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Home , Allylestrenol, Bufotoxin, Counterirritant, Dichloroacetamide, Diphenylbutylpiperidine, Distigmine

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Copyright © 2007, New Age International (P) Ltd., Publishers Published by New Age International (P) Ltd., Publishers

All rights reserved. No part of this ebook may be reproduced in any form, by photostat, microfilm, xerography, or any other means, or incorporated into any information retrieval system, electronic or mechanical, without the written permission of the publisher. All inquiries should be emailed to [email protected]

ISBN (13) : 978-81-224-2556-7

PUBLISHING FOR ONE WORLD NEW AGE INTERNATIONAL (P) LIMITED, PUBLISHERS 4835/24, Ansari Road, Daryaganj, New Delhi - 110002 Visit us at www.newagepublishers.com

This page intentionally left blank PrefacePreface

Pharmacology has undergone major intellectual changes in the recent years and has become increasingly important to all medical, dental and other health professionals. The graduate students of dentistry may have to handle medical emergency during various dental procedures on the dental chair. Besides this, dentists have to look into various drug associated interactions. The broad goal of teaching pharmacology to undergraduate students is to inculcate rational and scientific basis of therapeutics keeping in view the dental curriculum and profession. A sincere attempt has been made to present a complete text for undergraduate students of dentistry as per the new syllabus requirement (Dental Council of , BDS course regulation, 2006). The book is divided into thirteen sections, initial sections cover the general and autonomic pharmacology, followed by other sections of drug acting on different body systems. A detailed section is devoted only to dental pharmacology which covers all agents used in pharmacotherapy of dental conditions. The last section covers vaccine, sera and other immunological agents and drugs used in skin disorders. The chapters have been arranged in such a way that knowledge gained from initial chapters will be helpful to students for understanding subsequent chapters. The appendix contains the list of newly approved and banned drugs in India. The classification adopted in the books provides pharmacological distinction among latest drugs with doses and routes of administration along with leading trade name(s) available in Indian market, but it should not be construed as the recommendation of those particular brands. (viii)

Thanks are due to New Age International (P) Ltd., N. Delhi for their keen interest and attention in bringing out this book in its present form. Further, I am indebted to all my friends and well wishers for their support and encouragement. I would like to express my gratitude and indebtedness to all my family members for their sacrifice, affection and inspiration throughout the present work.

New Delhi Surender Singh (ix)

Contents

Preface (vii)

SECTION 1 General Principles of Pharmacology

1.1 Sources and Nature of Drug Dosage Form 3 1.2 Prescription Writing 15 1.3 Rational Use of Drugs & Drug Laws 19 1.4 25 (Absorption, Distribution, and of Drugs) 1.5 Pharmacodynamics (Mode of Action of Drugs) 39 1.6 Adverse Drug Reactions 47 1.7 Drug Interactions 51

SECTION 2 Drugs Acting on CNS 2.1 General Anaesthetics 61 2.2 Sedative & Hypnotics 69 2.3 Narcotic () 75 2.4 Non-Narcotic Analgesics (NSAID’s) 83 (x)

2.5 Psychotropic Agents 95 2.6 Antiepileptic Agents 105 2.7 Muscle Relaxants 111 2.8 Local Anaesthetics 115 2.9 CNS Stimulants 119 2.10 Drugs Used in Parkinsonism 123

SECTION 3 Drugs Acting on ANS 3.1 Sympathomimetics (Adrenergic Agents) 131 3.2 Treatment of Shock & Vasopressor Agents 141 3.3 Sympatholytics (Antiadrenergic Agents) 145 3.4 Parasympathomimetics ( Agents) 155 3.5 Parasympatholytics ( Agents) 161

SECTION 4 Drugs Acting on Cardiovascular & Urinary System 4.1 Cardiotonics (Cardiac Glycosides) 169 4.2 Antihypertensive Agents 175 4.3 Antianginal Agents 185 4.4 Antiarrhythmic Agents 189 4.5 Antihyperlipidemic Agents 195 4.6 Plasma Expanders 199 4.7 Diuretics and Antidiuretics 203

SECTION 5 Autacoids 5.1 Histamine and Antihistaminic Agents 215 5.2 and its Antagonists 221 5.3 Prostaglandins and Leukotrienes 225 5.4 Drugs Used in Cough and 229 (xi)

SECTION 6 Drugs Acting on Blood

6.1 COAGULANTS AND ANTICOAGULANTS 239 6.2 HAEMATINICS (Drugs Used in Anaemia) 247

SECTION 7 Drugs Acting on GIT 7.1 Laxatives and Antidiarrhoeal Agents 253 7.2 Emetics & Agents 257 7.3 Antacids and Antiulcer Agents 261

SECTION 8 Drugs Acting on Endocrine System

8.1 Anterior Pituitary 269 8.2 Antidiabetic Agents 275 8.3 & Sex Hormones 281 8.4 Thyroid & Antithyroid Agents 293 8.5 Hormonal Contraceptives 297

SECTION 9

9.1 Sulfonamides, Nitrofurans and Quinolones 303 9.2 Tetracyclines, Chloramphenicol and Chemotherapy of UTI 311 9.3 Beta Lactam 317 9.4 Aminoglycosides Antibiotics 327 9.5 Macrolide and Polypeptide Antibiotics 331 9.6 Antiviral Agents 337 9.7 Antifungal Agents 343 9.8 Antimalarial Agents 349 9.9 Antiamoebic and other Antiprotozoal Drugs 355 9.10 Agents 361 9.11 Chemotherapy of Tuberculosis 365 (xii)

9.12 Chemotherapy of Leprosy 369 9.13 Chemotherapy of Malignancy 371

SECTION 10 Vitamins and Trace Elements

10.1 Vitamins and Trace Elements 383

SECTION 11 Chelating Agents & Treatment of Poisoning

11.1 Chelating Agents & Treatment of Poisoning 395

SECTION 12 Dental Pharmacology

12.1 Antiseptics & Disinfectants 407 12.2 Astringent and Obtundents 413 12.3 Mummifying and Bleaching Agents 415 12.4 Styptics (Local Haemostatics) and Disclosing Agents 417 12.5 Dentifrices and Mouth Washes 419 12.6 Caries and Fluorides 423 12.7 Pharmacotherapy of Common Oral Conditions & Dental Emergencies 425

SECTION 13 Miscellaneous

13.1 Vaccines, Sera and Other Immunological Agents 431 13.2 Drugs Used in Skin Disorders 449

APPENDICES Appendix I : List of Recently Approved New Drugs and Combinations in India (During 1999-July 2006) 459 Appendix II : List of Banned Drugs and Fixed Dose Combinations in India (Updated till January 2007) 473 Index 477 Section 1 General Principles of Pharmacology This page intentionally left blank Sources and Nature ChapterChapter of 1.1.1 4 Drug Dosage Form

INTRODUCTION Pharmacokinetics deals with the alterations of the drug by the body which Pharmacology (derived from Greek words, includes absorption, distribution, binding/ pharmacon-drug; logos-discourse in) consists storage, biotransformation and excretion of of detailed study of drugs – its source, physi- drugs. cal and chemical properties, compounding, biochemical and physiological effects, phar- Toxicology deals with the side/adverse macodynamics (its mechanism of action), effects and other poisonous effects of drugs, pharmacokinetics (absorption, distribution, since the same drug can be a poison, biotransformation and excretion), therapeu- depending on the dose. tic and other uses of drugs. Chemotherapy deals with the effects of According to WHO definition ‘Drug is drugs upon microorganisms and parasites any substance or product that is used or intended to be used to modify or explore without destroying the host cells. physiological system or pathological states Pharmacology also includes certain for the benefit of the recipient’. allied fields as: Pharmacology has some major subdivi- Pharmacy is the science of preparation, sions: compounding and dispensing of drugs. It is Pharmacodynamics is the study of the concerned with collection, identification, biochemical and physiological effects of the purification, isolation, synthesis and stan- drugs and their mechanism of action. dardization of medicinal /pharmaceutical Pharmacotherapeutics deals with the substances. use of drugs in the prevention and treatment of diseases and it utilizes or depends upon Pharmacognosy deals with the study of the information of drug obtained by the sources of drugs derived from and pharmacodynamic studies. animal origin. 4 Section 1/ General Principles of Pharmacology

Materia-medica: This is an older term • Belladonna (): At- and deals with the source, description ropine group. (physical and chemical properties) and • Pilocarpus sp.: Pilocarpine. preparation of drugs. • Vinca (Vinca rosea): Vincristine, Pharmacopoeia is an official reference vinblastine. containing a selected drugs/medicinal • Rauwolfia serpentina (root): . preparations with their description, tests for • Coca (Erythroxylum coca): Cocaine. their identity, purity and and with their average doses. A few famous pharmacopoeia ii. Glycosides are ether like organic and other reference books are the Indian structure combined with sugars, the Pharmacopoeia (IP), the British Pharmacopoeia non-sugar component called aglycone (BP); the Pharmacopoeia (USP); or genin. The important glycosides are: the British Pharmaceutical Codex (BPC); the • Digitalis (Digitalis purpurea, Digitalis National Formulary (NF) i.e. British National lanata): Digoxin etc. Formulary (BNF) and National Formulary (NF) • Stropanthus (Stropanthus kombe): of India. It is necessary for understanding the Stropanthin etc. each aspects of pharmacology by dentists, as • Senna (Cassia acutifolia): Sennoside etc. they have to prescribe the drug for the treatment of various dental conditions in general and iii. Oils other concurrently disease with many of the a. Fixed oils are glycerides of oleic, palmitic dental patients. The dentists should be aware and stearic acids. Mostly fixed oils are of drug interactions and capable of handle any edible and used for cooking. The fixed emergency during any dental procedure. oils used as drug are: • Castor (Ricinus communis): Castor oil. SOURCES OF DRUGS • Olive (Olea europaea): Olive oil. ‘Drug’ is derived from French word ‘drogue’ • Cocoa butter (Theobroma cacao): means a dry herb. Drugs are obtained Theobroma oil used as emollient mainly from plants, animals, microbes and in skin cream and making sup- mineral sources, but a majority of them that positories. are used therapeutically are from synthetic • Cod oil and shark liver oil: or semi-synthetic products. Rich source of vitamin A and D. ORIGIN b. Volatile oil or essential oil contains The pharmacologically active compo- the hydrocarbon terpene. The nents in vegetable drugs are: important volatile oils are: • Turpentine oil, from species of i. Alkaloids are basic substances pines, used as a counterirritant. containing cyclic nitrogen. The important alkaloids are obtained from: • Lemon oil (from Citrus limon), used • (Papaver somniferum): Mor- as flavouring agent. phine group. • Peppermint, cardamom and fen- • Cinchona (Cinchona officinalis): Qui- nel used as carminative and nine etc. flavouring agent. Sources and Nature of Drug Dosage Form 5

• Oil of clove is mainly useful in FROM HUMAN BEING relieving pain in toothache. There are certain products which are iv. Resins are produced by oxidation and obtained from human being e.g. polymerization of volatile oils. The • Immunoglobulins: From blood. different types of resins are: • Oleoresins: Male fern extract used • Placental extract: From placenta. for tapeworm infestation. • Chorionic : From • Gum resins: Asafoetida, used as of pregnant women. carminative and antispasmodic. • Growth hormone: From pituitary • Oleo gum resin: Myrrh, it has a local gland. stimulant and antiseptic properties and generally used in mouthwash. FROM MICROORGANISMS • Balsams: Benzoin, used internally The different classes of drugs obtained/ as expectorant and externally as isolated from microbes are: astringent. • Balsam Tolu, used as stimulating • Penicillin: Penicillium chrysogenum expectorant. and notatum (Fungus). v. Gums are the secretory products of • Streptomycin: Streptomyces griseus plants. On hydrolysis they yield simple (Actino-mycetes). sugar like polysaccharides. They are • Erythromycin: Streptomyces erythreus pharmacologically inert substances (Actinomycetes). and mainly employed as suspending • Chloramphenicol: Streptomyces and emulsifying agent in various venezuelae (Actinomycetes). pharmaceutical products. The widely used preparations are gum • Tetracyclines: Streptomyces aureofaciens acacia and tragacanth. and rimosus (Actinomycetes). vi. Tannins are nonnitrogenous constitu- • Polymyxin B: Bacillus polymyxa. ents of plant. Chemically they are phe- • Bacitracin: Bacillus subtilis. nolic derivatives and are characterized by their astringent action. Tannins are • Nystatin: Streptomyces nouresi. generally employed in the treatment of • Griseofulvin: Penicillium griseofulvum. diarrhoea and burns. The important Apart from various other antibiotics plants which contains tannins are: Amla, Behera, Hirda (in combination obtained from microorganisms, there are form ‘Triphala’), Black catechu and other products that are also produced by Ashoka bark. microorganisms. They are: ANIMAL SOURCES • Streptokinase, an from gram The different animal products after positive cocci (Streptococcus pyogenes). purification in a suitable dosage form for the • Vitamin B12 (cyanocobalamin): treatment of disease are listed in table 1.1.1. Streptomyces griseus. 6 Section 1/ General Principles of Pharmacology

Table 1.1.1: Classification of different animal products used as drug and surgicals. Drug Category Animal source Insulin Hormone Pancreas of beef or pig Thyroid extract/thyroxine Hormone Thyroid gland Shark liver oil Vitamin A of shark and allied species Cod liver oil Vitamin A and D Livers of Gadus species Antisnake Immune serum Blood of horse Hyaluronidase Enzyme Testis of bull Pepsin Enzyme Stomach of beef and pig Surgical ligatures and sutures Used in surgery Intestinal tissues, tendons of animals.

ROUTES OF DRUG ADMINISTRATION is freely permeable to many fluids. Inflammatory and other related conditions The drugs can be administered by a variety which increase the cutaneous blood flow of routes, either locally or administered orally also enhance absorption of drugs. and by injection. To produce local effects, Absorption through the skin can be drugs are applied topically to the skin or enhanced by induction (rubbing the oily mucous membranes. To produce systemic vehicle preparation into the skin) also. effects drugs are administered orally, rectally, On the skin, drug is applied in the form parenterally or by inhalation route. of ointment, cream, lotion, paste, plaster, The choice of the route in a given powder etc. situation depends upon the drug and the The topical application is also used on patient’s condition (e.g. in unconscious and the mucous membranes i.e. nose, throat, eye, state), and urgency of treatment ear, bronchi, rectum, urethra, vagina and (whether the routine treatment or in rectum. emergency condition). In case of mouth and pharynx, the drug The important routes of administration is used in the form of throat paints, lozenges, are: gargles or mouth washes. LOCAL ROUTES In case of corneal application (in the form of ointments, drops), the drug may The dosage forms applied locally to the penetrate the anterior chamber and affect the skin are powders, paste, lotions, ointments, ciliary muscle. The nasal mucosa is treated creams, plasters and jellies. They are used with drug solution in the form of spray or for their antiseptic, , , irrigation. local anaesthetic and other related effects. The bronchial mucosa and lungs are The absorption of drug through the skin treated with inhalations, aerosols (in the form is proportional to the surface area covered of fine powder with the help of nebulizer) e.g. and to their lipid solubility. The dermis layer (ASTHALIN) inhaler. Sources and Nature of Drug Dosage Form 7

Drugs may also be administered locally • Unpalatable and other irritant drugs in the form of bougies, jellies for urethra, can not be administered. pessaries, vaginal tablets, creams and • Can not be used for unconscious and douches for vagina and suppositories for uncooperative patient. rectal administration. • May not be useful in the presence of Due to the rich blood and lymph supply vomiting and diarrhoea. to rectum the unionised and lipid soluble • Drugs, which can be destroyed by di- substances are readily absorbed from the gestive juices (i.e. insulin, penicillin rectum. The advantages of this route are G) or in liver (i.e. , nitro- that gastric irritation is avoided and easy glycerine) can not be administered administration by the patient himself. orally. Administration of drug in the form of • The absorption of certain drugs is liquid into the rectum is called enema, negligible e.g. streptomycin. which may be soap water or glycerine- vegetable oil. It is used to remove the Enteric Coated Tablets faecal matter and flatus and is The drugs which are destroyed by used in . Certain drugs are the gastric juices in the stomach, are administered rectally for producing coated with keratin, shellac and cellulose systemic effects also (e.g. aminophylline, acid phosphate. These substances are not indomethacin, paraldehyde etc.). dissolved by the acid juice of the stomach, but are dissolved in the SYSTEMIC ROUTES intestinal juice (alkaline) only, which is The drug administered through useful in: systemic routes (orally or parenterally), is • Preventing gastric irritation and absorbed into the blood, distributed along alteration of the drug in the stomach. through the circulation and produce their • To get the desired concentration of desired effects. the drug in intestine. Oral Route • To delay the absorption of the drug. This is the most commonly used route Time Release/Sustained Release Capsules for drug administration. It is also the safest, most convenient and economical. But, there It is a useful solid dosage form of drug, are some limitation of this route: where the particles of the drug dissolve at different time intervals. • Drug action is slow, thus not suitable for emergencies. The advantages of time-release prepara- tions are: • Incapability to absorb some drugs, due to their physical characteristics i.e. • Reduction in the frequency of admin- polarity of the drug. istration of drug. 8 Section 1/ General Principles of Pharmacology

• Maintenance of therapeutic effect for • Self is difficult. longer time. • Chances of local injury at the site of • To some extent decreased incidence of injection. undesired effects. The important parenteral routes are: • Appropriate for drugs with short half lives (less than 4 hours). Subcutaneous Sublingual Administration The non-irritant substances can be The highly lipid soluble and injected by this route. The rate of nonirritating drugs (i.e. nitroglycerine, absorption of drug is constant and slow to , ) in the provide a sustained effect. The site of form of tablets or pellet is placed under the injection is usually the outer surface of the tongue, where they rapidly dissolve and are arm, or front of the thigh. Self medication absorbed quickly in the general circulation. (e.g. insulin) is possible because deep The advantages of this routes are: penetration is not needed. Other drugs • Rapid onset of action. which are administered subcutaneously are • The degradation and metabolism of the , morphine and certain hormonal drugs in the stomach and liver is preparations. avoided The other related subcutaneous routes PARENTERAL ROUTES are dermojet (by which, drug is projected from a microfine orifice using a high - (par = beyond, enteral = intestinal) locity jet) and pellet implantation (which The administration of drugs by injection provides sustained release of the drug directly into the tissue fluid or blood without over weeks and months e.g. testosterone). having to cross the intestinal mucosa. Intramuscular The advantages of parenteral routes are: The soluble substances, mild irritants • Rapid action of drug. and suspensions can be injected by this • Can be employed in unconscious/ route in the large skeletal muscles (deltoid, uncooperative patients. triceps, gluteus maximus, rectus femoris • Drugs, which are modified by etc.). These muscles are less richly supplied alimentary juices and liver can be given with sensory nerves and are more vascular, by this route. so irritant solutions can be injected. Small • Drugs, which are not absorbed in small volumes (up to 2 ml) are injected into the intestine or irritate the stomach can be deltoid muscle, and small or large volumes administered by this route. (up to 10 ml) are injected into the gluteal Disadvantages are: mass. • Less safe, more expensive. The rate of absorption is reasonably • Inconvenient (painful) for the patient. uniform and the onset of action is rapid. Sources and Nature of Drug Dosage Form 9

Intravenous injected directly into the spinal The drug is injected as a bolus or infused subarachnoid space. This is also used to slowly directly into a vein to produce rapid produce spinal anaesthesia, or for action. It is also useful for certain irritant and introduction of a radio-opaque contrast- hypertonic solutions, as they are rapidly medium into the subarachnoid space for diluted by the blood. Drugs in an oily vehicle visualising the spinal cord. or those which precipitate blood constituents or haemolyze erythrocytes should not be Intramedullary given by this route. By this method, the drug is introduced Intravenous route is the most rapidly into the bone marrow of the sternum or tibia. effective and the desired blood concentration Blood is occasionally given by this route. can be obtained with a definite dose but at the same time it is the most dangerous route Intracardiac of administration. For once the drug is In sudden cardiac arrest and other injected there is no retreat. So, intravenous cardiac emergencies, the adrenaline is injection must usually be performed slowly directly injected into the heart by a long and with constant monitoring of the patient. needle in the left fourth intercostal space This route is usually reserved for emergencies close to the sternum. when a rapid action is required and infusion of large amounts of fluids to overcome Intraperitoneal dehydration or to supply nutrition to patients who can not take food/fluids orally. This route is a common laboratory procedure, but it is seldom employed Intradermal clinically in infants for giving fluids like The drug is injected into the skin raising glucose saline, as the peritoneum offers a a bleb. This route is employed for vaccination large surface for absorption. e.g. BCG vaccine and for testing the sensitivity e.g. penicillin injection. Intra-articular Certain drugs (i.e. glucocorticoids) can Intra-arterial be administered directly into a joint space This route is useful in diagnostic studies, for the treatment of local condition i.e. by which arterial blood sample may be rheumatoid arthritis. withdrawn for blood gas studies. Certain cytotoxic compounds are administered by INHALATION ROUTE intra-arterial perfusion in localised malignancies. The volatile liquids and gases are given by inhalation route. The drugs may be given as Intrathecal or Intraspinal solid particles, as nebulized particles from For local and rapid effect of drugs on the solutions or in the form of vapours. The meninges or cerebrospinal axis, drugs are volatile substances include gaseous 10 Section 1/ General Principles of Pharmacology anaesthetics, amyl nitrite and vapours of gargles, jellies, liniments, lotions, mouth liquid anaesthetics, gases like oxygen, washes, ointments, paints, paste, carbon dioxide and helium. poultices etc. Nonvolatile substances have to be Inhalation forms include aerosols, broken down into small particles, and then sprays etc. inhaled as aerosols. Drugs given by this route are quick- SOLID DOSAGE FORM (INTERNAL ly absorbed, which takes place from the USE) vast surface of alveoli and produce rap- Capsules: These are small gelatin id action. Various and contains shells. Capsules are of two types – mast cell stabilizers are used in the hard & soft capsules. treatment and prophylaxis of bronchial asthma i.e. salbutamol (ASTHALIN) Hard capsules are used for powdered and sodium cromoglycate (FINTAL) drugs e.g. capsules , tetracy- inhaler. cline. In hard capsules, certain sustained released substance, which gradually

DOSAGE FORMS AND ROUTES OF DRUG release the drug in the respiratory tract ADMINISTRATION (e.g. cap. theophylline).

