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THE STATE BUDEGET EDUCATIONAL ESTABLISHMENT OF THE HIGHER PROFESSIONAL EDUCATION «THE STAVROPOL STATE MEDICAL UNIVERSITY» OF THE MINISTRY OF HEALTH OF RUSSION FEDERATION

E.V.BEYER A.V.POPOV

GENERAL PHARMACOLOGY ACTING ON NERVOUS SYSTEM

Stavropol 2013 2

ГОСУДАРСТВЕННОЕ БЮДЖЕТНОЕ ОБРАЗОВАТЕЛЬНОЕ УЧРЕЖДЕНИЕ ВЫСШЕГО ПРОФЕССИОНАЛЬНОГО ОБРАЗОВАНИЯ «СТАВРОПОЛЬСКИЙ ГОСУДАРСТВЕННЫЙ МЕДИЦИНСКИЙ УНИВЕРСИТЕТ» МИНИСТЕРСТВА ЗДРАВООХРАНЕНИЯ РОССИЙСКОЙ ФЕДЕРАЦИИ

Э.В. Бейер А.В. Попов

УЧЕБНОЕ ПОСОБИЕ

ОБЩАЯ ФАРМАКОЛОГИЯ ВЕЩЕСТВА, ВЛИЯЮЩИЕ НА НЕРВНУЮ СИСТЕМУ

Ставрополь 2013 3

УДК 615.015 : 616.8 (07.07) ББК 52. 817 я73 Б 41

E.V.BEYER, A.V.POPOV. General Pharmacology. Drugs Acting on Nerv- ous System. The manual for foreign students of General Medicine and Dentistry in the English-speaking Medium. Stavropol: StGMU. – 2013. – 94 p.

The manual contains the basic data about General Pharmacology, Drugs Acting on Nervous System. The special attention is given to Principles of Prescription Order Writing. Topics for discussion, tasks for writing out the prescriptions, self-checking question, tests, and other reference information are included into the manual.Tasks to practical works are composed taking into consideration professional interests of med- ical students. The manual is intended for foreign students of General Medicine and Dentistry of the English-speaking Medium.

V.A. Baturin, D.M.S., Professor, the Head of Clinical Pharmacology, allergology and immunology Department of the Stavropol State Medical University. S.V. Znamenskaya, C.P.S., Associate Professor, Dean of the Foreign Students’ Faculty, the Head of Latin and Foreign Languages Department of the Stavropol State Medical University E.A. Manvelyan E.A., professor of department of medical biochemistry of North Caucasian State University.

УДК 615.015 : 616.8 (07.07). ББК 52. 817 я73 Б 41

Recommended for publication by the Cycle methodical committee for education of the foreign students of the Stavropol State Medical University

Recommended for publication by the Publishing council of the Stavropol State Medical University

© Stavropol State Medical University, 2013 4

УДК 615.015 : 616.8 (07.07) ББК 52. 817 я73 Б 41

E.В.Бейер, A.В. Попов. Общая фармакология. Лекарства, действую- щие на нервную систему. Учебное пособие для иностранных студентов специ- альностей «Лечебное дело» и «Стоматология» англоязычного отделения. Став- рополь: Изд-во СтГМУ.– 2013. – 90 с.

Учебное пособие содержит основные данные об общей фармакологии, о лекарствах, действующих на нервную систему. Особое внимание обращено на правила выписывания рецептов. Темы для дискуссии, задания для выписывания рецептов, вопросы для самоконтроля, тесты и другая справочная информация включены в учебное пособие. Задания для практической работы составлены с учетом профессиональных интересов студентов-медиков.

Рецензенты: В.А. Батурин, д.м.н., профессор, заведующий кафедрой клинической фар- макологии, аллергологии и иммунологии с курсом ПДО Ставропольского госу- дарственного медицинского университета. С.В. Знаменская, к.п.н., декан факультета иностранных студентов, заве- дующая кафедрой иностранных языков Ставропольского государственного ме- дицинского университета. Э.А. Манвелян, доктор фармацевтических наук, профессор кафедры ме- дицинской биохимии, клинической лабораторной диагностики и фармации ФГАОУ «Северо-Кавказский федеральный университет»

УДК 615.015 : 616.8 (07.07) ББК 52. 817 я73 Б 41

Рекомендовано к печати Цикловой методической комиссией Ставропольского государственного медицинского университета по обучению иностранных студентов

Рекомендовано к печати редакционно-издательским советом Ставропольского государственного медицинского университета

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Ставропольский государственный медицинский университет, 2013 Contents

UNIT 1. SOLID MEDICINAL FORMS ………………………………………..……5 UNIT 2. LIQUID MEDICINAL FORMS………………………………………….....9 UNIT 3. SOFT MEDICINAL FORMS……………………………………………...12 UNIT 4. GENERAL PHARMACOLOGY………………………………………….14 UNIT 5. TEST LESSON…………………………………………………………….23 UNIT 6. LOCAL ANESTHETICS………………………………………………….26 UNIT 7. DRUGS. CHOLINOCEPTOR . ANTICHOLINESTERASES…………………………………………………….…..31 UNIT 8. CHOLINOCEPTOR ANTAGONISTS. GANGLIONIC BLOCKERS NEUROMUSCULAR BLOCKING DRUGS……………………………………….37 UNIT 9. DRUGS AFFECTING THE SYMPATHETIC NERVOUS SYSTEM……44 UNIT 10. TEST LESSON. DRUGS ACTING ON AUTONOMIC NERVOUS SYSTEM…………………………………………………………………………….53 UNIT 11. GENERAL ANESTHETICS. -. …56 UNIT 12. ANALGESICS. ANTIEPILEPTIC DRUGS. ANTIPARKINSONIAN DRUGS…………………………………………………...63 UNIT 13. NEUROLEPTICS, ……………………………………..71 UNIT 14. DRUGS…………………………………………...78 UNIT 15. CNS . COGNITION ENHANCERS DRUGS (NOOTROPIC DRUGS)…………………………………………………………….84 UNIT 16. TEST LESSON. DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM…………………………………………………………………………….89

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Principles of Prescription Order Writing

UNIT 1. SOLID MEDICINAL FORMS

Pharmacology – is the study of drugs and their effects on life processes. A can be defined as a natural product, chemical substance, or pharmaceu- tical preparation intended for administration to a human or animal to diagnose or treat a disease. Pharmacology includes two parts: general pharmacology and particular phar- macology. The unit of general pharmacology is prescription order writing. Prescriptions are written by the prescriber to instruct the pharmacist to dispense a specific medication for a specific patient. Prescriptions contain the following elements to facilitate interpretation by the pharmacist: - Physician's name, address, and office telephone number - Date - Patient's name and address - Superscription (Rx how drug is to be taken) - Inscription (name and dosage of drug) - Subscription (directions to the pharmacist) - Signature or transcription (directions to the patient) - Refill and safety cap information - Prescriber's (physician's) signature - DEA number of physician required for controlled substances

Typical prescription form 7

There are three medical forms: solid medicinal forms, liquid medicinal forms and soft medicinal forms. The solid medicinal forms: powder (pulvis, ĕris m), tablet (tabuletta, ae f), dragee (dragee).

Powder (pulvis, ĕris m) Powder (pulvis, ĕris m) – a solid medicinal form intended for internal and exter- nal use. There are: simple powder, complex powder, dosed out powder, not dosed out powder.

Write out in prescription: 30,0 of Talc (Talcum). Take on the sites of a skin. Rp.: Talci 30,0 D.S. Take on the sites of a skin. (Give out. Indicate)

A simple powder. Not dosed out powder.

Write out in prescription: 30,0 of powder which consist of 5,0 of Anaesthesine (Anaesthesinum) and talc powder (25,0) (Talcum). Take on the sites of a skin. Rp.: Anaesthesini 5,0 Talci 25,0 M.f.pulv. (Mix, so that there is powder) D.S. Take on the sites of a skin A complex powder. Not dosed out powder.

Powders for internal application 8

Write out in prescription: 30 powders Analgine (Analginum) 0,5. Take 1 powder 3 times a day. Rp.: Analgini 0,5 D.t.d.N.30 (Give out such doses in the amount of) S. Take 1 powder 3 times a day. A simple powder. Dosed out powder.

Write out in prescription: 10 powders of Platyphylline hydrotartrate (Platyphyllini hydrotartras) 0,03 and Sodium (Natrii bromidum) 0,15. Take 1 powder 3 times a day. Rp.: Platyphyllini hydrotartratis 0,03 Natrii bromidi 0,15 M.f.pulv. D.t.d.N.12 S. Take 1 powder 3 times a day. A complex powder. Dosed out powder.

Capsule, gelatin capsule (capsula, ae f, c. gelatinosa) – solid dosed medicinal form in the form of coated drugs (coated with gelatin, starch or capsule another bi- opolymer); intended for internal use. Write out in prescription: 10 oleandomycin powders (Oleandomycinum) 0,25 in gel- atin capsules. Take 1 capsule 4 times a day. Rp.: Oleandomycini 0,2 D.t.d.N.20 in caps.gelat. (Give out such doses in the amount of 20 in gelatin capsules) S. Take 1 capsule 4 times a day.

Tablet (tabuletta, ae f) Tablet (tabuletta, ae f) a solid dosed medicinal form obtained by pressing the medicinal substance or a mixture of medicinal and accessory substances: intended for internal use. Write out in prescription: Analgin (Analginum) (each dose 0,5 g) tablets in the amount of 10. Take 1 tablet for the night. Rp.: Tab. (Tabulettam) Аnalgini 0,5 N(numero)10 D.S. 1 tablet every night at bedtime. A simple tablet.

Some of combination tablets are often given a generic name written in inverted commas: tabulettae «Codterpinum». 9

Write out in prescription: 10 tablets of «Codterpinum». Take 1 tablet 2 times a day. Rp.: Tab. «Codterpinum» N.10 D.S. Take 1 tablet 2 times a day.

Dragee (dragee) Dragee (dragee) – a solid dosed medicinal form obtained by layering medicinal and accessory substances on granules; Write out in prescription: «Revit» dragee in the amount of 50. Prescribe 1 dragee 2 times a day. Rp.: Dragee «Revit» D.t.d.N.50 S. Take 1 dragee 2 times a day.

Write out in prescription:

1. 100,0 of Urodanum. Take 1 teaspoon 3 times a day dissolved in 1 glass of water. 2. 20 powders of Pancreatinum 0,5. Take 1 powder 3 times a day. 3. 50 powders of Natrii para-aminosalicylas 1,0. Take 3 powders 3 times a day. 5. 20 powders containing 0,1 of Riboflavinum and 0,2 of Thiamini bromidum. Take 1 powder 3 times a day. 6. 15 powders containing 0,3 of Rutinum and 0,05 of Acidum ascorbinicum. Take 1 powder 3 times a day. 7. 10 powders Oxacyllinum-natrium 0,25 in gelatinous capsules. Take 1 capsule 4 times a day. 8. 50 tablets of Dexamethasonum 0,0005. Take 1 tablet 3 times a day. 9. 10 tablets of Phenolphtaleinum 0,1. Take 1 tablet every night at bedtime. 10. 10 tablets of Nitroglycerinum 0,0005. 1 tablet under tongue at attacks. 11. 20 tablets of Oxaphenamidum 0,25.Take 1 tablet 3 times a day before meal. 12. 20 tablets of Digitoxinum 0,0001. Take 1 tablet once a day 13. 40 tablets of Chinidini sulfas 0,05. Take a tablet 3 times a day 30 minutes prior to meal. 14. 20 tablets of «Theophedrinum». Take 1 tablet 3 times a day. 15. 100 tablets of «Vicalinum». Take 1 tablet 3 times a day. 16. 20 dragee containing 0,05 of Aminazinum. 1 dragee 2 times a day. 17. 20 dragee containing 0,025 of Diazolinum. 1 dragee 2 times a day.

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UNIT 2. LIQUID MEDICINAL FORMS There are: solution (solutio, ōnis f), suspension (suspensio, ōnis f), emulsion (emulsum, i n), infusion (infusum, i n), decoction (decoctum, i n), tincture (tinctura, ae f) extract (extractum, i n), mixture (mixtura, ae f)

Solution (solutio, ōnis f) Solution (solutio, ōnis f) is a homogeneous mixture composed of two or more substances. In such a mixture, a solute is dissolved in another substance, known as a solvent. A common example is a solid such as salt or sugar, dissolved in water. Solu- tion (solutio, ōnis f) – a liquid medicinal form obtained by dissolving one or more medicinal substances; intended for internal or external use or injections. A solvent is a liquid that dissolves a solid. In medicine, distilled water (aqua destillata), ethyl (spiritus, us m, aethylicus, a, um), glycerin (glycerinum) and liquid oils (such as – Oleum Vaselini, Oleum Olivarum, Oleum Persicorum) are used as a solvents. Therefore there are water, alcohol, glycerin and oil solutions. In prescribing water solutions the solvent (water) is not indicated. Drug concentration in solution is described in percentage, gramme and mass- volume ratio. Concentration is the measure of how much of a given substance there is mixed with another substance. Percentage solutions A percentage is a way of expressing a number as a fraction of 100 (per cent meaning "per hundred"). It is often denoted using the percent sign, "%". For example, 45 % (read as "forty-five percent"). Percentages are used to express how large one quantity is relative to another quantity. The first quantity usually represents a part of, or a change in, the second quantity. Percentage solutions. A 1% solution would have 1 g of solute dissolved in a final volume of 100 ml of solution. Write out in prescription: 20 ml of 0.1 % solution Еphedrini hydrochloridum. 5 drops into nose every 4 hours. Rp.: Sol. Еphedrini hydrochloridi 0.1 % -20 ml D.S. 5 drops into nose every 4 hours.

In prescribing oil solutions the solvent is indicated. Write out in prescription: 100 ml of 20 % Camphora oil solution. Take for massage. Rp.: Sol. Camphorae oleosae 20%-100ml. D.S. Take for massage

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Solutions for internal use They are doses by spoon (tablespoon, teaspoon) and drops. The volume of table spoon is 15 ml and tea spoon is 5 ml. There are 20 drops in 1 ml of water solution.

Write out in prescription: 100 ml of 10 % Calcii chloridum solution. Take 1 table- spoon 3 times a day. Rp.: Sol. Calcii chloridi 10% - 100ml. D.S. Take 1 tablespoon 3 times a day.

Solutions for injection An injection is a method of putting liquid into the body with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body. An injection follows a parenteral route of administration, that is, its effect is not necessarily local to the area in which the injection is administered; it is systemic. Solutions for injections are liquid sterility drug form intended for parenteral use. Most of them are produced by in ampoules and bottles. Write out in prescription: 10 ampoules containing 1 ml of 50 % Analginum solution. Take 1 ml intramuscularly once a day. Rр.: Sol. Аnalgini 50%-1 ml D.t.d. N 6 in ampull. S. Take 1 ml intramuscularly once a day. Write out in prescription: 10 ampoules containing 1 ml of 0.5 % Synoestrolum oil solution. Take 1 ml intramuscularly once a day. Rp.: Sol. Synoestroli oleosae 0,5%-1ml D.t.d.N. 10 in amp. S. Take 1 ml intramuscularly once a day.

Infusion An infusion is water in which plants with a desired flavour have been steeped. Medicinal raw materials are: flower (flos, floris m), leaf (folium, i n), fruit (fructus, us m), herb (herba, ae f), berries. Herbs or other plants can be placed in boiling water for a few minutes, and then discarded, and the water is drunk as a beverage. A common example is tea. Many other drinks, often called herbal teas, although they may contain no tealeaves, are prepared in this way. Lemon, , senna, apple, ginger, and a great many other plants are used individually or in combination. Infusions of this type are sometimes drunk for pleasure; others are claimed to be advantageous for health. Infusions are prepared with ratio 1:30 (1 part of medical plant infused in 30 parts of water). Infusions are prepared extemporaneous. Herbs, or 12 flowers or berries, infused in water (which does not need to be boiled) for about ten minutes and strained. Write out in prescription: 180 ml infusion of herb Adonidis vernalis 6,0. Take 1 ta- blespoon 2 times a day. Rp.: Inf. herbae Adonidis vernalis 6,0-180ml. D.S. Take 1 tablespoon 2 times a day. Decoction A decoction is a method of extraction of plant material, which includes, but is not limited to: (leaves, flowers, roots, bark, and rhizomes). Some teas would be considered a decoction. Decoctions, however, differ from most teas, infusions, because decoctions are usually boiled. Decoction involves first mashing, and then boiled in water to extract oils, volatile organic compounds. Decoctions are prepared with ratio 1:10; 1:20.

Write out in prescription: 200 ml decoction of 20,0 of Querqus bark. Take for oral rinsing. Rp.: Dec. corticis Quercus 20,0-200ml D.S. Take for oral rinsing. Tincture In medicine, a tincture (tinctura, ae f) is an alcoholic extract (e.g. of a herb) or solution of a non-volatile substance. Write out in prescription: 25 ml of tincture. Take 25 drops in 1 dose. Rp.: Tinct. Valerianae 25 ml D.S. Take 25 drops in 1 dose. Suspensions Suspension (suspensio, ōnis) is a fluid medicinal form in the form of a disper- sion system where a solid substance is suspended in fluid; intended for internal or ex- ternal use or injections. An example of a suspension would be sand in water.

Write out in prescription: 100 ml of Oletetrinum suspension. Take on 2 teaspoons 4 times a day. Rp.: Suspensionis Oletetrini 100 ml D.S. Take 2 teaspoons 4 times a day.

Write out in prescription 1. 20 ml of 5 % Еphedrini hydrochloridum solution. 5 drops into nose for every 4 hours. 13

2. 10 ml of 1 % Pilocarpini hydrochloridum solution. Eye drops. 2 drops 2 times a day. 3. 10 ml of 0.1 % Atropini sulfas solution. Take 5 drops 3 times a day. 4. 200 ml of 10 % Potassii chloridum solution. Take 1 table spoon 3 times a day. 5. 15 ml of 1 % Mentholum oil solution. 5 drops into nose. 6. 10 ml of 0.5 % Hydrocortisoni acetas suspension. Eye drops. 1-2 drops for every 4 hours. 7. 100 ml of Oletetrinum suspension. Take 2 tea spoons 4 times a day. 8. 200 ml of decoction from 20.0 of cortex Frangulae. Take table spoon for the night. 9. 25 ml of Valeriana tincture. Take 25 drops in 1 dose. 10. 10 ml of Belladonna tincture. Take 10 drops 2 times a day. 11. 15 ml of Lantosidum. Take 15 drops 3 times a day. 12. 15 ml of Adonisidum. Take 15 drops 2-3 times a day. 13. 10 ampoules containing 1 ml of 0.1 % Atropini sulfas solution. For hypodermic insertion by 1 ml. 14. 20 ampoules containing 1 ml of 0.1 % Synoestrolum oil solution. Take 1 ml in- tramuscularly once a day. 15. 10 ampoules containing 1 ml of 2 % solution of Promedolum. Take 1 ml intra- muscularly once a day. 16. 5 ml sterile 2 % Novocain solution. For anesthesias. 17. 20 ampoules containing 0.005 of Trypsinum crystallisatum. Contents of an am- poule to dissolve in 2-3 ml of isotoinic solution. For inhalations. 18. 10 bottles containing 0.1 of Lydasum. Before the use contents of a bottle to dis- solve in 1 ml of sterile 0.5 % Novocain solution, for intramuscular injection. 19. Mixture, 180 ml of extract which structure includes herba Thermopsidis 1: 400 and 0.2 of Codeini phosphas. Take 1 table spoon 3 times a day. 20. The mixture consisting of 180 ml of 2 % solution and Coffeinum-natrii benzoas 1.2. Take 1 table spoon 3 times a day.

