the drug is less potent than Indomethacin, it is useful therapy. In mild cases, symptomatic treatment is usu- in the treatment of rheumatoid arthritis, ankylosing ally sufficient. Increasing the urinary pH enhances the spondylitis, osteoarthritis, and acute gout. The adverse

64 reactions are similar to but less severe than those of NON-NARCOTIC ANALGESICS the other NSAIDs, including Indomethacin. Non-narcotic analgesics, unlike the NSAIDs, have little or no anti-inflammatory activity. They have a PYRAZOLON DERIVATIVES therapeutic advantage of narcotic analgesics in that they do not cause physical dependence or tolerance. This group of drugs includes Butadion, Analgin, Paracetamol (Acetaminophen) and Phenacetin act Antipyrine, Amidopyrine. All these drugs have been by inhibiting prostaglandin synthesis in the CNS. in clinical use for many years. Although not a first- This explains their antipyretic and analgesic proper- line drug, Butadion (Phenylbutazone) is the most ties. They have less effects on cyclooxygenase in pe- important from the therapeutic viewpoint. Antipy- ripheral tissues, which accounts for their weak anti- rine and Amidopyrine are seldom used today. Anal- inflammatory activity. Paracetamol and Phenacetin gin (metamizole) is not yet available in certain do not affect platelet function or increase blood clot- countries. ting time, and they lack many of the side-effects of Butadion (Phenylbutazone). Butadion has pow- Aspirin. [Note: Phenacetin can no longer be pre- erful anti-inflammatory effects but weak analgesic scribed in many countries because of its renal toxici- and antipyretic activities. Butadion is prescribed ty. However, it is present in some proprietary prepa- chiefly in short-term therapy when other NSAIDs rations.] have failed. The usefulness of Butadion is limited by Therapeutic uses. Paracetamol is a suitable substi- its toxicity. The most serious adverse effects are tute for the analgesic and antipyretic effects of Aspi- agranulocytosis and aplastic anemia. However, the rin in those patients with gastric complaints and in most common adverse effects are nausea, vomiting, those for whom prolongation of bleeding time would skin rashes, and epigastric discomfort. Other side ef- be a disadvantage or who do not require the anti-infects include fluid and electrolyte retention, diarrhea, flammatory action of Aspirin. Paracetamol is the an- vertigo, insomnia. Butadion reduces the uptake of io- algesic-antipyretic of choice for children with viral in- dine by thyroid gland, sometimes resulting in goiter fections or chicken pox (recall that Aspirin increases and myxedema. Because of all these potential side- the risk of Reye’s syndrome). effects, the drug should be given for short period of Pharmacokinetics. Paracetamol is rapidly absorbed time — up to 1 week only. from the GI tract. A significant first-pass metabolism occurs in the luminal cells of the intestine and in the hepatocytes. Phenacetin is largely converted to Para- OTHER AGENTS cetamol within 3 hours of administration. Under nor- Diclofenac. A cyclooxygenase inhibitor, Di- mal circumstances, paracetamol is conjugated in the clofenac is approved for long-term treatment of rheu- liver to form inactive glucuronidated or sulfated me- matoid arthritis, osteoarthritis and ankylosing tabolites. A portion of paracetamol is hydroxylat- spondilitis. It is more potent than Indomethacin. Di- ed to form N-acetyl-benzoquinoneimine — a highly clofenac accumulates in synovial fluid. The urine is reactive and potentially dangerous metabolite that re- the primary route of excretion. Its toxicities are simi- acts with sulfhydryl groups. At normal doses of Pa- lar to those of the other NSAIDs, e.g. GI problems racetamol, the N-acetyl-benzoquinoneimine reacts are common, and the drug can also give rise to ele- with groups of glutathione, forming a nontoxic sub- vated hepatic enzyme levels. stance. Paracetamol and its metabolites are excreted Mefenamic acid has no advantages over the other in the urine. Adverse effects. With normal therapeutic doses, NSAIDs as anti-inflammatory agent. Its side effects, Paracetamol is virtually free of any significant adverse such as diarrhea, can be severe and associated with in- effects. Skin rash and minor allergic reactions occur flammation of the bowel. Cases of hemolytic anemia infrequently. Renal tubular necrosis and hypoglycemic have been reported. coma are rare complications of prolonged large-dose Piroxicam is one of the oxicam derivatives that therapy. With large doses of Paracetamol, the availa- possesses anti-inflammatory, analgesic, and antipy- ble glutathione in the liver becomes depleted and N- retic activity. In recommended doses, Piroxicam ap- acetyl-benzoquinoneimine reacts with the sulfhydryl pears to be equivalent to Aspirin, Indomethacin, or groups of hepatic proteins, forming covalent bounds. Naproxen for the long-term treatment of rheumatoid Hepatic necrosis, a very serious and potentially life- arthritis or osteoarthritis. It may be tolerated better threatening condition, can result. Renal tubular necro- than Aspirin or Indomethacin. The principal advan- sis may also occur. [Note: Administration of N-ace- tage of Piroxicam is its long half-life (50 hours), tylcysteine, which contains sulfhydryl groups to which which permits the administration of a single daily the toxic metabolite can bind, can be life-saving if ad- dose. GI disturbances are encountered in approxi- ministered within 10 hours of the overdose.] mately 20% of patients. Ketorolac. This drug acts like other NSAIDs. In Available forms: addition to the oral rout, Ketorolac can be adminis- Paracetamol — in tablets 0.2 each tered intramuscularly in the treatment of postoperative Acetylsalicylic acid — in tablets 0.25; 0.5 (for adult) pain, and topically for allergic conjunctivitis. Ketoro- and 0.1 (for children) lac undergoes hepatic metabolism; the drug and its Phenylbutazone (Butadionum) — in tablets 0.15 metabolites are eliminated via the urine. It causes the (for adult) and 0.03; 0.05 (for children); 5% ointment same side effects as the other NSAIDs. 20.0

65 Ortophenum — in tablets 0.025 (for adult) and al, binding potency correlates with analgesia (Fig. 12). 0.015 (for children) each; in ampoules 2.5% solution The analgesic properties of the opioids are primarily 3 ml each by the µ-receptors; however, the k receptors on the dor- Sulindac — in tablets 0.1; 0.2; 0.4 each sal horn also contribute. The enkephalins interact Piroxicam — in tablets 0.01 each; in capsules 0.02 more selectively with the d receptors in the periphery. each The s receptors are less specific (e.g. the σ-receptor also binds nonopioid agents, such as the hallucinogen Phencyclidine). The s receptor may be responsible for the hallucinations and dysphoria sometimes associated with opioids. Lecture 14 Distribution of receptors. High densities of opioid NARCOTIC ANALGESICS receptors are present in five general areas of the CNS known to be involved in integrating information about pain. These pathways descend from the periaqueduct- This lecture presents the pharmacological proper- al gray (PAG) through the dorsal horn of the spinal ties of the opioids (opioid agonists) and the opioid an- cord. They have also been identified in the periphery. tagonists. Opioids are natural or synthetic compounds Brainstem. Opioid receptors mediate respiration, that produce morphine-like effects. The term opiates cough, nausea and vomiting, maintenance of blood is reserved for drugs, such as Morphine and Codeine, pressure, pupillary diameter, and control of stomach obtained from the juice of the opium poppy. All drugs secretions. of this category act by binding to specific opioid re- Medial thalamus. This area mediates deep pain ceptors in the CNS to produce effects that mimic the that is poorly localized and emotionally influenced. action of endogenous peptide neurotransmitters, the Spinal cord. Receptors in substantia gelatinosa are opiates (e.g. endorphins, and enkephalins). Although involved with the receipt and integration of incoming the opioids have a broad range of effects, their prima- sensory information. ry use is to relieve intense pain and the anxiety that Hypothalamus. Receptors here affect neuroendo- accompanies it, whether it be form surgery or as a re- crine secretion. sult of injury or a disease, such as cancer. However, Limbic system. These receptors probably do not ex- their widespread availability has led to abuse of these ert analgesic action, but they may influence emotion- opioids with euphoric properties. Antagonists that can al behavior. reverse the action of opioids are also very important Periphery. Opioids also bind to peripheral senso- clinically in cases of overdose. ry nerve fibers and their terminals. As in the CNS, they Opioid receptors. Opioids interact with protein re- inhibit Ca++-dependent release of excitatory, pro-in- ceptors on the membranes of certain cells in the CNS, flammatory substances (e.g. substance P) from these on nerve terminals on the periphery, and on cells of nerve endings. the GI tract. The major effects of the opioids are me- Immune cells. The role of these receptors has not diated by 4 families of receptors, designated by the been determined. Greek letters, µ, κ, σ and δ, each of which exhibits a Opioids are classified according to its affinity for different specificity for the drug(s) it binds. In gener- opioid receptors (Fig. 13).

κ Mainly agonist action at µ-receptors, Agonist action at receptors, with µ but some action on other receptors partial antagonist action at -receptors — Morphine — Pentazocine — Heroin — Codeine — Fentanyl

+ – + +

µ κ σ supraspinal analgesia spinal analgesia dysphoria respiratory depression sedation/dysphoria hallucinations euphoria/sedation pupil construction pupil dilation physical dependence decreased GI motility pupil construction

Fig. 12. Opioid receptors and effects of drugs

66 Strong Moderate Mixed agonists: agonists: agonist-antagonists: Antagonists: Morphine Codeine Buprenorphine Naloxone Promedolum Propoxyphene Pentazocine Naltrexone Methadone Fentanyl Heroin Fig. 13. Classification of opioids according to its affinity for opioid receptors

STRONG AGONISTS Emesis. Morphine directly stimulates the chemoreceptor trigger zone in the area postrema that causes Morphine is the major analgesic drug contained in vomiting. However, the emesis does not produce un- crude opium and is the prototype agonist. Codeine is pleasant sensation. present in lower concentrations and is inherently less GI tract. Morphine relieves diarrhea. It decreas- potent. These drugs show a high affinity for µ-recep- es motility of smooth muscle and increases tone. It tors, varying affinities for δ- and κ-receptors, and low increases pressure in the biliary tract. Morphine affinity for σ-receptors. also increases tone of the anal sphincter. Overall, Morphine produces constipation, with little toler- Morphine ance developing. Cardiovascular. Morphine has no major effect on the Mechanism of action. Opioids exert their major ef- blood pressure or heart rate except at large doses, when fects by interacting with opioid receptors in the CNS hypotension and bradycardia may develop. Because of and the GI tract. Opioids cause hyperpolarization of respiratory depression and carbon dioxide retention, nerve cells, inhibiting the nerve firing, and presynap- cerebral vessels dilate and increase cerebrospinal fluid tic inhibition of transmitter release. Morphine inhib- (CSF) pressure. Therefore, Morphine is usually con- its the release of many excitatory transmitters from traindicated in individuals with severe brain injury. nerve terminals carrying nociceptive (painful) stimuli; Histamine release. Morphine releases histamine it also decreases the release of substance P, which mod- from mast cells, causing urticaria, sweating, and va- ulates pain perception in the spinal cord. sodilation. Because it can cause bronchoconstriction, asthmatics should not receive the drug. Actions: Hormonal actions. Morphine inhibits release of Analgesia. Morphine causes analgesia (relief of gonadotropin-releasing hormone and decreases the pain without loss of consciousness). Opioids relieve concentration of luteinizing hormone, follicle-stimulat- pain both by raising the threshold at the spinal cord ing hormone, adrenocorticotropic hormone, and β-en- level, and more importantly, by altering the brain’s dorphin. Testosterone and cortisol levels decrease. perception of pain. Patients treated with Morphine are Morphine increases prolactin and growth hormone re- still aware of the presence of pain, but the sensation is lease by diminishing dopaminergic inhibition. It in- not unpleasant. creases antidiuretic hormone (ADH) and thus leads to Euphoria. Morphine produces a powerful sense of fluid retention. contentment and well-being. Euphoria may be caused Therapeutic uses: by stimulation of the ventral tegmentum. Analgesia. Despite intensive research, few other Respiration. Morphine causes respiratory depression drugs have been developed that are as effective in the by reduction of the sensitivity of respiratory center to treatment of pain (postoperative pain, pain of termi- carbon dioxide. This occurs with ordinary doses of Mor- nal illness and cancer pain, etc.). Opioids induce sleep, phine and is accentuated as the dose increases until, ul- and in clinical situations when pain is present and timately, respiration ceases. Respiratory depression is sleep is necessary, opiates may be used to supplement the most cause of death in acute opioid overdose. the sleep-inducing properties of benzodiazepines. Depression of cough reflex. Morphine and Codeine [Note: The sedative-hypnotic drugs are not usually an- have antitussive properties. In general, cough suppres- algesic, and may have diminished sedative effect in the sion does not correlate closely with analgesic and res- presence of pain.] piratory depressant properties of opioid drugs. The re- Relief of cough. Morphine suppresses the cough receptors involved in the antitussive action appear to be flex; however, Codeine is more widely used. Codeine different than those involved in analgesia. has greater antitussive action than Morphine. Miosis. The pinpoint pupil, characteristic of Mor- Pulmonary edema. Morphine is used to alleviate µ κ phine use, results from stimulation of - and -recep- the dyspnea of acute left ventricular failure and pul- tors. Morphine excites the Edinger-Westphal nucleus monary edema, in which to i.v. Morphine may be dra- of the oculomotor nerve, which causes enhanced para- matic. The mechanism underlying this relief is still not sympathetic stimulation of the eye. There is little tol- clear. It may involve an alteration of the patient’s re- erance to the effect, and all addicts demonstrate pin- action to impaired respiratory function and indirect of point pupils. This is important diagnostically, because the work of the heart due to reduced fear. most other causes of coma and respiratory depression Treatment of diarrhea. Morphine decreases the produce dilation of the pupil. motility of smooth muscle and increases tone. Synthet-

67 ic opioids also produce a decrease in bowel motility; Methadone causes a milder withdrawal syndrome, several of these, such as Loperamide are used exclu- which also develops more slowly than that seen dur- sively for this purpose. ing withdrawal from Morphine. Readily absorbed fol- Pharmacokinetics. Absorption of morphine from the lowing oral administration, Methadone has a longer GI tract is slow and erratic, and the drug is usually duration of action than does Morphine. Methadone not given orally. Codeine, by contrast, is well absorbed can produce dependence like that of Morphine. The when given by mouth. Significant first pass metabolism withdrawal syndrome is much milder but is more pro- occurs in the liver; therefore, i.m., s.c., or i.v. injec- tracted (days to weeks) than with opiates. tions produce more reliable responses. Opiates have been commonly taken for nonmedical purposes by in- Fentanyl halation of the smoke from burning crude opium, which provides a rapid onset of action. Fentanyl has 80 times the analgesic potency of Morphine rapidly enters all body tissues, including Morphine, and is used in anaesthesia. It has a rapid the fetuses of pregnant women, and should not be used onset and short duration of action (15 to 30 minutes). for analgesia during labor. Infants born of addicted When combined with Droperidol it produces a disso- mothers show physical dependence on opiates and ex- ciative anaesthesia (neuroleptanalgesia). Sufentanil, a hibit withdrawal symptoms. Only a small percentage of related drug, is even more potent than Fentanyl. Morphine crosses the blood-brain barrier, since Mor- phine is the least lipophilic of the common opioids. This Heroin contrasts with the more fat-soluble opioids, such as fen- Heroin does not occur naturally but is produced by tanyl and heroin, which readily penetrate into the brain acetylation of Morphine, which leads to a tree-fold in- and rapidly produce an intense “rush” of euphoria. crease in its potency. Its greater lipid solubility allows Morphine is metabolized in the liver to glucuro- it to cross blood-brain barrier more rapidly than Mor- nides. Morphine-6-glucuronide is a very potent analge- phine, causing a more exaggerated euphoria when the sic, whereas the conjugate at the 3-position is inactive. drug is taken by injection. Heroin is converted to Mor- The conjugates are excreted primarily in the urine. The phine in the body, but lasts about half as long. It has duration of action of Morphine is 4 to 6 hours in naїve no accepted medical use. individuals. [Due to the low conjugation capacity in neonates, they should not receive Morphine.] Omnoponum Adverse effects. Severe respiratory depression occurs. Other effects include vomiting, dysphoria, and Omnoponum is a mixture of purified opium alka- allergy-enhanced hypotensive effects. The elevation of loids that contains 48–50% of Morphine and 32–35% intracranial pressure, particularly in head injury, can of other alkaloids. Omnoponum produces a pattern of be serious. Morphine enhances cerebral and spinal effects quite similar to that of Morphine. Sometimes it ischemia. In prostatic hypertrophy, Morphine may is better tolerated than Morphine and appears to be cause acute urinary retention. A serious action is stop- less spasmogenic. page of respiratory exchange in emphysema or cor pul- monale patients. If employed in such individuals, res- Trimeperidine (Promedolum) piration must be carefully watched. Promedolum is a synthetic opioid with a structure Tolerance and physical dependence. Repeated use unrelated to Morphine. The pharmacological effects produces tolerance to the respiratory depressant, an- of Promedolum closely parallel but not identical those algesic, euphoric, and sedative effects of Morphine. of Morphine. Promedolum causes a depression of res- However, tolerance usually does not develop to the pu- piration. On i.v. administration, the drug produces a pil-constricting and constipating effects of the drug. decrease in peripheral resistance and an increase in pe- Physical and psychologic dependence readily occur ripheral blood flow. As with Morphine, Promedolum with Morphine and with some other agonists. With- dilates cerebral vessels, increases cerebrospinal fluid drawal produces a series of autonomic, motor and psy- pressure, and contracts smooth muscle (the latter to a chological responses that causes serious, almost un- lesser extent than does Morphine). In GI tract, bearable symptoms. However, it is very rare that the Promedolum impedes motility, and chronic use results effects are so profound as to cause death. in constipation. Promedolum does not cause pinpoint pupils, but rather causes pupil to dilate because of an Methadone atropine-like activity. Promedolum provides analge- Methadone is a synthetic, orally effective opioid sia for any type of severe pain. Unlike Morphine, it is that is approximately equal in potency to Morphine, not clinically useful in the treatment of diarrhea or but induces less euphoria and has a longer duration of cough. Promedolum produces less of an increase in uri- action. Methadone has its greatest action on µ-recep- nary retention than does Morphine. tors. The analgesic activity is equivalent to that of Morphine. The drug is well absorbed when administered orally. The miotic and respiratory depressant ac- MODERATE AGONISTS tions of Methadone have average half-lives of 24 hours. Codeine Methadone is used in the controlled withdrawal of addicts from Heroin and Morphine. Orally adminis- Codeine is a much less potent analgesic than Mor- tered, Methadone is substituted for the injected opio- phine, but it has a higher oral efficacy. Codeine shows id. The patient then slowly weaned from Methadone. good antitussive activity at doses that do not cause

68 analgesia. The drug has a lower abuse potential than antagonists rapidly reverse the effect of agonists, Morphine and rarely produces dependence. Codeine such as Heroin, and precipitate the symptoms of opi- produces less euphoria than Morphine. Codeine is of- ate withdrawal. ten used in combination with Aspirin or Paracetamol. [Note: In most nonprescription cough preparations, Naloxone codeine has been replaced by newer drug, such as Dextromethorphan, a synthetic cough depressant that Naloxone is used to reverse the coma and respira- has no analgesic action and a low potential for tory depression of opioid overdose. It rapidly displac- abuse.] es all receptor-bound opioid molecules and therefore is able to reverse the effect of a Heroin overdose. With- in 30 seconds of intravenous injection of Naloxone, the MIXED AGONIST-ANTAGONISTS respiratory depression and coma characteristic of high doses of heroin are reversed, causing the patient to be Drugs that stimulate one receptor but block anoth- revived and alert. Naloxone has a half-life of 60 to 100 er are termed mixed agonist-antagonists. The effects minutes. Naloxone is a competitive antagonist at µ, κ of the drugs depend on previous exposure to opioids. and δ-receptors, with a 10-fold higher affinity for µ- In individuals who have not recently received opioids, receptors than for κ. This may explain why Naloxone mixed agonist-antagonists show agonist activity and readily reverses respiratory depression with only min- are used to relieve pain. In the patient with opioid de- imal reversal of analgesia that results from agonist stim- pendence, the agonist-antagonist drugs may show pri- κ marily blocking effects, that is, produce withdrawal ulation of -receptors in the spinal cord. Naloxone pro- symptoms. Most of the drugs in this group cause dys- duces no pharmacological effects in normal individu- phoria, rather than euphoria, mediated by activation als, but it precipitate withdrawal symptoms in Mor- of σ-receptors. phine and Heroin abusers.

Pentazocine Naltrexone Pentazocine acts as an agonist on κ-receptors and Naltrexone has action similar to those of Naloxone. is a weak antagonist at µ- and δ-receptors. It also binds This drug has a longer duration of action than to σ-receptors, which may account for its dysphoric Naloxone, and a single oral dose blocks the effects of properties. Pentazocine promotes analgesia by activat- injected Heroin for up to 48 hours. Naltrexone is used ing receptors in the spinal cord, and is used to relieve in opiate-dependence maintenance programs and may moderate pain. In higher doses, the drug causes respi- also be beneficial in treating chronic alcoholism. ratory depression. High doses increase blood pressure and can cause hallucination, nightmares, tachycardia, Available forms: and dizziness. In angina, Pentazocine increases the Morphine hydrochloride — in tablets 0.01 each; in mean aortic pressure and pulmonary arterial pressure ampoules 1% solution 1 ml each and thus increases the work of the heart. The drug de- Codeine — in tablets 0.015 each creases renal blood flow. Despite its antagonist action, Pentazocine — in tablets 0.05 each; in ampoules 1 Pentazocine does not antagonize the respiratory de- ml (contain 0.03 of pentazocine) each pression of Morphine, but it can precipitate a with- Trimeperidine (Promedolum) — in tablets 0.025 drawal syndrome in a Morphine abuser. Pentazocine each; in ampoules 1% or 2% solution 1 ml should not be used with agonists such Morphine, since Fentanyl — in ampoules 0.005% solution 2 or 5 ml the antagonist action may block the analgesic effect each of Morphine. Tolerance and dependence develop on Naloxone hydrochloride — in ampoules 1 ml (con- repeated use. tain 0.0004 of naloxone) Naltrexone — in tablets 0.05 each Buprenorphine Although Buprenorphine is classified as a partial agonist acting on the µ-receptors, it behaves like Morphine in naїve patients. However, it can also an- Lecture 15 tagonize Morphine. Buprenorphine has a long duration of action because of its tight binding to the recep- NEUROLEPTICS tor. It is metabolized by the liver and excreted in the bile and urine. Adverse effects include respiratory de- The use of drugs with well-demonstrated effica- pression, decrease (or, rarely, increase) in blood pres- cy in psychiatric disorders has become widespread sure, nausea and dizziness. since the mid 1950s. In 1950, Chlorpromazine was synthesized in France. The recognition of its unique ANTAGONISTS effects by Laborit and its use in psychiatric patients by Deley and Deniker (1952) marked the beginnings The opioid antagonists bind with high affinity to of modern psychopharmacology. A report on Mep- opioid receptors but fail to activate the receptor-me- robamate by Berger (1954) marked the beginning of diated response. Administration of opioid antago- investigation of modern sedatives with useful an- nists produces no profound effects in normal indi- tianxiety properties. An antitubercular drug, Ipro- viduals. However, in patients addicted to opioids, niazid, was introduced in the early 1950s and was

69 soon recognized as a MAO inhibitor and antidepres- ceptors have been identified. The clinical efficacy of sant. In 1958, Kuhn recognized the antidepressant the traditional neuroleptic drugs correlates closely with effect of imipramine. The first of antianxiety ben- their ability to block D2 receptors in the mesolimbic zodiazepines, Сhlordiazepoxide, was developed by system. The action of the neuroleptic drugs are antag- Sternbach in 1957. During the 1960s the expansion onized by agents that raise dopamine concentration, of psychopharmacological research was rapid, and e.g. L-dopa and Amphetamines. many theories of psychoactive drug effects were in- Serotonin receptor-blocking activity in the brain. troduced. The clinical efficacy of many of these The newer “atypical” agents appear to exert part of agents was firmly established during that decade. their unique action through inhibition of serotonin (S) Today, about 10–20% of prescriptions are for med- receptors. Thus, Clozapine has high affinity for D1 α ications intended to affect mental processes, name- and D4, S2, muscarinic and -adrenoreceptors, but it ly, to sedate, stimulate, or otherwise change mood, is also a dopamine D2-receptor antagonist. Another thinking, or behavior. new agent, Risperidone, blocks S2-receptor to a great- Neuroleptic drugs (also called antischizophrenic er extent than it does D2-receptors. Both of these drugs drugs, antipsychotic drugs, or major tranquilizers) are exhibit a low incidence of extrapyramidal side ef- used primarily to treat schizophrenia but also effec- fects. tive in other psychotic states, such as manic states and Actions. The antipsychotic actions of neuroleptic delirium. The traditional neuroleptic drugs are com- drugs reflect blockade at dopamine/serotonin recep- petitive inhibitors at a variety of receptors, but their tors. However, many of these agents also block cholin- antipsychotic effects reflect competitive blocking of ergic, adrenergic, and histamine receptors, causing a dopamine receptors. The drugs vary in their potency, variety of side effects. but no one drug is clinically more effective than an- Antipsychotic actions. The neuroleptic drugs re- other. In contrast, the newer “atypical” antipsychotic duce the hallucinations and agitation associated with drugs appear to owe their unique activity to blockade schizophrenia by blocking dopamine receptors in the serotonin receptors. Neuroleptics are not curative and mesolimbic system of the brain. These drugs also have do not eliminate the fundamental thinking disorders, a calming effect and reduce spontaneous physical but often do permit the psychotic patient to function movement. In contrast to the CNS depressants, such in a supportive environment. as barbiturates, the neuroleptics do not depress intel- Schizophrenia is a particular type of psychosis, that lectual function of the patient, and motor incoordina- is, a mental disorder caused by some inherent dysfunction is minimal. The antipsychotic effects usually take tion of the brain. It is characterized by delusions, hal- several weeks to occur. lucinations (often in the form of voices), and thinking Extrapyramidal effects. Parkinsonian symptoms, or speech disturbances. This mental disorder is a com- akathisia (motor restlessness), and tardy dyskinesia mon affliction, occurring among about 1% of the pop- (inappropriate postures of the neck, trunk, and limbs) ulation, or at about the same incidence as diabetes mel- occur with chronic treatment. Blocking of dopamine litus. Schizophrenia has a strong genetic component receptors in the nigrostriatal pathway probably caus- and probably reflects some fundamental biochemical es these unwanted parkinsonian symptoms. Clozapine abnormality, possibly an overactivity of the mesolim- and Risperidone exhibit a low incidence of these symp- bic dopaminergic neurons. toms. The neuroleptic drugs can be divided into five ma- Antiemetic effect. With the exception of Thiori- jor classes based on the structure of the drugs (Fig. 14). dazine, most of the neuroleptic drugs have antiemetic This classification is of modest importance, because effects that are mediated by blocking D2 receptors of within each chemical group, different side chains have the chemoreceptor trigger zone of the medulla. profound effects on the potencies of the drugs. The Antimuscarinic effect. All of the neuroleptics, par- management of psychotic disorders can typically be ticularly Thioridazine and Aminazine, cause anti- achieved by familiarity within the effects of one or two cholinergic effect, including blurred vision, dry mouth, drugs in each class. sedation, and inhibition of gastrointestinal and urinary smooth muscle, leading to constipation and urinary re- Mechanism of action: tention. Dopamine receptor-blocking activity in brain. All Other effects. Blockade of α-adrenegic receptors of the neuroleptics block dopamine receptors in the causes orthostatic hypotension and lightheadedness. brain and in the periphery. Five types of dopamine re- The neuroleptics also alter temperature-regulating

Phenothiazines Butyrophenones Thioxanthenes Indoles Others

Aminazine Haloperidol Thiothixene Reserpine Risperidone Fluphenazine Droperidol Clozapine Promethazine Sulpiride Trifluoperazine

Fig. 14. Classification of neuroleptics

70 mechanism and can produce poikilothermy (body tem- Lecture 16 perature varies with the environment). In the pituitary, TRANQUILIZERS (ANXIOLYTICS) the neuroleptics block D2 receptors, leading to an increase in prolactin release. Therapeutic uses: Treatment of schizophrenia. The neuroleptics are Anxiety is an unpleasant state of tension, apprehen- the only efficacious treatment of schizophrenia. Not sion, or uneasiness — a fear that seems to arise from all patients respond, and complete normalization of an unknown source. Disorders involving anxiety are behavior is seldom achieved. The traditional neurolep- the most common mental disturbances. The symptoms tics are most effective in treating positive symptoms (de- of severe anxiety are similar to those of fear (such as, lusions, hallucinations and thought disorders). The tachycardia, sweating, trembling, palpitations) and newer agents with serotonin blocking activity are ef- involve sympathetic activation. Episodes of mild anx- fective in many patients resistant to the traditional iety are common life experiences and do not warrant agents, especially in treating negative symptoms of treatment. However, the symptoms of severe, chronic, schizophrenia (withdrawal, blunted emotions, reduced debilitating anxiety may be treated with antianxiety ability to relate to people). drugs (sometimes called anxiolytic or minor tranqui- Prevention of severe nausea and vomiting. The lizers), and/or some form of psycho- or behavioral ther- neuroleptics are useful in the treatment of drug-in- apy. Since all of the antianxiety drugs also cause se- duced nausea. (Scopolamine, a muscarinic antago- dation, the same drugs often function clinically as both nist, is the drug of choice for the treatment of motion anxiolytic and hypnotic agents. sickness. In the XIX century, bromide salts and compounds Other use. The neuroleptic drugs may be used as similar in effects to alcohol, including Paraldehyde and tranquilizers to manage agitated and disruptive behav- Chloral hydrate, were introduced in medical practice ior. Neuroleptics are used in combination with narcotic as sedatives. These were followed in the early 1900s analgesics for treatment of chronic pain with severe by the introduction of barbiturates. The barbiturates anxiety. Aminazine is used to treat intractable hiccups. were the dominant antianxiety agents throughout the Droperidol is a component of neuroleptanaesthesia. first half of this century. However, by the 1950s con- Promethazine is not a good antipsychotic drug, but the cern had arisen about their propensity to induce toler- agent is used in treating pruritus because of its anti- ance, physical dependence, and potentially lethal re- histaminic properties. actions during withdrawal, and this encouraged the Adverse effects. Adverse effects of the neuroleptic search for safer agents. Compounds such as Mep- drugs occur in practically all patients and are signifi- robamate were the initial result. But they also shared cant in about 80%. Although antipsychotic drugs have many of the undesirable properties of barbiturates. an array of adverse effects, their therapeutic index is These properties included an unclear separation be- high. tween their useful antianxiety effect and excessive se- Parkinsonian effects. The inhibitory effects of dation. This set the scene for the discovery of Chlo- dopaminergic neurons are normally balanced by the rdiazepoxide in the late 1950s and introduction more excitatory actions of cholinergic neurons. Blocking than a dozen benzodiazepines since that time. This dopamine receptors alter this balance, causing a rela- class of sedatives has come to dominate the market and tive excess of cholinergic influence and resulting in ex- medical practice. trapyramidal motor effects. A new, nearly normal balance can be achieved by administration of an anti- BENZODIAZEPINES cholinergic drug, such as Cyclodolum. Other effects. Drowsiness occurs due to CNS de- Benzodiazepines are the most widely used anxio- pression, usually during the first 2 weeks of treatment. lytic drugs. They have largely replace barbiturates and Confusion is sometimes encountered. The neuroleptics Meprobamate in the treatment of anxiety, since the produce dry mouth, urinary retention, constipation, benzodiazepines are most effective and safer. Approx- and loss of accommodation. They block α-adrenergic imately 20 benzodiazepines are currently available. receptors, resulting in lowered blood pressure and or- Mechanism of action. The mechanism of action of thostatic hypotension. The neuroleptics depress the benzodiazepine derivatives has already been discussed hypothalamus, causing amenorrhea, infertility, and in details in the previous lecture (see hypnotics). They impotence. bind to specific receptors in the CNS. The result is to enhance the effects of gamma-aminobutyric acid Available forms: (GABA); an important inhibitory neurotransmitter that Chlorpromazine hydrochloride (Aminazinum) — in acts by opening chloride ion channels into cells). dragee 0.025; 0.05 or 0.1 each; in ampoules 2.5% so- Actions. The benzodiazepines have no antipsychot- lution 1; 2; 5 or 10 ml ic activity, nor any analgesic action and do not affect Trifluoperazine (Triftazinum) — in tablets 0.001; the autonomic nervous system. All of the benzodi- 0.005 or 0.01 each; in ampoules 0.2% solution 1 ml azepines exhibit the following actions to a greater or each lesser extent: Haloperidol — in tablets 0.0015 or 0.005 each; in Reduction of anxiety. At low doses, the benzodi- ampoules 0.5% solution 1 ml each azepines are anxiolytic. They are thought to reduce Clozapine (Azaleptinum) — in tablets 0.025; 0.1 anxiety by selectively inhibiting neuronal circuits in each; in ampoules 2.5% solution 2 ml each the limbic system of the brain.

71 Sedative and hypnotic actions: All of the benzodi- bution for most benzodiazepines are about 1 to 3 lit- azepines used to treat anxiety have some sedative prop- ers per kilogram. erties. At higher doses, certain benzodiazepines pro- The pharmacokinetic parameters for these agents duce hypnosis (artificially-produced sleep). can often be misleading because active metabolites Anticonvulsant: Several of the benzodiazepines with long half-lives can markedly alter the duration of have anticonvulsant activity and are used to treat epi- effects. For example, the formation of Nordiazepam lepsy and other seizure disorders. from Diazepam can extend the duration of effect by Muscle relaxant: The benzodiazepines relax the two-fold or three-fold. The benzodiazepines can be spasticity of sceletal muscle, probably by increasing roughly divided into short-, intermediate- and long-act- presynaptic inhibition in the spinal cord. ing groups (Table 5). Therapeutic uses: Most benzodiazepines, including Chlordiazepoxide Anxiety disorders. Currently, the most useful an- and Diazepam, are metabolized by the hepatic microsom- tianxiety drugs are the benzodiazepines. These drugs al metabolizing system to compounds that are also ac- should not be used to alleviate the normal stress of tive. For these benzodiazepines, the apparent half-life of everyday life, but should be reserved for continued the drug represents the combined actions of the parent severe anxiety, and then should only be used for short drug and its metabolites. The benzodiazepines are ex- periods of time because of addiction potential. The creted in urine as glucuronides or oxidized metabolites. longer acting agents such as Diazepam, are often pre- Dependence. Psychological and physical depend- ferred in those patients with anxiety that may require ence on benzodiazepines can develop if high doses of treatment for prolonged periods of time. The antianx- the drug are given over a prolonged period. Abrupt dis- iety effects of the benzodiazepines are less subject to continuation of the benzodiazepines results in with- tolerance than the sedative and hypnotic effects. For drawal symptoms, including confusion, anxiety, agi- panic disorders, Alprazolam is effective for short- and tation, restlessness, insomnia, and tension. Because of long-term treatment, although it may cause with- the long half-lives of some of the benzodiazepines, drawal reactions in about 30% of sufferers. withdrawal symptoms may not occur until a number Sleep disorders. Not all of the benzodiazepines of days after discontinuation. Benzodiazepines with a are useful as hypnotic agents, although all have sed- short elimination half-life, such as Triazolam, induce ative and calming effects. The most commonly pre- more abrupt and severe withdrawal reactions. scribed benzodiazepines for sleep disorders are long- Adverse effects. Drowsiness and confusion are the acting Nitrazepam, Phenazepam, and Flurazepam, in- two most common side effect of the benzodiazepines. termediate-acting temazepam, and short-acting Tri- Ataxia occurs at high doses and precludes activities azolam. that require motor coordination, such as driving an au- Seizures. Diazepam is the drug of choice in ter- tomobile. Cognitive impairment (decreased long-term minating status epilepticus and grand mal seizures. recall and acquisition of new knowledge) can occur. Clonazepam is useful in the chronic treatment of epi- Triazolam, the benzodiazepine with most rapid elimi- lepsy. nation, often show a rapid development of tolerance, Muscular disorder. Diazepam is useful in the treat- early morning insomnia and daytime anxiety, along ment of skeletal muscle spasms such as occur in mus- with amnesia and confusion. Benzodiazepines poten- cle strain, and in treating spasticity from degenera- tiate alcohol and other CNS depressants. However, tive disorders, such as multiple sclerosis and cerebral they are considerably less dangerous than other anxi- palsy. olytic and hypnotic drugs. As a result, a drug overdose Pharmacokinetics. The benzodiazepines are li- is seldom lethal, unless other central depressants, such pophilic and are rapidly and completely absorbed af- as alcohol, are taken concurrently. ter oral administration and are distributed through- Precautions. Use benzodiazepines cautiously in out the body. Diazepam reaches peak concentration treating patients with liver diseases. They potentiate in about an hour in adults, and as quickly as 15 to alcohol and other CNS depressants. Benzodiazepines 30 minutes in children. Alprazolam, Chlordiazepox- are, however, considerably less dangerous than other ide, and Lorazepam have intermediate rates of ab- anxiolytic and hypnotic drugs. As a result, a drug over- sorption. Most of the benzodiazepines are bound to dose is seldom lethal, unless other central depressants, plasma protein to a great extent (85 to 95%) — a fac- such as alcohol, are taken concurrently. tor that limits the efficacy of dialysis in the treatment Benzodiazepine antagonist. Flumazenil is a GABA of acute poisonings. The apparent volumes of distri- receptor antagonist that can rapidly reverse the effects

Table 5. Groups of benzodiazepines according to the duration of action Long-acting Intermediate-acting Short-acting 1–3 days 10–20 hours 3–8 hours Diazepam Alprazolam Triazolam Chlordiazepoxide Lorazepam Oxazepam Fenazepam Temazepam Flurazepam

72 of benzodiazepines. The drug is available by i.v. ad- Lecture 18 ministration only. The onset is rapid but duration is short, with a half-life of about one hour. Frequent ad- ANTIDEPRESSANT DRUGS ministration may be necessary to maintain reversal of benzodiazepines. Affective disorders — major depression and mania OTHER ANXIOLYTIC AGENTS (or bipolar manic-depressive illness) — are characterized by changes in mood as the primary clinical man- Other drugs that have been used in the treatment ifestation. Depression is different from schizophrenia, of anxiety include the propanediol carbamates (Mep- which produces disturbances in thought. The symptoms robamate), certain anticholinergic agents (Amizil), an- of depression are intense feeling of sadness, hopeless- tihistamines, etc. Many of these uses are now virtual- ness, despair, and inability to experience pleasure in ly obsolete. usual activities. Mania is characterized by the oppo- Meprobamate. The properties of Meprobamate re- site behavior, that is, enthusiasm, rapid thought and semble those of the benzodiazepines (anxiolytic, sed- speech patterns, and extreme self-confidence and im- ative-hypnotic, muscle relaxant, and anticonvulsive paired judgment. All clinically useful antidepressant actions). However, Meprobamate present additional problems, particularly its liability to produce toler- drugs (also called thymoleptics) potentiate, either di- ance, physical dependence, severe withdrawal reac- rectly or indirectly, the action of noradrenaline, tions, and life-threatening toxicity with overdosage. dopamine, and/or serotonin in the brain. This, along Amizylum. Amizytlum is a centrally acting mus- with other evidence, led to biogenic amine theory, carinic antagonist with anxiolytic effect. Its side effects which proposes that depression is due to a deficiency qualitatively resemble the belladonna alkaloids. of monoamines such as noradrenaline and serotonin Buspirone. Buspirone represents an entirely new in certain key sites in the brain. Conversely, mania is class of drugs useful in the treatment of generalized envisioned as caused by overproduction of these neu- anxiety disorders. It has an efficacy comparable to the rotransmitters. benzodiazepines. The action of Buspirone appear to Classification of antidepressants: be mediated by serotonin (5-HT1A) receptors, although other receptors could be involved, since Buspirone dis- — Inhibitors of neuronal reuptake: plays some affinity for DA2 dopamine receptors and a) nonselective (tricyclic/polycyclic antidepres- 5-HT2 serotonin receptors. The mode of action thus dif- sants): Amitriptyline, Imizine (Imipramine), Mapro- fers from that of benzodiazepines. Further, Buspirone tiline, Amoxapine; lacks anticonvulsant and muscle-relaxant properties. b) selective serotonin reuptake inhibitors: Fluoxet- The frequency of adverse effects is low. Sedation and ine, Paroxetine, Trazodone. psychomotor and cognitive dysfunction are minimal, — Monoamine oxidase inhibitors: Nialamide, and dependence is unlikely. Buspirone has the disad- phenelzine, Tranylcypromine vantage of a slow onset of action. — Drugs used to treat mania: lithium salts

Available forms: Diazepam — in tablets 0.01 each TRICYCLIC/POLYCYCLIC Alprazolam — in tablets 0.25 or 0.5 each ANTIDEPRESSANTS Oxazepam — in tablets 0.1 Amizylum — in tablets 0.001 or 0.002 each. Mechanism of action: Inhibition of neurotransmitter uptake. Tricyclic antidepressants (TCAs) inhibit the neuronal reuptake of noradrenaline and serotonin into presynaptic nerve terminals. This leads to increased concentration of Lecture 17 monoamines in the synaptic cleft, resulting in antidepressant effect. This theory has been discounted by PSYCHOSEDATIVE AGENTS some because of several observations. E.g. the potency in blocking neurotransmitter uptake often does not cor- A sedative drug (or dose of a drug) produces decrease relate with antidepressant effects. Further, blockade of in psychomotor activity and calms the recipient. In con- reuptake occurs immediately after administration of the trast to anxiolytics, this group of agents depresses the drug, but the antidepressant effect of the TCA requires central nervous system in a relatively nonselective fash- several weeks of continued treatment. It has been sug- ion. Many drugs share central depressant action. gested that monoamine receptor densities in the brain Traditionally, the following drugs (or doses of may change over a 2 to 4 week period with drug use drugs) used as sedatives: and may be important in the onset of activity. — long-acting and intermediate-acting barbiturates Blocking of receptors. The TCAs also block serot- in low doses (1/5–1/10 of a hypnotic dose); oninergic, α-adrenergic, histamine, and muscarinic re- — sodium bromide or potassium bromide; ceptors. It is not known which, if any, of these accounts — plant extracts (Valeriana officinalis, Leonurus for the therapeutic benefit. cardiaca); Actions. TCAs elevate mood, improve mental alert- — complex mixtures containing sedative agents. ness, increase physical activity, and reduce morbid pre- occupation in 50 to 70% of individuals with major de- Available forms: pression. The onset of the mood-elevation is slow, re- Tincture of Valerian — in bottles 30 ml each quiring 2 weeks or longer. These drugs do not produce 73 stimulation or mood elevation in normal individuals. Therapeutic uses. The primary indication for Fluox- Drugs can be used for prolonged treatment of depres- etine is depression, where it is as effective as the tricy- sion without loss of effectiveness. clic antidepressants. Fluoxetine is effective in treating Therapeutic uses. The TCAs are effective in treat- bulimia nervosa and obsessive-compulsive disorder. ing severe major depression. Some panic disorders also The drug has been used for a variety of other indica- respond to TCAs. Imipramine has been used to con- tions, including anorexia nervosa, panic disorder, pain trol bed-wetting in children (older than 6 years) by associated with diabetic neuropathy, and for premen- causing contraction of the internal sphincter of the strual syndrome. bladder. At present it used cautiously, because of the Pharmacokinetics. Fluoxetine is slowly cleared from inducement of cardiac arrhythmias and other serious the body, with a 1 to 10-day half-life for the parent cardiovascular problems. compound, and 3 to 30-day for the active metabolites. Pharmacokinetics. The TCAs are well absorbed Fluoxetine is administered orally; with a constant upon oral administration, and because of their li- dose, a steady-state plasma concentration of the drug pophilic nature, are widely distributed and readily is achieved after several weeks of treatment. Fluoxet- penetrate into the CNS. This lipid solubility also caus- ine is a potent inhibitor of a hepatic cytochrome P-450 es these drugs to have long half-lives, for example, 4 isoenzyme responsible for the elimination of tricyclic to 17 hours for Imipramine. The initial treatment pe- antidepressants, neuroleptics, some antiarrhythmic and riod is typically 4 to 8 weeks. These drugs are metab- β-blockers. [Note: About 7% of the population lack this olized by the hepatic microsomal system and conju- P-450 enzyme and therefore metabolize Fluoxetine gated with glucuronic acid. Ultimately, the TCAs are very slowly.] excreted as inactive metabolites via the kidney. Adverse effects. Commonly observed adverse effects Adverse effects: are nausea, insomnia, anorexia, weight loss, sexual Antimuscarinic effects. Blockade of acetylcholine dysfunction. Loss of libido, delayed ejaculation and receptors leads to blurred vision, xerostomia (dry anorgasmia are probably under-reported side effects mouth), urinary retention, constipation, and aggrava- often noted by clinicians, but are not prominently fea- tion of glaucoma and epilepsy. tured in the list of standard side effects. Overdoses of Cardiovascular. Increased catecholamine activity Fluoxetine do not cause cardiac arrhythmias but can results in cardiac overstimulation, which can be life- cause seizures. [In a report of patients who took an threatening in case of overdoses. Blockade of α-adren- overdose of Fluoxetine (up to 1200 mg compared with ergic receptors may cause orthostatic hypotension and 20 mg/day as a therapeutic dose) about half of the pa- reflex tachycardia. In clinical practice this is the most tients had no symptoms.] serious problem in the elderly. Sedation. Sedation may be prominent, especially Other SSRIs during the first several weeks of the treatment. Precautions. The tricyclic antidepressant should be Other antidepressant drugs that primarily affect se- used with caution in manic-depressive patients, since rotonin reuptake include Trazodone, Fluvoxamine, they may unmask manic behavior. The TCAs have a Paroxetine and others. These SSRIs differ from Fluox- narrow therapeutic index; e.g. 5 to 6 times the maxi- etine in their relative effects on the reuptake of serot- mal daily dose of Imipramine can be lethal. Depressed onin and noradrenaline. They do not seem to be more patients who are suicidal should be given only limited efficacious than Fluoxetine, but their profiles of side quantities of these drugs. effects are somewhat different. There is a high variability among patients in the rate of elimination of these drugs (including Fluoxetine), and failure to tolerate SELECTIVE SEROTONIN-REUPTAKE one drug should not preclude a trial of another SSRI. INHIBITORS The selective serotonin-reuptake inhibitors (SSRI) MONOAMINE OXIDASE INHIBITORS are a new group of chemically unique antidepressant Monoamine oxidase (MAO) is a mitochondrial en- drugs that specifically inhibit serotonin reuptake. Com- zyme found in neuronal and other tissues, such as the pared with tricyclic antidepressant, the SSRIs cause gut and liver. In the neuron, MAO functions as a “safe- fewer anticholinergic effects and lower cardiotoxicity valve” to inactivate any excess neurotransmitter ty. However, the newer SSRIs should be used cautious- molecules (Noradrenaline, Dopamine, and Serotonin) ly until their long-term effects have been evaluated. that may leak out of synaptic vesicles when the neuron is at rest. The MAO inhibitors inactivate the en- Fluoxetine zyme, permitting neurotransmitter molecules to escape Actions. Fluoxetine is the prototype of antidepres- degradation and therefore to accumulate within the pr- sant drugs that selectively inhibit serotonin reuptake. esynaptic neuron. First generation of MAO inhibitors Fluoxetine is as effective as tricyclic antidepressants (Nialamide) blocks MAO irreversibly; in contrast, in the treatment major depression. The drug is free of second generation is reversible MAO inhibitors (Pirlin- most of the troubling side effects of TCAs, including dole, Incazanum). Use of MAO inhibitors is now lim- anticholinergic effects, orthostatic hypotension, and ited because of the complicated dietary restrictions re- weight gain. Fluoxetine is preferred over TCAs by non- quired of patients taking these drugs. specialists who write most of the prescriptions for anti- Mechanism of action. MAO inhibitors form com- depressant drugs. As a result, Fluoxetine is now the most plexes with the enzyme, causing irreversible (Niala- widely prescribed antidepressant in many countries. mide) or reversible (Pirlindole, Incazanum) inactiva- 74 tion. This results in increased stores of Noradrenaline, of patients exhibiting mania and hypomania. Although Serotonin and Dopamine within the neuron, and sub- many cellular processes are altered by treatment with sequent potentiation of their actions. These drugs inhibit lithium salts, the mode of action is unknown. Lithium not only MAO in brain, but oxidases that catalyze oxi- is given orally, and the ion is excreted by the kidney. dative deamination of drugs and potentially toxic sub- Lithium salts are very toxic. Their safety factor and stances, such as tyramine, which is found in certain therapeutic index are extremely low comparable to foods. The MAO inhibitors therefore show a high inci- those of digitalis. Adverse effects include ataxia, trem- dence of drug-drug and drug-food interactions. or, confusion, and convulsions. Lithium causes no no- Although MAO is fully inhibited after several days ticeable effect on normal individuals. It is not a seda- of treatment, the antidepressant action is delayed sev- tive, euphoriant or depressant. eral weeks. Most MAO inhibitors have a mild amphetamine-like stimulant effect (Table 6). Available forms: Therapeutic uses. MAO inhibitors are indicated for Pirlindole — in tablets 0.025 or 0.05 each depressant patients who are unresponsive or allergic Imipramine — in tablets 0.025 each; in ampoules to tricyclic antidepressants. Patients with low psycho- 1.25% solution 2 ml motor activity may benefit from the stimulant proper- Fluoxetine — in capsules 0.02 each ties MAO inhibitors. These drugs are also useful in the treatment of phobic states. Pharmacokinetics. These drugs are well absorbed on oral administration. Antidepressant effect requires 2 to 4 weeks of treatment. Enzyme regeneration, when Lecture 19 irreversibly inactivated, usually occurs several weeks PSYCHOSTIMULANTS. after termination of the drug. Thus, when switching antidepressant agents, a minimum of 2 weeks delay NOOTROPIC DRUGS must be allowed after termination of MAO-inhibitor therapy. Adverse effects. Severe and often unpredictable side This section describes two groups of drugs. The first effects limit the widespread use of MAO inhibitors. For group, the genuine psychostimulants, cause excitement example, tyramine, contained in certain foods, such as and euphoria, decrease feelings of fatigue, and in- aged cheeses, chicken liver, beer, and red wines, is nor- crease motor activity. The second group includes drugs mally inactivated by MAO in the gut. Individuals, re- with some psychostimulant effects. ceiving a MAO inhibitor are unable to degrade According to this psychostimulants are classified tyramine obtained from the diet. Tyramine causes the into release of large amount of stored catecholamines from — Genuine psychostimulants: the nerve terminals, resulting in hypertension, tachy- a) methylxanthines — Caffeine, Caffeine-benzoate cardia, cardiac arrhythmias, headache, nausea, and sodium; stroke. Patients must therefore be educated to avoid b) benzoylmethylecgoine — Cocaine; tyramine-containing foods. Phentolamine or Prazosin c) phenylalkilamines — Amphetamine (Phenami- are helpful in the management of tyramine-induced num); hypertension. Other possible side effects of treatment d) phenylalkylsydnonimes — Mesocarb. with MAO inhibitors include drowsiness, orthostatic — Cerebroactive drugs (cerebral activators): hypotension, blurred vision, dryness of the mouth, dys- a) nootropic and GABA-ergic agents — Piracetam uria, and constipation. MAO inhibitors and SSRIs (Nootropil), Pyritinol, Aminalon (Gamma-aminobu- should not be coadministered due to the risk of life- tyric acid), Pantohamum (Hopantenic acid); threatening “serotonin-syndrome”. Both drugs required b) adaptogenes and miscellaneous agents with stim- washout periods of 6 weeks before administering the ulant activity — preparations of Ginseng, Eleuthero- other. coccus, etc.

LITHIUM SALTS METHYLXANTHINES Lithium salts are used prophylactically in treating Methylxanthines include Theophylline found in tea, manic-depressive patients and in the treatment manic Theobromine found in cocoa, and Caffeine. Caffeine, episodes. They are also effective in treating 60 to 80% the most widely consumed stimulant in the world, is

Table 6. Psychotropic spectra of action of the antidepressant drugs Psychostimulant effect Antidepressant effect Sedative effect

1234123456789012345678901234567890

1234123456789012345678901234567890 123412345678901234567890123456789MAO inhibitors 0 1234123456789012345678901234567890

1234567890123456789012345678901212

1234567890123456789012345678901212Imipramine

1234567890123456789012345678901234

1234567890123456789012345678912340

123456789012345678901234567890Amitriptyline 1234

75 found in highest concentration in coffee but is also ilar to that caused by Amphetamine. Like Ampheta- present in tea, cola drinks, chocolate candy, and cocoa. mine, Cocaine can produce hallucinations, delusions, Mechanism of action. The methylxanthines may act and paranoia. Cocaine increases motor activity, and by several mechanisms, including increase in cAMP at high doses cause tremors and convulsions, followed and cGMP caused by inhibition of phosphodiesterase, by respiratory and vasomotor depression. and blockade of adenosine receptors. Peripherally, Cocaine potentiates the action of no- Actions: radrenaline and produces the “fight or flight” syn- CNS. The caffeine contained in 1 to 2 cups of cof- drome characteristic of adrenergic stimulation. This is fee (100 to 200 mg) cause a decrease in fatigue and associated with tachycardia, hypertension, pupillary increased mental alertness as a result of stimulating dilation, and peripheral vasoconstriction. the cortex and other areas of the brain. Consumption Therapeutic uses. Cocaine has a local anaesthetic of 1.5 g of caffeine (12 to 15 cups of coffee) produces action that represents the only current rationale for anxiety and tremors. The spinal cord is stimulated only the therapeutic use of Cocaine; Cocaine is applied by very high doses (2 to 5 g) of caffeine. topically as a local anaesthetic during eye, ear, nose, Cardiovascular system. A high dose of caffeine has and throat surgery. The local anaesthetic action of positive inotropic and chronotropic effects on the heart. Cocaine is due to a block of voltage-activated sodi- [Note: Increased contractility can be harmful to pa- um channels. [Note: Cocaine is the only local anaes- tients with angina pectoris. Accelerated heart rate can thetic that causes vasoconstriction. This effect is re- trigger premature ventricular contractions in others.] sponsible for the necrosis and perforation of the na- Diuretic action. Caffeine has a mild diuretic action sal septum seen in association with chronic inhala- that increases urinary output of sodium, chloride, and tion of cocaine powder.] potassium. Pharmacokinetics. Cocaine is self-administered by Gastric mucosa. Since all methylxanthines stimu- chewing, intranasal snorting, smoking, and intrave- late secretion of hydrochloric acid (HCl) from the gas- nous injection. Peak effect occurs at 15 to 20 min af- tric mucosa, individuals with peptic ulcers should ter nasal intake of Cocaine powder, and the high dis- avoid beverages containing methylxanthines. appears in 1 to 1.5 hours. Rapid but short effects are Pharmacokinetics. The methylxanthines are well achieved following i.v. injection of Cocaine, or by absorbed orally. Caffeine distributes throughout the smoking the free base form of the drug (“crack”). Be- body, including brain. The drugs cross the placenta cause the onset of action is most rapid, the potential to the fetus and are secreted into the mother’s milk. All for overdosage and dependence is greatest with i.v. in- the methylxanthines are metabolized in the liver, and jection and crack smoking. the metabolites are then excreted in the urine. Adverse effects. The toxic response to acute cocaine Adverse effects. Moderate doses of Caffeine cause ingestion can precipitate an anxiety reaction that in- insomnia, anxiety, and agitation. A high dosage is re- cludes hypertension, tachycardia, sweating, and par- quired to show toxicity, which is manifested by emesis anoia. Like all stimulant drugs, Cocaine stimulation and convulsions. The lethal dose is about 10 g for Caf- of the CNS is followed by a period of mental depres- feine (about 100 cups of coffee), which induces cardi- sion. Addicts withdrawing exhibit physical and emo- ac arrhythmias. Death from Caffeine is thus highly un- tional depression as well as agitation. These symptoms likely. Lethargy, irritability, and headache occur in can be treated with benzodiazepines or phenothi- users who have routinely consumed more than 600 mg azines. of Caffeine per day (roughly 6 cups of coffee) and then Cocaine can induce seizures as well as fatal cardi- suddenly stop. ac arrhythmias. Intravenous Diazepam and Pro- pranolol may be required to control Cocaine-induced Cocaine seizures and arrhythmias, respectively. Cocaine is an inexpensive, widely available, and Amphetamine highly addictive drug (e.g. as it has been estimated, Cocaine is currently abused daily by over 3 million Amphetamine shows neurologic and clinical effects people in the United States). that are quite similar to those of Cocaine. Mechanism of action. The primary mechanism of Mechanism of action. As with Cocaine, the effects action is blockade of noradrenaline, serotonin, and of Amphetamine on the CNS and peripheral nervous dopamine reuptake into the presynaptic terminals from system are indirect; that is, they depend upon an ele- which these transmitters are released. This block po- vation of the level of catecholamine transmitters in tentiates and prolongs the CNS and peripheral ac- synaptic spaces. Amphetamine, however, achieves this tions of these catecholamines. In particular, the pro- effect by releasing intracellular stores of catecho- longation of dopaminergic effects in the brain’s pleas- lamines. Since Amphetamine also blocks MAO, high ure system (limbic system), produces the intense eupho- level of catecholamines are readily released into syn- ria that Cocaine initially causes. Chronic intake of aptic spaces. Despite different mechanisms of action, Cocaine depletes Dopamine. This depletion triggers the behavioral effects of Amphetamine are similar to the vicious cycle of craving for Cocaine that tempo- those of Cocaine. rarily relieves severe depression. Actions. The major cause of the behavioral effects Actions. The behavioral effects of Cocaine result of Amphetamine is probably due to release of dopami- from powerful stimulation of the cortex and brainstem. ne rather than release of noradrenaline. Amphetamine Cocaine acutely increases mental awareness and pro- stimulates the entire cerebrospinal axis, cortex, brain duces a feeling of well-being and euphoria that is sim- stem, and medulla. This leads to increased alert-

76 ness, decreased fatigue, depressed appetite, and in- lism, neurotransmitter modulation, improvement of somnia. In high doses, convulsions can ensue. These neuronal integration, etc. CNS stimulant effects of Amphetamine and its de- Piracetam. It is a cyclic GABA derivative, but has rivatives have led to their use in the therapy of de- no GABA like activity. Piracetam has been claimed pression, hyperactivity in children, narcolepsy, and to improve ATP/ADP ratio in telencephalon, stimulate appetite control. synaptic transmission. It is believed also to act by pro- In addition to its marked action on the CNS, Am- tecting altered brain metabolism. phetamine acts on the adrenergic system, indirectly Pyritinol. It consists of two pyridoxine (vit. B6) stimulating the receptors through noradrenaline re- molecules, joined through a disulfide bridge, but has lease. no vitamin B6 activity. It is claimed to improve regional Therapeutic uses. Factors that limit the therapeutic blood flow in ischemic brain areas, activate cerebral usefulness of amphetamine include psychological and metabolism, increase glucose uptake in brain, etc. physiological dependence similar to those with Co- Clinical indication for Piracetam, Pyritinol and caine, and the development of tolerance to the euphoric other nootropic agents include: and anorectic effects with chronic use. [Note: Less tol- — transient ischemic attacks, cerebrovascular ac- erance to the toxic CNS effects (e.g. convulsions) de- cidents — stroke; velops.] — mental retardation in children; Attention deficit syndrome. Some young children — sequelae of head injury, brain surgery; are hyperkinetic and lack the ability to be involved in — organic psycho-syndromes; any one activity for longer than a few minutes. Am- — senile dementia and confusional states of old phetamine and more recently Amphetamine derivative age; Methylphenidate alleviate many of the behavior prob- — concentration and memory defects. lems associated with this syndrome, and reduce the hy- The above therapeutic field is commercially high- perkinesia that the children demonstrate. Their atten- ly profitable. Cerebroactive drugs have been briskly tion is thus prolonged, allowing them to function bet- promoted by manufacturers and wishfully prescribed ter in a school atmosphere. by physicians. However, precise trails have been Narcolepsy. Methylphenidate and Amphetamine shown that in many cases the initial enthusiasm about are used to treat narcolepsy, a disorder marked by an “cerebroactive drugs” was merely wishful thinking. But uncontrollable desire for sleep. they continue to be prescribed in the absence of any Pharmacokinetics. Amphetamines are completely thing better. absorbed from the GI tract, metabolized by the liver, and excreted in the urine. Amphetamine abusers often Available forms: administer the drugs by i.v. injection and by smoking. Caffeine-sodium-benzoate — in tablets 0.1; 0.2 (for The euphoria caused by amphetamine lasts 4 to 6 adult) and 0.075 (for children); in ampoules 10% or hours, or 4 to 8 times longer than the effects of co- 20% solution 1 or 2 ml caine. The Amphetamines produce addiction — de- Mesocarb — in tablets 0.005 or 0.025 each pendence, tolerance and drug-seeking behavior. Piracetam — in capsules 0.4 each; in tablets 0.2 Adverse effects. Undesirable side effects of amphet- each; in ampoules 20% solution 5 ml each amine usage include insomnia, irritability, weakness, Phenibut-anvi — in tablets 0.25 each dizziness, tremor, and hyperactive reflexes. Ampheta- mine can also cause confusion, delirium, panic states, and suicidal tendencies, especially in mentally ill patients. Chronic Amphetamine use produces a state of “Amphetamine psychosis” that resembles an acute Lecture 20 schizophrenic attack. Overdoses of Amphetamine are ANALEPTICS treated with Aminazine, which relieves the CNS symp- α toms as well as the hypertension because of its -block- These are drugs which stimulate respiratory and ing effects. cardiovascular centers. They have resuscitative val- In addition to its CNS effects, Amphetamine caus- ue in coma or fainting. Analeptics do stimulate res- es palpitations, cardiac arrhythmias, hypertension, piration in subconvulsive doses, but margin of safe- anginal pain, and circulatory collapse. Headache, ty is narrow; the patient may get convulsions while chills, and excessive sweating may also occur. Amphet- still in coma. Mechanical support to respiration and amine should not be given to patients receiving MAO other measures to improve circulation are more ef- inhibitors. Amphetamine acts on the GI tract, causing fective and safe. They are not dependable for long anorexia, nausea, vomiting, and abdominal cramps, term support. Situations in which they may employed and diarrhea. are: hypnotic drug poisoning; failure to ventilate spontaneously after general anaesthesia; apnoea in NOOTROPIC DRUGS premature infant, etc. More information about analeptics see in lecture “Drugs used in respiratory dis- “Nootropic” means a drug that selectively im- eases”. proves higher telencephalic integrative activities (cognitive function, learning, memory etc.). They are Available forms: thought to bring about their effects by improvement in Sulfocamphocainum — in ampoules 10% solution cerebral circulation, activation of neuronal metabo- 2 ml each

77 EXAMINATION QUESTIONS (D). It has a long duration of action following intravenous infusion. 1. A patient whose anaesthesia is being managed (E). It does not produce chest wall rigidity. only with isoflurane (Forane) delivered at an inspired concentration near the MAC occasionally moves and 5. Patients with coronary artery disease are par- exhibits facial grimacing, apparently in response to ticularly challenging for anaesthesia, since alterations surgical manipulation of the bowel. These responses in vascular responsiveness and myocardial function are may put them at risk. In this respect, which statement (A). Natural consequences of physical manipula- correctly describes the cardiovascular action of an tions that induce noxious sensory input to the agent or agents that should be taken into account when CNS. planning anaesthesia for such patients? (B). An indication that neuromuscular blocking (A). All halogenated hydrocarbon inhalational agents should be administered without delay. anaesthetics sensitize the myocardium to cat- (C). Not likely to be blocked by coadministering echolamine-induced cardiac arrhythmias. an analgesic drug such as morphine. (B). Halogenated hydrocarbon inhalational (D). Signs suggesting that the patient should be agents reduce cardiac output equally well. given twice the MAC of isoflurane. (C). Sevoflurane (Ultane) directly stimulates sym- (E). Not avoidable because the bowel is unusual- pathetic function. ly sensitive to physical manipulation. (D). Reflex sympathetic stimulation is a major component of halothane’s (Fluothane) cardi- 2. A hypotensive patient suspected of having inter- ovascular profile. nal bleeding is given a dose lower than the usual (E). Several halogenated hydrocarbons produce amount of an intravenous anaesthetic. An acceptable vascular relaxation to reduce blood pressure. level of anaesthesia occurs. How is it possible to achieve anaesthesia in this patient with a dose of an- 6. The mechanism of anaesthesia remains an ac- aesthetic that may be inadequate in a normotensive pa- tive area of research. Which statement best describes tient with adequate blood volume? significant developments in this area of scientific in- (A). Enzymatic activity of hepatic enzymes is vestigation? compromised when blood pressure is low. (A). Anaesthetics are physically attracted to the (B). More anaesthetic appears in the brain and aqueous phase of neuronal membranes. redistribution of the intravenous drug to tis- (B). Anaesthesia is associated with interactions of sues with reduced blood flow is compromised the agents with a single unique site on the when hemorrhagic shock occurs. GABAA receptor. (C). The diffusion of lipid-soluble drugs through (C). Anaesthesia ultimately occurs as Cl moves out the blood-brain barrier is enhanced. of neuronal cells, an action that makes the (D). Tissues with a characteristically high blood cells less excitable. flow per unit mass receive less blood and less (D). Although some exceptions occur, a correla- anaesthetic when blood volume is low. tion between anaesthetic potency and their oil- (E). Anaesthetics bind more readily to tissue re- water partition coefficient suggested a unitary ceptors when hypotension and poor oxygen- hypothesis for the production of anaesthesia. ation occur. (E). Enantiomers of inhalational agents provide support for the Meyer Overton rule. 3. With which hypothetical anaesthetic would you expect anaesthetic partial pressure to be achieved rel- 7. Which of the following opioids has an analgesi- atively quickly? cally active metabolite? (A). An agent that is highly soluble in blood and (A). Naloxone. other body tissues. (B). Meperidine. (B). An agent with a low MAC (in range less than (C). Propoxyphene. 1% in the inspired air). (D). Codeine. (C). An agent with a high Ostwald solubility co- (E). Nalmefene. efficient. (D). An agent whose rate of rise of partial pres- 8. Which of the following statements about Celecox- sure in the lung is influenced minimally by ib is true? uptake into the blood. (A). It irreversibly acetylates the COX-2 enzyme. (E). An agent supplied as a gas rather than one (B). It inhibits both the inducible and constitutive supplied as a volatile liquid. COX-2 enzyme. (C). It produces no GI bleeding. 4. Remifentanil (Ultiva) has recently gained pop- (D). It is indicated only for the disease, osteoar- ularity as a high-dose opioid anaesthesia because thritis. (A). It induces anaesthesia in patients faster than (E). It increases healing of GI ulcers. any other drug. (B). Phenylpiperidine-type opioids releases hista- 9. Morphine produces an analgesic effect due to mine from mast cells. (A). A block of potassium efflux from the neuron. (C). It is metabolized by nonspecific esterases in (B). An increase in c-AMP accumulation in the red blood cells and other tissues. neuron.

78 (C). A decrease in intracellular calcium in the neu- (C). Gastric ulceration; heavy alcohol use increas- ron. es the susceptibility of an individual to ibu- (D). Interaction with a Gs protein in the neuron. profen-induced GI toxicity. (E). An increase in calcium channel phosphoryla- (D). Confusion and ataxia; these CNS toxicities tion in the neuron. of ibuprofen are additive with those of ethanol. 10. κ-Opioid receptor activation is required to ob- (E). Eosinophilia; this rare complication of ibu- serve profen therapy is exacerbated by the immu- (A). Respiratory depression. nosuppression frequently seen in alcoholics. (B). Bradycardia. (C). Miosis. 15. Etanercept produces its antirheumatic effects (D). Mydriasis. by direct (E). Hypocapnia. (A). Inhibition of cAMP phosphodiesterase in monocytic lineage leukocytes. 11. Which of the following statements about fenta- (B). Selective inhibition of COX-2. nyl patches is true? (C). Enhancement of leukotriene synthesis at the (A). They produce no respiratory depression. expense of prostaglandin synthesis. (B). They produce anaesthesia and analgesia. (D). Reduction of circulating active TNF-a lev- (C). They produce no constipation. els. (D). They can be used during pregnancy. (E). Inhibition of the production of autoantibod- (E). They cannot be used in nonambulatory pa- ies. tients. 16. An advantage of celecoxib over most other 12. A man aged 74 has moderate hypertension con- NSAIDs is trolled with Hydrochlorothiazide 12.5 mg once daily and (A). Less inhibition of PGE2 effects on the gas- losartan 50 mg once daily. He is prescribed rofecoxib tric mucosal. 50 mg once daily to control osteoarthritis pain. After 3 (B). Less risk of bronchospasm and hypersensitiv- months of this therapy, his blood pressure begins to rise. ity reactions. Once-daily dosing allows the This increase in blood pressure is most likely due to patient convenience. (A). Inhibition of COX-2 by Rofecoxib, which (C). Less risk of harm to the developing fetus in leads to decreased renal blood flow. the third trimester. (B). Increased metabolism of Losartan due to in- (D). Greater degree of efficacy in the treatment duction of CYP2C9 by rofecoxib. of rheumatoid arthritis. (C). Increased excretion of Hydrochlorothiazide due to increased renal blood flow (caused by 17. Opisthotonos is a convulsive condition that is rofecoxib). often associated with the ingestion of strychnine. This (D). Arteriolar contraction in the peripheral cir- condition is associated with all of the following EX- culation caused by inhibition of COX-1 by rofecoxib. CEPT (E). Weight gain caused by rofecoxib’s ability to (A). Antagonism of the inhibitory amino acid neu- decrease basal metabolic rate. rotransmitter glycine. (B). The predominance of glycine as an inhibito- 13. The use of low-dose methotrexate in the treat- ry amino acid transmitter in the spinal cord. ment of rheumatoid arthritis is most frequently (C). Antagonism of the inhibitory amino acid neu- (A). Reserved for cases in which NSAIDs no long- rotransmitter GABA. er adequately control pain and stiffness. (D). The convulsions lead to tonic extension of the (B). Initiated only after significant joint destruc- body and all limbs. tion. (C). Contraindicated in individuals being treated 18. Which of the following classes of agents is use- with NSAIDs. ful in the treatment of attention deficit hyperkinetic (D). Used for pregnant women, since it is the disorder? DMARD with the least fetal toxicity. (A). Analeptic stimulants. (E). Initiated early in the course of moderate to (B). Benzodiazepines. severe forms of the disease. (C). Xanthines. (D). Psychomotor stimulants. 14. A 52-year-old woman with a history of eczema (E). Phosphodiesterase inhibitors. and heavy alcohol use begins taking Ibuprofen to control hip and knee pain due to osteoarthritis. Over the 19. Which of the following mechanisms of action course of 6 months, as the pain worsens, she increases account for the effects of all analeptic stimulants ex- her dosage to a high level (600 mg four times daily). cept strychnine? What toxicity is most likely to occur, and why? (A). Antagonism of chloride ion influx at the (A). Abnormal heart rhythms; alcohol induces cy- GABA receptor-chloride channel complex. tochrome P450 isozymes that convert Ibupro- (B). Increased release of catecholamines from fen to a cardiotoxic free radical metabolite. CNS neurons. (B). Necrotizing fasciitis; eczema predisposes an (C). Inhibition of cholinesterase leading to in- individual to this toxicity of Ibuprofen. creased acetylcholine levels.

79 (D). Antagonism of CNS adrenoceptors to reduce 25. A 33-year-old woman has a 15-year history of inhibition produced by catecholamines. alcohol abuse. She comes to the emergency department (E). Antagonism of nicotinic receptors that inhib- for treatment of injuries received in a fall. She says she it motor neuron activity. has been drinking heavily and almost continuously for 2 weeks, and she wants to stop. Which of the follow- 20. The CNS stimulation produced by methylxan- ing drugs would most effectively and safely lessen the thines, such as caffeine, is most likely due to the an- intensity of her withdrawal syndrome? tagonism of which of the following receptors? (A). Buspirone. (A). Glycine receptors. (B). Chlordiazepoxide. (B). Adenosine receptors. (C). Chloral hydrate. (C). Glutamate receptors. (D). Midazolam. (D). GABA receptors. (E). Zolpidem. (E). Cholinergic muscarinic receptors. 26. A 23-year-old medical student has to make a 21. Cardiac stimulation is an adverse effect asso- presentation before his classmates. He is very anxious ciated with the use of the psychomotor stimulants, about this presentation and reports that on one previ- such as amphetamine. Which of the following mech- ous occasion the sweating and palpitations that ac- anisms is most likely responsible for this peripheral company his stage fright were so intense that he was effect? unable to complete his presentation. Pretreatment with (A). Inhibition of vagal tone through an action in which of the following drugs would relieve his symp- the CNS. toms without making him drowsy? (B). Indirect sympathomimetic effects in the pe- (A). Alprazolam. riphery due to release of norepinephrine. (B). Zephalon. (C). Inhibition of a GABA-mediated negative (C). Chloral hydrate. chronotropic effect at the heart. (D). Propranolol. (D). Antagonism of muscarinic receptors in the (E). Diazepam. heart. (E). Blockade of ganglionic transmission at sym- 27. A 10-year-old boy with generalized tonic sei- pathetic ganglia in the periphery. zures is seen by his dentist at a routine checkup. The dentist observes that the patient has an overgrowth of 22. A 21-year-old man is a full-time college student gum tissue. The patient was most likely receiving who also works 25 hours per week. Over the past 3 which of the following agents? months he has become increasingly anxious. He says (A). Ethosuximide. he is tired most of the time and has trouble concentrat- (B). Clonazepam. ing on his studies. Which of the following drugs would (C). Primidone. be the most appropriate initial pharmacologic treat- (D). Phenytoin. ment for his anxiety? (E). Zonisamide. (A). Phenobarbital. (B). Alprazolam. 28. The metabolism of which AED frequently dis- (C). Zolpidem. plays zero-order kinetics following moderate to high (D). Hydroxyzine. therapeutic doses? (E). Propranolol. (A). Carbamazepine. (B). Phenytoin. 23. A 33-year-old woman has recently undergone (C). Valproic acid. a divorce. She reports that although she is exhausted, (D). Ethosuximide. it usually takes her 2 or more hours to fall asleep at (E). Zonisamide. night. Which of the following drugs would help relieve her sleep disturbance while being least disruptive to 29. Many anticonvulsant drugs, as a major part of REM sleep? their mechanism of action, block the sodium channel, but (A). Triazolam. other effective agents do not use this mechanism. Which (B). Chloral hydrate. of the following anticonvulsants has the ability to block (C). Zolpidem. T-calcium currents as its primary mechanism of action? (D). Amobarbital. (A). Ethosuximide. (E). Hydroxyzine. (B). Phenytoin. (C). Topiramate. 24. A 54-year-old man is scheduled for an elective (D). Carbamazepine. colonoscopy that will take approximately 20 minutes. (E). Lamotrigine. Which of the following drugs would be most likely to produce the desired anaesthesia and antero-grade am- 30. A 14-year-old patient is diagnosed with absence nesia? epilepsy. Any of the following drugs could be consid- (A). Buspirone. ered a reasonable choice to prescribe EXCEPT (B). Zephalon. (A). Ethosuximide. (C). Midazolam. (B). Phenobarbital. (D). Chlordiazepoxide. (C). Carbamazepine. (E). Hydroxyzine. (D). Valproic acid.

80 31. Which of the following agents has the capacity (D). Clozapine. to inhibit the reuptake of GABA into neurons and glia? (E). Carbamazepine. (A). Zonisamide. (B). Vigabatrin. 38. Tardive dyskinesia after long-term antipsychot- (C). Tiagabine. ic administration is thought to be due to (D). Ethosuximide. (A). A decrease in dopamine synthesis. (E). Gabapentin. (B). Enhanced stimulation of D2 dopamine auto- receptors. 32. Which of the following antidepressants is most (C). Loss of cholinergic neurons in striatum. selective for inhibition of neuronal reuptake of serot- (D). Up-regulation of striatal dopamine receptors. onin? (E). Increased tolerance to antipsychotic agents. (A). Mirtazapine (Remeron). (B). Venlafaxine (Effexor). 39. Which neuroleptic agent has the lowest likeli- (C). Bupropion (Wellbutrin). hood of producing tardive dyskinesia? (D). Sertraline (Zoloft). (A). Imipramine. (E). Imipramine (Tofranil). (B). Chlorpromazine. (C). Clozapine. 33. In a patient with a seizure disorder, which anti- (D). Fluoxetine. depressant is contraindicated? (E). Thiothixene. (A). Nefazodone (Serzone). (B). Fluoxetine (Prozac). 40. Which clinical condition poses the greatest (C). Venlafaxine (Effexor). concern to a patient on antipsychotic therapy? (D). Mirtazapine (Remeron). (A). Epilepsy. (E). Bupropion (Wellbutrin). (B). Nausea associated with motion sickness. (C). Manic phase of bipolar disorder. 34. Mr. Smith is 28 years old and has no active (D). Hallucinogen-induced psychosis. + medical problems. He has been treated with Li for (E). Tourette’s syndrome. manic-depressive illness for 1 year, and his mood has been stable. He now reports the gradual onset of fa- 41. Mr. James began haloperidol therapy for schiz- tigue, weight gain, and cold intolerance. Which sin- ophrenia and within several weeks developed brady- gle laboratory test is most likely to lead to the correct kinesia, rigidity, and tremor. Though his psychoses diagnosis? were well controlled, he was switched to another agent, (A). TSH (thyroid-stimulating hormone). thioridazine, which proved to be as effective as ha- (B). Hepatic function panel. loperidol in managing his primary condition and did (C). Glucose tolerance test. not result in the undesirable symptoms. The most like- (D). Hematocrit. ly explanation for these observations is that (E). Serum prolactin level. (A). Haloperidol acts presynaptically to block dopamine release. 35. Which of the following antidepressants requires (B). Haloperidol activates GABA-ergic neurons therapeutic blood monitoring for safe use? in the striatum. (A). Paroxetine (Paxil). (C). Haloperidol has a low affinity for D2-rece- (B). Phenelzine (Nardil). ptors. (C). Nortriptyline (Pamelor). (D). Thioridazine has greater α-adrenergic block- (D). Venlafaxine (Effexor). ing activity than haloperidol. (E). Bupropion (Wellbutrin). (E). Thioridazine has greater muscarinic blocking activity in brain than haloperidol. 36. Which of the following statements about antidepressant medications is most appropriate? 42. Which drug may be useful in the management (A). They all have a delay of approximately 48 of the neuroleptic malignant syndrome, although it can hours for onset of benefit. worsen the symptoms of schizophrenia? (B). There are large differences in efficacy among (A). Risperidone. individual agents. (B). Thiothixene. (C). Some benefit is expected in 65 to 80% of pa- (C). Haloperidol. tients treated with an antidepressant for ma- (D). Bromocriptine. jor depression. (E). Valproic acid. (D). The major contribution of the newer antidepressants lies in the marked improvement in duration of action. ANSWERS 37. Which of the following agents possesses pharmacological actions characterized by high antipsy- 1. (A). Unless supplemented with strong analgesic drugs such as opioids, most general anaesthetics allow chotic potency, high potential for extrapyramidal tox- reflex reactions to painful stimuli, which may include icity, and a low likelihood of causing sedation? movement and autonomic reflex changes. Even though (A). Thioridazine. these reflex changes occur, if adequately anaesthetized, (B). Haloperidol. patients will not experience the noxious stimulus. To give (C). Flumazenil. this patient a neuro-muscular blocking agent without in-

81 itially evaluating the adequacy of anaesthesia would be associated with high doses of phenylpiperidine opioids a mistake. A lawsuit is almost certain, should the patient in particular, and no evidence suggests that remifentanil be inadequately anaesthetized and complain postopera- would be any less likely to cause such an effect. tively of being aware but paralyzed. If it is determined 5. (E). Reduced peripheral vascular resistance occurs that the patient is receiving adequate anaesthesia (i.e. eval- with most halogenated hydrocarbons, and reflex tachy- uate the delivery of gas, and check other reflexes such as cardia may be a concern. Halothane may be the clearest corneal), the use of a neuromuscular blocking drug may exception, since there appears to be a balance between be acceptable if movement is interfering with the proce- relaxation and constrictor influences in various vascu- dure. Morphine may be a reasonable supplement to an- lar beds with this agent so that total peripheral resist- aesthetic management to inhibit reflex reactions to nox- ance changes very little. Halothane is the agent of con- ious stimuli. Raising the inspired concentration of iso- cern when sensitization of the myocardium to catecho- flurane may further blunt reflex reactions to noxious lamine-induced arrhythmias may be important, such as stimuli. However, it may not be a wise choice, since mul- during incidences of hypercapnia. Sevoflurane does not tiples of MAC may cause greater instability of physio- directly influence sympathetic function. However, reflex logical functions (i.e. cardiovascular function). Use a bal- tachycardia can occur. Reflex sympathetic stimulation is anced anaesthetic approach with adjunctive agents. The blocked by halothane. In fact, this may be an advantage gut is quite responsive to noxious insult, but the reflex of the drug in physiologically risky patients when swings responses are still inhibited with proper analgesics, so in blood pressure are likely to be frequent. muscular movement is avoidable. 6. (D). Although few contend that a unitary hypothe- 2. (B). Perfusion of the brain is preserved when hem- sis will explain anaesthesia, the Meyer Overton rule was orrhage occurs. Thus, a greater proportion of the initial among the first explanations provided by the scientific dose of anaesthetic should appear in the brain, and a dose community. The correlation remains significant, as it sug- smaller than what is needed for a normovolemic patient gests that sites of action for various anaesthetics may re- is all that is required. Also, since flow to tissues associ- side near (or the agent must pass though) hydrophobic ated with redistribution of the drug and termination of tissue components. Also, physical disruption of mem- anaesthesia is compromised, anaesthesia should be deep brane function may yet be found to play a role for at and extended. Titrate this patient to a safe level of effect. least some agents. Option (A) is the reverse of the true While poor perfusion of the liver may reduce the expo- interaction. Several sites on the GABA receptor complex sure of drugs to metabolic enzymes, most intravenous may be involved. Cl moves inward to cause cells to be- anaesthetics rely very little on hepatic clearance to ter- come less excitable. Enantiomers, which have nearly iden- minate the anaesthetic effect when a single bolus is ad- tical physical properties but different potencies, challenge ministered. Furthermore, the question implies a direct the Meyer Overton rule. influence of blood pressure on the efficiency of hepatic 7. (D). The purpose of this question is to identify first enzymes, and there is no evidence to support such a con- opioids that produce analgesia and then those with a me- tention. Option (C) is not true. The opposite of option tabolite that compounds the analgesic effects of the drug (D) is true. No evidence exists that binding of anaesthet- by being an active analgesic. Naloxone and nalmefene are ics is altered by these conditions. not analgesics but opioid antagonists. Codeine is metab- 3. (D). Anaesthetics with low blood and tissue solu- olized to an active analgesic metabolite, morphine. Mepe- bility require minimal uptake from the lung, as alveolar ridine and propoxyphene have nonanalgesic, excitatory, partial pressure equilibrates with tissue. Remember, al- and proconvulsant metabolites. veolar partial pressure is the driving force to establish 8. (B). The purpose of this question is to clarify the tension gradients throughout the body. Thus, when up- uses and limitations of use of the COX-2 selective intake is low and alveolar tension rises quickly, blood and hibitor celecoxib. Celecoxib, by inhibiting COX-2 re- brain (which receives a high blood flow) equilibrate with versibly, will block the activity of both injury induc- gaseous agents quickly, and anaesthesia is induced rela- ible COX-2 and the small amount of constitutive COX- tively rapidly. A gas that is highly soluble in tissues re- 2. COX-2 inhibition has been shown to produce some quires a greater accumulation from the lung before par- GI bleeding, albeit less than with the nonselective COX tial pressure equilibria are attained, since with greater inhibitors. If a patient has ulcerations and bleeding, uptake the rate of rise of the alveolar tension to the in- COX-2 inhibitors will prolong healing by blocking spired level is slower. Although a relationship exists be- the protective effects of COX-2 in the GI tract. Celecox- tween MAC and blood solubility with respect to anaes- ib is indicated for both osteoarthritis and rheumatoid thetic concentration in the tissues, the association sug- arthritis. gested by choice (B) is opposite the expectation. Consid- 9. (C). The purpose of this question is to clarify the er the implications of the Meyer Overton rule. An agent cellular mechanism of analgesia produced by morphine. with a high Ostwald solubility coefficient is one of the First, morphine blocks the transmission of nociceptive more soluble agents in tissue, so the explanation of op- impulses. In that case, the relevant question is how noci- tion (A) applies. Option (E) has no apparent bearing on ceptive impulses are transmitted via the release of pro- the rate of rise of the alveolar partial pressure in brain, nociceptive neurotransmitters. The question then is to alveolus, or any other tissue. determine which intracellular process favors a block of 4. (C). Remifentanil has become popular as a compo- release of neurotransmitters. The correct answer is (C) be- nent drug in the technique of total intravenous anaes- cause calcium is required for neurotransmitter release. thesia as a consequence of this feature. It is distribution Blocking potassium efflux and increasing calcium chan- of blood to the brain, not specific pharmacological prop- nel phosphorylation produce functional depolarization erties, that primarily controls the rate of induction of and neurotransmitter release. Opioids are coupled to Gi anaesthesia with IV agents. Phenylpiperidines as a class (inhibitory proteins) that decrease cAMP. of opioids are less likely to produce histamine release. 10. (C). The purpose of this question is to clarify the Moreover, histamine release may complicate anaesthetic functional significance of the activation of opioid recep- management (e.g. bronchoconstriction and hypotension), tor types. Respiratory depression and bradycardia are µ so if it were an action of remifentanil it would be a neg- associated with the 2-opioid receptor. Mydriasis is as- ative feature. Remifentanil’s duration of action is short sociated with the σ-receptor, which is no longer thought because it is rapidly metabolized. Chest wall rigidity is of as opioid. Opioids, via respiratory depression, induce

82 hypercapnia, a build-up of carbon dioxide. The clinically 19. (A). Analeptic stimulants, such as pentylenetetra- relevant sign of opioid overdose and opioid use is mio- zol and picrotoxin, act by inhibiting chloride influx at κ sis, pinpoint pupils, mediated by -receptor activation. the GABAA receptor-chloride channel complex. This an- 11. (E). Fentanyl patches have the same effect as fen- tagonism can occur through interaction with one of sev- tanyl, only in a time-release manner. Thus, the purpose eral binding sites or allosteric modifiers of receptor-chan- of the question is delineation of opioid effects — respi- nel function. ratory depression and constipation. The respiratory de- 20. (B). Methylxanthines have been proposed to be pression is life-threatening when the patch is used in non- inhibitors of phosphodiesterase, which would elevate in- ambulatory patients, and it is therefore contraindicated tracellular levels of cAMP. However, the concentration for that purpose. Similarly, fentanyl is a teratogenic drug of cAMP that is required for such action is above the contraindicated for use during pregnancy. The fentanyl threshold of CNS stimulation. Since the methylxan- patch does not induce anaesthesia (loss of consciousness) thines are relatively potent antagonists of adenosine and but does produce analgesia. since adenosine has been shown to be a reasonably po- 12. (A). By blocking renal prostaglandin synthesis, tent inhibitor of both central and peripheral neurons, the COX-2 inhibitors, such as rofecoxib, decrease the blood most likely mechanism by which CNS stimulation oc- flow to the juxtaglomerular apparatus, thus stimulating curs is through antagonism of adenosine receptors. the release of renin and subsequent Na+ retention and 21. (B). Psychomotor stimulants such as amphetamine blood pressure elevation. Rofecoxib is neither metabo- are also indirectly acting sympathomimetics that in- lized nor induced by CYP2C9. It decreases rather than crease the release of catecholamines from sympathetic increases renal blood flow and does not increase the ex- nerve terminals. While amphetamine and other congeners cretion of hydrochlorothiazide. Item (D) is incorrect be- possess additional actions on peripheral sympathetic cause rofecoxib has very little effect on COX-1 and pros- nerves, this is the most likely explanation for the cardi- taglandins are not a major controlling factor of periph- ac stimulation observed following the administration of eral vascular tone. Rofecoxib does not decrease basal met- these agents. abolic rate. 22. (B). The young man’s anxiety is probably caused 13. (E). Treatment guidelines suggest the use of by the stress induced by a full college curriculum along DMARDs early in the course of rheumatoid arthritis to with working 25 hours per week. A benzodiazepine an- slow the joint deterioration associated with the disease. tianxiety agent would help relieve his symptoms. Methotrexate is the DMARD of choice for people with 23. (C). Zolpidem is effective at relieving sleep-onset moderate to severe forms of rheumatoid arthritis. Al- insomnia. The other agents listed could also induce sleep, though NSAIDs can decrease methotrexate clearance, although each would be expected to produce more dis- NSAIDs can be safely used with the low doses of meth- ruption of sleep rhythm than would zolpidem. otrexate used in the therapy of rheumatoid arthritis. 24. (C). Midazolam, like all benzodiazepines given in Methotrexate is highly teratogenic and should not be sufficient dose, has the capacity to produce anterograde used by women who are or may become pregnant. amnesia. It is also available in an injectable form and 14. (C). The likelihood of gastric ulceration and GI frequently is used as an anaesthetic agent during short bleeding is increased by heavy alcohol use, poor health, procedures. advanced age, long-term NSAID use, and use of drugs 25. (B). Chlordiazepoxide, through its metabolites, has such as corticosteroids and anticoagulants. Ibuprofen is a relatively long biological half-life. It will prevent many not converted to a cardiotoxic metabolite. Dermal tox- of the severe symptoms of acute alcohol withdrawal. Bus- icities, such as epidermal necrolysis, are rare complica- pirone is not a sedative and will not suppress alcohol tions of ibuprofen therapy, but necrotizing fasciitis is withdrawal. The other agents have sedative properties and not one of them. Confusion and ataxia are not side ef- could potentially suppress alcohol withdrawal but each fects associated with ibuprofen, nor is eosinophilia. has a much shorter biological half-life than chlo- 15. (D). Etanercept is a recombinant fusion protein rdiazepoxide. consisting of two TNF receptor domains linked to one 26. (D). As a β-adrenoceptor blocker, Propranolol can IgG Fc molecule. It binds to soluble TNF-α and TNF-β relieve many of the symptoms of stage fright. For this and forms inactive complexes. It does not directly affect use it can be taken once a few hours before the perform- cAMP phosphodiesterase, leukotriene synthesis, or au- ance. Chronic dosing is usually not necessary. The other toantibody production. agents produce sedation. 16. (A). Celecoxib selectively inhibits COX-2, so it 27. (D). This is a rather specific effect of phenytoin. does not inhibit the constitutive activity of COX-1 in the Although the gum tissue can be cut back and in some regulation of gastric acid secretion. When prostaglandin cases overgrowth prevented with good oral hygiene, this synthesis by COX-1 or COX-2 is blocked, eicosanoids is a source of embarrassment to the patient and consti- are shifted into the leukotriene pathway, so bronchos- tutes a deterrent to the use of this agent. pasm and hypersensitivity reactions are favored. The 28. (B). Phenytoin is one of a handful of drugs that dem- shorter half-life of celecoxib does not allow once-daily onstrates zero-order (or saturation) kinetics. If a patient is dosing. This drug is no less able than other NSAIDs to showing signs of toxicity to phenytoin, it is important to close the ductus arteriosus during the third trimester. measure blood levels, since the likelihood that phenytoin None of the NSAIDs is empirically more efficacious than is demonstrating zero-order kinetics is very high. the others; a patient’s own response and side effects de- 29. (A). Ethosuximide has no effect on blocking the so- termine the best drug for him or her. dium channel at therapeutics doses; however, it is very 17. (C). Glycine is the major inhibitory amino acid effective in blocking the T-calcium current in the thera- transmitter in the spinal cord, and strychnine is a rela- peutic dose range. All other choices block the sodium tively selective antagonist of glycine. Strychnine has very channel at therapeutic doses, and it is acknowledged that little if any action at the GABA receptor-chloride chan- this is their sole (or major) mechanism of action. nel complex. 30. (C). The only drug listed that would be expected 18. (D). Attention deficit-hyperkinetic disorder and at- to offer no benefit to a patient with absence seizures is tention deficit disorder are among only a few approved carbamazepine. In fact, there is clinical evidence that it uses of the psychomotor stimulants of the amphetamine may actually increase the incidence of absence seizure ep- type. isodes.