A dosage form is a medicated product Soft capsules are used for oils and specially designed for administration solution of active drugs e.g. cap. vitamins depending upon the routes to the patient for A, A & D, E, garlic pearls, seven seas etc. the diagnosis and treatment of disease. Soft capsules are also used for semisolid The dosage form is broadly divided into (ointment) e.g. eye applicaps of chloromycetin. solid dosage form, liquid dosage form and Granules: These are mixture of active inhalations which are used both internally medicament, sugar and some flavouring as well as externally. agent and then moistened to produce a Solid dosage form includes capsules, coherent mass which is then passed granules, effervescent granules, powders, through a sieve to form a granule. Gran- tablets, insufflations, suppositories ules are the unusual means of adminis (pessaries, bougies and ear cone) etc. tering drug that possess an unpleasant taste e.g. PAS (para-amino salicylic acid) Semisolid/liquid dosage form granules. includes elixirs, emulsions, gels, linctus, mixtures, drops, solutions, syrups, Effervescent granules: It is a mixture tinctures, applicators, creams, enema, of citric and tartaric acids with sodium Sources and Nature of Drug Dosage Form 11 bicarbonate and usually some sweetening • Soluble tablets: agents (saccharin or glucose) may be – Are dissolved in water to form added. solution for internal and external use (gargles) e.g. tab Disprin. The powder granules should be – Also used for parenteral adminis- dissolved with a prescribed amount of water tration called hypodermic tablets and taken when it produce effervescence e.g. e.g. sulphate tablets. ENO powder used for , • Scored tablets: flatulence and heartburn etc. – They may be easily divided if Powder: Powder are medicaments in smaller doses are required (e.g. tab. dried form. The powders are of different types: Analgin).

• Simple or compound powder: The • Lozenges: – Are solid preparation consisting simple powder contain just one active mainly of sugar and gum and ensures ingredient (e.g. acetylsalicylic acid slow release of medicaments and powder) and compound powder generally used for local action e.g. contain more than one active ingredient. cough remedies – Strepcils, Vocacil. • Powders enclosed in cachets (e.g. • Pastilles: ALCOPAR, ORS powder) and in – Are solid medicated preparation capsules (e.g. ampicillin powder). intended to dissolve slowly in the • Effervescent powder. mouth and softer than lozenges. • Powder for external use e.g. • Chewable tablets: NEBASULF, powder, – Are chewed in the mouth for oxide powder, talc etc. Tooth powder systemic action e.g. tab. Digene, may also be classified under this group. vitamin C (Suckcee), • Powder with metal (e.g. mercury with (for paediatric use) etc. chalk) used as purgative. • Buccal or sublingual tablets: • Powder use after reconstitution e.g. syr. – Are chewed and placed under the ampicillin for paediatric use. tongue. When it dissolved and exert their action e.g. tab. nitroglycerine. Tablets: These are the most extensively used solid dosage form containing • Implants: granulated or powdered drugs that are – Are tablets use for sustained action and implanted under the skin e.g. compressed or moulded into different Deoxycortone acetone (for shapes. These are different types of tablets contraception). according to their size, shape and uses: • Depot tablets: • Simple tablets: – Are compressed tablets used for – Are disintegrated readily e.g. tab sustained systemic action e.g. tab. aspirin. Asmapax Depot for asthmatic patients. 12 Section 1/ General Principles of Pharmacology

 Enteric-coated tablets: • Moulded pessaries (as suppositories). – Are coated with keratin, cellulose • Compressed pessaries – in different acetate phthalate, which do not shapes. dissolve in the stomach and only Bougies used for nasal and urethral dissolve in alkaline juice of the administration of drugs. intestine where the drug is liberated e.g. tab. erythromycin. Ear cone for administration of drugs in ear. SOLID DOSAGE FORM (EXTERNALLY Plasters are solid adhesive (with cloth) USED) preparation applied to the skin to protect, Collodions: These are the fluid preparation soothe and lessen pain e.g. Mustard plaster, intended for external use. The vehicle of Capsicum plaster. collodion are volatile (e.g. ethyl ) in nature and when applied on the skin (with SEMISOLID/LIQUID DOSAGE FORM brush or rod) evaporates to the skin and leaving (INTERNAL USE) a flexible, protective film. The film producing Aqua are aqueous solution of volatile agent is pyroxylin (nitrocellulose) and for substance used as solvent in certain flexibility colour oil is added. pharmaceutical preparation to mask the It is generally used for small cuts and disagreeable taste of drug e.g. peppermint abrasions. water. Dusting powder are free flowing and Cachets are providing a means of very fine in nature for external use. administering nauseous or disagreeable Insufflations are dusting powder powder in a tasteless form. consisting medicaments that are blown by Elixir are liquid, oral preparation of an insufflator (similar to atomiser) into potent or nauseous medicaments, which are various body cavities, nose, throat, ear etc., pleasantly flavoured and coloured with where it would be difficult to apply the suitable agents. powder directly. Emulsions are suspensions of fats or Suppositories are conical or ovoid shape oils in water with the inclusion of an solid preparation made up of fat (cocoa suitable emulsifying agent (e.g. gum butter oil or theobroma oil), a wax or a acacia, gum tragacanth) e.g. Castor oil glycerine-gelatin jelly. They are used for emulsion, Cod liver oil emulsion for insertion into the rectum, where they melt, internal use. One such emulsion is also dissolve and disperse and exert their action used externally e.g. benzyl benzoate – local as well as systemic. emulsion. Pessaries are the same as suppositories Gels are the aqueous colloidal suspension for introduction into vagina. Pessaries are of insoluble medicaments (e.g. of two type: hydroxide as antacid in Digene gel). Sources and Nature of Drug Dosage Form 13

Linctus are viscous, liquid oral SEMISOLID/LIQUID DOSAGE FORM preparation containing high proportions of (EXTERNAL USE) syrup (sugar) and glycerin (for viscosity and Applications are liquid or semi-liquid its sweet nature) which produce a preparation applied to the skin, and are demulcent affect on the mucous membrane usually emulsion or suspension in nature of the throat. (e.g. application). Mixture are liquid oral preparation, Creams are semisolid preparation where the medicaments are in solution or (usually emulsion) for external use. They are suspension form. Mixture are generally not oily and non-greasy in nature. formulated for a long life and prepared freshly. Ear/eye/nasal drops are solution of drugs that are instilled into a ear, eye and Paediatric drops are liquid oral nose with a dropper. The eye drops are preparation of small dose giving by a sterile solutions. calibrated dropper intended for paediatric use. Enema are solution, suspension or Solution are aqueous solution emulsion (oil/water type) of medicament containing one or more drugs. They are intended for rectal administration. divided into different categories: Gargles are aqueous solution used to • Solution in dosage form for oral use/ prevent and for treatment of throat external use e.g. strong iodine solution, . hydrogen peroxide solution. Irrigators are medicated solution used • Parenteral solution are sterile liquid or to treat urinary bladder, vagina and less suspensions packaged in sterile often the nose infections. They are containers, intended for parenteral administered with a help of catheter (in administration. bladder), vulcanite (for vagina) which are There are other type of solutions that made up of thin, soft rubber or plastic tube. are used for peritoneal dialysis, The nose irrigator is made up of glass. anticoagulant solution, bladder irrigation and certain dermatological solution Jellies are transparent or translucent, intended for application to broken surface. non-greasy medicated semi-solid Syrups are the liquid oral preparation preparation used externally, sometime made in concentrated sugar solution, mainly containing local anaesthetic agent also e.g. for paediatric use and for drugs which are Lignocaine jelly. unpleasant in taste. Liniments are liquid, semi-liquid and Tinctures are the concentrated alcoholic some-times semi-solid preparation used preparation of vegetable drugs made by externally on the skin. Liniments are maceration process. (e.g. Tr. opium, Tr. counter-irritant and stimulating type and are lemon) used in different pharmaceutical massaged or rubbed into the skin, and must preparation for oral use. Tr. Benzoin Co. is not be applied to the broken skin e.g. used externally. liniment turpentine. 14 Section 1/ General Principles of Pharmacology

Lotions are liquid preparation applied They afford greater protection and are more to skin without friction. Lotions are used for absorptive. The base may be anhydrous or soothing, astringent and antipruritic affects water soluble e.g. zinc oxide paste. e.g. calamine lotion. Poultices are paste like preparation for Mouth washes are liquid preparation external application to reduce similar to gargles but are use for oral due to its heat retaining capacity. After hygiene. heating, the preparation is spread thickly on a dressing gauze and applied as hot as Ointments are semi-solid greasy patient can bear it, to the affected area. preparation for local application to the skin, rectum and mucous membrane also. The INHALATION FORM ointment base is usually anhydrous and Aerosols are suspension of fine, solid contain the medicaments in solution or or liquid particles in a medium like air or suspension. Ointments are used for its oxygen and administered with the help of soothing, astringent, antiseptic and other nebulizers. They are used to apply drugs selected actions e.g. chloromycetin eye to the respiratory tract in asthmatic ointment. patients e.g. Asthalin (salbutamol) inhaler, Paints are liquid preparation containing Fintal (sodium cromoglycate) inhaler. volatile solvent which quickly evaporate to Sprays are preparation of drugs in oil leave a dry and resinous film of or water, usually administered by atomizer medicaments on the skin. or nebulizer. They are applied to the Throat paints are more viscous in nature mucosae of nose or throat e.g. Tyrothricin (due to the high proportion of glycerine) which spray. being sticky and adhere to the affected site and Vitrellae are thin walled glass capsules prolongs the action of the drug. containing volatile substance (drops) (e.g. Pastes are semi-solid preparation for ex- amyl or octyl nitrite) and protected by ternal application that differ from similar absorbent cotton wool and an outer silk bag. products (i.e. ointment) in containing a high This capsule is crushed and the vapours are proportion of finely powdered medicaments. inhaled in the treatment of angina.

 ChapterChapter Prescription 1.1. 4 2 Writing

Prescription is an order for medication illness is a private matter which must be written/issued by a physician, dentist or respected. other registered medical practitioner and it There are two types of legal prescription is a part of the professional relationship according to Drugs and Cosmetics Act; those among the physician, pharmacist and that can be obtained by prescription only and patient. It can also be defined as signed those that may be purchased without a pre- written order by a physician to pharmacist with certain directions for dispensing the scription and one termed as non-prescription prescribed drugs/formulations and their drugs or over-the-counter (OTC) drugs. uses by the patient. It is the pharmacist’s While a prescription can be written on responsibility in this relationship to provide any peice of paper (but it should contain quality patient and pharmaceutical care that all legal elements), it usually takes a spe- meets the medication needs of the patient. cific printed form on pad that contains It is also the responsibility to advise the blank spaces for the required informa- physician of drug sensitivities the patient tion. In certain emergency conditions it may have, previous adverse drug reactions may be communicated telephonically or or allergy, or other that the directly to the pharmacist by electronic patient may be taking which may alter the means. efficacy or safety of the newly or previously prescribed drugs. ELEMENTS OF THE PRESCRIPTION Since pharmacist is the key person between physician and patient, he must Prescription usually are written on printed establish and maintain the trust of the pad of blanks, which consists of following physician and patient. The important part parts. in this relationship includes maintaining (i) Name and address of the prescrib- confidentiality. The medication being taken er: Most prescription blanks are by a patient and the nature/severity of the imprinted with the name, address, 16 Section 1/ General Principles of Pharmacology

telephone numbers and other perti- scribed, unless substitution of an nent information (such as availabil- equivalent product is permitted by ity of the physician at particular time, the prescriber. Prescriptions requir- if a physician is practicing in more ing the pharmacist to mix ingredi- than one hospitals) of the physician ents are termed compound prescrip- or his/her practice site. These print- tions, which containing the names ed information clarifies the physi- and quantities of each ingredients, cian’s name when it is signed illeg- required and quantities of ingredi- ibly and address, telephone no. etc. ents to be used may be indicated in which facilitates additional profes- the metric or apothecary system of sional communication if required. weighs and measure. Subscription: (ii) Patient’s name, age, sex, address (v) This part of prescrip- and date: The date of prescription tion consists of directions to the should be written near the top of pharmacist for dispensing or pre- prescription form or at the beginning paring the prescription. With of the chart order. The patient’s decreasing frequency of com- name, age, sex and address are pounded prescriptions in a major- necessary on the prescription and ity of prescriptions, the subscription should be clearly spelled out. only consists the name of dosage from (as , capsule, syrup etc.) (iii) Superscription: It consists of Latin and the number of dosage units to symbol Rx meaning take thau or you be supplied. take and it has been believed to be an Signatura: innovation to Horus and Jupiter, the (vi) The word, usually abbre- mark thou father of Gods whose help is wished viated sigma or sig means . to make the prescription effective. This part includes the direction for the patient. The instructions on how (iv) Inscription: It is the principal part and when to take medications, the or body of the prescription which duration of therapy must be specify the medication, its strength, explained to each patient by the phy- the dosage and direction for use by the patients. When writing the drug sician and by the pharmacist. To help name, either the brand name (pro- patients remember to take their prietary name) or generic name medication, physicians often give an (non-proprietary name) may be instruction that particular medication used. Now a days, the majority of be taken at or around meal times prescriptions are written for medi- and at bed time. The direction for cations which are already prepared use must be clear and understand- in various dosage forms by phar- able to the patient and concise to maceutical manufacturers. Phama- avoid any toxicity and to obtain the cists are required to dispense the maximum benefit from therapy. trademarked products when pre- (table 1.2.1) Prescription Writing 17

(vii) Prescriber’s signature and registra- number of respective medical or tion number: This part consists of dental council which is also required prescriber signature and registration as per law by every country.

Table 1.2.1 Some commonly used Latin abbreviations in prescription writing: Abbreviation Latin name English meaning ad ad up to ad lib ad libitum as desired aq. aqua water q.s. quantum sufficiat as much as it sufficient collut. collutorium a mouth wash garg. gargarisma a gargle liq. liquor a solution past pasta a paste pign pigmentum a paint o.d once in die once daily b.i.d bis in die twice a day q.i.d quarter in die four times a day s.o.s. si opus sit if needed prim. luc prima luce early in the morning o.m. omni name every morning o.h. omni hora every hour n. nocte at night o.n. omni nocte every night h.s. hora somni at bed time a.c. anti cibos before meals p.c. post cibos after meals i.c. inter cibos between meals/food pulv. pulvis powder sol. solutio solution stat. statim at once tab. tabella teblet caps. capsula capsule tr. tinctura tincture ung. unguentum ointment ex.lact. exlacte with milk ex. aq. ex aqua with water p.r.n. pro re nata occassionally dol. urg. dolore urgente when the pain is severe This page intentionally left blank Rational Use of Drugs ChapterChapter & 1.1. 3 4 Drugs Laws

knowledge about drugs and the RATIONAL USE OF DRUGS ability to deal with the patient and the Rational use of drugs means using drugs pharmaceutical companies will make which are safe and effective. These drugs it easier for the doctors to select the should be available at reasonable prices and right formulation. could be stored conveniently. The drug The rational use of drugs can be should be the appropriate drug for the accomplished by applying the following disease, should be administered at the right approach: dose for the right period of time. 1. Patients’ problem: Try to find an Following factors lead to irrational explanation for the patients’ problem. prescribing. Take a detailed history of the illness and the drug history of the patient. I. A large number of commercial 2. Diagnosis: An accurate diagnosis is a preparation: There are large number of prerequisite for rational therapy. commercial preparations available in 3. Therapeutic objectives: This should be the market. It is difficult for the arrived at from the prognosis of the physicians to make a rational choice disease or relieving a symptom or pre- from the wide range of drugs available. venting a disease or a combination of However, by applying sound criteria these. for selection the most appropriate drug 4. Selection of drug treatment (drug): could be chosen. The approach towards selection of a II. Physician’s decision making process: drug treatment is divided into two The knowledge about the pharmaco- phases: logical properties of the drugs, an a. Determine the options available to ability to deal with demanding patient treat a health problem. Sometime and aggressive drug promotion by simple advice may be all that is pharmaceutical companies all influ- necessary and drug therapy may not ence the prescriber. An up-to-date be needed. 20 Section 1/ General Principles of Pharmacology

b. Evaluate the drugs on the basis of have special importance in certain the following criteria: Efficacy, situations where onset and duration of safety, suitability, cost, ease of ad- drug effect is to be considered. ministration and storage require- • Safety: Drug with fewer serious side ments. effects in normal doses should be 5. Start the treatment: Describe the drug preferred. and start drug administration. Inform • Suitability: Dosage forms should be the patient about the beneficial effects such that it does not only guarantee the as well as side effects of the drugs and desired effect but can also be handled how to deal with. easily by the patient and due 6. Result of treatment: The results of the consideration should be given for drug therapy should be assessed peri- contraindications and interactions. odically. • Cost: More expensive dosage forms may be an important factor for non- RATIONAL PRESCRIBING compliance. So, the cost factor should Rational prescribing is to prescribe drugs to be considered while selecting a drug. treat a particular health problem effectively The less expensive drug treatment may and safely at an affordable cost. Therefore be preferred. selection of a drug to treat a particular disor- • Storage conditions: If all other things der should be based on a systematic approach are equal then the drug which can be towards its rational use. stored more easily should be selected. II. Monitoring of treatment: The treat- I. Selection of a drug: If a drug is really ment can be monitored by the follow- needed to treat a health problem, then ing methods: its selection involves the following i. Passive monitoring: Information is steps: given to the patient regarding the i. Accurate diagnosis is the prerequi- possible side effects with the site for rational therapy. However, necessary cautions. The patient is if a tentative diagnosis is made due therefore well informed and able to to the limited local resources, then do his monitoring. it should be reviewed in the light of ii. Active monitoring: Make an another response to the therapy. appointment for active determination ii. Select group of drugs effective to of relief or side effects due to drug treat the particular health ailment. therapy. iii. Compare the effective groups of Knowledge about the drugs are drugs and then select a drug on the constantly changing. New drugs are basis of following criteria: introduced in the market and more • Efficacy: Efficacy of a drug is not only information about existing drugs appear based on pharmacodynamic but also on constantly. Therefore the doctor has to keep pharmacokinetic parameters, which themselves updated. Rational Use of Drugs & Drugs Laws 21

SELECTION OF ESSENTIAL DRUGS Schedule M (Good Manufacturing Essential drugs are those drugs that Practice – GMP) and schedule Y satisfy the health needs to the majority of (clinical trials etc.) were introduced in the population. These should always to 1988. available in adequate quantities and in Drugs and Cosmetics Rules have been appropriate dosage forms. divided into 18 parts each dealing with a particular subject. There are 2 schedules to The selection of the essential drugs the Act and 26 schedules to the Rules, which should be based on the established health need for the drugs. The list should be are as follows: reviewed periodically. Changes in the SCHEDULES TO THE ACT essential drugs list are made according to changes in the health needs, epidemiology First Schedule – Names of Books under of the diseases for which the drugs are Ayurvedic, Siddha and Unani Tibb systems. prescribed and on therapeutic advances. Prior to independence, a Health Survey and The WHO list of Essential Drugs Development Committee was appointed in the published at regular intervals is a model list Year 1943. The committee underscored the which could be used at the national, future role to be played by the indigenous regional, hospital and primary health centre systems of medicine of India. In 1946, the levels (given in appendix III). conference of Health Ministers resolved that adequate provisions should be made at the DRUGS LAWS Centre and provinces for research in indigenous systems of medicine, Ayurveda and Unani. The The Drugs and Cosmetics Act, 1940 and rules conference also recommended for starting 1945 have been passed with the objectives of educational and training institutions of these regulating the import, manufacture, systems. In pursuance of the recommendations distribution and sale of drugs & cosmetics. The of the Health Ministers’s conference, a number Act and rules have been amended from time of committees were appointed by the to time and the latest and major amendment Government of India, famous of them being was made in 1982. Schedules G & H have been Colonel R.N. Chopra (1946) and C.G. Pandit revised and new schedule X have been added (1949) Committees. These committees and schedules E, I & L have been deleted. recommended detailed outline for the According to the Act, now there are four categories of drugs: development of Indian systems of medicine. The Government of India established in i. Drugs specified in schedule C, C & X. 1 1969 a Central Council for Research in In- ii. Drugs not specified in schedule C, C 1 dian Medicine and Homeopathy & X. (CCRIMH) to develop scientific research in

iii. Drugs specified in schedule C & C1 different branches of Indian systems of (excluding those specified in schedule X). medicine – Unani Medicine, Ayurveda, iv. Drugs specified in schedule X. Siddha, Yoga, Naturopathy and Homeopa- 22 Section 1/ General Principles of Pharmacology

Table 1.3.1: Schedules to the rules •A: Proforma for application for the licences, issue and renewal of licences, for sending memoranda under the Act. •B: Rates of fee for test or analysis by the Central Drugs Laboratory or the Government Analyst. •C: List of biological and special products whose import, sale, distribution and manufacture are governed by special provisions.