UNIT 3. SOFT MEDICINAL FORMS

There are: Unguent, ointment (unguentum, i n), paste (pasta, ae f) and suppos- itory (suppositorium, i n). Unguent, ointment (unguentum, i n) – soft medicinal form of viscous consist- ence. Ointments are received by mixing various medicinal substances (Lat. basis) with form-building substances (constituens). As basis, substances or the mixes of substances possessing high smearing ability and well mixing up, but not reacting with medicinal substances and not changing the properties under influence of light and air 14 are usually used. Some products of oil refining (Vaseline), animal fats, waxes (lano- lin) and synthetic substances correspond to these specified requirements. Ointments, as a rule, are not dosed out like medicinal forms, therefore in reci- pes them write out in total. Ointments may be simple or complex. Simple ointments consist only of two components (basis and constituens). Complex ointments contain more than two components in their structure. Write out in prescription: 50,0 of 5 % Anaesthesini ointment. Apply twice- daily to affected skin. Rp.: Ung. Anaesthesini 5% - 50,0 D.S. Apply twice-daily to affected skin.

Paste (pasta, aef) is version of ointment which contains powdery substances more than 25 %. The quantity of a powder does not exceed 65 %. At a body temperature paste are softened. Pastes are kept on a skin longer time then ointments. They possess adsorbing and drying properties. Pastes are not dosed out like medicinal forms. They write out in total. Write out in prescription: 50,0 of Zinci oxydi paste. Apply to affected skin. Rp.: Pastae Zinci oxydi 50,0 D.S. Apply to affected skin.

Suppository (suppositorium, i n) is a medicinal form which is solid at room temper- ature and expands or dissolves at body temperature; it is introduced into the body cavity. This medicinal form is inserted either into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository) where it dissolves. Suppositories are used to deliver both systemically-acting and locally-acting medications. Write out in prescription: 10 «Bethiolum» suppositories. Take 1 suppository twice-daily into the rectum. Rp.: Supp. «Bethiolum» N. 10. D.S. Take 1 suppository twice-daily into the rectum.

Write out in prescription: 1. 50.0 of 0.5 % Neomycinum sulfas ointment. For applying on the affected area of the skin. 2. 10.0 of 1 % Tetracycline hydrochloridum ointment. To apply on the affected area of the skin. 3. 10.0 of Nystatinum ointment. To apply on the affected area of the skin. 4. 10.0 of Erythromycinum ointment. On the skin. 15

5. 25.0 of Heparinum ointment. To apply on the affected area of the skin. 6. 50,0 of Zinci oxydi paste. Apply to affected skin. 7. 20 rectal suppositories “Bethiolum”. 1 suppository 2 times a day per rectum. 8.12 rectal suppositories “Neoanusolum”. 1 suppository 2 times a day per rectum.

UNIT 4. GENERAL PHARMACOLOGY

General pharmacology is divided into two main subdivisions, pharmacoki- netics and .

TOPICS TO DISCUSS 1. Pharmacokinetics. Definition. 2. Mechanisms of drug penetration through membranes. Dependence of a drug penetration on their lipid-solubility. Penetration of weak acids and bases through cell membranes (dependence on the pH of the medium and the pKa). 3. Routes of drug administration. The main characteristics. 4. Drug absorption. Dependence of drug absorption on routes of administration. The main mechanisms of drug absorption after oral, intramuscular and subcu- taneous administrations. 5. Bioavailability. Factors that influence bioavailability after oral administration. First-pass effect. 6. Distribution of drugs in the body. Penetration through the blood-brain barrier. 7. Accumulation of drugs in the body. Binding of drugs to plasma proteins. 8. Apparent volume of distribution: definition, dependence on drug concentration in body fluids. 9. Drug biotransformation (metabolism). Phase I and phase II reactions. The main changes in the properties of drugs (lipophilicity, hydrophilicity, activity, toxici- ty) caused by their metabolism. 10. Excretion of drugs. Routes of excretion. 11. The main pharmacokinetic parameters characterizing drug elimination: the rate constant for drug elimination, half-life, clearance. 12. Pharmacodynamics. Definition (pharmacological effects, mechanisms of drug action, localization of drug action). 13. The main molecular targets for drug action. 14. Specific receptors: the main properties and functions. Membrane and intracel- lular receptors. Division of membrane receptors according to transduction mechanism. Characteristics and examples of each receptor type. 15. Drug-receptor binding (types of bonds, reversible and irreversible binding). Affinity. 16

16. Intrinsic activity. Agonists (full, partial). Antagonists. 17. Graded dose-response curve. Efficacy. Potency. The characteristics of efficacy and potency: Emax and ED50. 18. Combined drug administration (synergism, potentiation, additive effect, antag- onism). Pharmacological antagonism (competitive and noncompetitive antago- nism). 19. Tolerance. The mechanisms of tolerance: de-sensitization of receptors, loss of receptors, depletion of , etc. 20. Drug dependence (definition, types and characteristics of drug dependence). 21. Adverse and toxic effects of drugs. 22. Drug allergy. Idiosyncrasy. 23. Mutagenicity, carcinogenicity, teratogenicity of drug. Background information Pharmacokinetics is the fate of drugs within the body. Pharmacokinetics involves absorption, distribution, metabolism, and excretion (ADME) of drugs. Absorption – the process of getting a drug from its site of delivery into the blood- stream. The main mechanisms of penetration across membranes include: passive dif- fusion, active transport, facilitated diffusion, pinocytosis. Most drugs move down their concentration gradients from an area of high con- centration to an area with a lower drug concentration. This movement, called passive diffusion, requires no energy expenditure but depends on the size (molecular weight) of the drug and the lipid solubility of the drug. Most drugs cross biologic barriers by passive diffusion. For drugs that are absorbed by passive diffusion, the lipid solubility of the drug is a key determinant for predicting how well the drug will be absorbed. Drugs that are lipid soluble easily pass through the lipid bilayer of cell walls. On the other hand, a few drugs cross biologic barriers using active transport mechanisms. In this case, the drug moves "uphill" against its concentration gradient – from an area of low concentration to an area with higher concentration. This type of transport requires energy expenditure, typically ATP. Some ions, vitamins, and ami- no acids are absorbed in this way. Pharmacodynamics is the study of the detailed mechanism of action by which drugs produce their pharmacological effects. This study starts at the binding of a drug to its target receptor or enzyme, continues through a signal transduction pathway by which the receptor activates second messenger molecules, and ends with the ultimate description of intracellular processes altered by the impact of the drug. There is also a quantitative aspect to pharmacodynamics in characterizing the dose- response curve, which is the relationship between drug dose and the magnitude of the pharmacological effect. Pharmacodynamics provides a scientific basis for the se- 17 lection and use of drugs to counteract specific pathophysiologic changes due to dis- ease or trauma.

CHOOSE THE MOST APPROPRIATE RESPONSE 1. Essential drugs are: A. Life saving drugs B. Drugs that meet the priority health care needs of the population C. Drugs that must be present in the emergency bag of a doctor D. Drugs that are listed in the pharmacopoia of a country 2. An orphan drug is: A. A very cheap drug B. A drug which has no therapeutic use C. A drug needed for treatment or prevention of a rare disease D. A drug which acts on Orphanin receptors 3. Drug administered through the following route is most likely to be subjected to first-pass metabolism: A. Oral B. Sublingual C. Subcutaneous D. Rectal 4. Transdermal drug delivery systems offer the following advantages except: A. They produce high peak plasma concentration of the drug B. They produce smooth and noniluctuating plasma concentration of the drug C. They minimize interindividual variations in the achieved plasma drug concentration D. They avoid hepatic first-pass metabolism of the drug 5. In addition to slow intravenous infusion, this of the following routes of admin- istration allows for titration of the dose of a drug with the response: A. Sublingual B. Transdermal C. Inhalational D. Nasal insufflation 6. Compared to subcutaneous injection, the intramuscular injection of drugs: A. Is more painful B. Produces faster response C. Is unsuitable for depot preparations D. Carries greater risk of anaphylactic reaction 18

7. Select the route of administration which carries the highest risk of adversely af- fecting vital functions: A. Transdermal B. Intrathecal injection C. Intravenous injection D. Intramuscular injection 8. Alkalinization of urine hastens the excretion of: A. Weakly basic drugs B. Weakly acidic drugs C. Strong electrolytes D. Nonpolar drugs 9. Majority of drugs crosses biological membranes primarily by: A. Passive diffusion B. Facilitated diffusion C. Active transport D. Pinocytosis 10. Diffusion of drugs across cell membrane: A. Is dependent upon metabolic activity of the cell B. Is competitively inhibited by chemically related drugs C. Is affected by extent of ionization of drug molecules D. Exhibits saturation kinetics 11. The most important factor which governs diffusion of drugs across capillaries other than those in the brain is: A. Blood flow through the capillary B. Lipid solubility of the drug C. pKa value of the drug D. pH of the medium 12. Active transport of a substance across biological membranes has the following characteristics except: A. It is specific B. It is pH dependent C. It is saturable D. It requires metabolic energy 13. Bioavailability of drug refers to: A. Percentage of administered dose that reaches systemic circulation in the unchanged form B. Ratio of oral to parenteral dose C. Ratio of orally administered drug to that excreted in the faeces 19

D. Ratio of drug excreted unchanged in urine to that excreted as metabo- lites 14. The most important factor governing absorption of a drug from intact skin is: A. Molecular weight of the drug B. Site of application C. Lipid solubility of the drug D. Nature of the base used in the formulation 15. The following attribute of a drug tends to reduce its volume of distribution: A. High lipid solubility B. Low ionisation at physiological pH values C. High plasma protein binding D. High tissue binding 16. Marked redistribution is a feature of: A. Highly lipid soluble drugs B. Poorly lipid soluble drugs C. Depot preparations D. Highly plasma protein bound drugs 17. The blood-brain barrier, which restricts entry of many drugs into brain, is consti- tuted by: A. P-glycoprotein efflux carriers in brain capillary cells B. Tight junctions between endothelial cells of brain capillaries C. Enzymes present in brain capillary walls D. All of the above 18. Which of the following is not true of the blood-brain barrier: A. It is constituted by tight junctions between the endothelial cells of brain capillaries and the glial tissue B. It allows passage of lipid soluble drugs into the brain C. It limits entry of highly ionized drugs into the brain D. It regulates passage of substances from brain into blood 19. Weakly acidic drugs:

A. Are bound primarily to a: acid glycoprotein in plasma B. Are excreted faster in alkaline urine C. Are highly ionized in the gastric juice D. Do not cross blood-brain barrier 20. High plasma protein binding: A. Increases volume of distribution of the drug B. Facilitates glomerular filtration of the drug C. Minimises drug interactions D. Generally makes the drug long acting 20

21. The plasma protein bound fraction of a drug: A. Contributes to the response at the given moment B. Remains constant irrespective of the total drug concentration C. Remains constant irrespective of the disease state D. Is not available for metabolism unless actively extracted by the liver 22. Biotransformation of drugs is primarily directed to: A. Activate the drug B. Inactivate the drug C. Convert lipid soluble drugs into nonlipid soluble metabolites D. Convert nonlipid soluble drugs into lipid soluble metabolites 23. A prodrug is: A. The prototype member of a class of drugs B. The oldest member of a class of drugs C. An inactive drug that is transformed in the body to an active me- tabolite D. A drug that is stored in body tissues and is then gradually released in the cir- culation 24. The most commonly occurring conjugation reaction for drugs and their metabolites is: A. Glucuronidation B. Acetylation C. Methylation D. Glutathione conjugation 25. Microsomal enzyme induction can be a cause of: A. Tolerance B. C. Psychological dependence D. Idiosyncrasy 26. Which of the following types of drug metabolizing enzymes are inducible: A. Microsomal enzymes B. Nonmicrosomal enzymes C. Both microsomal and nonmicrosomal enzymes D. Mitochondiial enzymes 27. Induction of drug metabolizing enzymes involves: A. A conformational change in the enzyme protein to favour binding of sub- strate molecules B. Expression of enzyme molecules on the surface of hepatocytes C. Enhanced transport of substrate molecules into hepatocytes D. Increased synthesis of enzyme protein 21

28. Drugs which undergo high degree of first-pass metabolism in liver: A. Have low oral bioavailability B. Are excreted primarily in bile C. Are contraindicated in liver disease D. Exhibit zero order kinetics of elimination 29. Glomerular filtration of a drug is affected by its: A. Lipid solubility B. Plasma protein binding C. Degree of ionization D. Rate of tubular secretion 30. Which of the following is not a primary/fundamental, but a derived pharma- cokinetic parameter: A. Bioavailability B. Volume of distribution C. Clearance D. Plasma half life 31. The loading dose of a drug is governed by its: A. Renal clearance B. Plasma half life C. Volume of distribution D. Elimination rate constant 32. What is true in relation to drug receptors: A. All drugs act through specific receptors B. All drug receptors are located on the surface of the target cells C. Agonists induce a conformational change in the receptor D. Partial agonists have low affinity for the receptor 33. Drugs acting through receptors exhibit the following features except. A. Structural specificity B. High potency C. Competitive antagonism D. Dependence of action on lipophilicity 34. Study of drug-receptor interaction has now shown that: A. Maximal response occurs only when all receptors are occupied by the drug B. Drugs exert an ‘all or none’ action on a receptor C. Receptor and drugs acting on it have rigid complementary ‘lock and key’ structural features D. Properties of «affinity» and «intrinsic activity» are independently variable 35. A partial can antagonist the effects of a full agonist because it has: A. High affinity but low intrinsic activity 22

B. Low affinity but high intrinsic activity C. No affinity and low intrinsic activity D. High affinity but no intrinsic activity 36. Agonists affect the receptor molecule in the following manner: A. Alter its sequence B. Denature the receptor protein C. Alter its folding or alignment of subunits D. Induce covalent bond formation 37. Receptors perform the following function/functions: A. Ligand recognition B. Signal transduction C. Both ligand recognition and signal transduction D. Disposal of agonists and antagonists 38. All of the following subserve as intracellular second messengers in receptor me- diated signal transduction except: A. Cyclic AMP B. Inositol trisphosphate C. Diacyl glycerols D. G proteins 39. The receptor transduction mechanism with the fastest time-course of response ef- fectuation is: A. Adenylyl cyclase-cyclic AMP pathway

B. Phospholipase C-IP3: DAG pathway C. Intrinsic ion channel operation D. Protein synthesis modulation 40. Down regulation of receptors can occur as a consequence of: A. Continuous use of agonists B. Continuous use of antagonists C. Chronic use of CNS D. Denervation 41. When therapeutic effects decline both below and above a narrow range of doses, a drug is said to exhibit: A. Ceiling effect B. Desensitization C. Therapeutic window phenomenon D. Nonreceptor mediated action 42. 'Drug efficacy' refers to: A. The range of diseases in which the drug is beneficial 23

B. The maximal intensity of response that can be produced by the drug C. The dose of the drug needed to produce half maximal effect D. The dose of the drug needed to produce therapeutic effect 43. Which of the following is always true: A. A more potent drug is more efficacious B. A more potent drug is safer C. A more potent drug is clinically superior D. A more potent drug can produce the same response at lower dos- es 44. Interindividual variations in equieffective doses of a drug are most marked if it is disposed by: A. Glomerular filtration B. Tubular secretion C. Both glomerular filtration and tubular secretion D. Hepatic metabolism 45. The pharmacokinetics of drugs in the neonate differs from that in adults, because their: A. Intestinal transit is fast B. Drug metabolizing enzymes are overactive C. Tubular transport mechanisms are not well developed D. Glomerular filtration rate is high 46. An undesirable effect of a drug that occurs at therapeutic doses and can be pre- dicted from its pharmacological actions is called: A. Side effect B. Toxic effect C. Allergic reaction D. Idiosyncrasy 47. Which of the following is a type B (unpredictable) adverse drug reaction: A. Side effect B. Toxic effect C. Idiosyncrasy D. Physical dependence 48. A 'toxic effect' differs from a 'side effect' in that: A. It is not a pharmacological effect of the drug B. It is a more intense pharmacological effect that occurs at high dose or after prolonged medication C. It must involve drug induced cellular injury D. It involves host defense mechanisms 24

49. The following statement is true in relation to 'drug toxicity' and 'poisoning': A. The two terms are synonymous B. When a toxic effect requires specific treat ment, it is called poisoning C. A toxic effect which endangers life by markedly affecting vital functions is called poisoning D. Toxicity is caused by drugs while poisoning is caused by other harmful chemi- cals 50. An immunologically mediated reaction to a drug producing stereotyped symptoms unrelated to its pharmacodynamic actions is: A. Hypersensitivity B. Supersensitivlty C. Intolerance D. Idiosyncrasy 51. Drugs producing allergic reactions generally act as: A. Complete antigens B. Haptenes C. Antibodies D. Mediators 52. The following allergic drug reaction is caused by circulating antibodies: A. Serum sickness B. Anaphylactic shock C. Systemic lupus erythematosus D. Angioedema 53. The essential feature in drug addiction is: A. Physical dependence B. Psychological dependence C. Both physical and psychological dependence D. Psychiatric abnormality 54. Adaptive neurophysiological changes produced by repeated administration of a drug, which result in the appearance of characteristic withdrawal syndrome on dis- continuation of the drug is called: A. Drug addiction B. Drug abuse C. Psychological dependence D. Physical dependence

UNIT 5. TEST LESSON Write out in prescription 1. 100,0 Urodanum. Take 1 teaspoon 3 times a day dissolved in 1 glass of water. 25