83 31. (C). Tiagabine is the first agent that has been shown with a D2-receptor antagonist causes depolarization in- to elevate GABA levels by inhibiting the reuptake of this activation of dopamine neurons with diminished trans- neurotransmitter at neuronal and glial sites in the brain. mitter production and release. However, a decrease in Vigabatrin can also elevate GABA levels, but it does so dopamine synthesis has not been linked with tardive dys- by inhibiting the metabolism of GABA. kinesia. On the contrary, lower dopamine tone would 32. (D). Mirtazapine acts at serotonin and adrenergic more resemble a parkinsonian state, whereas in tardive receptors and does not effect reuptake of neurotransmit- dyskinesia, antidopaminergic drugs tend to suppress the ters. Venlafaxine is a mixed serotonin-norepinephrine re- dyskinetic symptoms, and dopaminergic agonists wors- uptake inhibitor. Bupropion inhibits norepinephrine en the condition. Therefore, it is generally accepted that and dopamine reuptake. Imipramine is a TCA with up-regulated dopamine receptors underlie tardive dysk- mixed serotonin and norepinephrine properties. Sertra- inesia. There is no evidence that the antipsychotics lead line belongs to the class of antidepressants know as the to loss of striatal cholinergic neurons. SSRIs and selectively blocks neuronal reuptake of sero- 39. (C). Tardive dyskinesia is an extrapyramidal re- tonin. action that occurs most commonly after long-term ad- 33. (E). Nefazodone, Fluoxetine, Mirtazapine, and Ven- ministration of high-potency butyrophenone, thioxan- lafaxine have minimal effects on seizure threshold. Bu- thene, or phenothiazine. Thus, thiothixene is not a good propion in its original formulation caused seizures in 4 choice. Chlorpromazine is a low-potency phenothiazine in 1,000 patients. Although this has been reduced with agent with moderate potential to cause extrapyramidal the slow release form of the medication (Wellbutrin SR), signs. Clozapine is well known to have the lowest po- it remains a contraindication to prescribe this medica- tential for producing tardive dyskinesia during chron- tion to patients with a history of seizures. ic therapy. It has other undesirable side effects, but clin- 34. (A). Approximately 5% of patients taking lithi- ical experience with other newer atypical antipsychot- um over the long term develop hypothyroidism, and thy- ics is not sufficient to establish their potential for caus- roid status should be followed as routine care for these ing this disorder. Imipramine and fluoxetine are anti- patients. Mr. Smith’s symptoms are classic for hypothy- depressants. roidism. Impairment in glucose metabolism, hepatic func- 40. (A). The question concerns actions of antipsychotic tion, red blood cell production, and prolactin secretion agents that may have untoward consequences when com- are not typical complications of lithium therapy. bined with other coincident or preexisting medical con- 35. (C). Nortriptyline (Pamelor) is a TCA, and as a class ditions. These drugs have an activating effect on the EEG these drugs require at least one steady-state blood level in epileptic patients and thus may worsen that condition. to safely and effectively use the medication. Paroxetine, Generally, the antipsychotics have antiemetic properties venlafaxine, and bupropion have not had blood levels but generally are more potent than is necessary to treat correlated to response, and their relatively low toxicity motion sickness. The other three conditions listed (C), does not require therapeutic blood monitoring. Nardil (D), and (E) are indications for the use of antipsychotic is a MAOI, which can be lethal in overdose, but blood agents. levels are not used to monitor for efficacy or toxicity. 41. (E). The question concerns the emergence of par- 36. (C). All agents have a delay of approximately 48 kinsonian signs relatively early in a patient’s therapy for hours. There are no significant differences in efficacy schizophrenia and their elimination by switching treat- among the individual agents. The major contribution of ment to a second agent, thioridazine. Haloperidol has the newer antidepressants is in their improved safety and high affinity for D2-dopaminergic receptors and is well tolerability. known to have a high potential for causing these kinds 37. (B). The question describes the pharmacological of extrapyramidal signs. The drug has no direct action profile of a high-potency classical antipsychotic agent, on GABAergic neurons and does not act presynaptical- most likely of the butyrophenone or phenothiazine class. ly to affect dopamine release. While thioridazine binds Thioridazine is a low-potency piperidine phenothiazine to D2-dopaminergic receptors with an affinity similar to α agent with significant affinity for 1-adrenergic and mus- that of haloperidol, it also has much greater antimuscarinic receptors, having a high potential for sedation as carinic activity. This latter action can compensate for a side effect. Haloperidol is a high-potency butyrophenone dopamine receptor blockade in the nigrostriatal tract, so with its primary action at the D2 dopaminergic receptor, that extrapyramidal function is more appropriately main- so it produces a significant incidence of extrapyramidal tained. Thioridazine has greater α-adrenergic blocking ac- toxicity and little sedation. Clozapine is a low-potency tivity than Haloperidol, but this is not thought to play atypical antipsychotic that binds primarily to D4, 5-HT2, a role in elimination of the parkinsonian signs. and at-receptors and possesses very little extrapyrami- 42. (D). The neuroleptic malignant syndrome is an in- dal toxicity but significant sedative and autonomic side frequent extrapyramidal reaction with a relatively high effects. Flumazenil is a benzodiazepine antagonist, and rate of lethality. It is marked by muscle rigidity, high carbamazepine is an anticonvulsant; neither possesses fever, and autonomic instability. It may result from too- significant antipsychotic properties. rapid block of dopaminergic receptors in individuals 38. (D). This question concerns the most important who are highly sensitive to the extrapyramidal effects of extrapyramidal reaction to long-term antipsychotic ad- antipsychotic drugs. Management consists of control of ministration tardive dyskinesia and its generally accept- fever, use of muscle relaxants, and administration of the ed basis. Although some tolerance to the sedative effects dopamine agonist Bromocriptine, which is likely to wors- of antipsychotics can occur, there is no evidence linking en the psychotic symptoms. Choices (A) to (C) are an- this to tardive dyskinesia. Antipsychotic agents enhance tipsychotics and would likely worsen neuroleptic malig- dopamine synthesis acutely by blocking D2-autorecep- nant syndrome. Valproic acid has antimanic, antimi- tors by which the transmitter normally inhibits graine, and anticonvulsant properties, but it is not used dopamine cell firing and synthesis. Long-term treatment to treat the syndrome in question.

84 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM

Lecture 21 Sources. Official digitalis is the dried leaf of the foxglove plant, Digitalis purpurea. Digitalis lanata CARDIAC GLYCOSIDES leaves are used in Europe and are the source of certain purified preparations. Strophanthus is obtained from the seeds of the Strophanthus Kombe or Hispid- The cardiac glycosides are a group of chemically us; ouabain is derived from Strophanthus gratus. similar compounds that can increase the contractility Chemical nature. Each glycoside molecule consists of the myocardium and are therefore widely used in of aglycone (or genin) attached to glycone (from one treating heart failure. to four molecules of sugar). The particular sugars mod- A large number of plats extracts containing cardi- ify water and lipid solubility, potency, and the phar- ac glycosides have been used by native in various parts macokinetic properties, while pharmacologic activity of the world as arrow and ordeal poisons. Squill was resides in the aglycone. Basic structure of the aglycone known as a medicine to the ancient Egyptians. is a cyclopentaneperhydrophen nucleus to which is at- The Romans employed it as a diuretic, heart ton- tached an unsaturated lactone ring. The aglycones are ic, emetic, and rat poison. The dried skin of the com- chemically related to bile acids, sterols, and steroid mon toad has been used for centuries as a drug by Chi- hormones. nese. Digitalis or foxglove was mentioned in 1250 in Congestive heart failure (CHF). CHF is a condi- the writings of Welsh physicians. tion in which the heart is unable to transfer venous re- In 1775, Dr. William Withering was making a rou- turn into adequate cardiac output. CHF can be caused tine journey from Birmingham (England) to see patients by an impaired ability of the cardiac muscle to con- at the Stafford Infirmary. While the carriage horses tract or by an increased workload imposed on the were being changed half way, he was asked to see an heart. CHF is accompanied by abnormal increases in old dropsical woman. He thought she would die and blood volume and interstitial fluid; the heart, vein, and so some weeks later, when he heard of her recovery, capillaries are therefore generally dilated with blood. was interested enough into the cause. Recovery was at- Hence the term “congestive” since the symptoms in- tributed to an herb tea containing foxglove as an include pulmonary congestion with left heart failure and gredient. He began to investigate its properties, try- peripheral edema with right heart failure. Underlying ing it on the poor of Birmingham, whom he used to causes of CHF include arteriosclerotic heart disease, see without fee each day. Withering found that fox- valvular heart disease, dilated cardiomyopathy, and glove extracts caused diuresis in some edematous pa- congenital heart disease. The most common cause of tients. He defined the type of patients who might ben- heart failure is left systolic dysfunction secondary to efit from it, and equally important he standardized coronary artery disease. his foxglove leaf preparations and was able to lay The therapeutic goal for CHF is to increase car- down accurate dosage schedules. Crude foxglove prep- diac output. Three classes of drugs have been shown arations are called ‘digitalis’. In 1785, William With- to be clinically effective in reducing symptoms and ering published his famous book entitled An Account prolonging life: 1) vasodilators that reduce the load of the Foxglove and Some of Its Medical Use: With on the myocardium; 2) diuretic agents that decrease Practical Remarks on Dropsy and Other Diseases. extracellular fluid volume; 3) inotropic agents that Apparently Withering did not associate digitalis ef- increase the strength of contraction of cardiac mus- fectiveness in dropsy (edema) with cardiac action of cle. [Note: These agents relieve the symptoms of car- the drug. Probably, John Ferrier in 1799 was the first diac insufficiency but do not reverse the underlying to ascribe to digitalis a primary action on the heart condition.] and to relegate the diuretic effect to a position of sec- Knowledge of the physiology of cardiac muscle ondary importance. Only subsequently was it estab- contraction is clearly essential to an understanding of lished that digitalis is valuable for the therapy of con- the compensatory responses evoked by the failing gestive heart failure. heart, as well as the action of drugs used to treat CHF.

85 PHYSIOLOGY OF MUSCLE ated muscle. The force of contraction of the cardiac CONTRACTION muscle is directly related to the concentration of free (unbound) cytosolic calcium. Therefore agents that in- The myocardium, like smooth and skeletal muscle, crease these calcium levels (or increase the sensitivity responds to stimulation by depolarization of the mem- of the contractile machinery to calcium) result in the brane; this is followed by shortening of the contractile force of contraction (inotropic effect). [Note: The ino- proteins and ends with relaxation and return to the rest- tropic agents increase the contractility of the heart by ing state. However, unlike skeletal muscle, which directly or indirectly altering the mechanisms that con- shows graded contractions depending on the number trol the concentration of intracellular calcium.] of muscle cells stimulated, the cardiac muscle cells are 1. Sources of free intracellular calcium: Ca++ comes interconnected in groups that respond to stimuli as a from two sources. The first is from outside the cell, unit, contracting together whenever a single cell is stim- where opening of voltage-sensitive Ca++ channels caus- ulated. es an immediate rise in free cytosolic Ca++. The sec- Action potential. Cardiac muscle cells are electri- ond source is the release of calcium from the sarcoplas- cally excitable. However, unlike the cells of other mus- mic reticulum and mitochondria, which further increas- cles and nerves, the cells of cardiac muscles show a es the cytosolic level of calcium. spontaneous, intrinsic rhythm generated by special- 2. Removal of free cytosolic Ca++: If free cytosolic ized “pacemaker” cells located in the sinoatrial (SA), level were to remain high, the cardiac muscle would and atrioventricular (AV) nodes. The cardiac cells also be in a constant state of contraction, rather than show- have an unusually long action potential, which can be ing a periodic contraction. Mechanisms of removal in- divided into five phases (0 to 4; Fig. 15). Na+, K+, Ca++ clude two alternatives. are the major ions contributing to depolarization and a. Sodium-calcium exchange: Ca+ is removed by a polarization of cardiac cells. These ions pass through sodium-calcium exchange reaction that reversibly ex- channels in the sarcolemmal membrane and thus cre- changes calcium ions across the cell membrane. This ate a current. The channels open and close at differ- interaction between the movement of Ca2+ and Na+ is ent times during the action potential; some respond significant, since changes in intracellular Na+ can af- primarily to changes in ion concentration, whereas fect cellular levels of Ca++. other are either adenosine triphosphate (ATP)- or volt- b. Uptake of Ca++ by the sarcoplasmic reticulum age-sensitive. and mitochondria: Ca++ is also recaptured by the sar- Cardiac contraction. The contractile machinery of coplasmic reticulum and the mitochondria. More than the myocardial cell is essentially the same as in a stri- 99% of the intracellular calcium is located in these or-

Na+ channels open (fast channels) The initial rapid phase of repolarization is due to: resulting in a fast inward current. 1) inactivation of Na+ channels; 2) K+ channels Upstroke ends as Na+ channels are rapidly open and close causing a transient outward rapidly inactivated. current.

‘PLATEAU’ Voltage-sensitive Ca++ channels mV open, resulting in slow inward (depolarizing) current that balances the slow (polarizing) outward leak of K+. 1

2 Ca++ channels close. K+ channels open resulting 0 in outward current and repolarization.

0 The spontaneous depolarization 3 brings the cells to the threshold of the next action potential.

-50 4

0 0.5 1.0 (second) Fig. 15. Action potential

86 ganelles, and even a modest shift between these stores CHF may have diastolic dysfunction — a term applied and free calcium can lead to the large changes in the when the ventricles’ ability to relax and accept blood concentration of free cytosolic calcium. is impaired by structural changes, such as hypertrophy. The thickening of the ventricular wall and subsequent decrease in ventricular volume decreases the abil- COMPENSATORY PHYSIOLOGICAL ity of heart muscle to relax. In this case, the ventricle RESPONSES IN CHF does not fill adequately, and the inadequacy of cardiac output is termed diastolic heart failure. The failing heart evokes three major compensatory mechanisms to enhance cardiac output (Fig. 16). Increased sympathetic activity. Baroreceptors sense DECOMPENSATED HEART FAILURE a decrease in blood pressure, and trigger activation of β-adrenergic receptors in the heart. This results in an If the mechanisms listed above adequately restore increase in heart rate and a grater force of contrac- cardiac output, then the heart failure is said to be com- tion of the heart muscle. In addition, vasoconstriction pensated. However, these compensations increase the (a1-mediated) enhances venous return and increases work of the heart and contribute to further decline in cardiac preload. These compensatory responses in- cardiac performance. If the adaptive mechanisms fail crease the work of the heart and, therefore, can con- to maintain cardiac output, the heart failure is termed tribute to the further decline in cardiac function. decompensated. Fluid retention. A fall in cardiac output decrease blood flow to the kidney, prompting the release of renin, THERAPEUTIC STRATEGIES IN CHF with a resulting increase in the synthesis of angiotensin ІІ and aldosterone. This result in increased peripher- Chronic heart failure is typically managed by real resistance and retention of sodium and water. Blood duction in physical activity, low dietary intake of so- volume increases and more blood is returned to the dium (less than 1,500 mg sodium per day), and treat- heart. If the heart is unable to pump this extra volume, ment with vasodilators, diuretics and inotropic agents. venous pressure increases and peripheral edema and Patients with CHF complain of dyspnea on exertion, pulmonary edema occur. These compensatory respons- orthopnea, paroxysmal nocturnal dyspnea, fatigue, es increase the work of the heart and, therefore, can and dependent edema. Positive inotropic agents en- contribute to the further decline in cardiac function. hance cardiac muscle contractility, and thus increase Myocardial hypertrophy. The heart increases in cardiac output. size, and the chambers dilate. Initially, stretching of the heart muscle leads to a stronger contraction of the heart. However, excessive elongation of the fibers re- DIGITALIS sults in weaker contraction. This type of failure is termed systolic failure and is a result of a ventricle un- The cardiac glycosides are often called digitalis able to pump effectively. Less commonly, patients with glycosides because most of the drugs come from the dig-

Cardiac failure

Venous pressure Cardiac output Sympathetic activity Blood pressure Renal blood flow Renin, angiotensin II Aldosterone Capillary filtration Sodium and water retention

Edema

Fig. 16. Compensatory physiological responses in congestive heart failure

87 italis (foxglove) plant. The cardiac glycosides increase Therapeutic uses. Digoxin therapy is indicated in cytoplasmic calcium concentration in the cardiac mus- patients with severe left ventricular systolic dysfunc- cle, thereby enhancing contraction of the atrial and tion after initiation of diuretic and vasodilator thera- ventricular myocardium (positive inotropic effect). The py. Digoxin is not indicated in patients with diastolic digitalis glycosides show only a small difference be- or right-sided heart failure. Dobutamine, another ino- β tween a therapeutically effective dose and doses that tropic agent ( 1-adrenergic agonist), can be given in- are toxic or even fatal. Therefore, the drugs have a low travenously in the hospital, but at present no good oral therapeutic index. The digitalis glycosides include dig- inotropic agents exist other than Digoxin. Patients with itoxin and the most widely used agent, Digoxin. mild to moderate heart failure will often respond to Mechanism of action: treatment with ACE inhibitors and diuretics and do not Regulation of cytosolic calcium concentration. require Digoxin. Digitalis is also used to slow ventricu- Cardiac glycosides combine reversibly with the sodi- lar rate in patients with atrial fibrillation or flatter (de- um-potassium ATPase of the cardiac cell membrane, creased conduction in AV node protects the ventricles resulting in an inhibition of pump activity (Fig. 17). from excessive bombardment in atrial dysrhythmias). This causes an increase in the intracellular sodium con- Pharmacokinetics. All cardiac glycosides possess centration, which favors the transport of calcium into the same pharmacologic actions, but they vary in po- the cell via the Na+/Ca++ exchange mechanism. The tency and pharmacokinetics (Table 7). Digoxin and elevated intracellular Ca++ levels result in an increase Digitoxin are absorbed after oral administration. Note in the systolic force of contraction. that Digitoxin binds strongly to proteins in the ex- Increased contractility of the cardiac muscle. An travascular space, resulting in a large volume of dis- increased myocardial contraction leads to a decrease tribution. Digoxin has the advantage of a relatively in end systolic volume, thus increasing the efficiency short half-life, which allows better treatment of toxic of contraction (increased ejection fraction). The result- reactions. Digoxin also has a more rapid onset of ac- ing improved circulation leads to reduced sympathet- tion, making it useful in emergency situations. Digox- ic activity, which then reduces peripheral resistance. in is eliminated largely unchanged in the urine. Digi- Together, these effects cause a reduction in heart rate. toxin is extensively metabolized by the liver before ex- Vagal tone is also enhanced so the heart rate decreas- cretion in the feces. es and myocardial oxygen demand is diminished. Adverse effects. Digitalis toxicity is one of the most [Note: In the normal heart, the positive inotropic ef- commonly encountered adverse drug reactions. Side fect of digitalis is counteracted by compensatory au- effects can be often managed by discontinuing glyco- tonomic reflexes.] side therapy, determining serum potassium levels, and if indicated, by giving potassium supplements. In gen- Basic effects of cardiac glycosides include: eral, decreased serum levels of potassium predispose a a. Positive inotropic effect (increased force of con- patient to glycoside toxicity. Severe toxicity resulting traction). in ventricular tachycardia may require administration b. Negative chronotropic effect (reduction in heart of antiarrhythmic drugs, and the use of antibodies rate). (FAB fragments) to the glycoside, which bind and in- c. Negative dromotropic effect (decreased or activate the drug. blocked atrioventricular conduction). Types of adverse effects include: d. Positive bathmotropic effect (increased myocar- Cardiac effects. The major effect is progressively dial excitability). more severe dysrhythmia, moving from decreased or blocked atrioventricular nodal conduction, paroxysmal The ECG effects of cardiac glycosides. PR inter- supraventricular tachycardia, premature ventricular val is prolonged (delayed conduction); QT interval is depolarization, ventricular fibrillation, and finally, to shortened (increased contractility); T wave becomes complete heart block. A decrease in intracellular potas- smaller or inverted. sium is the primary predisposing factor in these effects.

K+ Ca++ Ca++ Na+

1. Digitalis inhibits Na+-K+ exchange by Na+/K+-ATPase

Na+ K+ Ca++ Na+ Ca++

3. Increased Na+ leads 2. Intracellular to greater Ca++ influx Na+ increases

Fig. 17. Mechanism of action of cardiac glycosides

88 Table 7. Pharmacokinetic of cardiac glycosides

Digoxin Digitoxin Strophanthin Lipid solubility Medium High Low Oral availability ( % absorbed ) 75 >90 0 Half-life in body (hours ) 40 168 21 Plasma protein binding ( % bound ) 20–40 >90 0 % metabolized <20 >80 0 Volume of distribution (L/kg ) 6,3 0,6 18 Average digitalizing dose Oral 0.75–1.25 mg 0.8–1.2 mg i. v. 0.5–1.0 mg Average daily maintenance dose Oral 0.125–0.5 mg i. v. 0.25 mg 0.05–0.3 mg

Gastrointestinal effects. Anorexia, nausea, and Lecture 22 vomiting are commonly encountered adverse effects. ANTIANGINAL DRUGS CNS effects. These include headache, fatigue, confusion, blurred vision, alteration of color perception, Angina pectoris is the principal symptom of ischem- and haloes on dark objects. ic heart disease. Both the typical and variant forms of Dosage and administration. If there is no urgent angina may be manifested by sudden, severe, pressing need for an immediate effect, a maintenance dose can substernal pain that often radiates to the left shoulder be given daily by mouth and its effect evaluated after and arm. The pain of typical angina is commonly inappropriate intervals. A maximal effect will be duced by exercise, emotion, and is often associated achieved in approximately four elimination half-lives. with depression of the S-T segment of the ECG. The On the other hand, if it is desired to achieve a full ther- underlying pathological process is usually advanced apeutic effect fairly rapidly, it is necessary to give a atherosclerosis of the coronary vasculature. In con- large initial dose because of the relatively long half- trast, variant (Prinzmetal’s) angina is caused by va- time for elimination. sospasm of the coronary vessels and may not by asso- By tradition, the initial loading dose is called the ciated with severe atherosclerosis. digitalizing dose. The size of this dose may be diffi- Anginal attacks result from temporary ischemia of cult to estimate. In theory, it is the steady-state total the myocardium, such that blood flow is insufficient body store sufficient to cause the desired therapeutic to maintain adequate oxygenation. This can be due to effect. In practice, the digitalizing dose is selected from a decrease in myocardial blood flow, an increase in prior estimates (see table 7). The maintenance dose the requirement of the myocardium for oxygen, or both. must be equal to the daily loss. For digoxin, this is ap- Three classes of drugs are effective, either alone or proximately 35% of the total body store; for digitoxin combination, in treating patients with stable angina: in, approximately 10%. nitrates, β-blockers, and calcium channel blockers. All three of the drug groups useful in angina de- Available forms: crease myocardial oxygen requirement by decreasing Digitoxin — in tablets 0.0001 each; in supposito- peripheral vascular resistance, by decreasing cardiac ries 0.00015 each output, or in both ways. In some patients, a redistribu- Digoxin — in tablets 0.00025 (for adults) and tion of coronary flow may increase oxygen delivery to 0.0001 (for children) each; in ampoules 0,025% solu- ischemic tissue. In variant angina, the nitrates and the tion 1 ml each calcium channel blockers may also increase myocardial Celanidum (Lanatoside C) — in tablets 0.00025 oxygen delivery by reversing coronary arterial spasm. each; in ampoules 0.02% solution 1 ml each Strophanthin — in ampoules 0.025% solution 1 ml ORGANIC NITRATES each Corglyconum — in ampoules 0.06% solution 1 ml Organic nitrates (and nitrites) are simple nitric and each nitrous acid esters of alcohols. They differ in their vol- Panangin® — in patented dragee; in ampoules 10 atility; for example, isosorbide dinitrate is solid at ml each room temperature, nitroglycerin is moderately volatile, Unithiol — in ampoules 5% solution 5 ml each whereas amyl nitrate is extremely volatile. These com-

89 pounds cause a rapid reduction in myocardial oxygen Thirty to sixty percent of patients receiving intermittent demand followed by rapid relief of symptoms. They are nitrate therapy with long-acting agents develop head- effective in stable and unstable angina, as well as aches. High doses of organic nitrates can also cause pos- Prinzmetal’s or variant angina pectoris. tural hypotension, facial flushing, and tachycardia. Tolerance. Tolerance to the action of nitrates de- Nitroglycerin velops rapidly. It can be overcome by provision of a β daily “nitrate-free interval” to restore sensitivity to the Nitrates, -blockers, and calcium channel blockers drug. This interval is typically 6 to 8 hours, usually are equally effective for relief of anginal symptoms. How- at night because there is decreased demand on the ever, for prompt relief of an ongoing attack of angina heart at that time. Nitroglycerin patches are worn for precipitated by exercise or emotional stress, sublingual 12 hours and removed for 12 hours. However, Prinz- (or spray form) nitroglycerin is the drug of choice. metal’s or variant angina worsens early in the morn- Mechanism of action. The organic nitrates, such as ing, perhaps due to circadian catecholamine surges. Nitroglycerin, are thought to relax vascular smooth These patients’ nitrate-free interval should be late af- muscle by their intracellular conversion to nitrite ions ternoon. and to nitric oxide (NO), which in turn activates gua- nylate cyclase and increases the cells’ cyclic GMF. El- Isosorbide dinitrate evated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth Isosorbide dinitrate is an orally active nitrate. The muscle relaxation (Fig. 18). drug is not readily metabolized by the liver or smooth Actions on cardiovascular system. At therapeutic muscle and has a lower potency than Nitroglycerin in doses, Nitroglycerin has two major effects. First, it relaxing vascular smooth muscle. causes dilation of the large veins, resulting in pooling of blood in the veins. This diminishes preload (venous β return to the heart), and reduces the work of the heart. -ADRENERGIC BLOCKERS Second, nitroglycerin dilates the coronary vasculature, The β-adrenergic blocking agents suppress the ac- providing increased blood supply to the heart muscle. β tivation of the heart by blocking 1-receptors. They Nitroglycerin causes a decrease in myocardial oxygen also reduce the work of the heart by decreasing cardi- consumption because of decreased cardiac work. ac output and causing a slight decrease in blood pres- Pharmacokinetics. The time to onset of action var- sure. Propranolol is the prototype of this class of com- ies from one minute for nitroglycerin to more than one pounds, but other β-blockers, such as Metoprolol and hour for isosorbide mononitrate. Significant first pass Atenolol are equally effective. However, agents with metabolism of nitroglycerin occurs in the liver. There- intrinsic sympathomimetic activity (for example, Pin- fore, it is common to give the drug either sublingually dolol, and Acebutolol) are less effective in angina and or via a transdermal patch. should be avoided. The β-blockers reduce the frequen- Adverse effects. The most common adverse effect of cy and severity of angina attacks. These agents are Nitroglycerin, as well as other nitrates, is headache. particularly useful in the treatment of patients with myocardial infarction. The β-blockers can be used with nitrates to increase exercise duration and toler- Administered nitrates ance. They are, however, contraindicated in patients with diabetes, peripheral vascular disease, or chronic obstructive pulmonary disease.

Nitrites CALCIUM CHANNELS BLOCKERS The calcium channels blockers inhibit the entrance of calcium into cardiac and smooth muscle cells of the Nitric oxide (NO) coronary and systemic arterial beds. All calcium channels blockers are therefore vasodilators that cause a decrease in smooth muscle tone and vascular resistance. At clinical doses, these agents affect primarily cGMP the resistance of vascular smooth muscle and the myocardium. [Note: Verapamil mainly affects the myocardium, whereas Nifedipine exerts a greater effect on smooth muscle in the peripheral vasculature. Diltiazem Dephosphorylation of is intermediate in its actions.] myosin light chain Nifedipine Nifedipine functions mainly as an arteriolar vasodi- Vascular smooth lator. This drug has minimal effect on cardiac conduc- muscle relaxation tion or heart rate. Nifedipine is administered orally and has a short half-life (about 4 hours) requiring multiple dosing. The vasodilation effect of Nifedipine is Fig. 18. Mechanism of action of nitrates useful in the treatment of variant angina caused by

90 spontaneous coronary spasm. Nifedipine can cause Introduction to the arrhythmias. The heart contains flushing, headache, hypotension, and peripheral ede- specialized cells that exhibit automaticity, that is, they ma as side effects of its vasodilation activity. The drug can intrinsically generate rhythmic action potential in may cause reflex tachycardia if peripheral vasodila- the absence of external stimuli. These “pacemaker” tion is marked resulting in a substantial decrease in cells differ from other myocardial cells in showing a blood pressure. slow, spontaneous depolarization during diastole (Phase 4) caused by an inward positive current carried Verapamil by sodium and calcium currents. This depolarization is fastest in the SA node (the normal initiation site of Verapamil slows cardiac conduction directly and the action potential) and decreases throughout the nor- thus decreases heart rate and oxygen demand. Vera- mal conduction pathway through the AV node to the pamil causes greater negative inotropic effects than bundle of His and the Purkinje system. Dysfunction of does nifedipine, but it is a weaker vasodilator. Vera- the impulse generation or conduction at any of a pamil is contraindicated in patients with preexisting number of sites in the heart can cause an abnormality depressed cardiac function or AV conduction abnor- in cardiac rhythm. malities. It also causes constipation. Verapamil should The arrhythmias are conceptually simple — dys- be used with caution in digitalized patients, since it functions cause abnormalities in impulse formation increases Digoxin levels. and conduction in the myocardium. However, in the clinic, arrhythmias present as a complex family of dis- Diltiazem orders that show a variety of symptoms. For exam- Diltiazem has cardiovascular effects that are simi- ple, cardiac arrhythmias may cause the heart (1) to lar to those of Verapamil. It reduces the heart rate, al- beat too slowly (sinus bradycardia); (2) to beat too though to a lesser extent than Verapamil, and also de- rapidly (sinus tachycardia, atrial or ventricular pre- creases blood pressure. In addition, Diltiazem can re- mature depolarization, atrial flutter); (3) to respond lieve coronary artery spasm and is therefore particu- to impulses originating from sites other than the SA larly useful in patients with variant angina. The inci- node; or (4) to respond to impulses traveling along dence of adverse side effects is low. accessory (extra) pathways that lead to deviant depolarization (A-V reentry, Wolf-Parkinson-White Available forms: syndrome). In order to make sense of this large group Nitroglycerine — in bottles 1% spirit solution 5 ml of disorders, it is useful to organize the arrhythmias each; in tablets 0.0005 into groups according to the anatomic site of the ab- Sustac-mite and Sustac-forte — in tablets 0.0026 normality — the atria, AV node, or the ventricles. and 0.0064 correspondingly each Several commonly occurring arrhythmias are summa- Nitroderm® — transdermal patch (contains 0.05 of rized in the following figure. (Each of these abnor- nitroglycerin each) malities can be further divided into subgroups de- Isosorbide mononitrate — in tablets 0.02 or 0.04 pending on the ECG findings). each; in ampoules 1% solution 1 ml each Causes of arrhythmias. Most arrhythmias arise ei- Metoprolol — in tablets 0.1 each ther from aberrations in impulse generation (abnormal Nifedipine — in tablets 0.01 each automaticity) or from a defect in impulse conduction. Riboxinum — in tablets 0.2 each; in ampoules 2% Abnormal automaticity. The SA node shows the solution 10 ml each fastest rate of Phase 4 depolarization and therefore, exhibits a higher rate of discharge than that occurring in the pacemaker cells exhibiting automaticity. The SA thus normally sets the pace of contraction of the myocardium, and latent pacemakers are depolarized by Lecture 23 impulses coming from the SA node. However, if cardiac sites other than the SA node show enhanced auto- ANTIARRHYTHMIC DRUGS maticity, they may generate competing stimuli, and arrhythmia may arise. Abnormal automaticity may also occur if the myocardial cells are damaged, for ex- Drug therapy for cardiac arrhythmias is based on ample, by hypoxia or potassium imbalance. These cells knowledge of the mechanism, consequences, and nat- may remain partially depolarized during diastole and ural history of the arrhythmia to be treated and on a therefore can reach the firing threshold earlier than clear understanding of the pharmacology of the drugs normal cells. to be used. The latter includes knowledge of drug ac- Effect of drug on automaticity. Most of the an- tion on the electrophysiological properties of normal tiarrhythmic agents suppress automaticity (1) by de- and abnormal cardiac tissues, of their effects on the creasing the slope of Phase 4 (diastolic) depolariza- mechanical properties of the heart and vasculature, and tion and/or (2) by raising the threshold of discharge their effects on other organ systems. Optimal therapy to a less negative voltage. Such drugs cause the fre- of arrhythmias requires an appreciation of the phar- quency of discharge to decrease, an effect that is more macokinetic properties of antiarrhythmic drugs and pronounced in cells with ectopic pacemaker activity how they are affected by disease. Finally, a broad than in normal cells. knowledge of adverse effects of the agents and their Abnormalities in impulse conduction. Impulses potential interactions with other drugs is necessary to from higher pacemaker centers are normally conduct- monitor the course of therapy. ed down pathways that bifurcate to activate the entire

91 ventricular surface. A phenomenon called reentry can CLASS I occur if a uni-directorial block caused by myocardial ANTIARRHYTHMIC DRUGS injury or a prolonged refractory period results in an abnormal conduction pathway (Fig. 18). Reentry is The antiarrhythmic drugs can be classified ac- the most common cause of arrhythmias and can oc- cording to their predominant effects on the action cur at any level of the cardiac conduction system. For potential (Table 8). Although this classification is example, consider a single Purkinje fiber with two convenient, it is not entirely clear-cut, because many conduction pathways to ventricular muscle. An im- of the drugs have action relating to more than one pulse normally travels down both limbs of the con- class. Class I antiarrhythmic drugs act by blocking duction path. However, if myocardial injury results voltage-sensitive sodium channels. The decrease rate in a uni-directorial block, the impulse may only be of enter of sodium slows the rate of rise of Phase 0 conducted down path #1. If the block in pathway #2 of the action potential. Class I therefore generally is in the forward direction only, the impulse may trav- causes a decrease in excitability and conduction el in a retrograde fashion through pathway #2 and velocity. reenter the point of bifurcation. This short-circuit The class I drugs have been subdivided into three pathway results in reexcitation of the ventricular mus- groups according to their effects on the duration of the cle, causing premature contraction or sustained ven- action potential. Class IA agents slow the rate of rise tricular arrhythmia. of the action potential, thus slowing conduction, and Effects of drugs on conduction abnormalities. An- prolong the action potential and increase the ventricu- tiarrhythmic agents prevent reentry by slowing conduc- lar effective refractory period. Class IB drugs have lit- tion and/or increasing the refractory period required tle effect on the rate of depolarization, but rather they to convert a uni-directorial block into a bi-directorial decrease the duration of the action potential by short- block. ening repolarization. Class IC agents markedly depress the rate of rise of the membrane action potential, and therefore they cause marked conduction slowing but ANTIARRHYTHMIC DRUGS have little effect on the duration of the membrane ac- As noted above, the antiarrhythmic drugs can tion potential or the ventricular effective period. Class modify impulse generation or conduction. More than I drugs show a greater degree of blockade in tissues a dozen such drugs that are potentially useful in that are frequently depolarizing (for example, during treating arrhythmias are currently available. How- tachycardia). This property is called “use-dependence” ever, only a limited number of these agents are clini- and enables these drugs to block cells that are dis- cally beneficial in the treatment of selected arrhyth- charging at an abnormally high frequency without in- mias. terfering with the normal low-frequency beating of the For example, the acute termination of ventricular heart. tachycardia by Lidocaine or supraventricular tachycardia by Adenosine or Verapamil are examples in Quinidine which antiarrhythmic therapy results in decreased Quinidine is the prototype Class IA drug. morbidity. In contrast, many of the antiarrhythmic Mechanism of action. Quinidine binds to sodium agents are now known to have lethal proarrhythmic channels and prevents sodium influx, thus slowing the actions (Flecainide, Encainide, Moricizine), that is, rapid upstroke during Phase 0. It also decreases the to cause arrhythmias. slope of Phase 4 spontaneous depolarization.

a. Normal b. Uni-directorial Impulse travels in retro- block: grade direction and reenters the conduction Impulse blocked in pathway causing an ex- one direction tra or irregular heart beat.

Fig. 18. Phenomenon of reentry

92 Table 8. Mechanism of action of antiarrhythmic drugs Mechanism Classification of drug Comment of action IA N a+ channel blocker Slows Phase 0 depolarization IB Na+ channel blocker Shortens Phase 3 repolarization IC Na+ channel blocker Markedly slows Phase 0 depolarization II β-Adrenoreceptor blocker Suppresses Phase 4 depolarization III K+ channel blocker Prolongs Phase 3 repolarization IV Ca2+ channel blocker Shortens action potential

Actions. Quinidine inhibits ectopic arrhythmias otropic effect that is greater than the weak effect ex- and ventricular arrhythmias caused by increased au- erted by Quinidine and Procainamide, and unlike the tomaticity. Quinidine also prevents reentry arrhythmi- latter drugs, Disopyramide causes peripheral vaso- as by producing bi-directorial block through prolong- constriction. The drug may produce a clinically im- ing the effective refractory period. The drug has little portant decrease in myocardial contractility in pa- effect on normal automaticity. tients with preexisting impairment of left ventricular Therapeutic uses. Quinidine is used in the treatment function. Disopyramide is used for treatment of ven- of a wide variety of arrhythmias, including atrial, AV tricular arrhythmias as an alternative to Procaina- junctional, and ventricular tachyarrhythmias. Quini- mide or Quinidine. dine is used to maintain sinus rhythm after direct cur- Pharmacokinetics. Approximately one half of the rent cardioversion of atrial flutter or fibrillation and orally ingested drug is excreted unchanged by the kid- to prevent frequent ventricular tachycardia. neys. About 30% of the drug is converted by the liver Pharmacokinetics. Quinidine sulfate is rapidly and to the less active mono-N-dealkylated metabolite. almost completely absorbed after oral administration. Adverse effects. Disopyramide shows effects of anti- Adverse effects. A potential adverse effect of qui- cholinergic activity, for example, dry mouth, urinary nidine (or any antiarrhythmic drug) is exacerbation retention, blurred vision, and constipation. of the arrhythmia. Quinidine may cause SA and AV block, asystole, and ventricular tachycardia. Cardi- Lidocaine otoxic effects are exacerbated by hyperkalemia. Nau- sea, vomiting, and diarrhea are commonly observed. Lidocaine is a Class IB drug. The IB agents rap- Large doses may induce the symptoms of cinchonism, idly associate and dissociate from sodium channels. for example, blurred vision, tinnitus, headache, dis- Thus the actions of Class IB agents are manifested orientation, and psychosis. The drug has a mild α- when the cardiac cell is depolarized or firing rapid- adrenergic blocking action as well as an atropine-like ly. Class IB drugs are particularly useful in treating effect. ventricular arrhythmias. Lidocaine is the drug of choice for emergency treatment of cardiac arrhyth- Procainamide (Novocainamide) mias. Actions. Lidocaine, a local anaesthetic, shortens Actions. This Class A drug, a derivative of the lo- phase 3 repolarization and decreases the duration of cal anaesthetic Procaine (Novocain), shows action the action potential. Unlike Quinidine, which sup- similar to those of Quinidine. presses arrhythmias caused by increased normal auto- Pharmacokinetics. Procainamide is absorbed fol- maticity, Lidocaine suppresses arrhythmias caused by lowing oral administration. [Note: The intravenous abnormal automaticity. Lidocaine, like Quinidine, route is associated with hypotension occurs if the drug abolishes ventricular reentry. is too rapidly infused.] Procainamide has a relatively Therapeutic uses. Lidocaine is useful in treating short half-life of 2–3 hours. A portion of drug is ventricular arrhythmias arising during myocardial acetylated in the liver to N-acetylprocainamide ischemia, such as that experienced during a myocar- (NAPA), which is eliminated via the kidney. dial infarction. The drug does not markedly slow con- Adverse effects. With chronic use, Procainamide duction and thus has little effect on atrial or AV junc- causes a high incidence of side effects, including a re- tion arrhythmias. versible lupus erythematosus-like syndrome that devel- Pharmacokinetics. Lidocaine is given intravenous- ops in 25 to 30% of patients. Toxic concentrations of ly. The drug is dealkylated and eliminated almost en- Procainamide may cause asystole or induction of ven- tirely by the liver. tricular arrhythmias. CNS side effects include depres- Adverse effects. Lidocaine has a fairly wide toxic- sion, hallucination and psychosis. to-therapeutic ratio; it shows little impairment of left ventricular function, and has no negative inotropic ef- Disopyramide (Rythmilen, Rythmodan) fect. The CNS effects include drowsiness, slurred Actions. This class IA drug shows actions to those speech, paresthesia, agitation, confusion, and convul- of Quinidine. Disopyramide produces a negative in- sions; cardiac arrhythmias may also occur.

93 Flecainide that prolong the QT interval, the syndrome of torsade de pointes is a serious potential adverse effect, typi- Flecainide is a Class IC drug. These drugs slowly cally seen in 3 to 4% of patients. dissociate from resting sodium channels and show prominent effects, even at normal heart rates. These Amiodarone drugs are approved only for refractory ventricular arrhythmias. However, recent data have cast serious Actions. Amiodarone contains iodine and is relat- doubts on the safety of the Class IC drugs. ed structurally to thyroxine. It has complex effects showing Class I, II, III and IV actions. Its dominant effect is prolongation of the action potential duration CLASS II and the refractory period. Amiodarone has antiangi- ANTIARRHYTHMIC DRUGS nal as well as antiarrhythmic activity. The Class II agents include the β-adrenergic antag- Therapeutic uses. Amiodarone is effective in the onists. These drugs diminish Phase 4 depolarization, treatment of severe refractory supraventricular tach- thus depressing automaticity, prolonging AV conduc- yarrhythmia. Its clinical usefulness is limited by its tion, and decreasing heart rate and contractility. Class toxicity. II agents are useful in treating tachyarrhythmias Pharmacokinetics. Amiodarone is incompletely ab- caused by increased sympathetic activity. They are sorbed after oral administration. The drug is unusual also used for atrial flutter and fibrillation, and for AV in having a prolonged half-life of several weeks. Full nodal reentrant tachycardia. clinical effects may not be achieved until 6 weeks after initiation of treatment. Adverse effects. Amiodarone shows a variety of tox- Propranolol (Anaprilinum) ic effects. After long-term use, more than one half of Propranolol reduces the incidence of sudden ar- the patients receiving the drug show side effects suffi- rhythmic death after myocardial infarction (the most ciently severe to prompt its discontinuation. Some of common cause of death in this group of patients). The the more common effects include interstitial pulmonary mortality rate in the first year after a heart attack is fibrosis, GI tract intolerance, tremor, ataxia, dizzi- significantly reduced by Propranolol, partly because ness, hyper- or hypothyroidism, liver toxicity, photo- of its ability to prevent ventricular arrhythmias. sensitivity, neuropathy, muscle weakness, and blue skin discoloration caused by iodine accumulation in the Metoprolol and Pindolol skin. [Recent clinical trials have shown that Amiodar- one did not reduce incidence of sudden death or pro- β Propranolol is the -adrenergic antagonist most long survival in patients with congestive heart failure.] widely used in the treatment of cardiac arrhythmias. β However, 1-specific drugs, such as Metoprolol reduce the risk of bronchospasm, and drugs with partial ago- CLASS IV nist activity, such as Pindolol may decrease the fre- ANTIARRHYTHMIC DRUGS quency of cardiac failure. The Class IV drugs are calcium channel blockers. They decrease the inward current carried by calcium, CLASS III resulting in a decrease in the rate of Phase 4 sponta- ANTIARRHYTHMIC DRAGS neous depolarization and slowed conduction in tissues dependant on calcium currents, such as the AV node. Class III agents block potassium channels and thus Although voltage-sensitive calcium channels occur in diminish the outward potassium current during repo- many different tissues, the major effect of calcium- larization of cardiac cells. These agents prolong the channels blockers is on vascular smooth muscle and duration of action potential without altering Phase 0 the heart. of depolarization or the resting potential. Instead, they prolong the effective refractory period. Verapamil and Diltiazem Sotalol Verapamil shows greater action on the heart than on vascular smooth muscle, whereas nifedipine, a cal- Actions. Sotalol, although a class III antiarrhyth- cium channel-blocker used to treat hypertension exerts mic agent, also has potent β-blocker activity. Sotalol a stronger effect on vascular smooth muscle than on block a rapid outward potassium current. This block- the heart. Diltiazem is intermediate in its actions. ade prolongs both repolarization and the duration of Actions. Calcium enters cells by voltage-sensitive the action potential, thus lengthening the effective re- channels and by receptor-operated channels that are fractory period. controlled by the binding of agonists, such as catecho- Therapeutic uses. β-Blockers are used for the long- lamines, to membrane receptors. Calcium channels term therapy to decrease the rate of sudden death fol- blockers, such as Verapamil and Diltiazem, are more lowing an acute myocardial infarction. β-Blockers have effective against the voltage-sensitive channels, caus- modest ability to suppress ectopic beats and reduce my- ing a decrease in the slow inward current that triggers ocardial oxygen demand. They have strong anti-fibril- cardiac contraction. Verapamil and Diltiazem bind lar effects, particularly in the ischemic myocardium. only to open, depolarized channels. These drugs are Adverse effects. This drug also has the lowest rate therefore use-dependant, that is, they block most effec- of acute or long-term adverse effects. As with all drugs tively when the heart is beating rapidly, since in a nor-

94 mally paced heart, the calcium channels have time to OTHER ANTIARRHYTHMIC DRUGS repolarize, and the bound drug dissociates from the (CLASS V) channel before the next conduction pulse. Verapamil and Diltiazem are effective in treating arrhythmias that must traverse calcium-dependant cardiac tissues, Digoxin such as AV node. Digoxin shortens the refractory period in atrial and Therapeutic uses. Verapamil and Diltiazem are ventricular cells while prolonging the effective refrac- more effective against atrial than ventricular dysrhyth- tory period and diminishing conduction velocity in mias (Fig. 19). They are useful in treating reentrant Purkinje fibers. Digoxin is used to control the ventricu- supraventricular tachycardia and reducing ventricular lar response rate in atrial fibrillation and flutter. At rate in atrial flutter and fibrillation. In addition, these toxic concentrations, Digoxin causes ectopic ventricu- drugs are used to treat hypertension and angina. lar beats that may result in ventricular tachycardia Pharmacokinetics. Verapamil and Diltiazem are and fibrillation. [Note: This arrhythmia is usually absorbed after oral administration. Verapamil is ex- treated with Lidocaine or Phenytoin.] tensively metabolized by the liver; thus, care should be taken in administration of this drug to patients with Adenosine hepatic dysfunction. Adverse effects. Verapamil and Diltiazem have neg- Adenosine naturally occurs in nucleoside, but at ative inotropic properties and therefore may be con- high doses the drug decreases conduction velocity, pro- traindicated in patients with preexisting depressed car- longs the refractory period, and decreases automatici- diac function. Both drugs can also cause a decrease in ty in the AV node. Intravenous Adenosine is the drug blood pressure caused by peripheral vasodilation. of choice for abolishing acute supraventricular tachy-

Antiarrhythmic drugs Type of arrhythmia class I class II class III class IV Other

Atrial arrhythmias This common arrhythmia involves multiple ec- Atrial topic foci of atria creat- Quinidine Propranolol Verapamil Digoxin flutter ing a chaotic movement of impulses through the atria. The ventricular re- β-Blockers are the drugs of choice in atrial fibrillation be- sponse is rapid (100–150 cause they decrease heart rate and promote conversion to sinus beats per minute) and ir- rhythm. Long-term, low-dose anticoagulant therapy reduces the regular risk of stroke that is associated with atrial fibrillation atrial fibrillation Quinidine Propranolol Amiodarone Anticoagulant therapy

Supraventricular Conduction is slowed through the AV node with Propranolol, tachycardia Verapamil or Digoxin

AV nodal Propranolol Verapamil Digoxin reentry acute supra- Verapamil Adenosine ventricular This arrhythmia is a common cause of death in patients who had a myocardial tachycardia infarction. Cardiac output is impaired and tachycardia may deteriorate into ventricular fibrillation. Therefore, ventricular tachycardia requires prompt Ventricular tachycardia management acute ventricular Sotalol tachycardia Lidocaine Amiodarone ventricular Bretylium, fibrillation Lidocaine Amiodarone Epinephrine Key: – commonly used drugs – alternative drugs Fig. 19. Uses of antiarrhythmic drugs

95 cardia. It has low toxicity, but causes flushing, chest Proximal convoluted tubule. In the extensively con- pain and hypotension. Adenosine has an extremely voluted proximal tubule located in the cortex of the short duration of action. kidney, almost all of the glucose, bicarbonate, amino acids, and other metabolites are reabsorbed. Approxi- Available forms: mately two third of the Na+ is also reabsorbed in the Quinidine — in tablets 0.1 and 0.2 each proximal tubule; chloride and water follow passively Mexiletine hydrochloride — in capsules 0.05 and to maintain electrical and osmolar equality. If it were 0.2 each; in ampoules 2.5% solution 10 ml each not for the extensive reabsorption of solutes and water Pindolol — in tablets 0.005; 0.01 and 0.015 each; in the proximal tubule, the mammalian organism in ampoules 0.004% solution 2 ml each would rapidly become dehydrated and lose its normal Amiodarone — in tablets 0.2 each; in ampoules 5% osmolarity. solution 3 ml each Acid secretory system. The proximal tubule is the Verapamil — in tablets 0.04, 0.12 each; in am- site of the organic acid and base secretory system. The poules 0.25% solution 2 ml organic acid secretory system secretes a variety of organic acids (such as uric acid, some antibiotics, and diuretics) from the bloodstream into the proximal tubule’s lumen. Most diuretic drugs are delivered to the tubular fluid via this system. The organic acid secre- Lecture 24 tory system is saturable, and diuretic drugs in the DIURETIC DRUGS bloodstream compete for transfer with endogenous organic acids, such as uric acid. This explains the hyperuricemia seen with certain of the diuretic drugs, such Diuretics are agents that increase the rate of urine as Furosemide and Chlorothiazide. formation. Except for the osmotic diuretics, these agents Descending loop of Henle. The remaining filtrate, are ion transport inhibitors that decrease the reabsorp- which is isotonic, next enters the descending limb of tion of Na+ at different sites in the nephron. As a re- Henle and passes into the medulla of the kidney. The sult, Na+ and other ions such as Cl- enter the urine in osmolarity increases along the descending portion of greater amounts than normal along with water, which the loop of Henle because of the countercurrent mech- is carried passively to maintain osmotic equilibrium. anism. This results in a tubular fluid with a three-fold Diuretics thus increase the volume of the urine and of- increase in salt concentration. ten change its pH as well as the ionic composition of Ascending loop of Henle. The cells of the ascend- the urine and blood. The efficacy of the different class- ing tubular epithelium are unique in being impermea- es of diuretics varies considerably, with the increase ble to water. Active reabsorption of Na+, K+ and Cl- in secretion of Na+ varying from less than 2% for the is mediated by a Na+/K+/2Cl- cotransporter. Mg++ and weak, potassium-sparing diuretics, to over 20% for the Ca++ enter the interstitial fluid via the paracellular potent loop diuretics. Their major clinical use are in pathway. managing disorders involving abnormal fluid retention The ascending loop is thus a diluting region of the (edema) or in treating hypertension in which their di- nephron. Approximately 25–30% of the tubular sodi- uretic action causes a decreased blood volume, lead- um chloride returns to the interstitial fluid, thus help- ing to a reduction in blood pressure. Except for the os- ing to maintain the fluid’s high osmolarity. Since the motic diuretics, the diuretic drugs act directly on the loop of Henle is a major site of salt reabsorption, drugs tubular epithelia. For the most part, these direct ac- affecting this site, such as loop diuretics, are the most tions are site, i.e., a drug will act on one or another efficacious of all the diuretic classes. tubular segment, but not on all of them. However, sites Distal convoluted tubule. The cells of the distal that are not attacked directly may well be affected in- convoluted tubule are also impermeable to water. directly; a change in the behavior of one segment will About 10% of the filtrated sodium chloride is reab- alter conditions for the downstream segments. In this sorbed via a Na+/Cl- transporter, which is sensitive lecture, the diuretic drugs are discussed in the order to thiazide diuretics. Additionally, Ca++ excretion is of their site of action along the nephron. regulated by parathyroid hormone in this portion of Normal regulation of fluid and electrolytes by the tubule. kidneys. Approximately 16–20% of the blood plasma Collecting tubule and duct. The principal and in- entering the kidneys is filtrated from the glomerular tercalated cells of the collecting tubule are responsi- capillaries into Bowman’s capsule. The filtrate, al- ble for Na+-K+ exchange and for H+ secretion and K+ though normally free of proteins and blood cells, does reabsorption, respectively. Stimulation of aldosterone contain most low molecular weight plasma components receptors in the principal cells results in Na+ reabsorp- in approximately the same concentration as are found tion and K+ secretion. Antidiuretic hormone (ADH, in the plasma. These include glucose, sodium bicar- vasopressin) receptors promote the reabsorption of wa- bonate, amino acids, and other organic solutes, plus ter from the collecting tubules and ducts. electrolytes, such as Na+, K+, and Cl-. The kidney reg- Kidney function in disease. In many diseases the ulates the ionic composition and volume of the urine amount of NaCl reabsorbed by the kidney tubules is by the reabsorption or secretion of ions and/or water abnormally high. This leads to the retention of water, at five functional zones along the nephron, namely the an increase in blood volume, and expansion of the ex- proximal convoluted tubule, the descending loop of travascular fluid compartment, resulting in the edema Henle, the ascending loop of Henle, the distal convo- of the tissues. Several commonly encountered causes luted tubule, and the collecting duct. of edema include:

96 Congestive heart failure. The decreased ability of Premenstrual edema. Edema associated with men- the failing heart to sustain adequate cardiac output struation is the result of imbalances in hormones such causes the kidney to respond as if there were a decrease as estrogen excess, which facilitates the loss of fluid in blood volume. The kidney, as part of the normal into the extracellular space. Diuretics can reduce the compensatory mechanism, retains more salt and wa- edema. ter as a means of raising blood volume and increasing the amount of blood that is returned to the heart. How- ever, the diseased heart cannot increase its output, and CARBONIC ANHYDRASE increased vascular volume results in edema. INHIBITORS Hepatic ascites. Ascites, the accumulation of fluid Acetazolamide (Diacarb) is a sulfanilamide within the abdominal cavity, is a common complication of out antibacterial activity. Its main action is to inhibit cirrhosis of the liver. the enzyme carbonic anhydrase in the proximal tubule Increased portal blood pressure. Blood flow in the epithelial cells. However, carbonic anhydrase inhibi- portal system is often obstructed in cirrhosis, result- tors are more often used for their other pharmacologic ing in an increased portal blood pressure. Further, col- action rather than for their diuretic effect, because loidal osmotic presser of the blood is decreased as a these agents are much less efficacious than thiazides result of impaired synthesis of plasma proteins by the or loop diuretics. liver. Increased portal blood pressure and low osmo- Mechanism of action. Acetazolamide inhibits car- larity of the blood cause fluid to escape from the por- bonic anhydrase, located intracellularly and on the tal vascular system and collect in the abdomen. apical membrane of the proximal tubule epithelium Secondary hyperaldosteronism. Fluid retention is (Fig. 20). [Carbonic anhydrase catalyzes the reaction promoted by elevated levels of circulating aldosterone. + - of CO2 and H2O leading to H and HCO3 (bicarbo- This secondary hyperaldosteronism results from the nate).] The decreased ability to exchange Na+ for H+ decreased ability of the liver to inactivate the steroid in the presence of Acetazolamide results in a mild diu- + - hormone and leads to increased Na and water reab- resis. Additionally, HCO3 is retained in the lumen sorption, and exacerbation of fluid accumulation. with marked elevation in urinary pH. The loss of - Nephrotic syndrome. When damaged by disease, HCO3 causes a hyperchloremic metabolic acidosis the glomerular membranes allow plasma proteins to and decreased diuretic efficacy following several days enter the glomerular ultrafiltrate. The loss of protein of therapy. from the plasma reduces the colloidal osmotic pressure Therapeutic uses: resulting in edema. The low plasma volume stimulates Treatment of glaucoma. The most common use of aldosterone secretion through the renin — angiotensin Acetazolamide is to reduce the elevated intraocular — aldosterone system. This leads to retention of Na+ pressure of open-angle glaucoma. Acetazolamide de- and fluids, further aggravation of the edema. creases the production of aqueous humor, probably by

Acetazolamide

lumen blood

H2O + CO2 H2O + CO2 CO2

Carbonic anhydrase H2CO3 H2CO3

- + + - HCO3 H H HCO3

Na+ Na+ Na+

Fig. 20. Mechanism of action of Acetazolamide 97 blocking carbonic anhydrase in the ciliary body of the drug, but there is no rationale for administering two eye. It is useful in the chronic treatment of glaucoma loop diuretics concomitantly. High-ceiling diuretics but should not be used for an acute attack; Pilocarpine (along with hydration) are also useful in treating symp- is preferred for an acute attack because of its immedi- tomatic hypercalcemia because they increase Ca++ uri- ate action. nary excretion. Epilepsy. Acetazolamide is sometimes used in the Pharmacokinetics. Loop diuretics are administered treatment of epilepsy — both generalized and partial. orally or parenterally (i.v. or i.v.). Their duration of It reduces the severity and magnitude of the seizures. action is relatively brief, 1 to 4 hours. Often Acetazolamide is used chronically in conjunc- Adverse effects: tion with antiepileptic medication to enhance the ac- Ototoxicity. Hearing can be affected adversely by tion of these other drugs. the loop diuretics, particularly when used in conjunc- Mountain sickness. Less commonly Acetazolamide tion with the aminoglycoside antibiotics. Vestibular can be used in the prophylaxis of acute mountain sick- function is less likely to be disturbed, but it may be ness among healthy, physically active individuals who affected too. rapidly ascend above 10,000 feet. Acetazolamide giv- Hyperuricemia. Furosemide and Ethacrynic acid en nightly for 5 days before the ascent prevents the compete with uric acid for the renal and biliary secre- weakness, breathlessness, dizziness, nausea, and cer- tory systems, thus blocking its secretion and thereby ebral and pulmonary edema characteristic of the syn- causing or exacerbating gouty attacks. drome. Acute hypovolemia. Loop diuretics can cause a se- Pharmacokinetics. Acetazolamide is given orally vere and rapid reduction of blood volume, with the pos- once a day. sibility of hypotension. Adverse effects. Metabolic acidosis (mild), potassi- Potassium depletion. The heavy load of Na+ pre- um depletion, renal stone formation, drowsiness, and sented in the collecting tubule results in increased ex- paresthesia may occur. change of tubular Na+ for K+, with the possibility of inducing hypokalemia. The loss of K+ from cells in exchange for H+ leads to hypokalemic alkalosis. Potas- LOOP (OR HIGH-CEILING) sium depletion can be averted by use of potassium-spar- DIURETICS ing diuretics or dietary supplementation with K+. The term high ceiling has been used to denote a group of diuretics that have a distinctive action on THIAZIDES AND RELATED AGENTS renal tubular function. Furosemide, Bumetanide, Torsemide and Ethacrynic acid are four diuretics that The thiazides are the most widely used of the diu- have their major action on the ascending limb of the retic drugs. They are related in structure to the car- loop of Henle. Compared to all other classes of diu- bonic anhydrase inhibitors. The thiazides have signif- retics, these drugs have the highest efficacy in mobi- icantly greater diuretic activity than acetazolamide, lizing Na+ and Cl- from the body. Ethacrynic acid and they act on the kidney by different mechanisms. has a steeper dose-response curve than Furosemide; All thiazides affect the distal tubule, and all have equal it shows greater side effects than those seen with the maximum diuretic effect, differing only in potency, ex- other loop diuretics and is not as widely used. Bumeta- pressed on a per-milligram basis. nide is much more potent than Furosemide, and its use is increasing. Chlorothiazide Mechanism of action. Loop diuretics inhibit the Chlorothiazide, the prototype thiazide diuretic, - Na+/K+/Cl cotransport of the luminal membrane in the was the first modern diuretic that was active orally ascending limb of the loop of Henle. Therefore reab- and was capable of affecting the severe edema of cir- + + - sorption of Na , K , and Cl is decreased. The loop rhosis and congestive heart failure with a minimum diuretics are the most efficacious of the diuretic drugs, of side effects. Its properties are representative of the because the ascending limb accounts for the reabsorp- thiazide group, although newer derivatives such as tion of 25–30% of filtered NaCl and downstream sites Hydrochlorothiazide or Chlorthalidone are now used are not able to compensate for this increased Na+ load. more commonly. Actions. The loop diuretics act promptly, even Mechanism of action. The thiazide derivatives act among patients who have poor renal function or who manly in the distal tubule to decrease the reabsorp- have not responded to thiazides or other diuretics. [Note: tion of Na+ by inhibition of a Na+/Cl- cotransporter Loop diuretics increase the calcium content, while thi- on the luminal membrane. They have a lesser effect azide diuretics decrease the Ca++ concentration of the in the proximal tubule. As a result, these drugs in- urine.] The loop diuretics cause decreased renal vascu- crease the concentration of Na+ and Cl- in the tubular resistance and increased renal blood flow. lar fluid. The acid-base balance is not usually affect- Therapeutic uses. The loop diuretics are the drug ed. [Note: Because the site of action of the thiazides of choice for reducing the acute pulmonary edema of is on the luminal membrane, these drugs must be ex- congestive heart failure because of their rapid onset of creted into the tubular lumen to be effective. There- action. The high-ceiling diuretics are effective for the fore, with decreased renal function, thiazide diuret- treatment of edema of cardiac, hepatic, or renal ori- ics lose efficacy.] gin. In the management of refractory edema, the high- Actions: ceiling agents may be used in conjunction with other Increased excretion of Na+ and Cl-. Chlorothiazide types of diuretics, such as a thiazide or K+-sparing causes diuresis with increased Na+ and Cl- excretion,

98 which can result in the excretion of a very hyperosmo- longed biological half-life (40 hours). All thiazides are lar urine. This latter effect is unique among the other secreted by the organic acid secretory system of the diuretic classes, which are unlikely to produce a hyper- kidney. osmolar urine. The diuretic action is not affected by Adverse effects: the acid-base status of the body, nor does Chlorothi- Potassium depletion. Hypokalemia is the most fre- azide use change the acid-base status of the blood. quent problem encountered with the thiazide diuretics Loss of K+. Because thiazides increase the filtrate and can predispose patients on Digitalis to ventricu- arriving at the distal tubule, more K+ is also exchanged lar arrhythmias. Activation of the renin-angiotensin- for Na+. Thus, prolonged use of these drugs results in aldosterone system by the decrease in intravascular continual loss of the K+ from the body. Therefore, it is volume contributes significantly to urinary K+ losses. imperative to measure serum K+ once a month (more The K+ deficiency can be overcome by Spironolactone frequently at the beginning of therapy). Often, K+ can or by Triamterene. Low sodium diets blunt the potas- be supplemented by diet along, such as by increasing sium depletion caused by thiazide diuretics. the intake of citrus fruits, bananas, and prunes. In some Hyperuricemia. Thiazides increase serum uric acid cases, K+ salt supplementation may be necessary. by decreasing the amount of acid excreted by the or- Decreased urinary calcium excretion. Thiazides ganic acid secretory system. Being insoluble, the uric decrease the Ca++content of the urine by promoting the acid deposits in the joints, and an attack of gout may reabsorption of Ca++. This contrasts with the loop di- result in individuals predisposed to gouty attack. It is uretics, which increase the Ca++ concentration of the important, therefore, to perform periodic blood tests urine. for uric acid levels. Reduced peripheral vascular resistance. An initial Hyperglycemia. Patients with diabetes mellitus, reduction in blood pressure results from a decrease in who are taking thiazides, may become hyperglycemic blood volume and therefore a decrease in cardiac out- and have difficulty in maintaining appropriate blood put. With continued therapy, volume recovery occurs. sugar levels. However, there are continued hypotensive effects, re- Hydrochlorothiazide is a thiazide derivative that sults from reduced peripheral vascular resistance has proven to be more popular than the parent drug. caused by relaxation of arteriolar smooth muscle. This This is because it has far less ability to inhibit carbon- usually occurs prior to the diuretic effect. ic anhydrase as compared to Chlorothiazide. It is also Therapeutic uses: more potent, so that the required dose is considerably Hypertension. Clinically, the thiazides have long less than that of Chlorothiazide. On the other hand, been the mainstay of antihypertensive medication, the efficacy is the same as that of the parent drug. since they are inexpensive, convenient to administer, Chlorthalidone is a thiazide derivative that behaves and well tolerated. They are effective in reducing systo- like Hydrochlorothiazide. It has a very long duration lic and diastolic blood pressure for extended periods of action and therefore is often used to treat hyperten- in the majority of patients with mild to moderate es- sion. It is given once per day for this indication. sential hypertension. After 3–7 days of treatment, the blood pressure stabilizes at a lower level and can be maintained indefinitely by a daily dosage of the drug, THIAZIDE ANALOGS which causes lower peripheral resistance without hav- Metolazone is more potent than the thiazides and, ing a major diuretic effect. Many patients can be con- unlike the thiazides, causes Na+ excretion in advanced tinued for years on the thiazides alone, although a renal failure. small percentage of patients require additional medi- β Indapamide is a lipid soluble, nonthiazide diuret- cation, such as -adrenergic blockers. ic that has a long duration of action. At low doses, it Congestive heart failure. Thiazides can be the di- shows significant antihypertensive action with minimal uretic of choice in reducing extracellular volume in diuretic effects. Indapamide is often used in advanced mild to moderate congestive heart failure. If the thi- renal failure to stimulate additional diuresis on top of azide fails, loop diuretics may be useful. that achieved by loop diuretics. Indapamide is metab- Renal impairment. Patients with nephrotic syn- olized and excreted by the GI tract and kidneys; it drome accompanied by edema are initially treated with therefore is less likely to accumulate in patients with loop diuretics; only if this treatment fails, they are giv- renal failure and may be useful in their treatment. en Metolazone in conjunction with loop diuretic. Hypercalciuria. The thiazides can be useful in treating idiopathic hypercalciuria because they inhib- POTASSIUM-SPARING DIURETICS it urinary Ca++ excretion. This is particularly beneficial for patients with calcium oxalate stones in the uri- These agents act in the collecting tubule to inhibit nary tract. Na+ reabsorption, K+ secretion, and H+ secretion. Po- Diabetes insipidus. Thiazides have a unique abili- tassium-sparing diuretics are used primarily when al- ty to produce a hyperosmolar urine. Thiazides can be dosterone is present in excess. The major use of potas- substitute for the antidiuretic hormone in the treatment sium-sparing agents is in the treatment of hyperten- of nephrogenic diabetes insipidus. The urine volume sion, most often in combination with a thiazide. It is of such individuals may drop from 11 L/day to about extremely important that patients treated with any po- 3 L/day. tassium-sparing diuretic be closely monitored for po- Pharmacokinetics. The drugs are effective orally. tassium levels. Exogenous potassium supplementation Most thiazides take 1 to 3 weeks to produce a stable is usually discontinued when potassium-sparing diuret- reduction in blood pressure, and they exhibit a pro- ic therapy is instituted.

99 Spironolactone ties. For example, much like Spironolactone, they prevent K+ loss that occurs with thiazides and Furosem- Mechanism of action. Spironolactone is a synthet- ide. The side effects of Triamterene are leg cramps and ic aldosterone antagonist that competes with aldos- the possibility of increased blood urea nitrogen (BUN) terone for intracellular cytoplasmic receptor sites. as well as uric acid and K+ retention. The spironolactone-receptor complex is inactive, that is, it prevents translocation of the receptor complex into the nucleus of the target cell, and thus does not OSMOTIC DIURETICS bind to DNA. This results in a failure to produce proteins that are normally synthesized in response to al- The term osmotic diuretic is used for certain sol- dosterone. These mediator proteins normally stimu- utes that have the following attributes in common: (1) late the Na+-K+ exchange sites of the collecting tu- they are freely filterable at the glomerulus; (2) they bule. undergoes little or no reabsorption and (3) they are rel- Actions. In most edematous states, blood levels of atively inert by conventional pharmacological crite- aldosterone are high, which is instrumental in retain- ria. These agents are administered in sufficiently large ing Na+. When Spironolactone is given to a patient quantities to contribute significantly to the osmolarity with elevated circulating levels of aldosterone, the drug of the plasma, the glomerular filtrate, and the tubular antagonizes the activity of the hormone, resulting in fluid. Mannitol is the most frequently used of the os- retention of K+ and excretion of Na+. Where there are motic diuretics. Other agents include urea, glycerin, no significant circulating levels of aldosterone, such and isosorbide. Increase in diuresis is due to their as in Addison’s disease (primary adrenal insufficien- ability to carry water with them into the tubular flu- cy), no diuretic effect of the drug occurs. id. Only a small amount of additional salt may also Therapeutic uses: be excreted. Because osmotic diuretics are used to ef- Diuretic. Although spironolactone has the low effect increased water excretion, they are not useful in ficacy in mobilizing Na+ from the body in compari- treating conditions in which Na+ retention occurs. son with the other drugs, it has the useful property of They are used to maintain urine flow following acute causing the retention of K+. Because of this latter ac- toxic ingestion of substances capable of producing tion, Spironolactone is often given in conjunction with acute renal failure. Osmotic diuretics are a mainstay a thiazide or loop diuretic to prevent K+ excretion. of treatment for patients with increased intracranial Secondary hyperaldosteronism. Spironolactone is pressure, or acute renal failure due to shock, drug tox- the only potassium sparing diuretic that is routinely icities, severe traumatic injury, and management of used alone to induce net negative salt balance. It is par- hemolytic transfusion reactions. Maintaining urine ticularly effective in clinical situations associated with flow preserves long-term kidney function and may save secondary hyperaldosteronism. the patient from dialysis. [Note:Mannitol is not ab- Pharmacokinetics. Spironolactone is completely sorbed when given orally; the agent can only be given absorbed orally and is strongly bound to proteins. It intravenously.] is rapidly converted to an active metabolite, canrenone. The action of spironolactone is largely due to METHYLXANTHINES the effect of Canrenone, which has mineralocorticoid- blocking activity. Spironolactone induces hepatic cy- The Methylxanthines have long been known for tochrome P-450. their additional diuretic action. Of the Methylxan- Adverse effects. Because Spironolactone chemical- thines, Theophylline has the greatest action on kid- ly resembles some of the sex steroids, it does have min- ney. Although there is some controversy, theophyl- imal hormonal activity and may induce gynecomastia line-induced diuresis probably result from an increase in males and menstrual irregularities in females. Be- in renal blood flow and glomerular filtration rate. cause of this, the drug should not be given in high dos- This is most obvious in conditions that produce re- es on a chronic basis. It is most effectively employed ductions in these parameters, such as hypotension or in mild edematous state where it is given for a few days cardiac insufficiency. The methylxanthines are rare- at a time. At low doses, spironolactone can be used ly employed as primary diuretics. However, when chronically with few side effects. Hyperkalemia, nau- used for other purposes, particularly as bronchodila- sea, lethargy, and mental confusion can occur. tors, the coexistence of their diuretic action should be kept in mind. Triamterene and Amiloride Available forms: + Triamterene and Amiloride block Na transport Hydrochlorothiazide — in tablets 0.025 and 0.1 + + channels resulting in a decrease in Na -K exchange; each they have K+-sparing diuretic action similar to that of Furosemide — in tablets 0.04 each; in ampoules 1% Spironolactone. However, the ability of these drugs to solution 2 ml each block Na+-K+ exchange site in the collecting tubule Acetazolamide (Diacarbum) — in tablets 0.25 each does not depend on the presence of aldosterone. Thus, Triamterene — in capsules 0.05 each they have diuretic activity even in individuals with Ad- Triampur — in patented tablets (each contains Tri- dison’s disease. They, like Spironolactone, are not amterene and Hydrochlorothiazide) very efficacious diuretics. Both Triamterene and ami- Spironolactone — in tablets 0.025 each loride are frequently used in combination with other Mannite — in ampoules 15% solution 200, 400 and diuretics, usually for their potassium-sparing proper- 500 ml each

100 Lecture 25 dietary intake of sodium, obesity, and smoking all further predispose an individual to the occurrence of hy- DRUGS USED IN ARTERIAL pertension. HYPERTENSION Mechanisms for controlling blood pressure. Arte- rial blood pressure is regulated within a narrow range to provide adequate perfusion of the tissues without Hypertension is defined as a sustained diastolic causing damage of the arterial intima. Arterial blood blood pressure greater than 90 mm Hg accompanied pressure is directly proportional to the product of the by an elevated systolic blood pressure (>140 mm Hg). cardiac output and the peripheral vascular resistance: Hypertension results from increased peripheral vascu- Arterial Cardiac Peripheral pressure lar muscle tone, which leads to increased arteriolar re- ≈ × blood output resistance sistance and reduced capacitance of the venous system. Elevated blood pressure is an extremely common dis- In both normal and hypertensive individuals, car- order, affecting approximately 15% of the population diac output and peripheral resistance are controlled in developed countries. Although many of these indi- mainly by two overlapping control mechanisms: the viduals have no symptoms, chronic hypertension — ei- baroreflexes mediated by the sympathetic nervous sys- ther systolic or diastolic — can lead to congestive heart tem, and the renin — angiotensin — aldosterone sys- failure, myocardial infarction, renal damage, and cer- tem. Most antihypertensive drugs lower blood pressure ebrovascular accidents. The incidence of morbidity and by reducing cardiac output and/or decreasing periph- mortality significantly decreases when hypertension is eral resistance. diagnosed early and is properly treated. Baroreceptors and the sympathetic nervous system. Etiology of hypertension. Although hypertension Baroreflexes involving the sympathetic nervous system may occur secondary to other disease processes, more are responsible for the rapid moment-to-moment regu- than 90% of patients have essential hypertension, a lation of the blood pressure. A fall in blood pressure disorder of unknown origin affecting the blood pres- causes pressure-sensitive neurons (baroreceptors in the sure-regulating mechanism. A family history of hy- aortic arch and carotid sinuses) to send fewer impulses pertension increases the likelihood that an individu- to the cardiovascular centers in the CNS. This prompts al will develop hypertensive disease. Essential hyper- a reflex response of increased sympathetic and decreased tension occurs four times more frequently among parasympathetic output to the heart and vasculature, blacks than whites, and it occurs more often among resulting in vasoconstriction and increased cardiac out- middle-aged males than among middle-aged females. put (Fig. 21). These changes result in a compensatory Environmental factor such as a stressful lifestyle, high rise in blood pressure.

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Decrease in blood Increase in pressure blood pressure

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Fig. 21. Mechanisms increasing blood pressure

101 Renin — angiotensin — aldosterone system. The Individualized care. Certain subsets of the hyper- kidney provides for the long-term control of blood pres- tensive population respond better to one class of drug sure by altering the blood volume. Baroreceptors in the than another. For example, black patients respond kidney respond to reduced arterial pressure (and to well to diuretics and calcium channel blockers, but sympathetic stimulation of β-adrenoreceptors) by re- therapy with β-blockers or ACE inhibitors is often leasing the enzyme renin. less effective. Similarly, calcium channels blockers, This peptidase converts angiotensinogen to angi- ACE inhibitors, and diuretics are favored for treat- otensin I, which is in turn converted to angiotensin II ment of hypertension in the elderly, whereas β-block- in the presence of angiotensin converting enzyme ers and α-antagonists are less well tolerated. Further- (ACE). more, hypertension may coexist with other diseases Angiotensin II is the body’s most potent circu- that can be aggravated by some of the antihyperten- lating vasoconstrictor, causing an increase in sive drugs. For example, the Table 9 shows the pre- blood pressure. Furthermore, angiotensin stimu- ferred therapy in hypertensive patients with various lates aldosterone secretion, leading to increased concomitant diseases. In such cases, it is important renal sodium reabsorption and an increase in blood to match antihypertensive drugs to the particular pa- volume, which contribute to a further increase in tient. blood pressure. The hypertensive patient is usually asymptomatic and is diagnosed by routine screening before the oc- Classification of drugs currence of overt end-organ damage. Thus, therapy is Antihypertensive drugs can be classified according directed at preventing disease sequelae (that occur in to their sites of action. There is a variety of mecha- the future), rather than in relieving present discomfort nisms of action and some drugs appear under more than of the patient. The adverse effects associated with the one heading. hypertensive therapy may influence the patient more 1. Neurotropic: sedatives, anxiolytics, neurolep- the future benefits. Thus, it is important to enhance tics, and hypnotic drugs in low doses; compliance by carefully selecting a drug regimen that 2. Drugs acting at synaptic transmission: both reduces adverse effects and minimizes the number a) centrally-acting adrenergic drugs (Clonidine, α- of doses required daily. Methyldopa); b) adrenergic antagonists: — sympatholytics DIURETICS α α — -adrenergic blockers: 1) 1-blockers (Pra- β 2) α α Diuretics and/or -blockers are currently recom- zosin); 1- and 2-blockers (Phentolamine); β β β mended as the first-line drug therapy for hyperten- — -adenergic blockers: 1) nonselective 1- and 2- sion. Low-dose diuretic therapy is safe and effective blockers (Propranolol, Pindolol, Timolol); 2) selective β in preventing stroke, myocardial infarction, conges- 1-blockers (Atenolol, Acebutolol, Metoprolol); tive heart failure and total mortality. Recent data sug- — an α + β-blocker: Labetalol; gest that diuretics are superior to β-blockers in older c) cholinergic (ganglionic blockers): Benzohexo- adults. nium, Pentaminum; 3. Myotropic: a) calcium channels blockers: Verapamil, Diltiazem, THIAZIDE DIURETICS Nifedipine; b) phosphodiesterase inhibitors: Aminophylline, All oral diuretic drugs are effective in the treatment Papaverine; of hypertension, but the thiazides have found the most c) imidazole derivatives: Dibazole; widespread use. d) peripheral vasodilators: Hydralazine, Minoxi- Actions. Thiazide diuretics, such as Hydrochlo- dil, Diazoxide, Sodium nitroprusside, ganglionic block- rothiazide, lower blood pressure, initially by increas- ers; ing sodium and water excretion. This causes a de- 4. Drugs affecting blood volume and plasma en- crease in extracellular volume, resulting in a decrease zymes: in cardiac output and renal blood flow. With long- a) angiotensin converting enzyme inhibitors: Cap- term treatment, plasma volume approaches a normal topril, Enalapril; value, but peripheral resistance decreases. Spironol- b) diuretics. actone, a potassium-sparing diuretic, is often used Treatment strategies. Mild hypertension can be with thiazides. controlled with a single drug. More severe hyperten- Therapeutic use. Thiazide diuretics decrease blood sion may require treatment with several drugs that are pressure in both the supine and standing positions; selected to minimize adverse effects of the combined postural hypotension is rarely observed, except in eld- regimen. Treatment is initiated with any of four drugs erly, volume-depleted patients. These agents counter- depending on the individual patient: a diuretic, a β- act the sodium and water retention observed with oth- blocker, an ACE inhibitor, or a calcium channel blocker agents (for example, Hydralazine). Thiazides are er. If blood pressure is inadequately controlled, a sec- therefore useful in combination therapy with variety ond drug is added. A β-blocker is usually added if the of other antihypertensive agents including β-blockers initial drug was a diuretic, or a diuretic is added if the and ACE inhibitors. Thiazide diuretics are particu- first drug was a β-blocker. A vasodilator can be added larly useful in the treatment of black and elderly pa- as a third step for those patients who still fail to re- tients, and in those with chronic renal disease. Thi- spond. azide diuretics are not effective in patients with in-

102 Table 9. Individualized care of hypertension according to concomitant disease

Concomitant disease Drugs commonly used in treating hypertension

Angina pectoris Diuretics β-Blockers ACE Ca++blockers

Diabetes (insulin-dependant) ACE Ca++blockers

Hyperlipidemia ACE Ca++blockers

Congestive heart failure Diuretics ACE avoid verapamil

Previous myo-cardial infarction Diuretics β-Blockers ACE Ca++blockers

Chronic renal disease Diuretics β-Blockers ACE Ca++blockers

Asthma, chronic pulmonary disease Diuretics ACE Ca++blockers

KEY. drug — commonly used drug; drug — alternative drug adequate kidney function (creatinine clearance less terone. The prototype β-blocker is Propranolol, which β β than 50 mls/min). Loop diuretics may be required in acts at both 1- and 2-receptors. Newer agents, such β these patients. as Atenolol and Metoprolol, are selective for 1 recep- Pharmacokinetics. Thiazide diuretics can be admin- tors. These agents may be used in disease states such istered orally. They induce considerable disturbances as asthma, in which Propranolol is contraindicated due β in electrolyte balance. For example, blood levels of to its 2-mediated bronchoconstriction. K+ and Mg++ are reduced, and Ca++ is retained by the Therapeutic uses: body. Subsets of the hypertensive population. The β- Adverse effects. Thiazide diuretics induce hypoka- blockers are more effective for treating hypertension lemia and hyperuricemia in 70% of patients, and hy- in white than in black patients, and in young pa- perglycemia in 10% of patients. Serum potassium lev- tients compared to the elderly. [Note: Conditions el should be monitored closely in patients who are pre- that discourage the use of β-blockers (for example, disposed to cardiac arrhythmias and who are concur- severe chronic obstructive lung disease, congestive rently being treated with both thiazide diuretics and heart failure, occlusive peripheral vascular disease) digitalis glycosides. Diuretics should be avoided in the are more commonly found in the elderly and in dia- treatment of hypertensive diabetics or patients with betics.] hyperlipidemia. Hypertensive patients with concomitant diseases. The β-blockers are useful in treating conditions that may coexist with hypertension, such as supraventricu- LOOP DIURETICS lar tachyarrhythmia, previous myocardial infarction, glaucoma (applied topically), and migraine headache. The loop diuretics act promptly, even in patients β who have poor renal function or who have not respond- Pharmacokinetics. The -blockers are orally active. Propranolol undergoes extensive first-pass metabolism. ed to thiazides. The loop diuretics cause decreased re- β nal vascular resistance and increase renal blood flow. The -blocker may take several weeks to develop their [Note: Loop diuretics increase the Ca++ content of the full effects. ++ Adverse effects: urine, whereas thiazides decrease the Ca concentra- β tion of the urine. Common effects. The -blockers may cause CNS side effects such as fatigue, lethargy, insomnia, and hallucinations; these drugs can also cause hypoten- β-ADRENORECEPTOR sion. The β-blockers may decrease libido and cause BLOCKING AGENTS impotence; drug-induced sexual dysfunction can severely reduce patient compliance. β-Blockers and/or diuretics are currently recom- Alteration in serum lipid patterns. The β-blockers mended as first-line drug therapy for hypertension. may disturb lipid metabolism, decreasing high-densi- These drugs are efficacious but have some contraindi- ty lipoproteins (HDL) and increasing plasma triacylg- cations. lycerol. Actions. The β-blockers reduce blood pressure pri- Drug withdrawal. Abrupt withdrawal may cause marily by decreasing cardiac output. They may also rebound hypertension, probably as a result of up-reg- decrease sympathetic outflow from the CNS and inhibit ulation of β-receptors. Patients should be tapered off the release of renin from the kidneys, thus decreasing of β-blocker therapy in order to avoid precipitation of the formation of angiotensin II and secretion of aldos- arrhythmias. The β-blokers should be avoided in treat-

103 ing patients with asthma, congestive heart failure, and ANGIOTENSIN II ANTAGONISTS peripheral vascular diseases. The nanopeptide Losartan, a highly selective angiotensin II receptor blocker, has recently been ap- ACE INHIBITORS proved for antihypertensive therapy. Its pharmacologic effects are similar to ACE inhibitors in that it produc- The ACE inhibitors (Сaptopril, Enalapril) are es vasodilation and blocks aldosterone secretion. Its recommended when the preferred first-line agents (di- adverse effects profile is improved over the ACE inhib- uretics or β-blockers) are contraindicated or ineffec- itors, although it is fetotoxic. tive. Despite their wide-spread use, it is not clear if ACE inhibitors increase the risk of other major diseases. CALCIUM CHANNEL BLOCKERS Actions. The ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without re- Calcium channel blockers are recommended when flex increasing cardiac output, rate, or contractility the preferred first-line agents are contraindicated or (Fig. 22). These drugs block the angiotensin convert- ineffective. Despite their wide-spread use, it is not clear ing enzyme that cleaves angiotensin I to form the po- what effects antihypertensive therapy with these drugs tent vasoconstrictor, angiotensin II. These inhibitors has on major disease. One retrospective study suggests also diminish the rate of bradykinin inactivation. Va- that use of short-acting calcium channel blockers, es- sodilation occurs as a result of the combined effects of pecially in high doses, is associated with an increased lower vasoconstriction caused by diminished levels of risk of myocardial infarction. If confirmed in more rig- angiotensin II and the potent vasodilating effect of in- orous randomized trials, these finding will reinforce creased bradykinin. By reducing circulating angi- the importance of diuretics and β-blockers as first-line otensin II levels, ACE inhibitors also decrease the se- agents. cretion of aldosterone, resulting in decreased sodium The calcium channel blockers are divided into and water retention. three chemical classes, each with different pharmacok- Therapeutic uses. Like β-blockers, ACE inhibitors inetic properties and clinical indications: are most effective in hypertensive patients who are 1. Diphenylalkylamines. Verapamil is the only white and young. However, when used in combina- member of this class that is currently in clinical prac- tion with a diuretic, the effectiveness of ACE inhibi- tice. Verapamil is the least selective of any calcium tors is similar in white and black hypertensive pa- channel blocker, and has significant effects on both tients. Unlike β-blockers, ACE inhibitors are effec- cardiac and vascular musculature. It is used to treat tive in the management of patients with chronic con- angina, supraventricular tachyarrhythmias, and mi- gestive heart failure. ACE inhibitors are now a stand- graine headache. ard in the care of a patient following a myocardial 2. Benzothiazepines. Diltiazem is the only member infarction. of this class. Like Verapamil, Diltiazem affects both Adverse effects. Common side effects include dry cardiac and vascular smooth muscle cells; however, it cough, rashes, fever, altered taste, hypotension (in hy- has a less pronounced negative inotropic effect on the povolemic states), and hyperkalemia. Potassium sup- heart than does Verapamil. Diltiazem has a favorable plements or Spironolactone are contraindicated. An- side-effect profile. gioedema is a rare but potentially life-threatening re- 3. Dihydropyridines. This rapidly expanding class action. Because of the risk of angioedema and first of calcium channel blockers includes the first-genera- dose syncope, ACE inhibitors are first administered in tion Nifedipine, and newer agents Amlodipine, Fe- the physician’s office with close observation. Reversi- lodipine, Isradipine, Nicardipine, and Nisoldipine. ble renal failure can occur in patients with severe re- These second-generation calcium channel blockers dif- nal artery stenosis. ACE inhibitors are fetotoxic and fer in pharmacokinetics, approved uses, and drug in- should not be used in pregnant women. teractions. All the dihydropyridines have a much

Output of sympathetic us system Angiotensinogen Vasodilation Renin (from kidney) blood Angiotensin I decreased pressure Retention of Na+ Angiotensin II decreased and H2O