•C1: List of other special products whose import, sale, distribution and manufacture are governed by special provisions. •D: List of drugs exempted from the provisions of import of drugs.

•E1: List of poisonous substances under the Ayurvedic (including Siddha) and Unani systems of medicine. •F(i): Space, equipment and supplies required for a blood bank. (ii): Minimum requirement for grant of licence to procure blood components from whole human blood.

•F1 Part I: Provisions applicable to the production of bacterial and viral vaccines. Part II: Provisions applicable to the production of all sera from living animals. Part III: Provisions applicable to the manufacture and standardization of diagnostic agents (bacterial origin).

•F2: Standards for surgical dressings.

•F3: Standards for sterilized umbilical tapes. • FF: Standards for ophthalmic preparations. •G: List of substances that are required to be used only under medical supervision and which are to be labelled accordingly. •H: List of prescription drugs. •J: Diseases or ailments which a drug may not purport to prevent or cure. •K: Drugs exempted from certain provisions relating to the manufacture of drugs. •M: Good Manufacturing Practices (GMP) requirements of factory premises, plants and equipments.

•M1: Requirements of factory premises etc. for manufacture of homeopathic preparations.

•M2: Requirements of factory premises for the manufacture of cosmetics.

•M3: Requirements of factory premises for manufacture of medical devices. • N: List of minimum equipment for efficient running of a pharmacy. •O: Standards for disinfectant fluids. •P: Life periods of drugs.

•P1: Pack sizes of drugs. • Q Part I: List of dyes, colours and pigments permitted in cosmetics and soaps. Part II: List of colours permitted in soaps. •R: Standards for condoms made of rubber latex intended for single use and other mechanical contraceptives.

•R1: Standards for medical devices. •S: Standards for cosmetics. •T: Requirements of factory premises and hygienic conditions for Ayurvedic (including Siddha) and Unani drugs. • U: Particulars to be show in manufacturing, raw material and analytical records of drugs.

•U1: Particulars to be shown in manufacturing, raw material and analytical records of cosmetics. •V: Standards for patent or proprietary medicines. •W: List of drugs which are to be marketed under generic names only. •X: List of drugs whose import, manufacture and sale, labelling and packaging are governed by special provisions. •Y: Requirements and guidelines on clinical trials for import and manufacture of new drugs. Rational Use of Drugs & Drugs Laws 23 thy. Research activities in these systems III. Animal toxicity requirements for continued under the aegis of the CCRIMH clinical trials and marketing of a new until 1978, when it was split into four sepa- drug. rate research councils, one each for Unani IV. Number of animals for long term Medicine, Ayurveda and Siddha, Yoga and toxicity studies. Naturopathy, and Homeopathy, so as to V. Patient consent form for participation further develop these systems in conso- in a phase I . nance with the basic philosophies of the VI. Four groups of fixed dose combinations respective systems. Also, with a view to and their data requirements. streamlining education and regulating practice in Indian systems of medicine – NARCOTIC DRUGS & PSYCHOTROPIC Ayurveda, Unani Medicine and Siddha, the SUBSTANCES ACT & RULES Government of India set up by an Act of Opium was brought under legislature Parliament, Indian Medicine Central Coun- control as far back as in 1857. The primary cil Act 1970, the Central Council of Indian aim of the Opium Act was the protection Medicine (CCIM). of the public welfare by preserving health In 1995, the Government also set up a & eliminating undesirable social and full-fledged Department of India Systems of moral effects which are associated with Medicine & Homeopathy (ISM & H) in the indiscriminate use of opium. Govt. of Union Ministry of Health & Family Welfare India passed the Dangerous Drug Act in to further boost the development of Unani 1930 with a view to control certain Medicine and other Indian systems of operations in the dangerous drugs and to medicine. The Department of ISM & H has centralise and vest the same in the central been renamed as Department of Ayurveda, government. Yoga & Naturopathy, Unani, Siddha and Further to “consolidate and amend the Homeopathy (AYUSH). law relating to narcotic drugs, to make Second Schedule – Standard to be stringent provisions for the control and complied with by imported drugs and by regulation of operations relating to narcotic drugs manufactured for sale, sold, stocked drugs & psychotropic substances, and or exhibited for sale or distributed. concerned matters”, the “Narcotic Drugs & In addition the following appendices are Psychotropic Substances Act & Rules was also prescribed: passed in September 1985.

Appendix THE MEDICINAL & TOILET PREPA- I. Data required to be submitted with RATIONS (EXCISE DUTIES) ACT & application for permission to market a RULES new drug. The Medicinal and Toilet Preparation II. Format for submission of clinical trial Act was passed in 1955 and Rules were reports. passed in 1956 and came into force in April, 24 Section 1/ General Principles of Pharmacology

1957 to provide for the collection of levy and commodities including drugs. The Drugs collection of duties of excise on medicinal (Price Control) Order, 1955 has been and toilet preparations containing alcohol, promulgated to ensure equitable distribution narcotic drugs or narcotics. of essential bulk drugs and to fix the maximum retail prices of drug formulations. THE DRUGS & MAGIC REMEDIES (OBJECTIONABLE ADVERTISEMENTS) THE PREVENTION OF FOOD ACT ADULTERATION ACT & RULES The Drugs & Magic Remedies Act, 1954 Food & drugs are generally controlled was passed with the objective of controlling through a common administration i.e. FDA the advertisement of drugs in certain cases, (Food & Drugs Administration in various to prohibit the advertisements for certain states/country). The main objective of the purposes for remedies alleged to possess Prevention of Food Adulteration Act is to magic qualities and to provide for related make provision for the prevention of matters. The Act as well as Rules came into adulteration of food. The Act was passed in force in April, 1955 and was amended in 1954 & Rules under the Act were passed in 1963. 1955.

NEW DRUG POLICY THE MEDICAL TERMINATION OF The drug policy was announced for the (MTP) ACT & RULES first time in 1978 on the basis of the recom- The MTP Act, 1971, Rules 1971 and mendations of Hathi Committee report 1975. Regulation, 1975 provide for the termination To provide the new thrust and direction in the of certain by registered medical policy frame, some new modifications were practitioners and related matters. announced vide Drug policy, 1986. In 1994, new Drug policy guided the better & effec- THE POISONS ACT tive implementation of policy through newer The Poisons Act was passed in 1919 with provisions, rationalization, liberalization, the objective of consolidating and amending minimizing control on drug & pharmaceuti- the laws regulating the import, possession cal industry sector and encouraging the indig- for sale & sale of poisons. enous research & development. According to the provisions of the Act, THE DRUGS (PRICE CONTROL) the Central Government has been ORDER empowered to regulate the importation of Under section 3 of Essential Commodities poisons into India whereas the various state Act, 1955, the central government is governments have been empowered to make empowered to control the production, rules regarding the possession and sale of supply, distribution etc. of essential poison within their respective territories.

 Chapter Pharmacokinetics Chapter (Absorption, Distribution, Metabolism and Excretion ofofcretion 1.1. 4 4 Drugs)Drugs)Drugs)

Pharmacokinetics is the study, which It is the movement of drug with the determines the rapidity and concentration circulation from its site and route of of the drug in the body and its duration of administration. appearance at the target organ, i.e. onset, Biopharmaceutics is the study of factors time of peak action and duration of action influencing the extent and rate of absorption and by these also determine the route(s) and and release of a drug from its various frequency of administration of drug. physicochemical properties and dosage Drug administration Absorption forms and the therapeutic response obtained after its administration. Pharmaco- Distribution kinetic part The rate and total amount of drug absorbed is dependent upon many factors, which are: Metabolism BIOLOGICAL FACTORS Excretion The biological factors which affect the Concentration in blood (systemic circulation) drug absorption are:

Passage or Drug Through Body Membranes Target organ After a drug is administered in any form/route, it must reach the site of action Pharmacodynamic effect and remain there for a particular period, so Fig. 1.4.1: Scheme of pharmacokinetics and pharmaco- as to yield the desired effect. During their dynamic processes. way to site of action, drug molecules have to cross one or more membranous barrier, ABSORPTION which are lipoidal in nature, and having Absorption is the entry of drug with blood different sizes of pores. via the biological membrane from the site/ The substance with higher water route of administration. partition coefficient values can penetrate 26 Section 1/ General Principles of Pharmacology through natural membranes easily as Tetracycline, when given in full stomach, compared to those having lower value. The the blood level are reduced by 55 to 80% as natural substances like amino acids, bile compared with fasting individuals. The salts, glucose readily pass through body griseofulvin absorption is enhanced by membranes even if their molecules are too giving it with fatty meals. large. Bile salts have favourable effect on the absorption of drugs mainly due to their Site of Absorption surface activity. The site of absorption is mainly localised in mouth (for buccal administration), Routes of Administration stomach, intestines or colon. The drugs are mostly given by mouth, Certain vasodilators (like nitroglycerine) which is considered already in previous and hormones which can penetrate the sections, the other routes of administration buccal mucosal wall will only be kept in of drugs in relation to absorption are being buccal cavity or under the tongue. It discussed here. provides rapid onset of action and Parenteral administration: This route is prevention of gastrointestinal interactions. applicable for drugs which are inactivated by The absorption in stomach depends gastrointestinal tract or absorption is poor upon the gastric emptying, gastrointestinal when given orally or there is a urgency for motility and its pH. fast response in small dose. Intramuscular, • , which is absorbed in the intravenous, or subcutaneous routes are intestine fails to give quick relief if its commonly used. The intravenous injection (in emptying from the stomach is delayed. aqueous solution) is introduced directly into • Benzylpenicillin if allowed to stay the vein by which a rapid response is longer in the stomach, much of its produced. The subcutaneous injection are activity is lost. given through the layer of skin, while intramuscular injection, introduced through The other important factors controlling the skin layer deep into the muscle. The the rate of gastric emptying by influencing nature of intramuscular injection may be in the gastric motility are the volume of the aqueous or oily solution/suspension form. meal, its temperature, its viscosity and The aqueous solution will be rapidly physical position. absorbed as compared to oily solution or The gastrointestinal pH has its own suspension. So, the rate of absorption is effect on the drug absorption. The range of dependent on the nature of the preparation. pH in stomach is 1 to 3.6, in duodenum is 5 to 7 and 7 to 8 in ileum and colon. Inhalational administration: The absorption of drug takes places through Presence of Food and Other Salts lungs and the absorbing membrane is very Normally, the presence of food in the thin and surface area is quite large. The lipid GIT reduces the rate of absorption of drugs. soluble drugs are readily absorbed from the Pharmacokinetics 27 nasal mucosa, as these drugs diffuse more Salt Form rapidly. The sodium or potassium salts of weak Topical administration: It is employed acids have higher absorption rate than those for local action in the form of ointments, of acids themselves. For example, the creams, jellies etc. for its antiseptic and local biological activity of sodium salt of anaesthetic action. The lipid soluble drugs novobiocin (weak acid) is twice as compared penetrate the skin easily and rapidly. to its salt, and about 50 times larger in comparison to its free acid. Rectal administration: The drug is also administered rectally in the form of The dissolution rate of tolbutamide suppositories and enema preparations sodium is much greater than the rate of its which are absorbed from the colon. free acid.

PHYSICO-CHEMICAL FACTORS Crystal Form The physicochemical factors affecting The metastable forms are preferred in the absorption are lipid solubility, pharmaceutical preparations due to their dissolution rate, salt from complexation, higher solubility and dissolution rate e.g. the viscosity and drug stability in the GIT. amorphous form of novobiocin is absorbed readily as compared to its crystalline form. Lipid Solubility Dissociation Constant and pH Complexation The drug solution of weak acid in the The complexation of calcium of the stomach (pH = 1.0; acidic) will be in more mucosal cells reduces the absorption of unionized form, which is more lipid soluble certain drugs e.g. the barbiturates and and gets more easily absorbed in the stomach. sulfonamides. Presence of EDTA increases the absorption of . A solution of weak base in stomach, less unionized is most unabsorbable e.g. quinine. Viscosity The high pH in intestine favours the Viscosity limits the dissolution rate and absorption of weak bases. thereby affect the rapid absorption e.g. aqueous solution of sodium salicylate showed Dissolution Rate its rapid appearance in plasma while the same All the drugs in any solid dosage form drug in suspension form failed to reach the or suspension when administered will first target as quickly as with aqueous solution. change into drug solution in body fluids. So, dissolution rate is important factor affecting PHARMACEUTICAL FACTORS the rate of absorption. These factors are mainly related to the When a drug is more rapidly or various dosage form of pharmaceuticals. completely absorbed from solution, it is very Their absorption depends upon their likely that its absorption will be dissolution physical nature like aqueous solution, rate limited. suspension, powder, tablets, capsules etc. 28 Section 1/ General Principles of Pharmacology

Aqueous Solutions pharmaceutical additive e.g. dissolution can The aqueous solution are most quickly be increased by increasing the starch absorbed. But due to their poor stability, content, binders can retard the dissolution solubility limitation and packaging problems, as they delay disintegration. most of the drugs are not designed in aqueous solution unless unavoidably needed in some specific preparations. The bioavailability of any drug is defined In aqueous suspensions, the particle size as its rate and extent of absorption. This is is the important factor for their stability, dissolution and absorption of drug e.g. mainly used to describe the biological sulphadimethoxine when given in availability of a drug from a preparation and suspension form is absorbed much quickly is calculated/determined in terms of as compared when given in tablet form. amount or rate of presence of drug in various Penicillin V, when given in aqueous body fluids like blood, urine etc. suspension gives much higher initial blood level as compared to the tablets or capsules. It is also used to indicate a measurement of rate and relative amount of an Solid Forms – Powders, Capsules, Tablets administered drug in general circulation. Powder: When drug is given in the form Bioavailability, after determining the of powder its absorption is largely rate and amount of drug absorbed, and the dependent upon particle size, interaction with other diluents and dissolution rate. duration of drug’s presence in the body fluid gives an idea about the therapeutic The micronized powder gives much higher concentration in blood as compared efficiency and toxicity. to ordinary powder and tablets. The extent of absorption of a drug can Capsule: The absorption of capsule is be estimated by comparing the total area also dependent on their type e.g. hard under the drug concentration in the blood capsule and soft capsule. The hard capsule versus time curve or the total amount of dissolves much more readily in unchanged drug excreted in the urine after gastrointestinal tract as compared to soft administration of drug and compared to the capsules. administration of standard (standard may Tablets: After swallowing, the tablet be an intravenous injection, where the first disintegrates into granules and bioavailability of a drug reaches 100%). primary solid particles and then into For bioequivalence studies, the two solution by dissolution for absorption. formulations of same drug is administered There is a specific disintegration and orally as single dose. Figure 1.4.2 shows that dissolution time for each tablet specified in in the study the different parameters are the various pharmacopoeias. The obtained. Firstly the peak height which absorption of any tablets is dependent on represents the highest concentration of the their disintegration and dissolution time, drug reached in the blood at a particular which may be affected by adding certain time i.e. time of peak concentration. The area Pharmacokinetics 29 under the curve (AUC) represents the total The drug is distributed in such a pattern amount of drug absorbed into the which reflects physiological factors and circulation. physicochemical nature of drug. These The percent availability can also be patterns of distribution depend on various calculated from urine data: factors.             PLASMA BINDING     Percent availability = × Most of the drugs are transported bound   to nonspecific sites on plasma , mostly    α       to (for acidic drugs) and to 1-acid     (for basic drugs). Binding to other     proteins like and From blood data: generally occurs to a much smaller extent. The  binding is usually reversible and depends on × Percentage availability =   the individual compound.

AUC = Area under the curve (Total amount of The binding of drugs to plasma proteins drug absorbed into the circulation). limit its concentration in tissue and glomerular filtration of the drug. Since only DISTRIBUTION OF DRUG unbound drug is in equilibrium across membranes and this process does not After absorption, the drug may be distributed into various body fluids immediately change the concentration of like intestinal fluid, transcellular fluids free drug in the plasma. The free drug is e.g. fluids in the gastrointestinal tract, cleared from the plasma by the liver and CSF etc. kidneys, which is rapidly replaced by

Peak height concentration 5.0 Peak 4.0 • Time of real concentration Drug • 3.0 concentration • (µg/ml) Area under curve = Total 2.0 amount of drug absorbed • 1.0 • • • • • 123 45 678

Time after drug administration (hours)

Fig. 1.4.2: Drug concentration in the plasma after oral administration (area under the curve versus time plot). 30 Section 1/ General Principles of Pharmacology dissociation from plasma proteins and barrier, called blood-CSF (cerebrospinal redistribution from the tissue. fluid) barrier, which is located in the choroid Since, only unbound drug in the plasma plexus. The penetration of any drug through is available for distribution. Therefore, these barriers is dependent on their lipid higher the degree of protein binding, greater solubility and ionization. Both barriers are is the proportion which remains in the blood lipoidal in nature and restrict the entry of which makes the drug long acting, as bound non-lipid soluble drugs. Only lipid soluble fraction is not available for metabolism or drugs are able to penetrate and produce their action on central nervous system. The conversion unless it is actively excreted by best example is levodopa in the treatment the liver or kidney. of parkinsonism, the (which is Other drug reservoirs are cellular and ultimately required in the brain) does not fat reservoir. The accumulation of drug in enter the brain but its precursor levodopa the cells may be the result of active transport crosses the blood-brain barrier, changes into or binding. Many drugs are accumulated in dopamine and produce their action. muscle and other cells in higher concentration than in the extracellular fluids. PLACENTAL BARRIER Many lipid soluble drugs are stored in the The placental membranes are also neutral fat, and act as the important lipoidal in nature and lipophilic drugs (also reservoir. nonlipid soluble drugs to some extent) can REDISTRIBUTION easily cross the placental barrier. It is a contact between the foetal blood and the In general, the termination of drug effect is usually by metabolism and excretion, but maternal blood. Drugs are transferred it can also be due to the redistribution of through this barrier by simple diffusion drugs. The highly lipid soluble drugs when method, once across this, drug molecules given intravenously or by inhalation route, circulate in the foetal blood before diffusing the fat, muscle and tissue take up the drug back. (initially they are distributed in other organs like heart, kidney, brain etc.) by which the METABOLISM OF DRUGS plasma concentration falls and drug is Metabolism of drugs means chemical withdrawn for these sites. However, where alteration of the drug in the body i.e. drugs the same drug is repeatedly administered, are converted to their metabolites that are the drug action can be prolonged. more polar than the parent compound. Most BLOOD BRAIN BARRIER (BBB) drugs, are hydrophilic drugs and are not The capillary endothelial cells in the biotransformed and are excreted unchanged brain, small extracellular space, sheet of glial e.g. streptomycin, etc. The most cells lining the capillaries and the myelin lipid soluble drugs are readily absorbed sheath together constitute the barrier, so from the filtrate by diffusion through renal called blood-brain barrier. There is another tubular cells. Thus, the enzymatic biotrans- Pharmacokinetics 31 formation of drugs to more polar and less endoplasmic reticulum of the liver cells. The lipid soluble metabolites enhances their CYP important isoenzymes in human being excretion and reduce their volume of are CYP3A4/5, CYP2C19, 2CYP2D6, distribution. The primary site of drug CYP2C8/9, CYP2E1 and CYP1A1/2 which metabolism is liver. The other organs like are responsible for metabolism of large kidney, intestine, lungs and plasma are also number of drugs. Hydrolytic are involved in . mostly located in the cell cytoplasm or in Many active drugs, during metabolism plasma and conjugation enzymes are are converted into one or more active metabo- associated with cytoplasm and endoplasmic lites and produce effect due to the collective reticulum. effect of parent drug and their metabolites OXIDATION e.g. phenacetin is converted into , phenylbutazone into oxyphenbutazone, Oxidative reactions involve addition of primidone into phenobarbitone, amitrip- oxygen/negatively charged radical or removal of hydrogen/positively charged tyline into noriptyline, into radical. desimipramine and codeine into morphine. The different oxidative reaction are: Certain drugs (parent drug) are inactive as such and has little or no biological activity called ‘,’ but it is metabolized to a It may be followed by oxidation to form a pharmacologically active compound. For or in the case of oxidative dealkylation example, levodopa is converted into to form an unstable intermediate, examples dopamine which is effective in the treat- are: ment of parkinsonism, the anticancer drug Ring : Phenobarbital in to p-hydroxypheno- cyclophosphamide is biologically inert but hydroxylation barbital. is converted into a active cytotoxic com- into 7-β-hydroxycortisol. pound aldophosphamide, and another an- Epoxidation : Benzene into benzene 1,2-epoxide. ticancer drug fluorouracil is changed into N-oxidation : Drug containing amino groups can fluorouridine monophosphate, etc. undergo N-oxidation i.e. imipra- mine into imipramine N-oxide. The drug metabolism in liver usually O-dealkylation : This reaction probably involves undergoes three general types of enzymatic formation of an unstable hydroxy reactions: methyl intermediate i.e. codeine into morphine. 1. Oxidation-reduction and hydrolysis or Oxidative : into phenylpropa- stage I reaction. deamination none-2. 2. Conjugation or stage II reaction. REDUCTION The first stage I reaction i.e. oxidation- The different type of reduction reactions reduction are generated by a common are azo, nitro and keto group reductions. hydroxy-lating enzyme system (cytochrome The important one is azoreduction, and P450 system; CYP), which is located in example includes conversion of prontosil 32 Section 1/ General Principles of Pharmacology into sulfonamide, which was the first The examples are aspirin, phenacetin, antimicrobial agent in treating the systemic morphine, chloramphenicol, , bacterial infections. steroidal hormones etc.