2. 20 powders of Pancreatinum 0,5. Take 1 powder 3 times a day. 3. 50 powders of Natrii para-aminosalicylas 1,0. Take 3 powders 3 times a day. 4. 20 powders containing 0,1 of Riboflavinum and 0,2 of Thiamini bromidum. Take 1 powder 3 times a day. 5. 15 powders containing 0,3 of Rutinum and 0,05 of Acidum ascorbinicum. Take 1 powder 3 times a day. 6. 10 powders of Oxacyllinum-natrium 0,25 in gelatinous capsules. Take 1 cap- sule 4 times a day. 7. 50 tablets of Dexamethasonum 0,0005. Take 1 tablet 3 times a day. 8. 10 tablets of Phenolphtaleinum 0,1. Take 1 tablet every night at bedtime. 9. 10 tablets of Nitroglycerinum 0,0005. 1 tablet under tongue at attacks. 10. 20 tablets of Oxaphenamidum 0,25.Take 1 tablet 3 times a day before meal. 11. 20 tablets of Digitoxinum 0,0001. Take 1 tablet once a day 12. 40 tablets of sulfate Chinidini sulfas 0,05. Take tablet 3 times a day 30 minutes prior to meal. 13. 20 tablets «Theophedrinum». Take 1 tablet 3 times a day. 14. 100 tablets «Vicalinum». Take 1 tablet 3 times a day. 15. 20 dragee containing Aminazinum 0,05. 1 dragee 2 times a day. 16. 20 dragee containing Diazolinum0,025. 1 dragee 2 times a day. 17. 20 ml of 5 % Еphedrini hydrochloridum solution. 5 drops into nose for every 4 hours. 18. 10 ml of 1 % Pilocarpini hydrochloridum solution. Eye drops. 2 drops 2 times a day. 19. 10 ml of 0.1 % Atropini sulfas solution. Take 5 drops 3 times a day. 20. 200 ml of 10 % Potassii chloridum solution. Take 1 table spoon 3 times a day. 21. 15 ml of 1 % Mentholum oil solution. 5 drops into nose. 22. 10 ml of 0.5 % of Hydrocortisoni acetas suspension. Eye drops. 1-2 drops for every 4 hours. 23. 100 ml of Oletetrinum suspension. Take 2 tea spoons 4 times a day. 24. 200 ml of decoction from 20.0 of cortex Frangulae. Take table spoon for the night. 25. 25 ml of Valerian tincture. Take 25 drops in 1 dose. 26. 10 ml of Belladonna tincture. Take 10 drops 2 times a day. 27. 15 ml of Lantosidum. Take 15 drops 3 times a day. 28. 15 ml of Adonisidum. Take 15 drops 2-3 times a day. 29. 10 ampoules containing 1 ml of 0.1 % Atropini sulfas solution. For hypoder- mic insertion by 1 ml. 30. 20 ampoules containing 1 ml of 0.1 % Synoestrolum oil solution. Take 1 ml in- tramuscularly once a day. 26

31. 10 ampoules containing 1 ml of 2 % of Promedolum solution. Take 1 ml in- tramuscularly once a day. 32. 5 ml of sterile 2 % Novocainum solution. For anesthesias. 33. 20 ampoules containing 0.005 of Trypsinum crystallisatum. Contents of an ampoule to dissolve in 2-3 ml isotoinic solution. For inhalations. 34. 10 bottles containing 0.1 of Lydasum. Before the use contents of a bottle to dissolve in 1 ml of sterile 0.5 % Novocain solution, intramuscularly. 35. Mixture, 180 ml extract which structure includes herba Thermopsidis 1: 400 and Codeini phosphas 0.2. Take 1 table spoon 3 times a day. 36. The mixture consisting of 180 ml of 2 % sodium bromide solution and 1.2 Coffeinum-natrii benzoas. Take 1 table spoon 3 times a day. 37. 0.5 % Neomycinum sulfas ointment 50.0/ For applying on the affected area of the skin. 38. 10.0 Tetracycline hydrochloridum ointment of 1 %. To apply on the affected area of the skin. 39. 10.0 of Nystatinum ointment. To apply on the affected area of the skin. 40. 10.0 of Erythromycinum ointment. On the skin. 41. 25.0 of Heparinum ointments. To apply on the affected area of the skin. 42. 50,0 of Zinci oxydi paste. Apply to affected skin. 43. 20 rectal suppositories “Bethiolum”. 1 suppository 2 times a day per rectum. 44. 12 rectal suppositories “Neoanusolum”. 1 suppository 2 times a day per rec- tum.

TOPICS TO DISCUSS

1. Pharmacokinetics. Definition. 2. Mechanisms of drug penetration through membranes. Dependence of a drug penetration on their lipid-solubility. Penetration of weak acids and bases through cell membranes (dependence on the pH of the medium and the pKa). 3. Routes of drug administration. The main characteristics. 4. Drug absorption. Dependence of drug absorption on routes of administration. The main mechanisms of drug absorption after oral, intramuscular and subcutaneous administrations. 5. Bioavailability. Factors that influence bioavailability after oral administration. First-pass effect. 6. Distribution of drugs in the body. Penetration through the blood-brain barrier. 7. Accumulation of drugs in the body. Binding of drugs to plasma proteins. 8. Apparent volume of distribution: definition, dependence on drug concentration in body fluids. 27

9. Drug biotransformation (metabolism). Phase I and phase II reactions. The main changes in the properties of drugs (lipophilicity, hydrophilicity, activity, toxicity) caused by their metabolism. 10. Excretion of drugs. Routes of excretion. 11. The main pharmacokinetic parameters characterizing drug elimination: the rate constant for drug elimination, half-life, clearance. 12. Pharmacodynamics. Definition (pharmacological effects, mechanisms of drug action, localization of drug action). 13. The main molecular targets for drug action. 14. Specific receptors: the main properties and functions. Membrane and intracellu- lar receptors. Division of membrane receptors according to transduction mechanism. Characteristics and examples of each receptor type. 15. Drug-receptor binding (types of bonds, reversible and irreversible binding). Af- finity. 16. Intrinsic activity. Agonists (full, partial). Antagonists. 17. Graded dose-response curve. Efficacy. Potency. The characteristics of efficacy and potency: Emax and ED50. 18. Combined drug administration (synergism, potentiation, additive effect, antago- nism). Pharmacological antagonism (competitive and non-competitive antagonism). 19. Tolerance. The mechanisms of tolerance: de-sensitization of receptors, loss of receptors, depletion of neurotransmitters, etc. 20. Drug dependence (definition, types and characteristics of drug dependence). 21. Adverse and toxic effects of drugs. 22. Drug allergy. Idiosyncrasy. 23. Mutagenicity, carcinogenicity, teratogenicity of drug.

UNIT 6. PARTICULAR PHARMACOLOGY

Drugs Acting on Autonomic Nervous System. Drugs that Affect the Autonomic Nervous System and the Neuromuscular Junction. Local Anesthetics The nervous system consists of the central and peripheral ones. The central nervous system includes the brain and spinal cord, whereas the peripheral nervous system includes the autonomic nervous system and the somatic nervous system. Drugs alter nervous system function primarily by affecting neurotransmitters or their receptors. In some cases, drugs affect the synthesis, storage, release, inactiva- 28 tion, or neuronal reuptake of neurotransmitters. In other cases, they activate or block receptors. Most drugs are relatively specific for a particular neuro- transmitter or receptor. The spectrum of effects produced by a drug depends on the distribution of the affected neurotransmitters in the central and peripheral nervous systems. The actions of some drugs are localized to either the central or the peripheral nervous system, whereas the actions of other drugs (e.g., and ) affect both central and peripheral functions.

TOPICS TO DISCUSS 1. Local anesthetics: pharmacologic classes and agents. 2. Mechanism of action of local anesthetics. 3. Pharmacokinetics of local anesthetics: local action, systemic action (systemic ab- sorption, distribution, metabolism and excretion). 4. The sites of anesthesia: topical anesthesia, infiltration anesthesia, nerve block and field block anesthesia, spinal intrathecal anesthesia, epidural anesthesia, intravenous regional anaesthesia 5. Properties of selected local anesthetics: - Ester-Type Drugs (cocaine, novocaine (procaine), dicaine, benzocaine). - Amide-Type Drugs (lidocaine, bupivacaine, trimecaine, ultracaine). 6. Adverse effects and interactions.

Local anesthetics produce use-dependent blockade of nerve conduction and thereby prevent pain associated with surgical and diagnostic procedures. Autonomic and sensory nerves are blocked more easily than are nerves affecting proprioception, muscle tone, and somatic motor activity. Local anesthetics are weak bases. The non-ionized form permeates neuronal membranes, and the ionized form binds to the internal surface of sodium channels. Ester-type anesthetics (e.g., procaine and chloroprocaine) are converted to PABA and may elicit hypersensitivity reactions. Amide-type anesthetics (e.g., lidocaine and mepivacaine) produce fewer aller- gic reactions than do ester-type anesthetics. All local anesthetics can cause CNS and cardiac toxicity, including seizures and cardiac arrhythmias. Classification of local anesthetics Ester-Type Drugs: cocaine, novocaine (procaine), dicaine, benzocaine Amide-Type Drugs: lidocaine, bupivacaine, trimecaine, ultracaine

CHOOSE THE MOST APPROPRIATE RESPONSE 29

1. The clinically used local anaesthetics have the following common features except: A. They are amphiphilic weak bases B. They are used for surgery in non-cooperative patients C. In their use, care of vital functions is generally not needed D. They are safer than general anaesthetics in patients with respiratory and cardiovascular disease 2. The local anaesthetics having amide linkage differ from those having ester linkage in that the amidelinked local anaesthetics: A. Are not surface anaesthetics B. Have a shorter duration of action C. Are degraded in the plasma D. Do not show cross-sensitivity with esterlinked local anaesthetics 3. The following is not true of local anaesthetics: A. The local anaesthetic is required in the unionized form for penetrating the neuronal membrane B. The local anaesthetic approaches its receptor only from the intraneuronal face of the Na+ channel C. The local anaesthetic binds to its receptor mainly when the Na+ channel is in the resting state D. The local anaesthetic combines with its receptor in the ionized cationic form 4. Local anaesthetics block nerve conduction by: A. Blocking all cation channels in the neuronal membrane B. Hyperpolarizing the neuronal membrane C. Interfering with depolarization of the neuronal membrane D. Both 'B' and 'C' are correct 5. Sensitivity of a nerve fibre to blockade by lignocaine depends on: A. Whether the fibre is sensory or motor B. Whether the fibre is myelinated or nonmyelinated C. Internodal distances in the fibre D. Both 'B' and 'C' are correct 6. A resting nerve is relatively resistant to blockade by lignocaine compared to one which is repeatedly stimulated because: A. Lignocaine penetrates resting nerve membrane poorly B. Lignocaine binds more avidly to the inactivated Na+ channel C. Nerve impulse promotes ionization of lignocaine D. Nodes of Ranvier are inaccessible in the resting state 7. Which of the following is not the reason for greater susceptibility of smaller senso- ry fibres to blockade by local anaesthetics than larger motor fibres: 30

A. Sensory fibres are inherently more sensitive than motor fibres B. More slender fibres have shorter internodal distances C. Small sensory fibres generate higher frequency longer lasting action po- tential D. Smaller fibres have shorter critical lengths for blockade 8. Which sensation is blocked first by low concentrations of a local anaesthetic: A. Pain B. Temperature C. Touch D. Deep pressure 9. Injection of adrenaline along with a local anaesthetic serves the following purpose: A. Lowers the concentration of the local anaesthetic to produce nerve block B. Prolongs the duration of local anaesthesia C. Increases the anaesthetised area D. Reduces the local toxicity of the local anaesthetic 10. Adrenaline added to local anaesthetic solution for infiltration anaesthesia affords the following except: A. Prolongs the duration of local anaesthesia B. Makes the injection less painful C. Provides a more bloodless field for surgery D. Reduces systemic toxicity of the local anaesthetic 11. Toxicity of local anaesthetics involves the following organs except: A. Heart B. Brain C. Kidney D. Skin and subcutaneous tissue 12. Which of the following is a poor surface anaesthetic: A. Procaine B. Lignocaine C. Tetracaine D. Benoxinate 13. The local anaesthetic having high cardiotoxic and arrhythmogenic potential is: A. Lignocaine B. Procaine C. Bupivacaine D. Ropivacaine 14. Low concentration of bupivacaine is preferred for spinal/epidural obstetric anal- gesia because: A. It has a longer duration of action 31

B. It can produce sensory blockade without paralysing abdominal muscles C. It distributes more in maternal tissues so that less reaches the foetus D. All of the above are correct 15. Eutectic lignocaine-prilocaine has the following unique property: A. It causes motor blockade without sensory block B. By surface application, it can anaesthetise unbroken skin C. It is not absorbed after surface application D. It has strong vasoconstrictor action 16. Surface anaesthesia is usedforthe following except: A. Ocular tonometry B. Urethral dilatation C. Tooth extraction D. Anal fissure 17. In which of the following techniques the concentration of the local anaesthetic used is the lowest: A. Infiltration anaesthesia B. Nerve block anaesthesia C. Spinal anaesthesia D. Epidural anaesthesia 18. In spinal anaesthesia the segmental level of: A. Sympathetic block is lower than the sensory block B. Sympathetic block is higher than the sensory block C. Motor block is higher than the sensory block D. Sympathetic, motor and sensory block has the same level 19. The following factor is not involved in the causation of hypotension due to spinal anaesthesia: A. Histamine release B. Reduced sympathetic vasoconstrictor tone C. Decreased venous return from the lower limbs D. Bradycardia 20. Spinal anaesthesia is not suitable for: A. Vaginal delivery B. Lower segment caesarian section C. Prostatectomy D. Operations on mentally ill patients 21. Epidural anaesthesia differs from spinal anaesthesia in that: A. Epidural anaesthesia produces less cardiovascular complications B. Headache is more common after epidural anaesthesia 32

C. Blood concentrations of the local anaesthetic are lower after epidural an- aesthesia D. Greater separation between sensory and motor blockade can be ob- tained with epidural anaesthesia 22. Intravenous regional anaesthesia is suitable for: A. Orthopedic manipulations on the upper limb B. Vascular surgery on the lower limb C. Head and neck surgery D. Caesarian section

UNIT 7. CHOLINERGIC DRUGS.

Cholinoceptor Agonists. Anticholinesterases

Organization of efferent innervation Efferent innervation includes:  autonomic nervous system which regulates involuntary responses of the heart, blood vessels, other smooth muscle organs and glandular tissue;  somatic (motor) nerves innervating skeletal muscles and thus regulating vol- untary movement. The autonomic nervous system includes: parasympathetic and sympathetic di- visions. Autonomic nerve fibers interact with their target organs by a two-neuron pathway. The first neuron originates in the CNS and synapses outside the spinal cord with the second neuron lying in the ganglia, postganglionic fibers of which innervate the target organs. The parasympathetic nervous system arises from the brainstem and sacral re- gion of the spinal cord. Nearly all of the parasympathetic ganglia lie in or near the in- nervated organs. The sympathetic nervous system arises from thoracic and lumbar regions of the spinal cord. Sympathetic ganglia are located outside innervated organs and tissues and most of them lie in the sympathetic chains on either side of the vertebral column. The neurotransmitter released by preganglionic nerves in both parasympathetic and sympathetic ganglionic synapses is (ACh). ACh is also released by postganglionic parasympathetic nerves and operates as a neurotransmitter of para- sympathetic neuroeffector synapses. Somatic nerves release ACh as a neurotransmit- ter at neuromuscular junctions. Synapse is cholinergic if it uses ACh as its neuro- transmitter. 33

Norepinephrine is released by postganglionic sympathetic nerves and operates as a neurotransmitter in sympathetic neuroeffector synapses. These synapses are termed adrenergic synapses. The essential processes in synaptic neurotransmission include:  release of a neurotransmitter into the synaptic cleft;  stimulation of specific receptors on the postsynaptic membrane;  breakdown of a neurotransmitter in the synaptic cleft or its uptake by neurons or effector cells. Synthesis, storage and release of ACh ACh is an ester synthesised from and acetic acid (as acetyl-CoA) by choline acetyltransferase.It is stored in vesicles and released by a nerve action potential. Ach is produced in nerves and broken down by acetylcholinesterase (AChE). Acetylcholine receptors (AChR)

Main subdivision is into nicotinic (nAChR) and muscarinic (mAChR) subtypes.

 nAChRs are directly coupled to cation channels, and mediate fast excitatory synaptic transmission at the neuromuscular junction, autonomic ganglia, and various sites in the central nervous system (CNS). Muscle and neuronal nAChRs differ in their molecular structure and pharmacology.  mAChRs are G-protein-coupled receptors causing: o activation of phospholipase C (hence formation of inositol trisphosphate and diacylglycerol as second messengers) o inhibition of adenylyl cyclase o activation of potassium channels or inhibition of calcium channels.  mAChRs mediate acetylcholine effects at postganglionic parasympathetic syn- apses (mainly heart, smooth muscle, glands), and contribute to ganglionic exci- tation. They occur in many parts of the CNS.  Three main types of mAChR occur.

o M1 receptors ('neural') producing slow excitation of ganglia. They are se- lectively blocked by .

o M2 receptors ('cardiac') causing decrease in cardiac rate and force of contraction (mainly of atria). They are selectively blocked by gallamine.

M2 receptors also mediate presynaptic inhibition.

o M3 receptors ('glandular') causing secretion, contraction of visceral smooth muscle, vascular relaxation.

 Two further molecular mAChR subtypes, M4 and M5, occur mainly in the CNS. All mAChRs are activated by acetylcholine and blocked by . There are also subtype-selective agonists and antagonists. 34

TOPICS TO DISCUSS 1. Diagram of efferent innervation. Localizations of M-cholinoceptors and N- cholinoceptors (of ganglionic and muscle types) on the diagram. 2. Classification of drugs stimulating cholinergic neurotransmission.

3. Subtypes of M-cholinoceptors (M1, M2, M3): main localization and effects of stimu- lation. 4. Pharmacological effects of acetylcholine and . Therapeutic uses. 5. Classification of anticholinesterases. Mechanism of action. Pharmacological ef- fects. Therapeutic uses. Adverse effects. 6. Toxic effects of anticholinesterases. Agents used in the treatment of overdose with reversible and irreversible anticholinesterases. Acetylcholinesterase reactivators. Or- ganophosphate poisoning and its treatment. 7. M-cholinomimetics: pharmacological effects, therapeutic uses and adverse effects. 8. N-cholinomimetics: pharmacological effects and therapeutic uses.

Classification of drugs stimulating cholinergic neurotransmission

M-N-cholinomimetics (Parasympathomimetic)

Direct-acting cholinergic agonists M, N-cholinomimetics: Acetylcholine, Carbachol M-cholinomimetics: , , N-cholinomimetics: , Lobeline, Epibatidine. Indirect-acting (anticholinesterases) Reversible: Edrophonium, physostigmine, neostigmine, pyridostigmine, galantamine, rivastigmine, donepezil. Irreversible: Armine. Note: Direct-acting cholinergic agonists produce effects similar to activation of the parasympathetic nervous system. Anticholinesterases are referred to as indirectly act- ing cholinergic agonists because they do not interact with cholinoceptors. They inhib- it acetylcholinesterase and thus increase concentration of acetylcholine in the synap- tic cleft. Effects of anticholinesterases resemble the effects of acetylcholine in neuroeffector and neuromuscular synapses.