ACE inhibitors Levels of bradykinin

Fig. 22. Action of renin — angiotensin system

104 greater affinity for vascular calcium channels than for adequately to treatment with diuretics alone. Clonidine calcium channels in the heart. They are therefore par- does not decrease renal blood flow or glomerular fil- ticularly attractive in treating hypertension. Some of tration and therefore is useful in the treatment of hy- the newer agents, such as Amlodipine and Nicardipine, pertension complicated by renal disease. Clonidine is have the advantage that they show little interaction absorbed well after oral administration and is excret- with other cardiovascular drugs, such as Digoxin or ed by the kidney. Because it causes sodium and water Warfarin. retention, Clonidine is usually administered in combi- Actions. The intracellular concentration of calci- nation with a diuretic. Adverse effects are generally um plays an important role in maintaining the tone of mild, but the drug can produce sedation and drying of smooth muscle and in the contraction of the myocar- nasal mucosa. Rebound hypertension occurs following dium. Calcium enters muscle cells through special volt- abrupt withdrawal of Clonidine. The drug should there- age-sensitive calcium channels. This triggers release of fore be withdrawn slowly if the clinician wishes to calcium from the sarcoplasmic reticulum and mitochon- change agents. dria, which further increases the cytosolic level of calcium. Calcium channel antagonists block the inward α-Methyldopa movement of calcium by binding to L-type calcium α channels in the heart and in smooth muscle of the cor- This -adrenergic agonist diminishes the adrener- onary and peripheral vasculature. This causes vascu- gic outflow from the CNS, leading to reduced total pe- lar smooth muscle to relax, dilating mainly arterioles. ripheral resistance. Cardiac output is not decreased and blood flow to vital organs is not diminished. Be- Therapeutic uses. Calcium channel blockers have an α intrinsic natriuretic effect; therefore, they do not usu- cause blood flow to the kidney is not diminished, - ally require the addition of a diuretic. These agents are Methyldopa is especially valuable in treating hyper- useful in the treatment of hypertensive patients who tensive patients with renal insufficiency. The most com- also have asthma, diabetes, angina, and/or peripheral mon side effects are sedation and drowsiness. vascular disease. Pharmacokinetics. Most of these agents have short VASODILATORS half-lives (T1/2=3 to 8 hours) following an oral dose. Treatment is required three times a day to maintain The direct-acting smooth muscle relaxants, such as good control of hypertension. Sustained release prep- Hydralazine and Minoxidil, have traditionally not arations permit less frequent dosing. been used as primary drugs to treat hypertension. Va- Adverse effects. Although infrequent, side effects in- sodilators act by producing relaxation of vascular clude constipation in 10% of patients, dizziness, head- smooth muscle, which decreases resistance and there- ache, and a feeling of fatigue caused by a decrease in fore decreases blood pressure. These agents produce blood pressure. Verapamil should be avoided in pa- reflex stimulation of the heart, resulting in the com- tients with congestive heart failure due to its negative peting symptoms of increased myocardial contractili- inotropic effects. ty, heart rate, and oxygen consumption. These actions may prompt angina pectoris, myocardial infarction. Vasodilators also increase plasma renin concentration, α-ADRENERGIC BLOCKING AGENTS resulting in sodium and water retention. These undesirable side effects can be blocked by concomitant use Prazosin, Oxazosin and Terazosin produce a com- of a diuretic and a β-blocker. α petitive block of 1-adrenoreceptors. They decrease peripheral vascular resistance and lower arterial blood Hydralazine pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only mini- This drug causes vasodilation, acting primarily on mal changes in cardiac output, renal blood flow, and arteries and arterioles. This results in a decreased pe- glomerular filtration rate. ripheral resistance, which in turn prompts a reflex el- Therefore, long-term tachycardia and increased evation in heart rate and cardiac output. Hydralazine renin release do not occur. Postural hypotension may is used to treat moderately severe hypertension. It is occur in some individuals. Prazosin is used to treat almost always administered in combination with a β- mild to moderate hypertension and is prescribed in blocker (to balance the reflex tachycardia) and a diu- combination with Propranolol or a diuretic for addi- retic (to decrease sodium retention). Together, the three tive effects. Reflex tachycardia and first dose syncope drugs decrease cardiac output, plasma volume, and are almost universal adverse effects. Concomitant use peripheral vascular resistance. Adverse effects of hy- of a β-blocker may be necessary to blunt the short-term dralazine therapy include headache, nausea, sweat- effect of reflex tachycardia. ing, arrhythmia, and precipitation of angina. A lupus- like syndrome can occur with high dosage, but it is reversible on discontinuation of the drug. CENTRALLY-ACTING ADRENERGIC DRUGS Minoxidil Clonidine (Clophelinum) This drug causes dilation of resistance vessels (arterioles) but not of capacitance vessels (venules). Mi- α This 2-agonist diminishes central adrenergic out- noxidil is administered orally for treatment of severe flow. Clonidine is used primarily for the treatment of to malignant hypertension that is refractory to other mild to moderate hypertension that has not responded drugs. Reflex tachycardia may be severe and may re-

105 quire the concomitant use of a diuretic and a β-block- Clonidine (Clophelinum) — in tablets 0.000075 er. Minoxidil causes serious sodium and water reten- and 0.00015 each; in ampoules 0.01% solution 1 ml tion, leading to volume overload, edema, and conges- each tive heart failure. [Note: Minoxidil treatment also caus- Reserpine — in tablets 0.0001 and 0.00025 each es hypertrichosis (the growth of the body hair). This Atenolol — in tablets 0.1 each drug is now used topically to treat male pattern bald- Prazosin — in tablets 0.001 and 0.005 each ness.] Diltiazem — in tablets 0.03 and 0.06 each Papaverine hydrochloride — in tablets 0.04 each; in ampoules 2% solution 2 ml each HYPERTENSIVE EMERGENCY Nitroprusside sodium — in ampoules 0.025 and Hypertensive emergency is a rare, but life-threat- 0.05 each (to dilute in 500 ml of 5% solution of glu- ening situation in which the diastolic blood pressure cose) is either over 150 mm Hg (with systolic blood pres- Hydralazine (Apressinum) — in tablets 0.01 and sure greater than 210 mm Hg) in an otherwise healthy 0.25 each person, or 130 mm Hg in an individual with preexisting complications, such as encephalopathy, cerebral hemorrhage, left ventricular failure, or aortic stenosis. The therapeutic goal is to rapidly reduce blood Lecture 26 pressure. DRUGS USED IN HYPOTENSION Sodium Nitroprusside

Nitroprusside is administered intravenously, and Shock is a state of inadequate capillary perfusion causes prompt vasodilation, with reflex tachycardia. (oxygen deficiency) of vital tissues to an extent that It is capable of reducing blood pressure in all patients, adversely affects cellular metabolism (capillary en- regardless of the cause of hypertension. The drug has dothelium and organs) causing malfunction including little effect outside the vascular system, acting equal- release of enzymes and vasoactive substances, i.e. it ly on arterial and venous smooth muscle. [Note: Be- is a low flow or hypoperfusion state. cause Nitroprusside also acts on the veins, it can re- The essential element, hypoperfusion of vital or- duce cardiac preload.] Nitroprusside is metabolized gans, is present whatever the cause, whether the pump rapidly (t1/2 of minutes) and requires continuous in- failure (myocardial infarction), maldistribution of the fusion to maintain its hypotensive action. Sodium ni- blood (septic shock) or loss of total intravascular vol- troprusside exerts few adverse effects except for those ume (bleeding, or increased permeability of vessels of hypotension caused by overdose. Nitroprusside me- damaged by bacterial cell wall substances, by burns tabolism results in cyanide ion production, although or by anoxia). Function of vital organs, brain (con- cyanide toxicity is rare and can be effectively treated sciousness) and kidney (urine formation) are critical with an infusion of sodium thiosulfate to produce thio- indicators of adequacy of perfusion of these organs. cyanate, which is less toxic and eliminated by the kid- Treatment may be summarized: neys. [Note: Nitroprusside is poisonous if given orally 1. Treatment of the cause: pain, wounds, infections, because of its hydrolysis to cyanide.] adrenocortical deficiency. 2. Replacement of any fluid lost from the circula- Diazoxide tion; but extra fluid is dangerous when the primary Diazoxide is a direct acting arteriolar vasodilator. fault is in the heart or pulmonary circulation. It has vascular effects like those of hydralazine. For 3. Maintenance of the diastolic blood pressure and patients with coronary insufficiency, Diazoxide is ad- perfusion of vital organs (brain, heart, kidneys). ministered i.v. with a β-blocker, which diminishes re- Blood flow rather than blood pressure is of the flex activation of the heart. Diazoxide is useful in the greatest immediate importance for the function of vi- treatment of hypertensive emergencies, hypertensive tal organs. Hypotension due to low peripheral resist- encephalopathy, and eclampsia. Excessive hypoten- ance is of little importance if the patient is horizon- sion is the most serious toxicity. tal or tilted head down, for venous return to the heart, and so the cardiac output, are then maintained, and Labetalol blood flow to brain, myocardium and kidneys remains adequate until the diastolic blood pressure falls be- Labetalol is both an α- and β-blocker that has been low about 40 mm Hg. But low cardiac output is al- successfully used in hypertensive emergencies. Labeta- ways serious even though compensatory vasoconstric- lol does not cause the reflex tachycardia that may be tion maintains the arterial pressure, for blood flow is associated with Diazoxide. Labetalol carries the con- reduced. traindications of a nonselective β-blocker. The decision how to treat shock depends on assessment in the individual patient of the pathophysiology, Available forms: whether cardiac output, and so peripheral blood flow, Captopril — in tablets 0.025; 0.05 and 0,1 each is inadequate (low pulse volume, cold constricted pe- Ethacrynic acid — in tablets 0.05 each; in ampoules riphery), or whether cardiac output is normal and pe- 0.05 each (to dilute in physiologic solution before us- ripheral blood flow is adequate (good pulse volume and ing) warm dilated periphery) whether the patient is hypov-

106 olemic or not, or needs a cardiac inotropic agent, a as well as selectively modifying peripheral resistance vasoconstrictor or a vasodilator. increase flow to vital organs. In poisoning by cerebral depressant the principal Dopamine meets these requirements best. Where cause of hypotension is low peripheral resistance due high doses are being used and vasoconstriction predom- to sympathetic block. The cardiac output can be re- inates it may sometimes be useful to add a vasodila- stored by tilting the patient head down and by increas- tor, e.g. an α-adrenoreceptor blocking drug. As well ing the venous filling pressure by cautiously expand- as reducing peripheral blood flow, prolonged vasocon- ing the blood volume with plasma. Use of vascular striction reduces blood volume due to passage of fluid drugs is unnecessary and may be harmful. They do not into the extravascular space. Thus cessation of use may reproduce the pattern of the missing sympathetic (neu- be followed by a drop in cardiac output. rogenic) vasoconstriction. Dobutamine is used when cardiac inotropic effect In central circulatory failure (e.g. myocardial inf- is the primary requirement. arction) the cardiac output and blood pressure are low Noradrenaline is used when vasoconstriction is the due to loss of pumping power. Venous return (central first priority, plus some slight cardiac inotropic effect. venous pressure) is normal or high. Not surprisingly, Restoration of intravascular volume. Ideally the the use of drugs in low output due to acute myocardial transfusion should be similar to that which has been damage is disappointing. Vasoconstriction (by lost blood for hemorrhage, plasma for burns, saline for α-adrenoreceptor agonist), by increasing peripheral gastrointestinal loss. However, in an emergency, speed resistance, may raise the blood pressure by increasing of replacement is more important than its nature. Note afterload, but this can further reduce cardiac output. on dextrans (polysaccharides): Dextran 150, 110 or 70 β Cardiac stimulation with 1-adrenoreceptor agonist (these are the molecular weights in thousands; albu- may increase myocardial oxygen consumption and min MW is 69,000) can be used as plasma substitutes may cause a dysrhythmia. Dopamine and Dob- to restore volume; they are retained in the circulation utamine offer a reasonable choice. However, if there and largely eliminated by catabolism (Dextran 60 is is bradycardia, output can be increased by vagal block also called Polyglucin). Dextran 40 (Reopolyglucin) with Atropine. Digitalis is not useful in cardiogenic should not be used for this purpose; its small molecule shock. Vasodilators may be needed to treat severe means that it is rapidly (few hours) excreted by renal heart failure. glomerular filtration; it is concentrated in the urine In septic shock (caused by endotoxins from gram- and, especially if there is oliguria, this results in a high- negative organisms and other cell products from gram- ly viscous urine that blocks renal tubules causing acute positive organisms), the cardiac output may be low or renal failure. It is used to improve peripheral blood high, but vital organs are underperfused. First there flow by decreasing plasma sludging of cells, e.g. pe- is a peripheral vasodilation with eventual fall in arte- ripheral vascular disease and postsurgical thromboem- rial pressure. Blood is sequestrated in the periphery. bolism. Large volume of all dextrans (above 1.5 L) can The immediate aim of treatment is to restore cardi- interfere with platelet function. They also interfere ac output by increasing venous return to the heart. This with blood group cross-matching and clinical biochem- can be done by increasing intravascular volume (plas- ical measurements. Gelatin (MW approx. 30,000) are ma transfusion), keeping a close watch on central ve- alternatives to dextrans. nous pressure to avoid overload the heart. In addition a vasodilator drug may allow the release of the seques- Available forms: tered blood, and α-adrenoreceptor blockers (e.g. phen- Dobutamine — in ampoules 5% solution 5 ml each tolamine) have been used for this. Administration of a Dopamine — in ampoules 0.5% or 4% solution 5 vasodilator to a patient with a low blood volume is, of ml each course, disastrous. Noradrenaline hydrotartrate — in ampoules 0.2% Drugs that increase peripheral resistance (sym- solution 1 ml each α β pathomimetics with -effect and no 1-effect) are like- Prednisolone hemisuccinate — in ampoules 0.025 ly only to make matters worse by further reducing each (to dilute before using in 5 ml of sterile water) blood flow to vital organs. Noradrenaline does have Dextran 60 (Polyglucinum) — in bottles 100; 200 β some cardiac inotropic ( 1) effect and may be used if and 400 ml each substantial vasoconstriction is judged necessary. But Dopamine provides a “mix” of actions that is least likely to do harm and even may do good (α + β-effect + renal vasodilation). EXAMINATION QUESTIONS Adrenocortical steroids in enormous (and costly) doses (e.g. Dexamethasone 2–6 mg/kg i.v. as a single 1. A 40-year-old man goes to the emergency depart- injection, repeated in 2–6 hours and after that as clin- ment because of an intractable cough for the past few ical judgment counsels for a maximum of 2–3 days) days. No one else in his household has any cough, fe- may benefit by reducing the consequences of damage ver, upper respiratory infection, and so on. He was re- of cellular membranes by toxins or anoxia and so pre- leased from the hospital a week ago with the diagno- venting the release of biologically active damaging sis of idiopathic dilated cardiomyopathy following an substances. The effect probably has nothing to do with extensive evaluation that revealed normal coronary the ordinary actions of corticosteroids. Ordinary re- anatomy and a left ventricular EF of 38%. He was dis- placement doses are useless. charged with prescriptions for Digitalis, Furosemide, Choice of drug in shock. On present knowledge the Captopril, and Carvedilol. He has been more active best drug would be one that stimulates the myocardium and has noted improvement in his dyspnea and fatigue

107 that prompted his initial presentation 10 days ago. He (D). Binding to and inhibiting the Na-K ATPase appreciates all of the care that he received and apolo- enzyme in cardiac myocytes. gizes for making a fuss over the cough. He states that (E). Deactivation of the angiotensin receptor. his wife made him come in because she was concerned that it might be his heart. He states that the cough is 4. The combination of hydralazine and nitrates has different from the congested feeling he had 10 days ago. been shown to improve survival in patients of heart fail- On examination, he was afebrile; his heart rate was 60 ure. All of the following statements about this combi- beats per minute; blood pressure, 100/60. Neck veins nation are true except: were flat; carotid upstrokes were normal. Chest and (A). The combination serves to decrease both af- lungs were clear. Heart revealed a regular rate and terload and preload. rhythm without murmurs, gallops, or rubs. Abdomen (B). Prazosin is as effective as the combination in was soft and not tender. Bowel sounds were present with- treatment of congestive heart failure. out organomegaly. Extremities revealed no cyanosis, (C). The concept of afterload reduction is princi- clubbing, or edema. Chest radiograph and electrocar- pally derived from patients of significant mi- diogram revealed no acute changes and no active dis- tral regurgitation. ease. The physician was satisfied that he was hemody- (D). The VA cooperative study was a landmark namically stable and the cough was not resulting from trial demonstrating the beneficial effect of hy- worsening heart failure. What is a reasonable next step? dralazine and nitrate combination in patients (A). Admit to the hospital to exclude (rule out) a of heart failure. myocardial infarction. (B). Apply a PPD skin test to exclude tuber- 5. β-Blockers have been effective in the treatment culosis. of heart failure. They primarily exert their effect by (C). Substitute an angiotensin II receptor blocker (A). Binding to the receptor that binds Norepine- for the ACE inhibitor. phrine. (D). Provide reassurance and continue with cur- (B). Inducing a prominent diuretic effect. rent medications. (C). Increasing contractility. (E). Immediately stop the (β-adrenergic blocker, (D). Improving asthma control. Carvedilol. (E). Increasing heart rate to meet the additional demands placed upon the heart in CHF. 2. A 67-year-old woman has had fatigue and shortness of breath over the past few months. She has diabetes and hypertension for which she has been treated 6. A 45-year-old woman has had recurrent episodes for 25 years with appropriate medications. She is sta- of atrial fibrillation. She is receiving Phenytoin and tus post three myocardial infarctions (MI X3) and has Quinidine to control the atrial fibrillation. She is also known inoperable coronary artery disease and CHF. taking a low dose of diazepam for insomnia and es- She has been very compliant with her complicated trogen replacement therapy. You learn today that she medical regimen, which includes Digitalis, an ACE in- has been receiving Ciprofloxacin for a urinary track hibitor (Fosinopril), loop diuretic (Furosemide), (3- infection. The reason for her appointment today is that adrenergic receptor blocker (Carvedilol) and aldos- she has been having ringing in the ears, headache, nau- terone antagonist (Spironolactone). On examination sea, and blurred vision. She tells you that she is also she was noted to be in acute respiratory distress with having trouble hearing the television. You suspect drug a respiratory rate of 24, a heart rate of 60, and blood toxicity. The most likely agent is pressure of 110/60. She was anxious and uncomforta- (A). Ciprofloxacin. ble but polite and cooperative. Neck veins were ele- (B). Estrogen. vated to 8 cm with the patient partially supine. Lungs (C). Phenytoin. revealed rales to the angles of the scapulae bilateral- (D). Diazepam. ly. Heart revealed a third heart sound and a high (E). Quinidine. pitched holosystolic murmur at the apex consistent with mitral regurgitation. Abdomen was protuberant with 7. You are asked to treat a 55-year-old patient for a fluid shift consistent with ascites. Extremities revealed continuing ventricular arrhythmias. The patient is re- 2 to 3 + pretibial pitting edema bilaterally. What can ceiving Timolol drops for glaucoma, daily insulin in- the physician offer this woman? jections for diabetes mellitus, and an ACE inhibitor for (A). Intravenous (cAMP elevating) positive ino- hypertension. What pharmacological effect of Procain- tropic agents. amide made you to decide to use Phenytoin instead of (B). Vasodilator therapy with Hydralazine. Procainamide? (C). α-Adrenergic blockade with Prazosin. (A). The local anaesthetic effect of Procainamide (D). Stop the diuretic, Furosemide. would potentiate diabetes. (E). Stop the ACE inhibitor, Fosinopril. (B). The anticholinergic effect of Procainamide would aggravate glaucoma. 3. Digitalis functions to improve congestive heart (C). The hypertensive effects of Procainamide failure by would aggravate the hypertension. (A). Induction of emesis. (D). The local anaesthetic effect of procainamide (B). Activation of β-adrenergic receptors. would aggravate the hypertension. (C). Improving survival in patients of heart fail- (E). The cholinergic effects of Procainamide ure. would aggravate the diabetes.

108 8. Exercise-induced ventricular tachycardia in per- 14. A patient who has been taking propranolol for sons without overt cardiac disease is an example of de- a long period for secondary angina comes to your of- layed after-depolarizations and is characterized by an fice complaining of increased frequency of chest pains increase in intracellular ionized calcium. This type of on exertion. You decide to stop the Propranolol and arrhythmia is known to often respond well to which of give him Diltiazem because you suspect he has a mix- the following combinations? ture of secondary and primary angina. Why would (A). β-Blocker and ACE inhibitor. Diltiazem be more likely to relieve the angina if your (B). Calcium channel antagonist and ACE inhib- new diagnosis is accurate? itor. (A). Diltiazem produces a decrease in heart rate. (C). α-Blocker and ACE inhibitor. (B). Diltiazem dilates coronary blood vessels in (D). β-Blocker and calcium channel antagonist. spasm. (E). α-Blocker and calcium channel antagonist. (C). Diltiazem produces AV blockade. (D). Diltiazem reduces myocardial contractility. 9. Antiarrhythmic drugs are classified in four main (E). Diltiazem reduces afterload. groups based on their predominant mechanism of action. Antiarrhythmic agents in which class suppress 15. Metoprolol would produce which beneficial ef- abnormal automaticity and permit the sinoatrial node fect in a patient with secondary angina? to again assume the role of the dominant pacemaker? (A). A decrease in preload. (A). Class I. (B). An increase in collateral blood flow. (B). Class II. (C). An increase in afterload. (C). Class III. (D). An increase in diastolic filling time. (D). Class IV. (E). An increase in blood flow through a concentric stenosis. 10. Although most antiarrhythmic drugs (and indeed most drugs) are chemically synthesized, some 16. Which of the following statements most accu- compounds that occur endogenously in humans are rately characterize the cellular action of the calcium useful. Indicate which of the following agents occurs channel blockers? endogenously and is a useful antiarrhythmic agent. (A). Their interaction with membrane phospholi- (A). Phenytoin. pids results in a nonselective decrease of ion (B). Digoxin. transport. (C). Adenosine. (B). They inhibit the Na+-Ca++ exchanger in car- (D). Quinine. diac and smooth muscle. (E). Lidocaine. (C). They interact at three distinct sites at the L- type voltage-gated calcium channels. 11. A patient comes to your office with effort-in- (D). Their interaction with the sodium pump reduced angina and resting tachycardia. You choose the sults in an inhibition of calcium transport. following drug to treat the patient because it slows heart rate by blocking L-type calcium channels in the 17. Which of the following calcium channel block- SA node: ers would be most likely to suppress atrial tachyar- (A). Verapamil. rhythmias involving the A-V node? (B). Propranolol. (A). Nifedipine. (C). Nitroglycerin. (B). Verapamil. (D). Isosorbide dinitrate. (C). Nicardipine. (E). Metoprolol. (D). Amlodipine. 12. Which of the following hemodynamic effects of 18. All of the following statements are applicable Nitroglycerin are primarily responsible for the beneficial with regard to the systemic effects caused by Nifedipine results observed in patients with secondary angina? EXCEPT: (A). Reduction in the force of myocardial contrac- (A). It typically causes peripheral vasodilation. tion. (B). It often elicits reflex tachycardia. (B). Reduction in systemic vascular resistance (af- (C). It causes coronary vasodilatation and an in- terload). crease in coronary blood flow. (C). Increased heart rate. (D). Its benefit in the management of angina is (D). Reduction in venous capacitance (preload). related to the reduction in preload that it in- (E). Increased blood flow to the subepicardium. duces. 13. A woman is prescribed a combination of drugs 19. All of the following statements regarding the consisting of a nitroglycerin patch and a β-blocker, pharmacokinetics of calcium channel blockers are cor- such as Propranolol, to treat her attacks of secondary rect EXCEPT angina. Which effect of Propranolol would counter- (A). They are characterized by significant amount act an adverse effect of Nitroglycerin? (~ 90%) of protein binding. (A). A decrease in preload. (B). They undergo significant first-pass metabo- (B). A decrease in afterload. lism. (C). A decrease in heart rate. (C). Their half-life is not altered by hepatic cir- (D). An increase in myocardial contractile force. rhosis. (E). A reduction in coronary vasospasm. (D). They can be administered orally.

109 20. All of the following adverse effects are likely (B). Reduce the activity of the sympathetic nerv- to occur with long-term use of calcium channel block- ous system. ers EXCEPT (C). Be a potent positive inotropic at the heart. (A). Skeletal muscle weakness. (D). Relax vascular smooth muscle. (B). Flushing. (E). Reduce the growth of cardiovascular cell (C). Dizziness. types. (D). Headache. 27. The most potent vasoconstrictor known is 21. A 55-year-old patient has been referred to you. (A). Bradykinin. She complains about a skin rash and a cough. In the (B). Angiotensin II. course of history taking, she tells you that she takes (C). Angiotensin IV. high blood pressure medication but she doesn’t remem- (D). Natriuretic peptide. ber the name. You suspect a drug toxicity. Which of (E). Endothelin. the following antihypertensive agents is the patient most likely taking? 28. The mechanism of action of Сaptopril is (A). Captopril. (A). Angiotensin receptor antagonist. (B). Nifedipine. (B). ACE inhibitor. (C). Prazosin. (C). Aldosterone receptor antagonist. (D). Propanolol. (D). Bradykinin antagonist. (E). Clonidine. 29. L-Argenine serves as a precursor for 22. Which of the following compounds depends (A). Bradykinin. least upon the release of EDRF (nitric oxide) from en- (B). L-Citrulline. dothelial cells to cause vasodilation? (C). Nitrous oxide. (A). Bradykinin. (D). Atrial natriuretic peptide. (B). Histamine. (C). Minoxidil. 30. When a patient is treated with a thiazide diu- (D). Hydralazine. retic for hypertension, all of the following are likely (E). Acetylcholine. EXCEPT: (A). The fall of blood pressure that occurs in the 23. Which of the following antihypertensive drugs first 2 weeks of therapy results from a decrease is contraindicated in a hypertensive patient with a phe- of extracellular volume. ochromocytoma? (B). The sustained fall in blood pressure that oc- (A). Metyrosine. curs after several weeks of therapy is due to a (B). Labetalol. decrease of intravascular resistance. (C). Prazosin. (C). After the blood pressure is reduced, hypoka- (D). Phenoxybenzamine. lemia remains a complication. (E). Guanethidine. (D). Hyperuricemia may occur. (E). Hypoglycemia may occur. 24. Which of the following antihypertensive agents would decrease renin release? 31. Furosemide increases the excretion of all of the (A). Prazosin. following EXCEPT: (B). Clonidine. (A). Na+. (C). Captopril. (B). K+. (D). Nitroprusside. (C). Ca++ and Mg++. (E). Diazoxide. (D). Uric acid.

25. An accurate statement regarding the actions of 32. Which of the following drugs is an appropriate both ACE inhibitors and AT1 receptor antagonists is initial antihypertensive therapy in an otherwise healthy that adult with mild hypertension? (A). Both classes of drugs increase bradykinin. (A). Bumetanide. (B). Angiotensin II can act at the AT2 receptor (B). Triamterene. with both classes of drugs. (C). Hydrochlorothiazide. (C). Both classes of drugs reduce total peripheral (D). Aldactone. resistance. (D). Both classes of drugs decrease circulating an- 33. When Furosemide is administered to a patient giotensin II levels. with pulmonary edema, there is often symptomatic re- (E). Both classes of drugs are first-choice treat- lief within 5 minutes of starting treatment. This relief ments for congestive heart failure. is primarily due to: (A). A rapid diuretic effect. 26. Angiotensin II can (B). An increase in venous capacitance. (A). Increase the synthesis and release of aldos- (C). A direct effect on myocardial contractility. terone. (D). Psychological effects.

110 ANSWERS 11. (A). Verapamil is an L-type calcium channel blocker. Nitroglycerin and Isosorbide are both organic nitrates 1. (C). The most likely diagnosis is ACE inhibitor-in- and have no direct effect on L-type calcium channels at duced cough. A reasonable approach is to substitute an the SA node, while Propranolol and Metoprolol are β- ARB (angiotensin II receptor blocker) such as valsartan adrenoceptor blockers and will slow heart rate by block- or losartan for the ACE inhibitor, Сaptopril. Reassure and ing the actions of norepinephrine and epinephrine on β- encourage the patient and spouse that you think the cough receptors at the SA node. will resolve a few days after stopping the ACE inhibitor. 12. (D). Nitroglycerin can reduce preload, which in There is generally no benefit to trying any other ACE in- turn reduces wall tension and increases subendocardial hibitor, as the side effect is a class effect resulting from blood flow. Nitroglycerin also reduces afterload, but this enhanced kinin activity from ACE inhibition. Myocardial is a small effect compared to the reduction in preload. infarction is extremely unlikely in this patient based on Its effects on heart rate and contractility are minimal, the catheterization data showing normal coronary anato- and if anything reflex tachycardia and increase in con- my. Abrupt withdrawal of a 3-blocker may precipitate tractility would be detrimental effects of too much Ni- tachycardia and hypertension and should be avoided. troglycerin. 2. (A). This woman with CHF has obviously decom- 13. (C). Nitroglycerin can increase heart rate via an in- pensated despite compliance with standard care. She is crease in sympathetic tone to the heart due to an exces- symptomatic and may benefit from a short course of high- sive decrease in blood pressure; Propranolol would block intensity intravenous therapy with a cAMP-elevating the β-receptors responsible for the tachycardia. Pro- agent (e.g. Dobutamine, Milrinone, Amrinone). This may be pranolol does not decrease preload, and its effect to de- a reversible event or part of the inevitable decline of the crease afterload would exacerbate the decrease in after- disease process. Approximately 45% of CHF patients die load produced by nitroglycerin. Propranolol does not in- suddenly of a presumed electrical event (e.g. ventricular crease myocardial contractile force and could actually tachycardia, asystole). The others die slowly of progres- increase the incidence of vasospasm by unmasking sive deterioration. Many patients at the end stages of CHF α-adrenoceptors in the coronary blood vessels. prefer to try repeated outpatient in-otropic (cAMP elevat- 14. (B). Both diltiazem and propranolol would pro- ing) therapy for symptomatic relief even though it may duce the effects listed in (A), (C), (D), and (E). Only be associated with a higher incidence of sudden death. Diltiazem would dilate vessels in spasm. Propranolol would 3. (D). Inhibition of Na-K ATPase leads to an eleva- tend to produce vasoconstriction, not vasodilation. tion of intracellular Na+. This results in an increase in 15. (D). An increase in time spent in diastole would intracellular Ca++ and an enhanced myocardial contract- increase subendocardial blood flow. Metoprolol does not ibility. There is no definitive evidence that Digitalis im- decrease preload or increase afterload; in fact the oppo- proves survival of patients in heart failure, but it clearly site is likely to occur. Metoprolol does not affect collateral improves the symptoms of this condition. blood flow or flow through a concentric stenosis. 4. (B). Prazosin has been shown not to be as effective 16. (C). The available blockers act primarily at volt- as the combination of hydralazine and nitrates. agegated calcium channels of the L type. The three pro- 5. (A). The salutary effect of β-blockers appears to be totypes, Verapamil, Nifedipine, and Diltiazem, act at three due solely to its binding to the β-receptor, which pre- discrete sites at this channel. vents norepinephrine binding and stimulates cAMP for- 17. (B). The other three drugs (dihydropyridines) are mation. The other choices do not occur. characterized by relatively selective vasodilator effects 6. (E). Quinidine. These are the classic signs of cinchon- with little if any cardiac effects at doses employed clini- ism and are adverse effects of Quinidine and Quinine, con- cally for hypertension or angina. stituents of the cinchona tree. Some of these effects could 18. (D). The vasodilatory effects of Nifedipine are large- be seen as toxic effects of phenytoin. However, auditory ly restricted to arteries (and consequently the afterload). acuity is associated with cinchonism and not with pheny- It does not alter venous tone (and thus preload) signifi- toin toxicity. Nausea but not the other effects could be cantly. associated with ciprofloxacin. Excessive drowsiness would 19. (C). Since they are metabolized in the liver, he- be expected if diazepam were involved. These effects would patic cirrhosis can be expected to alter their half-life. not be expected with the estrogen replacement therapy. 20. (A). Skeletal muscles depend on the mobilization 7. (B). Anticholinergic agents, such as Procainamide of intracellular stores of calcium for their contractile re- and Disopyramide, are relatively contraindicated in pa- sponses rather than transmembrane flux of calcium tients with glaucoma. Procainamide is hypotensive rath- through the calcium channels. Therefore, skeletal muscle er than hypertensive. The local anaesthetic activity of weakness is not likely to occur. Procainamide would have no adverse interaction with the 21. (A). Although many drugs can evoke a reaction diabetes mellitus. such as a rash, a rash and a dry cough are well-recog- 8. (B). Each of these approaches would reduce the tis- nized side effects of angiotensin converting enzyme (ACE) sue calcium concentration and prevent arrhythmias. inhibitors, such as Captopril. Up to 20% of these patients Agents with α-blocking capacity would have no effect on may develop a cough with ACE inhibitors. The cause is calcium. Agents with ACE inhibitory activity would like- not known for certain, but it may be related to the accu- wise have no effect on calcium. mulation in the lungs of bradykinin or other inflamma- 9. (A). Class I agents suppress both normal Purkinje tory mediators. Inhibiting ACE leads to an increase in fiber and His bundle automaticity in addition to abnor- bradykinin, which is normally broken down by this en- mal automaticity resulting from myocardial damage. zyme. The rash was originally attributed to a sulfhydr- Class II drugs block β-adrenoceptors; class III drugs pro- yl group in Captopril but is known to occur with other long the membrane action potential by delaying repo- non-sulfhydryl-containing ACE-inhibitors. larization; and class IV drugs block the slow inward 22. (C). The vasodilation caused by bradykinin, his- movement of calcium ions. tamine, hydralazine, and acetylcholine depends in part 10. (C). Adenosine is a product of the metabolism of upon nitric oxide release from the endothelium. Minox- adenosine triphosphate. Phenytoin and Lidocaine are to- idil activates K+ channels, which results in vascular tally synthetic, while Digoxin occurs naturally in plants smooth muscle hyperpolarization and thereby relaxa- and Quinine occurs in the cinchona tree. tion.

111 23. (E). Guanethidine does not normally cause release 29. (C). Nitric oxide is an important compound that of catecholamines from the adrenal medulla. However, it acts as a biological messenger in many physiological re- may provoke the release of catecholamines from pheo- sponses. L-Citrulline is a product of the oxidation of L- chromocytoma. This action plus its ability to antagonize argenine in the formation of nitric oxide. Bradykinin is neuronal uptake of catecholamines could trigger a hy- formed from a precursor kininogen. pertensive crisis. The other drugs are good choices to low- 30. (E). There is no evidence that the thiazides have er blood pressure in a patient with pheochromocytoma: any effect on blood sugar. Initial reductions of blood Metyrosine, by decreasing synthesis; Labetalol, by block- pressure are due to decreased extracellular volume and ing both the α- and β-effects of the catecholamines; Pra- cardiac output. The beneficial effect of the sustained re- zosin and especially Phenoxybenzamine, by introducing a duction of blood pressure is due to reduced vascular re- fairly long α-blockade. sistance. Extracellular volume remains modestly reduced 24. (B). Clonidine is an antihypertensive because it de- and cardiac output returns to pretreatment levels. Hy- creases sympathetic outflow from the CNS to the periph- pokalemia does not ameliorate over time and is associ- ery and therefore reduces the sympathetically induced ated with an increased risk of ventricular fibrillation and stimulation of renin release. The sympathetic effect on malignant arrhythmias. The magnitude of hypokalemia renin release is mediated by β-receptors, so prazosin, an produced by thiazide and thiazide-like diuretics is dose α-blocker would not decrease release. Captopril is an dependent. However, the degree to which individual pa- ACE inhibitor and is likely to enhance renin release, al- tients are affected varies, though chronic administration though it would prevent the effects of renin by reducing of even small doses causes some K+ depletion. Hyperuri- the formation of angiotensin II. Nitroprusside and Dia- cemia is thought to have two causes. One is competition zoxide are directly acting vasodilators and will promote of the thiazide class of diuretics, which are weak organic renin release reflexively. acids, with uric acid for secretion by proximal tubules. 25. (C). ACE inhibitors increase circulating bradyki- This leads to diminished uric acid excretion. Serum con- nin levels, while AT1 receptor antagonists have no effect centrations of uric acid are further elevated by the re- on circulating bradykinin. The ability of converting en- duced extracellular volume. Diuretic-induced hyperuri- zyme inhibitors to increase bradykinin levels is thought cemia may cause acute gouty attacks. to contribute to the benefits of this class of drugs in the 31. (D). Increased Na+ excretion is a direct conse- treatment of hypertension and heart failure. With an quence of diuretic treatment. In thick ascending limbs, ACE inhibitor, the actions of angiotensin II at both the the site of furosemide action, calcium and magnesium AT1 and the AT2 receptor is decreased; however, with an transport is largely determined by the magnitude of so- AT1 receptor antagonist, angiotensin II can act at the AT2 dium absorption. Decreases of Na+ absorption are ac- receptor. Only ACE inhibitors decrease circulating an- companied by diminished Ca++ and Mg++ absorption. K+ giotensin II levels; the level of angiotensin II may actu- wasting is due to increased K+ secretion by late distal ally increase with an AT1 receptor antagonist because of tubules and collecting ducts. Uric acid excretion decreas- removal of the endocrine feedback loop. ACE inhibitors es as a consequence of competition for the proximal tu- have proven benefits in the treatment of congestive heart bule organic acid secretory mechanism. failure, while AT1 receptor antagonists are reserved for 32. (C). Although still highly controversial, the ini- therapy of patients who have significant adverse effects tial use of a thiazide diuretic for monotherapy has been from converting enzyme inhibition. recommended by the Joint National Committee on De- 26. (A). Angiotensin II has diverse physiological ef- tection, Evaluation and Treatment of High Blood Pres- fects, including stimulating the synthesis and release of sure. Triamterene and Aldactone are rarely used alone and aldosterone from the adrenal cortex. This effect of angi- exhibit no antihypertensive activity. A recent study found otensin II results in fluid and water retention. The other that the loop diuretics Bumetanide and Furosemide ef- answers are incorrect in that angiotensin II stimulates fectively reduced blood pressure. Serum lipid levels were the sympathetic nervous system, is a weak inotropic, less affected than with thiazide diuretics or Chlorthalidone. contracts vascular smooth muscle, and increases the However, thiazide diuretics are a more conservative and growth status of cardiovascular cell types. approved approach for the initial treatment of hyperten- 27. (E). Bradykinin and natriuretic peptide are va- sion that avoid the more dramatic fluid and electrolyte sodilators. Both angiotensin II and angiotensin IV are shifts that occur with loop diuretics. vasoconstrictors but not nearly as potent as any endothe- 33. (B). Intravenous Furosemide causes a significant lin peptide. decrease in pulmonary capillary wedge pressure and right 28. (B). Compounds that act as ACE inhibitors are atrial pressure, concomitantly decreasing stroke volume particularly useful for the treatment of hypertension and and increasing vascular resistance. This effect in many congestive heart failure. cases occurs before diuresis begins.

112 DRUGS AFFECTING THE METABOLISM

Lecture 27 stances, the atrophy of endocrine glands is possible, in result of which during sudden cessation of the treat- DRUGS AFFECTING THE ment “syndrome of breaking” (withdraw) may devel- ENDOCRINE SYSTEM op. It is characterized by symptoms of acute endocrine insufficiency.

Hormones are the biological active substances that are produced by endocrine glands. They possess high HORMONES OF PROTEIN AND activity being present in small doses. Hormones regu- AMINOACID STRUCTURE late processes of reproduction, growth, development of Hypothalamic and Pituitary Hormones organism and model it’s protective reactions. By chemical structure hormone drugs are divided Neuroendocrine control of metabolism, growth, into next groups: and certain aspects of reproduction is mediated by a — Substances of protein or peptide structure (drugs combination of neural and endocrine systems located of hypothalamus, pituitary, parathyroid and pancre- in the hypothalamus and pituitary gland (hypophysis). atic hormones, and calcitonin) The pituitary gland consists of anterior and interme- — Derivatives of aminoacids (agents of thyroid hor- diate lobes (adenohypophysis), and a posterior lobe mones) (neurohypophysis), which release a number of hor- — Steroid substances (drugs of adrenal cortex and mones that either control the secretion of other endo- gonadal hormones) crine glands or affect the metabolic actions of target tissues directly. The secretion of anterior lobe hor- Hormones interact with specific receptors, located mones is regulated by hormones formed in the hypoth- on cellular membranes or intracellularly. Hormones alamus. These hormones are small peptides that func- of protein structure predominantly bind with receptors tion as releasing or inhibiting hormones. The posteri- on cellular membranes. Mostly these receptors are co- or lobe hormones are synthesized in the hypothalamus operated with adenylate cyclase system, which stimu- and transported to the pituitary posterior lobe, from lating leads to increasing of cAMP forming, and it’s which they are released into the circulation. through protein kinases influence on intracellular proc- Six anterior pituitary hormones are recognized: esses. Adenylatecyclase, cAMP and calcium-ions are Somatotropin (growth hormone), Thyrotropin (TSH), mediators among receptors and intercellular process- Adrenocorticotropin (ACTH), Follicle-stimulating Hor- es. Steroid hormones enter cells of target tissues and mone (FSH), Luteinizing Hormone (LH), and Prolac- binds to an intracellular specific receptor. The hor- tin (PRL). mone receptor complex translocates into the nucleus Somatotropin (growth hormone) is a peptide hor- and binds to nucleotides on various genes and regu- mone. It’s deficiency leads to short stature. Somatotro- late their transcription and proteins synthesis. pin for pharmacologic use is produced with recom- Hormonal drugs are received from different sourc- binant DNA technology. Somatotropin can be admin- es. Some agents are extracted from correspondent ani- istered intramuscularly. Pharmacologic doses of mal gland (thyreoidine, bovine insulin), the other ones growth hormone cause longitudinal growth indirectly are synthesized (L-thyroxine, triiodothyronine). Also, via another class of peptide hormones, the somatome- hormones can be produced by recombinant DNA tech- dins, or insulin-like growth factors that are synthesized niques (human insulin) by inserting the human proin- predominantly in the liver. Also somatotropin stimu- sulin gene into E coli or yeast. lates growing of skeletal muscle and organs. It increas- Hormonal drugs are used for the treatment of en- es protein synthesis, which results in nitrogen retention. docrine diseases (substitutive, stimulating, and inhib- Somatotropin cause the retention of phosphorus, sodi- iting therapy) and nonendocrine diseases (allergic dis- um, and potassium through promotion of cellular orders, cancer). It is necessary to remember, that dur- growth. The metabolic action of growth hormone is an ing prolonged using of high doses of hormonal sub- initial insulin-like effect with increased tissue uptake

113 of both glucose and amino acids and decreased lipol- tially catabolized human FSH and LH extracted from ysis. Within a few hours, there is a peripheral insulin the urine of postmenopausal women. They are used in antagonistic effect with impaired glucose uptake and states of infertility to stimulate ovarian follicle devel- increased lipolysis. Somatotropin is indicated for long- opment in women and spermatogenesis in men and for term treatment of growth failure in children caused by pituitary or hypothalamic hypogonadism with infertil- pituitary growth hormone deficiency (pituitary dwarf- ity. In both sexes, they must be used in conjunction with ism). Adverse effects often include arthralgia and flu- a luteinizing hormone. Overstimulation of the ovary id retention. with HMG can lead to ovarian enlargement. Somatostatin is found in the hypothalamus. It has Luteinizing hormone acts on testicular Leydig cells been synthesized. Somatostatin has been shown to in- to stimulate testosterone production. In the ovary, LH hibit the release of growth hormone, glucagon, insu- acts on the mature follicle to induce ovulation, and it lin, and gastrin. Somatostatin has limited therapeutic stimulates the corpus luteum in the luteal phase of the usefulness because of its short duration of action (half- menstrual cycle to produce progesterone. Human cho- life 2–3 minutes) and its multiple effects on many se- rionic gonadotropin is a hormone produced by the hu- cretory systems. Octreotide is synthetic analogous of man placenta and excreted into the urine, whence it somatostatin. It is more potent than somatostatin in in- can be extracted and purified. It is very similar to LH hibiting growth hormone release. Because of this rela- in structure. HCG can be used in combination with hu- tively reduced effect on pancreatic β-cells, octreotide man menotropins to induce ovulation in women and has been particularly useful in treating acromegaly for stimulation of testosterone secretion by the testes and carcinoid tumors (gastrinoma, glucagonoma) with- of men with hypogonadotropic hypogonadism. HMG out provoking hyperglycemia. The serum half-life of and HCG are administered intramuscularly. Andro- octreotide is about 80 minutes. Adverse effects of ther- gen-dependent neoplasia and precocious puberty are apy include biliary sludge and steatorrhea. contraindications to HCG use. Thyrotropin is normally secreted as part of a feed- Gonadotropin-releasing hormone (GnRH) is pro- back system of thyroid hormone level regulation. It duced by hypothalamus and controls the release of go- stimulates each step of thyroid hormone synthesis, in- nadotropins (FSH, LH). Pharmaceutical GnRH is syn- cluding iodine uptake. In hyperthyroidism, the serum thetic. Analogs (e.g. Leuprolide, Nafarelin) are more thyrotropin level is suppressed. Therapeutic thyrotro- potent and longer-lasting than native GnRH. GnRH pin is prepared from bovine anterior pituitaries. Thy- and its analogs are administered parenterally. Pulsa- rotropin is used diagnostically to differentiate between tile intravenous administration stimulates FSH and LH primary and secondary hypothyroidism. Thyroid ten- secretion. Thus, GnRH is used to treat infertility derness and symptoms of hyperthyroidism may occur. caused by hypothalamic hypogonadism in both sexes. Thyrotropin-releasing hormone that is found in the hy- In contrast, GnRH administered continuously or pothalamus stimulates the pituitary to produce thyro- GnRH analogs administered in depot formulations in- tropin. Thyrotropin-releasing hormone stimulation of hibit gonadotropin release and induce hypogonadism. thyrotropin is blocked by thyroxine and potentiated by Leuprolide, Nafarelin are used to treat prostate can- lack of thyroxine. Protirelin is a synthetic analogous cer, uterine fibroids, and endometriosis. Danazol is of thyrotropin-releasing hormone. Protirelin is indicat- gonadotropin inhibitor. It suppresses the output of pi- ed as an adjunct for distinguishes between secondary tuitary gonadotropins (FSH, LH). As a result, anovu- (pituitary) and tertiary (hypothalamic) hypothy- lation and associated amenorrhea occur. Danazol is roidism. being used to treat gynecomastia, endometriosis, and Adrenocorticotropin primary endocrine function is menorrhagia. to stimulate synthesis and release of cortisol by the ad- Prolactin is the principal hormone that stimulates renal cortex. Corticotropin is an ACTH that is ob- the development of mammary glands and lactation. Its tained from porcine or bovine pituitary glands. Syn- preparation — Lactin is obtained from bovine pitui- thetic human ACTH is known as cosyntropin. Both tary glands. Lactin is available for use in lactation- animal and synthetic corticotropin are well absorbed deficient women in period following birth. For patients by the intramuscular route. Cosyntropin is preferred with symptomatic hyperprolactinemia, inhibition of because it is less antigenic. The biologic half-live of prolactin secretion can be achieved with Bromocrip- agents is under 20 minutes. The effects of long-acting tine and other dopamine agonists. Also bromocriptine repository forms of corticotropin persist for up to sev- may be used to treat acromegaly and Parkinson’s dis- eral days with a zinc hydroxide complex. Corticotro- ease. pin shares many actions of the corticosteroids due to The hormones of the intermediate lobe have its ability to increase endogenous corticosteroid syn- melanocyte-stimulating properties. Its preparation — thesis. Corticotropin is indicated as an aid in diagnos- Intermedin that is obtained from bovine pituitary gland ing adrenocortical insufficiency and after prolonged is used for the treatment of degenerative processes in using of glucocorticoids for restoring of adrenal’s cor- retina and hemeralopia (impairment of vision in re- tex functioning. But it may also cause depression of duced illumination) in eye-drops form. ACTH production. The toxicity of therapeutic doses Two posterior pituitary hormones are known: Va- of ACTH resembles that of the glucocorticoids with the sopressin and Oxytocin. Their structures are very sim- added mild virilism (hyperandrogenism) in women. ilar. Pharmaceutical vasopressin and oxytocin are syn- FSH stimulates gametogenesis and follicular devel- thetics. opment in women and spermatogenesis in men. It is In pharmacologic doses, Oxytocin can be used to needed for proper ovarian estrogenesis. Human men- induce uterine contractions and maintain labor. It can opausal gonadotropins (HMG) are a mixture of par- also be used for control of postpartum uterine hemor-

114 rhage. Oxytocin elicits milk ejection in lactating wom- basal metabolism and consequent increase oxygen en. Oxytocin is administered intravenously or intra- consumption of tissues and body temperature. They muscularly. It’s circulating half-life is 5 minutes. Con- speed up the catabolism of carbohydrates, fats, and traindications include fetal distress, prematurity, abnor- proteins. However, it potentiates the secretion and mal fetal presentation, cephalopelvic disproportion, and action of growth hormone. Many of the manifesta- other predispositions for uterine rupture. Desaminoox- tions of thyroid hyperactivity resemble sympathetic ytocin is a synthetic analog of oxytocin. It acts longer nervous system overactivity (tachycardia, cardiac ar- than parental agent and is used subglossal. rhythmia, tremor, excessive sweating, and nervous- Vasopressin (antidiuretic hormone, ADH) possess- ness). The secretion and degradation rates of hor- es antidiuretic and vasopressor properties. A deficien- mones, including catecholamines, cortisol, estrogens, cy of this hormone results in diabetes insipidus. Vaso- testosterone, and insulin, are affected by thyroid sta- pressin interacts with two types of receptors. V1-recep- tus. Diminished production of thyroid hormone (hy- tors are found on vascular smooth muscle cells and me- pothyroidism, myxedema) leads to clinical manifes- diate vasoconstriction. V2-receptors are found on re- tations of thyroid insufficiency, including low meta- nal tubule cells and mediate antidiuresis through in- bolic rate, tendency to weight gain, somnolence and creased water permeability and water resorption in the edema of subcutaneous tissue. Thyroid deprivation in collecting tubules. Vasopressin is administered by in- early life results in cretinism (mental retardation, travenous, intramuscular, or intranasal routes. The half- dwarfism). life of circulating ADH is approximately 20 minutes. Thyroid preparations may be synthetic (L-Thyrox- Desmopressin is a long-acting synthetic analog of va- ine, Triiodothyronine) or of animal origin (Thyreoi- sopressin with an antidiuretic-to-pressor ratio 4,000 dine). times that of vasopressin. Vasopressin and desmopressin Synthetic L-thyroxine is the preparation of choice are the alternative treatments of choice for pituitary di- for thyroid replacement because of its stability, lack abetes insipidus. Vasopressin (but not desmopressin) of allergenic foreign protein, and long half-life can cause vasoconstriction and should be used cau- (7 days), which permits once-daily administration. tiously in patients with coronary artery disease. Oral absorption of current preparations of L-Thyrox- ine is averaging 80%. Although Triiodothyronine (Liothyronine) is 3–4 times more active than L-Thy- THYROID AND ANTITHYROID roxine, it is not recommended for routine replacement DRUGS therapy because of its shorter half-life (24 hours), which requires multiple daily doses. Furthermore, be- The normal thyroid gland secretes the thyroid hor- cause of its greater hormone activity and consequent mones — triiodothyronine (T3) and tetraiodothyro- greater risk of cardiotoxicity, T3 should be avoided nine (T4, thyroxine). These hormones contain iodine in patients with cardiac disease. T3 is almost com- as an essential part of the molecule. Nearly all of the pletely absorbed (95%) and minimally interfered with iodide intake is via the gastrointestinal tract from by intraluminal binding proteins. Thyreoidine (Thy- food, water, or medication. Once taken up by the thyroid) is the preparation of bovine desiccated thyroid roid gland, iodide undergoes a series of enzymatic gland. It contains the combination of thyroid hor- reactions that convert it into active thyroid hormone. mones. Thyreoidine has variable hormone concentra- First of all iodide is oxidized to iodine, in which form tions and high protein antigenicity. it rapidly iodinates tyrosine residues within the thy- Thyroid hormones are indicated as replacement roglobulin molecule to form Monoiodotyrosine (MIT) therapy in the treatment of hypothyroidism. In gener- and Diiodotyrosine (DIT). This process is called io- al, L-thyroxine is the preferred thyroid hormone be- dide organification. Two molecules of DIT combine cause of the absence of variability. Triiodothyronine within the thyroglobulin molecule to form L-thyrox- is recommended because of its short half-life and read- ine (T4). One molecule of MIT and one molecule of ily reversible effects for initial therapy in myxedema DIT combine to form T3. Thyroid hormones are re- and myxedema coma. It may also be preferred when leased from thyroglobulin by proteolysis of thy- gastrointestinal absorption processes are impaired. roglobulin. T4 and T3 in plasma are reversibly bound Antithyroid drugs are used in case of hyperthy- to globulin. Thyrotropin (pituitary) stimulates the roidism. synthesis and release of T4 and T3. These thyroid hor- The thioamides Mercazolil (Methimazole) and mones, in a negative feedback fashion, act in the pi- Propylthiouracil are major drugs for treatment of tuitary to block the action of thyrotropin-releasing thyrotoxicosis. Mercazolil is about ten times more hormone and in the hypothalamus to inhibit it’s syn- active than Propylthiouracil. Mercazolil and Pro- thesis and secretion. pylthiouracil are rapidly absorbed. They are readily The free forms of thyroid hormones, T4 and T3 en- accumulated by the thyroid gland. The major action ter the cell. Within the cell, T4 is converted to T3, is to prevent thyroid hormones synthesis by inhibit- which is more potent than T4, and the T3 enters the nu- ing iodine organification. A single dose of Mercazo- cleus, where it binds to a specific receptor. Most of the lil exerts an antithyroid effect for longer than 24 effects of thyroid on metabolic processes appear to be hours; thus it can be used one time a day. Since the mediated by activation of nuclear receptors that lead synthesis rather than the release of hormones is af- to increased formation of RNA and subsequent protein fected, the onset of these agents is slow, often requir- synthesis. ing 3–4 weeks before stores of T4 are depleted. The Thyroid hormones have both catabolic (calorigen- adverse effects are rash, leukopenia, and goiter. It ic) and anabolic effects. Thyroid hormones increase can be explained by decreasing of thyroid hormones

115 level in blood that leads to increasing of thyrotropin PANCREATIC HORMONES AND synthesis. The last one stimulates thyroid gland ANTIDIABETIC DRUGS hypertrophy and hyperplasia. For preventing of goi- trogenic effect iodine drugs are used. Insulin is synthesized in β-cells islets of Langer- Potassium perchlorate (KClO4) can block uptake hans, which interspersed throughout the pancreatic of iodide by the gland. Since these effects can be over- gland. Insulin is a small protein that contains 51 ami- come by large doses of iodides, their effectiveness is no acids arranged in two chains linked by disulfide somewhat unpredictable. Potassium perchlorate is bridges. Within the β-cell, insulin precursor is pro- rarely used clinically because it’s mild antithyroid ac- duced and then proinsulin is hydrolyzed into insulin. tivity and adverse effects (leukopenia, anemia). Insulin releasing from pancreatic β-cells is stimulated Iodides — Potassium iodide, Sodium iodide — in response to a glucose, mannose, certain amino ac- have multiple effects on the thyroid gland. They de- ids (e.g. leucine, arginine), and vagal activity. Hyper- crease the thyrotropin synthesis. Also iodides inhibit glycemia results in increased intracellular ATP levels, hormone’s release and decrease the size and vascular- which close the ATP-dependent potassium channels, ity of the hyperplastic gland that make these drugs val- and results in depolarization of the β-cell and open- uable as preoperative preparation for surgery. Disad- ing of voltage-gated calcium channels. The resulting vantages of iodide therapy include an increase in int- increased intracellular calcium triggers secretion of the raglandular stores of iodine, which may delay onset hormone. The liver and kidney remove insulin from the of thioamide therapy or prevent use of radioactive io- circulation, presumably by hydrolysis of the disulfide dine therapy for several weeks. Iodide should not be connections through the action of insulinase. The half- used alone, because the gland will “escape” from the life of circulating insulin is 3–5 minutes. iodide block in 2–8 weeks. Adverse reactions include Once insulin has entered the circulation, it is acneiform rash (similar to that of bromism), swollen bound by specialized receptors that are found on the salivary glands, conjunctivitis, and rhinorrhea. membranes of most tissues. The full insulin receptor Radioactive iodine (I131) is used for treatment of consists of β-subunit, which is entirely extracellular thyrotoxicosis. It is concentrated by the thyroid gland. and constitutes the recognition site, and a β-subunit Its therapeutic effect depends on emission of β-rays that spans the membrane. The β-subunit contains a with an effective half-life of 5–8 days. Within a few tyrosine kinase. When insulin binds to the β-subunit weeks after administration, destruction of the thyroid at the outside surface of the cell, tyrosine kinase ac- parenchyma is evidenced by epithelial necrosis and fol- tivity is stimulated in the β-portion that leads to the licular disruption. series of phosphorylation within the cell. Finally, the The Calcitonin secreted by the thyroid gland. The insulin-receptor complex is internalized where insu- principal effects of Calcitonin are to lower serum cal- lin acts. cium and phosphate by actions on bone and kidney. Insulin promotes uptake of carbohydrates, pro- Calcitonin inhibits osteoclastic bone resorption. In the teins, and fats in most tissues. Also, insulin stimulates kidney, Calcitonin reduces both calcium and phos- protein and free fatty acid synthesis, and inhibits re- phate reabsorption. Also it decreases gastrin secretion lease of free fatty acid from adipose cells. Insulin in- and reduces gastric acid output. Human Calcitonin creases active glucose transport through liver, mus- monomer has a half-life of about 10 minutes. Salmon cle and adipose cellular membranes, and promotes Calcitonin (Miacalcin) has a longer half-life. Both hu- conversion of intracellular glucose and free fatty acid man calcitonin and Miacalcin are synthesized. In ad- to the appropriate storage forms (glycogen and trig- dition, Calcitonin is present in Calcitrin that is ob- lyceride, respectively). In the liver and muscles it in- tained from porcine thyroid gland. The ability of cal- hibits glycogenolysis and gluconeogenesis. In addi- citonin to block bone resorption and lower serum cal- tion, insulin decreases protein catabolism and ke- cium makes it a useful drug for the treatment of hyper- togenesis. calcemia and osteoporosis. Administered insulin substitutes for the lack of en- Parathormone (parathyroid hormone, PTH) is dogenous insulin secretion and partially corrects the produced by the parathyroid gland. PTH enhances disordered metabolism and inappropriate hyperglyc- calcium and phosphate absorption in the intestine. In emia of diabetes mellitus. They’re two types of diabe- bone, PTH increases the activity and number of os- tes mellitus. Type I diabetes (IDDM, insulin-depend- teoclasts, the cells responsible for bone resorption. It ent diabetes mellitus) is a catabolic disorder in which increases bone remodeling, a specific sequence of cel- circulating insulin is virtually absent. Exogenous in- lular events initiated by osteoclastic bone resorption sulin is therefore required. Type II diabetes (NIDDM, and followed by osteoblastic bone formation. In the non-insulin-dependent diabetes mellitus) represents a kidney, PTH increases the ability of the nephron to group comprising milder forms of diabetes that occur reabsorb calcium but reduces its ability to reabsorb predominantly in obese. Circulating endogenous insu- phosphate. Another important action of PTH on the lin is relatively inadequate because of tissue insensi- kidney is its stimulation of 1.25-dihydroxyvitamin D tivity. When dietary treatment fails to correct hyperg- production. All these effects result in increasing se- lycemia, sulfonylurea drugs are usually prescribed. rum calcium. Insulin therapy may be required to achieve satisfacto- Parathyreoidine is produced from bovine parath- ry glycemic control. yroid gland. It is injected intramuscularly or subcu- Three principal types of insulins are available (1) taneous. Its action starts in 4 hours and lasts for 24 short-acting — Insulin, (2) intermediate-acting — In- hours. Parathyreoidine is used for hypothyroid teta- sulin-Semilente, Insulin-Lente, (3) long-acting — In- ny treatment. sulin-Ultralente (Table 10).

116 Table 10. Pharmacokinetic of insulins Insulin type Onset of action, h Time to peak Duration of action Regular insulin 0.5–1 2–4 5–7 Insulin-Semilente 1–3 2–8 12–16 Insulin-Lente 1–3 8–12 18–28 Insulin-Ultralente 4–6 18–24 36

Short-acting insulin is dispensed as solutions and Sulfonylureas release insulin from β-cells and po- contains small amounts of zinc to improve their sta- tentiate the action of insulin on its target tissues. Sul- bility and shelf-life. Other insulins have been modi- fonylureas inhibit the efflux of potassium ion through fied to provide prolonged action and are dispensed the channel and results in depolarization. Depolari- as suspensions with varying concentrations of zinc in zation, in turn, opens a voltage-gated calcium chan- acetate buffer (Ultralente and Lente insulins). Con- nel and results in calcium influx and the release of pre- ventional subcutaneous insulin therapy presently con- formed insulin. Sulfonylurea drugs might restore pe- sists of split-dose injections of mixtures of short-act- ripheral tissue sensitivity to insulin. ing and intermediate-acting insulins or multiple dos- Sulfonylureas are absorbed from gastrointestinal es of short-acting insulin preprandial in association tract readily and completely. Mostly they bind with with any of insulin suspensions (Lente, or Ultralente) blood proteins (70–99%). Sulfonylureas are metabo- whose prolonged duration of action provides over- lized in liver and excreted mainly via kidneys. The night basal insulin levels. Clinical trials have dem- most serious adverse effect is hypoglycemia. Also di- onstrated that optimal time of pre-prandial subcuta- sulfiram-like reaction (flushing of the face, neck, and neous injection of regular human insulin is 30 min- arms) may occur with any of the sulfonylureas when utes before the meal. Short-acting soluble insulin is alcohol is ingested concurrently. the only type that should be administered intrave- There are two generations of sulfonylureas: first nously and it is particularly useful when the insulin generation are Butamide, Chlorpropamide; second requirement is changing rapidly, such as diabetic ke- generation are Glibenclamide, Glipizide. toacidosis or after surgery. Butamide (Tolbutamide) is well absorbed but rap- According to the sources insulins are divided into idly oxidized in the liver. Its duration of effect is rela- beef, pork, and human. The beef hormone is slightly tively short (6–10 hours). It is administered before each more antigenic than pork insulin. Human insulin, meal and at bedtime. Chlorpropamide has a long du- which is less expensive and immunogenic than pork in- ration of effect (24–48 hours) and is slowly metabo- sulin, has generally supplanted it. Currently, all insu- lized in the liver. The maintenance dose is given in the lins in Ukraine are available in a concentration of 40 morning. Potential for serious adverse effects is high units/ml. because of Chlorpropamide prolonged action. Also Hypoglycemic reactions are the most common com- Chlorpropamide can cause antidiuretic effect. Diabe- plication of insulin therapy. They may result from a tes patients who have not responded to Tolbutamide delay in taking a meal or an overdosing of insulin. The or Chlorpropamide may respond to the more potent symptoms of hypoglycemia are tachycardia, palpita- second-generation sulfonylureas. tions, sweating, tremulousness, nausea, and hunger. Duration of action of Glipizide and Glibenclamide They may progress to convulsions and coma if un- (Glibutide) is approximately 24 hours. These agents treated. In a case of mild hypoglycemia orange juice, should be ingested 30 minutes before breakfast, since glucose, or any sugar-containing beverage or food rapid absorption is delayed when the drug is taken with may be given. In case of unconsciousness the treat- food. The dose is given once a day. Serious adverse ment of choice is to give 20 ml of 40% glucose solu- effect occurs more often with glibenclamide than with tion by intravenous infusion or solutions of adrenaline Chlorpropamide and Glipizide, because of prolonged or glucagon injected either subcutaneously or intra- action of Glibenclamide. Gliclazide has the same se- muscularly. rum half-life and duration of action as Glibenclamide. Because sensitivity is often to non-insulin protein In addition, it reduces platelet adhesiveness and ag- contaminants, the new highly purified insulins have gregation and has fibrinolytic activity — hence Gli- markedly reduced the incidence of insulin allergy, es- clazide has prevent possible disorders of microcircu- pecially local reactions. Some diabetic patients have lation during diabetes mellitus. a high titer of circulating anti-insulin antibodies. This Second group of oral hypoglycemic compounds con- results in extremely high insulin requirements — often sists of the Biguanides. These agents reduce blood glu- more than 200 units daily. Atrophy or hypertrophy of cose even in the absence of pancreatic β-cell function. subcutaneous fatty tissue may occur at the site of in- Currently proposed mechanisms of action include direct jection. stimulation of glycolysis in tissues, with increased glu- Oral hypoglycemic drugs. The major oral medica- cose removal from blood, and slowing of glucose ab- tions currently available for treating hyperglycemia in sorption from the gastrointestinal tract. Biguanides non-insulin-dependent diabetics are the class of com- cause the accumulation of lactic acid in muscles (prob- pounds known as sulfonylureas. ably due to stimulation of anaerobic glycolysis). Bigua- 117 nides have been most often prescribed for patients with ma proteins. Free hormone diffuses across cell membranes refractory obesity. Buformin (Glibutide) and Metform- and complex with specific cytoplasmic receptors. These in belong to this group. They are well absorbed from complexes then enter the cell nucleus, bind to DNA, and the gastrointestinal tract. The onset of maximal hy- stimulate transcription of messenger RNA (mRNA) and poglycemic effect is 5 hours and duration of effect is 14 subsequent protein synthesis. Glucocorticoids in rapid hours. A common schedule would be to begin with a sin- feedback way suppress the synthesis of pituitary ACTH. gle daily tablet given for several days. If this is well tol- Most of the glucocorticoids are inactivated in the liver erated, to add a second tablet if hyperglycemia persists. by reduction and conjugation with glucuronic acid or The toxic effects of biguanides are gastrointestinal up- sulfate, and are excreted into the urine. set (nausea, vomiting, and diarrhea) and lactic acido- Effects of glucocorticoids. The glucocorticoids have sis. Biguanides does not provoke hypoglycemia. important dose-related effects on carbohydrate, pro- Glucagon is synthesized in α-cells of Langerhans tein, and fat metabolism. In the liver, glucocorticoids islets. The pharmacologic result of glucagon infusion increase glycogen deposition by stimulating glycogen is to raise blood glucose at the expense of stored he- synthase activity and increasing glucose production patic glycogen. Glucagon has a potent inotropic and from protein (gluconeogenesis). Glucocorticoids inhibit chronotropic effect on the heart. Thus, it produces an the peripheral glucose uptake and lead to hyperglyc- effect very similar to that of β-adrenoreceptor agonists emia. Glucocorticoids have catabolic effects in lym- without requiring functioning β-receptors. The major phoid and connective tissue, muscle, fat, and skin. In use of Glucagon is for emergency treatment of severe children, the catabolic effects of excessive amounts of hypoglycemic reactions in insulin-dependent patients glucocorticoid reduce growth. Glucocorticoids in- when unconsciousness precludes oral feedings and use crease lipolysis and mobilize fatty acids from adipose of intravenous glucose is not possible. tissues, leading to increased plasma fatty acid concentrations. Glucocorticoids increase bone resorption and Available forms: calcium excretion, and decrease gastrointestinal ab- Somatotropin — in bottles 5 ml (2 or 4 unites) sorption of calcium. These actions may lead to inhibi- Octreotide — in ampoules 0.00005; 0.0001 or tion of bone growth in children and adolescents and 0.0005 each the development of osteoporosis at any age. Gonadotropin chorionic — in bottles 500; 1000; Glucocorticoids have immunodepressive and anti- 1,500 or 2,000 unites each (to dilute in 1 ml solution, inflammation activities. Glucocorticoids decrease or for i.m. injection) prevent tissue responses to inflammatory processes, Danazol — capsules 0.1 or 0.2 each thereby reducing development of symptoms of inflam- Oxytocin — in ampoules 1 ml (5 unites) each mation without affecting the underlying cause. Gluco- Pituitrinum — in ampoules 1 ml (5 unites) each corticoids inhibit accumulation of inflammatory cells, Triiodothyronine hydrochloride — tablets 0.00002 including macrophages and leukocytes, at sites of in- or 0.000005 each flammation. They also inhibit phagocytosis, lysosom- L-Thyroxine — tablets 0.05 or 0,1 each al enzyme release, and release of several chemical me- Mercazolilum — tablets 0.005 each diators of inflammation. They reduce the permeabili- Calcitonin — in ampoules 1 ml (50 or 100 unites) ty of inflamed capillaries and reduce leukocyte adher- each ence to the capillary endothelium, leading to inhibi- Parathyroidinum — in ampoules 1 ml (20 unites) tion of both leukocyte migration and edema formation; each and diminish the activity of the phospholipase A2 with Insulin — in bottles 5 or 10 ml (1 ml contains 40 subsequent inhibition of the inflammation mediators unites) each synthesis (prostaglandins, thromboxanes, and leukot- Tolbutamide (Butamidum) — tablets 0.25 or 0.5 rienes) from arachidonic acid. each Mechanisms of immunosuppressant action may in- Glibenclamide — tablets 0.005 each volve prevention or suppression of cell-mediated (delayed Buformin — tablets 0.5 each hypersensitivity) immune reactions as well as more specific actions affecting the immune response. Glucocorti- HORMONES OF STEROID coids reduce the concentration of thymus-dependent lym- STRUCTURE phocytes (T-lymphocytes), monocytes, and eosinophils. They also decrease binding of immunoglobulin to cell Adrenocorticosteroids surface receptors and inhibit the synthesis, and release of interleukins, thereby decreasing T-lymphocyte blast- The adrenal cortex releases a large number of ster- ogenesis and reducing expansion of the primary immune oids that may be classified as those having important response. Glucocorticoids may also decrease concentra- effects on intermediary metabolism (glucocorticoids), tions of complement components and immunoglobulins. those having principally salt-retaining activity (min- The structural and functional changes in the lungs eralocorticoids), and those having androgenic or es- near term, including the production of pulmonary sur- trogenic activity. factant required for air breathing, are stimulated by glu- The glucocorticoids (corticosteroids) in humans are cocorticoids. Treatment of the mother with large doses cortisol (major) and cortisone. They are synthesized from of glucocorticoid reduces the incidence of respiratory cholesterol. The rate of their secretion changes in a cir- distress syndrome in infants delivered prematurely. cadian rhythm governed by irregular pulses of adreno- Steroids having glucocorticoid activity have become corticotropin (ACTH) that peak in the early morning important agents for use in the treatment of many in- hours and after meals. In plasma, they are bound to plas- flammatory and allergic disorders (Table 11).

118 Table 11. Main glucocorticoids and their biological activity Relative potency Biological (tissue) Glucocorticoids Glucocorticoid Mineralocorticoid half-life, h activity* activity** Short-acting Cortisone 0.8 ++ 8-12 Hydrocortisone 1 ++ 8-12 Intermediate-acting Methylprednisolone 5 0 18-36 Prednisolone 4 + 18-36 Triamcinolone 5 0 18-36 Long-acting Dexamethasone 20-30 0 36-54 Betamethasone 20-30 0 36-54

Note: *anti-inflammatory, immunosuppressant, metabolic effects; **sodium and water retention, potassium depletion.

Indications. Glucocorticoids are indicated for their Thanks to their bad absorption from the skin (that di- anti-inflammatory and immunosuppressant effects in minish their systemic effects) Flumethasone, Fluoci- the treatment of allergic disorders (allergic rhinitis, nolone are prescribed in ointment form for the treat- angioedema, anaphylactic reactions, bronchial asth- ment of dermatitis of different etiology. ma, transfusion reactions), collagen disorders (dermat- Adverse effects. When the glucocorticoids are used omyositis, vasculitis, lupus erythematosus, rheumatic less than 1 week, it is unusual to see serious adverse fever), dermatitis, autoimmune anemia, chronic hepa- effects. The major undesirable effects of the glucocor- titis, leukemia, ophthalmic disorders (iridocyclitis, ticoids are the result of their hormonal actions and lead keratitis). For most indications, glucocorticoid admin- to the clinical picture of iatrogenic Cushing’s syn- istration provides symptomatic relief but has no effect drome. The appearance of the face is altered by round- on the underlying disease processes. Use of these med- ing. Fat tends to be redistributed from the extremities ications does not eliminate the need for other thera- to the trunk and face. Over a period of time there can pies that may be required. appear such adverse effects as weight gain, thinning Glucocorticoids are indicated (in physiologic dos- of the skin (with striae), hyperglycemia, osteoporosis, es) as replacement therapy in the treatment of adrenal and hypertension. Wound healing is also impaired. insufficiency states. Cortisone, Hydrocortisone (Cor- Other serious complications include the development tisol), and Fludrocortisone are indicated for this pur- of peptic ulcers, bacterial and mycotic infections. Glu- pose because of their significant mineralocorticoid ac- cocorticoids (especially, cortisone and hydrocortisone) tivity (see table 11). Cortisone is transformed in the or- cause some sodium and fluid retention and loss of po- ganism to Hydrocortisone. It is used orally (tablets) tassium. or intramuscularly (suspension). Hydrocortisone can Nowadays antagonists of the synthesis or action of be injected intraarticulate (suspension) for the treat- the glucocorticoids are well-known. They can be used ment of arthritis or can be applied topically (ointment) in the treatment of Cushing’s syndrome. Mifepristone for dermatitis treatment. Fludrocortisone, a synthetic is a glucocorticoid antagonist that binds to glucocor- corticosteroid, is the most commonly prescribed salt- ticoid as well as to progesterone receptors. Metyrap- retaining hormone. one is an inhibitor of glucocorticoids and mineraloco- Natural glucocorticoids are used mostly in those rticoids synthesis. cases, when their mineralocorticoid activity is desira- The most important mineralocorticoid in humans is ble (adrenal insufficiency). However, agents having Aldosterone. However, small amounts of Desoxycorti- minimal mineralocorticoid activity are preferred in all costerone (DOC) are also formed and released. Its ac- other cases. This group includes Prednisolone, Meth- tions, effects, and metabolism are similar to aldoster- ylprednisolone, fluorinated glucocorticoids (Triamci- one. ACTH and angiotensin produce a stimulation of nolone, Dexamethasone, Betamethasone), and bis- aldosterone release. Also its secretion is enhanced by fluorinated glucocorticoids (Flumethasone, Fluoci- dietary sodium restriction. Mineralocorticoids act by nolone). It is considered, that presence of the Fluor binding to the receptor in the cytoplasm of cells of the atom in glucocorticoids molecule has decrease its min- kidneys collecting tubules. Aldosterone promotes the re- eralocorticoid activity and its absorption from the skin. absorption of sodium from urine by the distal renal tu- Prednisolone is used orally, topically. It must be in- bules, loosely coupled to the secretion of potassium ion. jected intramuscularly or intravenously for emerge Excessive levels of aldosterone lead to hypernatremia, states (anaphylactic reaction, bronchial asthma attack, hypokalemia, increased plasma volume, and hyperten- shock states of different etiology). In general, Triam- sion. Desoxycorticosterone acetate (DOCSA) is used in cinolone and Dexamethasone are produced as tablets. practice. It is prescribed in case of chronic adrenal 119 glands insufficiency, myasthenia and adynamia. Ad- Many agents of steroid estrogens are used in medi- verse effects of DOCSA are edema, hypertension. cine. They are Estrone, Estradiol dipropionate, and Spironolactone is steroid that competes with aldos- ethinyl Estradiol. Estrone and estradiol are produced terone for binding sites and decrease its effect periph- as oil solutions and are injected intramuscularly. Es- erally. It is used as diuretic drug (the lecture “Diuret- trone acts during 24 hours, however estradiol — 2–4 ic drugs”) and for the treatment of hyperaldosteronism. days. Ethinyl estradiol is a semisynthetic estrogen. It’s 50 times as much potent than estrone. Furthermore, ethinyl estradiol is available for ingestion. In addition THE GONADAL HORMONES. to the steroid estrogens, a variety of nonsteroidal com- ESTROGENS AND PROGESTINS pounds with estrogenic activity have been synthesized and used clinically. These include Hexestrol (Sy- The ovary has important gametogenic and hormo- noestrolum), Diethylstilbestrol. Hexestrol is the syn- nal functions. First of all hypothalamic produce Go- thetic analogue of estradiol. It is taken orally and in- nadotropin-releasing hormone (GnRH) which stimu- jected intramuscularly. lates the release of Follicle-stimulating hormone (FSH) Indications. Estrogens are indicated for replace- and Luteinizing hormone (LH) (see “Hypothalamic ment therapy in estrogen-deficient patients (upset of and pituitary hormones”). At the beginning of each cy- menstrual cycle — dysmenorrhea, amenorrhea, castra- cle, a variable number of follicles, each containing an tion, or menopause). They are indicated for complex ovum, begin to enlarge in response to FSH. After 5 or treatment of breast carcinoma in postmenopausal 6 days, one of the follicles begins to develop more rap- women and prostatic carcinoma in men. Estrogens idly. The granulosa cells of this follicle synthesize es- alone or combined with progestins can be used for con- trogens. When ovum is matured, follicle ruptures and traception. They have been used extensively to replace ovulation is appearing. Following the above events, estrogen in the treatment of vasomotor symptoms, and the cavity of the ruptured follicle fills is transformed osteoporosis associated with menopause. For this pur- to the corpus luteum. The cells of this structure pro- pose patients can use estrogens or their combination duce estrogens and progesterone for the remainder of with gestagens: Proginova (contains estradiol valerate; the cycle, or longer if pregnancy occurs. If pregnancy 21 dragee for month), Clinorm (two-phase agent; 9 dra- does not occur, the corpus luteum begins to degener- gee that contain estradiol valerate; 12 dragee — es- ate and ceases hormone production. The endometri- tradiol valerate + levonorgestrel (gestagen)). um, which proliferated during the follicular phase and Adverse effects. Estrogen therapy may cause men- developed its glandular structure during the luteal orrhagia, endometrial hyperplasia. They can be pre- phase, is shed in the process of menstruation. vented by administration of a progestin agent with es- The major estrogens produced by women are Es- trogen in each cycle. Nausea and breast tenderness are tradiol, Estrone, and Estriol. Estradiol appears to be common and can be minimized by using the smallest the major secretory product of the ovary. Most estro- effective dose of estrogen. Estrogen can lead to ne and estriol are formed in the liver from estradiol. cholestasis, thrombophlebitis, peripheral edema, and As noted above, estrogens are produced in the ovarian hypertension. Diethylstilbestrol should be avoided dur- follicle and in corpus luteum. During pregnancy, the ing pregnancy. fetoplacental unit synthesizes a large amount of estro- Nowadays antiestrogen agents are well known. gen. When released into the circulation, estradiol Tamoxifen is a competitive inhibitor of estrogen recep- binds strongly to a sex hormone-binding globulin. Es- tors and is extensively used in the palliative treatment trogens are metabolized in the liver and their conju- of breast cancer. It is a nonsteroidal agent that is giv- gated metabolites excreted in the bile. However, the en orally. conjugates may be hydrolyzed in the intestine to ac- Progesterone is the most important progestin in hu- tive, reabsorbable compounds. mans. It is synthesized in the ovary (corpus luteum), Physiologic effects. Free plasma estrogens enter the testis, adrenal, and in placenta during pregnancy. The cell and bind to their receptor. The receptor-hormone level of progesterone in the female is higher the luteal complex binds to nucleotides on various genes and reg- phase than during the follicular phase of the cycle. Pro- ulates their transcription and proteins synthesis. gestins enter the cell and bind to progesterone recep- Estrogens stimulate the development of the vagina, tors. The ligand-receptor complex binds to a response uterus, and uterine tubes as well as the growth of the element to activate gene transcription, resulting in an axillary and pubic hair. They stimulate stromal devel- increase in protein synthesis. Progesterone causes the opment and ductal growth in the breast and are respon- maturation and secretory changes in the endometrium sible for the accelerated growth phase and the closing that are seen following ovulation. Also it leads to re- of the epiphyses of the long bones that occur at puber- laxation of uterine smooth muscle and stimulation of ty. Estrogen also plays an important role in the devel- mammary alveolar tissue growth. Progesterone is re- opment of the endometrial lining (proliferation). Es- sponsible for pregnancy preservation. It also has de- trogens decrease the rate of resorption of bone. Estro- pressant and hypnotic effects on the brain. gens increase high-density lipoproteins level, slightly Progesterone is rapidly absorbed following admin- reduce low-density lipoproteins and cholesterol levels. istration by any route. It is almost completely metab- Estrogens enhance the coagulability of blood. They are olized in one passage through the liver, and for that responsible for estrous behavior in animals and influ- reason it is quite ineffective when administered orally. ence libido in humans. They facilitate the loss of in- In the liver, progesterone is metabolized and conjugat- travascular fluid into the extracellular space, produced with glucuronic acid. It is excreted into the urine. ing edema. A variety of progestin compounds have been synthe-

120 sized. In general, such compounds as Hydroxyproges- strual cycle and is usually administered once daily for terone (Oxyprogesterone) and Medroxyprogesterone 21 consecutive days. are the most closely related, pharmacologically as well The pregnancy rate with combination agents is es- as chemically, to progesterone. Hydroxyprogesterone timated to be about 0.5–1 per 100 woman years at risk. and Medroxyprogesterone have a long duration of ac- About 97% of patients will ovulate by the third post- tion. They are used in oil solution intramuscularly treatment cycle. Progestins and estrogens are also use- once in 7-14 days. Pregnine is 5 times weaker than pro- ful in the treatment of endometriosis. It is now clear gesterone. However, Pregnine is available for oral and that these compounds reduce the risk of endometrial subglossal (sublingual) route of using. and ovarian cancer. A group of testosterone-derivatives with progestin Adverse effects. Minor adverse effects are frequent, activity — Levonorgestrel, Norethisterone (Norethin- but most are mild and many are transient. Mild ad- drone) — has been introduced, principally as compo- verse effects are headache, nausea, mastalgia, break- nents of oral contraceptives. They do not support preg- through bleeding, weight gain, and edema. Severe ad- nancy in test animals, are more effective gonadotro- verse effects are rare and include increasing coagula- pin inhibitors, and may have minimal androgenic or bility of blood (risk of thromboembolic disease), hy- anabolic activity. pertension, reduction of glucose tolerance, cholestat- Progestins have been used in the first trimester of ic jaundice, depression. These drugs should be avoid- pregnancy to prevent habitual abortion or to treat ed in patients with estrogen-dependent neoplasm. threatened abortion, however their usefulness is doubt- These agents are contraindicated in adolescents in ful. Progestins are used for the treatment of amenor- whom epiphysial closure has not yet been completed. rhea in the presence of estrogen. They are useful in Small doses of progestins can be used for contra- producing long-term ovarian suppression for the treat- ception also. Progestin-only contraceptives alter cer- ment of dysmenorrhea, endometriosis, and for contra- vical mucus and endometrium so that sperm migration ception. Progestins may cause changes in menstrual into the uterus and probable implantation is inhibit- flow, edema, and hypertension. ed. In addition, continuous administration of the drugs It is already synthesized antiprogestin agent — decreases the ovum transport by altering motility in Mifepristone. It binds strongly to the progesterone re- fallopian tubes. Although progestin-only oral contra- ceptor and inhibits the activity of progesterone. Mife- ceptives are less effective than estrogen-progestin com- pristone is used for termination of early pregnancies. binations, they are particularly suited for use in patients for whom estrogen administration is undesirable. Orally can be taken Continuin, Microlut. Unlike CONTRACEPTIVES estrogen-progestin combinations, progestin-only oral contraceptives must be taken daily, without interrup- A large number of oral contraceptives containing tion, to be effective. The main adverse effect is inci- estrogens or progestins (or both) are now available for dences of abnormal bleeding. clinical use. Two types of preparations are used for Pregnancy can be prevented following coitus by oral contraception: (1) combinations of estrogens and the administration of large doses of estrogens or pro- progestins and (2) continuous progestin therapy. The gestins (postcoital contraceptives). For example Posti- estrogenic component of commercially oral contracep- nor (contain L-norgestrel). When treatment is begun tive combinations is Ethinyl estradiol. The progestin within 72 hours, it is effective 99% of the time. Post- component is Levonorgestrel, Norethisterone (Nore- coital contraceptives can be used no more than 4 times thindrone), or Norgestrel. The combinations of estro- a month. gens and progestins exert their contraceptive effect largely through selective inhibition of pituitary function that results in inhibition of ovulation. The combi- ANDROGENS, ANABOLIC STEROIDS nation agents also produce a change in the cervical AND ANTIANDROGENS mucus, endometrium, and uterine tubes, which decrease the likelihood of conception and implantation. The testis, like the ovary, has both gametogenic and Estrogen-progestin oral contraceptives are usual- endocrine functions. In humans, the most important an- ly classified according to their formulation. Monopha- drogen secreted by the testis (in the interstitial or Ley- sic preparations contain fixed-combination of estro- dig cells) is Testosterone. Endogenous plasma testoster- gen and progestin (Nonovlon, Rigevidon, and Micro- one is maintained and regulated by gonadotropins with- gynon). Biphasic (Anteovin) and triphasic (Trisis- in a normal range by a negative feedback system involv- ton, Tri-regol) preparations consist of 2 or 3 sequen- ing the hypothalamus and pituitary. In blood circulat- tially administered fixed combinations of estrogen ing testosterone is bound to sex hormone-binding glob- and progestin. Bi- and triphasic contraceptives are ulin. In many target tissues (for example in prostate), more physiological, because differences of estrogen- Testosterone is converted to dihydrotestosterone. Andro- progestin correlation imitate normal fluctuation of gens are highly lipid-soluble and enter cells of target female sex hormones. tissues by passive diffusion. Testosterone or dihydrotes- Most combinations are available as 21-day dosage tosterone binds to an intracellular androgen receptor. preparations. In establishing an oral contraceptive The hormone-receptor complex translocates into the dosage cycle, the menstrual cycle is usually considered nucleus and initiates or suppresses transcription, and to be 28 days. The first day of bleeding is counted as protein synthesis. In the liver testosterone is transformed the first day of the cycle. Administration of oral con- into non-active substances such as androsterone that is traceptives usually begins on the fifth day of the men- then conjugated and excreted into the urine.

121 Physiologic effects. Androgens stimulate sperma- actone, a competitive inhibitor of aldosterone (see “Di- togenesis, development of male sexual organs (semi- uretic drugs”) also competes for the androgen recep- nal vesicles, penis, and scrotum) and secondary sexu- tors in target tissues. It also reduces the synthesis of al characteristics (male hair, enlargement of the lar- testosterone. It is used for the treatment of hirsutism ynx, and thickening of vocal cords). Androgens in- in women. crease linear bone growth and bone density, and help fuse the epiphysial growth centers. They cause nitro- Available forms: gen retention that indicates an increasing of protein Cortisone — tablets 0.025 or 0.05; in bottles 10 ml synthesis within the body (anabolic effect). That leads (1 ml contains 0.025 g Cortisone acetate) to growing of skeletal muscles and parenchymal or- Prednisolone — tablets 0.001 or 0.005 each gans. They also stimulate erythrocyte production. Prednisolone hemisuccinate — in ampoules 0.025 The ethers of testosterone have been used extensively each (to dilute in 5 ml solution, for i.v. or i.m. injec- in clinics (Testosterone propionate and Testosterone enan- tions) thate). They are injected intramuscularly one time in 2 Dexamethasone — tablets 0.0005 each days or in 3–4 weeks correspondently. These derivatives Fluocinolone acetonide (Sinaflan) — 0.025% oint- are hydrolyzed to release free Testosterone at the site of ment 10.0 or 15.0 injection. Methyltestosterone is Testosterone derivative Desoxycorticosterone acetate — in ampoules 0,5% that is active when given by mouth (subglossal). oil solution 1 ml each; tablets 0.005 each (subglossal Indications. Androgens are used to replace or aug- usage) ment endogenous androgen secretion in hypogonadal Oestradiol dipropionate — in ampoules 0.1% oil men. Androgens have also been used in the treatment solution 1 ml each of breast cancer as a supplement to chemotherapy in Ethinylestradiol — tablets 0.01 or 0.05 each women until 60 years. Androgens are sometimes given Synoestrolum — in ampoules 0.1% or 2% oil solu- for the therapy of dysmenorrhea, postmenopausal syn- tion 1 ml each; tablets 0.001 each drome. In women, the administration of testosterone is Tamoxifen — tablets 0.01; 0.02 or 0.04 each associated with masculinize actions (virilism): hirsutism, Oxyprogesterone caproate — in ampoules 12.5% or acne, depression of menses, and deepening of the voice. 25% oil solution 1 ml Sodium retention and edema may appear also. Non-Ovlon (Ethinylestradiol + Norethisterone) — Anabolic steroids are synthetic derivatives of tes- patented tablets (21 tablets in package) tosterone. Chemical changes result in reduction of their Continuin — patented tablets (42 tablets in pack- androgenic properties comparatively with testosterone age) and retention of their anabolic features. Many anabol- Testosterone propionate — in ampoules 1% or 5% ic steroids are used in clinics: Methandrostenolone, oil solution 1 ml each Phenoboline (Nandrolone phenylpropionate), Retab- Methyltestosterone — tablets 0.005 or 0.01 each olil (Nandrolone decanoate). Phenoboline and Ret- Nandrolone (Retabolil) — in ampoules 5% oil so- abolil are used intramuscularly. Duration of action is lution 1 ml each 2–3 weeks. Methandrostenolone is used orally daily. Finasteride — tablets 0.005 each Anabolic steroids have been used for reversing of protein loss after trauma, surgery, or prolonged immobi- lization and in patients with debilitating diseases. An- abolic agents are indicated for the treatment of osteoporosis. These agents have been used to stimulate Lecture 28 growth in boys with delayed puberty. VITAMINS Since complete dissociation of anabolic and androgenic effects is not possible, anabolic steroids produce slight masculinize actions. In addition, anabolic ster- Vitamins (lat. vita, life, + amine) are the organic oids can cause nausea, edema, hypercalcemia, and up- substances, present in minute amounts in natural food- set of liver function. stuffs, that are essential to normal metabolism, usual- The potential usefulness of antiandrogens for the ly as coenzymes; insufficient amounts in the diet may treatment of patients producing excessive amounts of cause deficiency diseases. testosterone has led to the search for effective drugs Vitamins are usually divided into water-soluble and that can be used for this purpose. Since dihydrotesto- fat-soluble vitamins. Vitamins B1 (Thiamine), B2 (Ri- sterone appears to be the essential androgen in the pros- boflavin), PP (Nicotinic acid), B5 (Pantothenic tate, androgen effects in this tissues can be reduced by acid), B6 (Pyridoxine), B12 (Cyanocobalamin), B15 an inhibitor of 5α-reductase. Finasteride, an inhibitor (Pangamic acid), Bc (Folic acid), C (Ascorbic of this enzyme, produces a reduction in dihydrotesto- acid), P (group of bioflavonoids) are water-soluble. Vi- sterone levels. It has been reported to be moderately tamins A (Retinol), E (Tocopherol), K (Phylloqui- effective in reducing prostate size in men with benign none) belong to fat-soluble. prostatic hyperplasia. Cyproterone acetate is effective The organism’s needs in vitamins change in de- antiandrogen that inhibits the action of androgens at pendence on age, work, climate, character of feed- the target organ. These compounds have been used in ing, etc. The hard work, neuro-psychical stress, preg- women for the treatment of hirsutism and in men to de- nancy, and breast-feeding, hard climate conditions crease excessive sexual drive. Flutamide, is a compet- lead to the higher vitamin demands. Also it is higher itive antagonist at the androgen receptor that has been in children than in adults. Hypovitaminosis and avi- used in the treatment of prostatic carcinoma. Spironol- taminosis appear during the vitamin deficiency.