HYDROLYSIS Conjugation It is a cleavage of drug molecule by Sulfate conjugation is catalyzed by a fam- taking up a molecule of water. The most ily of enzymes known as ‘sulfotransferases’, hydrolytic enzymes are found outside the which are present in the cell cytoplasm of endoplasmic reticulum, and in higher liver and other organs. Example are chloram- concentrations in liver, kidney and plasma. phenicol and sex etc. The metabolism of an ester by an enzyme esterase results in the formation of an acid Acetylation and alcohol. The examples are meperidine, This reaction is catalyzed by enzymes procaina-mide, and etc. ‘N-acetyltransferases’ that utilize acetyl- Meperidine is catalyzed by esterases to be CoA as a cofactor, and are present in the cell changed into meperidinic acid and cytoplasm of the liver, intestine, kidney and procainamide is catalyzed by amidases. lung.

CONJUGATION REACTION (STAGE II Examples: OR SYNTHETIC REACTIONS)       The conjugation reaction involves the Isoniazid N-acetylisoniazid chemical combination of the reactive group  with a molecule provided by the body e.g. glucuronic acid, sulfate, glycine. This Other examples are sulfonamides, PAS conjugation reaction decreases the drug etc. activity to give a pharmacologically inactive compound, which is highly water soluble, Methylation that increases the rate of drug excretion. This reaction is catalysed by enzyme ‘methyl-transferases’ (catechol-o-methyl- Glucuronide Conjugation transferase) and generally uses S- This is the most common single adenosylmethionine as a methyl donor. metabolic reaction undergone by drugs, Examples are conversion of norepi-nephrine which occurs in the liver. These reactions are into normetanephrine, which has less than catalyzed by a family of enzymes known as one percent of the vasoconstrictor activity uridine diphosphate (UDP) glucuronyl of the parent compound. transferases. These enzymes are present in liver, kidney, intestine and lungs. Glutathione Conjugation The compounds with a hydroxyl or It is an important pathway in the carboxylic acid groups are easily conjugated detoxification of a large variety of chemical with glucuronic acid which is derived from toxic substances. Forming a mercapturate is glucose. normally a minor pathway like naphthalene Pharmacokinetics 33

(an aromatic compound) is excreted in the DISEASE CONDITIONS urine as N- derivatives called Patients with liver disease may exhibit as mercapturic acid. an increased sensitivity of many drugs. Patients with obstructive jaundice, hepatitis, Glycine Conjugation shows reduce ability to synthesize Certain drugs having carboxylic acid glucuronide and sulfate conjugates. groups are often inactivated by conjugation Experimentally induced obstructive with glycine for example, salicylic acid. jaundice in animals (by ligation of bile ducts) decreases rate of metabolism of certain FACTORS AFFECTING DRUG METABOLISM drugs like hexobarbitone, , AGE codeine etc. In general, infants and older (human or SEX animals) tend to be more sensitive to the The sex difference in the metabolism of action of the drugs. The impairment of drug drugs has not been observed in human metabolism in the new born infants usually beings. However, in rats, the pharmacological results from a diminished capacity to activity of a drug is more prolonged and the deactivate drugs and consequently to more toxicity more marked in females than males, prolonged pharmacological action and to a difference which has been attributed to the increased toxic reactions. more rapid metabolism of the drugs by the NUTRITION hepatic microsomal enzymes of the male rat. Protein or calcium deficiency impairs PREGNANCY drug metabolism in animals, due to de- During late pregnancy in rats, the creased activity of the microsomal enzymes conjugation of drugs with glucuronic acid of the liver. The sleeping time by (a major pathway for the deactivation of hexobarbitone is increased as a result of pro- drugs) is reduced to about 50%. Certain longed protein malnutrition. Acetylsalicylic oxidative metabolic transformations of acid has been shown to be more toxic to ani- drugs are also inhibited in pregnancy. mals on a diet deficient in protein and mag- nesium. HORMONAL EFFECTS The rates of metabolism are also The hormones of adrenal glands, thyroid impaired in vitamin deficiency states and pancreas exert various effects on the

(especially vitamin A, vitamin B2, C and E). metabolism of drugs. Adrenalectomy of cer- Starvation in mice leads to decrease in the tain species e.g. rat impairs the metabolism rates of metabolism of certain drugs like of certain drugs, which can be reversed by pethidine, acetanilide, hexobarbitone etc. administration of or . Ethanol increases the hepatic content of Administration of ACTH, adrenaline or thy- monooxygenase enzymes and cytochrome roxine impairs the hepatic microsomal me- P450 on chronic ingestion. tabolism of drugs. Thyroidectomy reduces the 34 Section 1/ General Principles of Pharmacology metabolism of a number of drugs like barbi- PHARMACODYNAMIC FACTORS turate induced sleeping time is prolonged in Effects of Protein Binding thyroidectomized animals. Alloxan or Acetylation of sulfonamides is reduced streptozotocin induced in rats also by protein binding, but the formation of reduced the metabolism of hexobarbitone glucuronide conjugates is unaffected. thus prolonging the sleeping time. EXCRETION OF DRUGS EFFECTS OF THE INTESTINAL MICROFLORA The excretion of drugs has been known to The metabolic transformation of take place through different routes mainly many drugs is catalysed by various kidneys, skin, lungs and alimentary tract. enzyme of the intestinal microflora. The Only few drugs are eliminated through skin anaerobic microflora and colon are rich and via lungs (only for volatile drugs like in reductases which may be responsible chloroform, ethyl alcohol, ether etc.). Drugs for a significant proportion of the which are poorly absorbed are excreted in azoreductase and nitroreductase activity. faeces. So kidneys serve as the primary and The enzymes and other factors that may major organ for removal of most drugs, produce change in the nature of intestinal which is constituted by the microunits microflora might also produce changes in called ‘nephron’. Three major processes the metabolism pattern of the drugs. that are involved in the excretion of drugs through kidneys are: GENETIC FACTOR – SPECIES i. Glomerular filtration, DIFFERENCES ii. Tubular secretion, and Species differences in the metabolism iii. Passive diffusion. of drug may be due to the difference in Glomerular filtration: The rate of the rate of metabolism or in their metabo- drug filtration is determined by the glom- lites difference. Certain drugs have been erular filtration rate (GFR) by using a sub- found safe and non-toxic in animals, but stance like ‘inulin’, which when injected when they were tested in human beings is filtered by the glomeruli and does not severe toxic effects were observed. For undergo either reabsorption or secretion example, when sulfanilamide was tested by the renal tubules. The highly protein in dog it was found safe and non-toxic, bound drugs like phenylbutazone, but when it was administered to human digoxin etc. are excreted slowly. Factors being, certain toxic effects like the hema- affecting the GFR of drug also can influ- turia, renal failure were observed. ence the rate of drug clearance. For ex- Likewise, in certain case it was opposite. ample inflammation of the glomerular In human beings, phenacetin is generally capillaries may increase GFR. Molecular free from toxic side effects, but in dogs it configuration of drugs may also influence undergoes deacetylation. the GFR. Pharmacokinetics 35

Tubular secretion: The active secretory The excretion of these drugs may be affected systems can rapidly remove the protein- in the presence of lung disease conditions, bound drugs from the blood and transport which may precipitate the drug toxicity. them into tubular fluid as the drugs that are bound to proteins are not readily available BILIARY EXCRETION for excretion by filtration. The drugs known Certain drugs are excreted in urine only to be secreted by organic anion secretory in small amounts but appear in high system (i.e. strong acids) are salicylates, concentrations in the bile for example, chlorothiazide, probenecid, penicillin etc. erythromycin, novobiocin, tetracycline, and cation (i.e. bases) includes phenolphthalein etc. The abnormality or any catecholamines, , histamine, disease related to liver may impair bile hexamethonium, morphine etc. secretion which can lead to the accumulation Passive diffusion: Passive diffusion can of certain drugs like probenecid, digoxin etc. occur in both the ways in proximal and distal This can also lead to decreased drug convoluted tubules. The lipophilic drug metabolism and decreased rates of secretion molecules are reabsorbed from the of drugs into bile. glomerular filtrate into the blood stream. Certain drugs that are secreted by the The pH of the urine can affect the rate of liver into the bile and then to small intestine passive diffusion and hence drug excretion. are not eliminated out through the faeces, The changes in urinary pH affect tubular so that the drugs will re-enter the blood that reabsorption of partially ionized drugs. The perfuses the intestine and again carried to effect of change in urinary pH on excretion the liver (repeatedly reabsorbed from the of drugs is more with the drugs having pH intestine and re-excreted in the bile) and values between 5 to 8. The excretion of basic thereby prolongs the action by the so called drugs can be increased by making the urine ‘enterohepatic circulation’. more acidic by using the acidifying salt i.e. ammonium chloride. EXCRETION IN OTHER BODY FLUIDS Sweat and Saliva PULMONARY EXCRETION The excretion of drugs through sweat Volatile lipophilic substances like and saliva is primarily dependent upon the volatile general anaesthetics, ethyl alcohol, diffusion of the non-ionized, lipophilic form paraldehyde are excreted by the lungs. These of the drug across the epithelial cells of the volatile substances and certain gases that glands. The compounds like lithium, enter the body through the respiratory tract and heavy metals are in the form of aerosol are excreted by this present in these secretions. route. Ethanol, having high blood gas Milk solubility is excreted very slowly by the The excretion of drugs into the mother’s lungs and nitrogen oxide, which are not very milk will depend upon the amount of drug soluble in blood, will be excreted rapidly. in blood, its lipid solubility and the extent

Pharmacokinetics 37

The figure shows the different types of produces its desired effect in a particular drugs with different plasma half life, but the time at receptor site and remain there at steady state concentration is maintained on therapeutic level for particular time and repetitive dosing in all the three type of drug. after that its therapeutic efficacy declines. So the next dose should be given in between this period so that the steady state concentration is maintained and no toxic Toxic level effects are produced due to high dose. A B C Steady state concentration Therapeutic The graph shows that the drug reaches level at the therapeutic level in 3½ hours after oral administration and achieve its peak Blood concentration concentration in 4½ hours and decreases Time (hour) below the mini-mum effective concentration Fig. 1.4.3: Drug concentration time curve of (MEC) in 10 hours. repeated dosing. 7 Drug : A = Drug with long plasma half life given in initial loading dose followed by 6 Toxic level [Minimum toxic constant maintenance dose. 5 concentration (MTC)] B = Drug with short plasma half life given 4 Therapeutic level in constant repetitive dose. 3 [Minimum effective C = Drug with long plasma half life given concentration (MEC)] in constant repetitive dose. 2 1 LOADING DOSE Plasma concentration (µg/ml) 2468 10 12 14 16 18 20 It is a single or many quickly repeated Time (hr.) doses given in the beginning of treatment to achieve target concentration rapidly. Fig. 1.4.4: Drug concentration in plasma vs time curve of drug administered orally. DOSAGE INTERNAL Now for maintaining the serum concen- tration above the MEC for longer duration, Most of the drugs are given in divided the second dose of drug should be given dose daily, the dosing interval is determined about 7 to 8 hours after the first dose, by the plasma half life. The drugs with long otherwise when it is given after 7 to 8 hours half lives may be given once or twice daily it will take extra time to reach the MEC or if while drugs with shorter plasma half lives it is given prior to 7 to 8 hours the second may require constant dosing or with short dose in combination with the first dose effect dosing interval. crosses the minimum toxic concentration When any drug is administered, it (MTC). 38 Section 1/ General Principles of Pharmacology

6 6

5 5 MTC MTC 4 4 MEC MEC 3 3

2 2 - Second - First dose - First - IInd 1 Plasma concentration (µg/ml) Plasma concentration (µg/ml) dose 1 dose dose

2468 10 12 14 24 68 10 12 14 Time (hr.) Time (hr.)

Fig. 1.4.5: Shows the administration of 2nd dose Fig. 1.4.6: Shows the administration of 2nd dose after between the 7-8 hours interval which maintains the 7-8 hours interval which does not maintain the drug drug plasma levels above minimum effective plasma concentration at MEC level. concentration.

6 MTC 5

4 MEC 3 — 2nd 2 dose —Ist 1 Plasma concentration (µg/ml) dose

24 68 10 12 14 Time (hr.)

Fig. 1.4.7: Shows the administration of 2nd dose before 7-8 hours interval which crosses the MTC which may produce toxic effects of drugs. ChapterChapter PharmacodynamicsPharmacodynamicsPharmacodynamics 1.1.5 4 (Mode(Mode of of Action Action ofof Drugs)

Pharmacodynamics is the study of drug ef- and often drugs like antibiotics, antacids, fects (biochemical and physiological) and and so many other drugs acts systemically. their mechanism of action. When the drug The proper localization of the site of reaches its site of action it has a pharmaco- drug action can be determined pharmaco- logical effect which may be responsible for logically. When a new drug is introduced an eventual therapeutic effect and also re- its screening gives an idea about the site and sponsible for the adverse effects as well as mechanism of drug action, for example, if some other effects which may be of no clini- any drug is said to be antihypertensive in cal importance. nature and by blocking this action by prior administration of an antihistaminic, it will SITE AND MECHANISM OF DRUG ACTION gives an idea that the drug may act in the The site of drug action means where a drug same place and same mechanism as hista- acts and mechanism means how the drug mine. The use of certain blocking agents also acts. Drug which act only at the site of help in suggesting the probable site of ac- application (i.e. localized region) are termed tion of drugs. as local or topical action for example, ointments, paste, creams and certain other TYPES OF DRUG ACTION local preparations used externally produce The drug may produce their effects by: only local effect. The local anaesthetics like lignocaine, procaine produce anaesthesia i. Stimulation. (local) in a localized region only. ii. Depression. The second type of action is systemic or iii. Irritation. general action which produce their action iv. Replacement. after absorption, for example, general v. Bactericidal and cytotoxic action. anaesthetics act centrally after absorption, Stimulation 40 Section 1/ General Principles of Pharmacology

STIMULATION production of endogenous components is Stimulation is an increase in the selective reduced e.g. thyroxine is used to replace activity of specialized cells, which increases the natural thyroid hormone secretion in secretion from a gland, for example, morphine hypothyroidism, insulin in diabetes stimulates vagus, stimulates mellitus, levodopa in parkinsonism, exocrine glandular secretions, high dose of CNS hydroxycobalamin (vitamin B12) and ferrous stimulant picrotoxin produces convulsions. salts in the treatment of conditions associated with their deficiency. DEPRESSION BACTERICIDAL AND CYTOTOXIC It is a reduction/decrease in the activity ACTION of specialized cells. For example barbiturates depress central nervous system, The bacteriostatic activity which is depresses myocardium. Certain drugs inhibition of growth and multiplication of stimulate one type of cells but depress others bacteria and bactericidal activity, which is e.g. morphine stimulates the vagus and bacterial death, is induced by certain types chemoreceptor trigger zone but depresses of antibiotics. Cytotoxic action is selective the vomiting and cough centres. Similarly for invading cancer cells and altering them acetylcholine stimulates intestinal smooth without affecting the host cells. muscle but depresses SA node in the heart. FACTORS MODIFYING DRUG ACTION IRRITATION It is the effect of drugs on the growth, The drug action can be modified either nutrition and morphology of living tissues quantitatively (in which the action of drug which induce a gross change in cellular is increased or decreased) or qualitatively function. Such drugs produce a nonselective, (in which the type of response is altered). often noxious effects and is particularly The factors are: applied to less specialized cells and causing a mild inflammation or irritation, corrosion 1. Age: In newborn infants, the and necrosis of cells. The other cellular glomerular filtration rate and tubular changes produced by irritation are transport is immature, which takes 5 to 7 precipitation of protein (astringent effect) months to mature. Also, the hepatic drug and when these agents as applied locally to metabolism capacity is also inadequate the skin to relieve deep seated pain by (that is why chloramphenicol can produce increasing the blood flow to the site (counter ‘grey baby syndrome’), and due to the higher irritant action) e.g. liniments to relieve permeability of blood brain barrier, certain muscular pain (turpentine oil liniment). drugs attain high concentration in the CNS. REPLACEMENT The dose of a drug for children is often It includes certain drugs, which are used calculated from adult dose. to replace some missing endogenous  Child dose = ×   component of the body or when the  

42 Section 1/ General Principles of Pharmacology drugs like morphine, barbiturates, phenothi- Tachyphylaxis is the rapid development azines, benzodiazepine can produce more of tolerance in which there is a marked CNS depression. reduction in response even after repeated doses of a drug. It is not necessary that In gastrointestinal disease: tolerance develop equally to all the action • The absorption of orally administered of the drug, e.g. tolerance of morphine drug is altered e.g. achlorhydria occurs to its analgesic and euphoric action reduces aspirin absorption. and not to its constipating and miotic • Absorption of amoxycillin is actions. Likewise in phenobarbitone, reduced in coeliac disease. tolerance occurs to its sedative action and Other important diseases in which the not to its anti-epileptic action. drug action is altered are: Cross tolerance is development of • The hyperthyroid patients are tolerance to pharmacologically related relatively resistant to inotropic drugs e.g. morphine and barbiturates. action but more prone to arrhythmic action of digoxin. CHEMICAL CHARACTER OF DRUGS • In congestive heart failure the drug STRUCTURE ACTIVITY elimination is retarded due to RELATIONSHIP (SAR) decreased perfusion and congestion of liver, also reduced glomerular The effect of certain structural filtration and increased tubular compounds in relation to its activity, reabsorption. duration of action and mechanism can be • In head injury, morphine (in normal altered by changing the structure of drugs dose) can cause respiratory failure. of known activity. A new product can show In severe pain, hypnotics may cause different reactions, different relation between the drugs and cell constituents and mental confusion. perhaps even new mechanism of action. 8. Tolerance: Tolerance is a condition The structure activity relationship is when there is a requirement of higher useful in synthesis of new active compounds dose of a drug to produce a given with more specific actions with lesser response. unwanted effect, and to know about their 9. Drug resistance: It is tolerance of mechanism of action. micro-organisms to inhibitory action of antimicrobials e.g. staphylococci to DRUG RECEPTORS penicillin. 10. Other drugs: Drugs may modify the The drug receptors are macromolecular sites response to each other by pharmacokinetic which are situated on the surface or inside or pharmaco-dynamic interaction between the effector cells with which specific them. combines to produce its response. Antago- Pharmacodynamics (Mode of Action of Drugs) 43 nist prevents the action of an agonist on a On the basis of affinity and efficacy, the receptor, but does not have any effect of its drugs can be classified as , which own (Fig. 1.5.1). have both affinity as well as high intrinsic Receptors are mostly protein macro- activity and can mimic the effects of the molecules. The cholinergic, adrenergic, hista- endogenous substance after combining with minergic and other receptors are ‘physiological the receptor (e.g. methacholine produces the receptors’ on which certain drugs act which effect of acetylcholine at cholinergic mediate the responses to transmitters, autacoids receptors). Antagonists have only the affinity etc. Another type of receptor is ‘drug receptors’, but no intrinsic activity. These drugs bind to which do not have any known physiological the receptor, but do not mimic (rather block) ligands, for example thiazide receptor, benzo- or interfere with the binding of an diazepine receptor etc. endogenous agonist (e.g. atropine block the effect of acetylcholine on cholinergic- muscarinic receptors). Partial agonists have + full affinity to the receptor but with lower Agonist Receptor Agonist- Response intrinsic activity [e.g. pentazocine is a partial receptor interaction agonist at µ receptor (subtype of receptor)]. Inverse agonist or negative + antagonists have full affinity towards the Antagonist - No receptor but their intrinsic activity is receptor response absolutely negligible and may be zero or in interaction minus.