CHOOSE THE MOST APPROPRIATE RESPONSE 1. Which of the following organs is innervated only by parasympathetic nerves: A. Iris muscles B. Ciliary muscle C. Sweat glands 35

D. Splenic capsule 2. The sympathetic and parasympathetic systems exert functionally opposite influ- ences on the following parameters except: A. Heart rate B. Atrial refractory period C. Pupil diameter D. Intestinal motility 3. The cotransmitter may serve the following function/functions: A. Regulate the release of the primary transmitter from the nerve ending B. Alter postjunctional action of the primarytransmitter C. Itself act as an alternative transmitter D. All of the above 4. The major postjunctional cholinergic receptor is of the muscarinic type at the fol- lowing site: A. Postganglionic parasympathetic B. Adrenal medulla C. Autonomic ganglia D. Neuromuscular junction 5. Pseudocholinesterase differs from true in that: A. It does not hydrolyse acetylcholine B. It hydrolyses acetylcholine at a slower rate C. It is more susceptible to inhibition by physostigmine D. It is the only form of circulating cholinesterase 6. The choline ester resistant to both true and pseudocholinesterase is: A. B. Bethanechol C. Benzoylcholine D. 7. Acetylcholine has no therapeutic application because: A. None of its actions are beneficial in any condition B. Its effects are transient C. It produces wide spread actions affecting many organs D. Both 'B' and 'C' are correct 8. Pilocarpine is used for: A. Glaucoma B. Paralytic ileus C. Urinary retention D. All of the above 36

9. The following inhibitor binds only to the anionic site of the cholinesterase en- zyme: A. Neostigmlne B. Physostigmine C. Edrophonium D. Dyflos 10. Reactivation of cholinesterase enzyme occurs on hydrolysis of the inhibitor by the same enzyme molecule in case of the following anticholinesterase: A. Edrophonium B. Neostigmine C. Dyflos D. Tacrine 11. The anticholinesterase action of edrophonium is short lasting because termina- tion of its action depends on; A. Dissociation and diffusion of the drug from the enzyme B. Hydrolysis of the drug by the enzyme C. Synthesis of fresh enzyme molecules D. A combination of the above three processes 12. The produce irreversible inhibition of cholinesterase because: A. They bind to an allosteric site of the enzyme resulting in unfavourable conformation of esteratic site to bind acetylcholine B. Regeneration time of the phosphorylated enzyme is longer than the turnover time of the enzyme molecules C. Phosphorylation results in rapid degradation of enzyme molecules D. They are neither metabolized nor excreted from the body 13. Neostigmine is preferred over physostigmine for treating myasthenia gravis be- cause: A. It is better absorbed orally B. It has longer duration of action C. It has additional direct agonistic action on nicotinic receptors at the muscle end plate D. It penetrates blood-brain barrier 14. The mechanism by which neostigmine improves contraction of myasthenic muscle involves: A. Repetitive binding of the acetylcholine molecules to the same receptors at the muscle endplate B. Diffusion of acetylcholine released from motor nerve endings to a wider area activating neighbouring receptors 37

C. Activation of motor end-plate receptors by neostigmine molecules themselves D. All of the above 15 Pyridostigmine differs from neostigmine in that: A. It is more potent orally B. It is longer acting C. It produces less muscarinic side effects D. It does not have any direct action on NM receptors 16 Edrophonium is more suitable for differentiating myasthenic crisis from cho- linergic crisis because of its: A. Shorter duration of action B. Longer duration of action C. Direct action on muscle end-plate D. Selective inhibition of true cholinesterase 17 Which of the following is a relatively cerebroselective anticholinesterase found to afford symptomatic improvement in Alzheimer's disease: A. Donepezil B. Gemfibrozil C. Pyridostigmine D. Pyritinol 18 Pilocarpine reduces intraocular tension in open angle glaucoma by: A. Contracting sphincter puptllae B. Increasing tone of ciliary muscle C. Reducing aqueous formation D. Enhancing uveo-scleral outflow 19 The site of action of miotics for therapeutic effect in angle closure glaucoma is: A. Canal of Schlemm B. Ciliary body C. Ciliary muscle D. Sphincter pupillae muscle 20 Neostigmine is beneficial in cobra envenomation because: A. It binds to and inactivates cobra toxin B. It reverses coma due to cobra toxin C. It counteracts the cardio- action of cobra toxin D. It antagonizes the paralysing action of cobra toxin 21 A suspected case of poisoning has been brought to the casualty with weakness, fainting, involuntary passage of urine and stools, profuse sweating, salivation, water- ing from nose and eyes. His pulse is 120/min, low volume, BP 90/60 mm Hg, respi- 38 ration shallow, pupil constricted, and muscles flabby with occasional fasciculations. Which is the most likely type of poisoning: A. Belladonna B. C. Anticholinesterase D. Dicophane (DDT) 22 Which is the most important drug in the treatment of poison- ing: A. Atropine sulfate B. PralidoxLme C. D. Adrenaline 23 Atropine does not antagonise the following feature of anticholinesterase poi- soning: A. Hypotension B. Central excitation C. Muscle paralysis D. Bronchoconstriction 24 Pralidoxime can reactivate cholinesterase enzyme that has been inactivated by: A. anticholinesterases B. Organophosphate anticholinesterases C. Both carbamate and Organophosphate anticholinesterases D. Reversible anticholinesterases

UNIT 8. CHOLINOCEPTOR ANTAGONISTS. GANGLIONIC BLOCKERS. NEUROMUSCULAR BLOCKING DRUGS

TOPICS TO DISCUSS 1. Classification of drugs inhibiting cholinergic neurotransmission. 2. Schematic diagram of efferent innervation. Localization of action of M- cholinoblockers, ganglion-blocking drugs, neuromuscular blocking drugs. 3. Pharmacological effects of M-cholinoblockers. Main therapeutic uses. Adverse effects. 4. Mechanisms of mydriasis and cycloplegia caused by atropine. Effect on intra- ocular pressure. The main uses of atropine in ophthalmology. Comparison with and . 5. Main therapeutic uses of atropine. Comparison of atropine with . Main therapeutic uses of scopolamine. 39

6. Toxic effects of atropine. Drugs used as antidotes for atropine overdosage. Poi- soning with atropine- and scopolamine-containing plants (e.g. deadly night- shade and angel's trumpet). Treatment of such intoxications. 7. Comparison of pirenzepine, and ipratropium with atropine. Com- parison of ipratropium and tiotropium. 8. Ganglion-blocking drugs. Characteristics of hexamethonium, trimethaphan, mecamylam-ine. 9. Pharmacological effects of ganglion-blocking drugs. Therapeutic uses and ad- verse effects. 10. Classification of neuromuscular blocking drugs based on the mechanisms of action. 11. Pharmacological effects, therapeutic uses and adverse effects of nondepolarizing neuromuscular-blocking drugs. Characteristics of tubocu- rarine, atracurium, pancuronium, mivacurium. Antagonists of nondepolarising neuromuscular-blocking drugs. 12. Succinylcholine. Mechanism of action. Therapeutic uses and adverse effects. Comparison with nondepolarising neuromuscular blockers.

Classification of drugs inhibiting cholinergic neurotransmission Muscarinic receptor-blocking drugs Belladonna Alkaloids: Atropine, Scopolamine, . Synthetic Muscarinic Antagonists: Ipratropium, Pylocarpine, Tropicamide Nicotinic receptor-blocking drugs Ganglion-blocking drugs: Hexamethonium, Trimethaphan Neuromuscular-blocking drugs Nondepolarizing drugs: Tubocurarine, Pancuronium, Atracurium, Vecuronium, Mivacurium Depolarizing drugs: Suxamethonium (Succinylcholine)

CHOOSE THE MOST APPROPRIATE RESPONSE

1 Initial bradycardia caused by intramuscular injection of atropine is believed to be caused by: A. Stimulation of medullary vagal centre B. Stimulation of vagal ganglia C. Blockade of M2 receptors on SA nodal cells D. Blockade of muscarinic autoreceptors on vagal nerve endings 2 Atropine does not exert relaxant/antispasmodic effect on the following muscle: A. Intestinal 40

B. Ureteric C. Bronchial D. Laryngeal 3 Atropine produces the following actions except: A. Tachycardia B. Mydriasis C. Dryness of mouth D. Urinary incontinence 4 The organ most sensitive to actions of atropine is: A. Gastric glands B. Salivary glands C. Urinary bladder muscle D. Heart 5 Hyoscine differs from atropine in that it: A. Exerts depressant effects on the CNS at relatively low doses B. Exerts more potent effects on the heart than on the eye C. Is longer acting D. Has weaker antimotion sickness activity 6 The quaternary analogues of belladonna alkaloids are preferred over the natural alkaloids for antisecretory/antispasmodic indications because: A. They have additional nicotinic receptor blocking activity B. They are incompletely absorbed after oral administration C. They are devoid of CNS and ocular effects D. Dose to dose they are more potent than atropine (Note: Many quarternary do have additional nicotinic blocking activ- ity and because of high ionization they are incompletely absorbed. But the reason for preferring them is lack of central and ocular effects. Most compounds are dose to dose less potent than atropine.) 7 Inhaled has the following advan tages except: A. It does not alter respiratory secretions B. Itdoesnotdepressairwaymucociliaryclearance C. It has faster onset of bronchodllator action than Inhaled salbutamol D. It only rarely produces systemic side effects 8 Which of the following drugs is primarily used in preanaesthetic medication and during surgery: A Glycopyrrolate B. Pipenzolate methyl bromide C. D. Dicyclomine 41

9 Children are more susceptible than adults to the following action ofatropine: A. Tachycardia producing B. Cycloplegic C. Gastric antisecretory D. Central excitant and hyperthermic 10 Glycopyrrolate is the preferred antimuscarinic drug for use before and during surgery because: A. It is potent and fast acting B. It has no central action C. It has antisecretory and vagolytic actions D. All of the above 11 Choose the relatively vasicoselective anticholinergic drug used for urinary fre- quency and urge incontinence due to detrusor instability: A. Pirenzepine B. C. Oxyphenonium D. Glycopyrolate 12 Which of the following mydriatics has the fastest and briefest action: A. Atropine B. C. Tropicamide D. Cyclopentolate 13 The following mydriatic does not produce cycloplegia: A. Phenylephrine B. Tropicamide C. Cyclopentolate D. Homatropine 14 The most suitable mydriatic for a patient of cornea/ulcer is: A Atropine sulfate B. Homatropine C. Cyclopentolate D. Tropicamide 15 The mydriatic incapable of producing cycloplegia sufficient for refraction test- ing in children is: A. Atropine B. Hyoscine C. Homatropine D. Cyclopentolate 1 6 Choose the correct statement about drotaverine: 42

A. It is a smooth muscle antispasmodic acting by non-anticholinergic mechanisms B. It is a papaverine congener used in peripheral vascular diseases C. It is a synthetic atropine substitute used to control diarrhoea

D. It is a M1/M3 selective antagonist used for spastic constipation 17 The most effective antidote for belladonna poisoning is: A. Neostigmlne B. Physostigmine C. Pilocarpine D. Methacholine 18 Atropine is contraindicated in: A. Pulmonary embolism B. Digitalis toxicity C. Iridocyclitis D. Raised intraocular tension 19 Choose the correct statement about nicotine: A. It selectively stimulates parasympathetic ganglia B. It has no clinical application C. It is used as an aid during smoking cessation D. It is used in Alzheimer's disease 20 Ganglion blocking drugs are no longer used in therapeutics because: A. They have few and weak pharmacological actions B. They produce many side effects C. They are inactive by oral route D. They have short duration of action 21 Which of the following drugs is a nondepoiarizing neummuscular blocker: A. Succinylcholine B. Vecuronium C. D. sodium 22 The site of action of d-tubocurarine is: A. Spinal internuncial neurone B. Motor nerve ending C. Muscle end-plate D. Sodium channels in the muscle fibre 23 At the muscle end-plate, d-tubocurarine reduces the: A. Number of Na+ channels B. Duration for which the Na+ channels remain open C. Ion conductance of the open Na+ channel 43

D. Frequency of Na+ channel opening 24 Depolarizing neuromuscularblockers differ from competitive blockers in the following attributes except: A. They induce contraction of isolated frog rectus abdomtnts muscle B. Ether anaesthesia intensifies block produced by them C. Tetanic nerve stimulation during partial depolarizing block produces well sustained contraction D. Neostigmine does not reverse block produced by them 25 Succinylcholine produces spastic paralysis in: A. Rabbits B. Frogs C. Birds D. Patients with atypical pseudocholinesterase 26 The fall in blood pressure caused by d-tubocurarine is due to: A. Reduced venous return B. Ganglionic blockade C. Histamine release D. All of the above 27 Select the skeletal that is commonly used for endotracheal in- tubation despite causing histamine release, K+ efflux from muscles and cardiovascuiar changes: A. Pipecuroniun B. Succinylcholine C. Pancuronium D. Cisatracurium 28 Neuromuscular blocking drugs do not produce central actions because: A. They do not cross the blood-brain barrier B. Nicotinlc receptors are not present in the brain C. They are sequestrated in the periphery by tight binding to the skeletal muscles D. They do not ionise at the brain pH 29 Pancuronium differs from tubocurarine in that: A. It is a depolarizing blocker B. Its action is not reversed by neostigmine C. It can cause rise in BP on rapid I.V. injection D. It causes marked histamine release 30 Which of the following drugs undergoes 'Hofmann' elimination: A. Succinylcholine B. Pancuronium 44

C. Vecuronium D. Atracurium 31 The neuromuscular blocker that does not need reversal of action by neostig- mine at the end of the operation is: A. d-Tubocurarine B. Doxacurium C. Pipecuronium D. Mivacurium 32 The most rapidly acting nondepolarizing neuromuscular blocking agent which can be used as an alternative to succinylcholine for tracheal intubation is: A. Rocuronium B. Pancuronium C. Doxacurium D. Pipecuronium 33 Succinylcholine is the preferred muscle relaxant for tracheal intubation be- cause: A. It produces rapid and complete paralysis of respiratory muscles with quick recovery B. It does not alter heart rate or blood pressure C. It does not cause histamine release D. It does not produce postoperative muscle soreness 34 Which of the following is applicable to mivacurium: A. It undergoes Hoffmann elimination B. It is the shortest acting nondepolarizing neuromuscular blocker C. It is excreted unchanged by kidney D. It does not cause histamine release 35 Neostigmine reverses the following actions of d-tubocurahne except: A. Motor weakness B. Ganglionic blockade C. Histamine release D. Respiratory paralysis 36 Postoperative muscle soreness maybe a side effect of the following neuromus- cular blocker: A. d-tubocurarine B. Succinylcholine C. Pancuronium D. Atracurium 37 The following antibiotic accentuates the nuromuscular blockade produced bypancuronium: 45

A. Streptomycin B. Erythromycln C. G D. Chloramphenicol 38 Dantrolene sodium reduces skeletal muscle tone by: A. Reducing acetylcholine release from motor nerve endings B. Suppressing spinal polysynaptic reflexes C. Inhibiting the generation of muscle action potential D. Reducing Ca2+ release from sarcoplasmic reticulum in the muscle fi- bre (p. 316) 39 Which of the following is a centrally acting skeletal muscle relaxant: A. B. Dantrolene sodium C. Quinine D. Decamethonium 40 Select the muscle relaxant that is used to control spasticity associated with up- per motor neurone paralysis: A. Vecuronium B. Succlnylcholine C. D.

41 The following is a skeletal muscle relaxant that acts as a central α2 adrenergic agonist: A. Tizanldine B. Brimonidine C. D. Quinine 42 Indications of centrally acting muscle relaxants include all of the following ex- cept: A. Balanced anaesthesia B. Traumatic muscle spasms C. Torticollis D. Electroconvulsive therapy

UNIT 9. DRUGS AFFECTING THE SYMPATHETIC NERVOUS SYSTEM

The sympathetic nervous system is an energy-expending system that has an ergotrophic function. Stimulation of this system leads to the "flight, fright, or fight" response characterized by increased heart rate, blood pressure, and respiration, an in- 46 creased blood flow to skeletal muscles, and mydriasis. Almost all postganglionic sympathetic neurons release norepinephrine (NE) as their neurotransmitter to alter the activity of the effector organs. A minor exception is the small number of anatomi- cally sympathetic neurons projecting to sweat glands and a few blood vessels that re- lease acetylcholine. NE released from sympathetic neurons activates adrenergic re- ceptors on exocrine glands, smooth muscle, and cardiac muscle to produce sympa- thetic responses. Drugs that facilitate or mimic the actions of the sympathetic nervous system are called sympathomimetics, adrenomimetics, or adrenergic agonists. Sympathomimetics constrict most arterioles and veins and can be used locally to re- duce bleeding, slow diffusion of drugs such as local anesthetics, decongest mucous membranes, and reduce formation of aqueous humor to lower intraocular pressure in glaucoma. Systemic administration of sympathomimetics increases peripheral vascu- lar resistance and mean arterial blood pressure and can increase blood pressure in hy- potensive states, including neurogenic shock. By increasing blood pressure, sympathomimetics cause a reflex slowing of heart rate, which can be used to treat paroxysmal atrial tachycardia. Drugs that block or reduce the actions of Epi or NE are called or adrenergic antagonists. Drugs that decrease sympathetic activity at vascular smooth muscle are used to treat essential hypertension and hypertensive emergencies as well as benign prostatic hyperplasia. Drugs that reduce the actions of NE and Epi on car- diac muscle are used to treat cardiac dysrhythmias, angina pectoris, and other cardiac disorders such as postmyocardial infarction. These drugs are also used in treating mi- graines, glaucoma, and essential tremor. Topics to discuss 1. Types and subtypes of adrenoceptors and their main localizations in organs and tissues. Diagram of adrenergic synapse with localization of adrenoceptors. 2. Classification of adrenergic drugs. 3. Direct-acting adrenoceptor agonists. Epinephrine: pharmacological effects on tone of vessels, blood pressure, automaticity of cardiomyocytes, heart rate, contractility, AV-conduction, intraocular pressure, bronchial tone, metabolic effects. Main therapeutic use and main adverse effects. 4. Indirect-acting adrenoceptor agonists (ephedrine). Mechanism of action, phar- macological effects, therapeutic uses and adverse effects. 5. Alpha-adrenergic agonists. Effects on the tone of blood vessels, blood pressure and heart rate. Therapeutic uses and main adverse effects. 6. Pharmacological effects and therapeutic uses of β-adrenomimetics. 7. αβ-adrenoblockers Labetalole: pharmacological effects, therapeutic uses and adverse effects. 47

8. Indirect (presynaptic) antagonist. Mechanism of action, main therapeutic uses and adverse effects. 9. Pharmacological effects of Alpha-adrenergic antagonists (action on vascular tone, arterial blood pressure, heart rate, tone of bladder neck, prostate capsule and urethra). Therapeutic uses and adverse effects. 10. Pharmacological effects of Beta-adrenergic antagonists. Therapeutic uses, ad- verse effects. 11. Selective β-adrenoblockers: metoprolol, atenolol. Main therapeutic uses, ad- verse effects. Comparison with nonselective adrenoblocking drugs.