122 Nowadays avitaminosis is observed comparatively Vitamin C is readily absorbed after oral adminis- seldom. Hypovitaminosis is more often observed. It tration. Ascorbic acid is widely distributed in body tis- is characterized by not determined symptoms (fa- sues. Large concentrations of the vitamin are found in tigue, headache, weakness, lowering of capacity for the liver, leukocytes, and adrenal glands. Mostly work, lowering of resistance for infections and other Ascorbic acid is metabolized to oxalates, which are diseases, etc.). Avitaminosis is the brightest appear- excreted in the urine. Large doses of ascorbic acid may ance of vitamin insufficiency. It is characterized by cause acidification of the urine, occasionally leading clearly expressed specific symptomatology and is stip- to precipitation of urate, oxalate stones, or drugs in ulated by full absence or prolonged vitamin deficien- the urinary tract. Ascorbic acid is used to prevent and cy. Reasons of vitamin’s deficiency in the organism to treat scurvy. It has been prescribed for hemorrhag- include low content of vitamins in meals (“alimenta- ic states, fever, infection, and trauma, poisoning by dif- ry” hypovitaminosis), disorders of vitamin’s absorp- ferent substances, anemia, atherosclerosis, peptic ul- tion from intestine that evoked by diseases of the GI cer, and the common cold. Ascorbic acid may be use- and liver (“secondary” or “endogenic” hypovitami- ful to treat idiopathic methemoglobinemia. Ascorbic nosis), and considerable increasing of dietary re- acid injection has been reported to be incompatible with quirements. However, prolonged overdosing of vita- many drugs. mins, usually fat-soluble (vitamins A, D), can cause Thiamine (vitamin B1, antineuritic vitamin) is a development of hypervitaminosis. water-soluble vitamin, which is present in many foods Vitamin drugs are used in substitutive, adaptive and including yeast, cereal grains, nuts, and meat. Thia- pharmacodynamic therapy. Substitutive vitamin ther- mine combines with Adenosine triphosphate (ATP) in apy is used during treatment of avitaminosis and hy- the liver, kidneys, and leukocytes to form thiamine di- povitaminosis. Adaptive vitamin therapy is used for phosphate (Thiamine pyrophosphate) which is a coen- bettering of organism’s adaptation for quickly chang- zyme in carbohydrate metabolism (in the decarboxy- ing conditions of environment (spring-autumn) and in lation of pyruvic and alpha-ketoglutaric acids). Thia- hard conditions (polar or tropical climate, climbing, mine diphosphate is also a coenzyme of transketolase work under surface of water, during flying by plains, in the utilization of glucose in the pentose phosphate etc.). Doses for substitutive and adaptive therapy are pathway. 2–3 times higher than physiologic dietary require- Thiamine deficiency leads to increased pyruvic and ments and are used for course therapy. lactic acids concentration in the blood (acidosis). The Pharmacodynamic vitamin therapy is used during organ systems principally affected by Thiamine defi- treatment of diseases that are not caused by vitamin’s ciency are the peripheral nervous system (polyneuri- deficiency. It’s basic difference from substitutive ther- tis), cardiovascular system (heart failure), and the GI apy is in using of higher vitamin’s doses, which doz- tract. In severe cases Thiamine deficiency results in ens and hundreds times exceed daily requirements. Ex- beriberi (paresis, paralysis) and encephalopathy syn- ample is using of vitamin D2 (Ergocalciferol) by drome. Administration of Thiamine completely reverses 100,000 IU per day for treating of tubercular lupus of the cardiovascular and GI symptoms of Thiamin defi- the skin. ciency; however, the degree of improvement in neurologic symptoms depends on the duration and severity WATER-SOLUBLE VITAMINS of the lesions. Following oral administration Thiamine is readi- Ascorbic acid (vitamin C, antiscorbutic vitamin) is ly absorbed; however, the total amount absorbed fol- a water-soluble vitamin, which is present in fresh fruit, lowing oral administration of a large dose is limited. vegetables, berries (wild rose). Citrus fruit are a par- GI absorption of Thiamine is decreased in alcoholics ticularly good source of vitamin C. Ascorbic acid is and in patients with cirrhosis or malabsorption. Thia- synthesized for use as a drug. Ascorbic acid is reversi- mine is rapidly and completely absorbed following in- bly oxidized to dehydroascorbic acid in the body. tramuscular administration. These two forms of the vitamin are believed to be im- Thiamine is used to prevent and to treat Thiamin portant in oxidation-reduction reactions: deficiency syndromes including beriberi, encephalopathy syndrome, and peripheral neuritis. It is also -2H used for the treatment of paresis, neuritis, heart fail- Ascorbic acid Dihydroascorbic acid ure, arrhythmia, and ketoacidosis. Thiamine com- +2H mercially is available in the form of Thiamin bromide or Thiamin chloride for oral and intramuscu- Ascorbic acid is required for collagen formation, lar administration. The probable adverse effect is tissue repair and preservation of blood vessel integri- hypersensitivity. ty. The vitamin is involved in tyrosine metabolism, con- Riboflavin (vitamin B2) is a water-soluble vitamin, version of Folic acid to Folinic acid, carbohydrate me- which is present in many foods including milk, meat, tabolism, synthesis of lipids and proteins, resistance to eggs, nuts, cereal grains, and yeast. In humans, an infections, and cellular respiration. In addition, Ascor- exogenous source of Riboflavin is required for tissue bic acid enhances the absorption of nonheme iron. respiration. Riboflavin is converted to the coenzyme, Ascorbic acid deficiency results in scurvy. Colla- Flavin mononucleotide (FMN) and Flavin adenine di- genous structures are primarily affected, and lesions nucleotide (FAD). These coenzymes act as hydrogen- develop in bones and blood vessels: ulceration of the carrier molecules for several enzymes (flavoproteins) gums hemorrhages into the skin and from the mucous involved in oxidation-reduction reactions of organic membranes, debility, and immunity impairment. substrates and in intermediary metabolism. Ribofla-

123 vin is also indirectly involved in maintaining eryth- nium and Nicotinic acid as well as Nicotinamide. These rocyte integrity. substances possess tranquilizer and hepatoprotective Riboflavin deficiency (ariboflavinosis) results in effects, that opens perspective of their purpose investi- cheilosis (angular stomatitis), glossitis, keratitis, ocu- gation. lar changes (photophobia, hemeralopia), and anemia. Vitamin B6 (as pyridoxine, pyridoxal, and pyridox- Riboflavin is readily absorbed from the upper GI amine) is a water-soluble vitamin, which is present in tract. FAD and FMN are widely distributed into body many foods including cereal grains, vegetables, liver, tissues, including GI mucosal cells, erythrocytes, and meat, and eggs. Pyridoxine, Pyridoxal, and Pyridox- the liver. Free Riboflavin is present in the retina. Vi- amine are converted to the active forms of the vitamin, tamin B2 is used to prevent Riboflavin deficiency and Pyridoxal phosphate and Pyridoxamine phosphate, to treat ariboflavinosis. Riboflavin may be useful in which act as coenzymes in a wide variety of reactions treating keratitis, iritis, skin and infection diseases. in nitrogenous metabolism. They are involved in Commercially available is Riboflavin (oral, topical), transamination, deamidation, and decarboxylation of Riboflavin mononucleotide (injection). Riboflavin is amino acids, in the conversion of Tryptophan to Nico- nontoxic. tinamide. Pyridoxine appears to be essential in the syn- Vitamin PP (B3) has two forms: Nicotinic acid (Ni- thesis of GABA within the CNS and in the synthesis of acin) and Nicotinamide (Niacinamide). Nicotinic heme. The vitamin is also involved in lipid metabolism. acid and Tryptophan (that is converted to Nicotina- Deficiency of the vitamin has rarely been identified mide) present in many stufts including yeast, meat, fish, in humans. Artificial Pyridoxine deficiency affects the milk, eggs, green vegetables, and cereal grains. Com- peripheral nerves (neuritis), CNS (seizure), skin (der- mercially available Nicotinic acid and Nicotinamide matitis), and the hematopoietic system (leukopenia). are prepared synthetically. Nicotinic acid is incorpo- Pyridoxine deficient state can occur during treatment rated into 2 coenzymes: Nicotinamide adenine dinu- of tuberculosis with Ioniazid that inhibits the conver- cleotide (NAD) and Nicotinamide adenine dinucleotide sion of Vitamin B6 to the Pyridoxal phosphate. phosphate (NADP). They act as hydrogen-carrier mol- Vitamin B6 is readily absorbed from the GI tract ecules in glycogenolysis, tissue respiration, and lipid following oral administration. It is stored mainly in the metabolism (more than 150 reactions). In large doses, liver. Pyridoxine is used to prevent and to treat Vita- Nicotinic acid (not nicotinamide) produces peripheral min B6 deficiency. Also it is indicated for the treatment vasodilatation, predominantly of cutaneous vessels in of hematopoietic upset (leukopenia, anemia), disorders the face, neck, and chest; decreases serum low-density of nervous system (neuritis, parkinsonism, and verti- lipoprotein concentrations; activates the fibrinolytic go), and hepatitis. system. Nicotinic acid reportedly increases gastric Commercially available form is Pyridoxine hydro- acid secretion. Vitamin PP deficiency results in pella- chloride (oral, injection). Long-term administration of gra that accompanied by dermatitis, diarrhea, and de- megadose of Pyridoxine can cause sensory neuropa- mentia (loss of cognitive functions). thy. Vitamin PP is readily absorbed from the GI tract Pantothenic acid (Vitamin B5) is a water-soluble following oral administration, as well as from subcu- vitamin, which is widely distributed in plant and ani- taneous and i.m. injection site. It is widely distributed mal tissues. Rich sources of Pantothenic acid include into body tissues. Metabolites of Vitamin PP are ex- meat, vegetables, cereal grains, eggs, and milk. Also creted in urine. it is synthesized in bowel by E. coli. In humans, an Vitamin PP is used to prevent and to treat nicotin- exogenous source of pantothenic acid is required for ic acid deficiency. Large doses of Nicotinic acid are intermediary metabolism of carbohydrates, proteins, used for the treatment of atherosclerosis (antilipemic and lipids. Pantothenic acid is a precursor of coen- agent); conditions associated with deficient circulation zyme A which is required for acetylation reactions in (e.g. peripheral vascular disease and vascular spasm), gluconeogenesis, in the release of energy from carbo- gastritis, and liver diseases. hydrates, in the synthesis and degradation of fatty ac- Large doses of Nicotinic acid can cause flushing ids, and in the synthesis of steroid hormones, acetyl- (face, neck), pruritus, heartburn, hypotension, and choline, and other compounds. headache. Long-term using of Nicotinic acid may im- Dietary deficiency of Pantothenic acid has not been pair glucose tolerance and lead to lipid dystrophy of clinically identified in humans. Experimentally pro- the liver (Methionine can prevent liver damage). duced Pantothenic acid deficiency resulted in drowsi- Nowadays some drugs include Nicotinic acid. For ness, fatigue, headache, paresthesia of legs, and GI example, Nicoverin (Nicotinic acid + Papaverine), complaints. Nicoshpan (Nicotinic acid + No-Spa). Papaverine and Pantothenic acid is readily absorbed from the GI No-Spa relieve smooth muscle spasm (spasmolytics) tract following oral administration. It is widely distrib- and Nicotinic acid enhances their action, especially uted into body tissues, mainly as coenzyme A. High- vasodilatation. Thus, Nicoverine and Nicospan are est concentrations are found in the liver and adrenal used for the treatment of hypertonia. Litonit (Lithium glands. Pantothenic acid is excreted unchanged. salt of Nicotinic acid) is known as tranquilizer. The The vitamin is commercially available as the cal- head of the pharmacology department of the Odessa cium salt (Calcium pantothenate). It has been used Medical University prof. V. Y. Kresyun investigated orally and parenterally. Calcium pantothenate is in- it. Nowadays Litonit is used for alcoholism treatment. dicated for the treatment of peripheral neuritis, toxi- Current work of the OGMU pharmacology department cosis during pregnancy, hepatitis, atony of the intes- is based on the study of neurotropic and hepatotropic tine, Streptomycin neurotoxicity, and catarrhal respi- activities of newly synthesized compounds of Germa- ratory disorders. Pantothenic acid is usually nontoxic

124 even in large doses. Allergic reactions to it have been Pyridoxine — powder; tablets 0.002; 0.005 or 0.01 reported occasionally. each; in ampoules 1% or 5% solution 1 ml each Pangamic acid Vitamin B15 is considered to vita- Potassium pantothenate — tablets 0.1 each; in am- min-like substances. It is donator of methyl groups and poules 10% solution 2 or 5 ml possesses anti-hypoxanthic action. It is used in a form Rutin — powder; tablets 0.02 each of Calcium pangamate during dystrophy of myocar- Hexavit — patented dragee dium, angina pectoris, atherosclerosis, diseases of the liver, and during treatment of alcoholism. Rutin (Vitamin P) unites group of bioflavonoids, FAT-SOLUBLE VITAMINS which are present in green tea, citruses, wild rose, etc. Together with Ascorbic acid it takes part in oxidiz- Vitamin A is a fat-soluble vitamin that is present ing-restoring processes and prevents forming of lipid’s in foods in a variety of forms: Retinol (Vitamin A1), peroxides. It increases firmness and lowers penetrabil- Dehydroretinol (Vitamin A2), and Retinoic acid. Vi- ity of capillaries. So, it is used in combination with tamin A is present in esterified form in eggs, milk, but- Ascorbic acid Ascorutin for the treatment of increased ter, and oily salt-water fish. Provitamin A carotenoid penetrability of vessels (capillary toxicosis, hemor- pigments (including α-, β-, and γ-carotene), the most rhagic diathesis), allergy, and polyarthritis. active of which is β-carotene, are present in green and Vitamin U is contained in cabbage, asparagus, yellow vegetables and fruit and are converted to retin- and fresh tomato. It is donator of methyl groups and ol in humans. takes part in oxidizing-restoring processes. It is used In humans, an exogenous source of Vitamin A is enterally during ulcerative disease of stomach and du- required for growth, vision, reproduction, and the in- odenum, gastritis, and colitis. tegrity of mucosal and epithelial surfaces. Vitamin A Vitamin B12 (Cyanocobalamin) and Folic acid has been reported to act as a cofactor in mucopoly- (Vitamin Bc, Pteroylglutamic acid) are discussed in saccharide synthesis. In the retina, Retinol is convert- lecture “Drugs influencing the erythropoiesis”. ed to the Aldehyde (retinal), which combines with Multivitamins. When a single vitamin deficiency is Opsin to form Rhodopsin, the visual pigment. Under evident, other vitamin deficiencies (clinical or subclin- the influence of light rhodopsin is split into retinal ical) often accompany it. Therapeutic multivitamin and opsin that accompanied with perceiving of light. preparations may, therefore, be useful in these patients. In darkness the resynthesis of Rhodopsin occurs. Therapeutic multivitamins may also be indicated in Thus, Rhodopsin is necessary for visual adaptation pathologic conditions in which nutritional requirements for darkness (Fig. 23). are greatly increased (e.g. alcoholism, hyperthy- Vitamin A deficiency leads to night blindness (nyc- roidism, severe illness or injury, cachexia) or in con- talopia or hemeralopia — impairment of vision in re- ditions in which absorption, utilization, or excretion duced illumination), xerophthalmia (dryness of the cor- of vitamins is abnormal (including malabsorption syn- nea) and keratomalacia (ulceration of the cornea), hy- dromes). perkeratosis of the skin, immunodeficiency, and epi- The vitamin combination chosen should fit the thelial metaplasia of mucous membranes that decrease needs of the individual patient. It should be remem- resistance to infections. That’s why, Vitamin A is bered that some vitamins (especially Vitamins A and known also as “anti-infection agent”. D) and many minerals may be toxic in large doses, and Vitamin A is readily and completely absorbed if dosage of multivitamin preparations containing these fat absorption is normal. Retinol esters are hydro- agents should take the patients dietary intake into ac- lyzed in the GI lumen by pancreatic enzymes and in count. Vitamins are usually administered orally; how- presence of bile. Retinol is absorbed and then reesteri- ever, the drugs may be given parenterally in patients fied, mainly to Retinyl palmitate. It is stored in the liv- in whom oral administration is not feasible, including er. Normal body stores of Vitamin A are sufficient to those receiving total parenteral nutrition. Multivita- meet the body’s requirements for several months. Reti- min injections are reportedly incompatible with i.v. nol is released from the liver bound to the plasma pro- solutions containing various drugs. Multivitamin prep- teins. Vitamin A metabolites are excreted in the urine arations are tablets or dragee “Hexavit”, “Pangex- and feces. avit”, “Decamevit”, “Aerovit”, “Glytamevit”, “Uni- cap”, etc. For instance, dragee “Hexavit” includes Vi- Visual pigment tamin A, B1, B2, PP, B6, C. (rhodopsin)

Available forms: Ascorbic acid — powder; tablets 0.05 or 0.1 each (for adults); tablets 0.025 each (for children); in ampoules 5% or 10% solution 1 or 2 ml Light Retinal + opsin Darkness Thiamine chloride — tablets 0.002; 0.005 or 0.01 each; in ampoules 2.5% or 5% solution 1 ml each Riboflavin — powder; tablets 0.002 each (for proph- +2H -2H ylaxis); tablets 0.005; 0.01 each (for treatment) Nicotinic acid — powder; 0.05 each; in ampoules Retinol 1% solution 1 ml Nicotinamide — powder; tablets 0.005 each (for prophylaxis); tablets 0.025 each (for treatment) Fig. 23. Synthesis and breaking of Vitamin A

125 Vitamin A is used to prevent and to treat symptoms Calcitriol and Calcifediol enhance the efficiency of of Vitamin A deficiency such as xerophthalmia and intestinal calcium and phosphorous absorption in the night blindness. Oral administration of water-miscible small intestine and stimulate renal reabsorption of cal- Vitamin A preparations may be useful in preventing cium and phosphate. They exhibit potent antiprolifer- deficiency in patients with malabsorption. Vitamin A ative and prodifferentiation effects. Recent evidence may be useful in infections, skin disorders (burns, ich- suggests that 24,25-dihydroxyvitamin D3 stimulates thyosis, and psoriasis), and however, other retinoids bone formation. Vitamin D deficiency results in skele- (e.g. Etretinate, Isotretinoin) are currently being inves- tal demineralization. In children, Vitamin D deficien- tigated for use in the treatment of these dermatologi- cy leads to rickets that is characterized by skeletal de- cal disorders. Vitamin A has been studied in animals formations (e.g. frontal bossing), and outward and in- as an anticarcinogen; further study in humans is need- ward deformities of the lower limbs resulting in bowed ed to determine efficacy. For clinical use, Vitamin A legs and knocked knees, respectively. In adults, Vita- is available as Retinol (Vitamin A alcohol) or esters min D deficiency leads to osteoporosis (reduced bone of Retinol formed from acetic and palmitic acids. Vi- mass) and osteomalacia (softening of the bones). Any tamin A activity is preferably expressed in Internation- alteration in cutaneous production of Сholecalciferol, al Units (IU). GI Vitamin D absorption, or metabolism of the vita- Doses of Vitamin A that do not exceed the physio- min to its active form (i.e. calcitriol) can result in it’s logic requirement are usually nontoxic. Effects of acute deficiency. overdosing are vomiting, diarrhea, confusion or unu- Vitamin D is readily absorbed from the GI tract sual excitement. Chronic overdosing includes bone or following oral administration. The presence of bile joint pain, painful hyperostosis of the bones (thicken- is required for its absorption. Vitamin D is incorpo- ing of bones), drying or cracking of skin, loss of hair, rated into chylomicrons and absorbed via the lym- unusual tiredness. Large doses of Vitamin A are tera- phatic system and then associates mainly with a spe- togenic in animals. Treatment of hypervitaminosis A cific α-globulin as well as Vitamin D hydroxylated consists of discontinuance of Vitamin A and sympto- metabolites. 25-hydroxylated vitamin D2, D3 are matic therapy as indicated. stored in fat and muscles. The metabolites of Vita- Group of Vitamin D (antirachitic vitamins) in- min D analogs are excreted principally in bile and cludes fat-soluble vitamins that possess antirachitic and feces. Activity of Ergocalciferol and Cholecalciferol hypercalcemia activity. Because they are activated in is expressed in IU. the body and have regulatory effects, they are some- For clinical use, Vitamin D is available as Chole- times considered hormones. Vitamin D analogs in- calciferol, Ergocalciferol,and Calcitriol. Vitamin D is clude Cholecalciferol Vitamin D3 and Ergocalciferol used to prevent or treat rickets, osteoporosis, hypoc- Vitamin D2. Vitamin D is present in fish oil, liver of alcemia tetany, and to manage psoriasis and hypopar- aquatic mammals (e.g. seals, polar bears), eggs, but- athyroidism. Administration of excessive doses of Vi- ter, and milk. Ergocalciferol is formed from ergos- tamin D may lead to hypervitaminosis D manifested terol. Cholecalciferol is formed from 7-Dehydrocho- by hypercalcemia. Early symptoms of hypercalcemia lesterol in the skin after exposure to ultraviolet light. may include weakness, drowsiness, metallic taste, vom- In the human body, Cholecalciferol is hydroxylated iting, vertigo, and bone pain. Later consequences of to Calcifediol (25-hydroxyvitamin D3) in the liver and hypercalcemia may include impairment of renal func- then to Calcitriol (1,25-dihydroxyvitamin D3) and Se- tion, osteoporosis, and metastatic calcification of or- cacalcifediol (24,25-dihydroxyvitamin D3) in the kid- gans and vessels. Treatment of Vitamin D intoxication neys (Fig. 24). Ergocalciferol has the same conversion consists of withdrawal of the drug, administration of as Cholecalciferol. fluids, corticosteroids, and calciuria diuretics (e.g. Furosemide and Ethacrynic acid). 7-dehydrocholesterol Vitamin E (antisterility vitamin) is a fat-soluble vitamin, which is present in many foods including in the skin vegetable oils, cereal grains, animal fats, meat, (ultraviolet exposure) eggs, fruits, and vegetables. The vitamin exists in a variety of forms: α-, β-, and γ-tocopherols. The most biologically active natural form of the vitamin is α- Cholecalciferol tocopherol. The exact biologic function of vitamin E in hu- in the liver mans is unknown, although the vitamin is believed to act as an antioxidant. It has been postulated that Vi- tamin E protects polyunsaturated fatty acids (which Calcifediol are components of cellular membranes) and other oxygen-sensitive substances (Vitamins A, C) from oxi- (25-hydroxyvitamin D3) dation. Vitamin E delays the accumulation of free in the kidneys radicals resulting in excessive lipid peroxidation. Thus, it limits atherosclerosis and CNS neuronal gen- Secacalcifediol Calcitriol eration (Alzheimer’s disease). Vitamin E also may in- (24,25-dihydroxy- (1,25-dihydroxy hibit platelet aggregation and adhesion. Vitamin E vitamin D3) vitamin D3) deficiency does not cause specific disease in adults; however, in premature neonates thrombosis and hemo- Fig. 24. Synthesis of Vitamin D3 lytic anemia may occur. In animals, avitaminosis E 126 is associated with infertility in male and spontaneous Collagenase is used to promote debridement of necrotic abortion in female, dystrophy of skeletal muscles and tissue in the treatment of severe burns and dermal ul- myocardium. cers. Pain and burning may occur at the site of Colla- Absorption of Vitamin E from the GI tract depends genase application. on the presence of bile and only half of the vitamin ob- Pepsin is the principal digestive enzyme (Pro- tained from dietary sources is absorbed. After absorp- tease) of gastric juice, formed from pepsinogen; it hy- tion, Vitamin E reaches the lymph circulation and then drolyzes peptide bonds at low pH values, reducing is transported with plasma proteins. Vitamin E is dis- proteins to smaller molecules. For medical purpose tributed to all tissues and is stored in adipose tissue. it is obtained from stomach mucous membrane of hog. Vitamin E is metabolized in the liver and excreted pri- Pepsin is indicated for replacement therapy of stom- marily in the bile. ach upset such as achlorhydria (absence of hydro- Vitamin E has been used for the treatment of ha- chloric acid in the gastric juice) or hypoacidity (low- bitual abortion, infertility, myodystrophy, dementia, er than normal level of hydrochloric acid). Natural angina pectoris, and thrombophlebitis. For drug use, gastric juice is digestive fluid secreted by the stom- Vitamin E is available as Tocopherol acetate. Vitamin ach glands of the dogs or horses. It normalizes secre- E is usually nontoxic; however, it may cause allergic tion and motility of the gastrointestinal tract. Abomin reactions and pain in site of injection. is received from the stomach mucous membrane of calf or lamb. It contains the summary of proteolytic enzymes. Gastric Juice and Abomin have the same indications as Pepsin. Pancreatin is a substance containing enzymes, Lecture 29 principally Amylase, Lipase, and Protease, obtained ENZYME PREPARATIONS AND from the pancreas of the cattle and hog. Pancreatin is used as replacement therapy in the symptomatic ENZYME INHIBITORS treatment of chronic pancreatitis, pancreatectomy, or other conditions in which pancreatic insufficiency impairs fat digestion. Pancreatic exocrine replace- Enzyme agents are the preparations of enzymes. ment therapy should not delay or supplant treatment They are widely used in medicine for the different pur- of the primary disorder. The medication is taken be- poses. The first enzyme agents group (Trypsin) is in- fore meals. Because pancreatin has a high purine con- dicated for purulent-necrotic processes; the second tent, hyperuricemia, uric acid renal stones may be group (Pancreatin) increases digestive activity; the seen as a side effect. Hypersensitivity reactions have third group (Streptokinase) has fibrinolytic properties; been reported. Panzynorm forte N (contain pancrea- the fourth group includes different enzyme drugs tin, bile extract, and extract of stomach mucous mem- (Lydase, Penicillinase). brane), Festal (pancreas enzymes and bile extract), Trypsin is a proteolytic enzyme that formed in the Mezym® forte (pancreas enzymes) are the digestive small intestine. It hydrolyzes peptides, amides, etc. enzyme replacement products also. They are used for Crystallized trypsin, a purified preparation of the pan- the treatment of digestive insufficiency of the gas- creatic enzyme. It is used in medicine for debridement trointestinal tract. (excision) of wounds and ulcers for dead tissues, fibrin, Fibrinolytic drugs (Fibrinolysin, Streptokinase, and viscous secretes. In addition it has anti-inflamma- and Urokinase) are discussed in the lecture “Drugs tory activity and permits antibodies, leukocytes, and used in disorders of coagulation”. antibiotics better access to the infected area. Trypsin Hyaluronidase (Lydase) is a protein enzyme that is non-active (safe) relatively for undamaged tissues. found widely distributed in nature. Hyaluronidase for It is used in inhalation for the cleaning of bronchi for injection is a sterile, dry, soluble enzyme product pre- viscous mucus or exudate during bronchitis, pneumo- pared from cattle’s testes. The potency of the drug is nia. Trypsin is injected intramuscularly or used topi- expressed in conventional units. Hyaluronidase modi- cally for the treatment of thrombophlebitis, parodon- fies the permeability of connective tissue through the titis, osteomyelitis, and purulent infections of soft tis- hydrolysis of hyaluronic acid. Occurring as one of the sues. The agent can irritate tissues at the site of its ap- principal viscous polysaccharides of connective tissue plication and can cause allergic reactions or intoxi- and skin, hyaluronic acid is one of the chief ingredi- cation that predominantly are evoked by absorption ents of the tissue cement, which offers resistance to the of necrotic tissues. Chymotrypsin is a proteinase of the diffusion of liquids through tissue. Hyaluronidase is gastrointestinal tract. It hydrolyzes proteins. Chymo- indicated in the treatment of ankylosis (stiffening) of trypsin is similar in indications to Trypsin. the joints and postburn scars. The enzyme also has- Deoxyribonuclease and Ribonuclease are the en- tens the disappearance of swelling after hemorrhage. zymes. They hydrolyze phosphodiester bonds in DNA Adverse effects from Hyaluronidase are rare. Occa- and proteins. These agents have the same to Trypsin sional sensitivity reactions (e.g. urticaria) have been using. Deoxyribonuclease and Ribonuclease are ob- reported. tained from the cattle pancreas as well as Chymot- Penicillinase is a β-lactamase enzyme, which de- rypsin and Trypsin. stroys all biosynthetic and majority of semisynthetic Collagenase is a proteolytic enzyme capable of spe- penicillins. It is produced by certain strains of mi- cifically hydrolyzing peptide bonds of collagen. The crobes (e.g. staphylococci). Penicillinase is used in enzyme debrides necrotic tissue without damaging case of acute or delays hypersensitivity for penicil- granulation tissue. It is derived from cattle pancreas. lins.

127 Asparaginase is an enzyme that is isolated for clin- 3. A patient with endometriosis who is being treat- ical use from various bacteria. The drug is used to treat ed with Leuprolide has hot flashes and dry skin and leukemia. It acts indirectly by catabolic depletion of vagina. What additional treatment would relieve these serum asparagine. These results in inhibition of pro- unpleasant effects? tein synthesis in neoplastic cells, requiring an exter- (A). Estrogen and Progesterone. nal source of asparagine (see lecture “Immunotropic (B). Ganirelix. agents”). (C). Testosterone. Enzyme inhibitors are discussed in other topics: (D). Bromocriptine. (1) proteinase inhibitors (Aprotinin (Contrykal)) one can see in lecture “Drugs used in gastrointestinal dis- 4. A 30-year-old woman has secondary amenorrhea eases”; (2) fibrinolytic inhibitors (Aminocaproic and serum prolactin levels of 75 ng/mL. She has visit- acid) see in “Drugs used in bleeding disorders”; (3) ed a fertility clinic to attempt to become pregnant. cholinesterase-inhibiting drugs (Neostigmine methyl- What treatment should be given? sulfate (Proserine)) see in “Cholinomimetics”; (4) (A). Clomiphene. monoamine oxidase (MAO) inhibitors (Nialamide) (B). Ganirelix. see in “Antidepressant agents”; (5) carbonic anhy- (C). Cabergoline. drase inhibitors (Acetazolamide (Diacarb)) see in (D). Estradiol. “Diuretic agents”; (6) xanthine oxidase inhibitors (Allopurinol) see in “Drugs used in gout”; (7) acetal- 5. Growth hormone deficiency in children must be dehyde dehydrogenase inhibitors (Teturamum) see determined by measuring hormone levels after giving in “The alcohols”. an agent that stimulates release because (A). Normal growth hormone secretion in chil- Available forms: dren is too low to be measured by current as- Retinol acetate — in bottles 3.44% oil solution 10 says. ml each; in ampoules oil solution 1 ml (contain 25,000; (B). Growth hormone secretion occurs only dur- 50,000 or 100,000 IU) each; in capsules 0.2 (3,300; ing sleep. 5,000 or 33,000 IU) each (C). Growth hormone secretion is episodic. Ergocalciferol — in dragee 500 IU each (for proph- (D). A different form of growth hormone is secret- ylaxis); in bottles 0.5% solution 5 ml (1 ml contain ed after stimulation. 200000 IU) each (for prophylaxis and treatment); in bottles 0.0625%; 0.125% or 0.5% oil solution 10 ml 6. During the period of withdrawal from extended each (1 ml contains 25,000; 50,000 or 200,000 IU cor- glucocorticoid therapy respondently) (A). Prompt recovery of the hypothalamic-pitui- Tocopherol acetate — in bottles 5%; 10% or 30% tary-adrenal axis results in restoration of en- oil solution 10; 20 or 50 ml each; in ampoules 5%; 10% dogenous corticotrophin release. or 30% oil solution 1 ml each (B). The patient may be eager to further reduce Trypsin crystallized — in bottles or in ampoules the dose of glucocorticoid. 0.005 or 0.01 each, to dilute in 2 or 20 ml of physio- (C). The physician should rapidly reduce gluco- logic solution before injection or applying correspond- corticoid therapy to physiological doses. ently (D). Patients should not require an increment in Pancreatin — in tablets 0.25 each steroid therapy during increased stress (e.g. Hyaluronidase (Lydase) — in bottles 64 conven- severe infection). tional units (CU) each, to dilute in 1 ml of physiolog- (E). The appearance of fever and malaise attrib- ic solution (for injection) uted to steroid withdrawal may be difficult to distinguish from reactivation of rheumatic disease.

EXAMINATION QUESTIONS 7. Which one of the following enzymes is required for cortisol biosynthesis? 1. A patient with severe diarrhea as a result of a (A). 21-hydroxylase. carcinoid tumor is a candidate for which of the follow- (B). 17,20 lyase. ing treatments? (C). Cyclooxygenase. (A). Pulsatile administration of GnRH. (D). 11-β-hydroxysteroid dehydrogenase-2. (B). Nasal administration of Desmopressin. (E). 18-hydroxylase. (C). Depot injections of Octreotide. (D). Oral administration of Bromocriptine. 8. The primary goal of glucocorticoid treatment in rheumatic arthritis is 2. The actions of ADH include all of the following (A). Suppression of inflammation and improve- EXCEPT ment in functional capacity. (А). Stimulation of ACTH release. (B). Eradication of all symptoms. (В). Stimulation of bile secretion. (C). Reversal of the degenerative process. (С). Constriction of most blood vessels. (D). Development of a sense of well-being in the (D). Stimulation of coagulation factor VIII pro- patient. duction. (E). Prevention of suppression of the hypothalam- (Е). Production of concentrated urine. ic-pituitary-adrenal axis.

128 9. The addition of a fluoride group on ring C of (C). They elevate the levels of prostaglandins cortisol to give 9-α-fluorocortisol through indirect mechanism. (A). Will shorten its half-life. (D). The effects of elevated thyroid hormones are (B). Will increase both glucocorticoid and min- directly antagonized by β-adrenoceptor ago- eralocorticoid activity. nists. (C). Shares an advantage over Cortisol in that sodium retention is not as marked at equipotent 15. The following statements regarding the mech- inflammatory doses. anism of action of thionamide drugs in the treatment (D). Will not cause suppression of the hypotha- of hyperthyroidism are true EXCEPT lamic-pituitary-adrenal axis when applied (A). The clinical effects are apparent soon after topically. administration. (E). Provides a steroid widely used in the treat- (B). The compounds inhibit the action of the en- ment of rheumatoid arthritis. zyme TPO. (C). The drugs inhibit thyroid hormone synthesis. 10. Dexamethasone (D). These drugs do not inhibit secretion of pre- (A). Is adequate replacement therapy in an existing stored thyroid hormone. adrenalectomized patient. (B). Has a half-life equivalent to that of Сortisol. 16. Why are elderly individuals more likely to be (C). Produces salt retention in therapeutic doses. Vitamin D deficient than young adults? All of the (D). Possesses most of the undesirable side effects choices are true EXCEPT of Сortisol. (A). They spend less time outdoors exposed to the (E). Has antiinflammatory potency equivalent to sun, which is important in the synthesis of Vi- that of Сortisol. tamin D. (B). Their appetite and intake of essential nutri- 11. Which answer is most appropriate for the ac- ents is diminished because of chronic medical tion of Ketoconazole? conditions associated with aging. (A). It has a single major action that is confined (C). The formation of the active form of Vitamin to the adrenal cortex. D is diminished by chronic liver and renal (B). It provides long term treatment for Cushing’s conditions. disease. (D). The Vitamin D receptor has less affinity for (C). It has an action on the adrenal cortex that is D3 with aging. irreversible. (D). Its action may be associated with liver dys- 17. A 48-year-old white man is noted to have oste- function. openia on a routine LS spine film while being evaluat- (E). It preferentially blocks Cortisol synthesis as ed for back pain. His bone density reveals osteoporo- opposed to testosterone production. sis of both his hip and LS spine. All of the choices are possible EXCEPT 12. All of the following are common adverse effects (A). He has been taking Gabapentin (Neurontin) associated with drug overdose of thyroid hormone re- for the past 2 years for a seizure disorder. placement therapy EXCEPT (B). He has Crohn’s disease and has had to take (A). Cardiac palpitation. Prednisone off and on since the age of 16. (B). Arrhythmias. (C). He has had multiple calcium kidney stones (C). Tachycardia. over the past few years and has been on a low- (D). Weight gain. calcium diet. (E). Heat intolerance. (D). He had glomerulonephritis at the age of 24 and developed chronic renal failure but re- 13. An adequate dietary intake of Iodine is essen- ceived a kidney transplant 10 years ago. tial to prevent hypothyroidism. In many areas of the (E). He drinks 2 to 3 glasses of wine each day at world, dietary Iodine intake is insufficient and must be dinner. supplemented. There is another element in which a dietary intake may be insufficient that is also associated 18. The main reason Metformin should not be used with thyroid hormone metabolism. This element is in patients with renal failure is that (A). Calcium. (A). It increases the risk of lactic acidosis. (B). Selenium. (B). It increases the risk of ketoacidosis. (C). Fluorine. (C). It causes development of congestive heart fail- (D). Sodium. ure. (E). Potassium. (D). It causes hepatic necrosis. (E). It causes hypoglycemia. 14. What is the primary reason for administering β-adrenergic receptor blocking drugs as adjunct ther- 19. Hypoglycemia is rarely seen with these drugs apy in the treatment of thyrotoxicosis? when used as monotherapy EXCEPT (A). They reduce the elevated thyroid hormone (A). Metformin. levels. (B). Rosiglitazone. (B). Many of the effects of elevated thyroid hor- (C). Miglitol. mones result from an increase in number of (D). Glyburide. β-adrenoceptors. (E). A, B, and C.

129 20. Breast cancer is the second most common can- 26. A patient comes into the clinic for a pregnancy cer in women. All of the following statements concern- test. It is positive. Which of the following should be ing breast cancer at true EXCEPT recommended? (A). Hormonal therapy is reserved for patients with (A). A multivitamin without iron. advanced metastases. (B). A multivitamin with iron. (B). Estrogen treatment is an acceptable form of (C). A diet rich in carrots. hormonal therapy. (D). No vitamin supplement. (C). Progestin treatment is an accepted form of (E). A Vitamin A supplement. hormonal therapy. (D). Tamoxifen is an accepted form of nonhormo- 27. Capillary fragility, malaise, and abnormal bone nal therapy. and tooth development describe a deficiency of which vitamin? 21. The mechanism of action of the compound (A). Vitamin A. RU486 is to (B). Vitamin B6. (A). Block estrogen binding to Ers. (C). Vitamin C. (B). Block progestin binding to progesterone re- (D). Riboflavin. ceptors. (E). Vitamin E. (C). Act as an estrogen agonist. (D). Act as a progesterone agonist. 28. Which vitamin can mask the symptoms of pernicious anemia by alleviating the anemia but not pre- 22. The formation of what as a principal precursor venting the neurological damage? of testosterone is considered the biosynthetic ratelim- (A). Vitamin B12. iting step? (B). Niacin. (A). Pregnenolone. (C). Folic acid. (B). Cholesterol. (D). Vitamin C. (C). Androstenediol. (E). Vitamin D. (D). Estrogen. (E). Progesterone. 29. An epileptic patient who is taking Phenytoin and Lamotrigine to control her seizures is in the first 23. Normal skeletal muscle cells month of pregnancy and definitely wants to have the (A). Typically lack androgen receptors and thus baby. What vitamin supplement would be essential? are not affected by high concentrations of tes- (A). Vitamin B6. tosterone. (B). Vitamin D. (B). Respond more readily to dihydrotestosterone (C). Vitamin C. than to testosterone. (D). Niacin. (C). Have higher levels of 5α-reductase than do (E). Folic Acid. prostatic tissue cells. (D). Use the androgen receptor to enhance protein anabolic activity. ANSWERS (E). Produce testosterone in response to FSH stimuli. 1. (C). Carcinoid tumors arise from neuroendocrine cells of the gut and secrete serotonin and gastrointestinal hormones, which activate the gastrointestinal tract 24. Upon examination, a 68-year-old married man and result in diarrhea. Most of these tumors have re- was found to have a greatly enlarged prostate. Which ceptors for somatostatin, which inhibit secretion when one of the following drugs is most likely to suppress activated, resulting in reduced activity of the gut. Oc- prostatic growth without affecting libido? treotide is a stable analogue of somatostatin that is ef- (A). Spironolactone. fective in treating carcinoid-induced diarrhea and that (B). Finasteride. may slow tumor growth. The long-acting form requires only monthly injections to maintain effective levels. (C). Ketoconazole. GnRH, Desmopressin, and Bromocriptine will not inhib- (D). Flutamide. it secretion from these neuroendocrine tumors. (E). Stanozolol. 2. (B). ADH has many actions through three receptors but does not affect bile secretion. It stimulates ACTH 25. A patient with pancreatic disease complains of release, although the predominant control occurs through difficulty driving at night because of vision problems. corticotropin-releasing hormone. It has pressor activity by causing smooth muscles cells of most blood vessels Ulceration of the cornea is detected on ophthalmic ex- to constrict. It stimulates production of coagulation fac- amination. Which of the following should be recom- tor VIII and von Willebrand’s factor, and it increases the mended? permeability of the collecting duct in the kidney to wa- (A). Supplementation with Vitamin B complex. ter, resulting in urine that has high osmolarity and low (B). Supplementation with Vitamin A. volume. (C). Decreased intake of Vitamin A. 3. (A). Endometriosis is growth of the endometrium (D). Supplementation of diet with more red beyond the uterine cavity. Leuprolide is a GnRH ana- meat. logue that suppresses LH and FSH when present contin- (E). Decreased Vitamin C intake. uously, resulting in endometrial atrophy and low estrogen levels, causing hot flashes and skin dryness; long-

130 term use may also reduce bone density. Low-dose estro- cipally for interim management of Cushing’s disease pri- gen and progesterone replacement therapy relieves the or to surgery or radiotherapy. Ketoconazole preferential- side effects caused by reduced estrogen levels, usually ly blocks the C17, 20 lyase reaction that is involved in without stimulating endometrial growth. However, the the synthesis of sex steroids. recent warning of relative cancer risk of estrogen-proges- 12. (D). The cardiac effects (A), (B), and (C) are symp- terone combinations as short-term versus long-term hor- toms of hyperthyroidism, as is (E). Instead of weight gain, monal replacement therapy must be carefully considered. a loss in body weight would be expected. Ganirelix, Testosterone, and Bromocriptine would not re- 13. (B). Selenium in the form of selenocysteine is relieve the side effects. quired for three enzymes that remove iodide from thy- 4. (C). High prolactin levels may cause amenorrhea roid hormones. There are no significant areas in which and infertility through mechanisms not understood. Pro- dietary intake of sodium or potassium are problems. Flu- lactin levels in normal women are less than 20 ng/mL. orine deficiency is not associated with thyroid hormone The primary control of prolactin is through inhibition metabolism. of secretion by dopamine from the hypothalamus. Ca- 14. (B). The symptoms of thyrotoxicosis are largely bergoline is a stable dopamine agonist that reduces pro- mediated through the adrenergic nervous system, and (3- lactin secretion. Clomiphene, an estrogen antagonist, is adrenoceptor blockers may ameliorate some of the man- used to stimulate LH and FSH release to enhance fertili- ifestations of the disorder. They have no effect on thy- ty but should not be used until it has been determined roid hormone levels or on prostaglandins. The effects are whether reducing prolactin levels alone is sufficient to directly antagonized by antagonists rather than agonists. cause fertility. Ganirelix and Estradiol are not useful in 15. (A). The clinical effects are not apparent until the treating infertility. preexisting intrathyroidal stores of thyroid hormone are 5. (C). Growth hormone secretion is episodic, and a depleted. This may take several weeks. This class of drugs single measurement without stimulation may give a false do inhibit the action of the enzyme TPO and thus inhib- impression of growth hormone levels that are too low it thyroid hormone synthesis. They do not inhibit secre- (<5 ng/mL). Growth hormone release occurs not only tion of preexisting stored thyroid hormone. immediately after sleep but also after eating and after ex- 16. (D). There is no evidence that affinity for D3 with ercise. A 20-kilodalton form of growth hormone is se- its receptor is altered during aging. Aging is associated creted with the normal 22-kilodalton form, but the former with Vitamin D deficiency for several reasons. It is im- is present in about one-fifth the amount. Both forms have portant for the elderly to receive Vitamin D supplemen- biological activity and are secreted basally and after stim- tation to prevent osteoporosis and the other problems ulation of growth hormone release. associated with hypocalcemia. If they have chronic liver 6. (E). Recovery from prolonged steroid therapy is or renal conditions, use of one of the specific metabo- slow, and the withdrawal may be unpleasant. The patient lites should be used, such as Calcitriol. may be reluctant to reduce the dose of steroid because of 17. (E). There is no good evidence that moderate its salutary effects on the psyche. Tapering the dose of amounts of alcohol contribute to osteoporosis. All of the steroid is important in steroid withdrawal; however, the other listed conditions can contribute to osteoporosis. patient may temporarily require a dose increase during Antiseizure medications interfere with activation of Vi- periods of heightened stress. tamin D; glucocorticoids stimulate bone resorption of cal- 7. (A). 17, 20 lyase is required for androgen synthe- cium; renal loss of calcium can result in secondary hy- sis, cyclooxygenase for prostaglandin production, 11-β- perparathyroidism; and organ transplantation is asso- hydroxysteroid dehydrogenase-2 acts as a reductase-con- ciated with osteoporosis because of the glucocorticoids verting cortisol to its inactive 11-keto derivative corti- and other immunosuppressive medications used. Indi- sone, whereas 18-hydroxylase is required for aldoster- viduals chronically taking these medications should take one production. a bisphosphonate for prophylaxis. In patients prone to 8. (A). Glucocorticoid treatment of rheumatoid ar- form kidney stones, a low dose of a thiazide diuretic will thritis does not eradicate all symptoms, nor does it re- often block the renal loss of calcium and prevent oste- verse the degenerative process. Suppression of the hy- oporosis and further stone formation. pothalamic-pituitary-adrenal axis is an unwanted side 18. (A). Metformin causes lactic acidosis in patients effect of glucocorticoid therapy. While development of a with renal failure and severe congestive heart failure. sense of well-being may be attributed to the relief of It does not increase the risk of ketoacidosis and has symptoms, it is not the primary basis for employing the shown a reduction in cardiovascular comorbidities in potent glucocorticoids. a large study. It is contraindicated in patients with se- 9. (B). The addition of a fluoride group to ring C of vere liver disease but does not cause hepatic necrosis. cortisol to give 9-α-fluorocortisol greatly increases and When used as monotherapy, Metformin rarely causes prolongs all biological activity. The result is an agent hypoglycemia. with potent glucocorticoid and mineralocorticoid activ- 19. (D). One of the most important therapeutic objec- ity, making it inappropriate to use in rheumatoid arthri- tives is to maintain normal glucose levels without pro- tis. Because of its potency and extended action, Fluoro- ducing frequent hypoglycemia. The main class of hy- cortisol will have a greater tendency to depress the hypoglycemic drugs that have a propensity to cause hypothalamic-pituitary axis than cortisol, even when ap- poglycemia are the sulfonylureas, of which glyburide is plied topically. one. This is not a problem with the other choices. 10. (D). Dexamethasone is a fluorinated glucocorticoid 20. (B). Estrogen therapy is contraindicated in the that is more potent and longer acting than Cortisol. While presence of breast cancer. Normal breast growth is stim- devoid of salt-retaining activity in therapeutic doses, this ulated by estrogens, and estrogen administration is there- glucocorticoid does possess most of the adverse effects fore contraindicated. Hormonal therapy is normally re- observed with Cortisol. Because it lacks mineralocorti- served for patients with advanced metastases. Surgery and coid activity, Dexamethasone is not used in replacement local irradiation are the preferred therapy for early breast therapy. cancer. Progestin treatment and Tamoxifen therapy are 11. (D). In addition to its ability to block steroid bi- both accepted forms of therapy. Both are more effective osynthesis, Ketoconazole is frequently used as an anti-fun- in treatment of cancers with high-affinity receptors for gal agent. Its action is readily reversible and is used prin- estrogen, progesterone, or both.

131 21. (B). RU 486 acts as a competitive progesterone an- mented vegetables, such as carrots. When a deficiency is tagonist and blocks progesterone binding at its receptors. diagnosed, it is appropriate to treat the patient with a It has no activity at estrogenic receptors. supplement rather than to rely on increased consump- 22. (A). In the Leydig cell the rate-limiting step in tes- tion of Vitamin A-rich foods. A patient with pancreatic tosterone synthesis is the enzymatic cleavage of side disease and malabsorption syndrome will need parenteral chains from cholesterol to form pregnenolone. supplementation. 23. (D). Skeletal muscle cells use the androgen recep- 26. (B). Pregnancy increases the need for vitamins and tor to bind testosterone that promotes the anabolic ef- iron in general. Folic acid has been shown to decrease the fect of this hormone. risk of neural tube defects, such as spina bifida. It is im- 24. (B). Finasteride is a 5a-reductase inhibitor, portant to assess the nutritional status of the patient to which essentially makes dihydrotestosterone unavaila- determine whether higher levels of Folic acid are needed. ble to the prostate but does not reduce serum testoster- Vitamin A is a teratogen and should not be given in high one levels. The decreased prostatic levels of dihydrotes- doses during pregnancy. tosterone frequently result in a size regression of the 27. (C). Early symptoms of Vitamin C deficiency, or prostate, while the relatively normal testosterone levels scurvy, include malaise. Hemorrhages, especially of the minimize a depressed libido. Flutamide and Spironolac- gums, may result from capillary fragility. tone exhibit antiandrogen effects by competing for the 28. (C). The only effective treatment of pernicious ane- androgen receptor; Ketoconazole inhibits testosterone mia is supplementation of Vitamin B12. It is important synthesis; and Stanozolol is an oral anabolic androgen to determine whether megaloblastic anemia is from a de- preparation. ficiency of folic acid or Vitamin B12. Treatment of Vita- 25. (B). Supplement with Vitamin A. Vitamin A defi- min B12-deficient anemia with Folic acid may result in neu- ciency symptoms include night blindness that can lead rological damage if Vitamin B12 is not adequately sup- to corneal ulceration. This deficiency can occur in pa- plemented. tients with impaired liver storage or fat malabsorption. 29. (E). Folic acid supplements should be given to all Dairy products, such as milk, are a good source of Vita- pregnant women. In addition, Phenytoin use is associat- min A. (β-Carotene, a vitamin A precursor, is found in pig- ed with lowered folate levels.

132 DRUGS INFLUENCING THE BLOOD SYSTEM

Lecture 30 agents in the intestinal lumen. Gastric resection decreases iron absorption by decreasing hydrochloric acid pro- DRUGS INFLUENCING THE duction. Iron is transported across the intestinal mucosal ERYTHROPOIESIS cell by active transport. The absorbed iron can combine with the protein apoferritin to yield ferritin and stored in mucosal cells which are exfoliated and excreted in Agents influencing the erythropoiesis are divided the feces or can be transported to the plasma where it is into drugs that stimulate the formation of erythrocytes bound to transferrin (globulin). Thus, iron is transport- (red blood cells) and drugs that inhibit erythropoiesis. ed to the developing erythroid cells in bone marrow. Drugs stimulating erythropoiesis are used for the treat- Iron can be stored in two forms: Ferritin and Hemo- ment of anemias. Anemia is a condition in which the siderin. Both Ferritin and Hemosiderin are stored in mac- number of red blood cells and the amount of hemo- rophages in the liver, spleen, and bone marrow. Most globin in the blood are less than normal. Nowadays of the iron liberated by destruction of hemoglobin is con- served and reused by the body. Excretion of iron occurs hypochromic and hyperchromic, hypo- and aplastic, hemolytic anemias are known. primarily as desquamation of cells of GI mucosa. Hypochromic anemia is characterized by a de- The only clinical indication for the use of iron preparations is the treatment or prevention of iron deficien- crease in the ratio of the weight of hemoglobin to the cy anemia. The treatment of iron deficiency anemia volume of the erythrocyte. It means that erythrocytes consists of administration of oral or parenteral iron contain less hemoglobin than they could have under preparations. Ferrous lactate, and Ferrous sulfate are optimal conditions. Mostly, hypochromic anemia is commercially available for oral administration. accompanied by iron deficiency state that’s why it sometimes is named as hypoferric anemia. 0 2+ 3+ Iron forms the nucleus of the heme, which when com- Fe , Fe , Fe bined with appropriate globin chains forms hemoglob- (from diet or drugs) in. Hemoglobin is a protein whose structure allows for  reversible binding of oxygen, providing the critical Fe3+ mechanism for oxygen transport from the lungs to oth- (gastrointestinal tract) er tissues. Ionic iron is a component of myoglobin and  enzymes necessary for energy transfer (e.g. cytochrome Fe2+ Ferritin oxidase, xanthine oxidase, and succinic dehydrogenase), ABSORPTION (gastrointestinal however the vast majority of iron is normally present in  mucosa) hemoglobin. In addition, iron is stored in the form of ferritin and hemosiderin (in the liver, spleen). Iron deficiency is commonly seen in children dur- Fe2+ (+transferrin) ing rapid growth periods, in menstruating women, and  (blood serum) in pregnant or lactating women. The most common cause of iron deficiency in adults, however, is blood Bone Supply Enzymes, loss. These situations are all associated with increased  marrow (liver, spleen, myoglobin bone marrow) iron requirements. STORAGE Iron is normally available in the diet from a wide Erythrocytes variety of foods but is especially abundant in meat pro- DISTRIBUTION tein (Fig. 25). Iron is absorbed only in ionic condition, especially in ferrous form (Fe2+). That’s why iron ab- EXCRETION sorption is increased in the presence of hydrochloric acid (via intestine, kidneys, sweat glands) (convert nonionic iron to ionic) and ascorbic acid (reduce ferric iron [Fe3+] to ferrous). Absorption is de- Fig. 25. Absorption, distribution, and excretion creased by the presence of chelators or complexing of iron 133 Also combine iron preparations such as Ferroplex® in the face of continued RNA and protein synthesis. (Ferrous sulfate plus Ascorbic acid), Ferramidum (com- This leads to production of large (macrocytic) eryth- plex compound of Iron with Nicotinamide) can be used. rocytes that have a high RNA:DNA ratio and are de- Oral iron preparations should be taken between meals fective in the sense that they are highly susceptible to for maximum absorption but may be taken with or af- destruction. Also, anemias caused by Vitamin B12 and ter meals, if necessary, to minimize adverse GI effects. Folic acid deficiency is called megaloblastic anemia. Adverse effects of oral iron therapy include teeth Vitamin B12 is a group of cobalt-containing sub- darkening, epigastric discomfort, dark stools, and con- stances (Сobalamins), having biologic activity in hu- stipation. These effects are usually dose-related and mans. Vitamin B12 is synthesized by microorganisms can often be overcome by lowering the daily dose of and it is present in many foods of animal origin, par- iron. It is postulated that iron interfere with hydrogen ticularly liver, kidney, fish, and meat; plants contain sulfide (H2S) that leads to the iron sulfide (FeS) pro- minimal amounts of the vitamin. Cyanocobalamin is duction. The last one can cause the teeth darkening. a Cobalamin that found in food. In humans, an exog- On the other hand, hydrogen sulfide is known as stim- enous source of Vitamin B12 is required for nucleopro- ulate of bowel motility, that’s why decreasing of free tein and myelin synthesis, cell reproduction, normal hydrogen sulfide volume associated with constipation. growth, and the maintenance of normal erythropoie- Parenteral therapy should be reserved for patients sis. Cells characterized by rapid division (e.g. epithe- that unable to tolerate or absorb oral iron and patients lial cells, bone marrow, and myeloid cells) appear to with extensive chronic blood loss. Parenteral iron have the greatest requirement for Vitamin B12. Coen- agents include Ferbitol, Fercoven, and Ferum-Lek. zyme B12 is essential for synthesis of Methionine. Vi- Ferbitol is injected intramuscularly, Fercoven is for tamin B12 also can be involved in maintaining sulfhy- intravenous injection, and Ferum-Lek can be used by dryl (SH) groups in the reduced form required by many both routes. Chest tightness, shock, hypotension, tach- SH-activated enzyme systems. Through these reac- ycardia, flushing, and arrhythmias have occurred in tions, Vitamin B12 is associated with fat and carbohy- patients receiving parenteral iron preparations. drate metabolism and protein synthesis. Vitamin B12 Large amounts of oral iron cause necrotizing gas- deficiency results in megaloblastic (pernicious) anemia troenteritis, with vomiting, abdominal pain, and of Addison-Biermer, GI lesions (glossitis) and neuro- bloody diarrhea followed by shock and dyspnea. Ur- logical damage (paresthesia, disorder of gait) that be- gent treatment of overdosing includes stomach lavage gins with an inability to produce myelin. with sodium bicarbonate solutions to form insoluble Vitamin B12 is absorbed from the small intestine fol- iron salts. Deferoxamine (iron chelating compound) lowing oral administration. In the stomach, free Vita- should be given by injection to bind iron. Appropriate min B12 (extrinsic Castle’s factor) is attached to intrin- supportive therapy for shock and dyspnea (heart gly- sic factor (IF or intrinsic Castle’s factor); IF, a glyco- cosides, hypertensive agents, and analeptics) must also protein secreted by the gastric mucosa, is necessary for be provided. active absorption of the vitamin from the GI tract. Ab- Some agents of cobalt are indicated for the treat- sorption of Cyanocobalamin following oral adminis- ment of the hypochromic anemia. One of them is Coa- tration is decreased by structural or functional dam- mide. It is a complex compound of cobalt with nicoti- age to the stomach or ileum. In the intestinal mucosal namide. Coamide stimulates erythropoiesis and pro- cell, Vitamin B12 is released from the Vitamin B12-If motes assimilating of iron. It is administered subcuta- complex and becomes rapidly bound to plasma pro- neously. In addition, copper-containing agent “He- teins. Vitamin B12 is distributed into the liver, bone mostimulin” (Copper sulfate, Ferrous sulfate, and dry marrow, and other tissues. dietary blood) is indicated for the treatment of hy- Cyanocobalamin is usually considered the Vitamin pochromic anemia as well as Nicotinic acid. B12 preparation of choice. It is used in the treatment Erythropoietin is a glucoprotein that stimulates of pernicious anemia and in patients with malabsorp- erythroid proliferation and differentiation. It is pro- tion of Vitamin B12, such as those with partial or total duced by the kidney in response to tissue hypoxia. gastrectomy, regional enteritis, and ileal resection. When anemia occurs, more erythropoietin is produced The drug has been used for the management of hepati- by the kidney. Recombinant human erythropoietin tis, neuralgia and neuropathies, and multiple sclero- (Epoetin alpha) is produced in a mammalian cell ex- sis. Vitamin B12 is usually nontoxic even in large dos- pression system using recombinant DNA technology. es; however, mild diarrhea, peripheral thrombosis, and Erythropoietin is indicated in the treatment of anemia itching have been reported. associated with renal failure, chronic inflammation, Folic acid (Vitamin Bc, Pteroylglutamic acid) is a AIDS, and cancer. compound composed of a pteridine heterocycle, p-Ami- Hyperchromic anemia is characterized by an in- nobenzoic acid, and Glutamic acid. It is present in a crease in the ratio of the weight of hemoglobin to the wide variety of foods, particularly liver, kidneys, yeast, volume of the erythrocyte. It means that the erythro- and leafy, green vegetables. Also it has been synthe- cytes contain more hemoglobin than normal. Usually sized in bowel by microflora. In man, an exogenous hyperchromic anemia is associated with Vitamin B12 source of Folate is required for nucleoprotein synthe- and/or folic acid deficiency. It leads to impaired DNA sis and the maintenance of normal erythropoiesis. Fol- synthesis, inhibition of normal mitosis, and abnormal ic acid is the precursor of active Tetrahydrofolic acid, maturation of the cells. These changes are most appar- which is involved in the biosynthesis of purines and ent in tissues where cells undergo rapid cell division, thymidylates of nucleic acids. The Folate cofactors are such as the bone marrow and the gastrointestinal epi- inter-convertible by various enzymatic reactions and thelium. It is characterized by diminished cell division serve the important biochemical function of donating

134 one-carbon units at various levels of oxidation. Impair- nary output, of blood pressure (hemodynamic action). ment of Thymidylate synthesis in patients with Folic Polyglucinum possesses more strong hemodynamic ef- acid deficiency is thought to account for the defective fect than Reopolyglucin. However, Reopolyglucinum DNA synthesis that leads to megaloblast formation improves microcirculation by diminished erythrocyte and megaloblastic and macrocytic anemias. aggregation and blood viscosity. About 70% of a dose Folic acid is absorbed rapidly from the small in- of Reopolyglucin are excreted unchanged in urine testine following oral administration. Tetrahydrofol- within 24 hours after administration. Polyglucinum is ic acid and its derivatives are distributed into all body not excreted by the kidneys but is slowly degraded to tissues; the liver contains about one-half of total body glucose. folate stores. Folic acid is largely metabolized in the Dextrans, especially Polyglucinum, are used for liver and is excreted by kidneys. fluid replacement and for plasma volume expansion in Folic acid is used for the treatment of megaloblas- the treatment of shock resulting from burns, surgery, tic and macrocytic anemias, resulting from Folate de- hemorrhage, or other trauma in which a circulating ficiency, megaloblastic anemias of pregnancy and in- volume deficit is present. Reopolyglucin is also used fancy, tropical sprue, megaloblastic anemia associat- for prophylaxis and treatment of thromboembolic com- ed with liver disease and alcoholism. It is used orally. plication, during extracorporeal circulation. Folic acid is relatively nontoxic. Allergic reactions to Adverse effects of dextrans include allergic reac- it have been reported rarely. tions such as urticaria, hypotension, and sometimes Drugs that inhibit erythropoiesis are used for the anaphylactoid reactions. Care must be taken in admin- treatment of polycythemia (erythremia). Bone marrow istering dextrans to patients with impaired renal func- hyperplasia and an increase of erythrocytes in blood tion, pulmonary edema, or congestive heart failure. characterize this disease. Radioactive phosphorus-32 Human’s albumin is a solution of serum albumin isotope (32P), which is a β-emitter, is used for poly- prepared from blood obtained from healthy human do- cythemia treatment. Also, it causes leukopenia and nors. Serum albumin is an important factor in the reg- thrombocytopenia. ulation of plasma volume through its contribution to the oncotic pressure of plasma. Intravenous administration of albumin human causes a shift of fluid from the interstitial spaces into the circulation, reducing he- moconcentration and blood viscosity, and raising of Lecture 31 blood pressure. Albumin contains amino acids and pro- BLOOD SUBSTITUTES vides modest nutritive effect. Albumin functions as a carrier of intermediate metabolites (bilirubin), trace metals, and some drugs, thus affecting their transport, DRUGS FOR PARENTERAL and inactivation. Human’s albumin solutions are used NUTRITIONAL THERAPY in the treatment of shock resulting from burns, surgery, and hemorrhage; of hypoproteinemia (hepatic cirrho- This group includes Hydrolysine, Aminocrovinum, sis, postoperative patients); of cerebral edema. Adverse and Polyamine. These drugs contain amino acids and reactions, which may be caused by allergy or protein are indicated for nutrition during therapy of cachex- overload, include chills, fever, vomiting. ia, unconscious state, starvation, pre- and postopera- Gelatinolum is an agent of split food gelatin. It is tive state. They should be used only when the gut can- used as a hemostat, plasma substitute, and protein food not be used (operation at gullet or stomach). Hydro- adjunct in malnutrition. lysin is obtained by hydrolysis of serum proteins of cat- Polyvinylpyrrolidone (Povidone) derivative solu- tle; Aminocrovinum is the hydrolysate of human blood tions are Neohaemodesum and Enterodesum. Polyvi- proteins; and Polyamine is the complex of 13 amino nylpyrrolidone is a synthetic polymer. All above-men- acids. Lipofundinum (Intralipid) is fat emulsion that tioned derivatives has low molecular weight (8,000 and produced from safflower oil. It contains emulsified fat 12,000). Also, these agents contain ions of sodium, po- particles, similar to naturally occurring chylomicrons. tassium, calcium, magnesium, and chlorine. Polyvi- Intravenous fat emulsion provides the patient requir- nylpyrrolidone binds with toxins in blood and elimi- ing parenteral nutrition with a source of calories and nate them quickly from organism. In addition, these the essential fatty acids (polyunsaturated). preparations improve the blood circulation in kidneys, enhance the diuresis, and can act as a plasma extend- er. Neohaemodesum is injected intravenously for dein- PLASMA SUBSTITUTES AND toxication that caused by gastrointestinal diseases (e.g. DEINTOXICATION SOLUTION the dysentery and salmonellosis), acute liver and kidney insufficiency, burns, etc. Quick infusion of Neo- Dextran 60 (Polyglucinum) and Dextran 40 (Re- haemodesum can diminish the blood pressure. Enter- opolyglucinum) are a glucose polymers (dextrans) with odesum has the same indications as Neohaemodesum average molecular weights of approximately 60,000 but it used orally. and 40,000 correspondently. The principal effect of Glucose (Dextrose) is a monosaccharide. It in- dextrans following intravenous administration is plas- creases blood glucose concentrations, provides calo- ma volume expansion, resulting from the drugs colloi- ries, induces diuresis depending on the volume admin- dal osmotic effect in drawing fluid from the intersti- istered. 5% Glucose solution is isotonic solution and tial to the intravascular spaces. Plasma volume expan- 40% Glucose solution is hypertonic. Glucose injections sion is accompanied by an increase of cardiac and uri- are used for the treatment of hypoglycemia, and as

135 source of calories and water for hydration/deintoxica- diseases (psoriasis, itching), hepatitis. For oral and in- tion during infection diseases, liver disorders, heart intravenous administration, the Gluconate, Lactate, and sufficient, shock, and collapse. Hypertonic glucose in- Chloride salts of calcium are available. jections are used to provide adequate calories in a min- Calcium salts, especially chloride, by any route of imal volume of water. Hyperglycemia may occur as a administration can produce irritation. They may cause result of the rate of administration or metabolic insuf- local necrosis if they will be injected subcutaneous. ficiency. Rapid injection may cause vasodilation, decreased blood pressure, and arrhythmias. Potassium is the major cation of intracellular flu- SALT SOLUTIONS id and is essential for maintenance of isotonicity and Solution of Sodium chloride provides electrolyte electrodynamic characteristics of the cell. Potassium supplementation. Sodium is the major cation of extra- is essential to transmission of nerve impulses, contrac- cellular fluid and functions principally in the control tion of muscles, gastric secretion, and renal function. of water distribution, fluid and electrolyte balance, and Potassium supplements are used for treatment of osmotic pressure of body fluids. Sodium is also asso- arrhythmias, potassium depletion. Conditions, which ciated with chloride and bicarbonate in the regulation may result in potassium deficiency, include vomiting, of acid-base balance. Chloride, the major extracellu- diarrhea, and administration of certain drugs includ- lar anion, closely follows the physiologic disposition ing diuretics, corticosteroids, and cardiac glycosides. of sodium. 0.9% solution of Sodium chloride is an iso- In addition, potassium chloride is a component of sev- tonic solution because it has approximately the same eral multiple electrolyte intravenous infusion fluids. osmotic pressure as body fluids. 3% and 5% Sodium For oral and intravenous administration, “Panan- chloride are the hypertonic solutions. Isotonic Sodi- gin” (Potassium asparaginate) and Potassium chlo- um chloride is used for extracellular fluid replacement ride are available. Hyperkalemia is the most common during shock or collapse; irrigation of wounds, eyes, hazard of potassium therapy. It is accompanied by noise, and mucosa; deintoxication during poisoning; paresthesia, arrhythmias, and vomiting. and dilution of drugs before their using. Hypertonic Sodium chloride is used in the management of puru- ACIDIFYING AND ALKALINIZING lent wounds (it promotes outflow of pus); uterine and AGENTS gastrointestinal bleeding; as weak antimicrobial agent. Excessive administration of Sodium chloride Ammonium chloride is an acid-forming salt that re- may result in hypernatremia and lose of bicarbonate sult from dissociation of the salt to an ammonium cat- with an acidifying effect. ion and a chloride anion. The chloride anion combines Ringer’s solution includes Sodium chloride, Sodi- with fixed bases in the extracellular fluid, thereby re- um bicarbonate, Potassium chloride, Calcium chloride ducing the alkaline reserve of the body and acidosis and water for injection. It has even more “physiolog- results. It increases sodium and water excretion that ic” content than 0,9% solution of Sodium chloride. leads to diuretic effect. Ringer’s solution has the same indication as Sodium Ammonium chloride is used orally. Also it increas- chloride. Such solutions as Quartasol®, Trisol®, es bronchial secretion and facilitates its expulsion. Acesol®, etc. contain sodium chloride and potassium Ammonium chloride is used for the treatment of meta- chloride; Quartasol® and Trisol® include sodium bi- bolic alkalosis, edematous conditions, and bronchitis. carbonate. These solutions decrease hypovolemia and It may cause metabolic acidosis and irritation of gas- blood viscosity, hinder the development of acidosis, tric mucosa. promote microcirculation, increase diuresis, and cause Hydrochloric acid (HCl) is the acid of gastric juice. deintoxication. Thus, they are used for the treatment It possesses strong irritant potency. It is used internal- of intoxication and hypohydremia during different dis- ly as diluted Hydrochloric acid for hypo- or achlorhy- eases (e.g. cholera, dysentery). dria. Sodium bicarbonate is an alkalinizing agent, which dissociates to provide bicarbonate ion. Sodium PREPARATIONS OF CALCIUM AND bicarbonate is used in the treatment of metabolic aci- POTASSIUM dosis, certain intoxications (e.g. Phenobarbital, and Salicylates), for increasing of the solubility of certain Calcium is essential to transmission of nerve im- weak acids (e.g. Sulfanilamides, Uric acid), for bet- pulses, contraction of muscles, bone formation, and tering of expulsion of the bronchial secretion during blood coagulation. Calcium also plays regulatory roles bronchial asthma. For the use of Sodium bicarbonate in the release of hormones, in the maintenance of the as an antacid, see “Antacids”. capillary permeability. Calcium deficiency is characterized by reduced bone mass (osteoporosis) and tetany Available forms: (twitches, cramps). Calcium is absorbed from the GI Cyanocobalamin — in ampoules 0.003%; 0.01%; tract. Vitamin D and parathyroid hormone increase the 0.02% or 0.05% solution 1 ml each capability of the absorptive mechanisms. More than 99% Folic acid — powder; in tablets 0.001 each of total body calcium is found in bone and teeth. Ferri lactate — in capsules 1.0 each Calcium salts are used for the treatment or preven- Haemostimulinum — in patented tablets tion of calcium depletion. Also, calcium therapy is used Ferrum-Lek — in ampoules solution 2 ml (for infor the treatment of heart arrest, allergic reactions, tramuscular injection) or 5 ml (for intravenous injec- bleeding, hyperpermeability of vessels (vasculitis), skin tion) each

136 Coamidum — in ampoules 1% solution 1 ml each trauma or surgery without impaired blood flow. Fibri- Aminocrovinum — in bottles 250 or 500 ml each nolysis regulates and delimits hemostasis. Polyglucinum — in bottles 100; 200 or 400 ml Bleeding and thrombosis are altered states of he- Reopolyglucinum — in bottles 100; 200 or 400 ml mostasis. Impaired hemostasis results in spontaneous Neohaemodesum — in bottles 100; 200 or 400 ml bleeding; stimulated hemostasis results in thrombus Sodium chloride — powder; in tablets 0.9 each; in formation. The drugs used to arrest bleeding and to ampoules 0.9% solution 5; 10 or 20 ml each; in bot- inhibit thrombosis are the subjects of this lecture. tles 0.9% solution 400 ml each Drugs that used for the prevention or treatment of Quartasol — in bottles solution 100; 200 or 400 thrombosis are the next: ml each 1. Anticoagulant drugs: Sodium hydrocarbonate — powder; in ampoules 4% a) anticoagulants of direct action (Heparin, Enox- solution 20 ml each; in suppository that contain 0.3; aparin, Sodium citrate, Hirudin); 0.5 or 0.7 of Sodium hydrocarbonate each b) anticoagulants of indirect action or oral antico- Glucose — powder; in tablets 0.5 or 1.0 each; in agulants (Neodicumarin, Syncumar, Phenylin). ampoules 5%; 10%; 25% or 40% solution 10; 20; 25 2. Antiaggregate drugs (Acetylsalicylic acid, or 50 ml each; in bottles 5%; 10%; 20% or 40% solu- Ticlopidine, and Dipyridamole). tion 200 or 400 ml each 3. Fibrinolytic drugs (Streptokinase, Strepto- Calci gluconate — powder; in tablets 0.5 each; in decase, Urokinase, and Alteplase). ampoules 10% solution 10 ml each Effects of agents that influence coagulation and fi- Potassium chloride — powder; in ampoules 4% so- brinolysis are illustrated in Fig. 26. lution 20 ml each Heparin is an anionic, sulfated glycosaminogly- can present in mast cells. Its average molecular weight is about 12,000. Heparin is strongly acidic and reacts with certain basic compounds resulting in a loss of pharmacologic activity. Commercial Lecture 32 Heparin is prepared from either porcine intestinal DRUGS USED IN DISORDERS OF mucosa or bovine lung tissue. Heparin potency is ex- COAGULATION pressed in IU. Actions. Heparin acts as a catalyst to markedly accelerate the rate at which Antithrombin III (heparin Hemostasis is the spontaneous arrest of bleeding cofactor) neutralizes Thrombin and activated coagu- from a damaged blood vessel. The immediate hemo- lation factor IX, X, XI, XII. In low doses Heparin pre- static response of a damaged vessel is vasospasm. With- vents the conversion of Prothrombin to thrombin and in seconds, platelets stick to the exposed collagen of in higher doses it inhibits the conversion of fibrinogen the damaged endothelium (platelet adhesion) and to to fibrin. Patients with familial antithrombin III defi- each other (platelet aggregation). This localized sta- ciency may appear to be resistant to the effects of sis triggers blood coagulation that is characterized by Heparin, since adequate levels of Antithrombin III are the transformation of soluble fibrinogen into insoluble necessary for the drug’s anticoagulant effect. fibrin. Blood coagulation and thrombus formation Heparin therapy produces prolongation of the ac- must be confined to the smallest possible area to tivated coagulation time, whole blood clotting time, achieve local hemostasis in response to bleeding from etc. Heparin clears lipemic plasma by stimulating of

Prothrombin Sodium citrate Ca2+ Aminocaproic acid activators

Streptokinase Heparin Alteplase

Synthesis of Prothrombin Thrombin Fibrinolysin Profibrinolysin prothrombin in blood in liver

Neodicumarin, Contrykal, Syncumar, Phenylin Aprotinin

Products of Fibrinogen Fibrin proteolysis — inhibiting action — stimulating action

Fig. 26. Direction of effects of agents that influence coagulation and fibrinolysis

137 lipoprotein lipase, which hydrolyze triglycerides to ORAL ANTICOAGULANTS free fatty acids and glycerol. Heparin in high doses has been reported to decrease on platelet aggrega- Coumarin anticoagulants tion. Coumarin anticoagulants (Neodicumarin, Syncu- Heparin is not absorbed from the GI tract and must mar) are the derivatives of 4-oxycoumarin. Indandi- be administered parenterally. The onset of anticoagu- one anticoagulant (Phenylin) is a derivative of indan- lant activity is immediate following direct intravenous dione. Coumarin and indandione derivatives are indi- injection and occurs within 30–60 minutes following rect-acting anticoagulants. subcutaneous. The duration of action is about 2–6 Actions. Coumarin and Indandione derivatives al- hours. The drug is metabolized in vessels endothelium ter the synthesis of blood coagulation factors II (Pro- and in the liver. thrombin), VII (proconvertin), IX (Christmas factor), Indications. Heparin is used for prophylaxis and and X (Stuart-Prower factor) in the liver by interfer- treatment of venous thrombosis, pulmonary embolism, ing with the action of Vitamin K, which is necessary chronic consumptive coagulopathies (disseminated infor the gamma-carboxylation of several glutamic acid travascular coagulation). Fixed low-dose subcutane- residues in the precursor proteins of these coagulation ous Heparin therapy is used for prevention of postop- factors. In adequate dosage, Phytonadione (Vitamin erative deep-vein thrombosis and pulmonary embolism K1) reverses the effect of coumarin and indandione dein patients undergoing major abdominal or thoracic rivatives on the hepatic synthesis of Vitamin K-depend- surgery who are at a risk of thromboembolic disease. ent coagulation factors. In contrast to Heparin, cou- Heparin is the anticoagulant of choice when an im- marin and indandione derivatives have no anticoagu- mediate effect is required. An oral anticoagulant (usu- lant effect in vitro. ally a Coumarin derivative) is generally used for fol- Because Coumarin and Indandione derivatives do low-up anticoagulant therapy after the Heparin ther- not alter catabolism of blood coagulation factors, de- apy has been established and when long-term antico- pletion of circulating functional Vitamin K-depend- agulant therapy is indicated. In first case therapy with ent coagulation factors must occur before effects of the two drugs should be overlapped for a short period the drugs become apparent. An anticoagulant effect of time. generally occurs within 24 hours following adminis- Adverse effects. Hemorrhage, the major adverse ef- tration of Neodicumarin, but peak anticoagulant and fect of heparin therapy, is an extension of the phar- antithrombogenic effects may be delayed for 72–96 macologic action of the drug and may range from mi- hours. Similarly, there is a period of latency follow- nor local ecchymosis to major hemorrhagic complica- ing discontinuance of the drugs until blood concen- tions. Nosebleed, hematuria, or tarry stools may be trations of functional Vitamin K-dependent coagula- noted as the first sign of bleeding or overdosage; easy tion factors return to pretreatment levels. Coumarin- bruising or petechiae may precede frank bleeding. or indandione-derivative therapy inhibits thrombus That’s why the coagulation time and whole blood clot- formation and may prevent extension of existing ting time should be determined during Heparin thera- thrombi. The drugs have no direct effect on estab- py in all patients. Discontinuance of Heparin will usu- lished thrombi. ally correct minor bleeding or overdosage within a few Neodicumarin, Syncumar, and Phenylin are well hours. If severe hemorrhage or overdosage occurs, pro- absorbed from the GI tract. Coumarin and Indandi- tamine sulfate should be administered immediately. In one derivatives are usually detectable in plasma with- adequate dosage, protamine sulfate neutralizes the an- in 1 hour following oral administration, and peak plas- ticoagulant effect of Heparin. Deep subcutaneous in- ma concentrations of the drugs are usually attained jection of Heparin may rarely cause local irritation, within 1–12 hours. They are 97% or more bound to hematoma, or cutaneous necrosis. plasma proteins, primarily albumin. Coumarin and In- Enoxaparin is a depolymerized Heparin. The av- dandione derivatives are hydroxylated by hepatic mi- erage molecular weight of Enoxaparin is approxi- crosomal enzymes to inactive metabolites. In general, mately one-third that of regular Heparin; therefore, Coumarin and Indandione derivatives are excreted in Enoxaparin is referred to as a low molecular weight bile as inactive metabolites, then they are reabsorbed, Heparin. Enoxaparin has less effect on Thrombin and excreted in urine. than does unfractionated Heparin. However, Enoxa- Indications. The most widely accepted indications parin has more antiaggregating properties. Compared for anticoagulant therapy include the treatment of ve- with unfractionated Heparin, Enoxaparin has great- nous thrombosis and pulmonary embolism and preven- er bioavailability after subcutaneous administration tion of these conditions in high-risk patients. A cou- and a longer half-life, allowing less frequent admin- marin derivative is generally used for follow-up anti- istration (1–2 times per day). Enoxaparin is used for coagulant therapy after the effects of full-dose heparin the prevention of postoperative deep-vein thrombosis. therapy have been established and when long-term an- The usual precautions and contraindications associ- ticoagulant therapy is indicated. ated with heparin anticoagulation therapy should be The efficiency of indirect-acting anticoagulants is followed in patients for whom Enoxaparin therapy is measured by prothrombin ration: it must be not less considered. than 40–50% (normal is 80–100%). Sodium citrate binds calcium ions in blood that pre- Adverse effects. Hemorrhage is the most common vents blood clotting. It is used as stabilizer of blood adverse effect of indirect-acting anticoagulants. If during its conserving. Hirudin is a powerful and spe- moderate or severe hemorrhage occurs or if the pro- cific Thrombin inhibitor from the leech, which is now thrombin time is excessively prolonged, the drug being prepared by recombinant DNA technology. should be discontinued immediately and Phytonadi-

138 one administered. Coumarin and Indandione deriva- Adverse effects. The most frequent and severe ad- tives should be used with caution in any condition verse effects of Streptokinase therapy are hemor- where added risk of hemorrhage is present. Concur- rhage, fever, and allergy. Severe spontaneous bleed- rent administration of numerous drugs has been re- ing has occurred during Streptokinase therapy. If se- ported to affect patient response to indirect-acting an- rious spontaneous bleeding occurs, Streptokinase ticoagulants. Nonsteroidal anti-inflammatory agents therapy should be terminated immediately. Plasma (Aspirin, Butadion (Phenylbutazone)) can inhibit volume expanders and aminocaproic acid may be platelet aggregation and displace of albumin-bound used. Streptokinase is strongly antigenic; repeated ad- indirect-acting anticoagulants, increasing their free ministration elicits antibodies that diminish the effect fraction. These changes can cause GI bleeding and of the drug and may cause allergic reactions, includ- peptic ulceration. Barbiturates and Rifampin cause ing anaphylaxis. a marked decrease of the anticoagulant effect by in- Streptodecase — is an agent of Streptokinase that duction of the hepatic enzymes that transform Neod- binds with polysaccharide water-soluble molecule. It icumarin. Cumarin derivatives potentiate the action ensures prolong releasing of Streptokinase. One infu- of the hypoglycemic agents and Diphenin (Pheny- sion of Streptodecase provides fibrinolytic effect dur- toin), because Coumarins inhibit hepatic metabolism ing subsequent 3 days. of these drugs. Urokinase is an enzyme produced by the kidneys and excreted in urine. Commercially available Uroki- nase is isolated from human kidney tissue cultures. The FIBRINOLYTIC AGENTS activity of Urokinase is expressed in IU. Urokinase has the same mechanism action as Streptokinase. The Fibrinolytic drugs rapidly lyse thrombi by catalyz- fibrinolytic effect of Urokinase usually disappears ing the formation of the serine protease Plasmin (Fi- within a few hours but increased thrombin time, de- brinolysin) from its precursor Zymogen, Plasminogen creased plasma levels of fibrinogen and plasminogen (Profibrinolysin). These drugs create a generalized may persist for up to 12–24 hours following discontin- lytic state when administered intravenously. Thus, uance of the infusion. both protective hemostatic thrombi and target throm- Agent reportedly is not absorbed from the GI tract. boemboli are broken down. Following intravenous infusion, the drug is rapidly Actions. Streptokinase is a nonenzymatic protein β cleared from the circulation. Urokinase is estimated produced by group C -hemolytic streptococci. The to have a plasma half-life of 10–20 minutes. Urokinase activity of streptokinase is expressed in IU. Streptoki- has the similar indications with Streptokinase. The nase promotes thrombolysis. Streptokinase converts most frequent and severe adverse effect of Urokinase plasminogen into the proteolytic enzyme plasmin. therapy is hemorrhage. In contrast to Streptokinase, Plasmin degrades fibrin, fibrinogen, and other plasma Urokinase is reportedly nonantigenic. procoagulant proteins. Plasmin is inactivated by cir- α Alteplase, a biosynthetic (recombinant DNA ori- culating inhibitors, including 2-antiplasmin. Plasmin gin) form of the enzyme human tissue-type plasmino- generated in the circulation is bound to antiplasmin gen activator (T-PA), is a thrombolytic agent. Endog- and is released at the thrombus site resulting in exter- enous human t-PA is a serine protease secreted princi- nal lysis. The effects of Streptokinase on coagulation pally by vascular endothelial cells. It may be activat- usually disappear within a few hours but may persist ed by several endogenous proteases, including Plas- for up to 12 hours after discontinuance of intravenous min, tissue Kallikrein, and Trypsin. infusion. Laboratory control during fibrinolytic ther- Alteplase is a thrombolytic agent. T-PA as well apy includes assure of thrombin time and fibrinogen as Streptokinase and Urokinase promote conversion amount. During the first few hours of streptokinase ther- of Plasminogen into form of Plasmin. During physi- apy, the drug may rapidly activate plasminogen and ologic fibrinolysis, the activity of circulating Plas- cause hyperplasminemia that may lead to coagulation min is inhibited rapidly (half-life approximately 100 defects. α msec) by 2-antiplasmin. The fibrinolytic activity of Streptokinase has been shown to decrease the vis- Plasmin is maintained within the thrombus because cosity of blood and plasma, and to decrease the eryth- the active sites of Plasminogen (and thus plasmin) at rocyte and platelet aggregation tendency, thus increas- α which fibrin binds are the same sites at which 2-an- ing blood flow and perfusion of collateral blood vessels. tiplasmin binds. Fibrin-bound plasmin within the Following intravenous infusion, Streptokinase is thrombus, therefore, is relatively protected from in- rapidly cleared from the circulation. The serum half- activation. Thrombolytic agents such as Streptoki- life is about 80 minutes. nase and Urokinase activate both fibrin-bound and Indications. Streptokinase is used as a thrombolyt- circulating Plasminogen indiscriminately; systemic ic agent in selected cases of myocardial infarction, pul- activation of Plasminogen results in the release of monary embolism, acute vein or arterial thrombosis. large amounts of Plasmin into the circulation that The drug is generally most effective in lysing recently leads to degradation of plasma procoagulant pro- formed thrombi. For example, Streptokinase therapy teins. Predominantly, Alteplase activates fibrin- should be initiated as soon as possible after myocar- bound plasminogen. dial infarction, preferably within 3–6 hours, since po- Alteplase is not absorbed after oral administration tential clinical benefit diminishes as the time period to and must be administered parenterally. It has the re- initiation of therapy increases. Streptokinase therapy semble uses to Streptokinase. The most frequent and should be initiated no later than 3 days, after the on- severe adverse effect of Alteplase therapy is hemor- set of the thromboembolic episode. rhage.