Fig. 1.5.1: Drug-receptor interaction: The agonist RECEPTOR TYPE completely fits (interact) with the receptor site to produce a pharmacological response and antagonist On the basis of molecular structure and only partially fit with the receptor site and is unable to nature of transduction mechanism, receptor produce any pharmacological response, and also prevents the agonist from combining with the can be classified into following categories: receptors. i. G-protein and second messengers. The ability of a drug to get bound to a ii. -gated channels. receptor is termed as the ‘affinity of the drug’ for the receptor. The ability of the drug iii. Cytokine receptors. to produce a pharmacological response after iv. kinases. its interaction with the receptor is known as v. Intracellular receptors. ‘intrinsic activity of the drug’, it also determines the degree of receptor response. COMBINED EFFECT OF DRUGS The agonists produce a maximal receptor response (high intrinsic activity), partial SYNERGISM agonists have intermediate intrinsic activity When two drugs are given simulta- and antagonists have low intrinsic activity neously, and the action of one drug is in- and high affinity for the receptors. creased by the other, they are treated as 44 Section 1/ General Principles of Pharmacology synergistic. In the synergism, the drugs can cyanomethaemoglobin and after sodium have action in the same direction or when thiosulphate injection forms sodium thio- given alone, one may be inactive. Synergism cyanate which is easily excreted in urine. can be additive or supradditive in nature. On receptor basis, drug antagonism will ADDITIVE be of two types competitive and noncompeti- tive antagonism. When the effect of two drugs are in the same direction. For example when aspirin COMPETITIVE ANTAGONISM is combined with paracetamol the combined In competitive antagonism, the effect is analgesic/antipyretic. antagonist binds with the same receptor as Another important example is agonist. If the log dose response curve with combination of theophylline and agonist is obtained in the presence of as , combination of antagonist, it will be found that antagonist sulfonamides as antibacterial etc. has no effect of its own and there is parallel SUPRADDITIVE rightward shift in the dose response curve of agonist (Fig. 1.5.2) with no change in In this the effect of combined therapy is shape, slope or maximum response. greater than the individual effect of the one drug. Examples are: In competitive antagonism, the antagonist reduces affinity i.e. potency of the • Levodopa and peripheral dopa- agonist. decarboxylase inhibitor, carbidopa or benserazide in the treatment of Example of competitive antagonism are: parkinsonism. • Acetylcholine (as agonist) – atropine (as • Sulfonamide and trimethoprim (well antagonist). known preparation ‘Septran’) as • Acetylcholine – d-tubocurarine. antibacterial. • Isoprenaline – . DRUG ANTAGONISM Antagonism describes the situation, when one drug decreases or inhibits the action of another. The antagonism may be physi- cal in which the physical property of the drug can affect the absorption of another drug, chemical in which two drugs react chemically and form a biologically inactive compound. This type of reaction may be used in the treatment of drug poisoning. For example in cyanide poisoning nitrites form methaemoglobin which has high af- Fig. 1.5.2: Log dose response curve showing finity for cyanide radical and forms competitive antagonism.

ChapterChapter Adverse Drug 1.1. 4 6 Reactions

withdrawal of narcotic drugs) and secondly, ADVERSE DRUG REACTIONS the effects which are individual to individual Adverse drug reaction is an undesired or like drug allergy (hypersensitivity to drugs), unintended effect of the drug, occurs at dose idiosyncracy. normally used by human being. The adverse Other types are teratogenicity (drug drug reaction requires treatment or decrease causing foetal abnormalities), carcinogenicity in dose if it is due to poisoning or overdose. (drug causing cancer), iatrogenicity (drug Adverse drug reaction may be defined induced diseases). as ‘any response to a drug which is noxious (injurious) and unintended, and which SIDE EFFECTS occurs at doses of an appropriately given drug used in man for prophylaxis, There are undesirable and unavoidable diagnosis or therapy excluding therapeutic pharmacological effect of the drug, which failures.’ occur at therapeutic dose. These unwanted effects of many drugs are based on their Adverse drugs reactions are not rare and pharmacological actions. Some important have increased in number, which may be examples are: due to irrational use of multiple drug • Atropine causes dryness of mouth as therapy, availability of most of the drugs as side effect which is due to its OTC (over the counter) i.e. without antisecretory effect, and due to this prescription and self medication by the action atropine is used in peptic patients. ulcer. Adverse effects can be based on the • Acetazolamide (a carbonic anhydrase pharmacodynamics of the drug i.e. side inhibitor) used as diuretic by increasing effects (occur at therapeutic dose of the drug), bicarbonate excretion and thus acidosis toxic effects (occurs at overdose or poisoning) occur as side effect which is related to and drug withdrawal symptoms (i.e. its pharmacological action. 48 Section 1/ General Principles of Pharmacology

Side effects are also based on different drug. It results from previous sensitization to facet of action (or side effects unrelated to the drug itself or a particular chemical with its pharmacological or therapeutic effect). similar structure. All antihistaminics except few newer The B-lymphocytes, when exposed to compounds e.g. astemizole, terfenadine etc. antigens mature into immunoglobulin cause sedation which is unrelated to its secreting cells after proliferation, which therapeutic action i.e. antiallergic action. often have the appearance of plasma cells. The history of pharmacology revealed that The immunoglobulins (Ig) are secreted certain drugs have been developed from the by B-lymphocytes in the later stage of their observation of their side effects for example development into plasma cells. IgG, IgA, sulfonamide produce hypoglycemia and acidosis as side effect, which further gave an idea IgM, IgE and IgD are immunoglobulins, out for developing a new compound related to of these IgG is the major one. sulfona-mide – sulfonylurea as hypoglycemic Based on the mechanism of immuno- agent and acetazolamide as diuretic. logical reactions, the allergic responses have been divided into four categories: TOXIC EFFECTS TYPE-I (ANAPHYLACTIC REACTION) Toxic effects develop due to excessive They are mediated by IgE . On pharmacological action of drug, which may be due to overdose or continuous use of exposure to the drug, antigen and drug for prolonged period. reaction takes place on mast cells and basophils releasing various mediators e.g. The overdose toxicity occurs when the histamine, leukotrienes, 5 hydroxytryptamine high dose of drug is required for the specific treatment or the drug is taken accidentally or (5-HT), prostaglandins etc., which are with the intention of suicide. The effects are responsible for immediate immune reactions predictable and dose related. For example like skin reaction, anaphylactic shock, asthma delirium by the use of atropine and respiratory etc. These reactions occur immediately after failure by morphine occur due to their challenge and are termed as immediate overdoses. The well known antitubercular hypersensitivity. drug, streptomycin causes vestibular damage and deafness on prolonged use. TYPE-II (CYTOLYTIC REACTION; DELAYED IGG/IGE MEDIATED) DRUG ALLERGY AND IDIOSYNCRASY These reactions are mediated by IgG and IgE antibodies, which bind to the target cells HYPERSENSITIVITY (DRUG ALLERGY) (cells in the circulating system). On Drug allergy is a cell-mediated immune reexposure antigen-antibody reaction takes reaction producing symptoms, which are place on the surface of these target cells and unrelated to the pharmacological effects of the cytolysis occur. Example are penicillin- Adverse Drug Reactions 49 induced hemolytic anaemia, sulfonamide- act directly on the foetus, or act indirectly on induced granulocytopenia and quinidine- placenta e.g., vitamin A, 5-HT. induced cytopenic purpura. It is clear that the major foetal damage occur by drug when it is taken in early TYPE-III (ARTHUS REACTION IGG pregnancy (i.e. first 2-9 weeks when MEDIATED) organogenesis takes place.) These reactions are predominantly me- The teratogenic drugs can affect diated by IgG. The antigen-antibody com- different stages of pregnancy i.e. plexes are deposited in the vascular endot- • At fertilization and implantation stage helium, where a destructive inflammatory (i.e. conception to 3 weeks). response occurs. Serum sickness, clinical • Organogenesis period (3 to 9 weeks), symptoms include fever, skin eruptions, ar- and thralgia and lymphadenopathy. The reac- • In growth and development period tion usually subsides in 6-12 days. (i.e., after 9 weeks). The drugs inducing serum sickness are The drugs, which are proven to be sulfonamides, penicillin etc. Sulfonamides teratogenic are , anticancer also cause Stevens-Johnson syndrome, a form drugs (specially methotrexate), sex of immune vasculitis, which is characterized hormones (, progestins, by the reactions including arthritis, nephritis, stilboesterol) , warfarin, myocarditis and certain mental symptoms. antithyroid drugs (which can cause foetal goitre and hypothyroidism), oral antidia- TYPE-IV (DELAYED betic drugs, and social drugs including HYPERSENSITIVITY) tobacco, alcohol etc. These reactions are mediated by production of sensitized T-lymphocytes. On CARCINOGENICITY contact with antigen, an inflammatory Certain drugs affect the and structural reaction is generated which includes contact changes in the . The drugs that dermatitis, fever and photosensitization. cause cancer are called as carcinogenic Drugs which cause these types of drugs, for example, oral contraceptives in- reactions are penicillin, sulfonamides, crease the incidence of benign liver tumors, tetracycline, phenylbutazone, salicylates etc. vaginal adenocarcinoma in the female off- springs of women who have taken stilboesterol during her pregnancy for abor- TERATOGENICITY tion purpose. Teratogenicity is derived from the word ‘teratos’ Drugs producing carcinogenic effects are mean ‘monster.’ Teratogens may act directly on anticancer/antineoplastic drugs, radioisotopes the foetus, e.g., thalidomide and anticancer drugs like P32, I131 and hormonal therapy etc. 50 Section 1/ General Principles of Pharmacology

MANAGEMENT OF POISONING IDIOSYNCRASY • Maintain a clear airway/adequate It is genetically determined abnormal ventilation (for inhaled poisons). reactivity to a drug. The abnormal reac- tion to the drug are precipitated some- • Washing the eyes and other surface of time because of genetically determined the body (for local poison entering from total absence or reduced activity of some the surface). enzyme in the body of the recipient, e.g., • Gastric lavage (with hypertonic saline primaquine produce haemolysis in indi- solution, injection for viduals with glucose-6-phosphate dehy- ingested poison). drogenase (G-6-PD) deficiency. Blacks • Activated charcoal (to bind the require higher concentration of atropine unabsorbed drug) 10-30 g in to dilate their pupil. Certain individuals suspension in 200 ml water. feel excitement and mental confusion af- • Identify the poison and specific ter taking barbiturates. The short acting antidotes should be given. skeletal muscle relaxant succinylcholine • Maintenance of blood pressure and may produce respiratory paralysis and other related body function by fluid prolonged apnea in individuals whose infusion, pressor agents, depending plasma contain an atypical pseudocho- upon the condition of the patient. linesterase enzyme. • The nonspecific antidotes are also given, for example anticonvulsants in POISONING convulsions. • Forced diuresis by furosemide, Poison is a substance which endangers life mannitol etc. and altering the urinary due to its toxic reaction/poisoning on certain pH– increasing the pH of urine favours vital functions in the body. The poisonous ionisation of acidic drugs like substances may be the , very high doses salicylates, phenobarbital etc. whereas of drug, industrial chemicals/gases, house- reducing the pH favours ionisation of hold chemical like -DDT, BHC, basic drugs like pethidine, etc. amphetamine etc. For the treatment of poisoning, a • Haemodialysis and haemoperfusion selective antidote (which antagonises the which is a passage of blood through a action) may be given e.g., nalorphine and charcoal or adsorbent resin column naloxone in case of morphine poisoning, may be instituted, depending upon the atropine in case of anticholinergic drugs, patient’s condition. dimercaprol in mercury and penicillamine (Detailed treatment of poisoning is in lead poisoning, etc. discussed in chapter 11.1)

 ChapterChapter Drug Interactions 1.1. 4 7

Drug interactions may be defined as an drug is effective only in very low per- alteration in duration and/or onset of action centage of patients. Likewise, in the of the pharmacokinetic and/or pharmaco- treatment of heart failure, a combined dynamic of one drug produced by another therapy of diuretic with vasodilator drug. The multiple drug therapy produced and/or has to be a combined effect, which may be antagonis- given to achieve a adequate cardiac tic or synergistic in nature. In antagonism output and control over edema. Mul- the effects of one drug are reduced or abol- tiple drug therapy also required in che- motherapy of cancer, tuberculosis and ished by the second drug, and in synergism certain infectious diseases. the effects may be additive or potentiative in nature, which may be harmful or useful • To minimize the side effects of drugs e.g. to supplement potassium by giving to the patient in a particular disease. potassium sparing diuretic with The clinically established drug digitalis. interactions can be minimized to some The use of combined drug therapy can extent by the avoidance of combined drug not be avoided in certain cases to attain a therapy, which are proven to be desired therapeutic level, but the risk of incompatible. incompatibility/interactions involved in the But, in certain cases, the single drug is treatment increases. effective only to a certain degree or stage of The drug interactions may be divided disease condition. The multiple/combined into: drug therapy is required in many medical i. Pharmacokinetic, which occur at the and dental conditions. level of absorption, distribution, • To produce a desired pharmacody- metabolism and excretion of one drug namic/ therapeutic effect which is not by another. obtained by single drug, e.g. in the ii. Pharmacodynamic, which occur at the site treatment of hypertension, a single of drug action involving the receptors. 52 Section 1/ General Principles of Pharmacology

Table 1.7.1: Drug interactions at the sites of absorption. i. Interaction due to the formation of chelate complex Antacids Tetracycline, isoniazid, , Decreased absorption chlorpromazine penicillamine, digoxin, ranitidine Antacids Bishydroxycoumarin Increased absorption Cholestyramine Warfarin, phenylbutazone, digitoxin, Decreased absorption cephalexin and chlorothiazide Activated charcoal Tolbutamide, theophylline, phenytoin, Decreased absorption digoxin, carbamazepine, Activated charcoal Piroxicam, theophylline & phenobarbital Increased absorption Mineral oils Fat soluble vitamins Decreased absorption Iron preparation Decreased absorption ii. Interaction due to the alteration in gastric pH Antacids Decreased absorption Cimetidine Tetracycline Decreased absorption iii. Interaction due to increase in gastric motility Digoxin, cimetidine Decreased absorption Metoclopramide Chlorothiazide, acetaminophen Increased rate of absorption iv. Interaction due to decrease in gastric motility Antacids Isoniazid, phenytoin, propranolol and Decreased rate of benzodiazepines absorption Bishydroxycoumarin Increased absorption v. Interaction due to alteration of gut Cimetidine Lidocaine, propranolol, verapamil, Increased absorption imipramine

Some important drug interactions at the PHARMACOKINETIC INTERACTIONS site of absorption are shown in table 1.7.1. The drug may interact with the another drug at any point during their absorption, Drug Interactions Involving Distribution distribution, metabolism and excretion. After absorbed into blood many drugs are bound to plasma proteins, the portion of Drug Interactions Involving Absorption the drug which is being transported in the Important drug interactions include bound form is inactive (pharmacologically) antacids which contain calcium, and only the free part or molecule that diffuse or aluminium that interfere with absorption into the tissues produce their effect. of tetracycline by forming a ‘chelate’ with the metals; carbonates prevent absorption The most important drug interaction of iron; cholestyramine interferes with the caused by displacement from plasma pro- absorption of certain drugs like warfarin, teins occur with coumarin anticoagulants. thyroxine and digitalis glycosides. Phenylbutazone displaces warfarin from its Drug Interactions 53 binding site thereby causing bleeding. Tolb- Table 1.7.2: Interactions caused by displacement of utamide is displaced by dicumarol resulting drugs from sites. in severe hypoglycemia (See table 1.7.2). Drug displaced Displacing agent Coumarin Diazoxide, ethacrynic acid, Drug Interactions During Metabolism phenylbutazone, NSAIDs This type of interaction occurs when the Tolbutamide Dicumarol, phenylbutazone metabolism of a drug is inhibited or Phenytoin Tolbutamide, NSAIDs decreased by another drug. Diazepam Heparin Certain drugs induce the hepatic NSAIDs = antiinflammatory drugs. microsomal enzyme system i.e. enzyme induction, which decreases the effectiveness Table 1.7.3: Drugs that induce the metabolism. of other drugs, for example, if phenobarbital Drug (inducing part) Drug induced is suddenly discontinued without lowering Chloral hydrate Bishydroxycoumarin the dosage of coumarin, severe hemorrhage Phenobarbital Bishydroxycoumarin, can occur. digitoxin, phenylbutazone, phenytoin Some important drug interactions Phenytoin Carbamazepine, cimeti- during metabolism are shown in table 1.7.3 dine, theophylline, oral & 1.7.4.

Drug Interaction During Excretion Table 1.7.4: Drugs inhibit the metabolism of other drugs. The renal drug clearance is influenced Drug causing inhibition Drug inhibited by alterations in glomerular filtration Bishydroxycoumarin Tolbutamide rate and tubular reabsorption or secretion Disulfiram Phenytoin, theophylline, warfarin rate. Isoniazid Phenytoin The tubular secretion of penicillin is Phenylbutazone Tolbutamide, phenytoin inhibited by probenecid, so that the blood concentration and its half life (therapeutic Ammonium chloride increases urinary effects) is prolonged with the simultaneous volume with acidification of urine. The use of these two drugs. Phenylbutazone can excretion of amphetamine is decreased in block the renal tubular reabsorption of uric relatively alkaline urine and has proved useful acid, leading to uricosuria. in ‘the treatment of amphetamine intoxication’. Quinidine inhibits the tubular secretion of digoxin which consequently raises the PHARMACODYNAMIC INTERACTIONS plasma digoxin concentration, which may Pharmacodynamic interactions take place be associated with toxicity. Certain other at the site of drug action. When two or more drugs also increase the digoxin concentra- drugs with similar pharmacological tion like verapamil, amiodarone, spirono- effects are administered together, an lactone etc. additive or synergistic effect is usually seen. 54 Section 1/ General Principles of Pharmacology

These type of interactions are of two types: which are enhanced by potassium The direct pharmacodynamic interactions depletion e.g., potassium-sparing occur when two drugs either act on the same diuretics, corticosteroids and site or on two different sites with a similar purgatives. effect. • Diuretics like frusemide may attenuate When two drugs act on same site, they the effects of oral hypoglycemic drugs. are either antagonist or synergist. For • Drugs like salicylates, dipyridamole, example: phenylbutazone decrease the ability Antagonism: Reversal of the effect of of platelets to aggregate, and thus with naloxone. impairing the haemostasis if war- Reversal of anticholinergic effects with farin induced bleeding occurs. and . • The nonsteroidal antiinflammatory Synergism: Increased anticoagulation of drugs like aspirin, indomethacin and warfarin with clofibrate, corticosteroids, phenylbutazone causes ulceration in tetracycline, vitamin K and naloxone. gastro-intestinal tract which provides Arrhythmias with the use of b-adreno- a site for bleeding in patients on receptor antagonists and verapamil together. anticoagulants. The indirect pharmacodynamic interac- The pharmacodynamic interactions are tions are unrelated to the effects of the ob- relatively common in practice, but they can ject drug, for example: be minimized if the interactions are antici- • Drugs which alter potassium con- pated and appropriate precautions are tent may have effect on the thera- taken by avoiding irrational and unneces- peutic effect of cardiac glycosides, sary drugs combination.

Table 1.7.5: Some clinically important drug interactions. Drug affected Drug interacting Effect Gastrointestinal system Carbenoxolone Amiloride, Inhibition of ulcer healing. Cimetidine Antacids Reduced absorption if taken simultaneously.

Metoclopramide Anticholinergic drugs such as atropine, Antagonism – they have opposing benzhexol, propantheline, narcotic effects on gastrointestinal activity. analgesics Cardiovascular system Antiarrhythmic drugs Any combination of two or more Increased myocardial depression. Disopyramide Potassium salts, amiodarone Hyperkalaemia, increased risk of ventricular arrhythmias due to prolongation of QT interval.

Contd..... Drug Interactions 55

Drug affected Drug interacting Effect Lignocaine, mexiletine, Diuretics: Bumetanide, ethacrynic acid, Antagonised by hypokalaemia. tocainide. frusemide, thiazides Lignocaine Cimetidine, propranolol Increased risk of lignocaine toxicity. Verapamil Beta-adrenoceptor blocking drugs Asystole, hypotension. Digoxin & other cardiac Diuretics: Bumetanide, ethacrynic acid, Increased toxicity. glycosides furosemide, thiazides Cholestyramine, colestipol Reduced absorption. Phenobarbitone, rifampicin Inhibition (Digitoxin only) Digoxin Amiodarone, quinidine, quinine Potentiation may occur. , verapamil Potentiation may occur. Diuretics Indomethacin Antagonism. Carbenoxolone, corticosteroids, corti- Hypokalaemia. cotrophin, antagonists: Captopril, potassium supplements, Hyperkalaemia. Amiloride, triamterene Heparin Aspirin, dipyridamole. Potentiation. Adrenaline, noradrenaline Beta-adrenoceptor blocking drugs Potentiation of hypertensive effect. Respiratory system Theophylline Cimetidine, erythromycin, influenza Potentiation. vaccine, oral contraceptives Carbamazepine, phenytoin, rifampicin, Plasma concentration of theophylline sulphinpyrazone may be reduced.

Antihypertensive drugs Captopril Antiinflammatory analgesics such Reduced effects. as indomethacin, phenylbutazone, corticotrophin, estrogens, oral con- traceptives Alcohol, antidepressants, hypnotics, Potentiation. sedatives, tranquillizers, , levodopa, vasodilators such as nitrates, nifedipine, verapamil Potassium supplements, potassium Hyperkalaemia. sparing diuretics. Beta-adrenoceptor blocking drugs Increased risk of clonidine with- drawal hypertension. Tricyclic Antagonism. Beta-adrenoceptor Indomethacin Antagonism of antihypertensive blocking drugs effect. Nifedipine Severe hypotension and heart failure occasionally. Sympathomimetic amines such as Severe hypertension reported. adrenaline, , phenyl- ephrine Cimetidine Potentiation possible because of reduced metabolism. Contd..... 56 Section 1/ General Principles of Pharmacology

Drug affected Drug interacting Effect Infections Aminoglycosides e.g. Ethacrynic acid, furosemide, skeletal Increased ototoxicity, increased gentamycin etc. muscle relaxants neuromuscular blockade. Cephalosporins Ethacrynic acid, furosemide, gentamycin Increased nephrotoxicity. Chloramphenicol Phenobarbitone Reduced plasma concentration of chloramphenicol & increased levels of phenobarbitone. Dapsone Probenecid Reduced excretion: Increased side effects. Griseofulvin Phenobarbitone Impairs absorption. Antacids, anticholinergic drugs, Decreased absorption. cimetidine, ranitidine Metronidazole Alcohol ‘Antabuse’ reaction. Tetracycline Antacids, dairy products, oral Reduced absorption. iron, sucralfate, zinc sulphate

Malignant disease & immunosuppression Azathioprine Allopurinol Potentiation: Increased toxicity. mercaptopurine Cyclosporin Ketoconazole Increased plasma concentration of cyclosporin. Methotrexate Aspirin, phenylbutazone, probenecid Delayed excretion: Increased toxicity. Antiepileptics, cotrimoxazole, pyrime- Increased anti-folate effect. thamine Central nervous system A. Analgesics Aspirin Metoclopramide Potentiation. Ketoprofen, Probenecid Increased plasma concentration. Paracetamol Cholestyramine, metoclopramide Reduced absorption. B. Antiepileptics General Tricyclic antidepressants, oral contra- Increased seizure activity. ceptives Carbamazepine Cimetidine, dextropropoxyphene, eryth- Potentiation. romycin, isoniazid Ethosuximide Carbamazepine Reduced plasma concentration of ethosuximide. Phenobarbitone, Phenytoin, sodium valproate Increased sedation, increased primidone blood levels of phenobarbitone.