Classification Adrenergic agonists I. Nonselective action – Alpha- and beta-adrenomimetics: 1) Direct (postsynaptic) agonist: epinephrine 2) Indirect (presynaptic) agonist (sympathomimetics): ephedrine II. Selective action: 1) Alpha-adrenomimetics: norepinephrine 2) Beta-adrenomimetics: isadrine Adrenergic antagonists I. Nonselective action – Alpha- and beta-adrenoblockers: 1) Direct (postsynaptic) antagonist: labetalol 2) Indirect (presynaptic) agonist (sympatholytics): reserpine II. Selective action: Alpha-adrenoblockers: Beta- adrenoblockers:

CHOOSE THE MOST APPROPRIATE RESPONSE

1. Which of the following is a noncatecholamine sympathomimetic: A. Adrenaline B. Ephedrine C. Dopamine D. Noradrenaline (Note: Ephedrine has no-OH group on the ring; hence it is a phenylamine.) 2. The rate limiting enzyme in the synthesis of catecholamines is: A. Tyrosine hydroxylase B. Dopa decarboxylase C. Dopamine β-hydroxylase D. Noradrenaline N-methyl transferase 48

3. The following type/types of noradrenaline uptake is/are blocked by reserpine: A. Axonal uptake B. Granular uptake C. Extraneuronal uptake D. All of the above

4. The β3 adrenoceptor differs from the other subtypes of β receptor in that it: A. Is not blocked by the conventional doses of propranolol B. Is located primarily in the heart C. Regulates blood sugar level D. Is not coupled to G proteins

5. The α2 adrenoceptors are: A. Located exclusively on the adrenergic nerve endings B. Prejunctional, postjunctional as well as extrajunctional in location C. Selectively activated by phenylephrine D. Selectively blocked by

6. The following is a selective α2 adrenoceptor antagonist: A. Prazosin B. Phentolamine C. Yohimbine D. Clonidine

7. The following sympathomimetic amine has agonistic action on α1 + α2 + β1 +

β3 adrenoceptors, but not on β2 receptors: A. Adrenaline B. Noradrenaline C. Isoprenaline D. Phenylephrine 8. The following action of adrenaline is mediated by both α and β receptors pro- ducing the same directional effect: A. Cardiac stimulation B. Intestinal relaxation C. Dilatation of pupil D. Bronchodilatation 9. The following action of adrenaline is not mediated by β receptors: A. Dilatation of blood vessels B. Dilatation of pupil C. Bronchodilation D. Renin release from kidney 10. Low doses of adrenaline dilate the following vascular bed: A. Cutaneous 49

B. Mucosal C. Renal D. Skeletal muscle 11. Vasomotor reversal phenomenon after administration of an α adrenergic block- er is seen with: A. Adrenaline B. Noradrenaline C. Isoprenaline D. All of the above drugs 12. Adrenaline is inactive orally because it is: A. Not absorbed from the gastrointestinal tract B. Destroyed by gastric acid C. Completely metabolized in the intestinal mucosa and liver before reaching systemic circulation D. Taken up by adrenergic nerve endings of the intestinal wall, liver and lungs 13. Adrenaline raises blood glucose level by the following actions except: A. Inducing hepatic glycogenolysis B. Inhibiting insulin secretion from pancreatic β cells C. Augmenting glucagon secretion from pancreatic α cells D. Inhibiting peripheral glucose utilization 14. The metabolic actions of adrenaline include the following except: A. Glycogenolysis in liver and muscle B. Inhibition of neoglucogenesis in liver C. Lipolysis in adipose tissue D. Release of potassium from liver followed by its uptake 15. Noradrenaline is administered by: A. Subcutaneous injection B. Intramuscular injection C. Slow intravenous infusion D. All of the above routes

16. Dopaminergic D1 and D2 as well as adrenergic α and β1, but not β2, receptors are activated by: A. Dopamine B. Dobutamine C. Methoxamine D. Phenylephrine 17. Dobutamine differs from dopamine in that: A. It does not activate peripheral dopaminergic receptors 50

B. It does not activate adrenergic β receptors C. It causes pronounced tachycardia D. It has good blood-brain barrier penetrability 18. Choose the drug which is used as a short-term inotropic in severe congestive heart failure and has selective adrenergic β1 agonistic activity but no dopaminergic agonistic activity: A. Dopamine B. Dobutamine C. Amrinone D. Salmeterol 19. Ephedrine is similar to adrenaline in the following feature: A. Potency B. Inability to penetrate blood-brain barrier C. Duration of action D. Producing both α and β adrenergic effects 20. At therapeutic doses, actions of amphetamine include the following except: A. Prolongation of attention span B. Wakefulness C. Lowering of seizure threshold D. Delaying fatigue 21. Vasoconstrictors should not be used in: A. Neurogenic shock B. Haemorrhagic shock C. Secondary shock D. Hypotension due to spinal anaesthesia 22. Adrenaline injected with a local anaesthetic: A. Reduces local toxicity of the local anaesthetic B. Reduces systemic toxicity of the local anaesthetic C. Shortens duration of local anaesthesia D. Makes the injection less painful 23. The most likely complication of prolonged use of nasal decongestant drops is: A. Atrophic rhinitis B. Hypertrophy of nasal mucosa C. Naso-pharyngeal monlliasis D. Blockage of eustachian tubes 24. Adrenergic neurone blocking drugs:

A. Block the action of adrenaline on neuronal α2 adrenoceptors B. Block both α and β adrenoceptor mediated effects of injected adrenaline C. Do not block any effect of injected adrenaline 51

D. Do not block the effects of sympathetic nerve stimulation 25. The nonselective α adrenergic blockers produce the following actions except: A Postural hypotension B. Bradycardia C. Miosis D. Inhibition of ejaculation 26. The drug which produces vasoconstriction despite being an α adrenergic blocker is: A. Phenoxybenzamine B. Ergotamine C. Dihydroergotoxine D. Tolazoline 27. The bladder trigone and prostatic muscles are relaxed by:

A. Adrenergic α1 agonists

B. Adrenergic α1 antagonists

C. Adrenergic α2 agonists

D. Adrenergic α2 antagonists 28. The primary reason for preferring phentolamine as the α adrenergic blocker for performing diagnostic test for pheochromocytoma is: A It produces rapid and short lasting α-adrenergic blockade

B. It equally blocks αl and α2 adrenoceptors C. It is the most potent α blocker D. It has no additional β adrenergic blocking property 29. Prazosin is an effective antihypertensive while nonselective α adrenergic blockers are not because: A. It is the only orally active α blocker B. It improves plasma lipid profile C. It does not concurrently enhance noradrenaline release D. It improves urine flow in males with prostatic hypertrophy 30. Select the drug which affords faster and greater symptomatic relief in benign hypertrophy of prostate: A Terazosin B. Desmopressin C. Finasteride D. Sildenafil 31. Select the drug which can improve urinary flow rate in benign prostatic hyper- trophy without affecting prostate size: A. Amphetamine B. Prazosin 52

C. Finasteride D. Goserelin

32. Which of the following is a selective αlA receptor blocker that affords sympto- matic relief in benign prostatic hypertrophy without producing significant fall in blood pressure: A. Terazosin B. Doxazosin C. Trimazosin D. Tamsulosin 33. Sildenafil is contraindicated in patients taking the following class of drugs: A. α-adrenergic blockers B. β-adrenergic blockers C. Organic nitrates D. Angiotensin converting enzyme inhibitors 34. What is true of Sildenafil: A. It enhances sexual enjoyment in normal men B. It delays ejaculation C. It improves penile tumescence in men with erectile dysfunction

D. It blocks cavernosal α2 adrenoceptors

35. The β adrenergic blocker having β1, selectivity, intrinsic sympathomimetic ac- tivity and membrane stabilizing property is: A. Carvedilol B. Atenolol C. Acebutolol D. Metoprolol 36. All of the following contribute to the antihypertensive action of propranolol except: A. Direct vasodilatation B. Decreased renin release from kidney C. Adaptation of blood vessels to reduced cardiac output D. Less noradrenaline release from sympathetic nerve endings (p. 125, 126) 37. The effect of propranolol on heart rate is least marked under the following condition: A. Physical exercise B. Rest C. Anxiety D. Sick sinus syndrome 38. Propranolol can be used to allay anxiety associated with: A. Chronic neurotic disorder 53

B. Schizophrenia C. Short-term stressful situations D. Endogenous depression 39. Propranolol does not block the following action of adrenaline: A. Bronchodilatation B. Lipolysis C. Muscle tremor D. Mydriasis 40. β-adrenergic blockers are indicated in the following conditions except: A. Hypertrophic cardiomyopathy B. Congestive heart failure C. Vasospastic angina pectoris D. Dissecting aortic aneurysm 41. In patients of congestive heart failure, β-adrenergic blockers: A. Are absolutely contraindicated B. Can prolong survival C. Can improve haemodynamics after compensation has been restored D. Both B and C are correct 42. The basis for use of β-adrenergic blockers in congestive heart failure (CHF) is: A. They exert positive inotropic effect in CHF B. They counteract deleterious effect of sympathetic overactivity on the myocardium C. They exert antiischaemic effect on the heart D. They prevent cardiac arrhythmias

43. Adrenergic β1, selective blockers offer the following advantages except: A. Lower propensity to cause bronchospasm B. Less prone to produce cold hands and feet as side effect C. Withdrawal is less likely to exacerbate angina pectoris D. Less liable to impair exercise capacity 44. The following is not a feature of cardioselective beta blockers, when compared to propranolol: A. They are ineffective in suppressing muscle tremor B. They are safer in diabetics C. They are less likely to cause bradycardia D. They are less likely to worsen Raynaud's disease 45. In a patient of myocardial infarction, β adrenergic blockers are used with the following aim/aims: A. To reduce the incidence of reinfarction B. To prevent cardiac arrhythmias 54

C. To limit size of the infarct D. All of the above 46. Labetalol has: A. More potent p adrenergic blocking than α blocking activity B. More potent β adrenergic blocking than α blocking activity C. Equal α and β adrenergic blocking activity

D. β1 agonistic activity in addition to α and β adrenergic blockade (p. 131) 47. Labetalol differs from propranolol in that:

A. It has additional αl blocking property

B. It is a selective β1 blocker C. It does not undergo first pass metabolism D. All of the above UNIT 10. TEST LESSON

Drugs Acting on Autonomic Nervous System

1. Local anesthetics: pharmacologic classes and agents. 2. Mechanism of action of local anesthetics. 3. Pharmacokinetics of local anesthetics: local action, systemic action (systemic absorption, distribution, metabolism and excretion). 4. The sites of anesthesia: topical anesthesia, infiltration anesthesia, nerve block and field block anesthesia, spinal intrathecal anesthesia, epidural anesthesia, in- travenous regional anaesthesia 5. Properties of selected local anesthetics: 6. - Ester-Type Drugs (cocaine, novocaine (procaine), dicaine, benzocaine). 7. - Amide-Type Drugs (lidocaine, bupivacaine, trimecaine, ultracaine). 8. Local anesthetics: adverse effects and interactions 9. Schematic diagram of efferent innervation: sites of action of cholinomimetics, anticholinesterases, cholinoblockers, adrenomimetics, adrenoblockers and ad- renergic neuron-blocking drugs. 10. Subtypes and main localizations of M-cholinoceptors in organs and tissues. Ef- fects of stimulation of these receptors. Regulation of gastric acid secretion. Transduction pathways in cardiomyocytes and smooth muscle cells. 11. Classification of drugs stimulating cholinergic neurotransmission. 12. Pharmacological effects of M-cholinomimetics and M, N-cholinomimetics (ac- tion on pupil size, intraocular pressure, accommodation, exocrine secretion, heart rate, vascular tone, arterial blood pressure, bronchial tone, intestinal mo- tility, tone of the urinary bladder). 55

13. Pilocarpine: mechanisms of action on intraocular pressure and accomodation, main therapeutic uses, adverse effects. 14. Bethanechol: pharmacological effects, mechanism of action, therapeutic uses, adverse effects. 15. Action of acetylcholine and M-cholinomimetics (bethanechol) on blood pres- sure and its mechanism. The change of this effect of acetylcholine and bethanechol in the presence of atropine. The difference between these drugs. 16. Classification of anticholinesterases. 17. Pharmacological effects of anticholinesterases (action on pupil size, intraocular pressure, accommodation, exocrine secretion, heart rate, arterial blood pres- sure, bronchial tone, intestinal motility, tone of the urinary bladder, neuro- muscular transmission). 18. Therapeutic uses and adverse effects of anticholinesterases. Characteristics of neostigmine, edrophonium, physostigmine, galan-thamine, rivastigmine. The main differences between these drugs. Irreversible anticholinesterases: thera- peutic uses of organophosphates (echothiophate and isoflurophate). 19. Toxic effects of anticholinesterases. Organo-phosphate poisoning and agents used in the treatment of these conditions. Acetylcholinesterase reactivation: pralidoxim. 20. N-cholinomimetics. Nicotine: pharmacological effects, uses to give up smok- ing. Acute intoxication and its treatment. The main pharmacological effects and therapeutic uses of lobeline. 21. Classification of drugs inhibiting cholinergic synapses. 22. M-cholinoblockers: atropine, scopolamine, pirenzepine, ipratropium, tiotropium, tropicamide. The main differences between these drugs. 23. Pharmacological effects of M-cholinoblockers (action on pupil size, intraocular pressure, accommodation, secretion of exocrine glands, heart rate, AV conduc- tion, bronchial tone, intestinal motility, tone of the urinary bladder). 24. Therapeutic uses and adverse effects of atropine and other M-cholinoblocking drugs. Toxic effects of atropine. Treatment of atropine overdose and poisoning with atropine-containing plants. 25. Ganglion-blocking drugs. Pharmacological effects (action on pupil size, ac- commodation, heart rate, vascular tone, blood pressure, intestinal motility, tone of the urinary bladder, secretion of salivary and bronchial glands and gastric acid secretion). 26. Therapeutic uses and adverse effects of ganglion-blocking drugs. 27. Characteristics of hexamethonium, trimethaphan, mecamylamine. 28. Classification of neuromuscular blockers. Mechanisms of action. Characteris- tics of tubocurarin, atracurium, pancuronium, mivacurium, succinylcholine. 56

29. Therapeutic indications and adverse effects of neuromuscular blockers. 30. Types and subtypes of adrenoceptors and their localization on the diagram of adrenergic varicosity. 31. The main localizations of adrenoceptor subtypes in organs and tissues. Effects of stimulation of these receptors. Transduction pathways in cardiomyocytes and smooth muscle cells. 32. Classification of drugs stimulating adrenergic neurotransmission. 33. Pharmacological effects of a,-adrenomimetics (action on vascular tone, blood pressure, heart rate, pupil size). Main therapeutic uses of phenylephrine. 34. Pharmacological effects of a2-adrenomimetics (action on vascular tone and NE release from postganglionic adrenergic nerve endings). Therapeutic uses of xylometazoline and naphazoline. 35. Clonidine. Pharmacological effects (action on vascular tone, heart rate, cardiac output, blood pressure). Mechanisms of central and peripheral action on blood pressure. Therapeutic uses and adverse effects. 36. Pharmacological effects of β1, β2-adrenomimetic isoproterenol (action on au- tomaticity, heart rate, contractility, AV-conduction, vascular tone, arterial blood pressure, bronchial tone) Therapeutic uses and adverse effects. 37. Pharmacological effects of β2-adrenomimetics (action on bronchial tone, vas- cular tone, arterial blood pressure, heart rate, tone and contractility of the my- ometrium). Main therapeutic uses and adverse effects. The difference between salbutamol (albuterol) and salmeterol. 38. Pharmacological effects of a β1-adrenomimetic dobutamine (action on the heart rate and contractility, AV conduction, automaticity). Therapeutic uses. 39. Pharmacological effects of epinephrine (action on the heart rate and contractili- ty, AV conduction, automaticity, vascular tone, arterial blood pressure, bron- chial tone, pupil size and intraocular pressure, glucose level in the blood and lipolysis). Therapeutic uses and adverse effects. 40. Pharmacological effects of norepinephrine (action on vascular tone, arterial blood pressure, heart rate). Therapeutic uses. 41. Pharmacological effects of ephedrine (action on the heart rate and contractility, AV conduction, automaticity, vascular tone, arterial blood pressure, bronchial tone, the CNS). Mechanism of action. Therapeutic uses and adverse effects. Tachyphylaxis. 42. Classification of drugs inhibiting adrenergic neurotransmission. 43. Classification of adrenoblocking drugs. 44. Pharmacological effects of nonselective oc-adrenoblocking drugs (action on vascular tone, arterial blood pressure, heart rate). Epinephrine reversal. Thera- 57

peutic uses and adverse effects. The difference between phentolamine and phenoxybenzamine. 45. Pharmacological effects of a,-adrenoblocking drugs (action on the vascular tone, arterial blood pressure, heart rate, tone of the bladder neck and prostate capsule). Therapeutic uses and adverse effects. The difference between prazosin, terazosin and tamsulosin). 46. Pharmacological effects of β-adrenoblocking drugs (action on heart rate and cardiac contractility, AV conduction, automaticity, renin release, tone of blood vessels, arterial blood pressure, bronchial tone, intraocular pressure). 47. Main therapeutic uses of β-adrenoblockers. Mechanisms of hypotensive, antianginal and antiarrhythmic effects. Therapeutic uses of propranolol. 48. Therapeutic uses of timolol. Mechanism of action on intraocular pressure. 49. Selective β1-adrenoblocking drugs. The difference between metoprolol, atenolol, betaxolol, esmolol, nebivolol. 50. Adverse effects of β-adrenoblockers associated with blockade of β1 and β2- adrenoceptors. Withdrawal syndrome. 51. α and β-adrenoblocking drugs. Pharmacological effects (action on the heart rate and cardiac contractility, tone of blood vessels, arterial blood pressure, bron- chial tone). Comparison of labetalol and carvedilol. Therapeutic uses and ad- verse effects. 52. Pharmacological effects and mechanisms of action of adrenergic neuron- blocking drugs (guanethidine and reserpine). Main therapeutic uses and adverse effects. 53. Action of phenylephrine (epinephrine, norepinephrine) and ephedrine on arte- rial blood pressure in the presence of reserpine. Mechanisms of interaction.

DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM

UNIT 11. GENERAL ANESTHETICS. SEDATIVE-HYPNOTICS. ETHANOL

The central nervous system (CNS) consists of the brain and spinal cord. Senso- ry information arrives to the CNS from the special senses and peripheral nerves and is integrated with memories and internal drive states to generate cognitive, emotional, and motor (behavioral) responses. This processing occurs because of the complex in- terplay of neurotransmitters and neuromodulators acting on their receptors to ex- cite or inhibit CNS neurons. In persons with brain disorders, structural or functional disturbances of CNS processing produce aberrant cognitive, emotional, or motor re- sponses. Brain disorders are seen in association with a variety of disease processes, including degenerative, ischemic, and psychological disturbances. 58

Most CNS drugs correct an imbalance in neurotransmitters or their recep- tors. Drugs are used to relieve the symptoms of brain dysfunction, but they usually do not correct the underlying disorder. Although short-term drug treatment may be effective in relieving acute symptoms such as pain and , drug therapy for many brain disorders is a life-long process.

TOPICS TO DISCUSS

1. Classifications of general anesthetics. 2. Mechanisms of action of inhalational anesthetics 3. Discribe stages induction by general anesthetics. 4. Pharmacological effects of inhalational anesthetics 5. Mechanisms of action of parenteral anesthetics. 6. Pharmacological effects of parenteral anesthetics. 7. Types of general anesthesia 8. Classifications of hypnotics. 9. Mechanisms of action of and . 10. Adverse effects of benzodiazepines as hypnotics. Effect on structure (re- bound effect on REM-sleep). 11. Adverse effects of barbiturates. Comparison with benzodiazepines. 12. . hydrate. . Main characteristics. 13. Ethanol. Absorption, distribution and metabolism. Pharmacological effects and their mechanisms. Clinical uses. 14. Ethanol dependence. Drugs used in the treatment of . Mechanism of disulfiram action.

BACKGROUND INFORMATION

Classification of General Anesthetics

INHALATIONAL ANESTHETICS Gases – Volatile liquids – Ether, , ,

PARENTERAL ANESTHETICS Barbiturates – Thiopental, Hexenal Nonbarbiturates – , General anesthetics include inhalational agents (e.g., nitrous oxide and halo- thane) and parenteral agents (e.g., ketamine and ). 59

The potency of inhalational anesthetics is expressed as the minimal alveolar concentration required to produce anesthesia. The potency is proportional to the oil: gas partition coefficient. The rate of induction of inhalational anesthetics is determined in part by the blood: gas partition coefficient. Nitrous oxide has a low coefficient and a rapid rate of induction. Halothane has a higher coefficient and a slower rate of induction. All inhalational anesthetics, except nitrous oxide, suppress respiratory function and decrease blood pressure in a dose-dependent manner. Parenteral anesthetics are used to induce anesthesia and to provide anesthesia during minor surgical and diagnostic procedures. They are also used in combination with other anesthetics during major surgical procedures.

Classification of hypnotics First generation Barbiturates: , Second generation Agonists of receptors: , , , , Third generation agonists of benzodiazepine receptors: ; ; Antihistamines (antagonists of Hl-receptors): , Agonists of MT1-, MT2-melatonin receptors: Melaxen, Sleep is a reversible state of reduced consciousness that is accompanied by characteristic changes in the EEG. Five distinct patterns of brainwave activity occur during sleep, grouped into the four stages of non-rapid eye movement sleep (NREM), and a pattern characterized by paralysis of voluntary muscles and quick, saccadic movement of the eye called rapid eye movement sleep (REM). As an individual falls asleep, the high-frequency and low-amplitude activity of the alert state gradually diminishes during stages 1 and 2 and is replaced by the low- frequency and high-amplitude activity of slow-wave sleep (stages 3 and 4). Over time, the individual returns to stage 1 and eventually to the REM stage. REM sleep is also known as paradoxical sleep because the EEG pattern is similar to the awake state. A normal adult cycles through the sleep stages about every 90 minutes. The term insomnia applies to a variety of sleep disturbances with difficulties in initiating sleep or maintaining sleep during the night. As a result, some patients can- not fall asleep; some awake very early or awake frequently at bedtime. One approach to therapy of insomnia is the use of sedative-hypnotics.

60

CHOOSE THE MOST APPROPRIATE RESPONSE 1. Which general anaesthetic selectively inhibits excitatory NMDA receptors: A. Thiopentone B. Halothane C. D. Ketamine 2. Which of the following is a sign of deep anaesthesia: A. Appearance of tears in eyes B. Resistance to passive inflation of lungs C. Fall in blood pressure D. Patient makes swallowing movements 3. The following factor delays induction with an inhaled general anaesthetic: A. Alveolar perfusion-ventilation mismatch B. Hyperventilation C. Low blood: gas partition coefficient of the anaesthetic D. Inclusion of 5% carbon dioxide in the inhaled gas mixture 4. The following anaesthetic can be used by the open drop method: A. Ether B. Desflurane C. Halothane D. Isoflurane 5. The following general anaesthetic has poor muscle relaxant action: A. Ether B. Nitrous oxide C. Halothane D. Isoflurane 6. Select the correct statement about nitrous oxide: A. It irritates the respiratory mucosa B. It has poor analgesic action C. It is primarily used as a carrier and adjuvant to other anaesthetics D. It frequently induces post anaesthetic nausea and retching 7. Ether is still used as a general anaesthetic in India, specially in peripheral hospi- tals because: A. It is nonexplosive B. It is pleasant smelling and nonirritating C. It induces anaesthesia rapidly D. It is cheap and can be administered without anaesthetic machine 8. As a general anaesthetic, halothane has the following advantages except: A. Very good analgesic action 61

B. Noninflammable and nonexplosive C. Reasonably rapid induction of anaesthesia D. Pleasant and nonirritating 9. The general anaesthetic having significant cardiodepressant property is: A. Halothane B. Enflurane C. Ether D. Nitrous oxide 10. Select the general anaesthetic that is particularly suitable for outpatient sur- gery because of quick recovery and short-lived post-anaesthetic psychomotor impairment: A. Ether B. Halothane C. Enflurane D. Desflurane 11. The anaesthetic action of thiopentone sodium is characterized by: A. Good muscle relaxation B. Poor analgesia C. Sensitization of heart to adrenaline D. No postoperative residual CNS depression 12. Disulfiram is used for the treatment of: A. Acute alcoholic intoxication B. Both physically and psychologically dependent alcoholics C. Alcoholics psychologically but not physically dependent on alcohol D. Both 'A' and 'B' are correct 13. Ethanol is used in poisoning because it: A. Antagonises the actions of methanol B. Stimulates the metabolism of methanol and reduces its blood level C. Inhibits the metabolism of methanol and generation of toxic me- tabolite D. Replenishes the folate stores depleted by methanol 14. Select the correct statement about benzodiazepines (BZDs): A. All BZDs facilitate GABA mediated Cl- influx into neurones B. Different BZDs exert the same degrees of , and anticovulsant actions C. The BZD receptor is homogeneous at all neuronal sites D. The muscle relaxant action of BZDs is not blocked by 15. The primary mechanism of action of benzodiazepines is: A. Dopamine antagonism 62

B. Adenosine antagonism C. Opening of neuronal chloride channels D. Facilitation of GABA-mediated chloride influx 16. At a single hypnotic dose, the pharmacokinetics of diazepam is characterized by: A. Slow elimination and little redistribution B. Slow elimination with marked redistribution C. Rapid elimination and marked redistribution D. Ultra rapid elimination 17. Which of the following statements is not true of zopiclone: A. It is a nonbenzodiazepine hypnotic with efficacy and safety similar to benzodiazpines B. It does not produce rebound sleep disturbances on discontinuation C. It does not act by potentiating GABA D. It is used to wean off insomniacs from regular benzodiazepine use 18. Zolpidem differs from diazepam in that: A. It is safer in overdose than diazepam B. Its hypnotic action shows little fading on repeated nightly use C. It causes more marked suppression of REM sleep D. It has more potent muscle relaxant action 19. The general principles in the use of hypnotics include the following except: A. A hypnotic may be used intermittently for up to 2-3 weeks in short-term insonia due to emotional stress B. In patients with chronic insomnia a hypnotic should be used regu- larly C. All hypnotics aggravate sleep apnoea D. A hypnotic with slow elimination is preferred in patients with early morn- ing awaening Multiple choice questions 20. Which of the following drugs stimulate GABA-ergic processes in the brain? A. Doxylamine B. C. Zolpidem D. 21. Nonbenzodiazepine agonists of benzodiazepine receptors are which of the fol- lowing? A. Zaleplon B. Phenobarbital 63

C. Zolpidem 22. Which of the following antihistamines are used as hypnotics? A. Diphenhydramine B. Loratadine C. Cetirizine D. Doxylamine 23. Which hypnotic drug is an aqonist of melatonin receptors? A. Phenobarbital B. Doxylamine C. Melaxene D. Ramelteon 24. Which of the following drugs are the first generation hypnotic? A. Phenobarbital B. Diazepam C. Amobarbital D. Flurazepam 25. Which of the following drugs are the second generation hypnotic? A. Phenobarbital B. Triazolam C. Amobarbital D. Flurazepam 26. Which of the following statements pertaining to hypnotics are correct? A. Doxylamine is an with sedative activity. B. Melatonin is a hormone of the pineal gland produced during dark- ness. C. Stimulation of melatonin receptors maintains the circadian rhythm underlying the normal sleep-wake cycle. D. Zaleplon is an antagonist of benzodiazepine receptors. E. Ramelteon is an agonist of melatonin receptors. 27. Which of the following statements concerning barbiturates are correct? A. They inhibit hepatic microsomal enzymes. B. They are considered safer drugs than benzodiazepines. C. They have narrow margin of safety. D. In toxic doses they cause deep respiratory depression. 28. Which of the following statements concerning the metabolism of ethanol are correct? A. Ethanol completely avoids first-pass effect. B. Ethanol is about 90% oxidized in the liver. C. Acetaldehyde is an intermediate metabolite of ethanol. 64

D. Ethanol elimination follows first-order kinetics. 29. Correct statements concerning chronic ethanolconsumption are all of the fol- lowing, except: A. Liver disease is the most common medical complication of alcohol abuse. B. Tolerance does not develop even after chronic alcohol use. C. The consumption of alcohol over a long period results in tolerance and dependence. D. Disulfiram promotes the acetaldehyde accumulation when used with al- cohol. 30. Disulfiram inhibits which of the following enzymes? A. Alcohol dehydrogenase B. Aldehyde dehydrogenase C. Monoamine oxidase D. Microsomal ethanol oxidizing enzymes

UNIT 12. OPIOID ANALGESICS. ANTIEPILEPTIC DRUGS. ANTIPARKINSONIAN DRUGS TOPICS TO DISCUSS 1. Classification of opioid analgesics. 2. Mechanisms of analgesic action of (diagram representing pain transmission pathway with descending antinociceptive system). 3. Central and peripheral effects of morphine. 4. Main therapeutic uses of morphine. 5. Other agonists of opioid receptors: codeine, fen-tanyl. Comparison with mor- phine. Therapeutic uses. Neuroleptanalgesia. 6. Subtypes of opioid receptors and their general characteristics. Agonists- antagonists and partial agonists of opioid receptors. Comparison with mor- phine. 7. Opioid overdosage and its treatment. Antagonists of opioid receptors. 8. Classification of antiepileptics according to their therapeutic uses. Therapeutic uses of individual drugs in different types of epilepsy. 9. The main adverse effects of benzodiazepines, phenobarbital, , car- bamazepine, sodium valproate. 10. The main approaches to the treatment of Parkinson's disease. Classification of antiparkinsonian drugs based on mechanism of action. 11. Levodopa. Mechanisms of action and penetration to the CNS. Levodopa — carbidopa combination. 65

12. Peripheral adverse effects of levodopa, their mechanisms and correction. 13. Central adverse effects of levodopa. On-off phenomenon and its correction. COMT inhibitors. 14. Dopamine receptor agonists. Comparison of bromocriptine and newer drugs (pramipexole and ropinirole). Adverse effects. 15. MAO-B inhibitor. Selegeline and its significance in the treatment of Parkin- son's disease. 16. Amantadine and its mechanisms of action. 17. Centrally-acting cholinergic antagonists. Mechanism of action and therapeutic uses in drug-induced parkinsonism. Adverse effects.

BACKGROUND INFORMATION Pain (the term is derived from the Latin «po-ena» – punishment) is described as an unpleasant sensory and emotional experience which is a reaction of the body to noxious stimulus* sufficient to cause tissue damage. Thus, pain has a protective early warning value. Under certain pathological conditions, intense pain may be caused by a weak noxious (hyperalgesia) and even non-noxious (allodynia) stimulus. Normally perception of pain begins with activation of nociceptors (high- threshold sensory endings of primary afferent fibres in peripheral tissues) by a nox- ious stimulus resulting in generation of action potential. produce their analgesic effect interacting with specific opioid receptors located in the brain and spinal cord. These receptors are divided into three major sub- types: mu-, kappa-, delta-. All these receptors are members of the G protein-coupled family. Morphine and other opioid agonists activate presynaptic mu, delta, or kappa opioid receptors on primary afferent neurons. These receptors are coupled negative- ly to adenylyl cyclase (AC) via G proteins. Inhibition of cyclic adenosine mono- phosphate (cAMP) formation leads to opening of potassium channels and closing of calcium channels. Potassium efflux causes membrane hyperpolarization. The closing of calcium channels inhibits the release of neurotransmitters, such as substance P. Opioid analgesics differ in their selectivity for opioid receptor subtypes and in- trinsic activity. There are full agonists of opioid receptors (with maximal intrinsic ac- tivity), partial agonists (with intrinsic activity less than maximal) and agonists — an- tagonists which stimulate one (mainly kappa -sybtype) and block another (mainly mu -subtype) of opioid receptors. Morphine stimulates all subtypes of opioid receptors (mu -receptors - to more extent). 66

Note: Tolerance develops to all opioid receptor ligands, irrespective of which type of receptors they act upon. Tolerance extends to most of the pharmacological effects of opioids such as analgesia, , and respiratory depression but develops to constipating and pupil-constricting effects to a lesser extent.

Classification of opioid analgesics Full agonists Natural opioids: Morphine, Codeine Synthetic opioids: Fentanyl, , Methadone Partial agonist Buprenorphine, Meptazinol Mixed agonists Pentazocine, Nalbuphine, Butorphanol Antagonists Naloxone, Naltrexone

Antiepileptic drugs Classification of antiepileptic drugs Drugs enhancing GABA-ergic activity Benzodiazepines: Diazepam, , Barbiturates: Phenobarbital GABA-transaminase inhibitor: Vigabatrin Inhibitor of neuronal GABA reuptake: Drugs inhibiting excitatory processes in the brain Sodium channel blockers: , Phenytoin, Lamotrigine Calcium channel blockers: Ethosuximide Drugs reducing glutamate-mediated excitation: Lamotrigine Drugs with mixed mechanisms of action: Sodium valproate (blocks sodium and calcium channels, increases GABA con- tent in the brain) (blocks sodium channels, inhibits glutamate action)

BACKGROUND INFORMATION Types of epilepsy Epilepsy is a chronic disorder characterized by recurrent seizures. Seizures result from abnormal discharge of cerebral neurons, starting locally and then often spread- 67 ing to other areas of the brain. The site of the primary discharge and the extent of its spread determine the symptoms that are produced. The accepted clinical classification of epilepsy recognizes two main categories: partial and generalized seizures. Partial seizures are those in which the discharge begins locally, and often remains localized. This may produce relatively simple symptoms without loss of conscious- ness, such as involuntary muscle contractions. More complex effects on conscious- ness, mood and behaviour, are often termed psychomotor epilepsy. Generalized seizures affect the whole brain, including the reticular system. Imme- diate loss of consciousness is a characteristic of these seizures. The main types are tonic-clonic seizures (grand mal) and absence seizures (petit mal). Tonic-clonic seizures consist of an initial strong contraction of the whole muscula- ture, causing a rigid extensor spasm, which is followed by a series of synchronous jerks. The patient remains unconscious for a few minutes and then recovers, feeling ill and confused. Absence seizures are less severe. The patient abruptly ceases whatever he was do- ing and recovers abruptly without any repercussions. Long-term drug therapy is required to prevent or reduce the recurrence of seizures (to control epilepsy). Uninterrupted seizures resulting from prolonged epileptic discharge are called sta- tus epilepticus. Convulsive episodes in status epilepticus last for several minutes and can be repetitive. As this prolonged epileptic discharge can cause neuronal death, sta- tus epilepticus needs to be stopped by intravenous administration of appropriate drugs.

Classification of Antiparkinsonian Drugs

Drugs enhancing dopaminergic activity Precursor of dopamine: Levodopa Drugs enhancing dopamine release: Amantadine Dopamine agonists: Bromocriptine, Pramipexole, Ropinirole MAO-B inhibitors: Selegiline Catechol-O-methyltransferase (CQMT) inhibitors: Entacapone Drugs inhibiting glutamatergic activity NMDA-receptor blocker: Amantadine Drugs inhibiting cholinergic activity Centrally acting cholinoceptor blockers: Trihexiphenidyl, Benztropine, Parkinson's Disease 68

Parkinson's disease is a progressive disorder of movement. The most prominent symptoms of the disease are: tremor at rest, muscle rigidity, bradykinesia. Parkinson's disease is associated with selective degenerations of dopaminergic neurons that originate in the substantia nigra of the midbrain and terminate in the ba- sal ganglia in the neostriatum. In normal state, dopamine released from dopaminergic nerve terminals sup- presses the intrinsic cholinergic neurons of the neostriatum that results in inhibition of acetylcholine (Ach) release. In Parkinson's disease, inhibitory dopaminergic control on neostriatal choliner- gic neurons is lost and Ach release increases. The imbalance between dopaminergic and glutamatergic systems also plays a role. In Parkinson's disease loss of inhibitory dopaminergic control on cholinergic neurons leads to predominant glutamate action. It results in stimulation of Ach release in the basal ganglia as well. There are three main approaches accepted in the treatment of Parkinson's disease: enhancement of dopaminergic activity, inhibition of glutamatergic activity, inhi- bition of cholinergic activity.