139 ANTIAGGREGATE AGENTS — Antagonists of anticoagulant drugs (Protamine sulfate, Vitamin K) Platelet function is regulated by two categories of — Inhibitors of fibrinolysis (Aminocaproic acid, substances. The first group consists of agents that in- Contrykal, Aprotinin, etc) duce the platelet aggregation, e.g. Thromboxane A2, — Coagulating substances of plant nature (leaf of Collagen, Thrombin, ADP, Calcium ions, Prostag- Nettle, Water pepper, etc.) landin E2, Serotonin, and Catecholamines. The second category contains agents that inhibit platelet ag- Thrombin is a hemostatic agent. It is commercial- gregation, e.g. Prostacyclin I2, AMP, Adenosine, ly available as a powder containing the protein sub- Methylxanthines, and Heparin. The prostaglandin stance prepared from prothrombin of human serum. Thromboxane A2 is an arachidonate product that Thrombin affects hemostasis principally by converting causes platelets to aggregate. It is synthesized in Fibrinogen to Fibrin. Agent is used topically as an aid platelets. Prostacyclin I2 is an arachidonate product in hemostasis when oozing blood and minor bleeding also, but it inhibits aggregation and adhesion of from capillaries and small venules is accessible. platelets. Prostacyclin I2 is formed in endothelium of Thrombin solutions may be used in conjunction with vessels wall. absorbable gelatin sponge for hemostasis. Gelatin in- Acetylsalicylic acid (Aspirin) inhibits the synthe- creases blood thickness. sis both of Thromboxane A2 and Prostacyclin I2 by in- Fibrinogen is prepared from normal human Plas- activation of the enzyme cyclooxygenase. However, ma. It is a coagulant (clotting factor II) and used as inhibition of cyclooxygenase in platelets is irreversi- an adjunct in the management of acute, congenital, ble, because the anuclear platelet cannot synthesize or acquired chronic hypofibrinogenemia. It is inject- new proteins, it cannot manufacture new enzyme dur- ed intravenously. Cryoprecipitate is a plasma pro- ing its 10-day lifetime. That’s why diminish of Throm- tein fraction and is obtainable from whole blood. It boxane A2 is more evident. Other salicylates and oth- is used to treat deficiencies of factor VIII in patients er nonsteroidal anti-inflammatory drugs also inhibit with hemophilia A and occasionally to provide Fi- Cyclooxygenase but have a shorter duration of inhibi- brinogen. tory action because their action is reversible. Daily Calcium ions stimulate forming of Thromboplastin, dose 325 mg of aspirin is approved for prophylaxis of transforming of Prothrombin to Thrombin and polym- myocardial infarction. The risk-versus-benefit measure erization of Fibrin. Calcium drugs are administered of Aspirin as a prophylactic drug is questionable for during hypocalcemia (transfusion of citrate blood), patients with peptic ulcer disease. during increased permeability of capillaries (hemor- Ticlopidine reduces platelet aggregation by inhib- rhagic vasculitis), before operations. iting the ADP pathway of platelets. Unlike Aspirin, the Protamine is a cationic protein that occurs in the drug has no effect on prostaglandin metabolism. It is sperm of certain species of fish. Commercially availa- used in the prevention of vascular events among pable Protamine sulfate is prepared from the sperm of tients with transient ischemic attacks, completed salmon. Protamine sulfate, which is strongly basic, strokes, and unstable angina pectoris. Adverse effects acts as a Heparin antagonist in vitro and in vivo by include nausea, diarrhea, hemorrhage, and, most se- complexing with strongly acidic Heparin to form a sta- riously, leukopenia. It is particularly useful in patients ble nonactive salt. Protamine sulfate is used in the who cannot tolerate aspirin. treatment of severe Heparin calcium or Heparin sodi- Dipyridamole (Curantyl) increases endogenous um overdosage. Hypersensitivity reactions including concentrations of adenosine and cyclic adenosine urticaria, angioedema, and anaphylactoid reactions monophosphate (cAMP) by inhibiting their destruc- have occurred occasionally after administration of Pro- tion. It is postulated that adenosine and cAMP are the tamine sulfate. platelet aggregation inhibitors. Also adenosine is a Vitamin K (antihemorrhagic vitamin) is a fat-solu- coronary vasodilator. Dipyridamole is indicated to ble substance. Two natural forms exist: Vitamins K1 prevent thromboembolic complications, in the treat- and K2. Vitamin K1 (Phylloquinone) is found prima- ment of occlusive vascular diseases as well as to reduce rily in leafy green vegetables. Vitamin K2 (Menaqui- the recurrence of transient ischemic attacks and risk none) is found in animal liver, and is synthesized by of reinfarction. intestinal bacteria in human organism. Vitamin K is Dipyridamole may preferentially dilate, and in- required for the synthesis of blood coagulation factors crease blood flow through, nondiseased coronary II (Prothrombin), VII (Proconvertin), IX (Christmas blood vessels, leading to a redistribution of blood factor), and X (Stuart-Prower factor) in the liver. In flow away from significantly stenotic coronary ves- adequate doses, Vitamin K reverses the inhibitory ef- sels. This “coronary steal” effect may lead to angina fect of Coumarin and Indandione derivatives on the pectoris. Dipyridamole dilates the blood vessels and synthesis of these factors. Vitamin K deficiency, which its using can be accompanied by hypotension, tachy- occurs in the presence of malabsorption syndromes cardia, and flushing. (colitis, enteritis, and jaundice), is associated with low blood level of Prothrombin and other coagulation fac- Drugs used in bleeding disorders are divided into: tors that is exhibited by bleeding. — Coagulant drugs: Phytomenadione (Phytonadione) is identical to a) drugs for topical using (Thrombin, Gelatin naturally occurring Vitamin K1. Like other lipid-sol- sponge); uble vitamins, Vitamin K1 is absorbed from the GI b) drugs for general using (Fibrinogen, Cryopre- tract only in the presence of bile salts. Vicasol (Me- cipitate). nadione) is the water-soluble salt of Vitamin K3. Vi-

140 casol is available both for oral using and for injec- Lecture 33 tion. Vitamin K is used in the treatment of bleeding that associated with hypoprothrombinemia, hemor- IMMUNOTROPIC AGENTS rhagic disease of the newborn. The hemostatic effect of Vitamin K is delayed for 6 hours. Vitamin K is relatively nontoxic; however, allergic reactions and The immune system is designed to protect the host thrombosis may appear. from invading pathogens and to eliminate disease. It Aminocaproic acid is an inhibitor of fibrinolysis. is provided by two major components: the innate and It inhibits the activation of profibrinolysin (Plas- the adaptive (acquired) immune systems. The innate minogen) and it also inhibits the action of Fibri- immune system is the first line of defense against an nolysin (Plasmin). Aminocaproic acid is rapidly and antigenic insult and includes physical (e.g. skin), bio- completely absorbed from the GI tract. It is excreted chemical (e.g. complement, lysozyme), and cellular in urine as unchanged drug within 12 hours follow- (macrophages, neutrophils) components. The adaptive ing the dose. Aminocaproic acid is used intravenous- immune system includes production of antibodies, ly as well as orally in the treatment of excessive bleed- which are the effectors of humoral immunity; and the ing resulting from systemic hyperfibrinolysis. Use of activation of lymphocytes, which are the effectors of the drug should be accompanied by laboratory tests cell-mediated immunity. The generation of specific im- to determine the degree of fibrinolysis present. Ad- munity requires the participation of antigen-presenting verse effects of Aminocaproic acid are mild. They in- cells (macrophages, Langerhans cells) and B-lym- clude vomiting, abdominal pain, diarrhea, dizziness, phocytes. Cell-mediated immunity is ensured mainly and fever. by T-lymphocytes that able to discriminate between Contrykal, Aprotinin, an animal origin drugs, are foreign (“non-self”) antigens and “self” antigens of the the serine protease (Trypsin, Kinins, Plasmin, etc.) in- host and to respond to a previously encountered anti- hibitors that inhibits fibrinolysis by free Plasmin. gen in a learned way by initiating a vigorous memory Aprotinin will reduce bleeding from many types of sur- response. gery, especially that involving extracorporeal circulation for open-heart procedures. It is currently approved IMMUNOSTIMULATING AGENTS for use in patients undergoing coronary artery bypass grafting who are at high risk of excessive blood loss. Such drugs can be used to increase the immune re- Contrykal inhibits Trypsin, Kinins, and Fibrinolysin. sponsiveness of patients who have immunodeficiency. It is used for the treatment of acute pancreatitis because The major potential uses are in immunodeficiency dis- it is associated with excessive serum level of proteas- orders, chronic infectious diseases, and cancer. es. The most serious adverse effects of these agents are allergic reactions. Classification of immunostimulating agents: Coagulating substances of plant nature (leaf of — Agents that stimulate nonspecific immunity nettle, water pepper, etc.) include tanning substanc- (Methyluracil, Pentoxil) es, Vitamins K, C, P, etc. They cause stabilizing ac- — Agents that mostly stimulate macrophages and tion on vascular wall and increase firmness of cap- T-lymphocytes (Sodium nucleate, BCG, Prodigi- illaries. They are used in form of decocts, tinctures, osan®, Pyrogenal®, Thymus agents, Levamisole, In- extracts during chronic bleeding (uterine, intestinal, terferon) etc.). — Agents that hasten macrophages and granulocytes formation (Filgrastim, Molgramostim) Available forms: — Agents that predominantly stimulate B-lym- Heparin — in bottles 5 ml (1 ml — 5,000; 10,000 phocytes (Myelopid) or 20,000 IU) each Ethyl biscoumacetate (Neodicumarin) — in tablets Methyluracil and Pentoxil are the derivatives of 0.05 or 0.1 each Pyrimidine. These drugs hasten cell regeneration, Ticlodipine — in tablets 0.25 each wounds healing; stimulate cellular and humoral immu- Dipyridamole — in tablets (or dragee) 0.025 or nity. They indicated in the cure of mild leukopenia, 0.075 each; in ampoules 0.5% solution 2 ml each badly closed wounds, burns, bone crash, and ulcer dis- Streptokinase — in bottles 100,000 or 250,000 IU ease of duodenum. Meth цyluracil and Pentoxil are each (to dilute in 50 ml of physiologic solution before well absorbed from the intestine. These drugs are good using) tolerated. However, Pentoxyl may cause gastrointes- Thrombin — in bottles or ampoules 0.125 IU each tinal disorders. (to dilute in 10 ml of physiologic solution before us- Sodium nucleate, a sodium salt of nucleic acid, is ing) formed by hydrolysis of yeast. It promotes the accel- Fibrinogen — in bottles 1.0 each (to dilute in 250 eration of restoring processes; stimulates leukopoiesis, ml of applied solution) cooperation of T- and B-lymphocytes, and phagocytic Protamine sulfate — in bottles 1% solution 5 ml properties of macrophages. Sodium nucleate is indi- each; in ampoules 1% solution 2 or 5 ml each cated for different diseases that accompanied with leu- Vicasol — powder; in tablets 0.015 each; in am- kopenia. poules 1% solution 1 ml BCG is a viable strain of Mycobacterium bovis that Aminocaproic acid — powder; in bottles 5% solu- has been used for immunization against tuberculosis. tion 100 ml each It has also been employed as a nonspecific adjuvant Folia Urtica — infusion, MD — 0.6 immunostimulator in cancer therapy (leukemia, can-

141 cer of intestine, bladder, and breast). BCG appears to mus. It is used locally in drops or inhalation for the act at least in part via activation of macrophages to treatment of allergic disorders of the upper respirato- make them more effective killer cells. ry ways (allergic rhinitis and sinusitis). Prodigiosan is a microbial polysaccharide that is Interferons belong to cytokines. They have antipro- extracted from Bac. prodigiosum. It stimulates cellu- liferative, antimicrobial, and antitumor effects (see lec- lar immunity (T-lymphocytes) and adrenal cortex. It ture “Antiviral agents”). The production of highly pu- postulates that Prodigiosan augments the interferon rified Interferons has been greatly facilitated by the synthesis. Prodigiosan is prescribed as adjuvant drug pharmaceutical application of gene cloning tech- in the treatment of diseases that characterized by de- niques. Three major classes of Interferons are now rec- pressed immunity. For instance, chronic inflammation ognized: α- (leukocyte), β- (fibroblast), and γ-(immune, processes, postoperative period, during antibiotic ther- T-lymphocyte). Each type can function as a potent cy- apy, badly closed wounds, etc. Agent is injected intra- tokine with complex antiviral and immunomodulato- muscularly once per 3–7 days. Fever, headache, ar- ry activity. γ-Interferon has the stronger action on the thralgia, and fatigue sometimes are observed after Pro- immunity than other Interferons. Interferons activate digiosan administration. macrophages, T-lymphocytes, and natural killer cells. Pyrogenal (Grecian: pyr- fire, gen- producing) is Natural α-interferon has been used for prophylaxis a microbial polysaccharide that is synthesized by Pseu- and treatment of the common cold virus’s infections domonas aeruginosa. It is a fever-inducing agent. Py- and herpes keratitis. Recombinant α-interferon (Re- rogenal is similar in action to Prodigiosan. In addi- aferon (Interferon alfa-2a), Intron A (Interferon alfa- tion, Pyrogenal stimulates the restoring of central and 2b)) is approved for the treatment of hepatitis B and peripheral nervous system; activates the disappearance C, leukemia, bladder and renal carcinoma, and ma- of scars. Pyrogenal is indicated in the treatment of lignant melanoma. Poludan® (Polyadenylic acid + chronic prostatitis, chronic inflammation of women re- Uridylic acid), Tilorone (Amixin) stimulates the syn- productive system, inflammation and damages of pe- thesis of endogenous interferon and thus possess anti- ripheral and central nervous system, and post-burn viral activity. Poludan is a topical agent for the treat- scars. Agent is prohibited during fever and pregnancy. ment of viral eyes diseases. Amixin is active in case of Levamisole was first synthesized for the treatment viral hepatitis B and C. of parasitic infections. Later studies suggested that Three cytokines with colony-stimulating properties it appears to act as an immunorestorative agent in the have been studied extensively and are now being used presence of immunosuppression, but does not stimu- in humans. They are Erythropoietin (see lecture late the immune response to above normal levels. “Drugs influencing the erythropoiesis”), Granulocyte Thus, it modulates the immune response or acts like Colony-stimulating factor (G-CSF), and Granulocyte- immunomodulating agent. Mechanism of action is macrophage colony-stimulating factor (GM-CSF). G- related to T-cell activation and proliferation, augmen- CSF stimulates mainly the forming of granulocytes. tation of monocyte and macrophage activity, and an GM-CSF promotes the forming of macrophages or ac- increase in neutrophil mobility, adherence, and chem- tivates combine granulocyte-macrophage colonies. Fil- otaxis. Levamisole is used for the treatment of both grastim (G-CSF) and Molgramostim (GM-CSF) are primary and secondary immunodeficiency, autoim- produced by recombinant techniques. These drugs has- mune disease, chronic and relapse infections, cancer, ten recovery from neutropenia in patients with malig- etc. It has also been widely tested in rheumatoid ar- nancies who are receiving chemotherapy and acceler- thritis and found to have efficacy. Agent is taken oral- ate marrow recovery after autologous bone marrow ly. However, it can induce severe agranulocytosis, transplantation. which required discontinuation of its use. Thus, Le- Myelopid is an immunomodulating agent of pep- vamisole therapy must be under regular leukocyte tide structure, which is received from cattle or porcine measurement. bone marrow tissue cultures. At immunodeficient pa- Thymalinum consists of a group of protein hor- tients it restores the indicators of T- and B-lym- mones synthesized by the thymus. These proteins have phocytes, restores the formation of antibodies, and pro- been isolated and purified from bovine thymus glands. motes the restoring of other indicators of humoral im- Thymalinum regulates the amount of T- and B-lym- munity. Myelopid is used in the cure of acquired im- phocytes and activates cell immunity. Thymalinum is munodeficiency states with predominant confound of used for the treatment of different states that are asso- humoral immunity, including postoperative aggrava- ciated with immunodeficiency and depression of hemo- tions, osteomyelitis, etc. Agent is injected subcutane- poiesis. For example, acute or chronic purulent proc- ously. Adverse effects include vertigo, fatigue, nausea, esses, burns, chemotherapy of patients with cancer, and fever. etc. Tactivin is an agent of protein structure, which is obtained from bovine thymus gland. It appears to convey T-cell specificity to uncommitted lymphoid stem IMMUNOSUPPRESSIVE AGENTS cells and to induce the maturation of pre-T cells. Tac- tivin increases the number of T-lymphocytes. It induc- Agents that suppress the immune system play an es enhanced production of interleukins. This agent is important role in the retention of organ or tissue grafts indicated for the treatment of T-lymphocyte deficien- and in the treatment of certain diseases that arise from cy states including psoriasis, leukosis, etc. Thymali- dysregulation of the immune response. There is defi- num and Tactivin are prohibited during pregnancy and nite overlap between the drugs used for immunosup- in case of hypersensitiveness to these drugs. Vilosenum pression and those used in cancer chemotherapy (cy- as well as previous drugs are an extract of cattle thy- totoxic drugs).

142 Classification of immunosuppressive agents: that reduces folic acid to tetrahydrofolic acid. Inhibi- — Alkylating agents (Cyclophosphane, Embichin, tion of tetrahydrofolate formation limits the synthesis Chlorbutin, and Busulfan) of purines, DNA and cell reproduction. Methotrexate — Antimetabolites (Mercaptopurine, Azathioprine, also has immunosuppressive activity, in part possibly Methotrexate, and Ftoruracil) as a result of inhibition of lymphocyte multiplication. — Anticancer antibiotics (Dactinomycin, Rubomy- It is completely absorbed from the GI tract. Methotrex- cin, Doxorubicin and Bruneomycin) ate is retained for several weeks in the kidneys and liv- — Alkaloids (Vinblastine, Vincristine) er. It is used orally, intravenously, and intramuscular- — Steroid hormones and their antagonists (Tamo- ly. Methotrexate has the similar uses and adverse ef- xifen, Leuprolide) fects with Mercaptopurine. — Enzymes (Asparaginase) Ftoruracil (Fluorouracil) is a fluorinated pyrimidine antagonist. It acts as an antimetabolite that in- The major clinically useful alkylating agents are hibits DNA and RNA synthesis. Ftoruracil is used for Cyclophosphane, Embichin (Mechlorethamine), the palliative treatment of carcinoma of the colon, rec- Chlorbutin, and Myelosan (Busulfan) are the most tum, breast, stomach, and pancreas that is not amena- useful. As a class, the alkylating agents exert cytotox- ble to surgery or irradiation. The major toxic effects ic effects via transfer of their alkyl groups to various of Ftoruracil are on the normal, rapidly proliferating cellular constituents. Alkylation of DNA within the nu- tissues particularly of the bone marrow and lining of cleus probably represents the major interactions that the GI tract. Anorexia, nausea, leukopenia, thrombo- lead to cell death. Cyclophosphane, Chlorbutin are cytopenia, and anemia occur commonly with Ftoru- used in the treatment of lymphocytic leukemia, lymp- racil therapy. holeukosis, Hodgkin’s disease, multiple myelosis, neu- Screening of microbial products has led to the dis- roblastoma, ovarian carcinoma, breast cancer, etc. covery of a number of growth inhibitors that have Myelosan used for specialized purposes for chronic proved to be clinically useful in cancer chemothera- myeloid leukemia. py. Many of these antibiotics bind to DNA through One of the major and dose-limiting adverse effects intercalation between specific bases and block the syn- of alkylating drugs is hematological toxicity. Hemat- thesis of new RNA or DNA (or both), cause DNA opoietic adverse effects include leukopenia, thrombo- strand scission, and interfere with cell replication. cytopenia, and anemia. Repeated blood counts are es- These agents possess also immunosuppressive proper- sential during administration of these agents because ties. Anticancer antibiotics include Dactinomycin, the development of severe leukopenia or thrombocyto- Rubomycin (Daunorubicin), Doxorubicin, Bruneo- penia necessitates interruption of therapy. Anorexia, mycin and others. In clinical use, all mentioned above nausea, and vomiting occur commonly with alkylat- drugs are administered by the intravenous route. ing drugs, especially at high doses. It is reported that Doxorubicin is one of the most important antican- these effects respond to treatment with antiemetics. cer drugs, with major clinical application in carcino- Mercaptopurine and Azathioprine are the chemi- mas of the breast, endometrium, ovary, testicle, thy- cal analogs of the physiologic purines. They are the roid, and lung. The major use of Rubomycin is in purine antagonist antimetabolites. Ultimately, the syn- acute leukemia. Dactinomycin is used in the complex thesis of RNA and DNA is inhibited. Absorption of treatment of Wilms’ tumor, chorioepithelioma, etc. Mercaptopurine from the GI tract is variable and in- Bruneomycin is indicated for lymphogranulomatosis, complete, but about 50% of a dose is usually absorbed. chronic lympholeukosis, Wilm’s tumor, etc. It is rapidly and extensively oxidized in the liver by In common with many other cytotoxic drugs, anti- the enzyme xanthine oxidase. Mercaptopurine is used cancer antibiotics cause bone marrow depression. All mainly for the treatment of acute leukemia. Adverse blood elements are affected, but platelets and leuko- hematopoietic effects include leukopenia, anemia, and cytes are affected most profoundly, and severe leuko- thrombocytopenia. Adverse GI effects include nausea, and thrombocytopenia sometimes occurs. Nausea and vomiting, diarrhea, anorexia, abdominal pain, and ul- vomiting, diarrhea, and oral ulcers may also be not- ceration of the intestinal epithelium. Also it is hepato- ed. Alopecia and various skin abnormalities occur oc- toxic. casionally. Azathioprine is well absorbed from the gastrointes- Vinblastine and Vincristine are the alkaloids de- tinal tract and is metabolized primarily to Mercaptop- rived from Vinca rosea, the periwinkle plant. Their urine. Although Azathioprine action is presumably mechanism of action involves depolymerization of mi- mediated by Mercaptopurine as the active form, it has crotubules, which are an important part of the cytoskel- been more widely used than Mercaptopurine for im- eton and the mitotic spindle. This results in mitotic ar- munosuppression in humans. Immunosuppression with rest at metaphase. Vinblastine has value in the treat- Azathioprine therapy seems to result from interference ment of systemic Hodgkin’s disease and other lympho- with nucleic acid metabolism at steps that are required mas. Vincristine has been used with considerable suc- for the lymphoid cell proliferation. Azathioprine to be cess for acute leukemia. These drugs produce nausea of definite benefits in maintaining renal allografts and and vomiting and marrow depression as well as alo- may be of value also in transplantation of other tis- pecia. In addition, Vincristine causes a significant in- sues. It has proved useful as well in cases of autoim- cidence of neurotoxicity, which limits its use to short mune diseases (rheumatoid arthritis, acute glomeru- courses. lonephritis, and Crohn’s disease). Steroid hormones (glucocorticoids, androgens, es- Methotrexate is a folic acid antagonist. Meth- trogens and their antagonists) bind to receptor proteins otrexate inhibits dihydrofolate reductase, the enzyme in cancer cells, and high levels of receptor proteins are

143 predictive for responsiveness of endocrine therapy. As AGENTS FOR THE TREATMENT OF in normal cells, steroid hormones form a steroid-recep- HYPERSENSITIVITY tor complex that ultimately binds directly to nuclear nonhistone protein of DNA to activate transcription of Whereas the normally functioning immune re- associated clusters of genes. sponse can successfully neutralize toxins and eliminate Glucocorticoids have immunosuppressive and anti- pathogens, clinical instances occur in which an inap- inflammatory properties. Administration of a glucocor- propriate response leads to extensive tissue damage (hy- ticoid (e.g. Prednisolone, Dexamethasone) reduces the persensitivity). Hypersensitivity can be classified, as size and lymphoid content of the lymph nodes and immediate or delayed depending on the time required spleen, though it has essentially no toxic effect on pro- for clinical symptoms to become manifest following liferating myeloid or erythroid stem cells in the bone exposure of the host to the sensitizing antigen. marrow. Their immunology effects are probably due Three categories of immediate hypersensitivity are to their ability to modify cellular functions rather than recognized. Type I hypersensitivity (anaphylaxis) re- direct cytotoxicity (see lecture “Drugs affecting the sults from cross-linking of membrane-bound IgE on endocrine system”). blood basophils or tissue mast cells by antigen. This Indications for glucocorticoids include autoimmune interaction causes cells to degranulate, releasing sub- disorders such as autoimmune hemolytic anemia, idi- stances (histamine, leukotrienes, etc.) that induce bron- opathic thrombocytopenic purpura, inflammatory bow- chospasm, collapse, or hay fever. Type II hypersensi- el disease, and lupus erythematosus. Corticosteroids tivity (cytotoxic reaction) results from the formation are also used liberally in organ transplant recipients. of antigen-antibody complexes between foreign anti- The glucocorticoid analogs have been useful in the gen and immunoglobulins. It results in lysis of cells that treatment of acute leukemia, lymphomas, myeloma, keep antigen. This type of hypersensitivity occurs dur- and other hematologic cancers. ing blood transfusion reactions and in hemolytic dis- The estrogen inhibitor tamoxifen has proved to be ease of the newborn. In both cases, antibodies are extremely useful for the treatment of breast cancer and formed against foreign red blood cell membrane anti- endometrial cancer. An antiandrogen, flutamide, has gens to which they bind. It can also be drug-induced been approved for use in the treatment of prostate can- and occurs during the administration of Levomycetin cer. Finasteride, a nonsteroidal inhibitor of 5α-testo- to allergic patients. In these patients, Levomycetin sterone reductase, the enzyme that converts testoster- binds to red blood cells or other host tissue to form a one to dihydrotestosterone, is approved only for the neoantigen that evokes production of antibodies capa- therapy of benign prostatic hyperplasia. ble of inducing complement-mediated cell lysis. Leuprolide is a synthetic peptide analog of natu- Type III hypersensitivity (immune complex reac- rally occurring gonadotropin-releasing hormone. It tions) is due to the presence of elevated levels of anti- inhibits the releasing of follicle-stimulating hormone gen-antibody complexes. The formation of these com- and luteinizing hormone. This results in reduced tes- plexes activates complement to produce components ticular androgen synthesis. The latter effect underlies that increase vascular permeability and recruit neu- the efficacy of this agent in the treatment of carcino- trophils to the site of complex deposition. It can cause ma of the prostate. skin rashes, glomerulonephritis, serum sickness, and Aminoglutethimide is an inhibitor of adrenal ster- arthritis. Delayed-type hypersensitivity is cell-mediat- oid synthesis. It also inhibits the extra-adrenal syn- ed. Delayed-type hypersensitivity is characterized by thesis of estradiol. Aminoglutethimide is effective in the influx of the activated macrophages and neu- the treatment of metastatic breast cancer in women trophils. The activated macrophages display increased whose tumors contain significant levels of estrogen phagocytic and antigen-presenting functions; and re- or progesterone receptors. Aminoglutethimide is nor- lease copious amounts of enzymes that contribute to mally administered with adrenal replacement doses the extensive tissue damage and local inflammation of hydrocortisone to avoid symptoms of adrenal in- (parasitic granuloma, nodular leprosy). sufficiency. Histamine is a physiologically active, endogenous Androgens, estrogens, and adrenocortical hor- substance that binds to and activates histamine H1- and mones all can produce fluid retention through their so- H2-receptors at various sites in the body causing char- dium-retaining effect. Prolonged use of androgens and acteristic allergic signs and symptoms. The principal estrogens will cause masculinization and feminiza- pharmacologic effects of histamine involve the stimu- tion, respectively. Extended use of the adrenocortical lation of gastric and bronchial secretions; microvas- steroids may result in hypertension, diabetes, in- cular dilation, hypotension (involving H1-, H2-recep- creased susceptibility to infection, and cushingoid ap- tors) and increased vascular permeability (H1-recep- pearance. tors); stimulation of the bronchial and gastrointestinal Asparaginase catalyzes the conversion of the ami- tract muscles. The term antihistamine has historically no acid asparagine to aspartic acid and ammonia. been used to describe drugs that act as H1-receptor an- Some leukemic cells are unable to synthesize aspar- tagonists. Drugs that antagonize H2-receptors (e.g. ci- agine, which is required for the synthesis of DNA and metidine, famotidine) are used for the lowering of gas- essential proteins. Because normal cells are able to tric acid secretion. Antihistamines competitively antag- synthesize asparagine, they are less affected by aspar- onize most of the smooth muscle stimulating actions aginase-induced depletion of the amino acid. Resist- of histamine on the H1-receptors of the GI tract, uter- ance to the cytotoxic effects of asparaginase develops us, large blood vessels, and bronchial muscle. Antihis- rapidly. Agent is used for the treatment of acute lym- tamines appear to act by blocking H1-receptor sites, phocytic leukemia. thereby preventing the action of histamine on the cell.

144 Classification of agents used for the treatment of It does not possess any intrinsic antihistamine, anti- hypersensitivity: inflammatory, glucocorticoid, or vasoconstrictive ac- 1. Agents used for the treatment of immediate type tivity. Cromolyn administered orally is indicated in the hypersensitivity: treatment of ulcerative colitis. Its inhalation is indi- a. Agents that decrease the releasing of histamine cated as first-line medication for the prevention of and other active substances — Cromolyn, Ketotifen, acute bronchospasm. Cromolyn inhalation is not indi- Glucocorticoids. cated for the relief of acute asthma attacks, especially b. Antihistamines — Diphenhydramine (Dime- in status asthmaticus, because it has no immediate bron- drolum), Promethazine (Diprazin), Diazolin (Meb- chodilating activity. hydroline + Zinc sulfate), Quifenadine (Phencarol), Ketotifen has antihistamine and antiallergic activ- Loratadine. ities. It is postulated, that Ketotifen inhibits mast cell c. Agents that bind with histamine — Histaglobu- release of histamine, leukotrienes, and other substances lin. that cause hypersensitivity. On the other hand, Keto- d. Agents that inhibit efferent limb of the allergic tifen blocks H1-receptors. Agent is well absorbed from response — Adrenomimetics, Aminophylline (Euphyl- gastrointestinal tract. The serum half-life is about 20 lin). hours. Ketotifen is used for the prevention of acute e. Agents that decrease the tissue damage — ster- bronchospasm, for the treatment of allergic bronchi- oid and non-steroid anti-inflammation drugs. tis, hay fever, and allergic dermatitis. Adverse effects 2. Agents used for the treatment of delayed type hy- include drowsiness and thrombocytopenia. persensitivity: Histaglobulin is a preparation of the human gam- a. Immunodepressive agents — Cyclosporine, Aza- ma globulin, containing the antibodies of normal thioprine. adults, and histamine. It is obtained from pooled liq- b. Agents that decrease the tissue damage — ster- uid human plasma from a number of donors. Hista- oid and non-steroid anti-inflammation drugs. globulin increases the production of antihistamine antibodies those results in higher ability of serum to in- Antihistamines include following drugs: Diphenhy- activate the histamine. It is used subcutaneously for dramine, Diprazin (Promethazine), Diazolin, Phen- the treatment of different allergic diseases including carol, Loratadine, etc. Diprazin, Dimedrolum are pos- bronchial asthma, dermatitis, etc. sess m-cholinolytic, ganglionblocking and sedative ef- Drugs that modify allergic responses act at several fects. The antiemetic, antimotion-sickness, and an- links in this chain of events. Glucocorticoids (Pred- tiparkinson actions of these antihistamines appear to nisolone) that are often used in severe allergic reac- result, at least in part, from their central anticholiner- tions including anaphylactic reaction, and probably gic and CNS depressant properties. Diprazin proba- blocks proliferation of the IgE-producing clones. In bly is the most potent antihistamines. Also it has addition, glucocorticoids increase the sensitiveness of α-adrenolytic activity (hypotensive action). Diazolin, adrenoreceptors to noradrenaline, thus they potentiate Phencarol, and Loratadine are poorly distributed into the action of adrenomimetics. In the efferent limb of the CNS at usual dosages. That’s why they do not the allergic response adrenomimetics (e.g. Adrenaline, cause sedative effect. Isoprenaline, Salbutamol) and direct spasmolytic Eu- Antihistamines generally are well absorbed follow- phyllin produce bronchodilation (see lecture “Adren- ing oral or parenteral administration. The duration of ergic agonists”). action is variable but allergic symptoms usually are For the treatment of delayed-type hypersensitivi- relieved for 3–6 hours after oral administration of most ty immunosuppressive agent’s glucocorticoids are antihistamines. Some antihistamines (e.g. Loratadine) used also. They have anti-inflammation activity (see exhibit prolonged duration of effect that lasts in ex- lecture “Drugs affecting the endocrine system”). Glu- cess of 24 hours. cocorticoids reduce the concentration of T-lym- Indications. Antihistamines are used for the treat- phocytes, monocytes, and eosinophils. They also de- ment of nasal allergies, allergic dermatosis, and aller- crease binding of immunoglobulin to cell surface re- gic conjunctivitis. Antihistamines are useful in the an- ceptors and inhibit the synthesis, and release of in- cillary treatment of pruritus, urticaria, angioedema, terleukins, thereby decreasing T-lymphocyte blast- and bronchospasm associated with anaphylactic reac- ogenesis and reducing expansion of the primary im- tions. Some antihistamines (e.g. Dimedrole, Diprazin) mune response. Glucocorticoids may also decrease are useful for the prevention and treatment of nausea, concentrations of complement components and immu- vomiting, and/or vertigo associated with motion sick- noglobulins. ness. They are used for their sedative effects as night- Cyclosporine is an antibiotic that appears to act at time sleep aids. an early stage in the antigen receptor-induced differ- Adverse effects include sedation, ranging from mild entiation of T-cells and blocks their activation. Recent drowsiness to deep sleep, anticholinergic effects (e.g. in vitro studies have indicated that Cyclosporine in- dryness of mouth, urinary retention, and visual distur- hibits the gene transcription of interleukins and other bances), and gastrointestinal disorders (e.g. anorexia, factors produced by antigen-stimulated T-cells. Cy- nausea, and vomiting). Also they potentiate the depres- closporine is an immunosuppressive agent in human sion of the CNS that caused by alcohol, neuroleptics, organ transplantation, after bone marrow transplan- narcosis agents. tation, and in the treatment of selected autoimmune dis- Cromolyn is an antiallergic drug. Cromolyn inhib- orders. Agent is given orally and intravenously. Tox- its mast cell release of histamine, leukotrienes, and icities include nephrotoxicity and transient liver dys- other substances that cause hypersensitivity reactions. function.

145 Available forms: 5. In what respect is the thrombolytic drug Retepla- Thymalinum — in ampoules 0.01% solution 1 ml se improved over older drugs like streptokinase? each (A). Reteplase may be taken orally. Myelopid — in bottles 0.003 each (to dilute in 1 (B). Reteplase is antigenic. ml of physiologic solution before using) (C). Reteplase binds to fibrin. Prodigiosan® — in ampoules 0.005% solution 1 (D). Bleeding does not occur with reteplase. ml each (E). Reteplase produces less thrombocytopenia. Levamisole — in tablets 0.05 or 0.15 each Azathioprine — in tablets 0.05 each 6. Cytotoxic agents such as Azathioprine are effec- Fluorouracil (Ftoruracil) — in ampoules 5% solu- tive immunosuppressants because they tion 5 ml each (A). Bind to and inactivate circulating immuno- Dimedrolum — powder; in tablets 0.02; 0.03 or complexes. 0.05 each; in ampoules 1% solution 1 ml each (B). Specifically inhibit IL-2 gene transcription. Loratadine — in tablets 0.01 each (C). Prevent the clonal expansion of T and B cells Ketotifen — in tablets or capsules 0.001 each by inhibiting purine synthesis. Cyclosporine — in capsules 0.05 or 0.1 each (D). Induce the synthesis of antiidiotype antibodies. (E). Alkylate and cross-link DNA, preventing blas- togenesis. EXAMINATION QUESTIONS 1. Which of the following statements describe 7. Interleukin-2 can be beneficial in the treatment why Warfarin is not used to prevent blood coagula- of AIDS because it can tion in blood collection devices used at blood donat- (A). Attach to the HIV virus, making it more sus- ing centers? ceptible to phagocytosis. (A). Warfarin does not bind to plastic tubing or (B). Bind to IL-2 receptors on responsive immune glass. cells and stimulate the production of T help- (B). The anticoagulant effect of Warfarin occurs er and T cytotoxic cells. only in vivo. (C). Cross-link antibodies on mast cell surfaces (C). Warfarin is a prodrug, which must be acti- leading to degranulation. vated in the liver into the active compound. (D). Activate the complement cascade by binding (D). The gastric enzymes needed to convert R-war- to the C5a fragment. farin into S-warfarin are unstable near plastic. (E). Inhibit T suppressor cell activity and there- (E). Warfarin is chemically unstable and is degrad- by stimulating the immune response ed unless made fresh and used immediately. 8. A 4-year-old boy has significantly reduced lev- 2. All of the following statements about Warfarin els of IgA, IgM, IgD and IgE in his blood. Testing are true EXCEPT? demonstrates that he did not develop the appropri- (A). An adverse drug reaction may occur if War- ate antibody titer following standard childhood vac- farin is displaced from plasma protein bind- cinations. The most probable cause of these deficien- ing sites. cies is (B). Warfarin crosses the placenta. (A). Deficiency in macrophage function that is (C). Drugs that are metabolized by the liver can preventing the proper presentation of antigens alter the anticoagulant effect of Warfarin. to T cells. (D). Warfarin is eliminated from the body un- (B). Lack of a specific component of the comple- changed in the urine. ment cascade. (E). Warfarin is a vitamin K antagonist. (C). Alcohol abuse by the mother during pregnancy. 3. Which of the following is an adverse effect asso- (D). A primary immunodeficiency disease that is ciated with pharmacotherapy using Heparin? blocking the maturation of B cells into plas- (A). An increase in the number of circulating ma cells. platelets (E). An autoimmune disease targeted at basophil (B). Thrombocytopenia surface receptors. (C). Purple toe syndrome (D). Teratogenicity to the fetus 9. Which of the following best describes the side (E). An increase in the circulating level of anti- effects of Cyclosporine therapy? thrombin III (A). Leukopenia, hypotension, hemolytic anemia. (B). Nephrotoxicity, neurotoxicity, hirsutism. 4. Which of the following is a drug that blocks the (C). Thrombocytopenia, hypokalemia. ADP receptor on the antiplatelet membrane? (D). Hemorrhagic cystitis, hypoglycemia. (A). Aspirin (E). Increase circulating immune complexes, car- (B). Abciximab diac arrhythmia. (C). Dipyridamole (D). Clopidogrel 10. The antigen-mediated release of histamine can (E). Eptifibatide (A). Be inhibited by the binding of histamine to H3-receptors on mast cells. 146 β (B). Be stimulated by ( 2-adrenoceptor agonists. the platelet glycoprotein IIb/IIIa receptor. Dipyridamole (C). Be initiated by organic bases such as mor- inhibits platelet cyclic AMP phosphodiesterase and raises phine without prior sensitization. cyclic AMP levels. Eptifibatide binds to the glycoprotein (D). Occur only in the tissues, not in the blood. IIb/IIIa complex. (E). Produce pain and itching through an effect 5. (C). Reteplase binds to fibrin to cause a selective activation of fibrin-bound plasminogen. All fibrinolyt- on sensory nerve endings. ic drugs are administered IV. Streptokinase is antigenic, whereas reteplase is not. Thrombocytopenia is not nor- 11. Effects mediated by the H1 histamine receptor mally caused by thrombolytic drugs. include 6. (C). Azathioprine is a phase-specific cytotoxic (A). Inhibition of gastric acid secretion. agent that functions by inhibiting purine synthesis. (B). Induction of hepatic cytochrome P450 en- The other answers are wrong because Azathioprine is zymes. nonspecific, is not an alkylating agent, has no effect (C). Maintenance of a wakeful state. on immune complexes, and does not induce antibody (D). Bronchodilation. synthesis. (E). Vasoconstriction of arterioles. 7. (B). IL-2 stimulates the immune system by binding to the IL-2 receptors on responsive immune cells, 12. All four types of histamine receptors causing differentiation and proliferation of T helper and T cytotoxic cells. It has no direct effect on the HIV virus, (A). Are found on the surface of mast cells and ba- complement or basophils. sophils. 8. (D). The boy has significantly reduced serum anti- (B). Are G protein-coupled. body levels and a reduced ability to mount an antibody (C). Modulate adenylyl cyclase activity. response to childhood vaccinations. The most probably (D). Are involved in the release of multiple neu- cause is a primary immunodeficiency disease affecting rotransmitters. humoral immunity. 9. (B). The primary side effect of Cyclosporine therapy is nephrotoxicity, occurring in up to 75% of cases. Unwanted hair growth and neurotoxicity are also com- ANSWERS monly noted. The other answers are wrong because Cy- closporine therapy is associated with hypertension, hy- 1. (B). Warfarin does not produce an anticoagulant perkalemia, and hyperglycemia. There are no references effect in vitro. It inhibits coagulation of blood only in vivo, because the effect depends upon Warfarin’s effect in to cyclosporine having cardiac or immune complex ef- the liver on the production of clotting factors. Warfarin fects or causing hemorrhagic cystitis. does not require conversion into an active drug. It in- 10. (E). Histamine inhibits its own release through an effect on H2-receptors on mast cells. Its release is inhib- hibits the post-ribosomal carboxylation of glutamic acid β residues in the vitamin K-dependent clotting factors. ited, not stimulated, by 2-adrenoceptor agonists. Organ- Therefore, Heparin rather than Warfarin is used when ic bases can displace histamine from its storage granules blood is collected from donors and stored. and cause non-antigen-mediated release of histamine; an- 2. (D). Warfarin is metabolized in the liver by P450 tigen-mediated release requires prior sensitization. An- enzyme system and is appreciably metabolized before it tigen-mediated histamine release occurs in both tissues is eliminated. Adverse drug reactions are seen in patients and blood. Histamine stimulates sensory nerve endings, taking Warfarin if a second drug displaces Warfarin from resulting in pain and itching. its protein binding sites in the blood or induces or in- 11. (C). Histamine stimulates gastric acid secretion hibits the hepatic P450 system. Warfarin can cross the through an effect on H2-receptors of gastric parietal cells. placenta and exert anticoagulant and other effects in the Although certain antihistamines are metabolized by cy- fetus at normal doses given to the mother. tochrome P450 enzymes, histamine does not induce their 3. (B). Thrombocytopenia is a frequent side effect as- production. Histamine helps to maintain a wakeful state sociation with Heparin. This reduction in the level of cir- through an effect on H1-receptors. Histamine-mediated culating platelets increases bleeding. Purple toes are en- bronchoconstriction is mediated by H1-receptors, while countered during Warfarin therapy. Heparin may be ad- histamine-mediated vasodilation occurs as a result of ministered to pregnant mothers without risk to the fe- stimulation of H1 and H2-receptors. tus. Heparin requires antithrombin III for its anticoagu- 12. (B). H2-receptors are found on the surface of mast lant action, but does not increase the level of this pro- cells and basophils. All four types of histamine recep- tein in the blood. tors belong to the G protein-coupled receptor superfami- 4. (C). Aspirin inhibits platelet cyclooxygenase. Ab- ly. Only H2-receptors are coupled to adenylyl cyclase ciximab, a monoclonal antibody, binds to and inhibits through the G protein Gs.

147 ANTIMICROBIAL, ANTIPROTOZOAL AND ANTIVIRAL DRUGS

Lecture 34 rode instruments. An antiseptic also should be non-irritating to tissues, produce minimum toxicity. DISINFECTANTS AND Spectrum activity of agent is the list of microorgan- ANTISEPTICS isms, that sensitive to him. Spectrum activity of majority of antiseptic/disinfectants is wide, reflecting non- selectivity of action. Antimicrobial drugs are the greatest contribution Evaluation of effectiveness of antiseptics, disinfect- of the present century to therapeutics. As the class they ants although seemingly simple in principle, is very com- are one of the most frequently used in medicine. plex. Factors in any evaluation include the intrinsic re- J. Zemmelweiss, the Hungarian obstetrician used sistance of the microorganism, the number of present lime for medicine stuff hands washing. An English sur- microorganisms, mixed populations of microorganisms, geon J. Lister suggested phenol as an antiseptic to sur- amount of present organic material (e.g. blood, feces, gery. Further development of antiseptics was based on tissue), concentration and stability of disinfectant or Pasteur’s discovery of pathogenic microorganisms and sterilant, time and temperature of exposure, pH, and researches of R. Koch, I. I. Mechnikov and others. hydration and binding of the agent to surfaces. Drug in this class differs from all others in that they designed to inhibit or to kill the infecting organism and Classification of disinfectants and antiseptics: to have minimal effect on the recipient. If agent pri- — Halogens (Chlorinated lime, Chloramine B, mary inhibits the germ growing, it acts bacteriostatic. Chlorhexidine, Iodinol (Iodine + Potassium iodine), Direct lethal action is the feature of bactericidal ac- Iodovidon (Povidone-Iodine)) tivity. A practical distinction between these two mech- — Oxidizing agents (Hydrogen Peroxide, Potas- anisms action is futile as these are often concentration sium permanganate) dependent action. — Acids (Salicylic Acid, Boric acid) Antimicrobial preparations are subdivided into the — Phenol derivatives (Phenol, Cresol, Resorcinol, following groups: disinfectants, antiseptics and chem- Vagotil) otherapeutic agents. — Aldehydes and alcohols (Formaldehyde, Glutar- Disinfectants are chemical agents that inhibit or kill aldehyde, Ethanol, Isopropanol) microorganisms on inanimate objects (walls, floor, air, — Metallic salts (Silver nitrate, Zinc sulfate, and and medical tools). The process of disinfection pre- Copper sulfate) vents infection by reducing the number of potentially Dyes or tints (Brilliant green, Ethacridine (Riva- infective organisms either by killing, removing, or di- nol), Methylene blue) luting them. — Detergents (Benzalkonium chloride (Roccal), Antiseptics are agents with sufficiently low toxici- Aethonium, Cerigelum, Decamethoxin, Soaps) ty for host cells that they can be used directly on the — Derivatives of different chemical groups (Nitro- skin, mucous membranes, or wounds. Disinfectants and fural (Furacilinum)) antiseptics can be used both for disinfecting of medi- — Agents from plant source (Novoimaninum, Chlo- cal tools and human skin depending on their concen- rophyllipt, and Lysocim) tration. There is considerable overlap and many agents are used in either way. HALOGENS Chemotherapeutic agents are used for germs killing inside the organism. Disinfectants and antiseptics Anti-germ activity of halogens depends on their differ from chemotherapeutic agents by their low par- ability to release chlorine and iodine. They form chlo- asite selectivity and high toxicity for systemic use. ric and iodic acids in water solutions. The latter re- A good disinfectant/antiseptic should be active lease atomic oxygen and haloids. These ions denature against all pathogens (bacteria, fungi, viruses, proto- proteins of germs and act bactericidal. zoa etc.), active even in the presence of blood, pus and Chlorine is a strong oxidizing agent and universal exudates. A disinfectant in addition should be not cor- disinfectant that is most commonly provided as a 148 5.25% sodium hypochlorite solution, a typical formu- The Hydrogen peroxide has high killing activity lation for household bleach. Chlorine is used to disin- and a broad spectrum against bacteria, spores, virus- fect urban water supplies. es, and fungi when used in appropriate concentration. Because chlorine is inactivated by blood serum, It has the advantage that its decomposition products feces, and protein-containing materials, surfaces are not toxic and does not injure the environment. Hy- should be cleaned before chlorine disinfectant is ap- drogen peroxide is powerful oxidizer that is used pri- plied. Solutions of chlorine are corrosive to aluminum, marily as antiseptic. Organisms with the enzymes cat- silver, and stainless steel. alase and peroxidase rapidly degrade hydrogen per- Chlorophores (Chlorinated lime, Chloramine B) are oxide. The innocuous degradation products are atom- compounds that slowly release hypochlorous acid ic and molecule oxygen, and water. Molecule oxygen (HOCl). Because of ease of handling, they are used in forms the foam that helps in loosing and removing preference to gaseous chlorine. These agents retain slough dead tissues. Hydrogen peroxide has been pro- chlorine longer and have a prolonged bactericidal ac- posed for wound irrigation, disinfection of respirators, tion. Chlorinated lime (bleaching powder) is obtained acrylic resin implants, plastic eating utensils, soft con- by the action of chlorine on lime. It is used as disin- tact lenses. Hydrogen peroxide has poor penetrabili- fectant for medical tools, drinking water, swimming ty and a transient action. pools and sanitizer for privies. Chloramine B may be Potassium permanganate. It liberates oxygen, used for disinfecting of clothes, skin and instruments, which oxidizes bacterial protoplasm, and MnO2, which are not made from metal. which cause astringent and irritating effects. Solution Chlorhexidine is a cationic biguanide with very low of Potassium permanganate is used for gargling, water solubility. Water-soluble chlorhexidine bigluco- douching, and irrigating cavities, urethra and wounds. nate is used in water-based formulations as an antisep- It has also been used for stomach wash in alkaloid poi- tic. It is most effective against gram-positive cocci and soning. It promotes rusting and is not good for surgi- less active against gram-positive and gram-negative cal instruments. rods. Spore germination is inhibited by Chlorhexidine. It is resistant to inhibition by blood and organic materials. Chlorhexidine is used in the treatment of in- ACIDS flammation of the oral mucosa caused by bacterial or fungal actions, for surgeon hands washing before op- Boric acid possesses fungistatic and weak bacteri- eration, for medical tools disinfection. Chlorhexidine ostatic properties. Drug has greater bacteriostatic ac- has a very low skin-sensitizing or irritating capacity. tivity in bases containing large amounts of water than Oral toxicity is low because chlorhexidine is poorly in fatty bases. Boric acid retards the growth of fungi absorbed through the alimentary tract. Chlorhexidine but is not fungicidal. Aqueous solutions of boric acid must not be used during surgery on the middle ear be- are used topically for ophthalmic irrigation to cleanse cause it causes sensor neural deafness. Similar neural and refresh irritated eyes. It is used topically as a skin toxicity may be encountered during neurosurgery. protection for relief of discomfort of chafed skin, dry Iodine is a rapidly acting, broad spectrum (bacte- skin, abrasions, or other skin irritations and has been rial, fungi, and viruses) microbicidal agent. Acts by used topically for the treatment of superficial fungal iodinating and oxidizing germ protoplasm. Iodine in infections; however, the drug is generally considered a 1:20,000 solution is bactericidal in 1 minute and kills as lacking substantial evidence of efficacy for these spores in 15 minutes. It is the most active antiseptic uses. for intact skin. It is not commonly used because of se- The risk of systemic toxicity from topical applica- rious hypersensitivity reactions, skin, irritation that tion of boric acid depends on the concentration used may occur and because of its staining of clothing and (more than 5%), age of the patient (children appear to dressings. be more susceptible), skin condition (increased with Iodophors are complexes of iodine with a surface- abraded, or macerated skin). Boric acid can produce active agent such as polyvinylpyrrolidone (Iodinole, Io- severe and fatal poisoning, consisting of GI disturbanc- dovidone). The amount of free iodine is low, but it is es, erythematosus skin eruptions, and signs of CNS released as the diluted solution. Iodophors retain the stimulation followed by depression. Treatment of acute activity of iodine. Iodophors are less irritating and less boric acid intoxication consists mainly of intensive likely to produce skin hypersensitivity than tincture of symptomatic and supportive therapy. iodine. They kill vegetative bacteria, mycobacterium, Salicylic acid has a potent keratolytic action and fungi, and lipid-containing viruses. They may be spori- a slight antifungal and antiseptic action when applied cidal upon prolonged exposure. Iodophors can be used topically to the skin. In low concentrations, the drug as antiseptics or disinfectants, the latter containing more has keratoplastic activity (activation of keratinization) free iodine. Dilution may release more free iodine. An and in higher concentrations (i.e. 1% or higher), the iodophor solution must be diluted according to the man- drug has keratolytic activity (causes peeling of skin). ufacturer’s directions in order to obtain full activity. At high concentrations, salicylic acid has a caustic effect. Salicylic acid is used topically for its keratolytic effect in controlling scaling dermatoses (seborrheic, OXIDIZING AGENTS psoriasis). It has also been used in the treatment of localized hyperkeratosis, such as occurs on the palms Oxidizing agent are free atomic oxygen releasers. and soles. Salicylic acid is not used systemically be- Atomic oxygen leads to irreversible damage of oxidiz- cause of its severe irritating effect on GI mucosa and ing-restoring reaction of germ. other tissues.

149 PHENOL DERIVATIVES water (100% Formalin). The 3.7% Formaldehyde (10% Formalin) solutions used for fixation of tissues and Phenol itself perhaps the oldest of the surgical dis- embalming may not be mycobactericidal. Including infectant/antiseptic. It is used to disinfect urine, feces, formaldehyde preparation decrease foot sweating. The and pus, for drug conservation. Phenol no longer used urinary antiseptic Hexamethylenetetramine (Methen- as an antiseptic because of its corrosive effect on tis- amine) acts by releasing Formaldehyde in acidic me- sues, its toxicity upon absorption, and its carcinogen- dium. It is used for urinary tract infections. ic effect. When swallowed (with suicidal purpose) it Those who handle Formalin can develop eczema- causes buccal, esophageal and stomach burns, excita- toid reaction. It has declared that formaldehyde is a tion, convulsions, respiratory paralysis and vascular potential carcinogen. collapse. Glutaraldehyde is less pungent and better steriliz- Phenol derivatives (Cresol, Resorcin, and Vagotil) ing agent than formalin. Solutions of 2% Glutaralde- are less toxic than phenol. Phenolic compounds dis- hyde are most commonly used. It is used for disinfec- rupt cell wall and membranes, precipitate proteins, tion or sterilization of instruments such as fiberoptic and inactivate enzymes. They are bactericidal (includ- endoscopes, respiratory therapy equipment, hemodia- ing mycobacteria), fungicidal, and capable of inacti- lyzers, and dental handpieces. vating lipophilic viruses. Cresol more active than phenol. It is used for hard surface decontamination in hospitals and laboratories, e.g. floors, beds, and counters METALLIC SALTS 1 or bench tops. Resorcin is /3 as potent as phenol. It also has keratolytic activity, that’s why resorcin em- Metals cause antiseptic action, because they eas- ployed on seborrheic dermatitis, eczema, acne as so- ily combine with sulfhydryl (SH) group of thiolic en- lution or ointment. Vagotil in addition acts on tri- zymes, thus stopping the oxidizing process of micro- chomonas — used for topical vaginitis treatment. organisms. When metal-ions interact with human pro- Detergents are often added to formulations to clean teins, physical properties of the protein are usually and remove organic material that may decrease the ac- altered; the protein may be denatured and precipita- tivity of a phenolic compound. Skin absorption and tion usually occurs. When the concentration of met- skin irritation still occur with phenol derivatives, and al is low, precipitation prevents deep tissue penetra- appropriate care is necessary in their use. They are tion and astringent action occurs. When the concen- not recommended for use in nurseries and especially tration of metal is high, membrane and intracellular bassinets, where their use has been associated with hy- structures are damaged and caustic or escharotic ac- perbilirubinemia. tion occurs. Metal-ions in the high concentration interact with sulfhydryl groups, inhibiting enzymes and altering cell ALDEHYDES AND ALCOHOLS membranes of human tissues, which leads to poisoning. The most distinct example is the case of mercury The two alcohols most frequently used for antisep- poisoning. Acute inhalation of elemental mercury va- sis and disinfection are Ethanol and Isopropyl alco- pors may cause chemical pneumonitis and noncardio- hol (Isopropanol). They are rapidly active, killing genic pulmonary edema. Acute gingivostomatitis may vegetative bacteria, M. tuberculosis, and many fungi occur, and neurologic sequelae (tremor, memory loss, and inactivating lipophilic viruses. They are not spor- fatigue, insomnia, and anorexia) may also ensue. icidal, may not be active against hydrophilic viruses, Acute ingestion of inorganic mercury salts, such as and lack residual action because it evaporates com- mercuric chloride, can result in a corrosive, potential- pletely. Alcohols probably act by denaturation of pro- ly life-threatening hemorrhagic gastroenteritis fol- teins. Alcohols have been used for skin disinfecting in lowed within days by acute tubular necrosis and olig- case of abrasion and before hypodermic injection. The uric renal failure. In addition to intensive supportive rapidity of antiseptic action increases with concentra- care, acute chelation with Dimercaprol (Unithiol) or tion up to 70% and decreases above 90%. At 90% con- Edetate calcium disodium (Calcium EDTA) may be centration they form a coagulum under which bacte- of value in diminishing nephrotoxicity after acute ex- ria could grow. posure to inorganic mercury salts. The sulfhydryl Alcohols are an irritant and should not be applied groups of dimercaprol form heterocyclic ring complex- to mucous coats. They are poor disinfectant for instru- es with heavy metals (particularly arsenic, mercury, ments — does not kill spores and promote rusting. and gold), and these complexes prevent or reverse the Aldehydes (Formaldehyde and Glutaraldehyde) binding of metallic cations to body ligands such as es- act by alkylation of chemical groups in proteins and sential sulfhydryl-dependent enzymes. The calcium in nucleic acids. Activated solutions are bactericidal, spo- Calcium EDTA can be displaced by divalent and tri- ricidal, fungicidal, and virucidal for both lipophilic valent metals to form stable soluble complexes which and hydrophilic viruses. They are not corrosive for can then be excreted in urine. metal, plastic, or rubber. Silver nitrate exhibits antiseptic, germicidal, astrin- Formaldehyde has a characteristic pungent odor gent, and caustic or escharotic activity. Inorganic sil- and is highly irritating to respiratory mucous mem- ver salts are strongly bactericidal. Silver nitrate, branes and eyes. Formaldehyde solutions are used for 1:100, has been most commonly used, particularly as high-level disinfection of hemodialyzers, preparation a preventive for gonococcal ophthalmitis in newborns. of vaccines, and preservation and embalming of tis- Silver nitrate touch is used for hypertrophied tonsilli- sues. Formaldehyde is available as a 37% solution in tis and aphthous ulcers.

150 Silver salts stain tissue black because of deposition been used as a urinary tract antibacterial agent (irri- of reduced silver. Contact of 1% silver nitrate solution gation), however, more effective agents have replaced with skin or other surfaces should be avoided since this medication. It is used as a bacteriological stain, staining of the skin may occur. Silver nitrate is caus- as a dye in diagnostic procedures, such as fistula de- tic and irritating to skin and mucous membranes. Cau- tection, and for the selective staining of certain body terization of the cornea and blindness may result from tissues during surgery. Methylene blue is indicated in repeated application of silver nitrate ophthalmic solu- the treatment of acquired and idiopathic methemoglo- tion. Mistaken or accidental single-dose administra- binemia. In low concentrations, it acts as a cofactor tion of 5–50% Silver nitrate solutions has reportedly to accelerate the conversion of methemoglobin to he- caused severe ocular injury including permanent cor- moglobin in erythrocytes. neal opacification and cataracts. Silver sulfadiazine slowly releases silver and is used to suppress bacterial growth in burn wounds. Collar- DETERGENTS gol (colloidal silver) and Protargol (protein silver) also slowly release silver ions, are not irritating. They are Detergents or surface-active compounds decrease used in cases of conjunctivitis, ulcers. surface tension of cell membrane act, thus alter its per- Zinc sulfate exhibits astringent and mild antisep- meability. There are two kinds of detergents. They are tic activity. These effects may result from precipitation cationic detergents (quaternary ammonium com- of protein by the zinc ion. Zinc sulfate is used in oph- pounds) and anionic detergents (soaps). thalmic solutions as an astringent for the temporary The quaternary ammonium compounds (“quarts”) relief of discomfort from minor eye irritation. It has are bacteriostatic, fungistatic, and sporostatic. They also been used in the treatment of angular conjuncti- highly effective against gram-positive bacteria and vitis. Zinc oxide being mildly antiseptic, it is popular moderately active against gram-negative bacteria. dermal protective and adsorbentive agent. Zinc is nec- Strains of M. Tuberculosis and Pseudomonas aerugi- essary for the proper functioning of over 200 metal- nosa are often resistant and they are not effective loenzymes. Physiological functions that are zinc de- against spore-forming organisms. pendent include cell growth and division, sexual mat- Quaternary compounds possess detergent, kerato- uration and reproduction, night vision, wound healing, lytic, and emulsifying action. They are used for sani- host immunity, taste acuity. tation of non-critical surfaces (floors, bench tops, etc). Copper sulfate as astringent and antiseptic has Quaternary compounds bind to the surface of col- been used for conjunctivitis, ureteritis and vaginitis loidal protein in blood, serum, to fibers present in cot- treatment. Copper is necessary for the proper function- ton, mops, cloths, and paper towels used to apply them, ing of many metalloenzymes. Physiological functions which can cause inactivation of the agent by remov- that are copper dependent include oxidation of iron, ing it from solution. Anionic detergents (soaps) inacti- erythro- and leukopoiesis, bone mineralization, elas- vate them. That is why before applying quaternary tin and collagen cross-linking, myelin formation, and ammonium compounds to the skin for preoperative dis- antioxidant protection of the cell. Such polyvitamins infection, all traces of soap should be removed with as “Quadevit”, “Complivit” include copper sulfate water and with 70% alcohol. (“Complivit” also contain zinc). The representatives of quaternary ammonium are Mercury is now rarely used as disinfectant/antisep- Roccal (Benzalkonium chloride), Aethonium, Cerige- tic. Mercurials are poor antiseptics with low therapeu- lum, Decamethoxin. tic index. But some are still used. For example Hydr- Properly diluted, Roccal is used for the preopera- argyrum amidochloride (ammoniated mercury) used tive disinfection of unbroken skin and prophylactic dis- for skin disease treatment. infection of the intact skin, in the treatment of superfi- Aluminum and lead preparations are used for anti- cial injuries and infected wounds. It is also used to pre- septic rinsing and applying. Aluminum hydroxide be- serve the sterility of surgical instruments and rubber ing an antacid is indicated for relief of symptoms as- articles during storage, and to preserve the sterility of sociated with hyperacidity (heartburn, acid indiges- ophthalmic solutions. Aethonium and Decamethoxin tion, and sour stomach). are used for the treatment of trophic ulcers, stomatitis, keratitis. Finally Cerigelum is used for hands washing of medicine staff before surgical treatment. DYES (TINTS) Soaps are anionic detergents. They are weak antiseptic and affect only gram-positive bacteria. Their Brilliant green active against fungi, staphylococ- usefulness primarily resides in their cleansing action. ci, and other gram-positive bacteria. Aqueous or alco- Other antiseptics can medicate soaps. hol solution is used on furunculosis, skin abrasion, cut- Furacilinum (Nitrofurazone) is a synthetic anti- ting, infected eczema. Staining is a disadvantage with bacterial nitrofuran derivative. Furacilinum acts by all dyes. Brilliant green is inactivated by blood serum, transforming it nitro-group into the amino-group that feces, and protein-containing materials. leads to inhibiting bacterial enzymes involved in car- Ethacridine lactate (Rivanol) influence mostly bohydrate metabolism. Organic matter (e.g. blood, gram-positive germs. It’s water solution, ointment, pus, serum) inhibits the antibacterial action of Fura- paste are used for wounds and cavities washing and in cilinum. Furacilinum has a wide spectrum of activity dermatology. against a variety of gram-positive and gram-negative Methylene blue has mild antiseptic activity that organisms, however, particularly it does not inhibit fun- may inhibit bacterial proliferation. Methylene blue has gi or viruses. Furacilinum may be active against or-

151 ganisms that have developed resistance to antibiotics trum is the list of infectious diseases, which can be and sulfanilamides. It is used topically in patients with cured by this agent. burns, for prophylaxis and treatment of infections of the skin and mucous membranes, middle and external The principles of effective chemotherapeutic actions ear caused by susceptible bacteria. Furacilinum solu- are the following: tions have been used as a bladder irrigant in catheter- — Rational choice of preparation according to clin- ized patients. ical and bacteriologic diagnosis Allergic contact dermatitis is the most frequently — Optimal dosage, way and interval between drug reported adverse effect of topical Furacilinum and has using occurred in approximately 1% of patients treated. — Beginning of therapy as soon as possible before Novoimaninum is anti-germ agent, obtaining from destructive changes of organs the plant Hypericum perforatum. It acts primary on — If the clinical improvements after 2–3 days gram-positive microorganisms, including penicillin-re- course are absent, the agent must be changed sistance staphylococci. Novoimaninum has used topical- — The therapy have been continued 2–3 days af- ly as solution for abscess and infective wound treatment. ter the clinical symptoms disappear Chlorophyllipt is a mixture of chlorophylls getting — Chemotherapy should be performed with other form Eucalyptus leaves and Myrta’s seeds. It can be remedies that enforce the immunity used for the treatment of burns, trophic ulcers. Lysocim is the protein structure enzyme. It is produced from hen egg protein. Lysocim breaks polycar- bohydrates of cell membrane, acts mostly on gram- positive germs. In addition it stimulates host non-spe- Lecture 35 cific resistance, causes anti-inflammation and muco- ANTIBIOTICS lytic action. Lysocim is used for chronic septic state, burns, conjunctivitis. It applies topically and injects intramuscularly. It has not irritant action. Antibiotics are the products of certain mycotic organisms, different bacteria. With the help of antibiot- Available forms: ics these microorganisms can suppress the growing of Chlorhexidine bigluconate — in bottles 20% solu- another microbes or kill them. Antibiotic, which tion 0.5; 3 or 5 liters each formed by alive organism, is biosynthetic (natural) an- Iodovidon (Povidone-Iodine) — in bottles 1% so- tibiotic, however after chemical conversions it becomes lution semisynthetic antibiotic. Finally, antibiotic that we get Hydrogen peroxide — in glasses 3% solution as a result of chemical reaction only named as synthet- Potassium permanganate — in bottles 0.01%; ic antibiotic. 0.1%; 0.5%; 2% solution In 1929 Alexander Fleming reported his discovery Boric acid — in bottles 0.5%; 1%; 2%; 3% spirit of first antibiotic — penicillin. In 1940 Chain, Florey solution 10 ml each succeeded in producing significant quantities of the first Hexamethylenetetramine — powder or tablets 0.25; penicillin and discovered its efficiency for infectious dis- 0.5 g each; in ampoules 40% solution 5; 10 ml each ease. Ermolyeva during World War II elaborated the Resorcin — powder; 2–5% solution (water or spir- commercial production of penicillin in the USSR. Wax- it); 5–20% ointment man made educing of streptomycin in 1944. Argent nitrate — powder; 0.25–2% or 2–10% solution; 1–2% ointment Classification of antibiotics according to a spectrum Zinc sulfate — powder; eyes drops in bottles 0.25% of their antimicrobial activity: or 0.5% solution 10 ml — With the main influence on the gram-positive Methylene blue — powder; 1% spirit or water solu- microbes: Penicillins; Cephalosporins; Macrolides; tion; in ampoules 1% solution of Methylene coeruleus reserve antibiotics (Lincomycin, Vancomycin) in 25% glucose solution 20; 50 ml — With main influence on the gram-negative mi- Ethacridine lactate — powder; in bottles 1% or 2% crobes: Aminoglycosides spirit solution 10 ml — Influencing both gram-positive and gram-nega- Decamethoxin — tablets 0.1 gram for solution pre- tive microbes: Tetracyclines; Levomycetin (Chloram- paring; in bottles 0.05% spirit solution 10 ml each phenicol) Furacilinum — powder; tablets 0.1 g (for ingestion) — Influencing both gram-positive and gram-nega- and 0.02 g (for solution preparing); ointment 0.2% tive microbes, and used locally: Polymyxins; Neomy- cin; Monomycin; Gramicidin — Antifungal antibiotics: Nystatin; Griseofulvin; ANTIMICROBIAL Amphotericin B CHEMOTHERAPEUTIC AGENTS — Anticancer preparations: Actinomycin, Olivomy- cin, Bruneomycin Chemotherapeutics are antimicrobial agents that are used for germs killing inside the organism; the an- Classification according to the mechanism of ac- timicrobial action usually occurs after they’re appear- tion: ing in the blood circulation system. — Antibiotics that inhibit bacterial microbe’s cell Spectrum of activity of agent is the list of microor- wall synthesis: penicillins, cephalosporins, and Van- ganisms, that are sensitive to it. Chemotherapeutic spec- comycin 152 — Antibiotics disordering permeability of microbe’s cochlear nerve); aminoglycosides and polymyxins can cell capsule (decreasing the surface straining or deter- cause nephrotoxic impairments while tetracyclines are gent effect): antifungal antibiotics, polymyxins hepatotoxic. — Antibiotics inhibiting synthesis of DNA, RNA: d. Endotoxic reaction that is usually appears at the Griseofulvin, Rifampicin, and anticancer antibiotics beginning of specific treatment of syphilis, typhoid fe- — Antibiotics inhibiting the protein synthesis of the ver, and meningitis. It may cause a state of shock, ac- microorganisms: macrolides, aminoglycosides, tetra- companied by severe diarrhea, fever, and leukopenia cyclines, and Levomycetin followed by leukocytosis. The reason of endotoxic reaction is releasing of endotoxin, which form an inte- Antibiotics can act bactericidal (penicillins, cepha- gral part of the cell wall of a variety of gram-negative losporins, aminoglycosides, polymyxins) and bacteri- bacteria. ostatic (macrolides, tetracyclines, levomycetin, antimy- The β-lactam antibiotics are the most frequently cotic antibiotics). Also antibiotics are divided into ba- used group of antibiotics. The β-lactam compounds are sic (main) agents and supplemental (reserve) agents. penicillins, cephalosporins, monobactams, carbapen- Usually, reserve antibiotics are less effective and more ems, and beta-lactamase inhibitors. toxic, than basic agents are. Thus, the reserve antibiotics are indicated only in case of resistance or hypersensitivity to basic antibiotics. PENICILLINS When the inhibitory or killing effects of two or more Penicillin is produced by different species of Peni- antimicrobials used together are significantly greater cillium cultures. It inhibits bacterial microbes cell wall than expected from their effects when used individual- synthesis. Penicillins are bactericidal agents. All pen- ly, synergism is said to result. For example, Ben- icillins are the derivatives of 6-aminopenicillanic acid, zylpenicillin in combination with Gentamicin is supe- which consists of thiazolidine ring and β-lactam ring. rior to monotherapy with Penicillin or Gentamicin for If the beta-lactam ring is enzymatically cleaved by the treatment of enterococcal endocarditis. Enzymat- β bacterial beta-lactamases, the resulting product, peni- ic inactivation of -lactam antibiotics is a major mech- cilloic acid lacks antibacterial activity. anism of antibiotic resistance. Several β-lactam + β- lactamase inhibitor combinations (e.g. Amoxicillin- Classification of drugs: Clavulanic acid) have been successful against a varie- — Biosynthetic penicillins: Benzylpenicillin sodi- ty of bacterial infections. um, potassium or novocain salts (Penicillin G); Phe- On the other hand, bacteriostatic agents such as tet- noxymethylpenicillin (Penicillin V); Bicillin-1 (Pen- racyclines and levomycetin can antagonize the action β icillin G Benzathine); Bicillin-5 of bactericidal cell wall-active agents (e.g. -lactam — Semisynthetic penicillins: antibiotics). The bactericidal effects of cell wall active a) penicillinase resistant agents: Oxacillin; Methi- agents require that the bacteria be actively growing cillin; Nafcillin; and dividing. This antagonistic interaction is thought b) extended-spectrum penicillins: Ampicillin, Amox- to be due to inhibition of bacterial growth by the bac- icillin and antipseudomonal penicillins: Carbenicillin, teriostatic agent. Tetracyclines and levomycetin have Carfecillin, Azlocillin. also been shown to antagonize the bactericidal effects of aminoglycosides. Also it is not recommended the con- The spectrums of activity of biosynthetic penicil- current using of agents with the similar adverse effect, lins include gram-positive cocci (staphylo-; pneumo- e.g. aminoglycosides with polymyxins. and streptococci), gram-negative cocci (meningo- and In spite of the specific activity of antibiotics, they gonococcus), anaerobes (Clostridium tetani, Cl. per- may cause some adverse effects. There are the follow- fringens). Some other organisms for which biosynthet- ing adverse effects, characteristic for antibiotics: ic Penicillin has good activity include Bacillus anthra- a. Allergic reactions of immediate and delayed cis, Corynebacterium diphtheriae, and Treponema Pal- types. Anaphylactic shock, angioneurotic laryngeal lidum. However, many strains of staphylococci pro- edema, exfoliative dermatitis, bullous erythema are the duce beta-lactamases, which destroy these penicillins. most hazardous. They are often caused by penicillins, Benzylpenicillin sodium and potassium are not ab- cephalosporins. sorbed from the gastro-intestinal tract, because they b. Disbacteriosis is the modification of normal gas- are destroyed in acidic medium of the stomach. After tro-intestinal microflora, with suppression of suscepti- i.m. injection peak of blood concentrations are usual- ble coliform organisms. It leads to superinfection — ly obtained within 30 min and stay during 3–4 h. For overgrowing of Pseudomonas, Proteus, Staphylococ- maintenance of blood stable concentration it must be ci, Clostridia, and Candida. This can result in intesti- administrated every 4 h. Benzylpenicillins are widely nal functional disturbances, anal pruritus, vaginal or distributed to most tissues and body fluids. They also oral candidiasis, staphylococcus enteritis, and hypo- cross the placenta and are distributed into breast milk. vitaminosis. Antibiotics with a wide efficiency spec- Distribution into the cerebrospinal fluid is low in sub- trum (Tetracyclines, Levomycetin, and Ampicillin) usu- jects with non-inflamed meninges, as is penetration ally cause such effect. into purulent bronchial secretions. c. Toxic reactions that are specific for antibiotics The normal half-life of benzylpenicillin sodium and and depend on the dose and therapy terms. For exam- potassium is approximately 30 min. Hepatic metabo- ple, Levomycetin causes bone marrow depression: re- lism accounts for less than 30% of the biotransforma- ticulocytopenia, anemia, and granulocytopenia. tion of benzylpenicillins. They are rapidly excreted by Aminoglycosides are neurotoxic (neuritis of vestibulo- the kidneys into the urine. About 10% of renal excre- 153 tion is by glomerular filtration and 90% by tubular se- Ampicillin, Amoxicillin are also available in com- cretion. Blood levels of all penicillins can be raised by bination with one of several beta-lactamase inhibitors: simultaneous administration of Probenecid, which im- Clavulanic acid, Sulbactam. The addition of a beta- pairs their tubular secretion. lactamase inhibitor extends the activity of these peni- Benzylpenicillin sodium and potassium are the drug cillins to include beta-lactamase-producing strains of of choice for the treatment of actinomycosis, anthrax, staphylococci as well as some beta-lactamase-produc- diphtheria, gonorrhea, scarlet fever, syphilis, and gas ing gram-negative bacteria. For example, Unasyn gangrene. They also are used in the treatment of bac- (Ampicillin + Sulbactam), Augmentin (Amoxicillin terial endocarditis, bacterial septicemia, sore throat, + Clavulanic acid). acute otitis media, bacterial pneumonia, rheumatic fe- Ampiox (Ampicillin + Oxacillin) is the combina- ver, bone and joint infections, skin diseases caused by tion of Ampicillin and Oxacillin. Thanks to that it’s susceptible organisms. active against both penicillinase-producing staphylo- Benzylpenicillin novocain dissolves slowly at the cocci and broad spectrum of gram-positive and gram- site of injection, maintaining therapeutic concentration negative microbes. during 8–12 h. It has been used 3–4 times a day intra- The antipseudomonal penicillins (Carbenicillin, muscularly. It has the same spectrum antimicrobial ac- Carfecillin, and Azlocillin) are also extended-spectrum tivity, as Benzylpenicillin sodium or potassium salts. penicillins, but they have less activity against gram- On the other hand, Benzylpenicillin novocain contains positive organisms than the natural penicillins or amp- Novocain, which increases the danger of allergic re- icillin; however, unlike the other penicillins, these pen- actions. icillins are active against some gram-negative bacilli, Bicillin-1 and Bicillin-5 are slowly released from including Pseudomonas aeruginosa, Proteus vulgaris. the i.m. injection site and hydrolyzed to benzylpeni- Carbenicillin is the first antipseudomonal carboxypen- cillin, resulting in serum concentrations that are much icillin. Carfecillin is the converted carbenicillin; it can lower but much more prolonged than other parenteral be used orally. It’s active in lower doses, than Carbe- penicillins. A single injection of Bicillin-1 or Bicillin- nicillin. The Ureidopenicillins, Azlocillin, resemble 5 intramuscularly once every 2–4 weeks is satisfacto- Carbenicillin except that it is also active against se- ry for the treatment of syphilis, and for prophylaxis lected gram-negative bacilli, such as Klebsiella pneu- or treatment of rheumatic fever. moniae, and more potent against Pseudomonas aeru- Phenoxymethylpenicillin is acid-resistant. It is in- ginosa, than Carbenicillin. dicated only in minor infections: prophylaxis of diph- Carbenicillin, Carfecillin, and Azlocillin are indi- theria and rheumatic fever, treatment of scarlet fever cated in the treatment of bone, joint, skin, and soft tis- and sore throat. It is prescribed four times a day. sue infections, endocarditis, septicemia, pneumonia, Oxacillin is resistant to staphylococcal penicilli- meningitis, intra-abdominal infections, prostatitis, fe- nase (β-lactamase). The sole indication for the use of male pelvic infections, and urinary tract infections this agent is infection by penicillinase-producing sta- caused by susceptible organisms. phylococci; however, it is less potent than Benzylpen- Adverse effects. The penicillins are remarkably non- icillin against penicillin-sensitive bacteria. Oxacillin toxic. Most of the serious adverse effects are due to hy- is acid-stable and reasonably well absorbed from the persensitivity. It is appearing quite frequent gut. It is widely distributed to most tissues and body (1–10%). All penicillins are cross-sensitizing and cross- fluids. It is ingested four times a day. For serious sys- reacting. Allergic reactions include fever, joint swell- temic staphylococcal infections, Oxacillin is given by ing, angioneurotic edema, pruritus, and rashes. Very intermittent intravenous infusion of 1–2 g every 4–6 rare anaphylactic shock may occur. In patients with h. Methicillin is no longer used because of its nephro- renal failure, penicillins in high doses can cause sei- toxicity. zures. Large doses of penicillins given orally may lead Ampicillin, Amoxicillin are extended-spectrum pen- to gastrointestinal upset, particularly nausea, vomit- icillins. These drugs retain the antibacterial spectrum ing, and diarrhea. Ampicillin has been associated with of Penicillin, differ in having greater activity against pseudomembranous colitis. Secondary infections such gram-negative cocci and bacteria such as Escherichia as vaginal candidiasis may occur. Ampicillin and coli, Shigella, and Salmonella species. Like ben- Amoxicillin can cause skin rashes that are not aller- zylpenicillin, they are inactivated by penicillinase. gic in nature. Ampicillin and Amoxicillin are acid-stable and relatively well absorbed, achieving serum concentrations within 1–2 h (for intramuscularly injection — 0.5 h). CEPHALOSPORINS Amoxicillin is better absorbed from the gut, than amp- First cephalosporin was obtained from culture of icillin. The duration of action is about 4–6 h. Ampi- Cephalosporium acremonium. Cephalosporins are sim- cillin is excreted in the bile in high concentrations. ilar to penicillins chemically, in mechanism of action, Amoxicillin is only oral penicillins, than can be taken and toxicity. Cephalosporins are more stable than pen- during mealtimes, all the other oral penicillins should icillins to many bacterial β-lactamases and therefore be given 1–2 h before or after eating to minimize bind- usually have a broad spectrum of activity. The nucle- ing to food proteins and acid inactivation. Ampicillin us of the cephalosporins is 7-aminocephalosporanic and Amoxicillin can be used for the treatment of bone acid. Cephalosporins can be classified into four major and joint infections, sore throat, bronchitis, pneumo- groups or “generations”, depending mainly on the nia, meningitis, bacillary dysentery, typhoid fever, sep- spectrum of antimicrobial activity. As a general rule, ticemia, urinary tract infections caused by susceptible first-generation compounds have better activity against organisms. gram-positive organisms and the later compounds ex-

154 hibit improved activity against gram-negative aerobic Cefuroxime is the only second-generation drug that organisms. crosses the blood-brain barrier, but it is less effective in treatment of meningitis than Ceftriaxone or Cefo- Classification of drugs: taxime and should not be used. However, Cefuroxime — First-generation cephalosporins: Cefazolin, Ce- more stable against certain β-lactamases. Cefuroxime phalothin, Cephaloridine, Cephalexin is commonly used to treat community-acquired pneu- — Second-generation cephalosporins: Cefaclor, monia because of its extend spectrum activity. Cefuro- Cefuroxime, Cefoxitin xime axetil, an oral prodrug of Cefuroxime, is hydro- — Third-generation cephalosporins: Cefotaxime, lyzed to Cefuroxime after absorption. It has been used Ceftriaxone, Cefixime to treat mild to moderate bronchitis, otitis media, skin — Fourth-generation cephalosporins: Cefepime, and soft tissue infections, uncomplicated gonococcal Cefpirome urethritis, and urinary tract infections. Cefoxitin has the greatest stability in the presence First-generation cephalosporins are active against of β-lactamases produced by the Bacteroides fragilis gram-positive cocci (pneumo-, strepto-, and staphylo- group. Because of its activity against anaerobes, Ce- cocci), Neisseria gonorrhoeae, Escherichia coli, Kleb- foxitin can be useful in such mixed anaerobic infec- siella pneumoniae, and Proteus mirabilis. They are tions as aspiration pneumonia, intra-abdominal and used to treat septicemia, bone and joint infections, otitis female pelvic infections. It is also used prophylactical- media, pneumonia, skin and soft tissue infections, in- ly to help prevent perioperative infections that may re- cluding burn wound infections, and urinary tract insult from colorectal surgery and appendectomies, and fections caused by susceptible bacterial organisms. in the treatment of penicillin-resistant strains of gon- These medications are possible alternatives to the pen- orrhea. icillins for staphylococcal and streptococcal infections. Cefaclor is more susceptible to β-lactamase hydrol- Cefazolin can be used intramuscularly or intrave- ysis compared with the other agents, and its utility is nously every 8 h (Table 12). Excretion is via the kid- correspondingly diminished. It has been primarily used ney. Cefazolin penetrates well into most tissues. It is to treat sinusitis, otitis, or lower respiratory tract in- the drug of choice for surgical prophylaxis because of fections, in which these organisms have an important its longer half-life. Cefazolin may be a choice in in- role. fections for which it is the least toxic drug (e.g. Kleb- Third-generation agents are less active against siella pneumoniae). Cephalexin is absorbed from the gram-positive cocci as are the first- and second-gener- gut to a variable extent. Urine concentration is usual- ation. However, in addition to the gram-negative bac- ly very high. It may be used for the treatment of uri- teria inhibited by other cephalosporins, third-genera- nary tract infections, for minor staphylococcal lesions, tion drugs are active against Serratia, Enterobacter as or for minor polymicrobial infections such as celluli- well as β-lactamase-producing strains of Haemophil- tis or soft tissue abscess. us and Neisseria. Ceftazidime and Cefoperazone are In general, second-generation cephalosporins are useful against Pseudomonas aeruginosa. Some cepha- active against organisms affected by first-generation losporins (Ceftriaxone, Cefotaxime) are able to cross drugs, but they have an extended gram-negative cov- the blood-brain barrier. erage, e.g. Proteus vulgaris, Enterobacter, Haemo- Third-generation cephalosporins are used in the philus influenzae. All second-generation cepha- treatment of serious gram-negative bacterial infections, losporins are less active against gram-positive bacte- including septicemia, bone infections, female pelvic ria than the first-generation drugs. Some Enterobacter and intra-abdominal infections, and urinary tract in- species can express a chromosomal beta-lactamase that fections caused by organisms that are resistant to most hydrolyzes second-generation cephalosporins (as well other drugs. Ceftriaxone and Cefotaxime are first-line as third-generation cephalosporins). drugs for treatment of gonorrhea, meningitis. They are

Table 12. Pharmacokinetics of cephalosporins

Bioavail- Protein Agent Half-life, h Dosing information ability, % binding, % Cefazolin/ i.m. 85 1.4–1.8 0.5 g 3 times a day Cephalothin/ i.m. 70 0.5–1.0 0.5 g 4 times a day Cephalexin/ oral 90–95 15–20 0.9–1.2 0.5 g 4 times a day Cefaclor/ oral 50–95 25 0.6–0.9 0.25 g 3 times a day Cefuroxime/ i.m. 50 1.2–1.9 0.75 g 3 times a day Cefoxitin/ i.m. 70–80 0.7–1.1 1–2 g 3 times a day Cefotaxime/ i.m. 38 1.0 0.5 g 2 times a day Ceftriaxone/ i.m. 85–95 5.8–8.7 1–2 g once a day Cefixime/ oral 40–50 65–70 3.0–4.0

155 the most active cephalosporins against penicillin-resist- (Pseudomonas, Enterobacter, Serratia), gram-positive ant strains of pneumococci and are recommended for organisms, and anaerobes. They are resistant to most empirical therapy of serious infections that may be β-lactamases. caused by these strains. Carbapenems penetrate body tissues and fluids The excretion of Сefoperazone and Сeftriaxone is well, including the cerebrospinal fluid; the half-life mainly through the biliary tract, and no dosage ad- is about 1–1.5 hours. Imipenem is inactivated by de- justment is required in renal insufficiency. The others hydropeptidase in renal tubules, resulting in low uri- are excreted by the kidney and therefore require dos- nary concentrations. Consequently, it is administered age adjustment in renal insufficiency. together with an inhibitor of renal dehydropeptidase, Cefepime is an example of a so-called fourth-gen- Cilastatin, for clinical use. Tienam (Imipenem + Cil- eration Сephalosporin. It is in many ways similar to astatin) is example of such combination. Meropen- third-generation agents, but it is more resistant to hy- em is not significantly degraded by renal dehy- drolysis by chromosomal beta-lactamases (e.g. those dropeptidase and does not require an inhibitor. It is produced by Enterobacter), that inactivate many of the primarily excreted unchanged by kidneys. The usual third-generation cephalosporins. It has good activity dose is given i.v. or i.m. every 6–8 hours. Carbapen- against Pseudomonas aeruginosa. The clinical role of ems are indicated in the treatment of intra-abdomi- Cefepime, which remains to be defined, will probably nal infections, skin and soft tissue infections caused be similar to that of the third-generation cepha- by susceptible organisms. They have the same mech- losporins except that it may be useful in treatment of anism action as Aztreonam. infections caused by Enterobacter. The most common adverse effects of carbapenems Adverse effects. Cephalosporins are sensitizing and are nausea, vomiting, diarrhea, skin rashes, and re- may elicit skin rashes, pruritus, fever, granulocytope- actions at the infusion sites. Carbapenems may lead nia, and hemolytic anemia. The frequency of cross-al- to seizures in patients with a prior history of seizures lergenicity between cephalosporins and penicillins is or CNS abnormality. Patients allergic to penicillins around 5–10%. Local irritation can produce severe or cephalosporins may be allergic to carbapenems as pain after i.m. injection and thrombophlebitis after i.v. well. injection. Renal toxicity, including interstitial nephritis has been caused by Сephaloridine. Moxalactam, Сefoperazone could cause hypoprothrombinemia, MACROLIDES bleeding disorders, and disulfiram-like reactions. Many second- and particularly third-generation ce- The macrolides characterized by a macrocyclic phalosporins are ineffective against gram-positive or- lactone ring (usually containing 14 or 16 atoms) to ganisms, especially methicillin-resistant staphylococ- which deoxy sugars are attached. Erythromycin is ob- ci and enterococci. During treatment superinfection, tained from Streptomyces erythreus (since 1952), Ole- mycosis may appear. andomycin — from Streptomyces antibioticus. Clari- thromycin and Azithromycin are semisynthetic derivatives of Erythromycin. Macrolides are effective MONOBACTAMS against gram-positive organisms (pneumo-, strepto-, staphylococci, and Corynebacteria), Mycoplasma, Le- The representative of this group is Aztreonam. β gionella, Chlamydia trachomatis, Helicobacter, This is drug with a monocyclic -lactam ring. Aztre- Treponema pallidum, and Rickettsia species. The an- onam inhibit bacterial cell wall synthesis and acts β tibacterial action of macrolides is bacteriostatic. They bactericidal. It is relatively resistant to -lactamases inhibit protein synthesis via binding to the ribosomal and active against gram-negative rods (including RNA and blocking aminoacyl translocation reactions. Pseudomonas, Klebsiella, Serratia, and Proteus mi- Activity is enhanced at alkaline pH. rabilis). However, it has no activity against gram-pos- Erythromycin base is destroyed by stomach acid itive bacteria or anaerobes. It resembles aminogly- and must be administered with enteric coating. Food cosides in its spectrum of activity. Aztreonam is giv- interferes with absorption. Bioavailability varies been i.v. or i.m. every 8 hours in a dose of 1–2 g. It is tween 30 and 65%, depending on the salt. The serum rapidly and widely distributed to body fluids and tis- half-life is approximately 1.5 h. Large amounts of an sues. The half-life is 1–2 h. It is excreted via kidneys administered dose are excreted in the bile and lost in (60–75% excreted unchanged). Aztreonam is indicat- feces. More than 90% of Erythromycin is hepatical- ed in the treatment of bacterial pneumonia, skin and ly metabolized. The absorbed drug is distributed soft tissue infections, urinary tract infections, gyne- widely except to the brain and cerebrospinal fluid. cologic and intra-abdominal infections, septicemia. Erythromycin is taken up by polymorphonuclear leu- Penicillin-allergic patients tolerate Aztreonam with- kocytes and macrophages. It traverses the placenta out reaction. Occasional skin rashes and phlebitis at and reaches the fetus. Duration of action is about 4– the injection site may occur. 6 hours. Erythromycin is the drug of choice in bronchitis, CARBAPENEMS sinusitis, acute otitis media, and diphtheria, in chlamydial or mycoplasmal infections. It is also useful as a The carbapenems are structurally related to β- penicillin substitute in penicillin-allergic individuals lactam antibiotics. Imipenem and Meropenem are the with infections caused by staphylococci (assuming that two that are available. They have a wide spectrum the isolate is susceptible), streptococci, pneumococci, with good activity against many gram-negative rods or Treponema pallidum.

156 Adverse reactions. Nausea, vomiting, diarrhea, and AMINOGLYCOSIDES hypersensitivity reactions occasionally accompany erythromycin administration. Erythromycins, partic- Aminoglycosides are a group that includes Strepto- ularly the estolate, can produce acute cholestatic hep- mycin, Neomycin, Kanamycin, Amikacin, Gentamicin, atitis. Erythromycin metabolites can inhibit cyto- Tobramycin, Sisomicin, and others. Aminoglycosides chrome P-450 enzymes and thus increase the serum have a hexose ring, either streptidine (in streptomycin) concentrations of Theophylline, oral anticoagulants, or 2-deoxystreptamine (other aminoglycosides), to and Cyclosporine. In general, Erythromycin has a low which various amino sugars are attached by glycosidic toxicity and can be taken by pregnant women (except linkages. They are water-soluble, stable in solution, and erythromycin estolate). Erythromycin-resistant strains more active at alkaline than at acid pH. emerge frequently; they may appear after the first Aminoglycosides bind to specific subunit ribosom- course therapy. That’s why the current utility of Eryth- al proteins and irreversible inhibit the protein synthe- romycin is limited. sis; they act bactericidal. The transport of aminogly- Oleandomycin is similar in antimicrobial activity cosides across the cell membrane into the cytoplasm and pharmacokinetic properties to Erythromycin. may be enhanced by cell wall-active drugs, such as Clarithromycin is derived from Erythromycin. Penicillin or Vancomycin; this enhancement may be This conversion improves acid stability and, therefore, the basis of the synergism. The spectrum of aminogly- oral absorption compared with Erythromycin. Its cosides covers aerobic gram-negative bacilli, and some gram-positive organisms. They are generally active mechanism of action is the same as that of erythro- against Pseudomonas, Escherichia coli, Proteus, En- mycin. Clarithromycin and Erythromycin are virtu- terobacter, Klebsiella, Serratia species, Enterococcus ally identical with respect to antibacterial activity faecalis and staphylococci. They are not active against except that Clarithromycin is more active against anaerobic organisms. Mycobacteria avium and Leprae, Toxoplasma gon- Aminoglycosides are absorbed very poorly from dii. Erythromycin-resistant streptococci and staphy- the gastrointestinal tract. After i.m. injection, lococci are also resistant to Clarithromycin. Clari- aminoglycosides are well absorbed, giving peak con- thromycin is well absorbed from the gastrointestinal centrations in blood within 1–2 h. Aminoglycosides tract; stable in gastric acid; food does not delay the have been administered in two or three equally divid- extent of absorption; bioavailability is approximate- ed daily doses. Aminoglycosides are highly polar ly 55%. It is widely distributed into tissues and flu- compounds that do not enter cells readily. They dis- ids. Clarithromycin is metabolized in the liver. The tributed primary to extracellular fluid (urine, serum, major metabolite is 14-Hydroxyclarithromycin, abscesses, and synovial fluids), however low concen- which also has antibacterial activity. The serum half- trations found in bile, breast milk, and cerebral spi- life depends on giving dose (about 4–7 hours). Excret- nal fluid. Also distributed to all body tissues, where ed by kidneys. The advantages of Clarithromycin aminoglycosides accumulate intracellularly. High compared with Erythromycin are lower frequency of concentrations found in highly perfused organs (liv- gastrointestinal intolerance and less frequent dosing. er, lungs, and kidneys), but lower concentrations are It can be taken twice daily. seen in muscle, fat, and bone. They cross the placen- Azithromycin 15-atom lactone macrolide rings ta. All aminoglycosides has a low protein binding compound is derived from Erythromycin. Its spectrum (0 to 10%). They are not metabolized. Aminoglyco- of activity and clinical uses are virtually identical to sides are cleared by the kidney. The normal half-life those of Clarithromycin. Azithromycin is slightly less in serum is 2–3 hours. active than Erythromycin and Clarithromycin against Aminoglycosides are indicated in the treatment of staphylococci and streptococci and slightly more ac- serious systemic infections caused by gram-negative tive against Haemophilis influenzae and Chlamydia. enteric bacteria for which less toxic antibacterials are Azithromycin differs from Erythromycin and Clarithro- ineffective or contraindicated. They are almost always mycin mainly in pharmacokinetic properties. It is rap- used in combination with a β-lactam antibiotic in or- idly absorbed and well tolerated orally. Food decreas- der to extend coverage to include potential gram-posi- es bioavailability of Azithromycin, which should be tive pathogens and to take advantage of the synergism administered 1 hour before or 2 hours after meals. between these two classes of drugs. However, Azithromycin penetrates into most tissues Adverse effects. All aminoglycosides are ototoxic (except cerebrospinal fluid) and phagocytic cells ex- and nephrotoxic. These effects are more likely to be tremely well, with tissue concentrations exceeding se- encountered when therapy is continued for more than rum concentrations by 10- to 100-fold. Drug is slowly 5 days, at higher doses, in the elderly, and in the set- released from tissues (tissue half-life of 2–4 days) to ting of renal insufficiency. Ototoxicity can manifest it- produce an elimination half-life approaching 3 days. self either as auditory damage (tinnitus and high-fre- These unique properties permit once-daily dosing and quency hearing loss); or as vestibular damage (verti- shortening of the duration of treatment in many cases. go, ataxia, and loss of balance). Nephrotoxicity re- For example, a single 1 g dose of Azithromycin is as sults in rising serum creatinine levels. Concurrent use effective as a 7-day course of Doxycycline for chlamy- with loop diuretics (Furosemide) or other nephrotox- dial cervicitis and urethritis. Azithromycin is indicat- ic antimicrobial agents (Amphotericin B) can poten- ed for treatment tonsillitis, bronchitis, pneumonia, tiate nephrotoxicity. In very high doses, aminoglyco- acute otitis media, cervicitis or urethritis, pelvic inflam- sides can produce a curare-like effect with neuromus- matory, skin and soft. It may cause nausea, vomiting, cular blockade that results in respiratory paralysis. and diarrhea. Hypersensitivity occurs infrequently.