Contd..... Drug Interactions 57

Drug affected Drug interacting Effect C. Psychotropic drugs Hypnotics & sedatives Alcohol, antidepressants, Potentiation. antihistaminics, narcotic analgesics Tricyclic anti- Alcohol Potentiation of sedative effect. depressants Oral contraceptives Reduced effect. derivatives Increased side effects. Imipramine Cimetidine Potentiation. Lithium Diuretics, diclofenac, indomethacin, Potentiation. phenylbutazone Acetazolamide, aminophylline, sodium Increased lithium excretion. bicarbonate Increased risk of extra pyramidal effects.

Endocrine system Antidiabetic drugs Alcohol Antabuse like reaction. Beta-adrenoceptor blocking drugs, Potentiation. MAO inhibitors Corticosteroids, corticotrophin, diazo- Antagonism. xide, diuretics (bumetanide, furosemide, thiazides), oral contraceptives Metformin Alcohol Increased risk of lactic acidosis. Corticosteroids, cortico- Diuretics (bumetanide, ethacrynic acid, Increased potassium loss. trophin furosemide, thiazides) Cortisone, , Barbiturates, carbamazepine, Reduced effect. , predni- phenytoin, primidone, rifampicin solone, . Oral contraceptives Barbiturates, carbamazepine, dichloral- Reduced effect. phenazone, phenytoin, primidone, rifampicin. Oral antibiotics such as ampicillin, Reduced effect. tetracycline

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General anaesthetics are the group of tion used is 70 percent N2O + 30 percent O2 drugs which bring about a reversible loss of along with some muscle relaxants or other pain sensation and consciousness. The depth potent anaesthetics. , if admin- of anaesthesia appropriate for the conduct istered along with air, it produces a stage of of surgical procedures can be achieved by a excitement and delirium and also produce wide variety of drugs, either alone or by a amnesia. Hence, the name ‘laughing gas.’ combination of drugs, each drug for a spe- It is eliminated unchanged from the cific purpose. General anaesthetics can be body, via the lungs. Despite its high fat solu- administered by a variety of routes, but in- bility, it is rapidly eliminated through lungs tra-venous or inhalation administration is within 2 to 5 minutes after its withdrawal. preferred, because the effective dose and the Nitrous oxide, due to its analgesic action time course of action are more predictable in subanaesthetic concentration, is employed when these techniques are used. for minor operation like tooth extraction, for The general anaesthetics are divided into obstetrical analysis, painful procedures such two main groups (table 2.1.1). as changing dressing of burns. It is cheap and very commonly used. INHALATIONAL ANAESTHETICS Prolonged administration of nitrous ox- ide as in cases of tetanus, may cause bone NITROUS OXIDE (N O) 2 marrow depression and agranulocytosis. It is a colourless, odourless, noninflammable gas which is approx. 1½ times heavier than CYCLOPROPANE air. It is non-irritating with a sweet taste. It is a colourless gas with sweet odour and Nitrous oxide is used for induction and taste, available as liquid under pressure. It maintenance of anaesthesia. It is widely produces analgesia without loss of conscious- used as carrier gas for other volatile agents ness in 1 to 2 percent concentration, in 6 to 8 in general anaesthesia. The usual concentra- percent it produces loss of consciousness while 62 Section 2/ Drugs Acting on CNS

Table 2.1.1: Classification of general anaesthetics. I. Inhalational anaesthetics i. Gases Nitrous oxide 70-80% with other agents Cyclopropane 5-25% ii. Volatile liquids Ether (Diethyl ether) 3-10% (TRILENE) 0.25-0.75% (FLUOTHANE) 0.5-2.0% Methoxyflurane (PENTHRANE) 0.1-0.3% (ETHRANE) 1-3.0% (FORANE) 0.8-2.0% II. Intravenous anaesthetics i. Ultra short acting barbiturates Hexobarbitone (sodium salt) Thiopentone sodium 3-5 mg/kg as 2.5% solution Methohexitone sodium (BREVITAL) 1-3 mg/kg as 1% solution ii. Non-barbiturate intravenous anaesthetics Propanidid (EPONTOL) 5-10 mg/kg as 5% solution (KETMIN) 2 mg/kg IV, 6.5-13 mg/kg IM (INNOVER) + Fentanyl Droperidol 2.5 mg + fentanyl 0.05 mg/ml; 4-6 ml is diluted in glucose solution and infused over 10 min Diazepam (CALMPOSE) 0.2-0.4 mg/kg slow IV (ATIVAN) 0.05-0.1 mg/kg slow IV 0.05-0.1 mg/kg slow IV

20 to 25 percent is required to produce surgi- dium to adrenaline and may produce a va- cal anaesthesia. It has a low blood solubility. riety of cardiac irregularities such as tachy- The induction and recovery are rapid and cardia and fibrillation. That is the reason for smooth. Blood pressure and cardiac contrac- avoiding cyclopropane anaesthesia in pheo- tility are well maintained with cyclopropane chromocytoma and thyrotoxicosis. Cyclo- even on prolonged administration. Muscle propane shock (in patients with sepsis) is relaxant activity is fairly good. Because of its another drawback, which produces a sud- highly inflammable and explosive nature, the den fall of blood pressure with collapse. close circuit has to be used to conserve the drug and to keep its concentration in the op- VOLATILE LIQUIDS erating room low. Because of its smooth induction and ETHER (DIETHYL ETHER) non-irritant to the respiratory passage, the It is a colourless, volatile liquid with a pun- danger of overdosage must be watched for. gent odour and produces irritating vapours Cyclopropane also sensitizes the myocar- which are inflammable and explosive. It is General Anaesthetics 63 one of the first substances to be employed pharyngeal reflexes in upper planes of sur- for general anaesthesia. It is a potent agent gical anaesthesia. and produces full anaesthesia when inhaled Halothane causes relatively greater de- in low concentration. A concentration of 10 pression of respiration. It inhibits intesti- to 15% in the inspired air is usually required nal and uterine contractions. Cardiac out- for induction. It produces prolonged and put is also reduced by 20 to 50 percent when unpleasant induction with salivation and anaesthesia is induced by inspiration of ha- marked respiratory secretions. For this at- lothane at 0.8 to 1.2 percent concentration, ropine must be given prior to anaesthesia for inhibition of these secretions. which is necessary for surgical anaesthesia. Heart rate is slowed during anaesthesia, Respiration and blood pressure are gen- tachyarrhythmias may also occur in the erally well maintained because of reflex presence of halothane. stimulation and high sympathetic tone. Halothane causes dose-dependent re- Because of its slow induction and recov- ductions of renal blood flow and glomeru- ery, irritant property and other disadvan- lar filtration rate as a result of fall in blood tages ether is rarely used these days and may pressure. be occasionally used as a supplement to ni- Hepatitis occurs in susceptible individu- trous oxide-oxygen mixture in children. als with repeated use. TRICHLOROETHYLENE It causes decrease in uterine muscle tone. It is a clear, colourless liquid with a char- Elimination of halothane may continue acteristic odour but a blue dye is added for for 24 to 48 hours after prolonged adminis- distinction from chloroform. It is a potent tration. Recovery is smooth and reasonably analgesic with a rapid onset of action but quick. It is currently one of the most popu- muscular relaxation with this agent is inad- lar anaesthetic used due to its non-irritant, equate. Induction and recovery are slow. non-inflammable, pleasant and rapid action. It may produce tachypnoea and brady- cardia and sensitizes the myocardium to ENFLURANE adrenaline and cardiac arrhythmias can oc- It is a clear, colourless, noninflammable cur probably due to hypoxic release of liquid with a mild, sweet odour and consid- adrenaline. ered to be a useful alternative to halothane. Now-a-days, it is occasionally used in Induction of anaesthesia, appropriate for obstetrics, burns dressings etc. as a self surgery may be achieved within 10 minutes medication analgesic. after approximately 4 percent enflurane in inhaled. Arterial blood pressure decreases HALOTHANE progressively as the depth of anaesthesia is It is a volatile liquid, non-irritant and increased with enflurane, about the same non-inflammable. It is most widely used degree as it does with halothane inhalation. volatile anaesthetic due to its smooth and The anaesthesia produces rapid induction rapid induction. It inhibits laryngeal and with quick recovery. 64 Section 2/ Drugs Acting on CNS

Enflurane can be used for prolonged these changes are rapidly reversed during operations such as cholecystectomy and recovery. other abdominal surgery which requires profound muscular relaxation. It stimulates METHOXYFLURANE salivary and respiratory secretions. Uterine It is a clear, colourless liquid with a relaxation is similar to halothane. sweet and fruity odour. It is noninflammable No unusual effect on the gastrointes- and non-explosive in air or oxygen in an- tinal tract has been reported with aesthetic concentrations. It is the most po- enflurane anaesthesia, however, certain tent inhalational anaesthetic which has a evidence of hepatic impairment has good analgesic and muscle relaxant prop- been obtained during and after surgi- erties. Renal blood flow, glomerular filtra- cal anaesthesia. Hepatic necrosis prob- tion rate and urine flow are reduced as with ably occurs with enflurane in rare the halothane. instances. It also produces the respiratory and car- Heart rate decreases little and reduction diovascular depression as with halothane of cardiac output is less marked. Fall in but bradycardia is more prominent. blood pressure is similar to that caused by Methoxyflurane damages renal tubules halothane, arrhythmias are rare. leading to inability to concentrate urine and ISOFLURANE uraemia. Because of its renal toxicity, it should not be used to achieve profound It is a isomer of enflurane and its chemi- anaesthesia nor for prolonged periods of cal and physical properties are similar to time. enflurane, but it is approximately 1½ times more potent, more volatile. It has a lower This agent is used due to certain advan- blood: gas solubility coefficient than tages i.e. it provides profound analgesia and enflurane. It produces rapid induction and good relaxation of skeletal muscles, uterine recovery. contractions are not inhibited and postop- erative and vomiting are not Systemic arterial blood pressure de- troublesome. But, due to its renal toxicity, creases progressively with increasing depth its use as a general anaesthetic is limited. of anaesthesia with isoflurane. It also in- creases heart rate but arrhythmias are not DESFLURANE precipitated. Isoflurane depresses respira- It is a noninflammable, non-irritant tion as concentration is increased. Uterine agent and chemically related to ether. Induc- and skeletal muscle relaxation is similar to tion with this agent is smooth and rapid. The enflurane. respiratory, hemodynamic and other During anaesthesia, depression of renal changes caused by desflurane are similar to blood flow, decrease in rate of glomerular those of isoflurane. This agent is undergo- filtration and urinary flow are reported but ing clinical trial. General Anaesthetics 65

SEVOFLURANE Because of its poor analgesic property, This is also a new compound and un- the painful procedures should not be car- dergoing clinical trial. It is noninflammable, ried out under its influence unless an opioid non-irritant agent. It produces more rapid or nitrous oxide has been given. induction and termination of anaesthesia Thiopentone depresses respiration tran- than observed with other inhalational siently. Blood pressure falls immediately agents. The respiratory and circulatory ef- after injection but recovers rapidly. It does fects of resemble those of not sensitize the myocardium to adrenaline. isoflurane. Thiopentone also has been sometimes used for rapid control of convulsions. INTRAVENOUS ANAESTHETICS Adverse effects include laryngospasm, which occurs generally when respiratory Intravenous anaesthetics are mainly used for secretions or other irritants are present. Shiv- rapid induction of anaesthesia, which is then ering and delirium may occur during recov- maintained by an inhalational agent. They ery. Postoperative pain induces restlessness. also serve to reduce the amount of mainte- Nausea and vomiting are uncommon. It can nance anaesthetics. precipitate acute intermittent porphyria in In this section the agents having anaes- susceptible individuals. thetic properties will be discussed. More de- tails of each class of drug and their uses in METHOHEXITONE SODIUM other circumstances are presented elsewhere. It is preferred to thiopentone sodium for short procedures and out patients due to its BARBITURATES rapid recovery. It is approximately three THIOPENTONE SODIUM times more potent than thiopentone sodium with quicker and briefer action. It is an ultra short acting thiobarbiturate. The sodium salts are highly soluble in water The only disadvantages associated with yielding a very alkaline solution (pH 10.5 to its use are that induction is less smooth, rest- 11), which must be prepared freshly before lessness is more common, as is coughing and injection. Induction is generally smooth and hiccup. takes approximately 10 to 30 seconds. NON-BARBITURATE INTRAVENOUS Thiopentone sodium is usually given as ANAESTHETICS 92.5 percent solution, initially 100 to 150 mg over 10-15 seconds and repeated if necessary PROPANIDID depending upon the patient’s response after It is an oily liquid eugenol derivative and 20-30 seconds. On repeated administration less potent than thiopentone. It is a very the extracerebral sites are gradually filled up short acting intravenous anaesthetic and and lower doses produces anaesthesia specially used for very short outpatient op- which lasts longer. erations and dental procedures. 66 Section 2/ Drugs Acting on CNS

Adverse effects include laryngospasm, The fixed dose combination of fentanyl high incidence of hypersensitivity reactions, (0.05 mg) and droperidol (2.5 mg/ml), 4 to tachycardia, respiratory depression and 6 ml is diluted in glucose solution and in- sometimes hypotension. Local irritation and fused IV over 10 minutes. thrombophlebitis occur due to the alkalin- Patient remains drowsy but conscious. ity of the solution. It is occasionally used as Respiratory depression is marked and pre- an alternative to thiopentone. dictable. There is slight fall in blood pres- sure. Heart rate often decreases but myocar- KETAMINE dium is not sensitized to adrenaline. It is a new non-barbiturate anaesthetic It is recommended for endoscopies, an- agent and pharmacologically related to giographies, burn dressings etc. , a hallucinogen. Intravenous ketamine produces unconsciousness and DIAZEPAM analgesia within 30 seconds. It can be given It may be used to produce light seda- by intramuscular route also. It acts on the tion and amnesia for unpleasant procedures cerebral cortex and subcortical areas. by intravenous injection. It has also been The drug increases the heart rate, car- used for induction and to supplement ni- diac output and blood pressure which is trous oxide anaesthesia. The benzodiaz- due to sympathetic stimulation. Respira- epines are further discussed in chapter tion is not depressed, muscle tone ‘Sedative and hypnotics’ in detail. increases and reflexes are not abolished during anaesthesia. Ketamine has been ETOMIDATE recommended for short operations, un- It is a new intravenous anaesthetic agent pleasant therapeutic and diagnostic pro- with poor analgesic property. It has a briefer cedures in children, operation in shocked duration of action than thiopentone. It pro- patients and in obstetrics. duces little cardiovascular and respiratory Adverse reactions include delirium, depression. A single intravenous dose pro- hallucinations and unpleasant dreams. It duces loss of consciousness within 10 sec- should not be used in hypertensives and in onds and a state of anaesthesia. patient with ischaemic heart disease. ALPHADONE FENTANYL-DROPERIDOL It is a slower acting anaesthetic COMBINATION which is a combination of two preganedione Fentanyl is a potent short acting analge- derivatives, alphaxolone and alphadolone sic related to pethidine and belongs to group acetate. It produces analgesia and sleep last- of 4-acyl-anilinopiperdines. Droperidol is a ing 20-30 minutes. It is less irritant, blood rapidly acting potent neuroleptic pressure and respiration are not much af- derivative related to halo- fected. It has been used as an inducing agent peridol. In combination, these agents pro- in place of thiopentone but due to hyper- duce a state of ‘neuroleptanalgesia.’ sensitivity reactions its use is very limited. General Anaesthetics 67

PREANAESTHETIC MEDICATION the amount of anaesthetic required. How- ever, they have certain disadvantages: Preanaesthetic medication refers to the use • They depress respiration. of drugs before the administration of an an- aesthetic agent, which makes it more pleas- • May cause fall in blood pressure during ant and safe to the patient anaesthesia. • Can precipitate asthma, as these drugs The aims of preanaesthetic medication are histamine liberators. are: • Pethidine may produce tachycardia by 1. Reduce the anxiety and apprehension its vagolytic action. without producing much drowsiness. • Morphine can interfere with pupillary 2. To facilitate a smooth and rapid signs of anaesthesia. induction. 3. To relieve preoperative and postopera- SEDATIVE-HYPNOTICS tive pain or to supplement the analge- The barbiturates like pentobarbitone, sic action of anaesthetics. secobarbitone or butobarbitone (100 mg oral) 4. To provide amnesia for preoperative have been used to provide sedation and to and postoperative period. relieve apprehension before operation. 5. To suppress respiratory and other Non-barbiturate sedatives like chloral secretions and vagal stimulation hydrate, paraldehyde and glutethimide may caused by anaesthetics. be used. 6. To minimize certain undesirable effects (50 mg IM), an produced by anaesthetic agents like antihistaminic with sedative, antiemetic and bradycardia and vomiting. anticholinergic properties is generally used To achieve all the objectives, a combina- in children as it causes little respiratory de- tion of 2 or 3 drugs is used depending on pression. the need. The commonly employed drugs are opioids, sedative-hypnotics, antianxiety ANTIANXIETY DRUGS agents, anti-, neuroleptics and The tranquillizers like benzodia- . zepines (diazepam 5-10 mg oral, or lorazepam 2 to 4 mg IM, IV are now OPIOIDS preferred for preanaesthetic medication These are the most commonly used because they produce tranquillity, have drugs. Morphine (10-15 mg IM), pethidine better muscle relaxant property and (50-100 mg IM) are frequently used drugs smoothen induction. Other tranquillizer for their sedative and analgesic property. compounds include which They reduce the anxiety and apprehension, possess sedative, antiemetic and produce pre- and postoperative analgesia, antihistaminic properties. They can be help in smooth induction. They also reduce given orally as well as parenterally. 68 Section 2/ Drugs Acting on CNS

ANTICHOLINERGICS (10 mg) or haloperidol (2-4 mg) IM are used Atropine (0.06 mg IM, IV) or scopola- as preanaesthetic medication. They reduce mine is generally given in combination with anxiety, emesis and help in smooth induction. morphine to block the vagal action so as to However, these compounds potentiate reduce the salivary and bronchial secretions. respiratory depression. They also prevent vagal bradycardia and ANTIEMETICS hypotension during operation. Hyoscine Droperidol and (25-50 mg produces amnesia and antiemetic effect also. IM) is sometime used for their antiemetic activity. Hydroxyzine has antianxiety, NEUROLEPTICS antihistaminic and anticholinergic proper- Chlorpromazine (25 mg), ties also.