CHOOSE THE MOST APPROPRIATE RESPONSE

1. Choose the correct statement about codeine: A. It has a lower oral: parenteral activity ratio than morphine B. It is devoid of abuse liability C. It is a weaker analgesic than morphine D. It is a more potent antitussive than morphine 2. The following opioid is more potent than morphine: A. Codeine B. Fentanyl C. Buprenorphine D. Pentazocine 3. Which of the following is an agonist-antagonist type of opioid analgesic: A. Codeine B. Pentazocine C. Fentanyl D. Buprenorphine 4. Pentazocine differs from morphine in that: A. It is Inactive by the oral route B. It does not produce physical dependence 69

C. It has a lower ceiling of analgesic effect D. Its action is not blocked by naloxone 5. The following antiepileptic drug is most likely to impair learning and memory, and produce behavioral abnormalities in children: A. Valproic acid B. Phenobarbitone C. Phenytoin D. Ethosuximide 6. The following drug displaces plasma protein bound phenytoin as well as de- creases its metabolism: A. Carbamazepine B. Sodium valproate C. Cimetidine D. Chloramphenicol 7. Sodium valproate has been shown to: A. Prolong neuronal Na+ channel inactivation B. Attenuate ‘T’ type Ca2+ current in neurones C. Inhibit degradation of GABA by GABA-transaminase D. D. All of the above 8. Despite having action, diazepam is not used in the treatment of epilepsy because: A. It is not effective orally B. It causes C. Its anticonvulsant action wanes off with chronic use D. D. Both 'B' and 'C' are correct 9. Which of the following is the most suitable drug for a 6-year-old girl suffering from absence seizures with occasional generalized tonic-clonic seizures: A. Ethosuccimide B. Sodium valproate C. Carbamazepine D. Phenytoin 10. The following drug/drugs does/do not produce any overt CNS effect in normal individuals but exert(s) clear cut therapeutic effect at the same dose in the pres- ence of a specific neurological/psychiatric disorder: A. B. Levodopa C. D. All of the above 70

11. Which of the following adverse effects of levodopa has a delayed onset and in- creases in severity with continued therapy: A. Nausea and vomiting B. Postural hypotension C. Cardiac arrhythmia D. Abnormal movements 12. The antiparkinsonian drug which acts by inhibiting the degradation of dopamine in the brain is: A. Carbidopa B. Amantadine C. Selegiline D. Bromocriptine

Multiple Choice Questions 13. Which of the following are antiepileptic drugs? A. Phenytoin B. Lorazepam C. Carbamazepine D. Benztropine 14. Which of the following drugs enhance GABA-ergic activity in the brain? A. Clonazepam B. Phenobarbital C. Carbamazepine D. Lamotrigine 15. Antiepileptics blocking sodium channels are which of the following? A. Topiramate B. Ethosuximide C. Carbamazepine D. Lamotrigine 16. Sodium valproate causes which of the following? A. Block of sodium channels B. Block of calcium channels C. Enhancement of GABA-ergic activity D. Reduction of glutamate-mediated excitation 17. Drugs used intravenously to stop the attacks in status epilepticus are which of the following? A. Phenobarbital-sodium B. Lamotrigine C. Diazepam 71

D. Ethosuximide 18. Which of the following statements concerning phenytoin are correct? A. It is effective against tonic-clonic and partial seizures. B. The therapeutic indication of the drug is tonic-clonic seizures only. C. It is used for absences. D. Sodium channel recovery from inactivation is inhibited by the drug. 19. Which of the following statements concerning ethosuximide are correct? A. It is the drug of choice for absences. B. The drug is used to prevent tonic-clonic seizures. C. The management of status epilepticus is also an indication for the drug. D. The inhibition of calcium current in the thalamus accounts for the therapeutic action of this drug. 20. Which of the following statements concerning benzodiazepines are correct A. Clonazepam is effective against absences. B. Diazepam is used intravenously to stop attacks in status epilepticus. C. Diazepam is the drug of choice for preventing tonic-clonic seizures. D. Tolerance does not develop to their anticonvulsant action. 21. The principal approaches to drug therapy of Parkinson's disease are which of the following? A. Increase of dopaminergic activity in the basal ganglia B. Increase of cholinergic activity in the basal ganglia C. Increase of glutamatergic activity in the basal ganglia D. Decrease of cholinergic activity in the basal ganglia E. Inhibition of glutamatergic activity in the basal ganglia 22. Which of the following drugs are used in the treatment of parkinsonism? A. Phenytoin B. Bromocriptine C. Lorazepam D. Levodopa 23. Which of the following are drugs enhancing dopaminergic activity in the basal ganglia? A. Amantadine B. Benztropine C. Biperiden D. Levodopa 24. Which of the following is the drug inhibiting glutamatergic activity in the basal ganglia? A. Levodopa B. Amantadine 72

C. Benztropine D. Bromocriptine 25. Which of the following are catechol-O-methyltransferase inhibitors? A. Levodopa B. Bromocriptine C. Entacapone D. Tolcapone 26. Which of the following statements concerning levodopa are correct? A. The drug is effective in reducing symptoms of Parkinson’s disease on its own. B. Antiparkinsonian effect of the drug is based on its conversion to do- pamine in the CNS. C. It crosses the blood-brain barrier by passive diffusion. D. It crosses the blood-brain barrier by carrier-mediated transport. 27. Which of the following statements concerning carbidopa are correct? A. It is an inhibitor of dopa decarboxylase. B. It penetrates the blood-brain barrier. C. Combined with levodopa it promotes the increase of levodopa level in the brain. D. It decreases the dopamine level in the peripheral tissue.

UNIT 13. NEUROLEPTICS, ANXIOLYTICS

TOPICS TO DISCUSS 1. Classification of neuroleptics. 2. General effects of typical drugs resulting from their action on dopaminergic system. Pharmacotherapeutic and adverse effects of typical anti- psychotics. Mechanisms of the effects. 3. Main pharmacological effects of chlorpromazine resulting from blockade of different types of receptors in the CNS and periphery. 4. Comparison of chlorpromazine, triphluopera-zine, , haloperidol and thiothixene: pharmacological effects, therapeutic uses. 5. General effects of drugs. The main differences between typical and atypical . 6. Individual characteristics of , , sulpiride and . 7. Classification of anxyolytics. 8. Pharmacological effects and mechanism of CNS depressant action of benzodi- azepines (based on the diagram of benzodiazepine — GABA receptor com- plex). 73

9. Pharmacological effects of benzodiazepines. Nonbenzodiazepine agonists of benzodiazepine receptors. Comparison with benzodiazepines. Main therapeutic uses and adverse effects of benzodiazepines. Antagonist of benzodiazepine re- ceptors. 10. Mechanism of anxiolytic action of . Pharmacological effects of buspirone. Comparison of benzodiazepines and buspirone. Psychosis is a mental disorder that involves a breakdown of the personality. Thought patterns and physical actions appear unrelated to real-life situations. The two major forms of psychotic illness arc schizophrenia and endogenous depression. Neurosis is an accumulation of anxiety and tension, which leads to emotional changes and abnormal behavior. Schizophrenia is a psychotic illness characterized by the symptoms which are divid- ed into: - positive (such as , delusions, thought disorder, agitation, aggressive behavior); - negative (such as loss of empathy, social isolation, flattening of emotional respons- es, poverty of speech). In schizophrenia, individuals are usually withdrawn, and behavior is inappropriate and highly unpredictable. Acute episodes of schizophrenia mainly include positive symptoms. Although pathogenesis of schizophrenia is far from being completely understood, pharmacological investigations and biochemical findings are consistent with the hy- pothesis about dopamine overactivity in some regions of the brain which arc associ- ated with the disease. Dopaminergic pathways in the brain include: • mesolimbic-mesocortical pathway which projects from cell bodies in the ventral mesencephalon to the limbic system and neocortex; block of dopamine D2-receptors in this patway is responsible for antipsychotic effect (mainly for relieving positive symptoms of schizophrenia); • nigrostriatal pathway which contains dopaminergic neurons originating in the substantia nigra of the midbrain and terminating in neo-striatim (caudate and puta- men); block of dopamine D2-receptors on cholinergic neurons in the neostriatum is responsible for parkinsonism (tremor, rigidity, bradykinesia) and some other extrapy- ramidal motor disturbances (e.g. acute dystonia, akathisia); • tuberoinfundibular pathway which connects arcuate nuclei and periventricular neurons to the hypothalamus and the pituitary; block of dopamine D,-receptors in this system is responsible for increase in prolactin release (as dopamine is a physio- logical inhibitor of prolactin secretion); 74

• trigger zone of vomiting centre; block of dopamine D2-receptors in this region is responsible for the antivomiting effect.

All drugs cause blockade of dopamine D2-receptors in these pathways and thus produce their therapeutic and adverse effects.

Note: The affinity of antipsychotics for D2-receptors correlates with antipsychotic efficacy (relieving of positive symptoms of schizophrenia) and degree of extrapyram- idal adverse effects as well.

Classification of neuroleptics

TYPICAL ANTIPSYCHOTIC DRUGS : Chlorpromazine, Trifluoperazine, Thioridazine Butyrophenones Haloperidol, : Thiothixene

ATYPICAL ANTIPSYCHOTIC DRUGS Clozapine, Olanzapine, Sulpiride, Risperidone Anxiety states Anxiety states are associated with excessive and unmotivated fear re- actions such as defensive behaviors, autonomic reflexes, negative emotions, etc. Anx- iety disorders have clinically different variants: - generalized anxiety disorder which is characterized by excessive anxiety when there are no clear reasons for it; - panic disorder – attacks of strong fear accompanied by such somatic symptoms as tachycardia, sweating, chest pain, trembling, etc; - phobias – excessive fears of specific things or situations, e.g. height, closed rooms, sea trips, beetles, etc. Specific drugs called anxiolytics are used for the symptomatic treatment of anxiety disorders.

Classification of anxiolytics I) Benzodiazepines short-acting (t1/2<6 hrs): triazolam, midazolam; intermediate-acting (t1/2 6-24 hrs): temazepam, lorazepam; long-acting (t1/2 >24 hrs): flurazepam, diazepam (Valium®) II) Non-benzodiazepines Buspirone, Propranolol

CHOOSE THE MOST APPROPRIATE RESPONSE

75

1. Which of the following is a high potency antipsychotic drug having minimal seda- tive and autonomic effects and no propensity to cause weight gain: A. Chlorpromazine B. C. Haloperidol D. Olanzapine 2. Clozapine is considered to bean atypical neuroleptic because: A. It has weak antidopaminergic action but high antipsychotic efficacy B. Its side effect profile is different from that of chlorpromazine C. It is not a derivative D. Both 'A' and 'B' are correct 3. The following adverse effect can occur even long after withdrawal of the of- fending drug: A. Paradoxical tachycardia B. Tardive dyskinesia C. Malignant hyperthermia D. Gynaecomastia 4. The extrapyramidal adverse effect of antipsychotic drug therapy which does not respond to central anticholinergics is: A. Parkinsonism B. Acute muscle dystonia C. Rabbit syndrome D. Tardive dyskinesia 5. The psychotic symptoms most benefited by neuroleptic drugs are: A. Judgement and memory impairment B. Loss of insight and volition C. Hallucinations, delusions and aggressive behaviour D. Apathy and social withdrawal 6. The following statement(s) is/are correct in relation to diazepam and chlorproma- zine: A. Both have anticonvulsant property B. Both do not carry abuse liability C. Both have antianxiety action D. All of the above are correct 7. Which of the following is a non-benzodiazepine anxiolytic: A. Chlorpromazine B. Buspirone C. Haloperidol D. Qxazepam 76

8. The following statement is correct about buspirone: A. It interacts with benzodiazepine receptor as an B. It is a rapidly acting anxiolytic, good for panic states C. It produces physical dependence and suppresses barbiturate withdrawal syndrome D. It has anxiolytic but no anticonvulsant or muscle relaxant proper- ty 9. The major constraint in the long term use of ben-zodiazepines for treatment of generalized anxiety disorder is: A. Development of tolerance to antianxiety action of the benzodiazepines B. Possibility of drug dependence C. Cardiovascular depression 10. The primary mechanism of action of benzodiazepines is: A. Dopamine antagonism B. Adenosine antagonism C. Opening of neuronal chloride channels D. Facilitation of GABA-mediated chloride influx 11. Which of the following statements is not true of zopiclone: A. It is a nonbenzodiazepine hypnotic with efficacy and safety similar to ben- zodiazepines B. It does not produce rebound sleep disturbances on discontinuation C. It does not act by potentiating GABA D. It is used to wean off insomniacs from regular benzodiazepine use 12. The following drug is used to reverse the CNS depression produced by diaz- epam: A. Dexamphetamine B. Doxapram C. Physostigmine D. D. Flumazenil 13. Select the correct statement about flumazenil: A. It is a CNS used as an antidote for benzodiazepine poisoning B. It is a CNS depressant but blocks the action of diazepam C. It has no CNS effect of its own but blocks the depressant effects of benzodi- azepines as well as barbiturates D. It has no CNS effect of its own but blocks the depressant effect of diaze- pam as well as stimulant effect of beta carbolines

Multiple choice questions 14. Antipsychotic drugs are which of the following? 77

A. Droperidol B. C. Clozapine D. Thioridazine 15. Which of the following antipsychotic drugs are phenothiazine derivatives? A. Droperidol B. Clozapine C. Thioridazine D. Thiothixene E. Chlorpromazine F. Trifluoperazine 16. Butyrophenone derivatives are which of the following? A. Thioridazine B. Thiothixene C. Haloperidol D. Trifluoperazine E. Droperidol 17. All of the following receptors are targets for chlorpromazine:

A. H1-histamine receptors

B. D2-dopamine receptors C. α-adrenoceptors D. m-cholinoceptors

E. 5-HT1A-receptors

F. 5-HT2-receptors. 18. Which of the following receptors are targets for clozapine? A. m-cholinoceptors B. a-adrenoceptors

C. 5-HT1A -receptors

D. 5-HT2 receptors

E. H1-histamine receptors 19. Which of the following receptors are blocked by clozapine to a more extent than by chlorpromazine?

A. D4-receptors

B. D2-dopamine receptors C. α-adrenoceptors

D. 5-HT2-receptors 20. Which of the following receptors are blocked by sulpiride? A. m-cholinoceptors B. α-adrenoceptors 78

C. D2-dopamine receptors

D. 5-HT2-receptors

E. H1-histamine receptors 21. Possible therapeutic uses of neuroleptics are which of the following? A. Schizophrenia B. Endogenous depression C. Emesis D. Status epilepticus E. Neuroleptanalgesia 22. Pharmacological effects of phenothiazine and butyrophenone derivatives are which of the following? A. Reduction of positive symptoms such as delusions and hallucinations B. Hypotension C. Agitation D. Extrapyramidal motor disturbances E. Antiemetic action F. Decrease of prolactin secretion G. Potentiation of action of general anesthetics and opioid analgesics 23. Short-acting benzodiazepines are which of the following? A. B. C. Diazepam D. Flurazepam E. Triazolam 24. Intermediate-acting benzodiazepines are which of the following? A. Lorazepam B. Diazepam C. Alprazolam D. Midazolam E. Flurazepam 25. Long-acting benzodiazepines are all of the following, except: A. Diazepam B. Midazolam C. D. Clonazepam E. Flurazepam. 26. Benzodiazepines can cause which of the following effects? A. Skeletal muscle relaxation B. Sedation 79

C. Insomnia D. Anterograde E. Improvement of learning ability 27. Main therapeutic uses of benzodiazepines are which of the following? A. Insomnia B. As a component of anesthesia C. Parkinson's disease D. Anxiety disorders E. Trigeminal neuralgia F. Spasticity from degenerative disorders 28. Which of the following statements concerning buspirone are correct? A. Unlike benzodiazepines it does not cause sedation or motor incoor- dination. B. Buspirone has high dependence potential with rapid appearance of with- drawal symptoms. C. The onset of action of buspirone is slow over several days. D. Buspirone potentiates the CNS depressant effects of sedative-hypnotics. E. It is ineffective in controlling panic attacks

UNIT 14. ANTIDEPRESSANT DRUGS

1. Classification of . 2. General mechanisms of antidepressant action. 3. Nonselective monoamine reuptake inhibitors. Tricyclic antidepressants (pharma- cological effects, mechanism of antidepressant action, clinical effectiveness, ad- verse effects, acute overdose and its treatment). 4. Selective serotonin reuptake inhibitors. Comparison with tricyclic antidepressants (pharmacological effects, clinical effectiveness, adverse effects). 5. Selective norepinephrine reuptake inhibitors. 6. Monoamine oxidase inhibitors. Comparison of nonselective and selective inhibi- tors (mechanisms of action, effectiveness, adverse effects). Interaction with drugs and food («cheese reaction*). 7. Atypical antidepressants (, ). General characteristics, adverse effects. 8. Drugs used in the treatment of bipolar affective disorder (manic-depressive ill- ness). Lithium and other mood-stabilizing drugs. Therapeutic uses of antidepres- sants.

AFFECTIVE DISORDERS 80

Affective disorders are also called mood disorders. The two most common af- fective disorders are major depressive disorder and bipolar disorder. The primary drugs used in their treatment are antidepressant drugs and mood-stabilizing drugs.

Clinical Findings

Major Depressive Disorder (unipolar depression) is characterized by de- pressed mood, loss of interest or pleasure in life, sleep disturbances, feelings of worthlessness, diminished ability to think or concentrate, and recurrent thoughts of suicide. Depressed patients can also be irritable or anxious.

Bipolar Disorder (previously called manic-depressive disorder) is character- ized by recurrent fluctuations in mood, energy, and behavior that encompass the ex- tremes of human experience. This disorder differs from major depression in that peri- ods of mania alternate or occur simultaneously with depressive symptoms. The clini- cal presentation varies widely. The manic phase is characterized by elevated mood, inflated self-esteem (grandiosity), increased talking (pressure of speech), racing thoughts (flight of ideas), increased social or work activity, and decreased need for sleep. Manic patients can become hostile and uncooperative. As the manic phase in- tensifies, some patients experience psychotic symptoms such as delusions. Typically, the manic phase occurs just before or just after a depressive episode. In many patients, depressive and manic episodes last several weeks or months. In some patients, however, the episodes change within hours or days (rapid cycling bipolar disorder).