157 Streptomycin is the oldest and best-studied of the ble and usually mild nephrotoxicity. Ototoxicity, aminoglycosides. It is obtained from a strain of Strep- which tends to be irreversible, manifests itself mainly tomyces globisporus. The antimicrobial activity of as vestibular dysfunction, perhaps due to destruction Streptomycin is typical of that of other aminoglyco- of hair cells by prolonged elevated drug levels. Loss sides. Resistance has emerged in most species, severe- of hearing can also occur. ly limiting the current usefulness of Streptomycin, with Tobramycin has an antibacterial spectrum simi- the exceptions listed below. Streptomycin is used pri- lar to that of Gentamicin. While there is some cross- marily as an antitubercular and is active against My- resistance between Gentamicin and Tobramycin, al- cobacterium tuberculosis and M. bovis. It is also con- though a few organisms resistant to Gentamicin re- sidered the drug of choice for the treatment of infec- main susceptible to Tobramycin. Tobramycin has al- tions caused by Francisella tularensis and Yersinia pes- most the same antibacterial spectrum as Gentamicin tis, and is often used to treat Brucella infections in com- with a few exceptions. Tobramycin is slightly more bination with Tetracycline. Penicillin plus Streptomy- active against Pseudomonas than others aminoglyco- cin is effective for enterococcal endocarditis. Fever, sides. Gentamicin and Tobramycin are otherwise skin rashes, and other allergic manifestations may re- completely interchangeable clinically. The pharma- sult from hypersensitivity to Streptomycin. Pain at the cokinetic properties of Tobramycin are virtually iden- injection site is common. The most serious toxic effect tical to those of Gentamicin. Like other aminoglyco- is disturbance of vestibular function. Vestibular toxic- sides, Tobramycin is ototoxic and nephrotoxic. Ne- ity tends to be irreversible. Streptomycin given during phrotoxicity of Tobramycin may be slightly less than pregnancy can cause deafness in the newborn. that of Gentamicin. Neomycin is a combination of antibiotics neomy- Sisomicin is similar in spectrum and indication to cins A, B, C, that synthesized by Actinomyces fradi- Gentamicin. But it has higher antimicrobial activity ae. It is active against gram-positive and gram-nega- and less toxic, than Gentamicin. tive bacteria and some mycobacteria. Streptococci are Amikacin is a semisynthetic derivative of Kanamy- generally resistant. A mechanism of antibacterial ac- cin; it is less toxic than the parent molecule. Amikacin tion is the same as with other aminoglycosides. Neo- is similar to Gentamicin and Tobramycin in its spec- mycin is not significantly absorbed from the gastroin- trum of activity; however, Amikacin has the advantage testinal tract. After oral administration, the intestinal of not being inactivated by the same enzymes. Thus, flora is suppressed or modified and the drug is excret- it therefore can be employed against some microorgan- ed in the feces. Excretion of absorbed drug is mainly isms resistant to the latter drugs. Many gram-negative through glomerular filtration into the urine. enteric bacteria, including many strains of Proteus, Neomycin is used widespread in bowel preparation Pseudomonas, Enterobacter, Serratia, and Mycobac- for colon surgery. This reduces the aerobic bowel flo- terium tuberculosis, including streptomycin-resistant ra with little effect on anaerobes. Also it can be pre- strains are inhibited by Amikacin. Like all aminogly- scribed for topical administration as solution or oint- cosides, Amikacin is nephrotoxic and ototoxic (partic- ment on infected surfaces or abscess cavities where in- ularly for the auditory portion of the eighth nerve). fection is present. Topically Neomycin can be added by glucocorticoids. Such combination will cause antimicrobial and anti-inflammatory effects. Resistance to LEVOMYCETIN neomycin appear more rare comparatively with other (CHLORAMPHENICOL) GROUP aminoglycosides. Neomycin is too toxic for parenter- Chloramphenicol (Levomycetin) can be isolated al use. It has significant nephrotoxicity and ototoxici- from cultures of Streptomyces venezuelae and can be ty. Auditory function is affected more than vestibular. synthesized chemically. It is soluble in alcohol but Deafness occurrs. poorly soluble in water. Levomycetin succinate, which Gentamicin is an aminoglycoside isolated from Mi- is used for parenteral administration, is highly wa- cromonospora purpurea. It is effective against both ter-soluble. It is hydrolyzed in vivo with liberation gram-positive and gram-negative organisms, and many of free Levomycetin. Levomycetin is a bacteriostatic of its properties resemble those of other aminoglyco- broad-spectrum antibiotic that is active against aer- sides. Gentamicin as much as Tobramycin, and Ami- obic both gram-positive and gram-negative organ- kacin are the most widely employed aminoglycosides isms, including Shigella species, Escherichia coli, at present. Gentamicin is used mainly in severe infec- Klebsiella pneumoniae, Proteus mirabilis. Bacteria tions, e.g. sepsis, intra-abdominal and urinary tract that are generally considered to be resistant to Levo- infections, meningitis, skin and soft tissues infections, mycetin include Pseudomonas aeruginosa, Entero- bacterial pneumonia caused by gram-negative bacte- bacter species, and Enterococcus faecalis. Forming ria that are likely to be resistant to other drugs. It is of resistance to Levomycetin is quite slow. Levomyc- also used concurrently with penicillins for bactericid- etin is a potent inhibitor of microbial protein synthe- al activity in endocarditis. Gentamicin should not be sis. It binds reversibly to the 50S subunit of the bac- used as a single agent to treat staphylococcal infec- terial ribosome. It inhibits the peptidyl transferase tions because resistance develops rapidly. step of protein synthesis. Gentamicin can be used i.v., i.m. or topically. The Levomycetin is rapidly and completely absorbed daily dose of gentamicin is divided into three equal from gastrointestinal tract (bioavailability — 80%). amounts and given every 8 h. Creams, ointments, or After absorption, it is widely distributed to virtually solutions have been used for the treatment of infected all tissues and body fluids, including the breast milk, burns, wounds, or skin lesions and the prevention of central nervous system and cerebrospinal fluid so that intravenous catheter infections. It can exhibit reversi- the concentration of Levomycetin in brain tissue may

158 be equal to that in serum. It crosses placenta. The The antibacterial activities of most tetracyclines are drug penetrates cell membranes readily. The protein similar. Differences in clinical efficacy are minor and binding is moderate (50%). Most of Levomycetin attributable largely to features of absorption, distri- (90%) is inactivated by conjugation with glucuronic bution, and excretion of individual drugs. They are acid in the liver. The therapeutic concentration of bacteriostatic for many gram-positive and gram-nega- drug in serum remains during 4–6 h. Excretion of active bacteria, including anaerobes, Escherichia coli, tive Levomycetin (about 10% of the total dose admin- Shigella, Rickettsia, Chlamydia, Mycoplasma, menin- istered) and of inactive degradation products occurs go- gono-, streptococci, and are active against some by way of the urine. The daily dose is divided in Protozoa, e.g. Amebas. three-four times. Absorption after oral administration is approxi- Because of this drug’s serious toxicity, Levomyc- mately 60–70% for Tetracycline, Oxytetracycline, and etin is indicated only for the treatment of serious in- Methacycline; and 95–100% for Doxycycline. A por- fections in which less toxic antibacterials are ineffec- tion of an orally administered dose of Tetracycline re- tive or contraindicated. Levomycetin is indicated for mains in the gut lumen, modifies intestinal flora, and the treatment of tularemia, plague, brucellosis, men- is excreted in the feces. Absorption is impaired by food ingitis, caused by Haemophilis influenzae, Neisseria (except Doxycycline), by cations Ca2+, Mg 2+, Fe2+, meningitidis; typhoid fever, caused by Salmonella or Al3+, and by alkaline pH. Tetracyclines are 40-80% typhi. It is also used in the treatment of rickettsial in- bound by serum proteins. Tetracyclines are distribut- fections. Levomycetin-resistance strains are appeared widely to tissues and body fluids except for cere- ing slowly. brospinal fluid. Tetracyclines tend to localize in bone, Adverse reactions. Occasionally nausea, vomiting, liver, spleen, tumors, and teeth. They cross the placenta and diarrhea develop. Oral or vaginal candidiasis may and are also excreted in milk. Tetracyclines are ex- occur as a result of alteration of normal microbial flo- creted unchanged mainly in bile and urine, mainly by ra. Levomycetin commonly causes a dose-related re- glomerular filtration. Some of the drug excreted in bile versible bone marrow depression: reticulocytopenia, is reabsorbed from the intestine (enterohepatic circu- anemia, and granulocytopenia. Aplastic anemia is an lation) and contributes to maintenance of serum lev- idiosyncratic reaction unrelated to dose. It tends to be els. 20–40% of tetracyclines in the body is excreted in irreversible and can be fatal. Hypersensitivity (rash, feces. Doxycycline, in contrast to other tetracyclines, pruritus, fever), neurotoxic reactions (confusion, head- primary is eliminated with feces (90%), does not accu- ache, and blurred vision) may elicit. mulate significantly in renal failure. Newborn infants lack an effective glucuronic acid Tetracyclines are classified as short acting (Tet- conjugation mechanism for the degradation and de- racycline, Oxytetracycline), intermediate acting toxication of Levomycetin. Consequently, when in- (Methacycline), or long acting (Doxycycline) based fants are given Levomycetin, the drug may accumu- on serum half-lives of 6–8 hours, 12 hours, and 16–20 late, resulting in the gray baby syndrome, with vom- hours, respectively. iting, flaccidity, hypothermia, gray color, shock, and Systemic tetracyclines are indicated in the treat- collapse. To avoid this toxic effect, Levomycetin ment of bronchitis, pharyngitis, pneumonia, sinusitis, should be used with caution in full-term and prema- septicemia, and intra-abdominal and genitourinary ture infants. tract infections. They can be used in the treatment of Levomycetin inhibits hepatic microsomal enzymes chlamydial infections, gonorrhea, bacillary and ame- that metabolize several drugs. Half-life is prolonged, bic dysentery, syphilis, trachoma, rickettsial infec- and the serum concentrations of Phenytoin, Tolbuta- tions, cholera. A Tetracycline — usually in combina- mide, and Chlorpropamide are increased. Like other tion with an aminoglycoside — is indicated for plague, bacteriostatic inhibitors of microbial protein synthe- tularemia, and brucellosis. sis, Levomycetin can antagonize bactericidal drugs Adverse reactions. Nausea, vomiting, stomatitis, such as penicillins or aminoglycosides. glossitis, and diarrhea are the most common reasons for discontinuing tetracycline medication. These effects are attributable to direct local irritation of the intesti- TETRACYCLINES nal tract. That’s why, i.v. injection can lead to venous thrombosis, i.m. injection produces painful local irri- The tetracyclines are a large group of drugs with tation. Tetracyclines modify the normal flora, with a common basic structure and activity. Tetracycline suppression of susceptible coliform organisms and over- is isolated from streptomyces; Oxytetracycline is de- growth of Pseudomonas, Proteus, staphylococci, rived from Streptomyces rimosus. Methacycline and Clostridia, and Candida. This can result in intestinal Doxycycline, semisynthetic antibiotics, are the deriv- functional disturbances, anal pruritus, vaginal or oral atives of Tetracycline and Oxytetracycline, respec- candidiasis, or pseudomembranous enterocolitis. tively. Free tetracyclines are substances of low solu- Tetracyclines are readily bound to calcium depos- bility. They are available as hydrochlorides, which ited in newly formed bone or teeth in infants and chil- are more soluble. Tetracyclines are broad-spectrum dren under 8 years of age. It can be deposited in the antibiotics that inhibit protein synthesis. Tetracy- fetal teeth, leading to fluorescence, discoloration, and clines bind reversibly to the 30S subunit of the bacte- enamel dysplasia; it can also be deposited in the bone, rial ribosome, blocking the binding of aminoacyl- where it may cause deformity or growth inhibition. It tRNA to the acceptor site on the mRNA-ribosome is also contraindicated during pregnancy. Sometimes complex. This prevents addition of amino acids to the hypersensitivity reactions (fever, skin rashes, and pho- growing peptide. tosensitization) may occur.

159 POLYMYXINS (burns, ulcers, abscesses) caused by susceptible microorganisms. Local reactions and hypersensitivity to top- The polymyxins are a group of basic peptides ac- ical administration are rare (Table 13). tive against gram-negative bacteria. They are formed Polymyxin B is used i.m., i.v. and orally. Poly- by Bacillus polymyxa. To this group belongs Poly- myxin B sulfates is not absorbed from the normal al- myxin M sulfate and Polymyxin B sulfate. The sul- imentary tract, thus it is used for the treatment of fates are water-soluble and very stable. Polymyxins enterocolitis, in bowel preparation for colon sur- are bactericidal for many gram-negative rods, includ- gery. Active blood level is low. Repeated injections ing E. coli, Shigella, and Pseudomonas. Gram-posi- may give a cumulative effect. The drug is excreted tive organisms, Proteus, and Neisseria are resistant. slowly by the kidneys. Tissue diffusion is poor and In susceptible bacterial populations, resistant mutants the drug does not pass the blood brain barrier into are rare. Polymyxins act like cationic detergents. They the cerebrospinal fluid. That’s why, in meningeal attach to bacterial cell membranes, increase its perme- infections, Polymyxin B sulfate should be adminis- ability, and microbes cell essential substance are go- tered only by the intrathecal route. It may be indi- ing outside. Polymyxins are active against extracel- cated for serious infections caused by susceptible lular microbes only. They also bind and inactivate en- strains, when less potentially toxic drugs are inef- dotoxin. fective or contraindicated. Polymyxin B is a drug Polymyxin M is not used for systemic administra- of choice in the treatment of infections of the uri- tion because of its poor tissue distribution, it substan- nary tract, skin, meninges, and bloodstream caused tial nephrotoxicity and neurotoxicity. Polymyxin M by Pseudomonas aeruginosa. It may be indicated for can be used locally. Commonly it is applied concur- the treatment of pneumonia, bacteremia caused by rently with neomycin to infected superficial skin lesions Klebsiella pneumoniae.

Table 13. Indications for using of basic and supplemental antibiotics Infections Antibiotic(s) of first choice Alternative antibiotic Staphylococci (susceptible Benzylpenicillin Cephalosporins, Macrolides Vancomycin, to benzylpenicillin) Phenoxymethylpenicillin Tienam Staphylococci Oxacillin, Vancomycin Cephalosporins, Macrolides (resistant to benzylpenicillin) Streptococci Benzylpenicillin, Ampicillin, Cephalosporins, Macrolides, Tetracyclines Aminoglycosides Pneumococci Benzylpenicillin, Ampicillin, Cephalosporins, Vancomycin Macrolides, Enterococci Benzylpenicillin + Gentamycin, Aminoglycosides, Vancomycin Ampicillin Meningococci Benzylpenicillin, Ampicillin Levomycetin, Cephalosporins, Gonorrhea Amoxicillin, Ampicillin Cephalosporins Benzylpenicillin, Ceftriaxone Syphilis Benzylpenicillin Macrolides, Tetracyclines Tetracyclines, Gas gangrene Benzylpenicillin Levomycetin, Cephalosporins, Clindamycin Tetanus Benzylpenicillin Tetracyclines, Cephalosporins, Clindamycin Diphtheria Macrolides, Benzylpenicillin Amoxicillin, Clindamycin Infections caused by Ampicillin, Cephalosporins Levomycetin, Gentamicin

Proteus morganii Pr. Gentamicin, Amikacin, Levomycetin, Tienam, Cephalosporins rettgeri, Pr. Vulgaris Carbenicillin Infections caused by Aminoglycosides, Aztreonam, Tienam, Cephalosporins III Pseudomonas aeruginosa Carbenicillin, Azlocillin Infections caused by E. coli Ampicillin, Cephalosporins III Azlocillin Aminoglycosides Abdominal typhoid Levomycetin Ampicillin, Tetracycline Bacillary dysentery Ampicillin Levomycetin, Tetracycline Brucellosis Tetracyclines (+Streptomycin) Levomycetin, Streptomycin Tularemia Tetracyclines Levomycetin, Streptomycin Plague Streptomycin + Tetracyclines Levomycetin, Streptomycin Cholera Tetracyclines Levomycetin Rickettsial infections Tetracyclines Levomycetin

160 Parenterally it should be given only to hospitalized branes and may selectively inhibit ribonucleic acid syn- patients, so as to provide constant supervision by a thesis. It is poorly absorbed from the intestinal tract physician. Patients with nephrotoxicity due to Poly- and is administered orally only for the treatment of myxin B sulfate usually show albuminuria, cellular antibiotic-associated enterocolitis caused by Clostrid- casts, and azotemia. Neurotoxic reactions may be ium difficile. Parenteral doses must be administered manifested by drowsiness, ataxia, perioral paresthe- intravenously. The drug is widely distributed in the sia, numbness of the extremities, and blurring of vision. body. 80-90% of the drug is excreted unchanged by The concurrent use of other nephrotoxic and neurotox- glomerular filtration. ic drugs, particularly aminoglycosides, cephaloridine The main indication for parenteral Vancomycin is should be avoided. The neurotoxicity of Polymyxin B sepsis or endocarditis caused by penicillin-resistant sulfate can result in respiratory paralysis from neu- staphylococci. Vancomycin is irritating to tissue, re- romuscular blockade, especially when the drug is giv- sulting in phlebitis at the site of injection. Ototoxicity en soon after anesthesia and/or muscle relaxants. As and nephrotoxicity are uncommon and mild with cur- with other antibiotics, use of this drug may result in rent preparations. However, administration with the superinfection, allergic reactions. It can cause severe other ototoxic or nephrotoxic drug, such as an pain at i.m. injection sites, and thrombophlebitis at i.v. aminoglycoside, increases the risk of this toxicity. injection sites. Fusidic acid is antibiotic broad-spectrum activity. Usually it is used as Fusidin sodium. It is active against staphylococci, meningococci, and gonococci. Fusidin DIFFERENT ANTIBIOTICS inhibits the protein synthesis; acts bacteriostatic. Well Lincomycin is elaborated by Streptomyces lincol- absorbed in the gastro-intestinal tract. It is distributed nensis. It resembles Erythromycin in activity. Strepto- widely to tissues and body fluids. Agent tends to local- cocci, staphylococci, pneumococci, and anaerobes ize in bones. Fusidin is metabolized in the liver and ex- (Bacteroides species, Clostridium tetani, Cl. perfrin- creted by bile. Primary Fusidin is indicated for the treat- gens) are inhibited by Lincomycin. Enterococci and ment of disease caused by penicillin-resistant staphylo- gram-negative aerobic organisms are resistant. cocci. Adverse effects: nausea, vomiting, rash, jaundice. Clostridium difficile, an important cause of pseudomembranous colitis, is resistant. Lincomycin, like Available forms: Erythromycin, inhibits protein synthesis. It is usually Benzylpenicillin-sodium — in bottles 250,000; considered bacteriostatic. Resistance to Lincomycin is 500,000; 1,000,000 unites each generally confers cross-resistance to other macrolides. Bicillinum-1 — in bottles 300,000; 600,000; Lincomycin rapidly absorbed from the gastrointes- 1,200,000 unites each Oxacillin-sodium — in bottles 0.25; 0.5 each; tab- tinal tract following oral administration; absorption de- lets or capsules 0.25; 0.5 creased when taken with food. It can be injected i.m. or Ampicillin trihydrate — tablets or capsules 0.25; 0.5 i.v. Widely and rapidly distributed to most fluids and each tissues, except cerebrospinal fluid; high concentrations Ampicillin-sodium — in bottles 0.25; 0.5 each in bone, bile, and urine. Lincomycin readily crosses the Carfecillin — capsules 0.25 each placenta; also distributed into breast milk. Biotransfor- Cefazolin — in bottles 0.25; 0.5; 1.0; 2.0; 4.0 each mation takes place in the liver. Half-life is about 4–6 Cefoxitin — in bottles 1.0; 2.0 each hours. Lincomycin is eliminated by urine and bile. Cefotaxime — in bottles 0.5; 1.0; 2.0 each The most important indication for Lincomycin is Aztreonam — in bottles 0.5; 1.0 each the treatment of severe infections caused by suscepti- Gentamycin sulfate — in bottles 0.08 each; in am- ble strains of streptococci, pneumococci, and staphy- poules 4% solution 1 ml or 2 ml each; 0.1% ointment lococci, as much as anaerobic infection. Lincomycin 10.0 or 15.0 forms a high antimicrobial concentration in bones, Amikacin sulfate — in bottles 0.1; 0.25; 0.5 each thus it can be used for the osteomyelitis treatment. Neomycin sulfate — tablets 0.1; 0.25 each; in bot- Common adverse effects are diarrhea, nausea, and tles 0.5 each (to dilute at the rate of 1 ml physiologi- skin rashes. Impaired liver function (with or without cal solution for 0.005 g); 0.5%; 2% ointment 15.0 or jaundice) and neutropenia sometimes occur. Pseu- 30.0 each domembranous colitis (severe diarrhea, fever), that fol- Erythromycin — tablets 0.1; 0.25 each; 1% oint- lowed Lincomycin administration, is caused by ment Clostridium difficile. This potentially fatal complication Azithromycin — capsules 0.125; 0.25 each; tablets must be treated with Metronidazole or Vancomycin. 0.5 each Clindamycin is a chlorine-substituted derivative of Tetracycline — tablets 0.05; 0.1; 0.25 each Lincomycin. It is similar in spectrum activity and us- Doxycycline hydrochloride — capsules 0.05; 0.1 ing to Lincomycin, however, it has higher antimicro- each; in ampoules 0.1 each bial activity. Chloramphenicol (Levomycetin) — tablets 0.25; Vancomycin is a glycopeptide antibiotic produced 0.5 g each; capsules 0.1; 0.25; 0.5 each by Streptococcus orientalis. Polymyxin M sulfate — in bottles 500,000; It is active mainly against gram-positive bacteria, 1,000,000 unites (to dilute at the rate of 1 ml physio- particularly staphylococci and anaerobes, including logical solution for 20,000 unites); tablets 500,000 Clostridium difficile. It is resistance to β-lactamase. unites each; liniment 30,0 Vancomycin inhibits cell wall synthesis. It also may Lincomycin hydrochloride — in ampoules 30% so- alter the permeability of bacterial cytoplasmic mem- lution 1; 2 ml; capsules 0.25 each

161 Lecture 36 Organisms initially sensitive to sulfanilamides may develop resistance. Sulfanilamide-resistant strains SULFANILAMIDES emerge frequently when therapy continues for 15 days or longer. Because of the availability of many safer and more effective antibiotics, sulfanilamides current Sulfanilamides (sulfonamides) are synthetic deriva- utility is limited. tives of p-aminobenzenesulfonamide (sulfanilamide). If the N4-amino group is replaced with radicals that can Classification of drugs: be converted to a free amino group in the body, the com- — Sulfanilamides which are well absorbed from pound retains antibacterial activity (Fig. 27). Substitu- gastro-intestinal system, with resorptive action: tion in the N1-amide group produces compounds vary- a) short acting (T1/2 about 8 h) — Streptocide, Sul- ing in solubility, protein binding, tissue distribution, fathiazole (Norsulfazolum), Sulfadimidine (Sul- and rate and mode of metabolism and excretion. Sulfa- fadimezinum), Sulfacarbamide (Urosulfanum), Sulfa- nilamides generally are insoluble in water. The drugs ethidole (Aethazolum); are weak acids and form salts with bases; their sodium b) intermediate acting (T1/2 lesser 12–14 h) — Sul- salts are very soluble in water. Solutions of the sodium fazinum (Sulfadiazine sodium), Sulfamethoxazole; salts of most sulfonamides are strongly basic. c) long action time (T1/2 about 24–28 h) — Sul- Prontosil (Red streptocide) was one of the dyes in- famethoxypyridazine (Sulfapyridazinum), Sulfamon- cluded by G. Domagk to treat experimental strepto- omethoxine, Sulfadimethoxine; coccal infection in mice at 1935 and found it to be high- d) ultra long action time (T1/2 about 65 h) — Sul- ly effective. Since that time the usage of sulfanilamides falene. has begun. All sulfanilamide medicines are the prod- — Sulfanilamides which are badly absorbed from ucts of streptocide amide group hydrogen atom replace- gastro-intestinal system, used for healing of intestinal ment by various radicals. The differences between them infections — Sulfaguanidine (Sulginum), Phthalylsul- are efficiency rate and terms only. fathiazole (Phthalazolum), Phthalylsulfapyridazine Mechanism of action. Sulfanilamides are structur- (Phthazinum) al analogs of PABA (paraaminobenzoic acid) and ap- — Combined preparations: pear to interfere with PABA utilization by competitive- a) combination with salicylic acid for healing of ly inhibiting the enzyme dihydropteroate synthase, non-specific ulceral colitis — Salazodin (Salazopyri- which catalyzes the formation of dihydropteroic acid dazinum), Salazosulphapyridine (Sulphasalazine); (a precursor of tetrahydrofolic acid), from PABA and b) preparations containing Trimethoprim — Cot- pteridine. Sulfanilamides are usually bacteriostatic in rimoxazole (Biseptol), Sulfatonum (Sulfamonometh- action. Only microorganisms that synthesize their own oxine + Trimethoprim). folic acid are inhibited by sulfanilamides; animal cells — Preparations for local use — Sulfacetamide and bacteria which are capable of utilizing folic acid (Sulfacyl-sodium), Maphenidum, Silver sulfadiazine. precursors or preformed folic acid (tetrahydrofolic Sodium salts of sulfanilamides acid) are not affected by these drugs. Novocain is a PABA derivative: it antagonizes sulfanilamides. The Approximately 70–90% of an oral dose of the ab- antibacterial activity of the sulfanilamides is report- sorbable sulfanilamides is reportedly absorbed from edly decreased in the presence of pus, blood or puru- the small intestine. Norsulfazolum, Sulfadimezinum, lent body exudate, because they contain purines and Aethazolum, and Urosulfanum are absorbed rapidly; Thymidine that decrease bacterial requirement for folic peak blood concentrations are usually obtained with- acid. in 2–4 hours. Sulfazinum, Sulfamethoxazole and Sul- Spectrum of activity. Sulfanilamides are active fapyridazinum are absorbed at a slower rate with peak against gram-positive bacteria including some strains blood concentrations occurring within 3–7 hours. Ab- of staphylococci, streptococci, Bacillus anthracis, sorbable sulfanilamides are widely distributed in the Clostridium tetani, and C. perfringens. The drugs are body. They may appear in breast milk, synovial and active in vitro against Enterobacter, Escherichia coli, cerebrospinal fluids. Sulfanilamides readily cross the Klebsiella, Proteus mirabilis, P. vulgaris, Salmonel- placenta. la, and Shigella. Sulfanilamides are active against Sulfanilamides are bound in varying degrees to some strains of Neisseria gonorrhea, Chlamydia tra- plasma proteins. Sulfazinum, Norsulfazolum are re- chomatis and also have some activity against Toxo- portedly 12–50% bound to plasma proteins and Sul- plasma gondii and Plasmodium. fadimethoxine and Sulfapyridazinum are reportedly 85–90% bound to plasma proteins. A portion of absorbed drug is mostly acetylated and also glucuronidated in the liver. The rate of sulfanilamides acetylation differ from each other — Uro- 41sulfanum, Aethazolum has the lowest extend, and NH2 SO2 NH2 Streptocide, Sulfadimezinum — the highest. The metabolites do not possess antibacterial activity. N4- acetyl metabolites are usually less soluble than the parent sulfanilamide, particularly in acidic urine, howev- Sulfanilamide er, glucuronide derivatives are water soluble. Sulfani- lamides and their metabolites are excreted mainly by Fig 27. Structure of sulfanilamides the kidneys via glomerular filtration. Alkalization of 162 the urine increases the solubility of sulfanilamides and nopyrimidine derivative, it selectively inhibits bacte- decreases tubular reabsorption, resulting in increases rial dihydrofolate reductase. The two drugs cause se- of renal excretion of the drugs. Except for the poorly quential block of folate metabolism (Fig. 28). Individ- absorbed sulfanilamides only small amounts of sulfa- ually both sulfanilamides and Trimethoprim are pri- nilamides are excreted in feces. marily bacteriostatic, but the combination becomes ci- The basic principles of sulfanilamide chemothera- dal against many organisms. Trimethoprim is about py are following. The first dose (blowing dose) of ab- 50,000 times more active against bacterial dihydro- sorbable sulfanilamides must be two times bigger than folate reductase than against mammalian enzyme. subsequent doses (keeping up dose), except Cotrimox- Thus, human folate metabolism is not interfered at an- azole. The sulfanilamide therapy has to be continued tibacterial concentration of Trimethoprim. during 2–3 days after clinical recover (“sulfanilamide Trimethoprim is usually given orally, alone or in train”). Patients also have to drink a lot (1.5–2 liters combination with Sulfamethoxazole, the latter chosen a day) of alkaline water. because it has a similar half-life. Trimethoprim is ab- Therapeutic uses sorbed well from the gut and distributed widely in body a. Urosulfanum, Aethazolum are highly soluble fluids and tissues, including cerebrospinal fluid. Be- (free as well as acetylated form) even in acidic urine cause Trimethoprim is more lipid-soluble than Sulfam- — crystalluria is less likely. More than 60% are ex- ethoxazole, it has a larger volume of distribution than creted unchanged in urine. They are highly desirable the latter drug. Therefore, when 1 part of Trimetho- for urinary tract infections, including pyelonephritis, prim is given with 5 parts of Sulfamethoxazole (the ra- pyelitis. They must be taken four times a day. tio in the formulation), the peak plasma concentrations b. Norsulfazolum, Sulfadimezinum are also rapid- are in the ratio of 1:20, which is optimal for the com- ly absorbed, very little acetylated and quickly excret- bined effects of these drugs in vitro. About 65–70% of ed in urine. They can be used for the treatment of men- each participant drug is protein-bound, and 30–50% ingitis, pneumonia and other infection diseases. In ad- of the sulfanilamide and 50–60% of the Trimethoprim dition Sulfadimezinum is indicated for toxoplasmosis (or their respective metabolites) are excreted in the and gonorrhea. urine within 24 hours. c. Sulfazinum has slower oral absorption and uri- Sensitive to Trimethoprim-Sulfamethoxazole com- nary excretion. It is used on twice daily schedule for bination are Escherichia coli, Salmonella typhus, Pro- pneumonia, bronchitis, and malaria treatment. teus mirabilis, and Klebsiella pneumonia, Entero- d. Sulfapyridazinum, Sulfadimethoxine are highly bacter, Pneumocystis carinii, many stains of Staphy- protein bound, lipid soluble, and slowly excreted sul- lococcus. A combination of Trimethoprim-Sulfameth- fanilamides. They used once a day for the treatment oxazole is effective treatment for chronic bronchitis, of pneumonia, otitis, bile duct and urinary tract infec- pneumonia, urinary tract infections (cystitis, pyelone- tions, malaria, lepra, Sulfapyridazinum — also for phritis, pyelitis), prostatitis, shigellosis, typhoid fever, meningitis. and many others. It is the agent of choice Pneumo- e. Sulfalene is ultra long acting compound, action cystis carinii pneumonia, especially in patients with lasting more than 7 days. It has been used in the treat- AIDS. It may be used for gram-negative bacterial sep- ment of malaria, infections of bile duct and urinary sis, including that caused by some multiple-drugresist- tract. Sulfalene can be taken orally 0.2 g (1 tab) every ant species such as Enterobacter and Serratia. day or 2 g once a week. Trimethoprim produces the predictable adverse ef- f. Sulginum, Phthalazolum have N4 as well as N1 fects of an antifolate drug, especially megaloblastic substitution. That’s why, they are not active as such anemia, and leukopenia. This can be prevented by the and are not absorbed in the small intestine. In the bow- simultaneous administration of folinic acid, 6–8 mg/ el, bacteria split off the N4 substitution to release sul- d. In addition, the combination Trimethoprim-Sulfam- fanilamide, which is active locally. These agents have been used for colitis, gastroenteritis, and dysentery and for preparation of bowel before colonic surgery. Small PABA Pteridine amount of sulfanilamide that gets absorbed can cause toxicity including crystalluria. Sulfanilamides g. Salazopyridazinum, Salazosulphapyridine are spitted by intestinal microflora to yield Sulfapyridazi- Dihydropteroate num and 5-aminosalicylate in first case; Sulfapyrid- synthase ine and 5-aminosalicylate in second case. They are widely used in ulcerative colitis, enteritis, and other Dihydropteroic inflammatory bowel diseases. Salicylate is released in acid the colon in high concentration and is responsible for an anti-inflammatory effect, the major source of bene- Trimethoprim Glutamine acid fit from this drug. Comparably high concentrations of salicylate cannot be achieved in the colon by oral in- Dihydrofolate take of ordinary formulations of salicylates because of reductase severe gastrointestinal toxicity. In addition, it was found to suppress the disease in significant number of Tetrahydrofolic acid rheumatoid arthritis patients. (reduce form of folic acid) h. Cotrimoxazole is the combination of Sulfameth- oxazole with Trimethoprim. Trimethoprim is a diami- Fig 28. Mechanism of action of Cotrimoxazole

163 ethoxazole may cause all of the untoward reactions as- Lecture 37 sociated with sulfanilamides. Sulfatonum is combination of Sulfamonomethox- ANTIMICROBIALS — ine (0.25 g) with Trimethoprim (0.1 g). It’s character- DERIVATIVES OF DIFFERENT istic is similar to Cotrimoxazole. i. Sulfacyl-sodium ophthalmic solution or ointment GROUPS is effective treatment for bacterial conjunctivitis and as adjunctive therapy for trachoma. It has been most NITROFURANE DERIVATIVES commonly used for treatment and prevention of gonococcal ophthalmitis, including newborns. These are the medicines of a great efficiency spec- j. Mafenide is used topically to prevent bacterial trum. Their mechanism of action is the turning of ni- colonization and infection of burn wounds. It is not tro-group into the amino-group and germs cellular res- inactivated by PABA. piration suppression. Medium concentrations are bac- k. Sulfazinum silver is a much less toxic topical sul- teriostatic, large doses become bactericide. fanilamide and is preferred to mafenide for prevention Microorganism’s resistance to nitrofuran deriva- of infection of burn wounds. It slowly releases silver tives develops slowly. No cross-resistance to antibiot- and are used to suppress bacterial growth in burn ics or sulfanilamides occurs. They may be combined wounds. with penicillins, streptomycin, other aminoglycosides Adverse effects of the sulfanilamides are numerous. and tetracyclines. Although serious, in some cases fatal, reactions have Furazolidone is broad-spectrum anti-infective that been reported, they occur infrequently. Various der- is effective against most gastrointestinal tract patho- matoid reactions, including rash, eosinophilia, pru- gens. Furazolidone is active in vitro against Entero- ritus, photosensitivity, Stevens-Johnson and serum bacter aerogenes, Escherichia coli, Proteus species, sickness syndrome have been reported. Acute hemo- Salmonella species, Shigella species, and staphyloco- lytic anemia may occur as a result of sensitization or cci. It is indicated in the treatment of bacterial diarrhea glucose-6-phosphate dehydrogenase (G-6-PD) defi- caused by susceptible organisms. Furazolidone is in- ciency. Adverse hematoid effects, including methemo- dicated in the treatment of lambliasis (giardiasis) globinemia, sulfhemoglobinemia, leukopenia, aplas- caused by Giardia lamblia, and for the treatment of tic anemia, thrombocytopenia, have been associated trichomoniasis. with sulfanilamide therapy. Renal damage, manifest- It is well absorbed following oral administration. ed by kidney stone formation, renal colic, toxic ne- It is rapidly and extensively metabolized. Furazo- phrosis is usually a result of crystalluria caused by lidone and Nitrofurantoin (Furadoninum) may cause precipitation of the sulfanilamide and/or its acetyl the dark yellow to brown discoloration of urine. Fura- derivative in acid urine. Urinary alkalization may be zolidone also acts as a monoamine oxidize (MAO) achieved by administering 2.5–4 g of sodium bicar- inhibitor. That’s why concurrent use of MAO inhibi- bonate orally every 4 hours. Nausea or vomiting, tors, tyramine- or other high pressor amine-contain- gastroenteritis, diarrhea also have been reported. Ad- ing foods and beverages, such as cheese; beer; li- verse neurology effects, including headache, dizzi- queurs; smoked or pickled meat, or fish; and any over- ness, mental depression, fatigue, and acute psycho- ripe fruit with Furazolidone may precipitate hyper- sis may occur. tension. Drug interactions. Sulfanilamides may potentiate Patients should be advised not to drink alcoholic the effects of coumarin anticoagulants and oral antid- beverages while taking Furazolidone and for 4 days iabetic agents by displacing them from their protein- after discontinuing it, because concurrent use of alco- binding sites. Some sulfanilamides may inhibit metab- hol with Furazolidone may rarely result in a di- olism of phenytoin and should be used with caution in sulfiram-like reaction, characterized by facial flush- patients receiving the drug. Since Hexamethylenete- ing, difficult breathing, slight fever, and tightness of tramine (Methenamine) requires acidic urine for its the chest. antibacterial effect, the drug should not be used con- Hypersensitivity reactions (fever; itching; joint comitantly with less soluble sulfanilamides (e.g. Sul- pain; skin rash or redness) hemolytic anemia in glu- fazinum) which may crystallize in acidic urine. cose-6-phosphate dehydrogenase deficiency patients, and gastrointestinal disturbances (abdominal pain, diarrhea, nausea, or vomiting) also may appear during Available forms: Furazolidone be used. Aethazolum — powder or tablets 0.5 g each. Nitrofurantoin (Furadoninum) is indicated in the Sulfamethoxypyridazine — powder or tablets 0.5 g treatment of urinary tract infections caused by suscep- each. tible strains of Escherichia coli, enterococci, Staphy- Phthalylsulfathiazole (Phthalazolum) — powder lococcus aureus, Enterobacter species, and Proteus or tablets 0.5 g each. species. Bactrim (480) — tablets, including 80 mg trimeth- Nitrofurantoin is rapidly and completely absorbed oprim and 400 mg sulfamethoxazole; Bactrim (120) in the small intestine. About 30–40% of Nitrofuranto- — tablets, including 20 mg trimethoprim and 100 mg in is rapidly excreted unchanged. Therapeutic concen- sulfamethoxazole (for children). trations are achieved only in the urine, serum concen- Sulfacyl-sodium — powder, in ampoules 30% so- trations are very low. lution 5 ml each; in bottles 30% solution 5 or 10 ml Gastrointestinal disturbances and hypersensitivity each (eyes drops). reactions are the principal side effects of Furadoninum.

164 Hemolytic anemia can occur in glucose-6-phosphate Ciprofloxacin, Pefloxacin, and Ofloxacin are in- dehydrogenase deficiency patients. Furadoninum also dicated in the treatment of urinary tract infections (cys- antagonizes the action of nalidixic acid. Both Fura- titis, and pyelitis); bacterial prostatitis caused by sus- zolidone and Furadoninum should preferably be tak- ceptible organisms. Ciprofloxacin and Ofloxacin are en with food or milk. This minimizes gastrointestinal indicated in the treatment of bone and joint infections; irritation. skin and soft tissue infections; chronic bronchitis; pneumonia caused by susceptible organisms. Also they are indicated in the treatment of endocervical and urethral QUINOLONES infections caused by N. gonorrhea. Finally parenter- Quinolones are active against most of gram-nega- al Ciprofloxacin is indicated in the treatment of septi- tive organisms, including Proteus species, Klebsiella cemia caused by E. coli or S. typhi. species, Enterobacter species, Salmonella species, Adverse effects. Fluoroquinolones at an alkaline pH Shigella species, and Escherichia coli. The majority may form crystals that have resulted in crystalluria. of staphylococci strains are susceptible to quinolones. Because normal urinary pH is acidic (approximately Quinolones appear to act by inhibiting bacterial DNA 5 to 6) crystalluria is very unlikely to occur. They also synthesis. may lead to diarrhea, nausea or vomiting, hypersen- Nalidixic acid (Negram®) is the first antibacteri- sitivity reactions, photosensitivity, CNS toxicity (diz- al quinolone. It is the derivative of Naftiridin. It is bac- ziness; headache; drowsiness; insomnia; tremor). Very teriostatic or bactericidal depending on the concentra- rarely seizure and acute psychosis may appear. Fluo- tion. Resistance may develop rapidly during treat- roquinolones are not recommended for use during preg- ment. nancy, breast-feeding, in children, and adolescents be- Nalidixic acid rapidly and almost completely ab- cause they have been shown to cause arthropathy in sorbed from the gastrointestinal tract. Since nalidixic immature animals. acid achieves only low concentrations in the serum and Fluoroquinolones inhibit the cytochrome oxidizing is concentrated in the urine, it is indicated only in the (P-450) enzyme system of the liver that can intensify treatment of urinary tract infections. Half-life of nali- the effect of agents, which metabolized by these en- dixic acid in serum is about 1 to 2.5 hours; in urine – zymes. For instance, concurrent use of Theophylline 6 hours. It crosses the placenta and is excreted in (Aminophylline, Caffeine) with fluoroquinolones may breast milk. result in a prolonged theophylline elimination half-life, The main side effects are diarrhea, nausea, vomit- increased serum concentration, and increased risk of ing, hypersensitivity, dizziness, headache, seizures, theophylline-related toxicity. photosensitivity (increased sensitivity of the skin to sunlight). Since nalidixic acid and other related com- 8-OXYQUINOLINES pounds have been shown to cause arthropathy in immature animals, use is not recommended in first 8-Oxyquinolines (8-hydroxyquinoline) possess an- three months of pregnancy and in children up to 2 timicrobial, antiprotozoal, and antifungal activity. years of age. Representatives of this group are Chlorquinaldol, Oxolinic acid (Gramurin) is similar in structure and complex agent Attapulgite, and Nitroxoline (5-NOK). function to Nalidixic acid. It has higher antimicrobial Chlorquinaldol is used for the treatment of intes- activity, than Nalidixic acid, but more neurotoxic. tine infection diseases such as dysentery, salmonello- Fluoroquinolones are synthetic fluorinated ana- sis, intestine infections caused by staphylococci, Pro- logs of Nalidixic acid. Fluorinated derivatives (Cip- teus species, and other Enterobacter species. In addi- rofloxacin, Ofloxacin, and others) have greatly im- tion it may be prescribed for amebiasis and lamblia- proved antibacterial activity compared with nalidix- sis. Chlorquinaldol is used orally. Most of an oral dose ic acid and achieve bactericidal levels in blood and of the drug is not absorbed from the gastro-intestinal tissues. Their spectrum of antimicrobial activity is tract but is excreted in feces. It acts primarily in the similar to first quinolones. In addition fluoroquinolo- intestinal lumen. nes act on Pseudomonas, Neisseria, and Campylo- Adverse gastro-intestinal effects of Chlorquinaldol bacter, intracellular pathogens such as Legionella, include nausea, vomiting, epigastric burning and pain, Chlamydia, and some Mycobacteria, including M. allergic reactions. The drug can cause optic neuritis, tuberculosis. Anaerobes generally are resistant. Fluo- optic atrophy, and peripheral neuropathy, especially roquinolones block bacterial DNA synthesis by inhib- in children. Permanent loss of vision has occurred. Dys- iting bacterial topoisomerase II (DNA gyrase) that esthesia and weakness are reported to occur common- is required for normal transcription and replication. ly in adults. Duration of Chlorquinaldol therapy less During fluoroquinolone therapy, resistant organisms than 7 days. emerge, especially among staphylococci, streptococ- Attapulgite is similar in activity and indications to ci, pseudomonas. Chlorquinaldol. After oral administration, the fluoroquinolones are Nitroxoline is distinguished by rapid absorption well-absorbed (bioavailability of 80–95%) and dis- from the gastrointestinal tract. It is excreted mainly by tributed widely in body fluids and tissues. They bad- kidney mostly unchanged; thus it is concentrated in the ly bind with serum proteins. Serum half-life range urine. Nitroxoline can be used for urinary tract infec- from 4 hours (Ciprofloxacin) up to 8 hours (Pe- tions (pyelitis, cystitis). It causes the yellow discolor- floxacin and Ofloxacin). The fluoroquinolones are ation of urine. In general it has low toxicity. Some- excreted mainly by the kidney mostly unchanged. times nausea and allergic reactions may occur.

165 IMIDAZOLE DERIVATIVES Lecture 38 Metronidazole acts microbicidal against most ob- ANTITUBERCULOSIS DRUGS ligate anaerobic bacteria and protozoa (Trichomonas vaginalis, Giardia lamblia, and Entamoeba histolytica) by undergoing intracellular chemical reduction. Tuberculosis, mycobacterial infection are among Reduced Metronidazole interacts with DNA to cause the most difficult of all bacterial infections to cure. The inhibition of nucleic acid synthesis and cell death. lipid-rich mycobacterial cell wall is impermeable to Metronidazole is indicated in the treatment of proto- many agents. A substantial proportion of mycobacte- zoal diseases (amebiasis, lambliasis, trichomoniasis), rial organisms are intracellular, and inaccessible to bone, pelvic and intra-abdominal infections, endocar- drugs that penetrate poorly. Finally, mycobacteria are ditis, septicemia caused by anaerobic bacteria notorious for their ability to develop resistance to any (Bacteroides and Clostridium species). It is indicated single drug. Combinations of drugs are required to over- for the prophylaxis of perioperative infections during come these obstacles and to prevent emergence of re- colorectal surgery. Metronidazole can be prescribed sistance during the course of tuberculosis treatment. In for adjunct treatment of Helicobacter pylori-associ- practice, therapy is initiated with a 3–4-drug regimen. ated gastritis. The response of Mycobacterium tuberculosis to chem- Metronidazole is well absorbed orally. It is widely otherapy is slow, and treatment must be administered distributed to tissues and fluids of the organism; it for 6–12 months. crosses the placenta and blood-brain barrier, also. The half-life is about 8–10 hours. Metronidazole and its Classification of antituberculosis agents: metabolites mostly eliminated by kidneys that cause — Basic (first-line) agents: the red to brown discoloration of urine. a) antibiotics — Streptomycin, Rifampicin; Adverse effects of Metronidazole are dry mouth, b) synthetic drugs — Isoniazid, Ethambutol. an unpleasant or sharp metallic taste, diarrhea, nau- — Supplemental (second-line): sea or vomiting, loss of appetite, hypersensitivity, leu- c) antibiotics — Cycloserine, Kanamycin; kopenia, and vaginal candidiasis. It is contraindicat- d) synthetic drugs — Ethionamide, Pyrazinamide, ed during active organic disease of the CNS, preg- Para-aminosalicylate sodium. nancy, breast-feeding. Metronidazole should not be used concurrently with, or for at least 1 day follow- Usually, basic agents are more effective and less ing, ingestion of alcohol, because disulfiram-like ef- toxic, than reserve agents are. Thus, basic agents are fects may occur. the drugs of first choice. The alternative drugs are usu- Tinidazole is similar in structure and function to ally considered only in the case of resistance to the Metronidazole. It is indicated in the treatment of drugs of first line and in case of the toxic effects. As a amebiasis, lambliasis, and trichomoniasis. It acts long- rule, synthetic drugs act on mycobacteria only. How- er than Metronidazole. ever, antituberculosis antibiotics are the broad-spectrum antimicrobial agents. Rifampicin is a semisynthetic derivative of Rifamy- QUINOXOLINE DERIVATIVES cin, an antibiotic produced by Streptomyces mediter- Chinoxydin and Hydroxymethylhinoxilindioxide ranei. It is active in vitro against gram-positive and (Dioxydinum) are active against Proteus vulgaris, gram-negative cocci, some enteric bacteria (E. coli, Cyanobacteria, Escherichia coli, Salmonella and Salmonella, some strains of Pseudomonas and Pro- Shigella species, staphylococci, Clostridium species. teus), and Mycobacteria. Administration of Rifampicin These agents are indicated for severe purulent in- as a single drug quickly selects the highly resistant or- flammation, such as pyelocystitis, cholecystitis, ab- ganisms. Rifampicin binds strongly to the bacterial scess of lungs, empyema, septicemia, that caused by DNA-dependent RNA polymerase and thereby inhib- susceptible organisms. The agents can be used only its RNA synthesis. Human RNA polymerase does not in adults. Usually, Chinoxydin is taken orally and bind rifampin and is not inhibited by it. Rifampicin is Dioxydinum — locally, intracavitary and intrave- bactericidal for Mycobacteria. It can kill microorgan- nous. During treatment of nausea, vomiting, dizzi- isms that are poorly accessible to many other drugs, ness, headache, allergic rash, seizure of the skele- such as intracellular organisms and those sequestered tal muscle can appear. in abscesses and lung cavities. Rifampicin is well absorbed after oral administra- Available forms: tion. Being lipid-soluble, Rifampicin diffuses well to Furazolidone, Furadoninum — tablets 0.05 g each most body tissues and fluids, including the cerebros- Nalidixic acid — capsules or tablets 0.5 g each pinal fluid. Therapeutic concentrations are achieved Ofloxacine — tablets 0.2 g each in the saliva, sputum, bones, and pleural cavity. It Ciprofloxacine — tablets 0.25; 0.5; 0.75 g each, in crosses the placenta and is distributed into breast bottles 0.2% solution 50 or 100 ml each milk. Rifampicin is relatively highly protein-bound Chlorquinaldol — tablets 0.03 (for children) or 0.1 drug (90%). Agent rapidly deacetylated by auto-in- gram each duced microsomal oxidative enzymes to metabolites. Nitroxoline — tablets 0.05 g each Rifampicin excreted mainly through the liver into bile Metronidazole — tablets 0.25; 0.5 g each; vaginal and then undergoes enterohepatic recirculation. The suppositories 0.5 g Rifampicin half-life initially 3–5 h; with repeated ad- Chinoxydin — tablets 0.25 g each ministration, half-life decreases to 2–3 h.

166 Rifampicin can be administered orally or i.v. The Ethambutol is a synthetic, bacteriostatic antitu- usual daily dose for adult is about 0,6 g given once a bercular agent. It diffuses into mycobacteria and sup- day. Rifamycin can be used i.v., i.m. or locally. Ri- presses multiplication by interfering with RNA syn- fampicin is effective in tuberculosis and in leprosy. Ri- thesis. Ethambutol is well absorbed from the gut. fampicin therapy is also indicated for treatment of Agent is widely distributed to most tissues and body bronchitis, pneumonia, osteomyelitis, and biliary tract fluids except cerebrospinal fluid. The most common infections caused by susceptible infections. Rifampicin serious adverse event is retrobulbar neuritis causing imparts a harmless reddish-orange color to urine, loss of visual acuity and red-green color blindness. sweat, and tears. This dosage-related side effect which appears after 2 Occasional adverse effects include itching, rash, months of therapy. Thus, periodic visual acuity test- diarrhea, stomach cramps, and leukopenia. It may ing is desirable. Ethambutol is contraindicated dur- cause cholestatic jaundice and occasionally hepatitis ing pregnancy. (Table 14). Rifampicin induces microsomal enzymes Cycloserine, a broad-spectrum antibiotic, is bacte- (e.g. cytochrome P-450), which increases the elimina- ricidal for Mycobacteria. Cycloserine is an analog of tion of numerous other drugs including oral anticoag- the amino acid D-alanine. It inhibits bacterial cell wall ulants, some anticonvulsants, and contraceptives. Ri- synthesis. Cycloserine is rapidly and almost completely fampicin is not recommended during pregnancy, absorbed from the gastro-intestinal tract following oral breast-feeding, and hepatitis. administration. It is distributed widely, to most body The mechanism of action and the pharmacologic fluids and tissues. The most serious toxic effects are features of Streptomycin have been discussed in lec- peripheral neuropathy and central nervous system dys- ture “Antibiotics”. Streptomycin sulfate remains an function, including dizziness, muscle twitching or trem- important drug in the treatment of tuberculosis, espe- bling, anxiety, nervousness, drowsiness, and night- cially when an injectable drug is desirable, principal- mares. These may be minimized by glutamic acid, py- ly in individuals with severe forms of tuberculosis, e.g. ridoxine, and ATP. meningitis, disseminated disease. Kanamycin is antibiotic of aminoglycoside group. Isoniazid, introduced in 1952, is the most active It has the same mechanism of action, spectrum activi- drug for the treatment of tuberculosis. It is the hy- ty, and pharmacokinetic as streptomycin. Kanamycin drazide of isonicotinic acid. The Isoniazid structure has been used for treatment of tuberculosis caused by is similar to Pyridoxine. Isoniazid may be bacterio- streptomycin-resistant strains. static and bactericidal. It is active against both extra- Ethionamide is chemically related to Isoniazid. Its cellular and intracellular organisms. Isoniazid inhib- mechanism of action is not known exactly, but it ap- its synthesis of mycolic acids, which are essential com- pears also to block the synthesis of mycolic acids. It is ponents of mycobacterial cell walls. Isoniazid-resist- rapidly and fully absorbed from the gastrointestinal ant mutants occur in susceptible mycobacterial popu- tract following oral administration; widely distribut- lations less frequent than streptomycin or rifampicin ed to most tissues and fluids. Agent may cause the in- ones. tense gastric irritation, which accompanied by nausea, Isoniazid is readily absorbed from the gastrointes- vomiting, loss of appetite, and abdominal pain. Ortho- tinal tract. It diffuses readily into all body fluids and static hypotension, peripheral neuritis, and skin rash tissues, including CNS and cerebrospinal fluid. Isoni- azid crosses the placenta and is distributed into breast milk. Metabolism of Isoniazid, especially acetylation Table 14. Typical adverse effects of by liver N-acetyltransferase, is genetically determined. antituberculosis agents The average concentration of isoniazid in the plasma of rapid acetylators is about 1/3 to 1/2 of that in slow acetylators and average half-lives are less than 1 hour and 3 hours, respectively. Patients who are slow acetylators may be more prone to development of adverse effects and may require lower doses. Isoniazid excreted by the kidneys within 24 hours; more than

90% of the Isoniazid excreted as the acetylated form Group Agents GI upset CNS toxicity Neuritis Ototoxicity Visual upset Hepato-toxicity Nephro-toxicity Allergic reactions Super-infections in fast acetylators and less than 90% in slow acetylators. The typical adult daily dose of Isoniazid is 300– I Rifampicin ++++ 600 mg given 1–3 times a day. In case of serious in- Streptomycin ++ ++ fections or gastrointestinal disturbances it can be used i.m., i.v., or in inhalation. Isoniazid ++ + Peripheral neuritis (unsteadiness, numbness, tin- Ethambutol ++ + gling, burning, or pain in hands and feet) can observed in patients, because Isoniazid acts as Pyridoxine (vi- II Cycloserine ++ tamin B6) antagonist, hampering the conversion of py- Kanamycin +++ ridoxine into its active form. Pyridoxine is recommended for patients with conditions predisposing to neurop- Ethionamide ++ athy. CNS toxicity, which is less common, includes Pyrazinamide ++ memory loss, psychosis, and seizures. Fever and skin P-aminosalicylate rashes are occasionally seen. Diarrhea, vomiting, and ++ hepatitis also may appear. sodium

167 can occur. Ethionamide is also hepatotoxic. Adverse same mechanism of action as arsenic compounds, effects may be alleviated by nicotinamide. however, bismuth compounds are less toxic. After i.m. Pyrazinamide is a relative of Nicotinamide. Tu- injections they are released slowly. Adverse effects are berculosis bacilli develop resistance to Pyrazina- grey gingival colour (bismuth edge), gingivitis, sto- mide fairly readily. It is rapidly and completely ab- matitis, gastrointestinal disturbances, dermatitis, and sorbed from the gastrointestinal tract. Pyrazinamide renal upset. Sodium and Potassium iodide are used has distributed widely, to most fluids and tissues. in the late period of syphilis for enhance gumma dis- Major adverse effects of Pyrazinamide include hepa- similation. totoxicity (in 1–5% of patients), vomiting, drug fever, and hyperuricemia, which may provoke acute Available forms: gouty arthritis. Biiochinolum — in bottles 100 ml each Para-aminosalicylate sodium (PASA) is structurally similar to para-aminobenzoic acid (PABA) and to the sulfanilamides. It is a folate synthesis antagonist that is active almost exclusively against Myco- bacterium tuberculosis, acts bacteriostatic. It is rap- Lecture 40 idly and well absorbed from the gastrointestinal tract. ANTIPROTOZOAL DRUGS Agent diffuses readily into various body fluids except the cerebrospinal fluid. Gastrointestinal symptoms such as anorexia, nausea, diarrhea, and epigastric ANTIMALARIAL DRUGS pain are often accompany full doses of p-aminosalicylate sodium. Hypersensitivity reactions, hepatitis, Four species of Plasmodium are responsible for hu- crystalluria, granulocytopenia, goiter or myxedema man malaria: P. vivax and P. ovale that cause three- may occur. day malaria; P. malariae (four-days malaria) and P. falciparum (tropical malaria). The transmitter of Plas- Available forms: modium is mosquito. The sporozoites that develop in Rifampicin — tablets or capsules 0.05; 0.15 g each; the mosquito are then inoculated into humans at its in ampoules 0.15 g next feeding. In the first stage of development in hu- Isoniazid — powder; tablets 0.1; 0.2 or 0.3 g each; mans, the exoerythrocytic stage, the sporozoites mul- in ampoules 10% solution 5 ml each tiply in the liver to form tissue schizonts. Later, the Streptomycin sulfate — in bottles 0.25; 0.5; 1 g parasites escape from the liver into the bloodstream as each merozoites to initiate the erythrocytic stage. In this Cycloserine — tablets or capsules 0.25 g each stage they invade red blood cells, multiply in them, and Sodium para-aminosalicylate — powder; tablets or finally rupture the cells, releasing a new crop of mero- capsules 0.5 g each; in bottles 3% solution 250 ml or zoites. This cycle may be repeated many times. Mean- 500 ml each while, partly merozoites are transformed in gametocytes (the sexual stage) and they may be taken in by another mosquito, which becomes infected, by taking human blood that contains gametes. In P. vivax and P. ovale infections, sporozoites also induce in hepatic Lecture 39 cells the dormant stage (the hypnozoite) that causes ANTISYPHILITIC AGENTS subsequent recurrences (relapses) of the infection. Drugs that eliminate developing tissue schizonts or latent hypnozoites in the liver are called tissue schizon- Syphilis is infectious disease caused by Trepone- ticides (Fig. 29). Those that act on blood schizonts are ma pallidum and transmitted by direct contact, usual- blood schizonticides. Gametocides are drugs that pre- ly through sexual intercourse. For syphilis treatment vent infection of mosquitoes by destroying gametocytes there are prescribed antibiotics and organic com- in the human blood. Sporonticidal agents are drugs that pounds containing arsenic and bismuth. act on sporozoites noninfective in the mosquito. For For syphilis drugs of first choice are agents of Ben- causal malaria prophylactic are used sporonticides and zylpenicillin. They possess rapid and considerable tissue schizonticides (Pyrimethamine (Chloridin), Pro- treponemicidal action. Treponema pallidum is unable guanil (Bigumal), and Primaquine). However, blood to gain resistance to penicillins. In cases of allergic schizonticides are prescribed for abortion and preven- reactions, caused by penicillins, tetracyclines, mac- tion of malaria attacks. Gametocides are useful for so- rolides and cephalosporins are used, though their effi- cial chemoprophylaxis of malaria spreading. ciency is lower than of penicillins. Organic arsenic-containing compound is Myarse- Classification of antimalarial drugs: nolum. Mechanism of action is the binding of arsenic Blood schizonticides: Chloroquine, Mefloquine, with sulfhydrate groups of treponema enzymes and Quinine, Chloridin, Bigumal, and sulfanilamides. cessation of their activity. Because of Myarsenolum Tissue schizonticides: toxicity and the availability of a number of more ef- a. Agents that act on preerythrocytic forms (tissue fective agents, Myarsenolum current utility is limit- schizonts) — Chloridin, Bigumal, Primaquine; ed. The adverse effects are encephalopathy, periph- b. Agents that active against para-erythrocytic eral neuropathy, renal and hepatic dysfunction. Bis- forms (hypnozoites) — Primaquine, Quinocide. muth agents (Biiochinolum, Bismoverol) have the Gamete-tropic drugs: 168 c. Gametocidal drugs — Chloroquine, Primaquine, It is well absorbed. The drug is highly bound to plas- Quinocide. ma proteins and concentrated in red blood cells. Its d. Sporontocidal agents — Chloridin, Bigumal. elimination half-life varies from 13 to 33 days. Meflo- Chloroquine is a synthetic 4-aminoquinoline. Chlo- quine is used one time for malaria treatment and once roquine is a highly effective blood schizonticide and a week for prophylaxis. Drug may lead to gastroin- is most widely used in chemoprophylaxis and in treat- testinal disturbances, headache, and dizziness. In high ment of malaria attacks. It is also moderately effec- doses visual disturbances can occur. tive against gametocytes. Chloroquine acts by block- Primaquine is a synthetic 8-aminoquinoline deriv- ing the synthesis of DNA and RNA in both mammali- ative. It is active against the primary exoerythrocytic an and protozoal cells. Within the parasite, the drug stages and late hepatic stages of Plasmodium. Pri- interferes with the parasite’s ability to metabolize and maquine is gametocidal against the four malaria spe- utilize erythrocyte hemoglobin. Selective toxicity for cies. The mechanism of action based on Primaquine’s malarial parasites depends on a chloroquine-concen- ability to bind to and alter the properties of DNA. At trating mechanism in parasitized cells. Also chloro- high doses, it may suppress myeloid activity. After oral quine has anti-inflammatory activity. It has been use- administration, the drug is usually well absorbed, and ful in the treatment of autoimmune disorders and for then is almost completely metabolized and excreted in amebic liver abscess. the urine. Its plasma half-life is 3–8 hours. Primaquine It is rapidly and almost completely absorbed from is widely distributed to the tissues, but only a small the gastrointestinal tract, reaches maximum plasma amount is bound there. It infrequently causes nausea, concentrations (50–65% protein-bound) in about 3 epigastric pain, abdominal cramps, and headache. The hours, and is rapidly distributed to the tissues. From more serious adverse effects, leukopenia and methemo- tissues it is slowly released and metabolized. It is ex- globinemia (manifested by cyanosis) are rare. Pri- creted in the urine with a half-life of 3–5 days. Renal maquine may cause hemolysis in persons with glucose- excretion is increased by acidification of the urine. 6-phosphate dehydrogenase (G6PD) deficiency. Qui- Gastrointestinal symptoms, pruritus, blurring of vision nocide is similar in structure and function to Pri- appear during prolonged treatment of autoimmune dis- maquine. eases. Chloroquine cumulation may contribute to the Quinine, the principal alkaloid derived from the development of irreversible retinopathy, hepatoxicity, bark of the cinchona tree, has been used in malaria heart disorders. suppression and treatment for more than 300 years. Chloridin (Pyrimethamine) and Bigumal (Pro- Although superseded by other antimalarials, following guanil) are blood schizonticides. Chloridin is a deriv- the development of widespread resistance to chloro- ative of Diaminopyrimidine related to Trimethoprim quine and other drugs, Quinine has again become an (lecture “Sulfanilamides”). Bigumal is a biguanide de- important antimalarial. Quinine is a rapidly acting, rivative. Chloridin and Bigumal are dihydrofolate re- highly effective blood schizonticide. The mechanism ductase inhibitors (folic acid antagonists, antifols). of action based on quinine’s ability to bind to and al- They have a higher affinity for plasmodial dihydro- ter the properties of DNA. Agent is rapidly absorbed folate reductase than the human enzyme. Resistance and is widely distributed in body tissues. When taken to them is widespread in certain areas. orally, Quinine commonly causes gastric irritation. Both Chloridin and Bigumal are slowly but ade- The drug causes hypersensitivity reactions, myocar- quately absorbed from the gastrointestinal tract. Chlo- dial depression and slight increasing of the uterus ridin has an elimination half-life 3–4 days and Bigu- mal — 16 hours. Therefore, in prophylaxis, Bigumal must be administered daily, whereas Chloridin can be INFECTION OF HUMAN given once a week. Chloridin and Bigumal are used for personal malaria prophylaxis. Also they are indicated in combination with sulfanilamides or/ and Chlo- Sporozoites (in blood) roquine in the treatment of malaria. Metakelfin contains Chloridin and Sulfalene; Fansidar includes Chlo- ridin and Sulfadoxine. Such combination is the example of effect potentiation. Finally, Chloridin is used for Para-ery- Preery- toxoplasmosis treatment. throcytic throcytic Chloridin and Biguanide can cause nausea, skin stage stage rashes, and alopecia. In the high doses Chloridin is (in liver) (in liver) used in toxoplasmosis, side effects of folic acid deficiency (megaloblastic anemia, agranulocytosis, and thrombocytopenia) are common. Also in high doses, Erythrocytic stage Qunine Chloridin neurologic symptoms (headache, insomnia, depression, Chloroquine ataxia, tremors, and seizures) may occur. Because PRIMAQUINE Chloridin is teratogenic in animals, it should be avoided during the first trimester. Bigumal is considered safe Sexual stage — gametocytes in pregnancy. Mefloquine is used in prophylaxis and treatment of chloroquine-resistant and multidrug-resistant malar- INFECTION OF MOSQUITO ia. Mefloquine hydrochloride is a synthetic 4-quino- line methanol derivative chemically related to quinine. Fig. 29. Activity of antimalarial agents

169 tonus. A less common effect is cinchonism that includes absorbed erratically, and may induce vomiting. headache, slight visual disturbances, dizziness, and When given parenterally, it is stored primarily in the mild tinnitus. Hemolysis may occur in G6PD-deficient liver, lungs, and kidneys. The drug is cumulative; it persons. is eliminated slowly via the kidneys more than month. Quinacrine a 9-aminoacridine, is a blood schizon- Serious toxicity is common if they are given for more ticide that can effectively suppress all four types of hu- than 10 days. Therefore, use of this drug for more man malaria. The mechanism of action based on than 7–8 days is contraindicated. Hospitalization acrichine’s ability to bind to and alter the properties with careful supervision is essential. Pain in the area of DNA. Nowadays acrichine superseded by chloro- of the injection is frequent. Nausea and vomiting, quine. Its disadvantages include occasional drug de- which occur infrequently, are thought to be central posits that turn the skin yellow and rare psychotic re- in origin. The most serious symptoms are depression actions. However, acrichine is indicated in the treat- of cardiac conduction and contraction, which may ment of lambliasis (giardiasis), leishmaniasis, and ces- cause a variety of atrial and ventricular arrhythmi- todiasis. as, heart failure, and hypotension. Generalized muscular weakness (tenderness, stiffness, aching, or tremors), paresthesia are often reported. It should not be TREATMENT OF AMEBIASIS used during pregnancy. Amebiasis is infection by the protozoan parasite The oral tetracyclines indirectly affect luminal Entamoeba histolytica. Usually it leads to amebic dys- amebas by inhibiting the bacterial associates of E. his- entery that associated by ulcerative inflammation of tolytica in the bowel lumen. Thus, the contents of ox- the colon. It also may be associated with amebic in- ygen in the bowel enhance that is harmful for ameba fection of other organs (liver, lungs). The choice of existing. drug depends on the desired site of drug action, i.e., in the intestinal lumen or in the tissues. ANTILEISHMANIC DRUGS Classification of antiamebic agents Infection with a species of Leishmania resulting in — Luminal amebicides. These agents act primarily a clinically ill-defined group of diseases may be divid- in the bowel lumen: Chiniofon, Chlorquinaldol ed into two types: visceral leishmaniasis (kala azar) — Agents that act against amebas in the bowel wall and cutaneous leishmaniasis. Transmission is by vari- and lumen: tetracyclines ous sandfly species. Treatment of leishmaniasis is not — Agents that act against amebas in the bowel wall satisfactory because of drug toxicity, the long courses and in the liver: Emetine required, treatment failures, and the frequent need for — Agents that act against amebas in the liver: Chlo- hospitalization. roquine The drugs of choice for visceral leishmaniasis are — Agents that act in any ameba’s localization: pentavalent antimony compounds (Solusurminum, So- Metronidazole dium stibogluconate). Solusurminum is a frequently used drug. It binds with thiolic group of leishmania Metronidazole is the drug of choice in treatment enzymes which leads to their inactivation. Solusurmi- of intestinal and extraintestinal amebiasis. The mech- num is injected i.v. The duration of treatment is about anism of action and the pharmacologic features of 3–4 weeks. The adverse effects are nausea, headache, Metronidazole have been discussed in lecture “Anti- skin rashes, and leukopenia. Hypotonia; liver, renal, microbials — derivatives of different groups”. How- and heart damages may appear. In case of Solusurmi- ever, it is only partially effective and not adequate as num overdosing Unithiol can be prescribed. Sodium luminal amebicides. That’s why, for amebic dysentery stibogluconate can be administered i.m. or i.v. Most treatment Metronidazole is used concurrently with lu- common adverse effects are gastrointestinal symptoms minal amebicides. Chiniofon is the derivative of 8-oxyquinolines. and rash. For cutaneous leishmaniasis the following Agent is effective against organisms in the bowel lu- drugs are useful: Quinacrine or Chloroquine (lecture men but not against trophozoites in the intestinal wall “Antiprotozoal drugs”), Aminoquinoline, Monomy- or extraintestinal tissues. Ninety percent of the drug cin (lecture “Antibiotics”), Amphotericin B (lecture is not absorbed. Thus, it produces a high amebicidal “Antifungal agents”). Aminoquinoline is the quino- concentration in lumen. Chiniofon is a drug of low line derivative. It is effective in the treatment of cuta- toxicity, but still it may cause diarrhea, optic neuri- neous leishmaniasis as well as toxoplasmosis, lam- tis, and peripheral neuropathy. Intetrix®, derivative bliasis, and collagen diseases. Aminoquinoline is of 8-oxyquinolines, is a patented drug. One tablet of well-tolerated, sometimes gastrointestinal disturbanc- Intetrix includes two active substances, which are sim- es, headache and allergic reactions may appear. ilar to Chlorquinaldol. It is highly active against both gram-positive and gram-negative microbes in the ANTILAMBLIAL DRUGS bowel. Also, Intetrix is antiamebic and antifungal drug. Lambliasis (giardiasis) is infection caused by pro- Emetine is the alkaloid of ipecacuanha root. It tozoan parasite Giardia lamblia that may cause di- acts on organisms in the bowel wall and other tissues arrhea, dyspepsia, and occasionally malabsorption in but not on amebas in the bowel lumen. Emetine blocks humans. For lambliasis treatment can be used metro- the synthesis of protein in ameba. The agent is ad- nidazole (see “Imidazole derivatives”), Furazolidone ministered parenterally, because oral preparation is (“Nitrofuran derivatives”), and Aminoquinoline. 170 ANTITRICHOMONADAL DRUGS sis the drug should be taken with food containing fat, which enhances absorption. Mebendazole inhib- Trichomoniasis caused by infection with a species its glucose uptake by parasites, decreasing forma- of protozoan of the genus Trichomonas; often used to tion of ATP. As a result, intestinal parasites are im- designate trichomoniasis vaginitis. For trichomonia- mobilized or die slowly. Less than 10% of orally ad- sis treatment can be prescribed Metronidazole, Tri- ministered Mebendazole is absorbed. The absorbed chomonacide, and Furazolidone. Trichomonacide is a drug is rapidly metabolized in the liver. Within 24- relative of Aminoquinoline. It can be taken locally or 48 hours, it is excreted mostly in the urine, either orally. It has irritate potency. Acetarsol (Osarsol), ar- unchanged or as metabolites. A dosage of 100 mg senic compound, is seldom used for topical treatment twice daily for 3 days is used for adults. Treatment of trichomoniasis. can be repeated in 2–3 weeks. Cure rates are 90- 100% for ascaridiasis and trichocephaliasis. Meben- ANTITOXOPLASMOSIS AGENTS dazole has a low incidence of adverse effects. Rash, nausea, vomiting, diarrhea, and abdominal pain Toxoplasmosis caused by the protozoan parasite have been reported infrequently. The drug is con- Toxoplasma gondii that can produce a variety of syn- traindicated during pregnancy. dromes in humans, such as fever, encephalomyelitis, Albendazole is similar in structure and activity with retinopathy, maculopapular rash, myalgia, myocar- Mebendazole. It is also the drug of choice in echinoc- ditis, and lymphadenopathy. For its treatment can be occosis and cysticercosis. Agent rapidly undergoes taken Chloridin (“Antimalarial agents”), sulfanila- first-past metabolism in the liver to active metabolite. mides. During pregnancy sulfanilamides are prefer- In large part, it binds to protein and is distributed to able. the tissues, including bile and cerebrospinal fluid, and enters hydatid cysts. When used for 1–3 days, Alben- Available forms: dazole infrequently may cause nausea, diarrhea, head- Chloroquine — powder; tablets 0.25 g each; in am- ache, dizziness, and insomnia. In 3-month treatment poules 5% solution 5 ml courses for echinococcosis rash or pruritus, leukope- Chloridin — powder; tablets 0.005 or 0.01 g each nia were observed. Because the drug is teratogenic and Bigumal — powder; tablets or dragee 0.1 g (for embryotoxic in some animal species, it should not be adults) and 0.05 g (for children) used in pregnancy. Primaquine — tablets 0.003 or 0.009 g each The Piperazine adipinate is alternative drug in Metronidazole — tablets 0.25 or 0.5 g each; vagi- the treatment of ascaridiasis. Cure rates are over nal suppository 0.5 g 90% when patients are treated for 2 days. Also it can Chiniofon — powder; tablets 0.25 g each be used for enterobiasis treatment. Piperazine caus- Intetrix — patented capsules es paralysis of nematodes by blocking Acetylcholine Solusurminum — in ampoules 20% solution 10 ml at the myoneural junction. Thus, the paralyzed each roundworms are unable to maintain their position in Aminoquinoline — powder; tablets 0.025 or 0.05 g the host and are expelled live by normal peristalsis. each No pre- or posttreatment cathartics are used. Mild adverse effects occur occasionally, including nausea, diarrhea, abdominal pain, and headache. Pa- tients with epilepsy may have an exacerbation of seizures. Lecture 41 Pyrantel is a broad-spectrum anthelmintic highly ANTIHELMINTIC DRUGS effective for the treatment of enterobiasis, ascaridiasis, and ancylostomiasis. Cure rates are greater than 95%. The drug causes stimulation of ganglionic recep- Anthelmintic drugs are used to eradicate or re- tors and worm paralysis, which is followed by expul- duce the numbers of helminthic parasites in the in- sion from the host’s intestinal tract. Because it is poorly testinal tract or tissues of the body. According to absorbed from the gastrointestinal tract, it is active their localization helminths can be divided into in- mainly against luminal organisms. traintestinal and extraintestinal groups. Also Adverse effects are infrequent and mild. They include helminths are distinguished as nematodes (round- vomiting, diarrhea, abdominal cramps, dizziness, worms) and platyhelminthes (flatworms). The last headache, insomnia, and rash. one includes cestodes (tapeworms) and trematodes Levamisole is highly active for the ascaridiasis (flukes, sucklings). Most anthelmintics in use today treatment. It causes contracture of ascaris that follows are active against specific parasites (Table 15). by it paralysis. In addition, levamisole inhibit a suc- Therefore, parasites must be identified before treat- cinate dehydrogenase (essential enzyme) of helminth. ment is started, usually by finding the parasite or Agent is rapidly absorbed from the gastrointestinal eggs in the feces, urine, blood, sputum, or tissues of tract. The Levamisole half-life is about 3 to 4 hours. the host. It is eliminated mostly via kidney (70% over 3 days). Mebendazole (Vermox) is a synthetic benzimi- Levamisole is a single dose drug for ascaridiasis treat- dazole that has a wide spectrum of antihelmintic ac- ment. Also Levamisole has immunomodulating prop- tivity. It has been approved for use in ascaridiasis, erties. Side effects of Levamisole are usually mild and trichocephaliasis, ancylostomiasis, and enterobiasis. transitory. It may lead to gastrointestinal disturbanc- In the treatment of trichinellosis and echinococco- es and leukopenia.

171 Table 15. The basic agents, which are used in the treatment of helminthiasis

Class Helminthiasis Localization Mebendazole Albendazole Piperazine adipinate Pyrantel Levamisole Naphthammonum Praziquantel Niclosamide Aminoacrichinum Diethylcarbamazine Ivermectin Chloxyle Antimony sodium tartrate Bithionol Ascaridiasis + + + + + + Enterobiasis + + + + N Ancylostomiasis + + + + + Trichocephaliasis + + Taeniarhynchiasis + + + Intraintestinal C Taeniasis + + Diphyllobothriasis + + + Trichinellosis + N Filariasis + + Echinococcosis + + C Cysticercosis ± + + Schistosomiasis + + T Fasciolopsis + + +

Extraintestinal Opisthorchiasis + + + N — Nematodes; C — Cestodes; T — Trematodes.

Naphthammonum (Bephenium hydroxynaph- ness and drowsiness, patients should not drive and thoate) primarily has been approved for Ancylostomia- should be warned if their work requires physical cosis treatment. It is less useful in the treatment of as- ordination or alertness. caridiasis, trichocephaliasis, and enterobiasis infec- Niclosamide (Phenasalum) is a drug of choice for tion. Naphthammonum causes contracture of nema- the treatment of most tapeworm infections. It appears todes that follows by their paralysis. The agent is badly to be minimally absorbed from the gastrointestinal absorbed in the gastrointestinal tract. There are spe- tract. Scoleces and segments of cestodes are rapidly cial tablets of Naphthammonum, which are dissolved killed on contact with Phenasalum due to the drug’s in the lower part of the small intestine — in the basic inhibition of oxidative phosphorylation. With the place of Ancylostoma localization. Nausea, vomiting, death of the parasite, digestion of scoleces and seg- and diarrhea can appear in the period of Naphtham- ments begins. A single 2 g dose of Phenasalum results monum using. in cure rates of over 85% for Diphyllobothrium latum Praziquantel is effective in the treatment of schis- and about 95% for Taenia saginata. Phenasalum tosome infections of all species and most other trem- should be given in the morning on an empty stomach. atode and cestode infections, including cysticercosis. The tablets must be chewed thoroughly and are then The drug’s safety and effectiveness as a single oral swallowed with water. Posttreatment purges to expel dose have also made it useful in mass treatment of sev- the worm are not necessary. Two hours after Taenia eral infections. Praziquantel is a synthetic isoquino- solium treatment an effective purge (such as 15–30 g line derivative. Praziquantel increases cell membrane of magnesium sulfate) should be given to eliminate all permeability to calcium, resulting in marked contrac- mature segments before ova can be released, that will tion, followed by paralysis of worm musculature. It prevent cysticercosis. Adverse effects are infrequent, is rapidly and well absorbed after oral administra- mild, and transitory. Nausea, vomiting, diarrhea, and tion. Cerebrospinal fluid and bile concentrations of skin rash may occur. praziquantel reach 14–20% of the drug’s plasma con- Aminoacrichinum is relative of Acrchinum (see centration. Most of the drug is rapidly metabolized “Antimalarial drugs”). It has been used for the treat- to inactive products; the half-life of the drug is 0.8– ment of diphyllobothriasis, hymenolepiasis, and Tae- 1.5 hours. Excretion is mainly via the kidneys (60– niasis, however it’s less effective agent than Phena- 80%). The adverse effects are headache, nausea, vom- salum and Praziquantel. In addition, Aminoacrichi- iting, abdominal pain, loose stools, and myalgia. num is used for the treatment of Trichomoniasis vagin- The only specific contraindication is ocular cysticer- itis. It has high irritate potency, thus after ingestion cosis; parasite destruction in the eye may cause ir- Aminoacrichinum can cause stomach ache, nausea, reparable damage. Because the drug induces dizzi- and vomiting. 172 Diethylcarbamazine citrate (Ditrazine citrate) is a Lecture 42 drug of choice in the treatment of Filariasis (Wuchere- riasis, Loiasis). It alters microfilariae surface structure, ANTIFUNGAL AGENTS making them more susceptible to destruction by host defense mechanisms. Adult parasites are killed more slowly. Ditrazine is rapidly absorbed from the gas- Antifungal agents can be dividing into three main trointestinal tract. Adverse reactions may be caused by groups: to the agent itself and also occur as a result of the re- 1. Agents for the treatment of system mycosis (His- lease of foreign proteins from dying worms in sensi- toplasmosis, Blastomycosis, Coccidia mycosis) — Am- tized patients. For instance, headache, weakness, an- photericin B, Amphoglucaminum (Amphotericin B + orexia, nausea, vomiting, dizziness, and sleepiness are Methylglucamine), Mycoheptinum, azole derivatives. observed. Antihistamines may be given for the first 4– 2. Agents for the treatment of dermatomycosis (ep- 5 days of Ditrazine therapy to reduce the incidence of idermophytosis, microsporiasis, and trichophytosis): allergic reactions. a) antibiotic — Griseofulvin; Ivermectin also indicated for Filariasis (On- b) azole derivatives — Miconazole, Itraconazole chocercosis) treatment. In comparison studies, iver- and Fluconazole; mectin is more effective than Ditrazine. Ivermectin c) derivatives of undecylenic acid (Zincundanum®, appears to paralyze nematodes by intensifying Undecinum®); GABA-mediated transmission of helminths. Ivermec- d) different chemical groups representatives — Ter- tin is given only orally. The drug is rapidly ab- binafine, Octicylum (Octilcyclopronancarbonic acid), sorbed; it has a wide tissue distribution. It appar- Nitrofungin, and iodine including agents. ently enters the eye slowly and to a limited extent. 3. Agents for the treatment of candidamycosis: The adverse effect of Ivermectin includes the reac- a) antibiotics — Nystatin, Levorin; b) other agents — Clotrimazole, Decamine. tion which caused by killing of microfilariae: fever, headache, dizziness, weakness, rash, diarrhea, joint Amphotericin B is a polyene antifungal antibiotic and muscle pains, hypotension, lymphadenitis, and produced by Streptomyces nodosus. It remains the drug peripheral edema. of choice for nearly all life-threatening mycotic infec- Chloxyle is the drug of choice for the treatment of tions. Amphotericin B is selective in its fungicidal ef- Fasciolopsis and Opisthorchiasis. The agent is slowly fect. The agent binds to ergosterol, a cell membrane absorbed from the gastrointestinal tract; mainly it is sterol, and alters the permeability of the cell by form- excreted with feces. Two days before and during treating pores in cell membrane. The pore allows the leak- ment fat-food and alcohol are prohibited for patients. age of intracellular ions and macromolecules, eventu- It has been taken 2 g of Chloxyle powder every 10 min ally leading to cell death. Amphotericin B is poorly (total dose — 10 g). Adverse effects are drowsiness, absorbed from the gastrointestinal tract; thus it is used pain in the liver region, arrhythmia, and hypersensi- intravenously. The serum half-life is approximately 15 tivity reactions. days. The drug is widely distributed in tissues, but only Bithionol is the drug of choice for the treatment of 2–3% of the blood level is reached in cerebrospinal flu- fasciolopsis. The agent is well absorbed in the gas- id, thus occasionally necessitating intrathecal thera- trointestinal tract. Excretion appears to be mainly via py for certain types of fungal meningitis. Anemia, hy- the kidney. Adverse effects are generally mild. Di- pokalemia, renal function impairment are the most sig- arrhea and abdominal cramps are most common. An- nificant toxic reactions. Fever, muscle spasms, vomit- orexia, nausea, vomiting, dizziness, and headache ing, and hypotension can appear during infusion of the may also occur. drug. Amphotericin B should be given only to hospi- Antimony sodium tartrate was for many years the talized patients, so as to provide constant supervision principal drugs for the treatment of schistosomiasis, by a physician. but because of it’s toxicity and difficulty of adminis- Amphoglucaminum is a synthetic derivative of Am- tration, using of Antimony sodium tartrate is limit- photericin B. It is well absorbed from the gastrointes- ed. Adverse effects are strong vomiting, skin rashes, tinal tract and less toxic than parental agent. Myco- arthralgia, and anaphylactic reactions. In case of heptinum is similar in structure and function to Am- overdosing, Unithiol is indicated. Niridazole is the photericin B. drug of choice for the treatment of schistosomiasis. Azoles are synthetic compounds that can be classi- It is readily absorbed orally. The most frequent ad- fied as either imidazoles or triazoles. The imidazoles verse effects are neurotoxicity (dizziness, headache, consist of Ketoconazole, Miconazole, and Clotrima- drowsiness), gastrointestinal disorders, and allergic zole. The triazoles include Itraconazole and Flucona- reactions. zole. The antifungal activity of azole drugs results from the reduction of ergosterol synthesis. The effect Available forms: is fungistatic or may be fungicidal, depending on agent Mebendazole — tablets 0.1 each concentration. The most common adverse reaction is Pyrantel — tablets 0.25 each; in bottles 5% suspen- relatively minor gastrointestinal upset. All azole drugs sion 15 ml inhibit the mammalian cytochrome P450 system of en- Praziquantel — tablets 0.6 each zymes to some extent. For instance, the metabolism of Diethylcarbamazine citrate (Ditrazine citrate) — cumarin anticoagulants, oral antidiabetic drugs and tablets 0.05 or 0.1 each Diphenin in the liver will slow down; thus the thera- Chloxyle — powder peutic effects of those agents will enhance and prolong.