 Sedative ChapterChapter PharmacodynamicsPharmacodynamics (Mode of& Action of Drugs) 2.21. 4 Hypnotics

Sedative (anxiolytic) are the agents which Pain: Barbiturates do not have any an- reduce anxiety and exert a calming effect algesic effect. with little or no effect on motor or mental Anaesthesia: The ultra short acting bar- functions. biturates produce general anaesthesia (de- Hypnotics are the drugs which produce tails are given in chapter ‘General drowsiness and encourage the onset and anaesthetics’). maintenance of sleep. They are classified Anticonvulsant action: In anaesthetic into different categories (Table 2.2.1.) dose all barbiturates e.g. phenobarbitone, mephobarbitone possess anticonvulsant ac- BARBITURATES tion. Phenobarbitone is drug of choice for Barbiturates are the derivatives of the treatment of grandmal epilepsy (details barbituric acid. They are general CNS are given in chapter ‘Antiepileptic drugs’). depressants. They can cause sedation, CVS: In hypnotic dose, hypotension and hypnosis and general anaesthesia decrease in heart rate occurs. In toxic dose, depending upon the particular barbiturates there is a severe decrease in blood pressure used and its dose. due to ganglionic blockade. Pharmacological Actions Respiration: In higher dose, barbiturates depress the respiration. It depresses the sen- CNS: Barbiturates produce depression sitivity of respiratory centre to CO . of central nervous system in dose dependent 2 manner. In small dose, barbiturates relieve GIT: They depress the tone and motil- anxiety and are generally used as sedative. ity of GIT, but thiobarbiturates may stimu- In hypnotic dose, it produces sleep resem- late the intestinal smooth muscles. bling normal physiological sleep. Hypnotic Kidney: They directly depress the tubu- dose of barbiturates produce motor incoor- lar reabsorption of sodium, reduce urine dination. flow and increase ADH release. 70 Section 2/ Drugs Acting on CNS

Table 2.2.1: Classification of sedative and hypnotics. I. Barbiturates Phenobarbitone (LUMINAL) 15-30 mg TDS (as sedative) 60-100 mg HS (as hypnotics) Butobarbitone (SONERYL) 15-30 mg TDS, 100-200 mg HS Pentobarbitone (NEMBUTAL) 30 mg TDS, 100 mg HS Secobarbitone (LIPATON) 30 mg TDS, 100 mg HS II. Benzodiazepines i. Used as hypnotics Diazepam (CALMPOSE) 5-10 mg HS Nitrazepam (NITROSUN) 5-10 mg HS Midazolam (FULSED) 0.02-0.1 mg/kg/hr IV infusion ii. Used as antianxiety agents Diazepam (CALMPOSE) 2-10 mg BD-TDS Chlordiazepoxide (LIBRIUM) 10-25 mg BD-TDS Lorazepam (TRAPEX) 1-2 mg BD-TDS (oral/IM) Alprazolam (ALPRAX) 0.5-4 mg/day Oxazepam (SEREPAX) 15-30 mg OD-TDS iii. Used as antiepileptic agents Diazepam 10-25 mg/day IM/IV Clonazepam (CLONOTRIL) 0.5-4 mg TDS III. Newer nonbenzodiazepine compounds Zopiclone (ZOPICON) 7.5 mg HS Zolpidem (SOBRIUM) 10 mg HS Zaleplon (ZAPLON) 10 mg HS

Liver: They induce microsomal drug Adverse Effects metabolising enzyme thus they increase the Intolerance effects include , rate of metabolism of number of drugs. vomiting, diarrhoea, nausea. Pharmacokinetics Hangover especially with long acting barbiturates. Excitement and restlessness, They are well absorbed from the GIT. neuralgic pain, allergic reactions include They are widely distributed in body. Rate swelling and erythematous dermatitis. They of entry into CNS is dependent on lipid solu- produce physical dependent and have abuse bility. Ultra short acting barbiturates are potential. highly lipid soluble and quickly enter the brain. Redistribution to various tissues ter- Therapeutic Uses minate their action and they are slowly re- leased from the tissues and gradually • To produce hypnosis. metabolised in the liver. They are partly • To produce sedation. metabolised and partly excreted unchanged • Anticonvulsant action: Phenobarbital is in urine. drug of choice. Sedative & Hypnotics 71

• For general anaesthesia: Ultra short agents exhibit good efficacy, are relatively acting barbiturates are used. safe and have minimum toxicity. They are • As preanaesthetic medication. indicated for short term relief of anxiety. • As obstetrical analgesia. Benzodiazepines have no action on respira- tion and cardiovascular system. They have Barbiturate Poisoning no action on other body systems. They have It produces severe toxic manifestations. a muscle relaxant action, probably due to Either suicidal or accidental intake of toxic CNS depressant action and have anticonvul- doses of barbiturates is characterized by sant action. They have lower abuse liabil- depressed respiration, circulatory shock, ity. Benzodiazepines when administered pupils are initially constricted & then dilated cause sedation, hypnosis, muscle relaxation, due to asphyxia, hypothermia, renal failure relieve anxiety and some have anticonvul- and pulmonary complications such as acute sant action. pulmonary edema. Benzodiazepines exert their pharmaco- logical effect mainly by potentiation of Treatment of Acute Barbiturate Poisoning neural inhibition in CNS which is medi- • Gastric lavage to remove unabsorbed ated by GABA. drug. Emesis can be produced by apomorphine and activated charcoal is Pharmacokinetics administered to adsorb the unabsorbed The pharmacokinetic profile is different drug. with different compounds. Diazepam after • Maintenance of respiration: oral administration is completely and rap-  Oxygen inhalation. idly absorbed from the proximal small in-  Endotracheal intubation or tracheo- testine. Oxazepam is least rapidly absorbed stomy. while lorazepam is an intermediately ab-  Mechanical ventilation. sorbed between these two. They are • Intravenous fluids. metabolised in liver by dealkylation and • Forced diuresis: Diuretics like mannitol hydroxylation and excreted in urine as glu- and furosemide can be used. curonide conjugates. They cross the placen- tal barrier and are secreted in milk. • Alkalinization. • Prophylactic antimicrobial therapy to Adverse Reactions avoid any secondary e.g. The common side effects are drowsiness, and infection due to lethargy, ataxia. They also cause behavioural tracheostomy or urinary catheterization. changes and dose dependent impairment of • Dialysis (peritoneal or haemodialysis). visual motor coordination. Other side effects which occur rarely are vertigo, headache, BENZODIAZEPINES allergy, photosensitization, leucopenia, im- Benzodiazepines are commonly used paired sexual function and menstrual irregu- anxiolytics in clinical practice because these larities. 72 Section 2/ Drugs Acting on CNS

Therapeutic Uses lorazepam is approximately 90 percent bound to plasma proteins. It is conjugated • As antianxiety agent. to inactive glucuronide metabolite and is • As hypnotic. excreted in urine. • As anticonvulsant. The most frequent adverse reactions • As preanaesthetic medication. reported are sedation, followed by DIAZEPAM dizziness, weakness and unsteadiness. Less frequent adverse reactions include Being highly lipophilic it is quickly ab- disorientation, depression, nausea, change sorbed from the gastrointestinal tract. The in appetite, headache, sleep disturbance, kinetics of redistribution of diazepam is agitation, dermatological symptoms complicated by enterohepatic circulation. including very serious reactions, eye- Initially there is high concentration in CNS function disturbance, together with various after intravenous injection, then due to redis- gastrointestinal symptoms and autonomic tribution of drug the concentration starts fall- manifestations. The incidence of sedation ing in brain. It has a plasma half life of more and unsteadiness increases with age. than 20 hours. Diazepam is metabolised in It is used in anxiety disorders or anxiety liver to pharmacologically active metabolite, associated with depressive symptoms, as desmethyldiazepam which has a long pre-surgical medication. plasma half life (80 hrs). It crosses the pla- cental barrier and when given before labour OXAZEPAM may cause hypotonia and mild respiratory It is used in tension, anxiety disorders, depression in neonates. anxiety associated with alcohol withdrawal, It is indicated as hypnotic, in anxiety, agitation and irritability in older patients tension, muscle spasm, psychosomatic and and psychoneurosis. behaviour disorders, dysmenorrhoea, cere- Adverse effects include sedation, ver- bral palsy, upper motor neuron spasticity, tigo, dizziness, disorientation, blurred vision sedative for surgical procedures, labour, and dependence. tetanus, eclampsia and epilepsy. MIDAZOLAM LORAZEPAM Midazolam is a new, short acting ben- It provides prompt relief from a variety zodiazepine with sedative properties, twice of symptoms associated with anxiety and in as potent as diazepam. It is also used as an anxiety associated with depression. anaesthetic inducing agent. It is readily absorbed when given orally. The mechanism of action of midazolam Peak concentrations in plasma occur ap- though not clearly understood is probably proximately 2 hours following administra- similar to other benzodiazepines i.e. through tion. The halflife of unconjugated lorazepam interference with GABA reuptake. It has a in human plasma is approximately 12 to 16 relatively high affinity for benzodiazepine hours. At clinically relevant concentration, receptors. Sedative & Hypnotics 73

It is rapidly absorbed following intra- Alprazolam has caused a lower inci- muscular administration with more than 90 dence of drowsiness, light-headedness and percent bioavailability. depression than diazepam. Alprazolam, like Adverse effects include local effects like other benzodiazepines, has the potential for redness and phlebitis, apnoea (usually seen the development of tolerance and with- on IV administration). Rarely nausea, vom- drawal symptoms, although the incidence iting, headache, drowsiness, hiccups and is lower than that seen with other benzodi- retrograde amnesia may occur. azepines. Alprazolam’s potential for drug dependence is less in comparison to other It is indicated for preoperative sedation, benzodiazepines. conscious sedation prior to short diagnostic or endoscopic procedures, induction of gen- It is used in the management of eral anaesthesia prior to administration of generalised anxiety disorder or the short other anaesthetic agents. term relief of symptoms of anxiety. It is also indicated for the treatment of panic disor- ALPRAZOLAM ders with or without agoraphobia.

CNS agents of the 1,4 benzodiazepine CHLORDIAZEPOXIDE class presumably exert their effects by binding at stereo specific receptors at It is the first benzodiazepine used clini- several sites within the central nervous cally. Adverse effects include nausea, ver- system (CNS). Alprazolam like other tigo, headache and skin rash. benzodiazepines exerts its anxiolytic It is indicated in fear, anxiety, tension, action by potentiating GABA activity. pre and postoperative apprehension GABA is a neurotransmitter which inhib- behavioural disorders, insomnia and emo- its the CNS activity. Alprazolam acts tional disturbances. preferentially in midbrain, ascending CLONAZEPAM reticular formation (which maintains wakefulness) and on limbic system It acts by enhancing GABA induced in- (thought and mental functions). crease in conductance of chloride in neurons. The pharmacological effects of After oral administration, over 80 per- alprazolam do not differ appreciably cent of clonazepam is absorbed. It is exten- from those of diazepam. However, sively bound to plasma proteins and is alprazolam is about 10 times more potent widely distributed. It is metabolised and the than diazepam. metabolites are excreted in urine. Following oral administration, alprazolam Adverse effects include impaired alert- is readily absorbed. Peak concentration in the ness, amnesia, drowsiness, lethargy, respi- plasma occur in one to two hours following ratory depression, salivary and bronchial administration. Alprazolam and its metabo- hypersecretion in infants, behavioural prob- lites are excreted primarily in the urine. lems, muscle weakness, vertigo, ataxia and Alprazolam is 80% bound to plasma proteins. dizziness. 74 Section 2/ Drugs Acting on CNS

It is indicated in typical and atypical Zolpidem is rapidly absorbed and has a absence seizure, infantile spasms, myoclonic quick onset of hypnotic action. Bio- epilepsy, atonic seizures, minor motor sei- availability is 70 percent following oral zures of childhood, refractory grandmal administration and the drug demonstrates epilepsy or temporal lobe epilepsy and sei- linear kinetics in the therapeutic dose range. zures not controlled by conventional Peak plasma concentration is reached at 0.5 antiepileptics. and 3 hours. The elimination half-life is short. It is 92% plasma protein bound and is NEWER COMPOUNDS metabolised in liver to inactive metabolites. It is eliminated in the urine and in the faeces. ZOPICLONE Adverse effects include diarrhoea, nau- It is a novel hypnotic belonging to sea, vomiting, vertigo, dizziness, headache, cyclopyrrolone derivative. It is useful in short drowsiness, nightmares, asthenia, memory term management of insomnia and has low disturbances, depression, confusion, diplo- abuse potential. pia, tremor and ataxia. Zopiclone exhibits anticonvulsant, It is indicated in short term management muscle relaxant and hypnosedative proper- of insomnia. ties similar to benzodiazepines. ZALEPLON Zopiclone is rapidly absorbed after oral dosing. Its elimination half-life period is 3.5- It is a nonbenzodiazepine hypnotic. 6 hours. It is mainly excreted in urine. Zaleplon interacts and binds selectively to the brain omega-1 receptor situated on the alpha Adverse effects include metallic or bit- subunit of the GABA receptor complex. ter after-taste, nausea, vomiting, allergic skin A reaction, irritability, hallucinations, depres- It is rapidly and almost completely sion, amnesia and confusion. absorbed following oral administration. It undergoes significant presystemic metabo- It is indicated in treatment of transient, lism, all the metabolites are pharmacologi- situational and chronic insomnia, insomnia cally inactive. secondary to psychiatric disorders. Adverse effects include dizziness, am- ZOLPIDEM nesia, headache, tremor, nausea, abdominal Zolpidem is a non-benzodiazepine hyp- pain, dyspepsia, anorexia, eye pain, asthe- notic of the imidazopyridine class. It is a nia, malaise and myalgia.

GABAA receptor agonist selective for It is indicated in short term management omega-1 receptor subunit. of insomnia.  ChapterChapter PharmacodynamicsPharmacodynamicsNarcoticNarcotic AnalgesicsAnalgesics (Opioids)(Opioids) 2.31. 4 (Mode(Opioids) (Opioids)(Opioids)of Action of Drugs)

Analgesics are the drugs (natural or syn- NATURAL COMPOUNDS thetic origin) which relieve pain by acting on CNS or peripheral pain mechanism without causing loss of consciousness. MORPHINE Dental pain is the initial sign of any den- Opium is the milky exudate obtained by tal disease which is usually acute in incising the unripe seed capsule of the nature. In dentistry, non-steroidal anti- poppy plant Papaver somniferum and mor- inflammator drugs (NSAID’s) are phine is the most important alkaloid of commonly employed for dental pain and opium. Morphine produces analgesia inflammation which may be due to caries, through action in the brain and spinal abscess tooth extraction or after any den- tal procedures. Analgesics can be divided cord, that contain peptides possessing into two main groups: opioid like pharmacological action. These endogenous substances are known as a. Opioid/narcotic/morphine like an- endogenous opioid peptides (earlier algesics. known as endorphin & now known as b. Nonopioid/nonnarcotic/aspirin βββ-endorphin). like analgesics. Drugs obtained from morphine are Morphine and other opioids exert their known as opioids or narcotic analgesics. pharmacological actions by acting on dif- ferent receptors namely mu (µ), kappa (κκκ) The opium is obtained from the opium and delta (δδδ). poppy Papaver somniferum. It contains two type of alkaloids e.g. phenanthrene deriva- Analgesic, respiratory, depression as tives (morphine, codeine & thebaine) and well as euphoria produced by morphine benzyl isoquinoline derivatives ( result mainly from action at mu recep- and ). tors. Most of the currently available nar- The opioid analgesics are classified as cotic analgesics act primarily on the mu in table 2.3.1. receptors. 76 Section 2/ Drugs Acting on CNS

Table 2.3.1: Classification of narcotic analgesics. I. Natural alkaloids Morphine (as sulphate; MORCONTIN) 0.2-0.8 mg/kg BD, IM/SC Codeine (as phosphate) 20-60 mg/day II. Semisynthetic compounds Pholcodeine (ETHNINE) 10-30 mg/day Diacetyl morphine () 3-5 mg/day IM/SC Other semisynthetic agents are , oxymorphone, oxycodone, , dihydro- codeine etc. III. Synthetic compounds Pethidine (as hydrochloride) 50-100 mg/day IM/SC Fentanyl (as citrate; FENDROP) 50-100 µg/day IM/IV (PYSEPTONE) 5-10 mg/day oral/SC Dextropropoxyphene (DEXOVON) 65-130 mg/day (TRANDOL) 50-100 mg BD-TDS Ethoheptazine (EQUAGESIC) 75-150 mg/day Newer compounds include sufentanil, alfentanil etc.

Delta and kappa receptors can also con- fectively than sharp intermittent pain and tribute to analgesia, particularly at spinal is very effective in visceral pain. level. Although morphine also acts on kappa Morphine also produces a sense of anxi- and delta sites but it is not clear that up to ety, known as dysphoria. The morphine pro- what level they contribute in its analgesic duces euphoria (which makes morphine as action. one of the main drugs of abuse) and analge- sia by acting on higher centres and spinal Pharmacological Actions cord. Effect on CNS: The main action of mor- On intrathecal injection, it acts on substan- phine is CNS depression which further re- tia gelatinosa of dorsal horn of spinal cord and sults in analgesia, depression of respiratory inhibit the release of excitatory transmitters. centre, cough centre and sleep. In addition At supraspinal sites, it acts on medulla, mid it causes euphoria or dysphoria and depen- brain, limbic and cortical areas. dence. Action on eye: Morphine causes con- Analgesia: Morphine produces analge- striction of pupil (miosis) due to action on sia by elevation of pain threshold, thereby reducing the perception of pain. It also al- oculomotor nerve nucleus. tered psychic reaction to pain which may be Action on respiration: Morphine de- associated with feeling of well being e.g. presses the medullary respiratory centre in euphoria. It also produces lethargy and medulla oblongata and by reducing the sen- sleep, morphine relieves all types of pain, sitivity of the medullary respiratory centre but dull constant pain is relieved more ef- to increased plasma CO2. The rise in arterial Narcotic Analgesics (Opioids) 77

CO2 causes an increase in cerebrospinal fluid in body temperature. It also depresses tem- pressure. perature regulating centre. Action on cough centre: Morphine sup- Pharmacokinetics presses cough reflexes, but cough suppres- sion by opioids may allow accumulation of Morphine orally is less effective and respiratory secretions and may produce air- absorption is very slow. It has variable and way obstruction. high first pass metabolism when given by subcutaneous route, its analgesic effect starts Chemoreceptor trigger zone (CTZ): within 10 minutes which persists for 4 to 5 Morphine stimulates CTZ and produces hours and by IV route, it produces immedi- nausea and vomiting. These effects are more ate action. In plasma, it binds to plasma pro- marked in upright position due to vestibu- teins (approx. 30%). In liver it is metabolized lar involvement. by conjugation to glucuronic acid to form Vagal centre: Morphine stimulates the active and inactive products, which are ex- vagal centre and produces bradycardia. creted in urine. It is also excreted though bile Effect on GIT: It increases the tone of and in the faeces. smooth muscle as well as sphincters but at Adverse Reactions the same time it decreases the propulsive movements and gastrointestinal secretions CNS side effects include confusion, anxi- are diminished, the overall action is consti- ety, lethargy, nausea and vomiting. GIT re- pation. lated effect is constipation. Other side effects are urinary retention, dry mouth, miosis, Other smooth muscle: Morphine causes dysphoria, hypotension, skin rash, itching bronchoconstriction which is due to hista- and urticaria. Tolerance, drug dependence mine release and may be dangerous in pa- and drug abuse are the main drawbacks of tients suffering from bronchial asthma. morphine. Morphine also cause flushing and itch- ing of skin due to histamine release. Acute Overdose/Toxicity (Morphine Urinary system: Morphine causes Poisoning) spasm of detrusor as well as sphincters of It is characterised by respiratory depres- urinary bladder and causes distension, ur- sion, miosis, cyanosis, reduced body tem- gency and difficulty in micturition. perature, urinary retention, hypotension, Endocrine system: Morphine and other pulmonary edema and coma. opioid analgesics stimulate the release of The acute poisoning can be treated by: vasopressin and and inhibit the • Maintenance of airway and oxygen in- release of , ACTH and halation. Maintenance of BP. follicle stimulating hormone. • Specific antagonists: Naloxone 0.4-0.8 Metabolism: Morphine decreases the mg IV; alternatively nalorphine (3-5 mg metabolic rate which can lead to decrease IV) can be given. 78 Section 2/ Drugs Acting on CNS