Biogenic Amine Hypothesis According to the biogenic amine hypothesis, mood disorders result from ab- normalities in serotonin, norepinephrine, or dopamine neurotransmission. Sero- tonergic fibers projecting from the raphe nuclei in the midbrain to limbic structures are important in regulating mood, among other functions. The serotonergic system is activated during behavioral arousal and increases cortical awareness of emotional re- actions to environmental events. It is believed that impaired serotonin neurotransmis- sion can decrease cortical responsiveness to emotional activation, leading to affective dysfunction and depression. Noradrenergic fibers that project from the locus ceruleus to the cerebral cortex can also play a role in depression, as can dopaminergic fibers innervating the nucleus accumbens. Evidence also links depression with abnormal circadian rhythms and mela- tonin regulation. Melatonin, the principal mediator of biologic rhythms, is known to suppress the activity of serotonergic neurons. Investigators postulate that excess mel- 81 atonin production contributes to the development of depression. This hypothesis is particularly relevant to seasonal affective disorder, which usually occurs during the winter months, when daylight is reduced and melatonin levels are increased. Abnor- malities in melatonin and serotonin metabolism can also contribute to the sleep dis- turbances seen in patients with affective disorders. The biogenic amine hypothesis is supported by the fact that all antidepressant drugs act to increase serotonin, norepinephrine, or dopamine neurotransmission in the brain. Most antidepressant drugs increase the synaptic concentration of serotonin, and this leads to down-regulation of presynaptic autoreceptors. Investigators believe that the down-regulation, in turn, increases the firing rate of serotonergic neurons and thereby produces the delayed therapeutic effect of antidepressant drugs. Recent data that antidepressant medications produce an increase in the rate of appearance of new neurons, called neurogenesis, in the brain of nonhuman mammals suggest a novel mechanism of antidepressant drug action. Studies have yet to show the correlation between increased appearance of brain neurons and the clinical effec- tiveness of antidepressants, but this interesting finding provides another view to the possible causes of depression and its treatment. Classification of antidepressant drugs

I. MONOAMINE REUPTAKE INHIBITORS Nonselective monoamine (serotonin and noradrenaline) reuptake inhibitors (tricyclic antidepressants): Imipramine, Amitriptiline Selective serotonin reuptake inhibitors: Selective noradrenaline reuptake inhibitors: II. MONOAMINE OXIDASE (MAO) INHIBITORS Nonselective irreversible MAO inhibitors: , Tranylcypromine Selective reversible MAO-A inhibitors: Moclobemide III. MISCELLANEOUS (ATYPICAL) ANTIDEPRESSANTS: Trazodone, Mirtazapine,

CHOOSE THE MOST APPROPRIATE RESPONSE 1. Adaptive changes in brain monoamine turnover due to blockade of noradrenaline 5-HT reuptake is credited with the following effect: A. Antipsychotic B. Antianxiety C. Antiparkinsonian D. Antidepressant 2. The selective serotonin reuptake inhibitors have overcome the following iimitation(s) of typical tricyclic antidepressants: 82

A. Frequent anticholinergic, sedative and hypotensive side effects B. High risk of cardiac arrhythmias and seizures in overdose C. Delayed response D. Both 'A' and 'B' are correct 3. The tricyclic antidepressants are also effective in the following psychiatric disor- ders except: A. Schizophrenia B. Obsessive-compulsive disorder C. Bulimia D. Phobic states 4. Indications of tricyclic antidepressants include the following except: A. Attention deficit-hyperactive disorder in children B. Mania C. Prophylaxis of migraine D. Panic disorder 5. The main mechanism of action of tricyclic antidepressants is which of the fol- lowing? A. Direct stimulation of adrenergic and sero-toninergic receptors B. Inhibition of monoamine oxidase C. Inhibition of NE and serotonin reuptake by monoaminergic nerve terminals 6. Fluoxetine causes which of the following? A. Inhibition of monoamine (serotonine, norepinephrine, dopamine) reuptake B. Selective inhibition of MAO-A C. Selective inhibition of norepinephrine reuptake D. Selective inhibition of serotonin reuptake E. Inhibition of both MAO-A and MAO-B 7. Sedative effect of antidepressants mainly correlates with the blockade of which of the following receptors? A. M-cholinoceptors B. 5-HT-serotonin receptors

C. H1-histamine receptors D. α-adrenoceptors

Multiple choice questions 8. Amitriptyline interacts with which of the following molecular targets? A. Transport protein for serotonin reuptake B. Transport protein for dopamine reuptake 83

C. Monoaminooxidase (MAO)-A D. Transport protein for norepinephrine (NE) reuptake E. m-cholinoceptors

F. H1-histamine receptors 9. Amitriptyline causes which of the following? A. Analgesia B. Insomnia C. Agitation D. Constipation E. Urinary retention F. Postural hypotension G. Sedation 10. Atropine-like effects of amitriptyline are which of the following? A. Dry mouth B. Sedation C. Blurred vision D. Constipation E. Urinary retention F. Postural hypotension G. Tachycardia 11. Which of the following are therapeutic uses of tricyclics? A. Insomnia B. Epilepsy C. Major depression D. Cardiac arrhythmias E. Chronic neuropathic pain F. Mania 12. Which of the following effects are common to both tricyclic antidepressants and fluoxetine? A. Sedation B. Conversion to active metabolite(s) C. Strong antimuscarinic effect D. The delay for 2-3(4) weeks of antidepressant effect E. Interaction with MAO inhibitors F. Cardiotoxic effect 13. Which of the following statements concerning fluoxetine are correct? A. It is likely to be more effective than tricyclics. B. It causes insomnia rather than sedation. C. It resembles tricyclics in their toxic cardiovascular effects. 84

D. Acute toxic effects are much less than with tricyclics. 14. Which of the following effects are caused by non-selective MAO inhibitors? A. Increase of serotonin, norepinephrine and dopamine cytoplasmic concentration in nerve terminals B. Increase of serotonin, norepinephrine and dopamine vesicular stores in nerve terminals C. Sedation D. CNS stimulation E. Atropine-like effects F. Postural hypotension 15. Which of the following statements correctly describe "cheese reaction"? A. It is caused by nonselective MAO inhibitors if patients eat tyramine- contaning food (e.g. ripe cheese). B. The use of both selective and non-selective MAO-inhibitors is likely to cause "cheese reaction" with the same frequency. C. Inhibition of both MAO-A and MAO-B results in elevation of blood level of tyramine causing rise in blood pressure. 16. Which of the following effects are caused by moclobemide? A. Selective inhibition of MAO-A B. Selective inhibition of MAO-B C. Inhibition of both MAO-A and MAO-B D. Insomnia E. Sedation 17. Which of the following drugs are referred to as atypical antidepressants? A. Fluoxetine B. Trazodone C. Imipramine D. Mirtazapine. 18. Sedation is mainly caused by which of the following antidepressants? A. Fluoxetine B. Amitriptyline C. Trazodone D. Imipramine E. Phenelzine F. Mirtazapine G. Moclobemide 19. Which of the following antidepressants possess the CNS stimulant effect? A. Fluoxetine B. Amitriptyline 85

C. Moclobemide D. Imipramine E. Phenelzine F. Mirtazapine

UNIT 15. CNS STIMULANTS. COGNITION ENHANCERS DRUGS (NOOTROPIC DRUGS)

1. Classifications of CNS stimulants. 2. Pharmacological effects of . Mechanisms of CNS stimulant ac- tion of amphetamines (based on the diagram of monoaminergic synapses). 3. Main therapeutic uses and adverse effects of amphetamines. 4. Mechanisms of pharmacological effects and therapeutic uses of caffeine. 5. Comparison of amphetamines and caffeine. 6. Classifications. Mechanism of action and therapeutic uses of respiratory stimu- lants (analeptics). 7. Cognition enhancing drugs: classification, clinical use.

BACKGROUND INFORMATION

Comparison of CNS stimulants Amphetamines act at monoaminergic synapses by releasing monoamines, especially NE and DA in the brain and spinal cord. The main central effects of amphetamines include: — increase of motor activity — increase of mental and physical performance and alertness — decrease of fatigue and need of sleep — excitement — euphoria and drug dependence — anorexia (decrease of appetite) The main peripheral effects of amphetamines depend mostly on NE release and in- clude rise in blood pressure and inhibition of gastrointestinal motility, as well as car- diac arrhythmias in high doses. Discontinuation of amphetamines results in with- drawal syndrome the main symptoms of which include prolonged sleep, fatigue and hunger. is the amphetamine drug which is the most commonly used: — in narcolepsy (a disorder, in which the patient suddenly and unpredictably falls asleep at frequent intervals during a day); — to control hyperkinetic children in attention deficit syndrome. 86

Caffeine, theophylline, theobromine are methylxanthine alkaloids occurring natu- rally in some plants and widely consumed in the form of beverages such as tea (con- tains caffeine and theophylline), coffee (primarily contains caffeine), cocoa (caffeine and theobromine), cola drinks. The CNS stimulation caused by these beverages pre- dominantly results from the action of caffeine. Similar to amphetamines, caffeine reduces fatigue and improves mental perfor- mance. Unlike amphetamines, it stimulates respiratory and vasomotor centre in the medullary region of the brain (analeptic effect), produces less motor stimulation and does not cause euphoria and psychosis. Tolerance develops very slowly and much less than with amphetamines. Withdrawal effects are also very slight.Peripheral ef- fects of methylxanthines include increase in heart rate, relaxation of smooth muscle (bronchial, vascular), and stimulation of diuresis. The clinical use of respiratory stimulants {analeptics) is limited due to a very nar- row margin of safety between respiratory stimulation and convulsions. Doxapram and amiphenazol have bigger margin of safety and therefore are sometimes used in acute respiratory failure.

Alzheimer's disease is a type of progressive dementia for which no cause is known and no cure has been found. In the United States, Alzheimer's disease ac- counts for about 60% of all cases of dementia in patients over 65 years of age and is associated with more than 100,000 deaths each year. The disease has a tremendous negative impact on patients and their families because of its devastating effects on the cognitive, emotional, and physical function of the patient with Alzheimer's disease Alzheimer's disease results from the destruction of cholinergic and other neu- rons in the cortex and limbic structures of the brain, particularly the amygdala, ba- sal forebrain, and hippocampus. Major changes in these structures include cortical at- rophy, neurofibrillary tangles, and neuritic plaques containing β-amyloid protein. The cholinergic neurons destroyed in Alzheimer's disease originate in Meynert's nucleus (nucleus basalis) in the forebrain. These neurons project to the frontal cortex and hippocampus, and they have a critical role in memory and cognition. Classification of Psychomotor Stimulants

Drugs with direct action: Methylxantines (Caffeine, theophylline) Drugs with indirect action: Phenylethylamines (Ampetamine, fenfluramine)

Classification of respiratory stimulants Drugs with direct action: caffeine, doxapram, prethicamide Drugs with reflex action: lobeline 87

Drugs with mixed action: nikethamide, carbogen

Classification of cognition enhancing drugs:

Racetams: pyracetam, anyracetam Synaptotropic drugs: Cholinergic activators (tacrine, rivastigmine) GABAergic drugs (hopaten, ) Glutaminergic drugs (glycine, glutamic acid) Dopamine agonists (levodopa, selegiline) Vasoactive cerebral protector: cavinton, , pyritinol, ginkgo biloba Neuropeptides, hormones: semax, melatonine

CHOOSE THE MOST APPROPRIATE RESPONSE 1. The neurotransmitter system in the brain most affected in Alzheimer's dis- ease is: A. Glutaminerglc B. Gabaergic C. Dopamlnergic D. Cholinergic 2. Hepatotoxicity has markedly restricted use of the following cerebroselective anticholinesterase in Alzheimer's disease: A. Rlvastigmine B. Tacrine C. Galantamlne D. Donepezil 3. The following is true of rivastigmine except: A. It is a relatively selective inhibitor of Gl isoform of acetylcholinesterase B. It has been found to retard disease progression in Alzheimer's dis- ease C. It affords measurable improvement in Alzheimer's disease symptom score D. It enhances cerebral cholinergic transmission with only mild peripheral effect 4. Select the drug that improves some symptoms in Alzheimer's dementia by increasing brain acetylcholine levels: A. Pemoline B. Donepezil C. Nicergoline 88

D. Piribedil 5. Select the correct statement abut donepezil: A. It is a topical carbonic anhydrase inhibitor used in glaucoma B. It is a catechol-O-methyl transferase inhibitor used as adjuvant in parkinson's disease C. It is a cerebroselective anticholinesterase that affords symptomat- ic improvement in Alzheimer's disease D. It is a synthetic with antiemetic property 6. Pyritinol (pyrithioxine) is used as: A. Analeptic drug B. Cognition enhancing drug C. Antiepileptic drug 7. All of the following are pharmacological effects of methylxanthines, except: A. Stimulation of hydrochloric acid secretion B. Relaxation of bronchial smooth muscle C. Increase of glomerular filtration rate D. Sedation E. Direct stimulation of the heart rate. F. Antidepressant drug

Multiple choice questions 8. Which of the following groups of drugs are psychomotor stimulants? A. Methylxanthines B. Benzodiazepines C. Phenothiazines D. Amphetamines E. Barbiturates 9. Which of the following drugs are psychomotor stimulants? A. Codeine B. Methylphenidate C. Bromocriptine D. Caffeine 10. Which of the following are the mechanisms of CNS stimulant action of am- phetamines? A. Release of intracellular stores of NE and dopamine B. Inhibition of phosphodiesterase C. Blockade of adenosine receptors D. Inhibition of reuptake of NE and dopamine 89

11. All of the following are the behavioral effects of amphetamines, EXCEPT: A. Reduction of fatigue B. Increase of alertness C. Increase of motor activity D. Drowsiness E. Excitement. 12. Amphetamines can cause which of the following effects? A. Increased mental alertness B. Anorexia (reduced appetite) C. Euphoria D. Hypotension 13. The main consequenses of chronic amphetamines use are which of the follow- ing? A. Drowsiness B. Drug dependence C. Tolerance D. Increased appetite E. Insomnia 14. Which of the following are therapeutic uses of methylphenidate? A. Insomnia B. Narcolepsy C. Hypertension D. Attention deficit syndrome in children 15. Mechanisms of action of methylxanthines are which of the following? A. Inhibition of phosphodiesterase B. Inhibition of MAO C. Blockade of adenosine receptors D. Inhibition of adenylate cyclase E. Release of NE 16. Methylxanthines include: A. Theophylline B. Cocaine C. Caffeine D. Nicotine E. Theobromine. 17. Peripheral effects of caffeine are which of the following? A. Direct relaxation of smooth muscles B. Mild diuretic action 90

C. Bradycardia D. Direct positive chronotropic effect E. Inhibition of gastric acid secretion 18. Which of the following are common central effects of caffeine? A. Reduction of fatigue B. Increase in mental performance C. Sedative effect D. Decrease of motor activity E. Insomnia F. Stimulation of respiratory and vasomotor centers

UNIT 16. TEST LESSON DRUGS ACTING ON THE CENTRAL NERVOUS SYSTEM

I. Drug classifications Classifications of: 1. general anesthetics; 2. hypnotics; 3. antiepileptic drugs (based on therapeutic uses); 4. antiepileptic drugs (based on mechanisms of action); 5. antiparkinsonian drugs; 6. opioid analgesics; 7. centrally acting nonopioid analgesics; 8. antipsychotic drugs; 9. antidepressants; 10. anxiolytics; 11. CNS stimulants.

II. Mechanisms of action 1. Mechanism of CNS depressant action of benzodiazepines and barbiturates (based on the corresponding diagram). 2. Mechanism of analgesic action of morphine, buprenorphine, butorphanol. 3. Mechanism and sites of action of levodopa, selegiline, amantadine, bromocriptine, entacapone in Parkinson's disease (based on the diagrams of dopaminergic synapse and nigrostriatal pathway). 4. Mechanism of antipsychotic action of chlorpromazine. 91

5. Mechanism of action of tricyclic antidepressants, fluoxetine and MAO inhibi- tors (based on the diagram of monoaminergic synapses). 6. Mechanism of anxiolytic action of buspirone. 7. Mechanism of CNS stimulant action of amphetamines (based on the diagram of monoaminergic synapses). 8. Mechanism of pharmacological effects of caffeine.

III. Pharmacological effects 1. Pharmacological effects of general anesthetics: , enflurane, nitrous oxide, thiopental, ketamine. 2. Pharmacology of ethanol. 3. Pharmacological effects of morphine. 4. Comparison of agonists, agonists-antagonists and partial agonists of opioid re- ceptors. 5. Pharmacological effects of benzodiazepines. 6. Comparison of flurazepam and Zolpidem. 7. Comparison of benzodiazepines and barbiturates. 8. Comparison of benzodiazepines and nonbenzodiazepine agonists of benzodiaz- epine receptors. 9. Pharmacological effects of levodopa. 10. Pharmacological effects of chlorpromazine. 11. Comparison of pharmacological effects of chlorpromazine and haloperidol. 12. The main differences between typical and atypical antipsychotics. 13. Comparison of pharmacological effects of chlorpromazine and clozapine. 14. Pharmacological effects of sulpiride and risperidone. 15. Pharmacological effects of tricyclic antidepressants amitriptyline and imipra- mine. 16. Comparison of tricyclic antidepressants and fluoxetine. 17. Pharmacological effects of MAO inhibitors. 18. Pharmacological effects of lithium carbonate. Pharmacological effects of amphetamines. 19. Pharmacological effects of caffeine. 20. Comparison of amphetamines and caffeine. 21. Pharmacological effects of analeptics.

IV. Therapeutic uses Clinical uses of: 1. benzodiazepines; 2. buspirone; 92

3. barbiturates; 4. ethosuximide, sodium valproate, lamotridgine; 5. opioid analgesics; 6. imipramine and amitriptyline; fluoxetine; 7. carbamazepine and phenytoin; 8. chlorpromazine, haloperidol; droperidol, olanzapine; 9. lithium carbonate; 10. methylphenidate; caffeine; 11. levodopa.

V. Adverse effects 1. Adverse and toxic effects of barbiturates. Treatment of overdose. 2. Adverse effects of benzodiazepines. Overdose and its treatment. The antagonist of benzodiazepine receptors. 3. Comparison of adverse effects: a) benzodiazepines and barbiturates; b) benzodiazepines and nonbenzodiazepine agonists of benzodiazepine re- ceptors. 4. Adverse effects of levodopa (peripheral and central). Drugs which are used to correct adverse effects of levodopa. 5. Adverse effects of morphine. Overdose and its treatment. Antagonists of opioid receptors. 6. Comparison of adverse effects between agonists and agonists-antagonists of opioid receptors. 7. Adverse effects of chlorpromazine associated with blockade of D2-receptors in the CNS and blockade of autonomic receptors. 8. Comparison of adverse effects of: a) chlorpromazine and haloperidol; b) chlor- and clozapine; c) clozapine and olanzapine. 9. Adverse and toxic effects of tricyclic antidepressants. Overdose and its treat- ment. Comparison of adverse effects of tricyclics and fluoxetine. 10. Adverse effects of MAO inhibitors. Drug and food interaction («cheese ef- fect»). 11. Adverse and toxic effects of ethanol. Chronic alcohol consumption and drugs used in its treatment. 12. Adverse and toxic effects of general anaesthetics: a) inhaled anaesthetics (halo- thane, enflurane, ), b) intravenous anaesthetics. 13. Adverse effects of amphetamine. Comparison of adverse effects of ampheta- mines and caffeine. 14. Drug dependence: definition, drugs causing dependence. 93

BIBLIOGRAPHY

94

CONTENTS

95

PRACTICAL CLASSES IN PHARMACOLOGY

Part I

General Pharmacology. Drugs Acting on Nervous System

The Manual for foreign students of General Medicine and Dentistry in the English-speaking Medium

E.V.BEYER A.V.POPOV

ПРАКТИЧЕСКИЕ ЗАНЯТИЯ ПО ФАРМАКОЛОГИИ

Часть I

Общая фармакология. Лекарства, действующие на нервную систему

96

E.В.БЕЙЕР A.В. ПОПОВ

Учебное пособие для иностранных студентов специальностей «Лечебное дело» и «Стоматология» англоязычного отделения

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