173 Miconazole can be used in enteral way or i.v. in Nystatin is active against most Candida species the treatment of systemic (endemic) mycoses. Also it is and is most commonly used for suppression of local useful for local treatment of dermatomycosis (dermat- candidal infections. Some common indications in- ophytosis, tinea) and candidamycosis. The adverse ef- clude oropharyngeal thrush, gastrointestinal and vag- fects are burning and redness of skin, rash, or other inal candidiasis, and skin candidal infections. Cand- sign of skin irritation, thrombophlebitis in site of in- ida, a species ordinarily a part of humans normal gas- jections. The systemic using of Miconazole is prohib- trointestinal flora, but which becomes pathogenic ited during pregnancy and hepatitis. Ketoconazole is when there is a disturbance in the balance of flora or prescribed for oral and topical usage. The agent is var- in debilitation of the host from other causes. Nysta- iable absorbed from the intestine; the serum half-life is tin is a polyene antibiotic much likes Amphotericin 7–8 hours. Ketoconazole has the same indication as Mi- B and has the same pore-forming mechanism of ac- conazole, however Ketoconazole is more toxic. Ketoco- tion. It is currently available in tablets, ointments, nazole inhibition of human cytochrome P450 enzymes and suppositories for application to skin and mucous interferes with biosynthesis of adrenal and gonadal ster- membranes. Nystatin is not absorbed from the gas- oid hormones, producing endocrine effects such as gyne- trointestinal tract. As a result, it produces a high an- comastia, infertility, and menstrual irregularities. tifungal concentration at the intestine. Nystatin has Itraconazole is available in an oral formulation. a little significant toxicity. Sometimes, it can cause Like Ketoconazole, its absorption is increased by low gastrointestinal disturbances (diarrhea, nausea or gastric pH and it poorly penetrates into the cerebrospi- vomiting, stomach pain). Levorin is similar in mech- nal fluid. Itraconazole is the most potent of the availa- anism of action and indications to Nystatin. It has ble azoles. It is the azole of choice in the treatment of higher anti-candidamycosis activity, than Nystatin. dermatomycosis, systemic mycoses. It interacts with he- However, Levorin is more toxic. patic microsomal enzymes to a lesser degree than Ke- For candidamycosis treatment are used Clotrima- toconazole. Fluconazole is distinguished from the oth- zole, Decamine as well. Clotrimazole, an imidazole er azole medications by good cerebrospinal fluid pene- derivative, is active against Candida species and der- tration and excellent bioavailability by the oral route. matophytes. In connection with its high toxicity, clot- That’s why, it is the azole of choice in the treatment of rimazole is now used only in topical therapy. De- mycotic meningitis. It is also effective for mucocutane- camine (Dequalinium), a quaternary ammonium com- ous candidamycosis. Fluconazole has the least effect on pound, possess antibacterial and antifungal (Candida, hepatic microsomal enzymes. As a result, this drug has dermatophytes) activity. It can be prescribed in oint- a wide therapeutic window, which permits more aggres- ment or caramel. The last one has to be taken under sive dosing than with any other azole. the tongue or beyond of cheek. Decamine is well-tol- Griseofulvin is a fungistatic drug derived from a spe- erated agent. cies of Penicillium. Its only use is in the systemic treatment of dermatomycosis. Griseofulvin inhibits the syn- Available forms: thesis of mycotic nucleic acids. Absorption is variable Amphotericin B — in bottles 50,000 unites powder and improved being given with fatty foods. Griseoful- each vin is deposited in newly forming skin where it binds Amphoglucaminum — tablets 0.1 (10000 unites) to keratin, protecting the skin from new infection. It each must be administered for 2–6 weeks for skin and hair Isoconazole — 1% cream 20,0 infections to allow the replacement of infected keratin Fluconazole — capsules 0.05; 0.1; 0.15 or 0.2 each; by the resistant structures. The serum half-life is ap- in bottles 0.2% solution proximately 24 hours. Adverse effects are diarrhea, Griseofulvin — tablets 0.125 each; 2.5% liniment nausea, headache, dizziness, insomnia, allergic reac- 30.0 tions, and hepatitis. Griseofulvin is not recommended Terbinafine — tablets 0.125 or 0.25 each; 1% oint- during pregnancy since it has been shown to be em- ment bryotoxic and teratogenic in rats. Nystatin — tablets 250,000 or 500,000 unites each; Terbinafine, a fungicidal agent, is used in the treat- vaginal suppository 250,000 or 500,000 unites each; ment of dermatomycosis, especially onychomycosis. It ointment 15 g (1 g contains 100,000 unites) is available in an oral formulation. Like griseofulvin, Terbinafine is a keratophilic medication. It inhibits the ergosterol biosynthesis. One tablet given daily for 12 weeks achieves an up to 90% cures rate for onychomy- Lecture 43 cosis and is more effective than Griseofulvin or Itraco- nazole. Adverse effects are rare, consisting primarily ANTIVIRAL AGENTS of gastrointestinal upset and headache. Undecylenic acid and undecylenate salts (e.g. ointments Zincundanum®, Undecinum® (Undecylenic Viruses are obligate intracellular parasites; their acid + Cuprum undecylenate)) are topical anti-der- replication depends primarily on synthetic processes matomycosis agents. The drugs usually are used in of the host cell. Consequently, antiviral agents must be combination. Preparations containing the drugs are active inside the host cell. Nonselective inhibitors of applied topically twice daily after cleansing the affect- virus replication may interfere with host cell function ed area. In addition, iodine including agents, Nitro- and produce toxicity. fungin, and Octicylum are indicated for the topical According to the chemical structure, antiviral treatment of dermatomycosis. agents are classified as:

174 — synthetic agents — analogs of nucleosides agents, such as a protease inhibitor, is one strategy to (Acyclovir, Idoxuridine, Ribavirin, Zidovudine), enhance antiviral activity and retard the development amantadine derivatives (Rimantadine), and different of resistance. The most common adverse effect is mye- chemical groups representatives (Oxolin (Tetraoxo- losuppression, resulting in anemia or neutropenia. tetrahydronaphthaline dihydrate), Florenalum (Flu- Indinavir is a specific inhibitor of the human im- orenonylgluoxal bisulfite); munodeficiency virus protease, an enzyme essential for — biological preparations — Interferons. the production of mature, infectious virions. It is approved for the treatment of individuals with human im- Acyclovir is an acyclic guanosine derivative with munodeficiency virus infection. Oral bioavailability is clinical activity against herpes simplex viruses and excellent. The most common adverse effects reported against varicella-zoster virus. Agent requires three thus far are indirect hyperbilirubinemia and nephro- phosphorylation steps for activation and is converted lithiasis. Indinavir is inhibitor of as well as substrate to the mono-, di- and triphosphate compounds. Because for cytochrome P450. Thus, numerous complex drug in- it requires the viral kinase for the first phosphoryla- teractions can occur. tion, acyclovir is selectively activated and the triphos- Rimantadine, an amantadine derivative, inhibit phate accumulates only in infected cells. Acyclovir tri- uncoating of the viral RNA of influenza A within in- phosphate inhibits the viral DNA polymerase and infected host cells, thus preventing its replication. It is corporates into the viral DNA. Oral and topical acy- effective in the prevention of influenza A virus infec- clovir is effective for treatment of primary infection tion. The most common side effects are gastrointesti- and recurrences of genital and labial herpes. Intrave- nal intolerance and central nervous system effects (e.g. nous Acyclovir is the treatment of choice for herpes nervousness, drowsiness). simplex encephalitis. The bioavailability of the oral Ribavirin is a Guanosine analog that is phosphor- formulation is 20%. Acyclovir is cleared primarily by ylated intracellularly by host cell enzymes. Its mech- kidneys. The half-life is 3–4 hours. Agent well diffus- anism of action appears with synthesis of Guanosine es into most tissues and body fluids, including cerebro- triphosphate and inhibition of RNA polymerase of cer- spinal fluid. Acyclovir is generally well tolerated. tain viruses, including influenza A and B, parainflu- Nausea, diarrhea, and headache have occasionally enza, and respiratory syncytial virus. Ribavirin is ad- been reported. Intravenous infusion may be associat- ministered in aerosolized form to patients with respi- ed with renal insufficiency or neurologic toxicity (the ratory syncytial virus bronchiolitis or pneumonia, re- latter may include tremors or delirium). ducing the severity and duration of illness. I.v. Riba- Ganciclovir is similar in structure, mechanism of virin decreases mortality in Lassa fever and other vi- action, and activity to acyclovir. However, its activi- ral hemorrhagic fevers. Aerosolized Ribavirin is gen- ty against cytomegalovirus is up to 100 times greater erally well tolerated but may cause conjunctival or than that of acyclovir. Ganciclovir is available in i.v. bronchial irritation. Systemic administration of Riba- formulations. The oral bioavailability of ganciclovir virin is associated with dose-dependent anemia and is poor (6–9%). Ganciclovir is indicated for the treat- bone marrow suppression. The drug is contraindicat- ment of cytomegalovirus retinitis and colitis inpatients ed in pregnancy due to possible teratogenicity. with AIDS. The most common side effect of treatment Oxolin and Florenalum are the topical agents that with Ganciclovir is myelosuppression, particularly neu- adopted for the treatment of skin and mucous mem- tropenia. Central nervous system toxicity (headache, brane viral infections (mostly herpes). These agents changes in mental status, seizures) has been reported have direct virucidal activity. They are too toxic for also. Due to the high toxicity and mutagenic and tera- systemic administration. Oxolin and Florenalum can togenic potential of Ganciclovir, use during pregnan- cause irritation in place of their application. cy should be avoided. Interferons are a group of endogenous proteins that Idoxuridine is a Thymidine analog. It has the sim- exert virus-nonspecific antiviral activities. Three ma- ilar mechanism of action with Acyclovir. Idoxuridine jor classes of Interferons are now recognized: α- (leu- is used topically in the treatment of herpes keratitis, kocyte), β- (fibroblast), and γ- (immune, T-lym- because it is too toxic for systemic administration (leu- phocyte). Each type can function as a potent cytokine kopenia). with complex antiviral and immunomodulatory activ- Zidovudine (Azidothymidine) is a Deoxythymi- ity. They are not directly antiviral but appear to func- dine analog. After entering the cell by passive diffu- tion by causing elaboration of effector proteins in in- sion, Zidovudine is phosphorylated via three cellular fected cells, resulting in such effects as inhibition of kinases; the triphosphate is an inhibitor of the reverse viral penetration or uncoating, mRNA synthesis and transcriptase. Zidovudine has activity against human translation, or virion assembly and release. Agents of immunodeficiency virus. Resistance typically occurs natural a-interferon as well as recombinant α-interfer- after prolonged therapy. Zidovudine is available in i.v. on (Reaferon), which produced by genetic engineer- and oral formulations. It is well absorbed from the gut ing, are mostly used in clinics. Natural α-interferon and distributed to most body tissues and fluids, includ- have been used an intranasal route for prophylaxis and ing the cerebrospinal fluid. Substantial first-pass me- treatment of the common cold viruses infections (In- tabolism to an inactive glucuronidated metabolite re- terferon) and an intraconjunctival way for the treat- sults in a systemic bioavailability of approximately ment of herpes keratitis (Interlock). 65%. The serum half-life is only 1 hour. Clinical effi- Recombinant α-interferon is approved for the treat- cacy is limited by the relatively rapid development of ment of hepatitis B and C, leukemia, bladder and re- resistance, particularly when used as monotherapy. nal carcinoma, and malignant melanoma. Recom- The combination of Zidovudine with one or two other binant β-interferon (Betaferon) is used for the treat-

175 ment of multiple sclerosis. Adverse effects of inetrfer- (C). Immunity. ons include neutropenia, anemia, skin rashes, fever, (D). Resistance. myalgia, and fatigue. Poludan, Amixin stimulate the (E). Selective toxicity. synthesis of endogenous interferon and thus possess antiviral activity. Poludan is a topical agent for the 6. A 24-year-old AIDS patient is interested in start- treatment of viral eye diseases. Amixin is active in case ing chemoprophylaxis for Pneumocystis pneumonia of virus’s hepatitis B and C. (PCP) and cerebral toxoplasmosis. He has no drug allergies. Which of the following prophylactic agents is Available forms: appropriate for the prevention of both PCP and cere- Interferon — in ampoules (2 ml) powder bral toxoplasmosis? Acyclovir — in ampoules 0,25 (to dilute in 10 ml (A). Nitrofurantoin. physiological solution, for i.v. injection); tablets 0.2 (B). Trimethoprim-sulfamethoxazole. each; 3% ointment 4.5 or 5.0 (C). Norfloxacin. (D). Methenamine. (E). Nalidixic acid.

7. Urinalysis of a 38-year-old woman with recur- EXAMINATION QUESTIONS rent UTIs revealed pH 6.8, 30 to 50 WBC per high- 1. Choose the best answer. Selective toxicity is power field, and gram-negative bacilli identified as (A). What the drug does to the patient. Proteus mirabilis. Which of the following produces a (B). What the patient does to the drug. bacteriostatic urinary environment for P. mirabilis? (C). What the pathogen does to the patient. (A). Urease enzyme. (D). What the drug does to the pathogen. (B). Hippuric acid. (E). What the pathogen does to the drug. (C). Catalase enzyme. (D). Folic acid. (E). Coagulase enzyme. 2. A 60-year-old patient with AIDS presents to the emergency department with a temperature of 102°F, 8. A 3-day-old baby is given a presumptive diag- confused, and is going in and out of consciousness. He nosis of kernicterus. Which of the following mecha- exhibits rapid respiration and a blood pressure of 80/ nisms is involved in Sulfonamide-induced kernicter- 40. You determine that both the sputum and urine are us? negative by Gram staining. Which of the following is (A). Competes for the bilirubin-binding sites on the best choice? plasma proteins. (A). Administer Penicillin G intravenously. (B). Defective bilirubin hepatic conjugation and (B). Administer Vancomycin. metabolism. (C). Administer Clindamycin and Amikacin. (C). Physiological jaundice due to destruction of (D). Send a clinical sample to laboratory to find fetal red blood mass. out what the organism is before treating. (D). Pregnancy-induced hepatic congestion and cholestasis. 3. The term magic bullet was coined for (E). Primary biliary cirrhosis of the liver. (A). Ehrlich discovering the drug Salvarsan for the treatment of syphilis. 9. A 6-year-old relatively healthy boy is diagnosed (B). Fleming discovering the antibacterial effect with external otitis and was prescribed a 7-day course of Penicillium notatum. of TMP-SMX. Which of the following is the basic (C). Florey showing the effectiveness of Penicil- mechanism of action of the sulfonamides? lin in patients. (A). Selective inhibition of incorporation of PABA (D). Wilson discovering the broad spectrum anti- into human cell folic acid synthesis. biotic Streptomycin. (B). Competitive inhibition of incorporation of PABA into microbial folic acid. 4. Choose the best answer for the following. The (C). Inhibition of transpeptidation reaction in bac- emergence of microbial antibiotic drug resistance terial cell wall synthesis. (A). Requires the concurrent administration of (D). Changes in DNA gyrases and active efflux more than one antibiotic. transport system resulting in decreased per- (B). Is a direct result of the use of antibiotics in meability of drug. livestock. (E). Structural changes in dihydropteroate syn- (C). Is a problem that was overcome by the devel thase and overproduction of PABA. opment of Vancomycin. (D). Is due in large part to the indiscriminate use 10. Evaluation of a yearly chest radiograph of a of antibiotics in humans. 73-year-old patient taking Nitrofurantoin prophylactically for recurrent UTIs revealed new findings of bi- 5. A patient refuses to continue to take Erythromy- lateral interstitial fibrosis. What is the possible ex- cin because it makes him vomit. This is an example of planation for the patient’s pulmonary presentation and which patient-drug-pathogen interaction? what is the next step? (A). Pharmacokinetics. (A). Acute urosepsis; add a broad-spectrum anti- (B). Pharmacodynamics. biotic to Nitrofurantoin.

176 (B). Possible allergic reaction to Nitrofurantoin; after she stopped the Ampicillin, she developed a rash. stop it immediately. Her physician noted symmetrical erythematous con- (C). Nitrofurantoin-resistant E. coli infection; stop fluent macular-papular eruptions on her extremities it immediately. with no urticaria. The physician diagnosed non-IgE- (D). Acute community-acquired streptococcal mediated Ampicillin eruption. Now the patient re- pneumonia; treat accordingly. turns with new fever and sore throat. She has no cough (E). Nitrofurantoin-induced hemolysis; requires or rash. Her physical examination is normal except permanent urinary catheter. for fever, tender anterior cervical lymphadenopathy, and tonsillar exudate. Her rapid streptococcal test of 11. A 16-year-old girl, a cystic fibrosis patient, is a pharyngeal specimen is positive. Which of the fol- diagnosed with a Ciprofloxacin-resistant Pseudomonas lowing would be the most appropriate treatment for aeruginosa lower respiratory tract infection. Bacteria this patient? acquire Quinolone resistance by which of the follow- (A). Amikacin. ing mechanisms? (B). Lomefloxacin. (A). Overproduction of PABA. (C). Metronidazole. (B). Changes in the synthesis of DNA gyrases. (D). Netilmicin. (C). Plasmid-mediated changes in efflux transport (E). Penicillin V. system. (D). Inhibition of synthesis of Peptidoglycan sub- 15. A 24-year-old man came to the public health units in bacterial cell walls. clinic because of a urethral discharge. He had had (E). Inhibition of Folic acid synthesis by block- unprotected intercourse with multiple partners. ing different steps. Physical examination revealed a purulent urethral discharge with no penile ulcers or vesicles. There was 12. A 32-year-old man with quadriplegia and no inguinal adenopathy. Gram stain of the discharge neurogenic bladder was admitted to the hospital from revealed gram-negative diplococci inside leukocytes. a long-term care facility. The patient had vomiting, The antibiotic used to treat the patient’s infection has fever, and cloudy urine. A year ago, the patient which of the following mechanisms of action? developed urticaria, wheezing, and hypotension within (A). Inhibits cell membrane integrity by binding an hour after his first dose of Nafcillin. Subsequently to ergosterols to create pores. his penicillin skin test was positive. During the current (B). Inhibits dihydrofolate reductase, thereby admission, the physician examiner noted fever, blocking formation of tetrahydrofolate re- quadriplegia, and chronic indwelling bladder catheter. quired for purine synthesis. Laboratory tests revealed leukocytosis in blood and (C). Inhibits KasA, a β-ketoacyl carrier protein urine. Urine stain showed gram-negative rods, and synthetase, thereby blocking mycolic acid syn- urine culture grew P. aeruginosa. Which of the thesis. following drugs would be most appropriate for this (D). Inhibits RNA synthesis by binding to the b- patient? subunit of DNA-dependent RNA polymerase. (A). Ampicillin-sulbactam. (E). Inhibits transpeptidase, thereby blocking (B). Aztreonam. crosslinking of peptides in cell wall murein (C). Cefazolin. (Peptidoglycan). (D). Imipenem-cilastatin. (E). Piperacillin-tazobactam. 16. Parents brought their 3-year-old boy to the outpatient clinic because of a facial rash. Today the 13. A 22-year-old woman had her first prenatal patient was one of several children sent home from day visit. Her physical examination was normal for a care because of similar rashes. Physical examination woman at 12 weeks’ gestation. Both the non- revealed a normal, healthy boy with discrete erythematous treponemal (Venereal Disease Research Laboratory) papular eruptions on his cheeks. There were no vesicles and fluorescent treponemal antibody tests were or bullae. The rash was covered with a honey crust, positive. She denied previous treatment for syphilis. suggesting impetigo. Which of the following treatments She could not recall signs or symptoms of primary or would be most appropriate? secondary syphilis in the past year. She had no (A). Dapsone. previous syphilis serology tests for purposes of (B). Dicloxacillin. comparison. Which of the following would be the best (C). Doxycycline. treatment for the patient? (D). Ketoconazole. (A). Benzathine penicillin G. (E). Penciclovir. (B). Doxycycline. (C). Spectinomycin. 17. Many antibiotics appear to have as their mech- (D). Streptomycin. anism of action the capacity to inhibit bacterial cell (E). Tetracycline. wall synthesis. This does not appear to be a mechanism of 14. A 26-year-old woman, a kindergarten teach- (A). Aminoglycosides. er, had pharyngitis last year treated with ampicillin (B). Penicillins. for 3 days. She stopped the Ampicillin when she (C). Bacitracin. learned her throat culture was negative. Three days (D). Cephalosporins.

177 18. Many antibiotics are not useful in treating in- (C). IV vancomycin. fections in the central nervous system because they do (D). IV polymyxin B. not readily penetrate the blood-brain barrier. Which (E). Trimethoprim-sulfamethoxazole. one of the following agents gets into the brain in reasonable concentrations? 24. Effective interventions for treating a minor sur- (A). Penicillin G. gical suture site infection should definitely include one (B). Ampicillin. of the following choices: (C). Cefotaxime. (A). Polymyxins. (D). Kanamycin. (B). Bacitracin. (E). Neomycin. (C). Triple antibiotics ( bacitracin, Polymyxin B, and neomycin) ointment. 19. Aminoglycoside antibiotics are frequently used in (D). IV Vancomycin. combination with the β-lactam antibiotics. Which of the (E). Observation. following choices best explains the rationale for this use? (A). The combination provides for a much great- 25. A urine culture in an asymptomatic female pa- er spectrum of activity. tient with an indwelling Foley catheter comes back with (B). A synergistic effect is often seen when the com- more than 50,000 colonies of enterococci. The urinal- bination is employed. ysis is unremarkable. The best course of action would (C). The β-lactam antibiotics prevent toxic effects be to of the aminoglycoside antibiotics. (A). Start IV Vancomycin to cover enterococci. (D). The combination decreases incidence of su- (B). Seek the newly approved drug Linezolid for perinfections. possibility of Vancomycin-resistant enterococci (VRE). 20. Patients with myasthenia gravis may exhibit (C). Initiate a Quinolone like Levofloxacin with greater toxicity to aminoglycosides than do patients broad-spectrum coverage for UTIs. without this condition. The most likely explanation is (D). Discontinue use of the Foley catheter if pos- (A). Aminoglycosides have muscarinic blocking sible and obtain follow-up cultures if she de- properties. velops symptoms. (B). Aminoglycosides cause an increased metab- (E). Watchful waiting. olism of acetylcholine. (C). Aminoglycosides cause a neuromuscular 26. Which glycopeptide or polypeptide antibiotic block by displacing Ca++ from the neuromus- is still investigational and not used in the United States cular junction. for parenteral therapy? (D). Aminoglycosides inhibit second messenger ac- (A). Polymyxins. tivity at the neuromuscular junction. (B). Vancomycin. (C). Teicoplanin. 21. As a class, the aminoglycoside antibiotics do (D). Bacitracin. not exhibit significant metabolism in the patient. The (E). Linezolid. most likely reason is that (A). Their chemical structure is unique and not 27. Which of the following best treats the initial prone to chemical reactions commonly seen stage of Lyme disease in adults? in drug metabolism. (A). Penicillin V. (B). The liver does not contain appropriate en- (B). Erythromycin. zymes to break down the compounds. (C). Clarithromycin. (C). The body apparently lacks a necessary co- (D). Doxycycline. factor for the metabolism of aminoglycosides. (E). Clindamycin. (D). Aminoglycosides do not readily get to the site of degradative enzymes. 28. Chloramphenicol is the drug of choice for which of the following? 22. A pediatric nurse is found to be colonized with (A). S. pneumoniae meningitis. MRSA in her nares during an outbreak investigation (B). B. fragilis in abdominal abscess infection. in the pediatric intensive care unit. The best strategies (C). H. influenzae epiglottitis. to eradicate her nasal carriage could be (D). Typhoid fever in the United States. (A). Parenteral therapy with IV Vancomycin. (E). Typhoid fever in some developing countries. (B). Oral Vancomycin. (C). Bacitracin ointment application to her nasal 29. A 39-year-old man has AIDS and a CD4 count passages. less than 50. Recently he has had chills and fever. Sev- (D). Polymyxins. eral blood cultures drawn especially for acid-fast ba- (E). A month-long furlough from patient care. cilli are positive. Which antibiotic should be included in a treatment regimen for this disease? 23. In the treatment of uncomplicated urinary tract (A). Tetracycline. infection caused by gram-negative bacteria, the thera- (B). Amoxicillin. py of choice would be (C). Cephalexin. (A). Teicoplanin. (D). Clarithromycin. (B). Bacitracin. (E). Doxycycline.

178 30. A 37-year-old postal worker has a job at a the drugs. Which of the following antituberculosis mail sort facility. An envelope that passed through drugs is responsible for his lack of color vision dis- the facility and was delivered to a governmental of- crimination? fice was noted upon opening to have anthrax spores. (A). Ethambutol. One of the postal worker’s fellow employees subse- (B). Ethionamide. quently developed inhalation anthrax. Because of (C). Aminosalicylic acid. this, medical authorities recommended that other (D). Rifampin. employees working at the same facility be tested and (E). Isoniazid. receive prophylactic antimicrobial therapy. The drug of choice is a Quinolone. However, this employ- 34. A 68-year-old white South African man receiv- ee has a history of allergy to Ciprofloxacin. Which ing treatment for lepromatous leprosy has increasing of the following antibiotics is also recognized as bered-brown pigmentation. Which of the following anti- ing effective prophylactic therapy for potential an- leprosy drugs is responsible for the patient’s skin pig- thrax exposure? mentation? (A). Amoxicillin. (A). Dapsone. (B). Erythromycin. (B). Rifampin. (C). Clarithromycin. (C). Clofazimine. (D). Doxycycline. (D). Capreomycin. (E). Clindamycin. (E). Thiacetazone.

31. An 18-year-old man sustains a minor lacera- 35. A 23-year-old college student is diagnosed with tion of his right forearm. Approximately 2 days later Neisseria meningitidis based on his clinical presenta- the laceration site becomes red and swollen. He also tion, gram-negative diplococci on Gram stain, and iso- begins to develop fever and chills. The patient eventu- lation of bacteria from cerebrospinal fluid. Which of ally goes to the local hospital’s emergency department. the following drugs can be used as a prophylactic By this point his forearm is swollen and the skin is light agent for roommates and other close contacts? brown. Cultures of his wound and two blood cultures (A). Amoxicillin. 15 minutes apart are obtained. Intravenous cepha- (B). Isoniazid. losporin is begun. However, over 3 days the discolor- (C). Dapsone. ation of his forearm begins to ascend to the upper arm (D). Clarithromycin. and shoulder. Blood cultures are positive in approxi- (E). Rifampin. mately 12 hours for gram-positive cocci in chains. 36. A 32-year-old Haitian man has acute-onset Wound cultures of the laceration also grow similar or- confusion and suicidal ideation. Two weeks ago he be- ganisms, and high-dose Penicillin G is prescribed. gan combination therapy for multi-drug resistant pul- What other antibiotic would be extremely useful in monary tuberculosis. He has a history of depression treating this condition? that required intermittent treatment in the past. Which (A). Gentamicin. of the following antitubercular agents is responsible for (B). Clindamycin. the patient’s neurological symptoms? (C). Ciprofloxacin. (A). Pyrazinamide. (D). Clarithromycin. (B). Aminosalicylic acid. (E). Chloramphenicol. (C). Cycloserine. (D). Rifampin. 32. A 35-year-old man under treatment for pulmo- (E). Ethambutol. nary tuberculosis has acute-onset right big toe pain, swelling, and low-grade fever. His physical examina- 37. Which drug, compared with the rest, would be tion was consistent with gouty arthritis, and he was expected to produce a significantly higher concentra- found to have high serum uric acid levels. Which of tion of active metabolite in cells infected with its tar- the following antituberculosis drugs is known to cause get virus? high uric acid levels? (A). Cidofovir. (A). Cycloserine. (B). Foscarnet. (B). Thiacetazone. (C). Oseltamivir. (C). Pyrazinamide. (D). Penciclovir. (D). Rifampin. (E). Lamivudine. (E). Aminosalicylic acid. 38. Which of the following drugs should not be giv- 33. A 26-year-old truck driver, a recent immi- en in combination with Zidovudine because of an in- grant from Mexico, could not obtain a Florida driv- creased risk of myelosuppression? ing license because of his poor performance in red- (A). Ganciclovir. green color vision discrimination. He denies any (B). Fomivirsen. family history of color vision-related problems in the (C). Rimantadine. past. He is taking a four-drug regimen for pulmo- (D). Famciclovir. nary tuberculosis. He does not recall the names of (E). Zanamivir.

179 39. Caitlyn Doe is a 24-year-old woman in her third mechanical ventilation. A month into her hospitaliza- month of pregnancy. She has had severe pain, swell- tion, surveillance sputum cultures reveal Aspergillus ing, and redness in both eyes for several days and has fumigatus, and a new infiltrate appears on her chest been unable to see well enough to go to work. Ms. radiograph. Which antifungal agent is recommended Doe’s physician diagnosed herpes simplex keratocon- for the treatment of invasive pulmonary aspergillosis junctivitis; the infection has spread deep into the sur- in this patient? rounding tissues. Which drug is indicated for HSV (A). Fluconazole. keratoconjunctivitis but is least likely to harm the fe- (B). Amphotericin B. tus? (C). Amphotericin B with 5-Flucytosine. (A). Cidofovir. (D). Capsofungin. (B). Docosanol. (E). Itraconazole. (C). Fomivirsen. (D). Acyclovir. 44. A 57-year-old man with extensive onychomy- (E). Ribavirin. cosis (fungal toenail infection) asks you for an evaluation. He requests a prescription for Itraconazole for 40. Mitchell Jones, a 35-year-old man, began treat- treatment of this problem after seeing a television ad- ment for hepatitis C with Interferon-a-2b and Ribavi- vertisement for this drug. He has chronic heartburn rin (Rebetron) 4 weeks ago. On returning to his doc- attributed to gastroesophageal reflux disease and is tor for routine monitoring of his blood count and liver treated with the proton pump inhibitor Omeprazole. function, he complained of general fatigue and exer- He is taking Lovastatin for treatment of hyperlipi- tion when walking. His hemoglobin, CBC, differential, demia. Three years ago he underwent cadaveric re- and platelet counts are shown in the accompanying ta- nal transplantation for end-stage kidney disease sec- ble. Which is the most likely explanation of any ab- ondary to polycystic kidney disease and is taking Cy- normality? closporin to prevent transplant rejection. In prescrib- (A). Ribavirin decreases erythrocyte counts. ing Itraconazole for this patient, what adjustments in (B). Interferon-a-2b decreases erythrocyte counts. his medication regimen do you recommend? (C). Interferon-a-2b elevates lymphocyte counts. (A). Discontinue Omeprazole and substitute the (D). A and B are true. H2 blocker Ranitidine. (E). A, B, and C are true. (B). Discontinue Omeprazole and substitute liquid antacids. 41. A 65-year-old man with acute leukemia recent- (C). Discontinue Omeprazole. ly underwent induction chemotherapy and subsequent- (D). Continue Lovastatin. ly developed neutropenia and fever (with no source of (E). Increase Cyclosporin dosing. fever identified). Fever persisted despite the use of empirical antibacterial therapy, and Amphotericin B has 45. A 35-year-old medical entomologist comes to been prescribed for possible fungal sepsis. Which lab- the hospital with chief complaints of fever, headache, oratory test is LEAST helpful in monitoring for toxic- and photophobia. This illness began about 6 days pri- ities associated with Amphotericin B? or to admission, when he returned from a 2-month vis- (A). Liver function tests. it to the jungles of Central and South America. On his (B). Serum potassium. return flight, about 6 days prior to admission, he de- (C). Serum magnesium. scribed having fever and shaking chills. He saw his (D). Serum blood urea nitrogen and creatinine. physician 2 days prior to admission; the physician (E). Hemoglobin and hematocrit. made a diagnosis of influenza and prescribed Tetra- cycline. On the day of admission, the patient had shak- 42. A 55-year-old obese woman with adult-onset ing chills followed by temperature elevation to 104°F diabetes mellitus has been receiving Amoxicillin for (40°C). Physical examination revealed a well-devel- treatment of an acute exacerbation of chronic bronchi- oped man who appeared ill. There is some left upper tis. After a week of therapy, the patient develops dys- quadrant tenderness but no organomegaly; blood pres- uria and increased urinary frequency. Urinalysis shows sure — 126/90; pulse — 120; and respirations — 22. 10 to 50 white blood cells per high-power field, and Laboratory findings were hemoglobin, 14.5 mg/dL Gram stain of urine shows many budding yeasts. Which (normal, 13.4-17.4 mg/dL); hematocrit, 45% (normal, antifungal agent would be best in treating this patient 40-54%); Giemsa-stained blood smear (thick and thin) for Candida cystitis? revealed Plasmodium vivax. What is the oral drug of (A). Oral Ketoconazole. choice to rid the blood of plasmodia? (B). Oral Fluconazole. (A). Primaquine. (C). Topical Clotrimazole. (B). Chloroquine. (D). Oral 5-Flucytosine. (C). Sulfadiazine. (E). Oral Itraconazole. (D). Quinine. (E). Mefloquine. 43. A 43-year-old woman recently underwent allo- geneic bone marrow transplantation after chemother- 46. A 27-year-old ecologist went to his physician apy failed in the treatment of metastatic breast carci- with an ulcer on his left wrist 8 weeks after returning noma. The patient has had a stormy hospital course from Panama. The patient noted a small pink papule after her transplant, with respiratory failure requiring that was pruritic (itchy) and enlarged and developed a

180 crusted appearance. This in time fell off, leaving an (C). Mebendazole. oozing shallow ulcer about 2 cm in diameter with in- (D). Metronidazole. durated margins. He applied over-the-counter topical (E). Meglumine antimonate. agents without clinical improvement. No fever or lymphadenopathy was present. Scrapings were taken from 49. The patient is a 12-year-old boy with fever and the raised margins of the ulcer and stained with Giem- vomiting. The fever began a month prior to admission, sa, revealing intra-cellular and free small, round and spiking to approximately 104°F (40°C) each day. The oval bodies measuring 2 to 5 mm in diameter. While family physician for a time entertained a presumptive this is suggestive of the Leishmania amastigote stage diagnosis of chloroquine-resistant malaria and pre- in the vertebrate host, culture confirmed it to be L. bra- scribed Mefloquine followed by a week of doxycycline, ziliensis panamensis. The patient had New World cu- without effect. Then, 2 days prior to admission, the pa- taneous leishmaniasis. What is the drug of choice? tient began vomiting after eating. About 4 months ear- (A). Praziquantel. lier the family visited their home of origin in Bihar state (B). Pyrimethamine-sulfadoxine. in nort-heast India. Physical examination revealed a (C). Pentavalent antimonials. thin, acutely ill child with a temperature of 103°F (D). Pyrantel pamoate. (39.4°C), pulse of 130, and respirations of 36. Posi- (E). Primaquine phosphate. tive finding on physical examination was a nontender distended abdomen with a liver edge palpable 5 finger 47. The patient is 43-year-old, Agency for Inter- breadths below the costal margin and a smooth, firm national Development worker with chief complaints of spleen extending to the umbilicus (hepatospleno- fever and headache. He recently returned from a trip megaly). The skin was dry and darkly pigmented. Lab- to western Kenya and Tanzania. While traveling oratory findings revealed hemoglobin of 8.5 mg/dL cross-country through the woodland and savanna by (normal, 13.4–17.4 mg/dL), white blood cell count Land Rover, he indicated that the cab appeared to be 3,900 cells/mm3 (normal, 4,000–12,000 cells/mm3), filled with tsetse flies of the genus Glossina. He was platelet count 99,000 cells/mm3 (normal, 150,000– bitten on the forearm and developed a painful chancre 400,000 cells/mm3). A bone marrow aspirate revealed with some exudate. Physical examination showed the characteristic amastigotes of L. donovani. Which of patient to be febrile, with a temperature of 102°F the following is the drug of choice for visceral leish- (38.8°C); he had tachycardia, with a pulse of 120 maniasis? beats per minute, and appeared acutely ill and lethar- (A). Liposomal Amphotericin B. gic. Low-grade posterior cervical lymphadenopathy (B). Albendazole. was present. There was no edema of the extremities, (C). Atovaquone. no organomegaly, and no abnormalities in his neuro- (D). Pyrimethamine-sulfadoxine. logical examination. Renal and hepatic functions were (E). Proguanil. normal. Giemsa-stained thick and thin blood smears examined to rule out malaria revealed trypomastigotes. 50. While serving with Doctors Without Borders in Parasites were also found in a drop of exudate from a Malaysia, you are seeing a patient who has intermit- needle aspiration of the chancre. A lumbar puncture tent cough, shortness of breath, and wheezing. Inves- revealed CSF having one white blood cell and two red tigation reveals eosinophilia, absence of micro-filaria blood cells with normal glucose and protein levels. No in the blood, and a chest radiograph showing scattered parasites were seen in a centrifuged sample of CSF. reticulonodular infiltrates. Which of the following What treatment is indicated for this patient? points is the most important if your diagnosis is tropi- (A). Sulfadoxine-pyrimethamine. cal pulmonary eosinophilia (TPE) ? (B). Chloroquine. (A). Symptoms get progressively worse and are not (C). Suramin. fluctuating. (D). Melarsoprol. (B). Absence of microfilariae in blood makes the (E). Metronidazole. diagnosis unlikely. (C). Eosinophilia, although commonly seen, is not 48. A 52-year-old real estate salesperson has a 2- usually very high. week history of watery diarrhea without blood. The (D). Ivermectin is the drug of choice. patient states that 4 to 5 weeks ago she and her hus- (E). Diethylcarbamazine is effective therapy. band visited Aspen, Colorado, on a backpacking va- cation and on occasion drank water from mountain 51. A 10-year-old girl in North Carolina has had streams. They were sure the water was potable, as the abdominal pain and cramps for the past few days. Her unspoiled, pristine area abounded with fish, beaver, examination produced normal findings except for non- and plant life. She states she has enjoyed perfect health specific abdominal discomfort with a complete blood except that she takes antacids for what she describes count showing anemia and 22% eosinophils (elevated). as gastroesophageal reflux disease. Her physical ex- A stool specimen revealed the characteristic eggs of A. amination produced unremarkable findings. Examina- lumbricoides. The drug of choice in treating this is tion of liquid stool revealed trophozoites and cysts of (A). Piperazine. G. lamblia. Which of the following is the correct treat- (B). Pyrantel pamoate. ment for this disease? (C). Mebendazole. (A). Melarsoprol. (D). Albendazole. (B). Mefloquine. (E). Thiabendazole.

181 52. A 15-year-old Hispanic boy is brought in with a week has proved to prevent both PCP and toxoplas- seizures. No prior history of fever, chills, trauma, or mosis in AIDS patients. Norfloxacin (C) and other sec- headaches was reported on admission. Computed to- ond-generation fluoroquinolones are known for their mography reveals three ring-enhancing cystic lesions antipseudomonal and Enterobacteriaceae activity. The in the brain parenchyma, and a diagnosis of neurocyst- antimicrobial activity is exerted through inhibition of DNA gyrase A and type IV topoisomerase. Methenamine icercosis is made. Initial therapy in the management (D) is active against various Enterobacteriaceae; it has of this condition should include no activity against protozoa. Formaldehyde denatures (A). Niclosamide. proteins and is bactericidal. Nalidixic acid (E) is used in (B). Praziquantel. urinary tract infections caused by Enterobacteriaceae (C). Albendazole. (e.g. E. coli, Klebsiella, and Proteus). It has no activity (D). Surgery. against protozoa. (E). Thiabendazole. 7. (B). Proteus species produce urease (A) that produces ammonia and urea, alkalizing urine. Urine requires 53. A patient with a history of frequenting sushi acidification for effective therapy. Hippuric (B), mandel- bars on the West Coast is admitted with abdominal ic, or ascorbic acids or methionine are urinary acidifying agents. The normal acidic urinary environment is dis- pain, weakness, irritability, and dizziness. His neuro- turbed by recurrent Proteus infections. Catalase (C) is logical examination produced normal findings even produced by staphylococcal spp. The catalase test differ- though he had some complaints of paraesthesias. Di- entiates Staphylococci from Streptococci. It has no uri- phyllobothriasis is diagnosed after stool studies are nary activity. Folic acid (D) is a water-soluble vitamin and done. Management of this tapeworm infection is with has no effect on urinary pH or acidification. Humans can- (A). Praziquantel or niclosamide. not synthesize folic acid, which must be obtained from (B). Ivermectin. the diet. A coagulase enzyme (E) is produced by Staphy- (C). Albendazole. lococcus aureus. Coagulase test differentiates S. aureus from other staphylococci. It has no urinary antimicro- (D). Vitamin B12. (E). Piperazine. bial activity. 8. (A). Sulfonamides (A) compete for bilirubin binding sites on plasma albumin and increase fetal blood levels of unconjugated bilirubin. Unbound bilirubin ANSWERS crosses the blood-brain barrier and can be deposited in the basal ganglia and subthalamic nuclei causing ker- 1. (D). A drug may be selective to a particular en- nicterus, a toxic encephalopathy. Defective bilirubin zyme system that is found only in the microbe and have hepatic conjugation (B) is due to glucuronyl transferase no harmful effect on the patient. An example is sulfona- deficiency resulting in Gilbert’s syndrome. When seen mides blocking the enzyme dihydropteroate synthesis. in adults it usually presents with jaundice that is pre- This is a necessary step in the synthesis of dihydrofol- cipitated by fasting. Physiological jaundice (C) usual- ic acid. Humans can use preformed Dihydrofolic acid and ly occurs in the newborn within a week of birth. It is do not need this enzymatic step to produce purines. due to the immature fetal acetyl-transferase system re- Pharmacodynamics describes what the drug does to the sulting in peripheral destruction of a large fetal red cell patient. Pharmacokinetics describes what the patient mass. Pregnancy-induced hepatic congestion (D), does to the drug. Sepsis describes what the pathogen cholestasis, and acute cholecystitis are seen in pregnant does to the patient. Resistance is what the pathogen does women, not in the newborn. Primary biliary cirrhosis to the drug. (E) is commonly seen in middle-aged women. It is a 2. (C). The patient is very ill, and you cannot afford chronic progressive autoimmune disorder requiring ster- to wait for the diagnosis. You administer a combination oids and sometimes liver transplant. of Clindamycin and Amikacin to ensure that you have cov- 9. (B). Humans cannot synthesize folic acid (A); diet erage for gram-negative and gram-positive organisms and is their main source. Sulfonamides selectively inhibit mi- anaerobes. Vancomycin and Penicillin G are effective against crobially synthesized folic acid. Incorporation (B) of Gram-positive organisms only. PABA into microbial folic acid is competitively inhibit- 3. (A). Ehrlich called Salvarsan the magic bullet for ed by sulfonamides. The TMP-SMX combination is syn- its nontoxic effect to humans and to its toxicity against ergistic because it acts at different steps in microbial fol- the organism responsible for syphilis. ic acid synthesis. All sulfonamides are bacteriostatic. In- 4. (D). The indiscriminate use of antibiotics in humans hibition of the transpeptidation reaction (C) involved in is the major reason for the emergence of microbial anti- the synthesis of the bacterial cell wall is the basic mech- biotic resistance. Such resistance, which is most appar- anism of action of β-lactam antibiotics. Changes in DNA ent in hospitals, has developed to all antibiotics, includ- gyrases (D) and active efflux transport system are mech- ing Vancomycin. The use of antibiotics in livestock has anisms for resistance to quinolones. Structural changes compounded the problem. (E) in dihydropteroate synthetase and overproduction of 5. (B). Pharmacodynamics describes what the drug PABA are mechanisms of resistance to the sulfonamides. does to the patient. Erythromycin stimulates gut moti- 10. (B). Acute urosepsis (A) is possible, but the pa- lin receptors and may induce nausea; this leads to the tient’s physical examination produced benign findings. patient refusing to continue therapy. Pharmacokinetics Adding a broad-spectrum antibiotic has no benefit with- describes what the patient does to the drug. Immunity is out evidence of active disease. Possible allergic reaction what the patient does to the pathogen; resistance is what (B) to Nitrofurantoin; it is appropriate to stop the drug the pathogen does to the drug; and selective toxicity is immediately to guard against one of three potential pul- what the drug does to the pathogen. monary reactions: 6. (B). Nitrofurantoin (A) is a urinary antiseptic agent 1) acute presentation with basilar infiltrate and pleu- active against many of the Enterobacteriaceae. Nitro- ral effusion, furantoin has no effect on Toxoplasma or P. carinii, as 2) chronic progressive bilateral interstitial fibrosis; both are protozoans. TMP-SMX (B) daily or three times 3) a subacute presentation.

182 Nitrofurantoin-resistant E. coli infection (C) and uro- bacterial transpeptidase and block cross-linking of pep- sepsis are possible in patients who are taking chronic tides in cell wall murein (peptidoglycan). Fluoroquinolo- prophylaxis, but his examination produced benign find- ne antibiotics inhibit DNA gyrase (topoisomerase) and ings. Acute community-acquired streptococcal pneumo- interfere with bacterial DNA transcription and replica- nia (D) shows one or more lobar infiltrates on radiogra- tion. Spectinomycin and Doxycycline inhibit bacterial prophy. The patient described has bilateral interstitial fibro- tein synthesis and act at the 30S ribosome subunit. Azi- sis. Nitrofurantoin-induced hemolysis (E) is possible in thromycin inhibits bacterial protein synthesis and acts at G6PD patients, but physical examination produced be- the 50S ribosome subunit. Trimethoprim inhibits dihy- nign findings; G6PD patients usually present with he- drofolate reductase and blocks formation of tetrahydro- maturia. folate required for purine synthesis. Rifampin inhibits 11. (B). Overproduction (A) of PABA is one of the re- RNA synthesis by binding to the subunit of DNA-de- sistance mechanisms of sulfonamides. Changes in the pendent RNA polymerase. Amphotericin B inhibits fun- synthesis of DNA gyrases (B) is a well-described mecha- gal cell membrane integrity by binding to ergosterols nism for Quinolone resistance. Plasmid-mediated resist- to create pores. Isoniazid inhibits KasA, a β-ketoacyl ance (C) does not occur with quinolones. An active efflux carrier protein synthetase, and blocks mycolic acid syn- system for transport of drug out of the cell has been de- thesis. scribed for Quinolone resistance, but it is not plasmid me- 16. (B). The patient has impetigo. The causative or- diated. Inhibition of structural blocks (D) in bacteri- ganism is either Streptococcus pyogenes (group A) or S. al cell wall synthesis is a basic mechanism of action of aureus. Recommended antibiotic treatment is Dicloxa- β-lactam antibiotics. Inhibition of folic acid synthesis cillin or Cloxacillin. Dapsone is used to treat skin infec- (E) by blocking different steps is the basic mechanism of tions with Mycobacterium leprae (leprosy) and to treat action of sulfonamides. brown recluse spider (Loxosceles) bites. Doxycycline is 12. (B). The patient has complicated urinary tract in- used to treat skin infections with Bacillus anthracis (an- fection and nonsevere sepsis syndrome caused by P. aer- thrax), Bartonella henselae (bacillary angiomatosis), Bor- uginosa. Effective antibiotics for Pseudomonas spp. include relia burgdorferi (Lyme disease, erythema migrans), Pro- Mezlocillin, Piperacillin, Piperacillin-tazobactam, Ticarcillin, pionibacterium acnes (acne vulgaris), Vibrio vulnificus and and Ticarcillin-clavulanate. The carbapenems (imipenem Vibrio damsela (hemorrhagic bullous cellulitis). The and meropenem) and the monobactam (aztreonam) are question does not provide historical or epidemiologi- also active against P. aeruginosa. Ampicillin-sulbactam cal information to support these diagnoses. Ketocona- and cefazolin are ineffective against P. aeruginosa. The zole is used to treat fungal infections of the skin (tinea history defines a patient with type I allergic hypersensi- capitis, tinea cruris, tinea corporis, tinea pedis, tinea tivity to penicillin. The patient should avoid drugs in versicolor). Dermatophyte infections are usually ery- the penicillin class, including Penicillin, Nafcillin, Oxacil- thematous, with vesicles, fissures, and scaling. Penciclovir lin, Cloxacillin, Dicloxacillin, Ampicillin, Amoxicillin, Ticar- is a treatment for herpes simplex virus infections includ- cillin, Piperacillin, and Mezlocillin. In addition, carbapen- ing herpes labialis fever blisters. ems (imipenem, meropenem) should not be administered 17. (A). The aminoglycosides appear to act by bind- to patients with a history of type I allergic response to ing to various sites on bacterial 30S ribosomal subunits penicillin or positive penicillin skin test. Cefazolin is a and disrupting the initiation of protein synthesis. The cephalosporin. Patients with type I allergy to Penicillin other agents appear to have the capacity to directly in- and positive penicillin skin test have a 5.6% rate of al- hibit bacterial cell-wall synthesis. lergic reactions to cephalosporins. Aztreonam may be 18. (C). The selection of agents to treat brain infec- used safely in patients with history of type I allergic re- tions is quite limited because most agents do not pene- sponse to penicillin. trate into cerebrospinal fluid or the brain itself. 13. (B). The patient is pregnant and has latent syphi- 19. (B). A synergistic effect when the combination of lis of indeterminate duration. The pathogenic organism an aminoglycoside and β-lactam antibiotic are adminis- is T. pallidum. Benzathine penicillin G is the drug of first tered concurrently is well documented. The reasons for choice for treating latent syphilis. Doxycycline and Tet- the synergistic response are not well documented but may racycline are alternatives treatments for non-pregnant pa- be related to the actions of the β-lactam antibiotic to raise tients with latent syphilis. Spectinomycin is not effective pH and oxygen tension in areas of abscess and thereby against syphilis; it is a treatment for disseminated gon- increase the penetrability of the aminoglycoside. orrhea in patients who are allergic to cephalosporins. 20. (C). Aminoglycosides can cause neuromuscular Streptomycin is not effective against syphilis. junction blockade by the mechanism of displacing Ca++ 14. (E). The patient has exudative pharyngitis, pre- from the neuromuscular junction and thus leading to sumably secondary to group A streptococcus. Antibiot- the Ca++-dependent prejunctional release of acetylcho- ic treatment is indicated to reduce the duration and se- line. This is of clinical significance only in patients verity of symptoms and to prevent acute rheumatic fe- with myasthenia gravis, hypocalcemia, and hypermag- ver. The antibiotic of first choice is penicillin V. Other rea- nesemia. sonable alternatives are benzathine Penicillin G, Erythro- 21. (D). Aminoglycosides do not penetrate most cells, mycin, Cephalosporin, Clindamycin, Azithromycin, and Clar- and most drug-metabolizing enzymes are found on the ithromycin. Amikacin, Lomefloxacin, Metronidazole, and inside of the cells. Therefore, aminoglycosides are poor- Netilmicin are not active against group A streptococcus. ly metabolized, and nearly all of an intravenous dose 15. (E). The patient has uncomplicated urethritis can be recovered in the urine. caused by N. gonorrhoeae. Effective antibiotics for gon- 22. (C). In an outbreak setting, involved hospital staff orrhea include cephalosporins (Ceftriaxone, Cefixime, may undergo culture investigation of their skin flora and Ceftizoxime, Cefotaxime, Cefotetan, Cefoxitin), fluoro-qui- orifices to determine the source of infection. Oral Vanco- nolones (Ciprofloxacin, Ofloxacin, Enoxacin, Lomefloxacin, mycin is not usually absorbed from the GI tract to be Gatifloxacin), and Spectinomycin. Gonorrhea is resistant effective, and IV Vancomycin is not indicated to eradicate to Trimethoprim and Rifampin. Amphotericin B is an an- colonization. Bacitracin ointment has been used with lim- tifungal drug, and isoniazid is an antimycobacterial ited success and may be an option, along with strict hand- drug. Neither has antigonococcal activity. Cepha- washing and isolation precautions. Polymyxins are ef- losporins and other β-lactam antibiotics act to inhibit fective topical agents for gram-negative infections. A fur-

183 lough from patient care responsibilities is unlikely to appears he is developing necrotizing fascitis, a serious eradicate her nasal colony. complication. Sometimes when a large amount of group 23. (E). Trimethoprim, which exhibits broad-spectrum A streptococcal organisms are present, Penicillin is not activity, with Sulfamethoxazole is active against most aer- effective. Clindamycin is usually very active against strep- obic and facultative gram-positive and gram-negative or- tococcal infections because the size of the bacterial inoc- ganisms. It is very effective in UTIs caused by gram-neg- ulum will not affect its efficacy. Actually, the treatment ative bacteria. Teicoplanin, Bacitracin, and Vancomycin are of choice for this condition is immediate and possibly antibiotics with limited spectra of gram-positive cover- repeated surgical debridement of the involved area. An- age. Although polymyxins are active against gramnega- tibiotics are supportive therapy. tive organisms, their only use is topical because of se- 32. (C). Pyrazinamide is known to cause hyperuri- vere nephrotoxicity associated with IV therapy. Alterna- cemia and precipitate gouty arthritis. Pyrazinamide-in- tive therapy would be to use Quinolone. duced gouty arthritis does not respond to urico-suric 24. (C). Minor suture irritation and superficial infec- therapy with Probenecid but may respond to acetylsali- tion can be treated topically. Effective agents in the ab- cylic acid. Cycloserine (A) can cause headaches, confusion, sence of culture results would be an ointment such as tri- tremors, and seizures, possibly secondary to low levels ple antibiotic, which has gram-positive and gram-nega- of magnesium in the cerebrospinal fluid; Cycloserine tive spectra. Generally, polymyxins are active only should be avoided in patients with epilepsy and mental against gram-negative organisms, and Bacitracin works depression. It is not associated with hyperuricemia. Thi- only against gram-positive organisms. Intravenous an- acetazone (B) is an antibiotic that is rarely used in tuber- tibiotics are not indicated unless this evolves into a deep- culosis. The most common adverse reactions are general er soft tissue infection. Observation without any active rashes and GI intolerance. Its use is not associated with management is unlikely to be successful. hyperuricemia. Rifampin (D) is associated with hepatitis, 25. (D). It is not unusual to get colonized by hospi- GI intolerance, drug interactions and a red-orange distal flora, especially with an indwelling Foley catheter. coloration of saliva, tears, and urine. It is not associat- If the patient does not have any clinical evidence of in- ed with hyperuricemia. Aminosalicylic acid (E) is some- fection, it is not necessary to start therapy with Vanco- times associated with sodium overload and fluid reten- mycin or for that matter, any antibiotic. Enterococcal UTI tion when large doses of the sodium salt of PAS is ad- can still be treated with penicillins, but they are increas- ministered; it is not associated with hyperuricemia. ingly resistant to penicillins and even Vancomycin. Since 33. (A). Ethambutol is associated with retrobulbar neu- susceptibility data are still pending, neither Vancomycin ritis, resulting in loss of central vision and impaired red- nor the new drug Linezolid is yet indicated. Levofloxacin, green discrimination. Ethionamide (B) is an analogue of although a good drug for UTIs, does not have entero- isonicotinic acid and is associated with GI intolerance coccal coverage. Discontinuation of the Foley catheter if and peripheral neuropathy, but not the optic neuritis or possible and follow-up appear to be the best option. color vision discrimination problems. Aminosalicylic acid Watchful waiting may not be effective because these pa- (C) can cause GI irritation and bleeding problems, so tients may go on to develop complicated UTIs. caution is required in peptic ulcer patients. It has no neu- 26. (C). Teicoplanin, although used in Europe, is not rological side effects. Rifampin (D) is associated with approved for use in the United States. It can be used to red-orange discoloration of saliva, tears, and urine but treat a variety of gram-positive infections and should be not the color vision problems. Isoniazid (E) is associated considered in resistant gram-positive infections as well. with peripheral neuritis in chronic alcoholics and mal- Bacitracin and polymyxins are topical agents with po- nourished individuals and requires pyridoxine supple- tential for serious nephrotoxicity when used parenteral- ments. It is not associated with optic neuritis. ly. Linezolid is recently approved for resistant gram-pos- 34. (C). Clofazimine has antilepromatous and antiin- itive infections (VRE and MRSA) and is available in the flammatory properties. Its most disturbing side effect is United States. red-brown pigmentation of the skin, particularly in 27. (D). Doxycycline is the preferred parenteral tetra- light-skinned persons. Dapsone (A) can produce rashes cycline for the primary state of Lyme disease in adults and erythema nodosum, including Stevens-Johnson syn- and children older than 8 years of age. Penicillin V (A) drome (dapsone dermatitis), but it is not associated with would be ineffective. Erythromycin (B) and Clarithromy- altered skin pigmentation. Rifampin (B) imparts a harm- cin (C) also are not effective against Borrelia burgdorferi, less red-orange discoloration of saliva, sweat, urine, fec- the gram-negative anaerobe organism responsible for es, tears, and contact lenses but is not associated with Lyme disease. skin pigmentation changes. Capreomycin (D) is similar 28. (E). Chloramphenicol is no longer the treatment of to Streptomycin and can cause ototoxicity and nephro- choice for any bacterial infection because of the poten- toxicity. Its use is not associated with skin discolora- tially fatal chloramphenicol-induced bone marrow sup- tion or pigment problems. Thiacetazone (E) is rarely used pression. In the past it has been used against the infec- in the treatment of leprosy. Rashes and GI intolerance tions indicated in choices (A), (B), (C), and (D). It remains are common side effects. It is not associated with any skin a major treatment for typhoid and paratyphoid fever in discoloration or pigment problem. some developing countries, since alternative drugs are 35. (E). Rifampin, commonly used in the prophylax- much more expensive. is of Neisseriae meningitidis, is given to individuals 29. (D). Clarithromycin is one of the recommended an- who are in close contact with someone having the dis- timicrobials for use in combination with other antimi- ease. Other drugs that can be used include Ciprofloxacin crobials in treating disseminated Mycobacterium avium and sulfonamides. Amoxicillin (A) is used as prophy- complex. laxis of endocarditis in patients with a history of en- 30. (D). Although Ciprofloxacin is the primary agent docarditis or a preexisting valvular heart disease. Iso- recommended for prophylaxis against anthrax, Doxycy- niazid (B) is a commonly used drug for latent tubercu- cline is an equally effective agent. Amoxicillin (A) is not losis infection in high-risk patients who are positive as effective. The macrolides (B) and (C) also are not as PPD and have a negative chest radiograph. Dapsone (C) effective. Clindamycin (E) is not indicated for this use. is used as a chemoprophylactic agent for Pneumocystis 31. (B). This individual most likely has a group A carinii pneumonia in AIDS patients who are allergic or streptococcal infection due to a minor wound. Now it intolerant to Trimethoprim-Sulfamethoxazole. Clarithro-

184 mycin (D) is used as a chemoprophylactic agent for MAC toxic agent is usually used only in combination therapy in AIDS patients. with a second antifungal agent (usually Amphotericin B) 36. (C). Cycloserine is associated with confusion, psy- in the treatment of systemic candidiasis or cryptococcal chosis, and suicidal ideation; symptoms are usually seen meningitis. within a week of therapy. Cycloserine should be avoided 43. (B). Amphotericin B remains the drug of choice in in patients with psychiatric disorders. Pyrazinamide (A) the treatment of disseminated or invasive fungal infec- is associated with a hepatic dysfunction that must be tions in immunocompromised hosts; bone marrow trans- closely monitored. Nearly all patients taking Pyrazina- plant recipients are the most heavily immunocompro- mide develop hyperuricemia. It has no neurological side mised patients encountered in the hospital setting. 5-Flu- effects. Aminosalicylic acid (B) is associated with GI in- cytosine has no significant activity against Aspergillus tolerance, especially acute bleeding, due to severe gastri- spp., and it has bone marrow toxicity as a common ad- tis. It has no neurological side effects. Rifampin (D) is as- verse effect; it should not be used in this setting. Fluco- sociated with hepatitis, drug interactions, red-orange dis- nazole has not been shown to be effective in the treat- coloration of body fluids, and rarely, the Flulike syn- ment of aspergillosis. Itraconazole has been reported to drome. It has no neurological side effects. Ethambutol (E) be effective as salvage treatment in patients with aspergil- is associated with retrobulbar neuritis and color vision losis if Amphotericin B therapy fails; it should not be used impairment. It may cause peripheral neuritis but is not as initial treatment in this setting. Capsofungin, a new associated with behavioral problems. echinocandin antifungal agent recently approved by the 37. (D). The conversion of Penciclovir to its active form U. S. Food and Drug Administration for the treatment requires initial monophosphorylation by viral thymi- of refractory aspergillosis when standard therapy with dine kinases, then conversion to its active triphosphate Amphotericin B fails, should also not be used to treat in- form by cellular enzymes. Thus, the concentration of Pen- vasive aspergillosis until more data showing efficacy are ciclovir triphosphate is particularly high in cells infected available. with its target viruses (e.g. HSV, VZV, HBV). Foscarnet is 44. (C). Patients receiving multiple medications may a pyrophosphate analogue that does not require activa- have adverse drug reactions when a new medication is tion. Oseltamivir is a neuraminidase inhibitor that is con- added to the regimen. Itraconazole requires an acidic gas- verted by hepatic esterases to its active form, Oseltamivir tric environment for absorption; any drug reducing gas- carboxylate. Lamivudine is converted to its active triphos- tric acid production (H2 blockers, proton pump inhibi- phate form by host cellular enzymes. tors) or neutralizing gastric acid (antacids) will signifi- 38. (A). Ganciclovir commonly causes myelosuppres- cantly reduce Itraconazole absorption. Itraconazole inhib- sion and may produce severe neutropenia when given in its the metabolism of Lovastatin and Simvastatin and combination with Zidovudine. Fomivirsen is most com- should not be prescribed with these β-hydroxy- β-meth- monly associated with iritis and other ocular informa- yglutaryl-coenzyme A reductase inhibitors. Itraconazole tion; Rimantadine with nausea, vomiting, anorexia, and will raise serum cyclosporin levels, resulting in cy- dizziness; Famciclovir with headache, nausea, diarrhea, closporin toxicity, unless Cyclosporin levels are closely and CNS effects; and Zanamivir with bronchospasm. monitored with dose reductions as indicated. 39. (D). Acyclovir is in pregnancy category B: animal 45 (B). The drug of choice for clinical cure of P. vivax studies have shown no evidence of harm to the fetus, but malaria is oral chloroquine. The only isolated reports no large, controlled studies of human outcomes have been of Chloroquine-resistant P. vivax are from the western Pa- performed. Cidofovir may be used to treat HSV that is re- cific, not Central and South America. The patient should sistant to acyclovir; however, it is embryotoxic and ter- become afebrile in 24 to 48 hours, and parasitemia should atogenic, and Ms. Doe should avoid it. Docosanol is used decline in 72 hours. Since P. vivax, known as benign ter- for cold sores and is not indicated for ophthalmic use. tian malaria, responds well to Chloroquine, there is no Fomivirsen is effective against CMV retinitis, not HSV kera- need to resort to parenteral Quinine or Quinidine or oral titis. Ribavirin is indicated for RSV infection and is also Mefloquine; these agents have cardiotoxic and neu-rotox- mutagenic, teratogenic, and embryotoxic. ic side effects. P. vivax also does not respond as well to 40. (D). Interferons and Ribavirin are both likely to the sulfonamides. In P. vivax and P. ovale infections, treat- cause anemia; the combination of these two agents in- ment with a blood schizonticide will result only in clin- creases this possibility. Interferons do not stimulate lym- ical cure, but radical cure requires additional treatment phocyte proliferation. with a tissue schizonticide, primaquine, to destroy exo- 41. (A). Nephrotoxicity is the most common and most erythrocytic stages responsible for relapses. The patient serious toxicity associated with Amphotericin B admin- should be checked for glucose 6-phosphate dehydroge- istration. This is manifested by azotemia (elevated serum nase deficiency before taking Primaquine. Also, Pri- blood urea nitrogen and creatinine), and by renal tubu- maquine is not effective against erythrocytic schizonts at lar acidosis, which results in the wasting of potassium pharmacological levels, so it cannot be used in place of and magnesium in the urine (leading to hypokalemia and Chloroquine. hypomagnesemia, requiring oral or intravenous replace- 46. (C). The first-line drug for cutaneous or mucocu- ment therapy). Normochromic normocytic anemia is also taneous leishmaniasis is Sodium stibogluconate (Pento- seen with long-term Amphotericin B administration. Ele- stam) or meglumine antimonate (Glucan-time). Antimo- vation of liver enzymes is not associated with the use of nials have not been approved by the U. S. Food and Drug Amphotericin B. Administration, but Sodium stibogluconate is obtained 42. (B). Oral Fluconazole is well absorbed from the from the Centers for Disease Control and Prevention. gastrointestinal tract, and 80% of drug is excreted into Clinical response is determined by species and resistance the urinary tract, allowing effective treatment of Candi- patterns of Leishmania and by host immunity. These da cystitis. Subtherapeutic concentrations of Itraconazole drugs are given by intravenous or intramuscular injec- and Ketoconazole are excreted into the urine; these agents tion. Phlebitis and pain are reduced when these drugs are are not effective in the treatment of Candida cystitis. Top- given intravenously. In advanced mucocutaneous leish- ical Clotrimazole would be effective in the treatment of maniasis Amphotericin B may be an alternative, especial- Candida vaginitis, which can cause dysuria, but would ly in areas of resistance to antimony drugs. Liposomal not be an effective treatment for cystitis. While 90% of 5- Amphotericin B is the drug of choice for visceral leishma- Flucytosine is excreted unchanged in the urine, this more niasis and has been used successfully in the treatment of

185 cutaneous and mucocutaneous disease. Pentamidine, Ke- mony drugs is widespread. This patient appears to have toconazole, and Itraconazole have been used effectively to acquired his infection there, where many infected pa- treat the cutaneous but not visceral form of leishmania- tients develop darkening of the skin, hence the name ka- sis. Pyrantel pamoate is a roundworm treatment and not laazar, or black sickness. Albendazole, an anthelmintic, indicated here. Primaquine phosphate is used to prevent has no role here. Atovaquone, Naphthoquinone, is used relapses in tertian malaria, and Praziquantel is the drug to treat malaria, babesiosis, and pneumocystosis. Py- of choice in treating tapeworm and fluke infections. Py- rimethamine-Sulfadoxine is used to treat malaria and tox- rimethamine-sulfadoxine is used to treat malaria and is oplasmosis. Proguanil inhibits the dihydrofolate re- sometimes combined with Quinine sulfate in Chloroquine ductase of malaria parasites and is used in combina- resistance. It is also used to treat toxoplasmosis when it tion with Atovaquone. is accompanied by Leucovorin (folinic acid). 50. (E). TPE is caused by microfilariae in the lungs 47. (C). Suramin is the drug of choice for the hemol- and hyperimmune responsiveness to bancroftian or ma- ymphatic stage of T. rhodesiense and T. gambiense with a layan filariasis. Paroxysmal respiratory symptoms may normal CSF examination. This drug is almost 100% ef- fluctuate in severity. Eosinophilia, almost always fective in eliminating trypanosomes from the blood of present, is usually very high, and the absence of micro- patients in the early stage of disease. Epidemiologically filariae in the blood does not rule out TPE. A presump- this patient appears to have East African trypanosomia- tive clinical diagnosis can be made by response to thera- sis caused by T. rhodesiense. Pentamidine isethionate results py without a lung biopsy. Diethylcarbamazine for 14 days in lower cure rates in T. rhodesiense infections than those is an effective therapy that can be repeated if symptoms with Suramin. Suramin does not cross the blood-brain persist. The role of Ivermectin in TPE has not been estab- barrier, so it is not effective for patients with meningoen- lished. cephalopathic involvement. Somnolence, or inability to 51. (D). Intestinal helminths produce mild disease concentrate, may be seen before the CNS is involved. with nonspecific findings. Piperazine or Pyrantel pamo- Treatment for CNS late-stage trypanosomiasis is Melar- ate may be used for the treatment of ascariasis. Meben- soprol; however, because of potential toxicity, this drug dazole is an effective drug to be taken for 3 days. Thia- is reserved for late-stage disease only. Metronidazole is bendazole is not used in this condition but is used com- used to treat amebiasis, not trypanosomiasis. Sulfadox- monly in strongyloidiasis. Albendazole at a single dose ine-pyrimethamine and Chloroquine are antimalarial and of 400 mg is the preferred mode of therapy. It is a con- are not used for this indication. Sulfadoxine-pyrimeth- venient agent for mass treatment programs that target amine with Leucovorin (folinic acid) can also be used to school children in endemic areas. treat Toxoplasma gondii. 52. (C). Albendazole (approved by the U. S. Food and 48. (D). Metronidazole is the drug most frequently rec- Drug Administration for this indication) has a 90% ef- ommended for treatment of this infection. Quinacrine has ficacy rate in neurocysticercosis. The initial therapy of been used in the past, but because of toxicity and lack of parenchymal disease with seizures should focus on availability it is not a first choice. Albendazole, not Me- symptomatic treatment with anticonvulsants. However, bendazole, has been used with a good outcome in giar- while destroying the cyst, Albendazole may result in a diasis. Mebendazole is used to treat roundworm infec- profound parenchymal brain reaction and in severe tions. Melarsoprol is used to treat advanced-stage CNS neurological defects or retinal damage (i.e. loss of vi- African trypanosomiasis. Mefloquine is an oral drug used sion and optic neuritis) in eye lesions. Corticosteroids to treat Chloroquine-resistant malaria. Meglumine anti- should be given concomitantly in these situations. In monate (Glucantime) or Sodium stibogluconate (Pentostam) ventricular disease with obstructive hydrocephalus, sur- is used to treat cutaneous or mucocutaneous leishmani- gery with shunting can be helpful. Treatment with asis by the IV route. Giardiasis, which may be chronic Niclosamide or Praziquantel should be considered later and the cause of malabsorption, sometimes requires mul- to eliminate the adult tapeworm in the gut and prevent tiple stool examinations or a duodenal aspirate. Infec- further reinfection. Neither Piperazine nor Thiabendazole tion may be through contaminated food or beverages or is effective in this indication. may be acquired through surface water contaminated by 53. (A). D. latum, the fish tapeworm acquired from mammals such as beavers. The risk of human infection consumption of raw fish in endemic areas, is best treat- appears increased in those with reduced gastric acid pro- ed with Praziquantel or Niclosamide. Ivermectin is effec- duction. tive for filarial infections, especially O. volvulus. Alben- 49. (A). Liposomal Amphotericin B was approved by dazole, although highly effective in some tapeworm in- the U.S. Food and Drug Administration to treat viscer- fections, is not used in fish tapeworm infections. Vita- al leishmaniasis. Pentavalent antimony compounds, min B12 deficiency is due to the parasite competing with Pentamidine, Amphotericin B, and Aminosidine (Paromo- the host for the vitamin, sometimes absorbing 80% of mycin) have all been demonstrated efficacious here. The ingested amounts. Patients may develop megaloblastic liposomal Amphotericin appears to be better taken up anemia and mild to severe central nervous system man- by the reticuloendothelial system, where the parasite re- ifestations (subacute combined degeneration of spinal sides, and partitions less in the kidney, where Ampho- cord). Mild B12 deficiency should be treated with vita- tericin B traditionally manifests its toxicity. In addi- min injections in addition to specific drug therapy. Pip- tion to being better tolerated by patients, it has proved erazine, a roundworm treatment, is not used for this in- to be very effective in India, where resistance to anti- dication.

186 DRUGS USED FOR PHARMACOTHERAPY OF DISEASES OF SPECIAL SYSTEMS

Lecture 44 and elevation of blood pressure. It is believed that the main effect of these medications is decreasing of the DRUGS USED IN appetite control center activity. Phepranonum and GASTROINTESTINAL DISEASES Desopimon (relatives of Amphetamine) are weaker than Amphetamine as appetite suppressants, but less stimulate the CNS and the cardiovascular system, seldom Many drugs discussed elsewhere in this collection causing drug addiction. Appetite suppressants are in- have applications in the treatment of gastrointestinal dicated in the management of exogenous obesity for diseases. M-cholinolytic agents inhibit the food-stim- short-term use (a few weeks) in conjunction with a regulated secretion of gastric acid and also affect intesti- imen of weight reduction based on caloric restriction, nal smooth muscle; these drugs are useful in some forms exercise, and behavior modification. of functional bowel disease. M-cholinomimetics stim- Adverse effects include insomnia, tachycardia, in- ulate smooth muscle and are used to promote gastroin- creasing of blood pressure, sleeplessness, accustoming testinal motility. Several other groups of medications and drug addiction. They are contraindicated during are used almost exclusively in gastrointestinal disease; hypertonia, disorders of cerebral blood circulating, these are grouped and discussed below according to thyrotoxicosis, diabetes mellitus, and epilepsy. their therapeutic uses. SUBSTANCES, STIMULATING AND DRUGS, REGULATING APPETITE INHIBITING SECRETIVE FUNCTION OF THE STOMACH These drugs are divided into drugs that increase and decrease appetite. Action is related with influence Drugs that stimulate stomach juice secretion are the on the appetite control center (centers of hunger and next: Pepsin, Natural Gastric juice, Abominum, and satiation), located in hypothalamus. Panzynorm (see lecture “Enzyme preparations and Drugs that increase an appetite include bitters (am- enzyme inhibitors”). They normalize secretion and ara). Bitters are the substances that possess strong bit- motility of the gastrointestinal tract and are indicated ter taste. Bitters irritate taste receptors of oral cavity and for replacement therapy of stomach upset such as stomach mucosa that cause reflective increasing of gas- achlorhydria (absence of hydrochloric acid in the gastric juice secretion and promote digestion. Bitters are tric juice) or hypoacidity. Pentagastrin is a synthetic used for the treatment of the atrophic gastritis, hypoa- analog of the natural hormone, gastrin. Pentagastrin cidity (lower than normal level of hydrochloric acid), as well as gastrin stimulate the secretion of hydrochlo- and anorexia (aversion to food). Bitters should be used ric acid, pepsin, and increases GI motility. It is useful for 15–30 minutes before meals. Agents include bitter as a diagnostic test for achlorhydria and hypersecre- (Amara) tincture, tincture of wormwood (Absinthium), tion of stomach juice. etc. Some taste substances (e.g. mint, pepper, and mus- Drugs, decreasing the secretive function of stomach, tard) also exhibit features of bitters. They contain ether include M-cholinolytics, ganglionblockers, and block- oil that stimulates an appetite. Bitters will be prohibit- ers of H2-histamine receptors, antacids, adsorbents, ed during hyperacidity, ulcer disease of stomach. Cy- astringents, and local anesthetics. Gastric acid secre- proheptadine (Peritol) is an antihistamine (H1) drug tion is under the control of histamine, acetylcholine, that stimulates the center of hunger in the CNS. It is and gastrin. The final common pathway is through the used for the treatment of anorexia. proton pump, H+/K+ ATPase. Appetite suppressants are sympathomimetic agents. H2(histamine)-receptors antagonists, e.g. Cime- They are Amfepramone (Phepranonum), Chlorphen- tidine, Ranitidine, Famotidine, and Nizatidine block- termine (Desopimon), and Mazindol. These agents ade H2-receptors of stomach mucosa that leads to re- have pharmacological effects similar to those of Am- duction in basal, food-stimulated, and nocturnal se- phetamine (Phenaminum), including CNS stimulation cretion of gastric acid. Many trials have demonstrat-

187 ed their effectiveness in promoting the healing of du- During interaction with acid, carbon dioxide is odenal and gastric ulcers and preventing their recur- formed, which stretches stomach and causes second- rence. H2-antagonists are rapidly and well absorbed ary wave of secretion. Absorbing into blood, sodium following oral administration. Food delays and may bicarbonate may cause systemic alkalosis. Magnesi- slightly decrease absorption of the drugs. For active um oxide, Aluminum hydroxide act slower, more du- ulcer, any H2-blocker can be given twice daily or rable, and more active than sodium bicarbonate. once at bedtime. Reversible hematologic abnormali- Magnesium oxide may cause purgative effect, how- ties have been a rare occurrence with all members of ever Aluminum hydroxide may cause constipation. this class of drugs. Cimetidine may cause reversible Calcium carbonate is slowly solubilized in the stom- gynecomastia. This has been reported only rarely ach. In high doses it may cause hypercalcemia and with Ranitidine and Famotidine. Cimetidine also slows alkalosis. hepatic microsomal metabolism of some drugs, such There are many complex antacids. They are Al- as Neodicumarin, Euphyllin, Diazepam, and Diphen- magel (Aluminum hydroxide and Magnesium oxide), in. Ranitidine appears to have less effect and Famo- Maalox (Aluminum and Magnesium hydroxide). tidine and Nizatidine no effect on hepatic drug me- These agents possess antacid, adsorptive, astringent, tabolism. and envelop activities. Also agents that contain bis- Cholinoreceptor antagonists (lecture “Cholinergic muth such as Vicair (Bismuth subnitrate, Magnesium antagonists”) such as M-cholinolytics (e.g. Atropine, carbonate, Sodium bicarbonate, and powder of Fran- Pirenzepine) and Ganglionblockers (e.g. Pempidine gula bark), De-Nol (Bismuth subcitrate) are well (Pirilenum), Pentaminum (Azamethonium bromide)) known. Bismuth salts have antacid and astringent ef- decrease the influence of nervus vagus that results in fects. In addition, De-Nol has mild activity against lowering of gastric juice secretion. Ganglionblockers Helicobacter pylori that is associated with gastritis and are now rarely used because they’re adverse effects. peptic ulcer. Pirenzepine, an antimuscarinic agent with activity rel- Antacids are used as an adjunct to physical and atively selective for gastric M1-receptors, is approved emotional rest, other drugs for the relief of peptic ul- for ulcer therapy. It may cause the disorder of accom- cer pain and to promote the healing of peptic ulcers, modation, dryness of mouth, but less frequent than oth- hyperacid gastritis. Antacids also are used for the re- er M-cholinolytics. lief of dyspepsia, heartburn, and sour stomach. Omeprazole irreversibly inhibits the gastric pari- Sucralfate is a gel (aluminum salt), which in acid etal cell proton pump, (H+/K+ ATPase). Inactivation surrounding forms glutinous and sticky substance, cov- of this enzyme system blocks the final step in the se- ering the ulcerous surface and protecting it from dam- cretion of hydrochloric acid by these cells. The drug ages. Sucralfate is not absorbed. Supplementary infor- requires activation in the acid environment of the se- mation about adsorbents, astringents, and local anes- cretory canaliculus of the parietal cell, i.e., it is a pro- thetics is discussed in lecture “Drugs that protect re- drug. Omeprazole inhibits basal and stimulated gas- ceptors”. tric acid secretion. Omeprazole is a more potent in- A great meaning in treatment of gastritis and ulcer disease of stomach and duodenum is taken by gastric hibitor of such secretion than are H2-receptor antagonists. Although Omeprazole has a short terminal protectors – drugs that increase protection function of plasma half-life, the drug has a long duration of ac- sputum and stableness of mucous layer (Carbenoxolo- tion (about 3 days). Omeprazole increases plasma ne, Misoprostol). Carbenoxolone increases secretion of gastrin concentrations via a negative feedback mech- sputum, forming it more glutinous. It may cause reten- anism resulting from decreased gastric acid secretion. tion of water in the organism, hypertension. Misopr- Omeprazole is approved for the treatment of gastric ostol is a synthetic prostaglandin E1 that increase sta- and duodenal ulcers as well as for prevention of re- bility of gastric mucous, lower secretion of hydrochlo- currence of duodenal ulcers. The initial dose is 20 mg ric acid and fasten secretion of sputum. Now are wide- once daily. Omeprazole is well-tolerated drug. How- ly used drugs, which promote stomach mucosa regen- ever, increase in gastric carcinoid tumors has been eration. Solcoseril, Vitamin U, anabolic steroids (Nan- observed during long-term Omeprazole exposure in drolone (Retabolil), Phenobolil, etc.), Riboxin and animals. Methyluracil refer to them. Gastric antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their EMETIC AND ANTIEMETIC DRUGS usefulness in peptic ulcer disease appears to lie in their ability to reduce gastric acidity. Antacid-induced in- Vomiting is a protective stomach reaction directed creases in gastric pH inhibit the proteolytic action of on its cleaning. Coordination of the complex motor ac- pepsin. Some antacids, such as aluminum hydroxide, tivity of the stomach and abdominal musculature takes have astringent action. Most antacids in current use place in the vomiting center, which is located in the have as their principal constituent magnesium or alu- reticular formation in the medulla. The vomiting cent- minum hydroxide, alone or in combination, and occa- er receives input from the chemoreceptor trigger zone sionally in combination with sodium bicarbonate or a located on the floor of the fourth ventricle, the vestib- calcium salt. ular apparatus, and other areas. Antacids include sodium bicarbonate, magnesium Vomiting can be evoked for turning out irritate and oxide, calcium carbonate, aluminum hydroxide, and toxic substances from the stomach (see lecture “Dugs a lot of complex drugs (e.g. Almagel, Maalox, Phos- that irritate receptors”). For that purpose Apomorphine phalugel, Vicair®, De-Nol, etc.). Sodium bicarbonate is used. It stimulates dopamine receptors of trigger possesses the most quick but short period of action. zone. Apomorphine is characterized by short period

188 of nausea. It is contraindicated during unconscious SUBSTANCES, INFLUENCING state, burns of esophagus and stomach by acid and al- MOTILITY OF THE INTESTINE kaline. Sometimes it is used during treatment of alcoholism for forming of negative conditional reflex on They are divided into: alcohol. — drugs, depressing intestine motility (antidi- Nausea and vomiting may be manifestations of a arrheal agents); wide variety of conditions, including pregnancy, mo- — drugs, increasing intestine motility (laxatives). tion sickness, gastrointestinal obstruction, peptic ulcer, drug toxicity, myocardial infarction, cancer chem- Diarrhea is a symptom of many diseases (poison- otherapy, etc. So choosing of antiemetic drugs is de- ing, infections, diseases of stomach and pancreas, etc.). termined by reasons, caused vomiting. For the diarrhea therapy its reason is necessary to con- The major categories of antiemetic agents include firm. If diarrhea is caused by infection process, anti- H1-antihistamines, neuroleptics, M-cholinolytics, microbial agents must be taken. In the treatment of un- Metoclopramide, and Ondansetron. complicated diarrhea that caused by modification of The antihistamines with good antiemetic activi- the intestinal flora by drugs (e.g. antibiotics) or dur- ty (e.g. Dimedrolum, Diprazin) possess significant ing different diseases one can use Chilac, Biphidum- antimuscarinic and sedative effects (see lecture “Im- bacterin, etc. These agents contain an acid-producing munotropic agents”). It appears probable that both intestine bacterium (e.g. Lactobacillus acidophilus) or of these actions and the H1-blocking effect contrib- its extract prepared in a concentrated, dried, and via- ute to the antiemetic efficacy. They are particular- ble culture for oral administration. ly effective for the nausea and vomiting associated As drugs for symptomatic diarrhea therapy are used with motion sickness, perhaps because of specific astringents, enveloping and adsorptive substances, depression of conduction in the vestibulocerebellum which possess non-specific anti-inflammatory and pro- pathway. Anticholinergic agents, especially Atro- tect intestine mucosa from irritating agents. M-cholino- pine, Scopolamine (Aeron), are also used to prevent lytics, ganglionblockers, and spasmolytics of Myotrop- motion sickness (see lecture “Cholinergic antago- ic action (Papaverine, No-Spa, Dibasolum, etc.) de- nists”). crease the tonus of smooth muscles of the intestine wall The neuroleptics block dopamine receptors in the that results in lowering of intestine motility. Lopera- trigger zone as well as other areas of the brain (see mide is a synthetic piperidine-derivative antidiarrheal lecture “Neuroleptics”). Chlorpromazine (Aminazi- agent. Drug binds with opioid receptors of the intes- num) and Haloperidol are often used as antiemetics. tine (like Morphine) and enhances contractions of in- Extrapyramidal symptoms (Parkinsonism) can be se- testinal circular musculature, thus increasing segmen- vere when large doses of neuroleptics are used. Thi- tation and retarding forward motion through the intes- ethylperazine is a Phenothiazine derivative (as Ami- tine. Loperamide is potent, specific, and long acting an- nazinum). Agent is a strong antiemetic, however it tidiarrheal agent. It has no analgesic activity. Lopera- causes mild extrapyramidal disorders. mide is used in the control and symptomatic relief of Metoclopramide promotes gastrointestinal motili- acute nonspecific diarrhea and of chronic diarrhea as- ty. In addition to its M-cholinomimetic properties, sociated with inflammatory bowel disease. Adverse ef- Metoclopramide is a potent dopamine antagonist. It fects of Loperamide are constipation, dizziness, and does not increase gastric or pancreatic secretion. These nausea. Also it has M-cholinolytic activity. drugs hasten esophageal clearance, raise lower es- Drugs that increase the motility of the intestine in- ophageal sphincter pressure, accelerate gastric emp- clude M- and M-, N-cholinomimetics (Aceclidine, Pro- tying, and shorten small intestine transit time. Meto- serinum, Galantamine, etc.). These agents stimulate clopramide’s central dopamine antagonist effect is tonus of nervus vagus that leads to the activation of thought to be responsible for its significant antiemetic smooth muscles of intestine wall and intestine motility properties. Metoclopramide injection is indicated for in general. Direct stimulating action on the intestine the prevention of nausea and vomiting associated with wall have purgatives. emetogenic cancer chemotherapy, in postoperative pe- Purgatives are the substances that fasten movement riod. Oral Metoclopramide is indicated in adults for of intestinal content and promote defecation. In de- the symptomatic treatment of heartburn and reflux es- pendence of mechanism of action they are divided into ophagitis, for correcting the slow gastric emptying. next groups: The most common side effects of Metoclopramide are — drugs, acting basically on small intestine (Cas- somnolence and nervousness. Parkinsonism has also tor oil); been reported. — drugs, acting basically on large intestine (leaves Ondansetron is a selective inhibitor of serotonin (5- of Senna, bark of Frangula, Phenolphthalein, Bisa- HT3) receptors. The antiemetic activity of ondanset- codyl); ron appears to be mediated both centrally and periph- — drugs, acting on all parts of the intestine (salt erally via inhibition of 5-HT3 receptors. Ondansetron laxatives — Magnesium sulfate); is used orally or intravenously for the prevention of — bulk laxatives (Agar, Methylcellulose, Bran); nausea and vomiting associated with emetogenic can- — stool softeners (Mineral oil, Vaseline). cer chemotherapy. Ondansetron appear to be more effective and better tolerated than the pharmacological- Castor oil is hydrolyzed in the upper small intes- ly less selective Metoclopramide and therefore may be tine to ricinoleic acid, a local irritant that increases preferred for the management of acute emetic effects intestinal motility. The onset of action is prompt (2–6 in many patients. hours) and continues until the compound is excreted

189 via the colon. It is administered during acute consti- b) drugs of plant origin: Cholosas (syrupus of wild pation. Castor oil is contraindicated during poisoning rose hips), Corn oil, etc.; by fat-dissolved substances. с) synthetic drugs: Hydroxymethylnicotinamide Bark of Frangula, leaves of Senna contain emodin (Nicodin), Cycvalonum, etc. alkaloids that are liberated after absorption from the 2. Drugs promoting bile excretion into duodenum: intestine and are excreted into the colon, where peri- a) drugs that increase tonus and motility of gall- stalsis is stimulated. Thus, their onset of activity is de- bladder, and accelerate its emptying (Cholokinetics): layed for 6–10 hours. So, they are usually administrat- Cholecystokinin, Pituitrinum, Magnesium sulfate, ed in the evening. These agents are used for the treat- Sorbitol, etc.; ment of chronic constipation. Adverse effects include b) drugs that decrease tonus of bile ducts and Od- spasm of the intestine, meteorism. Phenolphthalein di’s sphincter (Spasmolytics): Atropine, Platyphylli- and Bisacodyl, which are synthetic drugs, are also po- num, Papaverine, No-Spa, etc. tent colonic stimulants. They are absorbed in the small 3. Drugs that cause desaturation of the bile (Cholo- intestine and excreted in the large intestine, increas- lithics). ing its peristalsis. Saline cathartics (Magnesium sulfate) distend the Cholosecretics. Drugs of resorptive type action, bowel and stimulate its contractions. These nonab- which activate hepatocytes. Also they irritate the in- sorbable salts hold water in the intestine by osmotic testine chemoreceptors that in reflective way promotes force and cause distention. In result magnesium sul- bile secretion. In addition, drugs including bile can act fate increases the motility of all intestine. Saline ca- as substitutive agents. Cholesecretics are indicated dur- thartics serve for removal of ingested toxin and as co- ing insufficiency of bile production. They will be con- lonic lavage solutions, chiefly in preparation for ra- traindicated during acute and considerable liver de- diological or endoscopic procedures. It has to be ad- feats, obturation of bile ducts by gallstone, etc., be- ministrated with enough volume of warm water (1–2 cause they form additive loading on liver and may in- glasses). Potent laxative effect develops after 2–4 crease jaundice. hours. Magnesium sulfate is taken seldom because it Cholokinetics are used for the hypotonia of gall- impairs the absorption of nutritious substances in the bladder and bile ducts. Spasmolytics are used for re- intestine. moving of liver colic, Oddi’s sphincter spasm. Bulking laxatives. Agar and Methylcellulose are That classification is quite comparative, because swelling in the large intestine lumen that is associated drugs, stimulating the gall formation, at the same time with their enlargement. They distend the intestine and increase its excretion. And drugs, increasing the gall thereby stimulating its peristaltic activity. Bran (by- excretion, promote gall formation. The most impor- product of the milling of wheat, containing the indi- tant factor during treating of liver and gall-ducts dis- gestible cellulose) and other forms of vegetable fiber eases, is the bettering of gall outflow, what deletes have the same effect. Bulking laxatives are taken for it’s stagnation and absorption to blood, lower risk of chronic constipation. infection’s development in gall-ducts, and forming of Stool softeners become emulsified with stool. They gall-stones. serve to soften stool and make passage easier. Exam- Hepatoprotectors are the drugs that increase the re- ples are Mineral oil, Glycerin. They have weak laxa- sistance of hepatocytes membrane, induce the hepato- tive effect. Adverse effects include impairment of food cytes enzymes, and promote restoration of liver func- digestion, uncontrolled defecation, and soil of clothes. tion (synthesis of proteins, detoxication). As a rule, Purgatives are contraindicated during acute appen- these drugs possess antioxidant properties. These fea- dicitis and cholecystitis, peritonitis, mechanical im- tures are possessed by Silibinin (Legalon), Essentiale. passability of intestines, pinched hernia, bleeding in The last one includes essential (important) phospholi- GI tract, menorrhagia. They are to be carefully used pids, Vitamins (B , B , PP, etc.). Hepatoprotectors during pregnancy due risk of abortion. 6 12 are used for the treatment of hepatitis, cirrhosis. Chololithics are the drugs that cause desaturation HEPATOTROPIC DRUGS of the bile by increasing the ratio of bile acids to cholesterol. The reduced cholesterol saturation allows for Hepatotropic drugs consist of three groups. They the gradual solubilization of cholesterol from gall- are (1) bile-drive drugs, (2) hepatoprotectors, and (3) stones, resulting in their eventual dissolution. Cholino- chololithics. lytics are chenodeoxycholic acid (Chenofalk, Cheno- Bile-drive drugs regulate the bile production and diol) and Ursodeoxycholic acid (Ursofalk). Cholo- bile output. Lack of gall causes disorder of emulsion lithics are indicated for dissolution of cholesterol gall- and absorption of lipids, fat-dissolved vitamins as well stones in selected patients with uncomplicated gall- as development of putrid microflora in the intestine and stone disease and functioning gallbladder. depression of its motility.

Bile-drive drugs are divided as follows: DRUGS INFLUENCING 1. Drugs that stimulate bile production (Cholose- OUTSECRETIVE (EXOCRINE) cretics): FUNCTION OF PANCREAS a) drugs that contain bile: Allohol (consist of bile, garlic and nettle extracts, and activated carbon), They are divided into agents, which stimulate exo- Cholenzym (bile, dry powder of cattle pancreas and crine function of pancreas (bitters, Hydrochloric intestine), etc.; acid), agents for replacement therapy (Pancreatin, 190 Panzynorm forte, Festal, Mezym forte), and agents, BRONCHODILATORS AND OTHER which inactivate pancreas enzymes. Uses of replace- AGENTS USED IN BRONCHIAL ment therapy drugs are discussed in lecture “Enzyme ASTHMA preparations and enzyme inhibitors”. Agents, inhibiting pancreas enzymes are discussed below. Bronchial asthma is physiologically characterized Enzymes of pancreas take part in destruction of by widespread narrowing of the airways. It is a dis- proteins, fats and hydrocarbons. Usually in pancre- ease mediated by reaginic (IgE) antibodies bound to as enzymes are present in nonactive (pre-enzyme) mast cells in the airway mucosa. Bronchial spasm ap- form, which is transformed to active form in the in- pears in result of disorders in neural and humoral reg- testine lumen only. During acute pancreatitis, acti- ulation of bronchial muscle’s tonus. To neural factors β vation of enzymes especially proteolytic begins in are considered depression of 2-adrenoreceptors and gland tissues that lead to “self-destruction” of pan- activation of M-cholinoreceptors. Humoral factors, creas. Treatment of acute pancreatitis is directed on that provoke bronchial spasm, are mediators of aller- lowering of pancreatic secretion, using M-cholinolyt- gic reactions (histamine, serotonin, substance of ana- ics (Atropine, etc.) and inactivation of proteolytic en- phylaxis, etc.), that are excreted by basophilic cells zymes (Trypsin and Kallikrein) by using their inhib- and thrombocytes. Its pathologic features are contrac- itors (Contrykal, Trasylol). Contrykal is obtained tion of airway smooth muscle, mucosal thickening from from cattle lung or pancreas tissues. Its activity is ex- edema and cellular infiltration, and inspissation in the pressed in IU. Contrykal is injected intravenously airway lumen of abnormally thick, viscid plugs of mu- dropwise. The most serious adverse effect of this cus. Of these causes of airway obstruction, contraction agent is allergic reactions. of smooth muscle is most easily reversed by current therapy; reversal of the edema and cellular infiltration Available forms: requires sustained treatment with antiinflammatory Tincture amara — in bottles 25 ml agents. In case, when asthma has infective-allergic na- Mazindol — in tablets 0.001 each ture, antimicrobe drugs are also used. Panzynorm — in patented tablets Famotidin — in tablets 0.02 or 0.04 each Classification of bronchi widening (Broncholytics) Omeprazole — in capsules 0.02 each drugs: Almagel — in bottles 170 ml 1. β-Adrenomimetics: β β Apomorphine hydrochloride — powder; in ampoules a) nonselective 1+ 2-adrenomimetics (Orciprena- 1% solution 1 ml line, Isoprenaline (Isadrinum)) and α+β-adrenomi- Metoclopramide — in tablets 0.01 each; in am- metics (Adrenaline, Ephedrine); β poules 0.5% solution 2 ml b) selective 2-adrenomimetics (Salbutamol, Fenot- Ondansetron — in tablets 0.004 or 0.008 each; in erol, Terbutaline). ampoules 0.2% solution 2 ml or 4 ml each 2. M-cholinolytics (Ipratropium bromide, Atro- Loperamide — in capsules 0.002 each pine, Platyphyllinum). Magnesia sulfate — powder 30.0 (to dilute in Ѕ of 3. Myotropic drugs (Euphyllin, Theophylline, No- warm water, for one using, laxative) spa). Senadum — in patented tablets (contain extract of 4. Antiinflammatory, antiallergic and desensitizing leaves of Senna) drugs (glucocorticoids, Cromolyn-sodium, Ketotifen, Bisacodyl — in tablets 0.005 each H1-histaminoblockers). Cholenzym — in patented tablets 5. Complex drugs (Theophedrinum, Solutan, An- Cholosas — in bottles 300 ml tasman). Nicodin — in tablets 0.5 each No-spa — in tablets 0.04 each; in ampoules 2% so- The adrenoceptor agonists, discussed in detail in lution 2 ml each lecture “Adrenergic agonists”, have several pharma- Legalon — in patented dragee (Legalonum-70 and cologic actions that are important in the treatment of Legalonum-140) asthma — i.e. they relax airway smooth muscle and Contrykal — in bottles 10,000 IU; 30,000 IU or inhibit release of some broncho-constrictive substanc- 50,000 IU (to dilute before using content of the bottle es from mast cells. As in other tissues, the β-agonists in 300-500 ml of physiologic solution) stimulate adenylate cyclase and catalyze the formation of cAMP in the airway tissues. Although there is no evidence for direct sympathetic innervation of human airway smooth muscle, there is ample evidence for the presence of adrenoreceptors on airway smooth Lecture 45 muscle. The adrenomimetic agents that have been widely used in the treatment of bronchial asthma include DRUGS USED IN RESPIRATORY β adrenaline, ephedrine, isadrine, and a number of 2- DISEASES selective agents. Adrenaline (Epinephrine) is an effective, rapidly acting bronchodilator when injected subcutaneously. To this group are concerned drugs that are used for Because adrenaline stimulates β- as well as α-recep- the treatment of (1) bronchial constriction, (2) cough, tors, tachycardia, arrhythmias, worsening of angina (3) depression of respiratory, (4) pulmonary edema, pectoris, and hypertension are troublesome adverse ef- and (5) for the bettering of sputum expelling. fects. Compared with Adrenaline, Ephedrine has a

191 longer duration (4–6 hours), oral activity, more pro- does not readily enter the central nervous system. Its nounced central effects, and much lower potency. Ephe- effect appears after 20–30 min, reaches maximum with- drine acts at indirect way — it stimulates the releas- in 1.5–2 h and lasts for 4–8 h. ing of Noradrenaline from presynaptic membrane. It Theophylline as well as caffeine are the derivatives is prescribed in fixed-dose combination with spasmo- of methylxanthines. At high concentrations, it inhib- lytics (Theophylline), H1-histaminoblockers (Dimed- its the enzyme phosphodiesterase, which hydrolyzes role) in commercial formulations. cyclic nucleotides. This inhibition results in higher Isadrinum (Isoproterenol) is a potent bronchodi- concentrations of intracellular cAMP. This effect could lator; when inhaled as a microaerosol, it causes maxi- explain the cardiac stimulation and smooth muscle re- mal bronchodilation within 5 minutes. Isadrine has a laxation produced by these drugs, but it is not certain 60 to 90 minute duration of action. It stimulates both that sufficiently high concentrations are achieved in β β 1- and 2-receptors, that’s why it causes tachycardia, vivo to inhibit phosphodiesterase. Another proposed arrhythmias, and evokes the attack of angina pectoris. mechanism is the inhibition of cell surface receptors Because nonselective adrenomimetics cause more car- for adenosine that has been shown to cause contrac- β diac stimulation (mediated by 1 receptors), they are tion of isolated airway smooth muscle and to enhance β replaced by selective 2-adrenomimetics. histamine release from cells present in the lung. These β The 2-selective adrenoceptor agonist drugs are the effects are antagonized by Theophylline, which blocks most widely used adrenomimetics for the treatment of cell surface adenosine receptors. Besides broncholytic asthma at the present time. These agents are effective effect, theophylline dilates vessels of the lung, kidneys, after inhaled or oral administration and have a long heart, skeleton muscles, lowers hemodynamic loading β duration of action and significant 2 selectivity. Salb- on heart. It causes direct cardiotonic action and in- utamol (Albuterol), Terbutaline, and Fenoterol are creases oxygen needs. available as metered-dose inhalers. Bronchodilation is A lot of complex drugs include Theophylline. Eu- maximal by 30 minutes and persists for 3–4 hours. phylline (Theophylline + Ethylenediamine), Xanthi- Salbutamol and Terbutaline are also prepared in tab- nol nicotinate (Theophylline + Nicotinic acid), etc. let form. One tablet two or three times daily is the usu- are the most known. Euphyllin is well absorbed (90%) al regimen. Of these agents, only Terbutaline is avail- after enteral introducing. For removing of bronchial able for subcutaneous injection. The indications for asthma attack it is introduced intravenously or intra- this route are similar to those for subcutaneous adren- muscularly, however it causes irritate action. Thera- aline — severe asthma requiring emergency treatment. peutic effect lasts for 6 hours. Metabolism is done in β The principal adverse effects of selective 2-adrenom- the liver; it is slower during the depression of hepatic imetics are skeletal muscle tremor, nervousness, and enzymes, evoked by drugs (e.g. H2-histaminoblockers). occasional weakness. In such cases smaller doses of Euphylline are needed. Interest in the potential value of M-cholinolytics It is excreted by kidneys in form of metabolites (90%) has recently been increased by demonstration of the and in non-transformed form (10%). Adverse effects in- importance of the vagus in bronchospastic responses clude excitation of the CNS (anxiety, insomnia, trem- of laboratory animals and by the development of a po- or, cramps), tachycardia, arrhythmia, sometimes-car- tent agent that is poorly absorbed after aerosol admin- diac insufficiency. Xanthinol nicotinate is used for the istration to the airways and is therefore not associat- treatment of diseases that accompanied by vessel con- ed with systemic Atropine effects. traction (e.g. atherosclerosis). M-cholinolytics competitively inhibit the effect of Another spasmolytics are Papaverine, No-spa. They acetylcholine at muscarinic receptors. In the airways, have a direct relaxant effect on vascular, bronchial and acetylcholine is released from efferent endings of the other smooth muscle due to inhibition of the enzyme vagus nerves, and M-cholinolytics can effectively block phosphodiesterase and accumulation of cAMP in the the contraction of airway smooth muscle and the in- smooth muscles. These agents are indicated for the crease in secretion of mucus that occurs in response to treatment of spasm of the gastrointestinal tract, bron- vagal activity. Very high concentrations are required chi, etc. As a rule, Papaverine and No-spa are used in to inhibit the response of airway smooth muscle to non- combination with other broncholytics. muscarinic stimulation. This selectivity of muscarinic Anti-allergic, desensitizing and anti-inflammatory antagonists limits their usefulness in preventing bron- drugs include Cromolyn sodium, Ketotifen, Corticos- chospasm. teroids. M-cholinolytics are effective bronchodilators. Cromolyn sodium differs from most antiasthmatic When given intravenously, atropine, the prototypical medications in that it is only of value when taken pro- M-cholinolytic, causes bronchodilation at a lower dose phylactically. Cromolyn inhibits mast cell release of than that needed to cause an increase in heart rate. histamine, leukotrienes, and other substances that Deposition of the aerosol in the mouth frequently causes cause hypersensitivity reactions. When used as aero- a local drying effect. Adverse effects due to systemic sol (metered-dose inhalers), it effectively inhibits both absorption include urinary retention, tachycardia, loss antigen- and exercise-induced asthma, and chronic of visual accommodation, and agitation. use (four times daily) may reduce the overall level of Systemic adverse effects limit the quantity of Atro- bronchial reactivity; however, this drug has no effect pine sulfate that can be given, but the development of on airway smooth muscle tone and is ineffective in a more selective quaternary ammonium derivative of reversing asthmatic bronchospasm. Cromolyn is Atropine, Ipratropium Bromide (Atrovent), permits poorly absorbed from the gastrointestinal tract. For delivery of high doses to muscarinic receptors in the use in bronchial asthma, it must be applied topically airways because the compound is poorly absorbed and by inhalation. When given by inhalation or orally,

192 less than 10% is absorbed, and most is excreted un- (anti-cough, Antitussive) and drugs that better excre- changed. tion of sputum (Expectorants) are used for weakening Ketotifen has antihistamine and antiallergic activ- of cough. ities. It inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivi- Antitussive drugs are divided into 2 groups: ty. In addition, Ketotifen blocks H1-receptors. Agent — Drugs of central action (Codeine, Ethylmor- is well absorbed from the gastrointestinal tract. The phine, Glaucine) serum half-life is about 20 hours. Ketotifen is used for — Drugs of peripheral action (Prenoxdiazine the prevention of acute bronchospasm. Adverse effects (Libexin)) include drowsiness and thrombocytopenia. Like Cromolyn, corticosteroids do not relax air- Codeine and Ethylmorphine are the phenanthrene- way smooth muscle directly but reduce bronchial re- derivative opiate agonists that have antitussive prop- activity, increase airway caliber, and reduce the fre- erties. They cause suppression of the cough reflex by quency of asthma exacerbations if administered for a direct effect on the cough centre in the medulla of some time. Their effect on airway obstruction may be the brain. Also these agents have mild analgesic and due in part to their potentiation of the effects of β- sedative effects. Codeine and Ethylmorphine are well receptor agonists, but their most important action is absorbed from the GI tract. Following oral adminis- their inhibition of the eosinophilic airway mucosal tration, peak antitussive effects usually occur within inflammation in asthmatic airways. The principal 1–2 hours and antitussive activity may persist for 4 anti-inflammatory action is the inhibition of the re- hours. High doses of Codeine and Ethylmorphine can lease of arachidonic acid from cell membranes and cause depression of breathing centre, lowering of lung therefore reduction of the production of leukotrienes, ventilation, and constipation. Prolonged therapy may prostaglandins, and cytokines. Aerosol treatment is results in addiction (dependence). Glaucine is an al- the most effective way to decrease the systemic ad- kaloid of glaucium flavum. It depresses cough centre. verse effects of corticosteroid therapy. Inhalation of But it doesn’t inhibit breathing, doesn’t cause drug ad- lipid-soluble corticosteroid such as Beclomethasone diction and constipation. It possesses adrenolytic ef- makes it possible to deliver corticosteroids to the air- fect and may lower AP, so it is not recommended dur- ways with minimal systemic absorption. Effect devel- ing hypotonia. ops gradually, so it is not used for turning out of at- Libexin apparently inhibits cough production by tack. Because of severe adverse effects when given anesthetizing stretch receptors of vagal afferent fibers chronically, oral and parenteral corticosteroids in the bronchi, pharyngis, and trachea that mediate the (Prednisolone, Beclomethasone, Triamcinolone) are cough reflex. generally reserved for patients who require more ur- Antitussives are used in the symptomatic relief of gent treatment, i.e., those who have not improved ad- nonproductive cough during bronchitis, bronchial asth- equately with bronchodilators or who experience ma, pneumonia, etc. Since the cough reflex may be a worsening symptoms despite maintenance therapy. useful physiologic mechanism, which clears the respi- Adverse effects during short courses (less than 7 ratory passages of foreign material and excess secre- days) usually are absent, during prolonged using — tions and may aid, in preventing or reversing atelecta- hyperglycemia, hypertension, osteoporosis, adrenal sis, cough suppressants should not be used indiscrimi- cortex insufficiency, etc. may appear. A special prob- nately. lem caused by inhaled topical corticosteroids is the oc- According to the mechanism of action expectorants currence of oropharyngeal candidiasis. are divided into: Combined drugs (Theophedrinum, Solutan, Antas- — Drugs that stimulate the sputum expectoration man, etc.) are used for turning out and prophylaxis of (Secretomotor drugs) bronchial asthma attacks. Principe of combining is — Mucolytic agents based on synergetic interaction of the drugs with dif- Expectorants have been used in the symptomatic ferent mechanism of action. For example, Solutan (al- management of conditions such as chronic bronchitis, kaloids of Belladonna + Ephedrine + Sodium iodide, bronchiectasis, and bronchial asthma that are associ- etc), aerosol of Berodual (Fenoterol + Ipratropium ated with high sputum viscosity and hard expulsion of bromide), tablets of Theophedrinum (Theophylline + sputum. Ephedrine + extract of Belladonna), etc. Secretomotor drugs are subdivided into agents of reflective action and agents of resorptive action. It is ANTITUSSIVE AND EXPECTORANT postulated that expectorants of reflective action irri- DRUGS tate the stomach mucosa. Because stomach mucosa as well as bronchi is innervated by nervus vagus, the irri- Self-cleaning of mucosa of the respiratory ways tation of stomach activates the centre of nervus vagus from strange bodies is done by fastening of bronchial in medulla that results in hastening of bronchial gland glands secretion, increasing of epithelium’s activity and secretion, stimulation of bronchial epithelium and bron- bronchioles motility. Irritation of reflective zones, es- chioles peristalsis. It is accompanied by diluting of pecially in region of trachea’s bifurcation, is accom- sputum and mucus and their expelling by cough. Due panied by cough. Couch is a protective reaction, which to irritative properties, reflective expectorants in high promotes deleting of irritate agent from breathing doses may cause vomiting. Drugs of reflective action ways. But during inflammation of the mucosa, secret are administered primarily in form of infusions, de- becomes glutinous due to cumulated proteins, leuko- cocts, tinctures, extracts, mixtures, some (e.g. Ther- cytes and is hardly excreted. Drugs that depress cough mopsis) in form of tablets. For examples, infusion of

193 Thermopsis grass, Althea roots, tablets Mucaltin (con- Caffeine is described in lecture “Psychostimu- tains the extract of Althea root), etc. lants”. Analeptic effect appears during injection of To drugs of resorptive action are concerned sub- high doses that simulate centers of medulla. It causes stances with Iodine, Ammonium chloride, Sodium bi- expressed cardiotonic action. Caffeine is administered carbonate, etc. After absorption those drugs are ex- for the treatment of alcohol poisoning and during com- creted by bronchial glands, stimulating secretion and bined respiratory and cardiac insufficiency. motor function of epithelium and bronchioles. Final- Strychnine is an alkaloid from strychnos. It stimu- ly, they decrease the viscosity of mucus and promote lates all parts of the central nervous system, and was it expelling. Prolong iodine therapy may cause symp- used as an antidote for depressant poisons. It causes toms of iodism: rhinitis, salivation, lacrimation, rash. the bettering of vision, hearing, tactile sensitiveness, Hypersensitivity reactions to iodides may occur and muscular tonus, and metabolism. So, Strychnine causes may be manifested by angioedema, fever, arthralgia, general tone action and sometimes used for the treat- and eosinophilia. ment of chronic fatigue, hypotension, functional im- Mucolytics act directly on glutinous secret. They pairment of vision and hearing, etc. Strychnine blocks reduce the viscosity of purulent and nonpurulent pul- the inhibitory neurotransmitter, Glycine, and thus can monary secretions and facilitate their removal by cause convulsions. It is a potent chemical capable of coughing or postural drainage. Mucolytics are prote- producing acute or chronic poisoning of humans or olytic enzymes (Trypsin, Chymotrypsin, Deoxyribo- animals. nuclease), Acetylcysteine, Bromhexine, etc. Trypsin Cytiton and Lobeline are the N-cholinomimetics. hydrolyzes peptides, amides. Deoxyribonuclease hy- They stimulate respiratory centre in reflective way due drolyzes phosphodiester bonds in DNA and proteins. to excitation of N-cholinoreceptors in the carotid si- Bromhexine depolymerizes and hydrolyzes fibers of nus (carotid bulb). After intravenous injection of N- mucopolysaccharides. Also Bromhexine promotes the cholinomimetics one can see quick but short respirato- synthesis of surfactant (a surface-active agent that sta- ry stimulation. They are used for the treatment of re- bilize alveolar volume). Acetylcysteine reduces di- flective respiratory depression during different trau- sulfide linkages of mucoproteins. Predominantly muc- mas, inspiration of irritating substances and carbon olytics are administrated in inhalation route, except monoxide. Cytiton raises the blood pressure, thus it is Bromhexine that is used orally. Mucolytics are used recommended for the shock, collapse. in the adjunctive treatment of patients with abnormal, Analeptics of combined action both directly and in- viscid, or thick mucous secretions in such conditions directly (through the carotid sinus) stimulate respira- as pneumonia, bronchitis, emphysema, tracheobron- tory centre. Cordiaminum is a derivative of nicotinic chitis, bronchiectasis, etc. In general mucolytics are acid. It stimulates breathing and blood circulation due combined with antimicrobe drugs, broncholytics. to the stimulation of medulla centres. Also it directly stimulates heart activity. It is administered during STIMULATORS OF THE BREATHING weakening of breathing and blood circulation, caused (ANALEPTICS) by intoxication, infection disease, shock, etc. Camphor is a ketone distilled from the tree of Stimulators of respiratory and cardio-vascular cent- Cinnamonum camphora, and also prepared synthet- ers of medulla are used during depression of these cent- ically from oil of turpentine. Part of Camphor is ex- ers. Because they restore life-important functions creted through breathing ways that promotes expel- (breathing and blood circulation), they are called anal- ling of the sputum. Locally agent causes irritate and eptics (animate substances). Most analeptics in higher antiseptic action. It directly stimulates centers of the doses may cause cramps. Analeptics are the antagonists medulla. Also camphor stimulates the contractility of narcosis and soporific substances, alcohol, narcotic and metabolism of myocardium. Camphor increas- analgesics and cause “awakening” effect, which is char- es blood pressure due to narrowing of the vessels in acterized by smaller deepness and durability of narco- abdominal organs. In the same time it dilates ves- sis and sleep, restoring of reflexes, muscular tonus and sels of the brain, lungs, and heart. It is used in the consciousness. Mechanism of analeptic’s action is re- form of oil solutions subcutaneously for the treat- lated with increased excitability of neurons. ment of acute and chronic cardiac insufficiency, collapse, depression of the breathing centre, etc. Lo- Analeptics are divided into 3 groups: cally it is administered in the form of ointments dur- — Agents of direct action on breathing centre (Be- ing inflammatory processes, itch, for prophylaxis of megride, Strychnine, Caffeine) bedsores, etc. — Agents of reflective action (Lobeline, Cytisine Carbonic dioxide (CO2) is a potent respiratory (Cytiton)) stimulant. Inspiration of 3% CO2 increases the lung — Agents with combined action (Nikethamide ventilation 2 times. Carbonic dioxide can be used for (Cordiaminum), Camphor, CO2) inhalation separately or in combination with oxygen (Carbogen). Carbonic dioxide activates the cardio- Bemegride is used basically during poisoning by vascular centre. At the same time it dilates the smooth barbiturates and narcosis substances, for quick turn- muscles due to the direct action. Carbonic dioxide is ing out from narcosis. It is injected slowly intravenous- used for the stimulation of respiratory during poisons ly by 5–10 ml of 0.5% solution every 3–5 min up to by narcosis substances, Carbonic monoxide (CO), restoring of breathing, blood circulation and reflexes. during asphyxia of newborns. In higher doses CO2 Injecting has to be stopped on the first appearance of can cause hypercapnia, acidosis, and paralysis of cramp contraction of muscles. breathing centre.

194 DRUGS USED DURING Euphyllin — in tablets 0.015 each; in ampoules PULMONARY EDEMA 24% solution 1 ml each (for intramuscular injection) and 2,4% solution 10 ml each (for intravenous injec- Edema of lungs is accompanied by acute respiration) tory insufficiency, so it needs emergency therapy. Pul- Ketotifen — in capsules and tablets 0.001 each monary edema can be an aggravation of left-ventricu- Beclomethasone dipropionate — in aerosol lar cardiac insufficiency, poisoning by irritate gases, Glaucine hydrochloride — in tablets 0.05 each during uremia, anaphylactic shock, infections, cranio- Libexin — in tablets 0.1 each facial traumas, coma, etc. (Fig. 30). Mucaltin — in patented tablets The most characteristically features of pulmonary Acetylcysteine — in ampoules 20% solution 5 ml or edema are fear, cyanosis, bubbling respiratory with 10 ml each (for inhalation) and 10% solution 2 ml each pink foamy sputum. The main danger of pulmonary (for i.m. injection) edema is foaming of edema’s liquid in respiratory Camphor — in ampoules 20% oil solution 2 ml ways, which causes hypoxia. So, inhalation of anti- each foaming drugs, oxygen and also sucking of the foam Cordiaminum — in ampoules 2 ml each are necessary. Antifoaming substances are Ethyl spir- Bemegride — in ampoules 0.5% solution 10 ml it and Antifoamsilane. They diminish the foam’s sur- each face tension and transform foam into liquid, which vol- Cytiton — in ampoules 1 ml each ume considerably smaller. They are administered in form of inhalations with oxygen. Antifoamsilane doesn’t irritate breathing ways, doesn’t depress CNS and acts quicker than spirit. If pulmonary edema is associated with cardiac in- Lecture 46 sufficiency, cardiac glycosides (Strophanthin, Corgly- DRUGS INFLUENCING THE conum) are indicated. During edema that is associated with hypertension one can use ganglionblockers CONTRACTILE ACTIVITY OF (Hygronium, Benzohexonium), α-adrenolytics (Phen- UTERUS tolamine, Aminazinum), Myotropic vessel narrowing drugs (Sodium nitroprusside). Adrenomimetics (Phe- nylephrine, Ephedrine) are used in case of hypoten- They are divided into: sion. In addition during pulmonary edema are indicat- — substances, strengthening rhythmic contractions ed diuretics (Furosemide) that cause dehydration of of uterus (Oxytocin, Desaminooxytocin, Pituitrinum, lung parenchyma, glucocorticoids (Prednisolone) that Dinoprost, Dinoprostone, Pachycarpinum, and Pros- possess antiedematous and anti-inflammatory action, erinum); Narcotic analgesics (Morphine) that lower venous in- — substances, lowering tonus of uterine cervix (At- put to heart and blood-filling of lungs, depress short ropine sulfate, Dinoprost, Dinoprostone, Promed- breathing and coughing, cause sedative action. olum); — substances, increasing tonus of myometrium (Er- Available forms: got alkaloids, Cotarnine, Oxytocin, and Pituitrinum); Fenoterol — in aerosol 15 ml each — substances, weakening uterus contractions Terbutaline — in aerosol; in tablets 0.0025 each; (Fenoterol, Magnesium sulfate). in ampoules 0.05% solution 1 ml each Drugs, strengthening rhythmic contractions of uter- Ephedrine — powder; in tablets 0.000025 each; in us are indicated during weakness of labor activity, for ampoules 5% solution 1 ml each normalization of uterus involution in postpartum pe- Ipratropium bromide — in aerosol 15 ml each riod, during hypotonic uterus bleeding.

Analeptics of Medulla Antitussive drugs of direct action central action Respiratory centre Carotid 1 Cough centre sinus Antitussive drugs of Nucleus of nervus vagus peripheral action Analeptics of reflective 2 action 1 Lungs Secretomotor Secretomotor expectorants expectorants of resorptive of reflective action Stomach action; mucolytic agents

1- afferent fibers; 2- cholinergic fibers

Fig. 30. Main direction of agents that influence the respiratory organs

195 Oxytocin is a hormone secreted by the neurons of the 12th week of gestation) and to improve cervical in- the hypothalamus and stored in the posterior pituitary ducibility (cervical “ripening”) near or at term in preg- in mammals. Commercially available Oxytocin prep- nant women for labor induction. Adverse GI effects arations are prepared synthetically. Oxytocin stimu- (e.g. diarrhea), phlebitis, fever are the most frequent lates contraction of uterine smooth muscle by increas- adverse reactions of Dinoprostone. Since Dinopros- ing the sodium permeability of uterine myofibrils. High tone, like Dinoprost, is metabolized rapidly, discon- estrogen concentrations lower the threshold for uter- tinuing administration of the drug and supportive ther- ine response to Oxytocin. Uterine response to Oxytoc- apy are usually adequate treatments for serious adverse in increases with the duration of pregnancy. In the term effects. uterus, Oxytocin increases the amplitude and frequen- Dinoprost is similar in structure, action and uses cy of uterine contractions, which in turn tend to de- to Dinoprostone. It is administered intravenously, vag- crease cervical activity producing dilation and efface- inally, and as intra-amniotic injection. Dinoprost, un- ment of the cervix and to transiently impede uterine like Dinoprostone, causes bronchospasm. That’s why blood flow. Oxytocin elicits milk ejection in lactating it is not recommended during bronchial asthma. women. Also it produces vasodilation of vascular Pachycarpinum hydroiodide is a ganglionblocking smooth muscle, increasing renal, coronary, and cere- agent. It increases the tonus and force of the uterus bral blood flow. contractions. Agent lowers blood pressure, so it can be In pharmacologic doses, Oxytocin can be used for administered during labor in patients with hypertonia. induction and augmentation of labor. It can also be It is used intramuscularly, subcutaneously and orally. used for control of postpartum uterine hemorrhage. Pachycarpinum is indicated for the weakness of labor. Oxytocin is administered intravenously or intramus- Anti-cholinesterase substances (Proserinum) and β- cularly. Its circulating half-life is 5 minutes. Contrain- adrenoblockers (Propranolol) also stimulate activity dications include fetal distress, prematurity, abnormal of the uterus. fetal presentation, cephalopelvic disproportion, and M-cholinolytic (Atropine sulfate), prostaglandins other predispositions for uterine rupture. Desaminoox- (Dinoprost, Dinoprostone), and narcotic analgesic ytocin is a synthetic analog of Oxytocin. It acts long- (Promedolum) are used for the relaxation and soften- er than parental agent and used subglossal. ing the cervix of uterus, and bettering of labor current. Pituitrinum is an the extract of bovine pituitary Drugs, increasing tonus of myometrium are used gland. They contain two posterior pituitary hormones: basically during atonic uterine hemorrhages and for vasopressin and oxytocin. Pituitrine posseses the activ- fastening of uterine involution in postpartum period. ity of oxytocin, which is described beyond, and vaso- Mechanism of bleeding stop is related with stable in- pressin that cause vasoconstriction and hypertension. creasing of uterus tonus and pressing due to it of small These agents have the same indications as Oxytocin. vessels in myometrium. Prostaglandins are the class of physiologically ac- Ergot alkaloids are produced by Claviceps purpu- tive substances present in many tissues, with effects rea, a fungus that infects grain rye under damp grow- such as vasodilation, vasoconstriction, stimulation of ing or storage conditions. Ergot alkaloids are the de- intestinal or bronchial smooth muscle, uterine stimu- rivatives of lysergic acid. The main alkaloids are Er- lation, and antagonism to hormones influencing lipid gotamine and Ergometrine. Their effects include ago- metabolism. Prostaglandins as well as leukotrienes and nist, partial agonist, and antagonist actions at α- thromboxanes are synthesized from arachidonic acid adrenoreceptors and serotonin receptors. Ergotamine via a cascade pathway. Prostaglandin F2α (Dinoprost) and related compounds constrict most human blood and Prostaglandin E2 (Dinoprostone) possess ex- vessels in a predictable, prolonged, and potent man- pressed influence on contractility of myometrium. ner. In the same time, they blockade the response of Dinoprostone stimulates uterine and GI smooth α-receptors to other agonists including noradrenaline. muscle. Although it is believed that the drug exerts its Dihydroderivatives of ergot alkaloids have much more uterine effects via direct myometrial stimulation, the selective α-receptor-blocking actions and they cause exact mode of this and other actions has not been ful- vasodilation. ly elucidated. Dinoprostone increases the amplitude Ergot alkaloids possess stimulant action on the uter- and frequency of uterine contractions throughout preg- us. The uterus at term is more sensitive to Ergot than nancy, but uterine response to the drug increases with earlier in pregnancy and far more sensitive than the the duration of pregnancy. In early pregnancy, the nonpregnant organ. These drugs induce powerful and uterus is more responsive to Dinoprostone than to Ox- prolonged tonic contraction of the uterus. Ergometrine ytocin. Dinoprostone-induced uterine contractions are is more selective than other ergot alkaloids in affect- usually sufficient to cause evacuation of both the fetus ing the uterus and is the agent of choice in obstetric and the placenta. The drug also produces cervical di- applications of these drugs. Ergometrine can be ad- lation and softening. Dinoprostone causes stimulation ministrated enterally and parenterally. The onset of of the circular smooth muscle of the GI tract, causes action is 10–15 minutes after ingestion and lasts for a bronchodilation, and increases permeability of the ves- few hours. Certain of the naturally occurring alkaloids sels. Large doses of Dinoprostone may cause vasodi- are powerful hallucinogens. Lysergic acid diethyla- lation and hypotension. mide (LSD, “acid”) is the Ergot compound that most Dinoprostone is widely distributed in the mother clearly demonstrates this action. and is rapidly metabolized in the maternal lungs, kid- Even moderate Ergot doses produce a prolonged neys, and other tissues. and powerful spasm of the muscle quite unlike natural Dinoprostone is used intravenously to induce abor- labor. Their use at that time to accelerate delivery tion during the second trimester of pregnancy (beyond caused an asphyxia and fetus death. Therefore, ergot

196 derivatives are useful only for control of late uterine Lecture 47 bleeding and should never be given before delivery. In medical practice there are used: Galen’s (extract BASIC ACTIONS AND of thick ergot), neo-Galen’s drugs (Ergotal) and pure MEDICATIONS USED IN alkaloids (Ergometrine maleate, Methylergometrine, Ergotamine hydrotartrate). Ergotamine is used for the INTOXICATIONS AND treatment of migraine. Favorable effect of Ergotamine EMERGENCY STATES is related with weakening of cerebral vessel’s pulsation and lowering of irritation of the cerebral cover’s receptors. Poisonings may be caused by any kind of chemi- Ergot alkaloids are contraindicated during angi- cal compounds or liquids for technical used adopted na pectoris, atherosclerosis, and spasm of peripheral in technique, agriculture and household. Medicines vessels. They are excreted in breast milk, so they are may cause poisonings too. All poisonings are divided not to be used during feeding. into professional, household and medical ones. We are The accidental ingestion of ergot alkaloids in con- going to overview the first aid in cases of medical poi- taminated grain as well as overdosing ergot agents sonings. But they are effective in other cases too. causes Ergot poisoning (ergotism). The most dramat- Most frequent medical poisons are sleeping pills, ic effects of poisoning are hallucinations and convul- analgesics, neuroleptics, antiseptics, cardiac glyco- sions, prolonged vasospasm and damage of endotheli- sides, anti-cholinesterase agents, etc. The pattern and um that may result in gangrene, and stimulation of uter- severity of poisoning depends on its agent action. ine smooth muscle, which in pregnancy may result in Thus, anti-cholinesterase agents poisoning (caused by abortion. phosphoorganic compounds) is characterized by Cotarnine chloride also increases tonus of uterus cholinergic system enhanced symptoms. Alcohol, sleep- and administered orally and parenterally during uter- ing pills and drug intoxications are characterized by us bleeding. deep CNS depression. Expressed action during atonic uterus bleeding is Organism conditions and the way of poison en- exhibited by Oxytocin, Pituitrinum and prostagland- trance (oral, inhalation, skin, and mucous coat absorp- ins that are discussed beyond. tion) determine the severity of symptoms as well as the During atonic uterus bleeding some plant drugs are way of first aid. Children and elderly people are ex- used in form of extracts, decoctions and tinctures: tinc- tremely sensitive to poisons and demonstrate the cases ture of Barberries, Water paper, etc. of the most severe poisonings. Environmental factors Drugs, weakening contractile activity of myometri- like temperature, humidity and atmospheric pressure um are used, basically, for stopping of premature la- influence the poison activity too. bor and weakening of labor activity during fastened There are general and specific first aid means. They labor, for preventing of labor ways traumas. For those are designed to achieve the following results: β purposes 2-adrenomimetics (Fenoterol), Magnesium a) prevention of further poisons absorption; sulfate, substances for narcosis are used. b) chemical neutralizing of the absorbed poison or β Fenoterol (Partusisten) is a 2-adrenomimetic. It its elimination with a specific antidote; causes tocolytic (uterine relax) action. Also it leads to c) enhanced poisons extraction; bronchodilation. Agent is effective drug for prevention d) normalizing of organisms function by sympto- of premature labor and doesn’t cause negative action matic therapy. on fetus. It is administered intravenously by drops and The sooner you begin the first aid, the more chances orally in tablets. It may cause tachycardia, muscular of success you have. Each case may need the adjust- weakness, tremor, and hypotension. It is contraindi- ment of therapeutic pattern depending on the type and cated during cardiac defects, arrhythmia, thyrotoxi- severity of poisoning. Thus, abrupt respiratory depres- cosis, and glaucoma. sion claims urgent restoring of the gas exchange sys- Magnesium sulfate during parenteral administra- tem functions. tion decreases uterus contractions. It acts as calcium In the treatment of poisonings an important place antagonist. Also agent possesses sedative, hypotensive is engaged by antidote. Antidote is an agent that neu- effects. In higher doses — soporific, anticonvulsive, and tralizes a poison or counteracts its effects. There are narcosis effects occur. a few types of antidotes. Chemical antidote is a sub- Substances for narcosis (Nitrogen oxide, Ftorotan, stance that unites with a poison to form an innocuous Sodium oxybutyrate, etc.) and tranquilizers (Di- chemical compound (Unithiol, chelating compounds). azepam) as well as Progesterone, Tocopherol (Vita- Mechanical antidote is a substance that prevents the min E) inhibit contractile activity of uterus. absorption of a poison (activated carbon). Physiolog- ic antidote is an agent that produces systemic effects Available forms: contrary to those of a given poison. Oxytocin — in ampoules 1 ml and 2 ml that con- Prevention of poisons absorption. The pattern of tain 5 IU and 10 IU these actions depends on the way poison entrance into Dinoprostone — in tablets 0.0005 each; in am- the organism. Inhalation poisonings (caused by car- poules 5 ml each bon monoxide, nitric oxide, insecticides aerosols, pe- Ergometrine maleate — in tablets 0.0002 each; in troleum evaporations) claim immediate removal of ampoules 0.02% solution 1 ml each patient from the danger zone. Poisons should be re- Fenoterol (Partusisten) — in tablets 0.005 each; moved or washed away from skin and mucous coats. in ampoules 0.005% solution 10 ml Oral intake of poisons is managed by stomach rinsing 197 (lavage). The early it is done, the more effective it is. Complexons make chelate compounds with most of Repeated rinsing help in cases of poisoning with hard- metal ions and radioactive isotopes. These substances soluble powders and tablets that stay in stomach for a have low toxicity and are being extracted by kidneys. couple of hours. Tetacine-calcium (EDTA, Edetate calcium disodium), Inactivation and binding of the poison in the stom- the Calcium chelate of edetate (Ethylenediaminetetraac- ach should be performed simultaneously to rinsing. etate) disodium, is a chelating agent (complexon). The Potassium permanganate, tannin, activated carbon, calcium in calcium EDTA can be displaced by divalent egg whites and milk are used for these purposes. and trivalent metals, particularly lead, to form stable sol- Potassium permanganate causes the oxidation of uble complexes which can then be excreted in urine. Ad- organic poisons. However it is unable to react with in- ministration of calcium EDTA chelates greatly increas- organic compounds. Its water solution ratio is from es the urinary excretion of zinc, cadmium, manganese, 1:5000 to 1:10000. It should be removed from stom- iron, and copper. The manufacturer recommends that ach right after the rinsing due to its irritating proper- calcium EDTA injection be diluted with 0.9% sodium ties. chloride or 5% glucose injection for intravenous admin- Activated carbon (Charcoal) is a universal adsorb- istration. Calcium EDTA is used for the reduction of ent. Water suspension, containing 20–30 g of activat- blood and mobile depot lead in the treatment of acute ed carbon, is to be poured into the stomach. After the and chronic lead poisoning and lead encephalopathy. interaction with poison the suspension should be quick- Agent may also be beneficial in the treatment of poison- ly evacuated with the help of laxatives due to possible ing from other heavy metals such as chromium, manga- release of poison. nese, nickel, zinc, and possibly vanadium. The princi- Tannin sediments various poisons especially alka- pal and most serious toxic effect of calcium EDTA is re- loids. 0.5% solution of tannin is usually used. Remov- nal tubular necrosis, which tends to occur when the dai- al of the suspension due to possible poison release is ly dose is excessive and may result in fatal nephrosis. necessary also. Penicillamine is a monothiol-chelating agent, Eggs white form insoluble complex with poisons. which is a degradation product of penicillins. Penicilla- Milk acts in the same way but it is contradicted in case mine chelates copper, iron, mercury, and lead to form of poisonings by fat-soluble agents. stable soluble complexes, which are readily excreted Vomiting agents may be used in cases of impossi- by the kidneys. Copper is chelated by the combination bility of the gastric rinsing. Apomorphine hydrochlo- of 2 molecules of Penicillamine with 1 atom of the met- ride (0.5–1 ml of 0.5–1% injected subcutaneously) is al. Penicillamine is readily absorbed from the GI used most frequently. It is contradicted in case of pa- tract. Penicillamine is used to promote excretion of tients unconsciousness. copper in the treatment of Wilson’s disease (hepato- Salt laxatives (Sodium and Magnesium sulfate) are lenticular degeneration). Also it is used in the treat- used for poison removal from intestines. Sodium sul- ment of the active stage of rheumatoid arthritis. The fate is better then Magnesium sulfate, because the lat- mechanism of action of Penicillamine in the treatment ter causes CNS depression. of rheumatoid arthritis is not known but may be relat- Chemical neutralization of the absorbed poison and ed to inhibition of collagen formation. Adverse reac- usage of specific antidotes. There are certain com- tions include allergic reactions, nausea, leukopenia, pounds capable for neutralization of poison toxicity and proteinuria. by chemical binding or functional antagonism. They Deferoxamine chelates iron by binding ferric ions act by chemical or functional interaction with poisons. to its molecule. Deferoxamine-iron complex is formed Unithiol, Sodium thiosulfate, Complexons, Methemo- in many tissues, but mainly in plasma; this complex is globin-formers and Demethemoglobin-formers are the stable, water soluble, and readily excreted by the kid- examples of chemical concurrence interaction. neys. Deferoxamine appears to have a specific affini- Unithiol (Dimercaprol) can bind metal ions, met- ty for iron; this affinity is greater than that of other alloids and cardiac glycosides molecules due to its two chelating agents for iron. Deferoxamine is used in the SH groups, which can donate electrons for coordina- treatment of acute iron intoxication as well as chronic tion with the poison. Such bonding effectively prevents iron overload. interaction of the metal with similar functional groups Demethemoglobin-formers are the substances capa- of enzymes, coenzymes, cellular nucleophils, and ble of converting methemoglobin to hemoglobin. They membranes. Usually this medicine is used in cases of are Methylene blue (as a Chromosmone medicine) and poisonings by arsenic, mercury and gold. It is less ef- Cystamine. Methylene blue reduces methemoglobin to fective against bismuth, cobalt, cooper, zinc, nickel, hemoglobin. It is administered to patients who have polonium and cardiac glycosides. Complex of Unithi- been exposed to methemoglobin-forming compounds ol and poison is excreted by kidneys. Given intramus- (e.g. aniline, nitrites, local anesthetics, sulfanilamides) cularly, Unithiol is readily absorbed, metabolized, and and whose methemoglobin levels exceed 20 to 30%. excreted by the kidney in complex with poison within However, in higher doses Methylene blue promotes 4–8 hours. Adverse effects include hypertension, tach- methemoglobin forming that can be used for the treat- ycardia, vomiting, salivation, fever (particularly in ment of cyanide poisoning. children), and pain at the injection site. Physiologic antidote as it is mentioned above is an Sodium thiosulfate is an antidote in arsenic, mer- agent that produces systemic effects contrary to those cury, lead, and cyanide poisoning. Sodium thiosulfate of a given poison. Antidotes can concurrent with poi- forms with metals nontoxic sulfites and with cyanides son for the same substrate, e.g. receptor, enzyme (func- less toxic substances. Its 30% solution is injected in- tional antagonism). For example phosphoorganic sub- travenously. stances inactivate an enzyme acetylcholinesterase that

198 leads to exceed accumulation of acetylcholine. Choli- therapy according to blood pressure rate. Spirit and nesterase reactivators (Dipyroxime (Trimedoxime bro- Antifoamsilane inhalations are performed to manage mide), Isonitrosin) bind with phosphoorganic substanc- the foam; glucocorticoids, diuretics and ganglion- es and release acetylcholinesterase. Choline-blockers blockers are given depending on the indications. Bron- (Atropine) remove cholinomimetics (Muscarine, Pilo- chospasm can be managed by broncholytics (adreno- carpine) on M-cholinoreceptors; thus Atropine is use- mimetics, choline-blockers, Euphylline, etc). Hypox- ful during muscarine poisoning. The same concerns his- ia is managed by oxygen inhalation and special ap- tamine and anti-histamine substances, adrenoblockers paratus for respiration and blood circulation support. and adrenomimetics, Morphine and Nalorphine. Cardiac insufficiency claims glycosides with a Enhanced poison extraction. That is achieved by quick onset of action (Strophanthin, Corglyconum); organisms purifying. Large amounts of liquid and di- antiarrhythmics are used in cases of arrhythmia. uretics are to be taken (forced diuresis). It causes the Vascular tonus and blood pressure are decreased dilution of poison in tissues and decreases its concen- during most of poisonings. Hypotonia causes tissue tration while osmotic diuretics and furosemide enhanc- nutrition disorders, hypoxia, and poison retention. es its renal excretion. Drinks are given to conscious Hypotonia is managed with adrenomimetics (e.g. patients; unconscious ones receive 5% glucose solution Dopamine, Ephedrine, Adrenaline, Mesatonum (Phe- or isotonic sodium chloride solution intravenously. nylephrine) and Noradrenaline). Hypertension (poi- This method is effective only when kidneys are still ca- soning by vasoconstrictors) is the indication for the us- pable of excretion. Alkaline diuresis may aid in in- ing of Clophelinum, Magnesium sulfate, Phen- creasing renal clearance and reducing the elimination tolamine, Benzohexonium, Furosemide, etc. half-life of Salicylates and Phenobarbital (acids), be- Cholinomimetics and CNS agitators often cause cause the reabsorption of acids at alkaline pH is low- cramps. They are managed with narcosis agents, tran- er. And on the contrary, alcohol and amphetamine (al- quilizers (Diazepam), barbiturates (Thiopental), kaline compounds) are better excreted with acidic urine muscle relaxants, and Magnesium sulfate. that can be achieved by using of Ammonium chloride. Allergic reactions and especially anaphylactic Extracorporeal techniques include hemodialysis, shock first aid is urgent injections of adrenomimetics hemoperfusion, etc. that are used for different kinds of (Adrenaline), glucocorticoids (Prednisolone), anti- poisonings. histamines (Dimedrolum), broncholytics (Euphyllin), During the procedure hemodialysis of soluble sub- and cardiac glycosides (Strophanthin). stances and water from the blood by diffusion through Coma is the symptom of severe poisonings. It is pre- a semipermeable membrane is appearing. The separa- fer for the poisoning by CNS depressants. Treatment tion of cellular elements and colloids from soluble sub- is designed to support vital functions. Analeptic use stances is achieved by pore size in the membrane and should be extremely cautious in these cases. Pain syn- rates of diffusion. Hemodialysis is especially effective drome claims narcotic analgesics, which can inhibit in case of kidney insufficiency (Sublimate poisonings). the respiratory centre on the other hand. It promotes the evacuation of poisons with small mo- The support of acid-base balance and liquid-salt lecular weight. balance are extremely important in cases of poisonings Hemoperfusion is a method of detoxication. It con- therapy. Acidifying and alkalinizing agents, salt so- sists of blood passage through columns of adsorptive lutions are discussed in lecture “Blood substitutes”. material, such as Activated charcoal (Carbon), to re- Thus, first aid means depend on the kind of poi- move toxic substances from the blood. It is active soning and patients state. against poisons, diluted in blood. Hemoperfusion is useful for intoxication with a drug known to be me- Available forms: tabolized to a more toxic one and a drug known to Potassium permanganate — in bottles 0.01%; 0.1% produce delayed toxicity. solution Peritoneal dialysis is a removal from the body of Carbo activated — in tablets 0.25 or 0.5 each soluble substances and water by transfer across the per- Unithiol — in ampoules 5% solution 5 ml each itoneum, utilizing a dialysis solution which is intermit- Tetacine-calcium — in ampoules 10% solution 20 tently introduced into and removed from the peritoneal ml each cavity. Transfer of diffusible solutes and water between Penicillamine — in capsules 0.15 each the blood and the peritoneal cavity depends on the con- Chromosmon (Methylthioninium chloride) — in centration gradient between the two fluid compart- ampoules 10 ml and 20 ml each ments. Acute peritoneal dialysis is used principally to Ephedrine — in ampoules 5% solution 1 ml each treat patients with acute renal failure. Euphyllin — in ampoules 24% solution 1 ml each Supportive care (symptomatic therapy). Morbidi- (for intramuscular injection) and 2.4% solution 10 ml ty and mortality following an overdose are reduced by each (for intravenous injection) intensive appropriate symptomatic supportive therapy, Cortisone — in bottles 2.5% suspension 10 ml each which includes restoring of vital functions (cardiac sta- Benzohexonium — in ampoules 2.5% solution 1 ml tus, airway, and mental status). each Respiratory depression claims endotracheal intuba- Camphor — in ampoules 20% oil solution 2 ml tion, bronchial cleaning and artificial lung ventilation. each Respiratory centre depression is managed by analep- Bemegride — in ampoules 0.5% solution 10 ml tics (camphor, bemegride). Respiratory depression each caused by Morphine can be treated by Naloxone or Furosemide — in ampoules 1% solution 2 ml each Nalorphine. Pulmonary edema is treated with complex Diazepam — in ampoules 0.5% solution 2 ml each

199 β EXAMINATION QUESTIONS (B). Inhaled 2-adrenoceptor agonists only. (C). Inhaled corticosteroids only. 1. A 36-year-old woman with severe erosive es- (D). A combination of inhaled bronchodilators ophagitis is prescribed Pantoprazole. One of the most and inhaled corticosteroids. common adverse side effects of such therapy is which (E). Oral corticosteroids. of the following? (A). Vomiting. 8. Symptoms typically produced by inhaled β- (B). Constipation. adrenoceptor agonists include which of the following? (C). Headache. (A). Tachycardia, dizziness, and nervousness. (D). Heartburn. (B). Dysphonia, candidiasis, and sore throat. (E). Paresthesias. (C). Dyspepsia and Churg-Strauss syndrome. (D). Nausea, agitation, and convulsions. 2. While taking a NSAID for arthritis, a 65-year- (E). Muscle tremor, tachycardia, and palpita- old man developed a gastric ulcer. He was prescribed tions. Ranitidine for 8 weeks. This drug binds a receptor located where? 9. Which of the following is the drug of choice for (A). Nucleus. inducing labor? (B). Nucleolus. (A). Oxytocin. (C). Cytoplasm. (B). Misoprostol. (D). Cell membrane. (C). Methyl ergonovine. (E). Cell wall. (D). Dinoprostone. (E). Carboprost tromethamine. 3. A 20-year-old woman goes to the emergency department, stating that within the past hour she ingest- 10. Adverse reactions to the prostaglandin ana- ed “a handful of sleeping pills.” She is still awake. logue carboprost tromethamine include all of the fol- Which of the following drugs can be given to induce lowing EXCEPT vomiting? (A). Diarrhea. (A). Metoclopramide. (B). Fever. (B). Ipecac. (C). Water intoxication. (C). Morphine. (D). Nausea. (D). Promethazine. (E). Dyspnea. (E). Ondansetron. 11. All of the following are properties of magnesi- 4. A 17-year-old boy with a history of sulfa aller- um sulfate that may be related to its ability to relax gy is diagnosed with left-side ulcerative colitis after a uterine smooth muscle EXCEPT β-week history of bloody diarrhea and tenesmus. On (A). Uncoupling excitation-contraction in myome- examination he is afebrile and has no abdominal ten- trial cells through inhibition of cellular action derness. The appropriate drug therapy to institute ini- potentials. tially is which of the following? (B). Decreasing calcium uptake by competing for (A). Metronidazole. binding sites. (B). Sulfasalazine. (C). Activating adenylate cyclase. (C). Mesalamine. (D). Stimulating calcium-dependent ATPase. (D). Cyclosporine. (E). Antagonizing prostaglandin action. (E). Prednisone. 12. Which of the following is a special concern for 5. Gastric acid secretion is stimulated by the pres- the use of Indomethacin for inducing labor (tocolysis)? ence of (A). Fetal cardiac arrest. (A). Gastrin and acetylcholine. (B). Fetal gastrointestinal bleeding. (B). Histamine and motilin. (C). Fetal hematuria. (C). Norepinephrine and gastrin. (D). Closure of the fetal ductus arteriosis. (D). Norepinephrine and histamine. (E). Fetal muscular paralysis. (E). Acetylcholine and pepsin.

6. Which one of the following β-adrenoceptor agonists has such a slow onset of action that it is not indi- ANSWERS cated for the relief of acute asthma symptoms? (A). Salmeterol. (B). Albuterol. 1. (C). The most commonly reported side effects for all of the proton pump inhibitors are headache, diarrhea, (C). Epinephrine. and abdominal pain. Heartburn is improved by these (D). Terbutaline. agents. Vomiting, constipation, and paresthesias are not (E). Isoproterenol. typical side effects of proton pump inhibitors. 2. (D). Ranitidine is an H2-receptor antagonist. H2- re- 7. The standard treatment regimen for asthma is ceptors are found in the cell membrane of parietal cells, best described by which of the following? not in the nucleus, nucleolus, or cytoplasm. Mammalian (A). Theophylline and exercise. cells do not have cell walls.

200 3. (B). Two medicines, Ipecac and Apomorphine, induce as Misoprostol or Dinoprostone, may be better for women vomiting. Metoclopramide is a prokinetic with antiemet- with unfavorable cervices. Both Misoprostol and Dinopros- ic properties and therefore would have the opposite of tone are prostaglandin analogues. They cause changes in the desired effect. Morphine is an opioid with analgesic the substance of the cervix and uterine contraction. Al- and sedating properties. Promethazine and Ondansetron are though all agents used for labor induction carry the risk also antiemetics, not emetics. of uterine hyperstimulation, prostaglandins are more 4. (C). The information provided suggests the patient likely to cause hyperstimulation in women with favora- has mild to moderate disease. Initial therapy should be ble cervices. Furthermore, the current formulations of a 5-ASA containing product, which includes Sulfasala- prostaglandins do not allow for tight control of blood zine and Mesalamine. However, the patient has a sulfa al- levels and rapid clearance of medication if hyperstimu- lergy, precluding the use of Sulfasalazine. Metronidazole lation occurs. Methyl ergonovine is an α-agonist that caus- is useful in the treatment of some patients with Crohn’s es direct smooth muscle contraction. Carboprost trometh- disease. Cyclosporine has been used in patients with ful- amine is a methylated analogue of prostaglandin F2a It is minant ulcerative colitis. Prednisone may have to be add- highly potent in causing prolonged uterine contraction. ed to this patient’s therapy, but only if he fails to re- Both medications are used for the control of uterine spond to the Mesalamine. It should not be used initial- bleeding after delivery by causing tetanic uterine contrac- ly. tions. These medications are contraindicated for labor 5. (A). Gastrin, histamine, and acetylcholine stimu- induction in women with live fetuses. Both medications late gastric acid secretion. Pepsin is a digestive protein can be used in facilitating medical abortions. secreted by the stomach in response to a meal. Norepine- 10. (C). Carboprost tromethamine is methylated at the phrine is a neurotransmitter that does not affect gastric 15 position. This methylation causes the analogue to be acid secretion. 10 to 15 times more potent then the natural prostagland- 6. (A). The other agents have rapid onset and are ap- in. Smooth muscles that are especially sensitive to pros- propriate for acute symptomatic relief of asthma. taglandin F2a are uterine, gastrointestinal, and bronchi- β 7. (D). In all asthma treatment regimens, inhaled 2- al. The uterine sensitivity allows for the therapeutic effi- adrenoceptor agonists are used as bronchodilators as cacy. The gastrointestinal sensitivity causes the diarrhea needed to relieve acute symptoms. As asthma is an in- and nausea. Prostaglandins are involved in the pyretic flammatory disease of the airway, inhaled corticoster- response, and thus a side effect of their use may be fever. oids are also used as standard therapy to control symp- Oxytocin has antidiuretic hormone qualities, and with toms in all but the mildest cases. The potential for dan- prolonged use may cause water intoxication. gerous side effects and drug interactions has relegated 11. (E). Magnesium has no known effect on prostag- Theophylline, once a mainstay of asthma treatment, to landins. The mechanism of action by which Magnesium add-on therapy for hard to control symptoms. Inhaled sulfate causes smooth muscle contraction is complex and β 2-adrenoceptor agonists or inhaled corticosteroids are poorly understood. Magnesium sulfate uncouples excita- not typically used as monotherapy, although the former tion-contraction in myometrial cells through inhibition class of agent can be used alone for patients with very of cellular action potentials. Furthermore, Magnesium sul- mild symptoms. Because of extensive systemic side ef- fate decreases calcium uptake by competing for binding fects, oral corticosteroids are not typically used to treat sites, activating adenylate cyclase (reducing intracellular asthma except when symptoms cannot be controlled by calcium), and stimulating calcium-dependent ATPase, standard therapy. which promotes calcium uptake by sarcoplasmic reticu- 8. (A). Tachycardia, dizziness, and nervousness are of- lum. ten produced by larger doses of inhaled β-agonists. Dys- 12. (D). Indomethacin is a potent prostaglandin syn- phonia, candidiasis, and sore throat are associated with thesis inhibitor. Patency of the ductus arteriosis depends the use of inhaled corticosteroids. The emergence of on the formation of prostaglandins. Closure of the duc- Churg-Strauss syndrome, though uncommon, is associ- tus arteriosis can lead to fetal heart failure and death. ated with the use of oral leukotriene modulators. Theo- Also, fetal closure can lead to neonatal pulmonary hy- phylline produces a range of side effects, including nau- pertension. Neonatologists use Indomethacin for the sea, agitation, and life-threatening convulsions. Muscle treatment of neonatal patent ductus arteriosis, thus of- tremor and palpitations are frequently observed with oral ten obviating neonatal heart surgery. Prostaglandin (3-adrenoceptor agonists but rarely occur when these synthesis inhibitors are associated with bleeding. Al- agents are administered via inhalation. though bleeding is well documented in children and 9. (A). Oxytocin is considered the drug of choice for adults, the use of Indomethacin has not been shown to inducing labor. All other methods of labor induction are cause hematuria or gastrointestinal bleeding in the fe- compared to oxytocin to establish their efficacy. Data tus. There is some evidence, however, that maternal use demonstrate that Oxytocin is highly effective in induc- of Indomethacin may increase the risk of neonatal in- ing, establishing, and augmenting labor. Oxytocin is not traventricular hemorrhage. Neither muscular paralysis as effective for labor induction when a woman has a cer- nor cardiac arrest has been demonstrated in the fetus vix that is not favorable for labor. Another agent, such with maternal use of Indomethacin.

201 Appendix A MAIN INTERNATIONAL ABBREVIATIONS IN PHARMACOLOGY

A CVA cerebrovascular accident aa of each CVP central venous pressure ABG arterial blood gas ac before meals D ADH antidiuretic hormone /d per day ADL activities of daily living d daily ad lib as much as desired DC (D/C) discontinue ADT alternate-day therapy DJD degenerative joint disease ALT alanine aminotransferase DM diabetes mellitus AMA against medical advice DOE dyspnea on exertion AMI acute myocardial infarction DT delirium tremens AODM adult-onset diabetes mellitus Dx diagnosis ARC AIDS-related complex ASAP as soon as possible ASHD arteriosclerotic heart disease E AST aspartate aminotransferase ER emergency room ESR erythrocyte sedimentation rate (sed rate) et and B BE barium enema; base excess bid twice a day F BMR basal metabolic rate F Fahrenheit B&O belladonna and opium FBS fasting blood sugar BP blood pressure fl fluid BRP bathroom privileges fx fracture; fraction BUN blood urea nitrogen G C g gram Ca cancer; calcium GI gastrointestinal C&A clinitest and acetest gtt drop CAD coronary artery disease GU genitourinary caps capsules CBC complete blood count H CC chief complaint CCU Coronary Care Unit H hour CHF congestive heart failure HA headache CHO carbohydrate Hct hematocrit chol cholesterol Hgb hemoglobin CLL chronic lymphocytic leukemia hs hour of sleep CNS central nervous system HNT hypertension C/O complains of COPD chronic obstructive pulmonary disease CPK creatine phosphokinase I CRF chronic renal failure ICU intensive care unit C&S culture and sensitivity IM intramuscular CTZ chemoreceptor trigger zone I&O intake and output

202 IOP intraocular pressure prn as needed IPPB intermittent positive pressure breathing PT prothrombin time IU international units PZI protamine zinc insulin IV intravenous Q J qd every day JRA juvenile rheumatoid arthritis qh every hour (q2h, q3h, etc. – every 2 hours, every 3 hours, etc.) qid four times a day K qod every other day K potassium KVO keep vein open R RA rheumatoid arthritis; right atrium L RBC red blood cell LDH lactic dehydrogenase REM rapid eye movement LDL low-density lipoproteins RF rheumatoid factor LOC level of consciousness RHD rheumatic heart disease; LP lumbar puncture renal hypertensive disease lytes electrolytes ROM range of motion

M S mcg microgram SC subcutaneous MI myocardial infarction (heart attack) sed rate erythrocyte sedimentation rate (ESR) mL milliliter SGOT serum glutamic oxaloacetic transaminase MOM milk of magnesia SGPT serum glutamic pyruvic transaminase MS morphine sulfate; multiple sclerosis; SL sublingual mitral stenosis SOB shortness of breath SR sedimentation rate (ESR) STAT as soon as possible N N normal NG nasogastric T NPO nothing by mouth t temperature NS normal saline T3 triiodothyronine NGT nitroglycerin T4 thyroxine NVD nausea, vomiting, diarrhea; TB tuberculosis neck vein distension TEDS elastic stockings TIA transient ischemic attack tid three times a day O TKO to keep open O2 oxygen TLC tender living care OD right eye TM tympanic membrane OOB out of bed TPN total parenteral nutrition OU both eyes TPR temperature, pulse, respiration OTC over the counter (nonprescription) TSH thyroidstimulating hormone OS left eye U P UGI upper gastrointestinal PAT paroxysmal atrial tachycardia ung ointment PBI protein-bound iodine URI upper respiratory infection PC after meals UTI urinary tract infection PERRLA pupils equal, round, react to light and accommodation PERL pupils equal and react to light V PID pelvic inflammatory disease VS vital signs PKU phenylketonuria PND paroxysmal nocturnal dyspnea PO by mouth W postop after surgery WNL within normal limits preop before surgery Wt weight

203 Appendix B EXAMPLES OF COMBINATION DRUGS

ANTACID COMBINATIONS Marblen Liquid — calcium carbonate, magnesium carbonate Acid-X — calcium carbonate, acetaminophen Mintox — aluminum, magnesium hydroxide Advanced Formula Di-Gel — magnesium hydrox- Mintox Plus — aluminum hydroxide, magnesium ide, calcium carbonate, simethicone, sucrose hydroxide, simethicone, saccharin, sorbitol, sugar Alamag Plus — aluminum hydroxide, magnesium Mintox Suspension — aluminum hydroxide, mag- hydroxide, simethicone, parabens, sorbitol, saccharin nesium hydroxide, parabens, sorbitol, saccharin Alamag Suspension — aluminum hydroxide, mag- Mylagen Liquid — simethicone, parabens, sorbi- nesium hydroxide, sorbitol, sucrose, parabens tol sucrose Alenic Alka — aluminum hydroxide, magnesium tri- Mylanta — aluminum hydroxide, magnesium hy- silicate, sodium bicarbonate, calcium stearate, sugar droxide simethicone, sorbitol Almacone — aluminum hydroxide, magnesium hy- Mylanta Gelcaps — calcium carbonate, magnesi- droxide, simethicone um carbonate parabens Bromo-Seltzer Effervescent Granules — sodium bi- Mylanta Liquid — simethicone, sorbitol carbonate, acetaminophen, citric acid, sugar Nephrox Liquid — aluminum hydroxide, mineral oil Calcium Rich Rolaids — magnesium hydroxide, calcium carbonate Original Alka-Seltzer Effervescent Tablets — sodium bicarbonate, aspirin, citric acid, phenylalanine Citrocarbonate Effervescent Granules — sodium bicarbonate, sodium citrate anhydrous Riopan Plus — magaldrate, simethicone, sorbitol, sucrose Di-Gel Liquid — aluminum hydroxide, simethicone, saccharin sorbitol, parabens Riopan Plus Suspension — magaldrate, simethicone, saccharin sorbitol Extra Strength Maalox Suspension — aluminum hydroxide magnesium hydroxide, simethicone, pa- Rulox # 2 — aluminum, magnesium hydroxide, rabens sorbitol, saccharin simethicone Gas-Ban — simethicone, calcium carbonate Rulox Plus — aluminum hydroxide, magnesium hydroxide simethicone, sugar, saccharin, dextrose Gas-Ban DS Liquid — aluminum hydroxide, magnesium hydroxide, simethicone Rulox Suspension — aluminum hydroxide, magnesium hydroxide, parabens, sorbitol, saccharin Gaviscon Extra Strength Reliever Formula Liquid — aluminum hydroxide, magnesium carbonate, pa- Simaal Gel 2 Liquid — aluminum hydroxide, mag- rabens EDTA, saccharin, sorbitol, simethicone, sodi- nesium hydroxide, simethicone um alginate Tempo — aluminum hydroxide, magnesium hy- Gaviscon Liquid — magnesium carbonate, pa- droxide calcium carbonate, simethicone, sorbitol, corn rabens EDTA, saccharin, sorbitol, sodium alginate syrup Gelusil — aluminum hydroxide, magnesium hydroxide simethicone, dextrose, saccharin, sorbitol, sugar ANTIASTHMATIC COMBINATIONS Lowslum Plus Liquid — magaldrate, simethicone Maalox — aluminum, magnesium hydroxide Bronchial Capsules — theophylline, guaifenesin Maalox Plus — aluminum hydroxide, magnesium Brondelate Elixir — theophylline, oxtriphylline, hydroxide, simethicone, sugar guaifenesin Maalox Suspension — aluminum hydroxide, mag- Dilor-G Tablets — dyphylline, guaifenesin nesium hydroxide, saccharin, sorbitol, parabens Dyflex-G Tablets — dyphylline, guaifenesin Marblen — magnesium carbonate, calcium carbonate Glyceryl-T Liquid — theophylline, guaifenesin 204 Hydrophed Tablets — theophylline, hydroxyzine Tylenol Severe Allergy Tablets — diphenhydramine ephedrine sulfate HCl acetaminophen Lufyllin-EPG Tablets — dyphylline, ephedrine HCl guaifenesin, phenobarbitol ANTIHYPERTENSIVE Marax Tablets — theophylline, hydroxyzine, ephe- COMBINATIONS drine sulfate Mundrane GG Tablets — theophylline, guaifenes- Aldoclor — chlorothiazide, methyldopa in aminophylline anhydrous, ephedrine HCl pheno- Aldoril — hydrochlorothiazide, methyldopa barbital Apresazide — hydrochlorothiazide, hydralazine Primatene Dual Action Tablets — theophylline Avalide — hydrochlorothiazide, irbesartan ephedrine, guaifenesin Capozide — hydrochlorothiazide, captopril Primatene Tablets — theophylline, phenobarbital Chloroserpine — chlorothiazide, reserpine ephedrine HCl Combipres — clonidine, chlorthalidone Quadrinal Tablets — theophylline, theophylline calcium salicylate, ephedrine HCl, potassium iodide, Corzide — bendroflumethiazide, nadolol phenobarbital Demi-Regroton Tablets — chlorthalidone, reserpine Quibron Capsules — theophylline, guaifenesin Diovan HCT — hydrochlorothiazide, valsartan Slo-Phyllin GG Capsules — theophylline, guaifen- Diutensen-R Tablets — methyclothiazide, reserpine esin Enduronyl — methyclothiazide, desperidine Slo-Phyllin GG Syrup — theophylline, guaifenesin Esimil — hydrochlorothiazide, guanethidine mon- Tedrigen Tablets — theophylline, Phenobarbital, osulfate Ephedrine, HCl Hydrap-ES — hydrochlorothiazide, reserpine, hy- Theodrine Tablets — theophylline, ephedrine HCl dralazine HCl Theolate Liquid — theophylline, guaifenesin Hydropres-50 — hydrochlorothiazide, reserpine Hydro-Serp — hydrochlorothiazide, reserpine ANTIDIARRHEAL COMBINATIONS Hydroserpine Tablets — hydrochlorothiazide, reserpine Diasorb — activated attapulgite, sorbitol Hyzaar — hydrochlorothiazide, losartan potas- Donnagel — attapulgite, saccharin sium Kaodene Non-Narcotic — kaolin, pectin, bismuth Inderide — hydrochlorothiazide, propranolol HCl subsalicylate sucrose Inderide LA — hydrochlorothiazide, propranolol Kaolin w/ Pectin — kaolin, pectin HCl Kaopectate Maximum Strength — attapulgite, su- Lexxel Extended-Release — enalapril maleate, fe- crose lodipine Kapectolin — kaolin, pectin Lopressor — hydrochlorothiazide, metoprolol K-C — kaolin, pectin, bismuth subcarbonate, pep- Lotensin HCT — hydrochlorothiazide, benazepril permint flavor Lotrel — amlodopine, benazepril Marpres — hydrochlorothiazide, reserpine, hy- ANTIHISTAMINE AND ANALGESIC dralazine HCl COMBINATIONS Metatensin Tablets — trichlormethiazide, reserpine Minizide — polythiazide, prazosin Aceta-Gesic Tablets — phenyltoloxamine citrate, Prinzide — hydrochlorothiazide, lisinopril acetaminophen Rauzide Tablets — rauwolfia, bendroflumethiazide Coricidin HBP Cold and Flu Tablets — chlorpheniramine maleate, acetaminophen Regroton — chlorthalidone, reserpine Ed-Flex Capsules — phenyltoloxamine citrate, Salutensin Tablets — hydroflumethiazide, reser- acetaminophen salicylamide pine Major-Gesic Tablets — phenyltoloxamine citrate, Salutensin-Demi — hydrochlorothiazide, reserpine acetaminophen Ser-Ap-Es — hydrochlorothiazide, reserpine, hy- Percogesic — phenyltoloxamine citrate, acetami- dralazine HCl nophen Tarka — trandolapril, verapamil Percogesic Extra Strength Tablets — diphenhy- Teczem Extended-Release — diltiazem maleate, dramine HCl, acetaminophen enalapril maleate Phenylgesic Tablets — phenyltoloxamine citrate, Tenoretic — chlorthalidone, atenolol acetaminophen Timolide — hydrochlorothiazide, timolol maleate Tylenol PM Extra Strength Tablets — diphenhy- Tri-Hydroserpine — hydrochlorothiazide, reser- dramine HCl, acetaminophen pine hydralazine HCl

205 Uniretic — hydrochlorothiazide, moexipril HCl Aprodine Tablets — pseudoephedrine HCl, tripro- Vaseretic — hydrochlorothiazide, enalapril maleate lidine HCl Zestoretic — hydrochlorothiazide, lisinopril Benadryl Allergy & Sinus Tablets — pseudoephedrine HCl, diphenhydramine citrate, diphenhydramine Ziac — hydrochlorothiazide, bisoprolol fumarate HCl Bromfed Capsules — pseudoephedrine HCl, brom- ANTITUSSIVE COMBINATIONS pheniramine maleate Bromfed Syrup — pseudoephedrine HCl, bromphe- Alka-Seltzer Plus Cold and Flu Liqui-Gels — dex- niramine maleate tromethorphan HBr, pseudoephedrine HCl, acetaminophen Claritin D — pseudoephedrine HCl, loratadine Bromatane DX — dextromethorphan HBr, brom- Deconamine Syrup — pseudoephedrine HCl, chlo- pheniramine maleate, pseudoephedrine HCl rpheniramine maleate Cardec DM — dextromethorphan HBr, carbinox- Dynex Tablets — pseudoephedrine, guaifenesin amine maleate, pseudoephedrine HCl Ed A Hist Tablets — phenylephrine HCl, chlorphe- Coricidin HBP Cough & Cold Tablets — dex- niramine maleate tromethorphan HBr, chlorpheniramine, acetami- Genac Tablets — pseudoephedrine HCl, triprolid- nophen ine HCl Dimetane-DX Cough — dextromethorphan HBr Guaifed Capsules — pseudoephedrine, guaifenesin brompheniramine maleate, pseudoephedrine HCl Guiatuss PE Liquid — pseudoephedrine, guaifen- Hycodan Tablets or Syrup — hydrocodone bitar- esin trate homatropine MBr Histade Capsules — pseudoephedrine HCl chlo- Hydromide Syrup — hydrocodone bitartrate, hom- rpheniramine maleate atropine MBr Histatab Plus Tablets — phenylephrine HCl, chlo- Nucofed Capsules — codeine phosphate, pseu- rpheniramine maleate doephedrine HCl Histex Liquid — pseudoephedrine HCl, chlorphe- Promethazaine HCl/w Codeine Cough Syrup — co- niramine maleate deine phosphate, promethazine HCl Lodrane Liquid — pseudoephedrine HCl, brom- Quad Tann Tablets — carbetapentane tannate, pheniramine maleate chlorpheniramine tannate, phenylephrine tannate Phenergan VC Syrup — phenylephrine HCl, pro- ephedrine tannate methazine Robitussin Maximun Strength — dextromethor- Profen II Tablets — pseudoephedrine, guaifenesin phan HBr, pseudoephedrine HCl Pseudovent Capsules — pseudoephedrine, guaifen- Rynatuss Tablets — carbetapentane tannate, chlo- esin rpheniramine tannate, phenylephrine tannate, ephe- Respahist Capsules — pseudoephedrine HCl, drine tannate brompheniramine maleate Sudafed Non-Drowsy Severe Cold Formula Maxi- mum Strength Tablets – dextromethorphan HBr, pseu- Respaire-60 SR Capsules — pseudoephedrine, doephedrine HCl, acetaminophen guaifenesin Tannic-12 Tablets — carbetapentane tannate, chlo- Rinade B.I.D. Capsules — pseudoephedrine HCl, rpheniramine tannate chlorpheniramine maleate Tricodeine Cough & Cold Liquid — codeine phos- Robafen PE Liquid — pseudoephedrine, guaifen- phate pyrilamine maleate esin Trionate Tablets — carbetapentane tannate, chlo- Robitussin Cold Sinus and Congestion — pseu- rpheniramine tannate doephedrine guaifenesin, acetaminophen Tussafed Syrup — dextromethorphan HBr, car- Robitussin PE Liquid — pseudoephedrine, guaife- binoxamine maleate, pseudoephedrine HCl nesin Tussend Tablets — hydrocodone bitartrate, chlo- Rondec Tablets — pseudoephedrine HCl, carbinox- rpheniramine pseudoephedrine HCl amine maleate Vanex HD Liquid — hydrocodone bitartrate, chlo- Ryna Liquid — pseudoephedrine HCl, chlorphe- rpheniramine phenylephrine HCl niramine maleate Rynatan Tablets — phenylephrine tannate, chlorpheniramine tannate DECONGESTANT AND Severe Congestion Tussin Softgels — pseudoephe- EXPECTORANT COMBINATIONS drine guaifenesin Allegra-D Tablets — pseudoephedrine HCl, fex- Sinutab Nondrying Liquid Caps — pseudoephe- ofenadine HCl drine guaifenesin Allerfrim Syrup — pseudoephedrine HCl, triproli- Sudafed Cold and Allergy Maximum Strength — dine HCl pseudoephedrine HCl, chlorpheniramine maleate 206 Tanafed Suspension — pseudoephedrine, chlorphe- Maxzide-25MG — triamterene, hydrochlorothi- niramine tannate azide Versacaps Capsules — pseudoephedrine, guaifen- Modiuretic — amiloride, hydrochlorothiazide esin Spironolactone/hydrochlorothiazide — generic Triamterene/hydrochlorothiazide — generic DECONGESTANT, ANTIHISTAMINE, AND ANALGESIC COMBINATIONS ESTROGEN AND PROGESTIN Alka-Seltzer Plus Cold Medicine — phenylephrine COMBINATIONS HCl chlorpheniramine maleate, acetaminophen Activella — estradiol, norethindrone acetate Decodult Tablets — pseudoephedrine HCl, chlo- CombiPatch — estradiol, norethindrone rpheniramine maleate, acetaminophen Femhrt — ethinyl estradiol, norethindrone acetate Kolephrin Tablets — pseudoephedrine HCl, chlorpheniramine maleate, acetaminophen Ortho-Prefest — estradiol, norgestimate Simplet Tablets — pseudoephedrine HCl, chlo- Premephase — conjugated estrogens, medroxypro- rpheniramine acetaminophen gesterone acetate Sinutab Sinus Allergy, Maximum Strength — pseu- Prempro — conjugated estrogens, medroxyproges- doephedrine HCl, chlorpheniramine maleate, acetami- terone acetate nophen Tavist Allergy/Sinus/Headache Tablets — pseu- ESTROGEN AND ANDROGEN doephedrine HCl, clemastine fumarate, acetaminophen COMBINATIONS, ORAL AND TheraFlu Flu and Cold Medicine Original Formu- PARENTERAL la Powder — pseudoephedrine HCl, chlorpheniramine maleate, acetaminophen Depo-Testadiol — estradiol cypionate, testosterone Triaminic Cold, Allergy, Sinus Medicine — pseu- cypionate doephedrine HCl, chlorpheniramine maleate, acetami- Depotestogen — estradiol cypionate, testosterone nophen cypionate Tylenol Sinus NightTime Maximum Strength Tab- Duo-Cyp — estradiol cypionate, testosterone cypi- lets — pseudoephedrine HCl, diphenhydramine HCl, onate acetaminophen Estratest — esterified estrogens, methyltestosterone Estratest H.S. — esterified estrogens, methyltesto- DECONGESTANT, ANTIHISTAMINE, sterone AND ANTICHOLINERGIC Valertest No. 1 — estradiol valerate, testosterone COMBINATIONS enanthate AH-Chew Tablets — phenylephrine HCl, chlorpheniramine maleate, methscopolamine nitrate GLAUCOMA COMBINATIONS D.A. Chewable Tablets — phenylephrine HCl, chlo- E-Pilo — pilocarpine, epinephrine rpheniramine maleate, methscopolamine nitrate E-Pilo-2 — pilocarpine, epinephrine Dallergy Syrup or Tablets — phenylephrine HCl, E-Pilo-4 — pilocarpine, epinephrine chlorpheniramine maleate, methscopolamine nitrate P6E1 — pilocarpine, epinephrine Dehistine Syrup — phenylephrine HCl, chlorpheniramine maleate, methscopolamine nitrate Extendryl Syrup — phenylephrine HCl, chlorphe- GASTROINTESTINAL niramine maleate, methscopolamine nitrate ANTICHOLINERGIC COMBINATIONS Pannaz Tablets or Syrup — phenylephrine HCl, chlorpheniramine maleate, methscopolamine nitrate Antrocol Elixir — atropine sulfate, phenobarbital, alcohol Rescon-MX Tablets — phenylephrine HCl, chlorpheniramine maleate, methscopolamine nitrate Barbidonna — atropine, scopolamine HBr, hyoscyamine sulfate, phenobarbital Bellacane Elixir — atropine, scopolamine HBr, DIURETIC COMBINATIONS hyoscyamine Bellacane SR Tablets — l-alkaloids of belladonna, Aldactazide — spironolactone, hydrochlorothi- phenobarbital ergotamine tartrate azide Bellergal-S Tablets — l-alkaloids of belladonna, Amiloride/hydrochlorothiazide — generic phenobarbital ergotamine tartrate Dyazide — triamterene, hydrochlorothiazide Butibel Elixir — belladonna extract, butabarbital Maxzide — triamterene, hydrochlorothiazide sodium, alcohol, sucrose, saccharin

207 Butibel Tablets — belladonna extract, butabarbi- Vasocon-A Solution — naphazoline HCl, antazo- tol line phosphate Ophthalmic Antibiotic Combinations Chardonna-2 Tablets — belladonna extract, phe- AK-Poly-Bac Ophthalmic Ointment — polymyxin nobarbital B sulfate bacitracin zinc Donnatal Elixir — atropine, scopolamine HBr, AK-Spore — polymyxin B Sulfate, neomycin, baci- hyoscyamine HBr or sulfate, phenobarbital, alcohol, tracin zinc sucrose, saccharin Neosporin Ophthalmic Ointment — polymyxin B Donnatal Capsules and Tablets — atropine, scopo- sulfate neomycin, bacitracin zinc lamine HBr, hyoscyamine sulfate, phenobarbital Polysporin Ophthalmic Ointment — polymyxin B Folergot-DF Tablets — 1-alkaloids of belladonna, sulfate bacitracin zinc phenobarbital, ergotamine tartrate Polytrim Ophthalmic Solution — polymyxin B sul- Hyosophen Tablets — atropine, scopolamine HBr fate trimethoprim sulfate hyoscyamine sulfate, phenobarbital Librax Capsules — clindinium, chlordiazepoxide HCl PERIPHERAL VASODILATOR Phenerbel-S Tablets — l-alkaloids of belladonna, COMBINATIONS phenobarbital ergotamine tartrate Lipo-Nicin — niacin, niacinamide, vitamins C, B1, Spasmolin Tablets — atropine, scopolamine HBr B2, B6 hyoscyamine sulfate, phenobarbital

ISONIAZID COMBINATIONS SEDATIVE AND HYPNOTIC COMBINATIONS Rifamate — rifampin, isoniazid Tuinal — amobarbital, secobarbital Rifater — rifampin, isoniazid, pyrazinamide

LAXATIVE COMBINATIONS SKELETAL MUSCLE RELAXANT COMBINATIONS DDS 100 Plus Capsules — docusate, casanthranol Carisoprodol Compound — carisoprodol, aspirin Doxidan Capsules — docusate, casanthranol, sorbitol Flexaphen — chlorzoxazone, acetaminophen Nature’s Remedy — cascara sagrada, aloe, lactose Lobac — salicylamide, phenyltoloxamine, acetaminophen Peri-Colace — docusate, casanthranol, sorbitol, parabens Norgesic Forte — orphenadrine citrate, aspirin, caffeine Senokot-S tablets — docusate, senna concentrate, lactose Ophthalmic Decongestant and Antihistamine Norgesic — orphenadrine citrate, aspirin, caffeine Combinations Robaxisal — methocarbamol, aspirin Naphcon-A Solution — naphazoline HCl, phe- Sodol Compound — carisoprodol, aspirin niramine maleate Soma Compound — carisoprodol, aspirin

208 REFERENCES

1. Amidon G., Lee P., Topp E. (eds.). Transport 16. K. D. Tripathy. Essentials of medical pharma- Processes in Pharmaceutical Systems. — New York: cology. — 4th ed. — New Delhi: JAYPEE Brothers Decker, 2000. Medical publishers (P) Ltd., 1999. — 935 p. 2. Appenzeller O. The Autonomic Nervous System. 17. Kenakin T. P. Pharmacological Analysis of — 4th ed. — Amsterdam: Elsevier, 1990. Drug-receptor Interaction. — New York: Lippincott- 3. Basic and Clinical Pharmacology: in 2 parts / Raven, 1993. Edited by Bertram G. Katzung. — N.Y.: McGraw- 18. Kenakin T. P., Bond R. A., Bonner T. I. Defi- Hill, 1998. nition of pharmacological receptors. — Pharmacol Rev. — 1992. — V. 44. — P. 351-362. 4. Birkett D. J. Pharmacokinetics Made Easy. — Sydney: McGraw-Hill, 1998. 19. Klaassen C. D. Casarett and Doull’s Toxicolo- gy, the Basic Science of Poisons. — 6th ed. — New 5. Boyer J. L., Graf J., Meier P. J. Hepatic trans- York: McGraw Professional, 2001. port systems regulating pH, cell volume, and bile secretion. — Ann Rev Physiol, 1992. — V. 54. — P. 415-438. 20. Levy R. H. et al. Metabolic Drug Interactions. — Philadelphia: Lippincott, Williams & Wilkins, 2000. 6. Brass L. M. Physician’s drug handbook. — 7th ed. — Yale University School of Med., 1999. — 1224 p. 21. Muscholl E. The evolution of experimental pharmacology as a biological science: The pioneering 7. Briggs G. G., Freeman R. K., Yaffe S. J. Drugs work of Bucheim and Schmiedeberg. — Brit J Phar- in Pregnancy and Lactation. — 5th ed. — Baltimore: macol, 1995. — V. 116. — P. 2155-2159. Williams & Wilkins, 1998. 22. Mycek M. J., Harvey R. A., Champe P. C. Lip- 8. Brophy J. M., Joseph L., Rouleau J. L. Beta- pincott’s illustrated reviews: Pharmacology. — 2d ed. blockers in congestive heart failure: A Bayesian meta- — Lippincott Williams & Wilkins, 2000. — 514 p. analysis. — Ann. Intern. Med. — 2001. — V. 134. — 23. Nahata M. C. Variability in clinical pharma- P.: 550-560. cology of drugs in children. J Clin Pharmacol. Ther. 9. Brown B. L., Dobson P. R. Cell Signaling: Bi- 1992. — V. 17. — P. 365-368. ology and Medicine of Signal Transduction. — New 24. Oie S. Drug distribution and binding. J Clin York: Raven, 1993. Pharmacol 1986. — V. 26. — P. 583-586. 10. Burks T. F. Two hundred years of pharmacol- 25. Rochon P., Gurwitz J. H. Drug therapy. — ogy: A midpoint assessment. Proc West Pharmacol Soc, Lancet. — 1995. — V. 346. — P. 32-36. 2000. — V. 43. — P. 95-103. 26. Rowland M., Tozer T. N. Clinical Pharmacok- 11. Craig Charles R., Stitzel Robert E. Modern inetics. — 3rd ed. — Baltimore: Williams & Wilkins, Pharmacology with Clinical Applications. — 6th ed. 1995. — Philadelphia: Lippincott Williams & Wilkins, 2004. 27. Sally S. Rosch Introductory clinical pharma- — 800 p. cology. — 7th edition. — Lippincott Williams & 12. Foreman J. C., Johansen T. Textbook of Re- Wilkins, 2004. — 959 p. ceptor Pharmacology. — Boca Raton, FL: CRC, 28. Schumacher G. E. Therapeutic Drug Monitor- 1995. ing. — Norwalk, CT: Appleton & Lange, 1995. 13. Guarino R. A. (ed). New Drug Approval Proc- 29. Segal M. B. The Barriers and Fluids of the Eye ess. — New York: Dekker, 1992. and Brain. — Boca Raton, FL: CRC, 1989. 14. Haddad L. M., Shannon M. W., Winchester 30. Tillement J. P., Lindenlaub E. (eds). Protein J. F. Clinical Management of Poisoning and Drug Binding and Drug Transport. — New York: Liss, 1987. Overdose. — 3rd ed. — Philadelphia: Saunders, 1998. 31. Trevor A. J., Katzung B. G., Masters S. B. Kat- 15. Hayes A. W. Principles and Methods of Toxi- zung & Trevor’s Pharmacology: Examination and cology. — 4th ed. — Philadelphia: Taylor & Francis, Board Review. — 6th ed. — N.Y.: McGraw-Hill, 2002. 2001. — 662 p.

209 32. Lectures in general pharmacology. — 1st ed. / V. I. 35. Клиническая фармакология и фармакотера- Kresyun, V. V. Godovan, P. V. Antonenko, et al. — Odes- пия / Ю. Б. Белоусов, В. С. Моисеев, В. К. Лепа- sa: Odessa state medical university, 2001. — 325 p. хин. — 2-е изд., испр. и дополн. — М.: Универсум 33. Zhang Y., Benet L. Z. The gut as a barrier to Паблишинг, 1997. — 530 с. drug absorption: combined role of cytochrome P450 36. Машковский М. Д. Лекарственные средства: and P-glycoprotein. — Clin Pharmacokinet. — 2001. В 2-х т. — 15-е изд., новое. — М: ООО «Изд-во Но- — V. 40. — P. 159-168. вая Волна», 2004. 34. Годован В. В., Гайденко А. И. Врачебная ре- 37. Харкевич Д. А. Фармакология: Учебник. — цептура: Руководство для студентов-медиков и вра- 8-е изд., перераб., доп. и испр. — М.: ГЭОТАР- чей. — Одесса: ОДМУ, 2000. — 124 с. МЕД, 2004. — 736 с.

210 LIST OF ABBREVIATIONS

AC — acetylcholine ACE — angiotensin-converting enzyme ACTH — adrenocorticotropin ADH — antidiuretic hormone ADP — adenosine-diphosphate ATP — adenosine-triphosphate ATPase — adenosine triphosphatase AV — atrioventricular BBB — blood-brain barrier BUN — blood urea nitrogen cAMP — cyclic adenosine monophosphate CAT — choline acetyltransferase cGMP — cyclic guanosine-monophosphate CHF — congestive heart failure CNS — central nervous system COMT — catechol O-methyltransferase CSF — cerebrospinal fluid CVS — cardiovascular system DOC — desoxycorticosterone DOCSA — desoxycorticosterone acetate DOPA — dihydroxyphenylalanine ECG — electrocardiogram EDRF — endothelium-derived relaxing factor EPSP — excitatory postsynaptic potential FAD — flavin adenine dinucleotide FMN — flavin mononucleotide FSH — follicle-stimulating hormone G (g) — gram GABA — gamma-aminobutyric acid GI — gastrointestinal GI — gastrointestinal GnRH — gonadotropin-releasing hormone H (h) — hour HDL — high-density lipoproteins HETEs — hydroxyeicosatetraenoic

211 HMG — human menopausal gonadotropins HPETEs — hydroperoxyeicosateraenoic IF — intrinsic factor IM (i.m.) — intramuscular ISA — intrinsic sympathomimetic activity IPSP — inhibitory postsynaptic potential IU — international unites IV (i.v.) — intravenous Las — local anesthetics LH — luteinizing hormone LSD — lysergic acid diethylamide MAC — minimum alveolar concentration MAO — monoamine oxidase MD — moment dose NAD — nicotinamide adenine dinucleotide NADP — nicotinamide adenine dinucleotide phosphate NAPA — n-acetylprocainamide NO — nitric oxide NREM — non-rapid eye movement NSAIDs — nonsteroidal anti-inflammatory drugs PABA — paraaminobenzoic acid PAG — periaqueductal gray PASA — para-aminosalicylate sodium PIH — pregnancy-induced hypertension PRL — prolactin PTH — parathyroid hormone REM — rapid eye movement SA — sinuatrial SC (s.c.) — subcutaneous SH — sulfhydryl SSRI — serotonin-reuptake inhibitors T1/2 — half-life period TCAs — tricyclic antidepressants TSH — thyrotropin VMA — vanillylmandelic acid

212 CONTENTS

PREFACE ...... 7

MEDICAL PRESCRIPTION ...... 8 Lecture 1. Introduction to the medical prescription. Rules of prescription writing ...... 8

COMMON PHARMACOLOGY ...... 15 Lecture 2. Common pharmacology principles ...... 15 Examination questions ...... 21

DRUGS AFFECTING EFFERENT INNERVATION ...... 25 Lecture 3. Cholinergic agonists ...... 27 Lecture 4. Cholinergic antagonists ...... 30 Lecture 5. Adrenergic agonists ...... 35 Lecture 6. Adrenergic antagonists ...... 40 Examination questions ...... 43

DRUGS AFFECTING AFFERENT INNERVATION ...... 47 Lecture 7. Drugs that irritate receptors ...... 47 Lecture 8. Drugs that protect receptors ...... 48 Examination questions ...... 50

DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM ...... 51 Lecture 9. General anaesthetics ...... 51 Lecture 10. Ethyl alcohol (ethanol) ...... 54 Lecture 11. Hypnotic drugs ...... 55 Lecture 12. Anticonvulsants ...... 58 Lecture 13. Nonsteroidal anti-inflammatory drugs ...... 61 Lecture 14. Narcotic analgesics ...... 66 Lecture 15. Neuroleptics ...... 69 Lecture 16. Tranquilizers (anxiolytics) ...... 71 Lecture 17. Psychosedative agents ...... 73 Lecture 18. Antidepressant drugs ...... 73 Lecture 19. Psychostimulants. Nootropic drugs ...... 75 Lecture 20. Analeptics ...... 77 Examination questions ...... 78

213 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM...... 85 Lecture 21. Cardiac glycosides...... 85 Lecture 22. Antianginal drugs ...... 89 Lecture 23. Antiarrhythmic drugs...... 91 Lecture 24. Diuretic drugs ...... 96 Lecture 25. Drugs used in arterial hypertension ...... 101 Lecture 26. Drugs used in hypotension ...... 106 Examination questions ...... 107

DRUGS AFFECTING THE METABOLISM ...... 113 Lecture 27. Drugs affecting the endocrine system ...... 113 Lecture 28. Vitamins ...... 122 Lecture 29. Enzyme preparations and enzyme inhibitors ...... 127 Examination questions ...... 128

DRUGS INFLUENCING THE BLOOD SYSTEM ...... 133 Lecture 30. Drugs influencing the erythropoiesis ...... 133 Lecture 31. Blood substitutes...... 135 Lecture 32. Drugs used in disorders of coagulation ...... 137 Lecture 33. Immunotropic agents ...... 141 Examination questions ...... 146

ANTIMICROBIAL, ANTIPROTOZOAL AND ANTIVIRAL DRUGS...... 148 Lecture 34. Disinfectants and antiseptics...... 148 Lecture 35. Antibiotics ...... 152 Lecture 36. Sulfanilamides ...... 162 Lecture 37. Antimicrobials — derivatives of different groups ...... 164 Lecture 38. Antituberculosis drugs ...... 166 Lecture 39. Antisyphilitic agents ...... 168 Lecture 40. Antiprotozoal drugs ...... 168 Lecture 41. Antihelmintic drugs ...... 171 Lecture 42. Antifungal agents ...... 173 Lecture 43. Antiviral agents ...... 174 Examination questions ...... 176

DRUGS USED FOR PHARMACOTHERAPY OF DISEASES OF SPECIAL SYSTEMS...... 187 Lecture 44. Drugs used in gastrointestinal diseases ...... 187 Lecture 45. Drugs used in respiratory diseases ...... 191 Lecture 46. Drugs influencing the contractile activity of uterus ...... 195 Lecture 47. Basic actions and medications used in intoxications and emergency states ...... 197 Examination questions ...... 200

APPENDIX A ...... 202 APPENDIX B ...... 204 REFERENCES ...... 209 LIST OF ABBREVIATION ...... 211

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