• Stomach lavage with potassium per- • Postoperative pain. manganate. • Obstetrical analgesia. • Enhancing excretion of unabsorbed 2. In the suppression of cough and dysp- morphine from the intestine. nea (due to left ventricular failure and • Acidify the urine to enhance the renal pulmonary edema). excretion of morphine. 3. For sedation. Contraindications 4. In the treatment of diarrhoea. 5. As preanaesthetic medication. 1. Head injury, because morphine can 6. In the treatment of acute left ventricu- cause increase in intracranial tension, lar failure. cause marked respiratory depression 7. Use of opioids in dentistry is very limited. and certain physiological signs e.g. miosis and vomiting can interfere CODEINE with the assessment of clinical It is a methyl ester of morphine and less progress. potent analgesic than morphine. It is widely 2. Myxoedema patients are more sensi- used as antitussive agent. Pholcodeine is tive to morphine. also used as antitussive agent and causes 3. Bronchial asthma: Morphine releases less constipation (Details are given in chap- histamine which can trigger ter ‘Drugs acting on respiratory system’). bronchoconstriction. 4. In liver damage chance of cumulative SYNTHETIC COMPOUNDS toxicity is more. 5. In elderly patients, chances of urinary PETHIDINE retention are high. Pethidine is predominantly a µ agonist and 6. In hypotensive states, more fall in it exerts its action on the CNS and the neural blood pressure occurs due to morphine. elements in the bowel. In equianalgesic doses, pethidine produces as much sedation, respira- Therapeutic Uses tory depression and euphoria as does morphine. A few patients may experience dysphoria. 1. Analgesia: Morphine is used in the fol- lowing painful conditions: The analgesic effects of pethidine are detectable about 15 minutes after oral ad- • In the treatment of any severe, con- ministration, reach a peak in about two stant pain. hours and subside gradually over several • Visceral pain e.g. myocardial infrac- hours. Pethidine is absorbed by all routes of tion, pleurisy, vascular occlusion, administration, but the rate of absorption is renal and biliary colic. erratic after IM injection. Pethidine crosses • Traumatic pain e.g. long bone frac- the placental barrier. tures and burns. Pethidine is metabolized chiefly in the • Pain of terminal illness e.g. in can- liver, to mainly meperidinic acid and minor cer patients. metabolite , which are conju- Narcotic Analgesics (Opioids) 79 gated with glucuronic acid and excreted in pharmacology and side effects are similar to urine. Only a small amount of pethidine is that of morphine. It is used in the treatment of excreted unchanged. Pethidine differs from visceral pain and as an antitussive. It is also used morphine in that toxic doses sometimes as substitution therapy of opioid dependence. cause CNS excitation, characterized by trem- ors, muscle twitches and seizures; these ef- DEXTROPROPOXYPHENE fect are largely due to norpethidine. It is dextro isomer of propoxyphene Adverse effects include nausea, vomit- which is an analgesic and possesses antitus- ing, respiratory depression, dizziness, dys- sive property. It has low analgesic activity phoria, constipation, urinary retention. Tol- even half of codeine. It is metabolized in liver. erance develops to some of these effects and Side effects include vomiting, epigastric dis- it has abuse potential. tress and sedation. The demethylated me- It is mainly indicated for analgesia, as tabolite of propoxyphene is cardiotoxic. It is preanaesthetic medication, for epidural and used in the treatment of mild type of pain. intrathecal analgesia. TRAMADOL FENTANYL It is centrally acting synthetic analgesic It is a potent opioid analgesic. Chemi- compound that is not derived from natural cally it is N-phenyl-N-propanamide. It in- sources nor is chemically related to opiates. teracts predominantly with opioid µ-recep- It acts via opioid receptors in CNS to pro- tor in human brain, spinal cord and other duce analgesia and has no abuse potential. tissues. It exerts its principle pharmacologic It also inhibits the reuptake of noradrena- effects on the CNS. It is 80-100 times more line and serotonin. potent than morphine, both in analgesia and It causes less respiratory depression, se- respiratory depression. dation, constipation and urinary retention Adverse effects include respiratory de- than morphine. Its hemodynamic effects are pression (death from hypoventilation), de- minimal. pendence, apnoea, muscle rigidity, bradycar- Side effects include nausea, vomiting dia, arrhythmia, chest pain, GI symptoms, and dizziness. haemoptysis, , headache, It is indicated in moderate to severe, somnolence, confusion and hallucinations. acute or chronic pain and in painful diag- It is indicated as a narcotic analgesic nostic procedures and surgery; arthralgia, supplement in general or regional anaesthe- dental pain, musculoskeletal pain, pain as- sia, as an anaesthetic agent with oxygen and sociated with fractures, dislocation and skeletal relaxant in selected high risk pa- other related type of pain. tients (e.g. open heart surgery). ETHOHEPTAZINE METHADONE It is orally active analgesic, similar to It is synthetic compound having same or pethidine with low abuse potential. It is gen- more analgesic activity than morphine. It’s erally used in combination with nonsteroi- 80 Section 2/ Drugs Acting on CNS dal antiinflammatory drugs for mild to mod- actions are produced by kappa receptor ac- erate type of pain. tivation and antagonistic properties are due to action on mu receptor which antagonizes OPIOID AGONISTS/ANTAGONISTS all morphine actions (mainly reverses the analgesia and respiratory depression). It is They are classified as in table 2.3.2. used mainly in the treatment of acute mor- phine poisoning. PENTAZOCINE It is agonist-antagonist of morphine and NALBUPHINE is used as an analgesic. It exerts morphine like It is a strong kappa receptor agonist and action. It is a partial agonist at opioid receptors mu receptor antagonist. Its agonistic prop- and is effective in mild to moderate type of erty is approximately three to four times pain associated with surgery, trauma, burns, more than pentazocine and its antagonistic colics, toothache, cancer, in labour and as property is approximately 10 times more preanaesthetic medication. It is kappa receptor than pentazocine. It has less abuse liability agonist with weak mu antagonist or partial in comparison to pentazocine. It is useful antagonist properties. It causes tachycardia in postoperative pain, myocardial infarction and rise in BP due to sympathetic stimulation. and labour. Tolerance and dependence develops on repeated use. It is effective orally. It is oxidized BUPRENORPHINE and glucuronide conjugation occurs in liver It is a potent and long acting opioid with and excreted in urine. partial mu receptor agonist property. 25 times more potent than morphine. Effects NALORPHINE are similar to morphine but constipation is It is an N-allylnormorphine, semisyn- less marked. It undergoes extensive thetic congener of morphine. The agonistic presystemic elimination and therefore is

Table 2.3.2: Classification of opioid agonists and/or antagonists. I. Agonists-antagonists Pentazocine (PENTAWIN) 30-60 mg/day IM/SC (used as analgesic; 50-100 mg oral) Nalorphine (LETHIDRONE) 2-5 mg IM/IV (not used as analgesic) Nalbuphine 10-20 mg/day SC/IM/IV The other compounds which are agonist-antagonist are levallorphan and cyclazocine which are not used as analgesics. II. Partial/weak agonists Buprenorphine (TIDIGESIC) 0.2-0.4 mg TDS SL, 0.3-0.6 mg/day IM/slow IV 1-4 mg/day IM/IV III. Pure antagonists Naloxone (NARCOTAN) 0.4-0.8 mg/day IM/IV Naltrexone (NALTIMA) 50-100 mg/day Nalmefene 0.1-1.0 mg/day IM/IV Narcotic Analgesics (Opioids) 81 given by parenteral route. It is excreted un- It is inactive orally because of high first changed in urine. Side effects include dizzi- pass metabolism in liver. Metabolised by ness, sedation, miosis, respiratory depres- glucuronidation in liver. The main use of sion, sweating and vomiting. naloxone is in the treatment of acute opioid It is indicated in moderate to severe pain, overdose (acute morphine poisoning). It premedication to surgery, pain due to myo- also precipitates withdrawal syndrome cardial infarction and in postoperative pain. when administered to morphine addicts. The constricted pupils of addicts dilate af- BUTORPHANOL ter administration of naloxone. This has It is a kappa agonist. It produces anal- been used as a diagnostic tool for opioid gesia equivalent to nalbuphine and addiction. buprenorphine but produces more sedation. NALTREXONE It is used in postoperative pain and re- nal colic pain. It is a pure antagonist and chemically related to naloxone. It is more potent than NALOXONE naloxone and because of its longer dura- It is N-allyl analogue of oxymorphone, tion of action, it can be used as maintenance have a high affinity for mu receptor and drug for morphine addicts. It has no eu- lower affinity at delta and kappa sites. It phoric effect and no physical dependence selectively antagonizes the respiratory de- liability. It is effective orally. It is also pression produced by opioids. After intra- claimed to be beneficial in decreasing crav- venous administration, it antagonizes all ing for alcohol in alcoholics. Side effects actions of morphine. It also blocks the ac- include gastrointestinal disturbances and tions of endogenous opioid peptides. muscular pain.

 This page intentionally left blank Non-Narcotic ChapterChapter Analgesics (Mode of Action of Drugs) 2.4 (NSAID’s)(NSAID’s)(NSAID’s)

Non-steroidal antiinflammatory drugs verted in the body to salicylic acid and pro- (NSAIDs) are also known as nonopioid an- duce the pharmacological actions. algesics. They relieve pain without interact- Analgesic action: Salicylates relieve ing with opioid receptors and do not depress pain by both central and peripheral action. CNS and have no drug dependence or drug The site of action of central analgesia seems abuse property and possess antipyretic ac- to be the hypothalamus. It does not have tivity also. They act primarily on peripheral cortical action on the reaction component of pain mechanisms and also in CNS to raise the pain but raises the threshold to pain per- pain threshold. ception. Unlike morphine, they do not pro- They can be classified as in table 2.4.1. duce sedation and there is no drug tolerance NSAIDs exert analgesic, antipyretic, or dependence and are not effective against anti-inflammatory and related effects. Dur- visceral pain. ing pain, fever and inflammation the arachi- The peripheral component of their an- donic acid is liberated from the phospho- algesic action is due to the inhibition of lipid fraction of the cell membrane which is prostaglandin synthetase and thereby in- then converted to prostaglandins (PGs) via hibiting the synthesis of prostaglandins cyclooxygenase pathway (both COX-1 & (PGs) which sensitise the pain receptors to COX-2). COX-1 is present in kidney, stom- mechanical and chemical stimuli. Aspirin ach and blood vessels and COX-2 is present inhibits prostaglandin synthesis and blocks in activated leukocytes and other inflamma- the sensitization of pain mechanism. tory cells. They are useful in relieving all dull itching, throbbing pain of muscles and SALICYLATES joints, dysmenorrhoea, toothache, head- Salicylates are esters or salts of salicylic acid. ache etc. The NSAID’s are the mainstay for Acetyl salicylic acid (aspirin) is rapidly con- the management of acute dental pain. 84 Section 2/ Drugs Acting on CNS

Table 2.4.1: Classification of non-steroidal antiinflammatory drugs.

I. Salicylates and their congeners Acetyl salicylic acid (ASPIRIN, DISPRIN) 300-600 mg/day Sodium salicylate 1.5-6 g/day Salicylamide (SALAMIDE) 300-600 mg TDS-QID Diflunisal (DOLOBID) 500 mg BD-TDS II. Pyrazolone derivatives Phenylbutazone (ZOLANDIN) 200-600 mg/day Oxyphenbutazone (SIORIL) 200-600 mg/day III. Indole derivatives Indomethacin (INDOCAP) 25-50 mg BD-TDS Sulindac (CLINORIL) 100-200 mg BD IV. Propionic acid derivatives (BRUFEN) 400-800 mg TDS Naproxen (NAPRYN) 250 mg BD Flurbiprofen (FROBEN) 50-100 mg TDS V. Anthranilic acid derivatives Mefenamic acid (MEFTAL) 250-500 mg TDS Enfenamic acid (TROMARIL) 800 mg BD-TDS VI. Oxicam derivatives Piroxicam (DOLONEX) 20 mg OD-BD Tenoxicam (TOBITIL) 20 mg OD VII. Aryl acetic acid derivatives Diclofenac (VOVERAN) 50-150 mg BD-TDS, 25-75 mg IM Aceclofenac (ACECLO) 100-200 mg BD VIII. Para-aminophenol derivatives Paracetamol (CROCIN) 0.5-1 g TDS IX. Miscellaneous (newer compounds including selective COX-2 inhibitors) Nimesulide (NIMULID) 100 mg BD Ketorolac tromethamine (KETANOV) 40 mg/day (oral/IM) Celecoxib (ZYCEL) 100-200 mg OD-BD Nabumetone (NABUFLAM) 1-2 g/day X. Drugs for rheumatoid arthritis Gold compounds (Auranofin; GOLDAR) 6 mg/day OD-BD d-Penicillamine (CILAMIN) 125-250 mg OD then 250 mg BD Sulfasalazine (SALAZOPYRIN) 1-3 g/day Methotrexate (FOLITRAX) 2.5-15 mg/week XI. Drugs for gout Colchicine (COLCHICINDON) 0.25 mg to 10 mg (max.)/day Allopurinol (ZYLORIC) 200-800 mg/day Probenecid (BENCID) 500 mg-1 g BD Sulfinpyrazone (ARTIRAN) 200 mg BD (max 800 mg/day) Non-Narcotic Analgesics (NSAID’s) 85

Combination of two drugs e.g., paracetamol can cause uric acid retention while in higher + ibuprofen or diclofenac) also used for its dose, it also inhibits tubular reabsorption of additive effect. uric acid and have beneficial effect in gout Antipyretic action: Salicylates lower the by producing uricosuric action. elevated body temperature. Hypothalamic Acid-base and electrolyte balance: High thermoregulatory centre acts as a thermo- therapeutic dose especially when used in stat of the body which maintains the balance rheumatic fever, stimulates respiration and between heat production and heat loss. Sali- causes respiratory alkalosis. Reduction in cylates reset the hypothalamic thermostat bicarbonate and potassium level reduces the which is disturbed during fever. They do not buffering capacity of the extracellular and affect the heat production but they increase intracellular fluid. Hypokalemia may lead the heat loss by causing vasodilatation and to dehydration and hypernatremia. They sweating. The antipyretic action of salicy- also interfere with carbohydrate metabolism lates is probably due to the inhibition of PG resulting in accumulation of pyruvic acid synthesis. and lactic acid. Effect on respiratory system: Salicylates Effect on GIT: Aspirin and related com- stimulate respiration by increasing the con- pounds irritate gastric mucosa which may sumption of oxygen primarily by skeletal cause epigastric distress, nausea and vom- muscles and this results in increased pro- iting as a result of gastric irritation. The sali- duction of carbon dioxide, which leads to cylates are unionised at the pH of the stom- direct stimulation of the respiratory centre ach and can easily enter the mucosal cell in the medulla oblongata producing an in- and at the pH of the cell they get ionised crease in the depth and to some extent in thus unable to cross it and accumulate in- the rate of respiration. Toxic doses depress side the gastric mucosal cell and causing the respiratory centre. damage to the gastric mucosa and the dam- Antiinflammatory and antirheumatic aged mucosa permits back flow of H+ action: Salicylates suppress the clinical signs which may damage the endothelium of and symptoms of rheumatoid arthritis and submucosal capillaries and gastric bleed- other related inflammatory disorders by in- ing occurs. hibiting prostaglandin synthesis, reducing Metabolic effects: Salicylates cause un- the capillary permeability and inhibition of coupling of oxidative phosphorylation neutrophil aggregation. Salicylates by inhib- which leads to conversion of energy into iting the prostaglandin synthesis, prevent heat and may thus produce hyperpyrexia sensitization of the pain receptors to certain and increased protein catabolism. Larger biological amines such as histamine, 5-HT dose produces hyperglycemia and glyco- (serotonin) and bradykinin, the chemical suria in normal individual while in diabetic mediators of inflammation and pain. patient it produces hypoglycemia which Effect on kidney: In low doses, aspirin may be due to an enhanced peripheral utili- inhibits the tubular secretion of uric acid and zation of glucose and inhibition of 86 Section 2/ Drugs Acting on CNS neoglucogenesis induced by salicylates and within 24 hours and plasma half life is two related compounds. Chronic use can also to eight hours. After absorption, about 80 lead to negative nitrogen balance by in- percent of salicylate is bound to plasma pro- creased conversion of protein to carbohy- tein (mainly albumin) and rapidly distrib- drate. uted in the tissues. Aspirin is deacetylated Effect on blood: Platelets are the to salicylic acid which is the major circulat- important factors in thrombus formation ing and active form. Salicylates are mainly and aspirin has been shown to inhibit plate- metabolized in the liver and excreted in let aggregation. They reduce the blood urine in the form of conjugates with glycine prothrombin level by inhibition of pro- (mainly) and glucuronic acid. thrombin synthesis and prothrombin time Adverse Effects is prolonged. The aspirin suppresses the These include nausea, vomiting, gastric synthesis of thromboxane (TXA2) in the platelets. They also prolong the bleeding irritation and occult blood in stool. time due to prevention of platelet aggrega- Allergic reactions include urticaria, skin tion which may be due to inhibition of re- rash, rhinorrhoea, asthmatic attack and ana- lease of adenosine diphosphate (ADP) from phylactic reactions. the platelets by salicylates. Prolonged administration of salicylates Effect of CVS: In therapeutic doses, as- cause a syndrome called ‘salicylism’ which pirin has no direct effect on CVS but in larger is characterized by headache, dizziness, tin- doses, it can lead to increase in cardiac out- nitus, vertigo, difficulty in hearing, dimness put to meet increased peripheral oxygen of vision, mental confusion, drowsiness, demand and can cause direct vasodilatation. lethargy, hyperventilation and electrolyte Endocrine effects: Salicylates decrease imbalance. the plasma protein bound iodine due to dis- Overdose/acute salicylate poisoning is placement of thyroxine from prealbumin characterized by salicylism which consists and stimulation of central sympathetic cen- of tinnitus, vertigo and deafness, hyperther- tre causes release of adrenaline from the mia, toxic encephalopathy (agitation, con- adrenal medulla. fusion and convulsions followed by coma), dehydration (due to hyperpyrexia, sweating Pharmacokinetics and vomiting), disturbances of acid base Salicylates are well absorbed after oral balance and petechial haemorrhages. administration. They are absorbed from the stomach and largely from the upper part of Treatment of Overdose/Toxicity (Salicy- small intestine. After oral administration, late Poisoning) appreciable plasma concentrations are i. Gastric lavage. found within half an hour, peak plasma level ii. Intravenous fluid to correct dehydration. is achieved within two hours and approxi- iii. Cold water/alcohol sponges for hyper- mately 50 percent of the drug is eliminated thermia. Non-Narcotic Analgesics (NSAID’s) 87

iv. To prevent intracellular potassium loss, ing and morning stiffness in the rheu- potassium is given along with sodium matoid arthritis patients. bicarbonate. 5. Treatment of gout: In large dose, aspi- v. For ketoacidosis and hypoglycemia, rin is effective in the treatment of gout. glucose may be given. vi. In severe intoxication, dialysis (perito- 6. As antiplatelet agent: By inhibiting neal dialysis and haemodialysis) may platelet aggregation aspirin may lower be used. the incidence of reinfarction. It has been used to prevent the formation of plate- Therapeutic Uses let-fibrin thrombus in ischemic heart 1. In Dentistry: The NSAID’s are the disease patients. most important drugs for the manage- ment of acute dental pain. The particu- PYRAZOLONE DERIVATIVES lar drug may be selected on the basis of severity of pain and presence of PHENYLBUTAZONE other related symptoms e.g. for mild It is a potent antiinflammatory agent. It has to modrate pain, paracetamol is gen- poor analgesic and antipyretic action. erally recommended and in accute Mechanism of action is similar to other pain diclofenac alone or combined with paracetamol is generally pre- NSAIDs. ferred. But care must be taken when It is readily absorbed from the GI tract given to patient who is having peptic with peak plasma concentration occurring ulcer, asthama or any hypersensitivty two hours after ingestion. It is 98% bound history. to plasma proteins and it is extensively 2. As analgesic-antipyretic: Salicylates metabolised in the liver by oxidation and by are effective in the treatment of mild conjugation with glucuronic acid. to moderate types of pain. They are Adverse effects include nausea, epigas- used in the treatment of headache, tric distress, aplastic anaemia, vomiting, di- bodyache, arthralgias, neuralgias and arrhoea, peptic ulcer, depression, neutrope- dysmenorrhoea. They are also effective nia, hypothyroidism, skin rash and urticaria. in fever of any origin. 3. As an antiinflammatory: Salicylates It is indicated in ankylosing spondyli- are commonly used in the treatment of tis, rheumatoid arthritis, rheumatic fever, various inflammatory conditions such osteoarthritis, after blunt injuries, frac- as arthritis and fibromyositis. tures, tooth extraction, vasectomy and 4. As antirheumatic: Salicylates are the acute gout. drug of choice in the treatment of rheu- OXYPHENBUTAZONE matoid arthritis. In larger dose they suppress the swelling, immobility and It is a metabolite of phenylbutazone and redness of the joints involved. They are having similar pharmacodynamic and phar- also useful in the acute rheumatic fe- macokinetic properties and similar thera- ver. They produce relief in pain, swell- peutic uses. 88 Section 2/ Drugs Acting on CNS

INDOLE DERIVATIVES muscle spasm and rheumatic disorders. They are all well absorbed orally and are INDOMETHACIN highly bound to plasma proteins (90-99%). It is indole acetic acid derivative possess- Metabolized largely in liver by hydroxyla- ing potent antiinflammatory property and tion and glucuronide conjugation and ex- having a good analgesic and antipyretic ac- creted in urine as well as in bile. tion also. Mechanism of action is same as Adverse effects include nausea, vomit- other NSAIDs. ing, epigastric discomfort, dizziness, head- It is readily absorbed from the GI tract, ache, skin rash and thrombocytopenia. 99% bound to plasma proteins, distributed It is indicated in rheumatoid and osteo- into synovial fluid, the central nervous sys- arthritis, ankylosing spondylitis, mild to tem, placenta and breast milk. It is moderate pain including dysmenorrhoea, metabolised in the liver to glucuronide con- soft tissue injuries, fractures and postopera- jugates, excretion of metabolites is predomi- tive analgesia. nantly in the urine with some amount ap- pearing in the faeces. FLURBIPROFEN Adverse effects include nausea, vomiting, It is NSAID used in musculoskeletal and anorexia, gastric bleeding, diarrhoea, dizzi- joint disorders. It acts by inhibition of ness, frontal headache, confusion, depression, cyclooxygenase. psychosis, hallucination, leukopenia, epigas- tric distress and rarely aplastic anaemia. It is readily absorbed from GI tract and is 99% bound to plasma proteins. It is used in rheumatoid arthritis, osteo- Metabolised mainly by hydroxylation and arthritis, ankylosing spondylitis and gout. conjugation and excreted in urine.

SULINDAC KETOPROFEN It is a fluorinated derivative of in- It is an inhibitor of cyclooxygenase with domethacin, has longer duration of action analgesic, antiinflammatory and antipyretic and is used orally. It is prodrug, converted properties. to active sulfide metabolite. Readily absorbed from the GI tract. Food slows the rate of absorption but not the total PROPIONIC ACID DERIVATIVES bioavailability. Extensively bound to plasma The drugs like ibuprofen, flurbiprofen, proteins and substantial concentrations are ketoprofen etc. possess antiinflammatory found in synovial fluid. Metabolised mainly by conjugation with glucuronic acid and ex- property similar to aspirin but toxicity and creted mainly in the urine. adverse effects are fewer and of lesser in- tensity. These preparations alone and in NAPROXEN combination with other NSAIDs are used for After oral administration, it is fully treatment of inflammatory disorders, absorbed. It is 99% bound to plasma pro- Non-Narcotic Analgesics (NSAID’s) 89 teins and crosses placenta. The metabo- OXICAM DERIVATIVES lites of naproxen are almost entirely ex- creted in urine. Naproxen is more effica- PIROXICAM cious and better tolerated. It is also longer acting and has the advantage of twice Piroxicam is a new NSAID and has anti-in- daily dosing. flammatory, analgesic and antipyretic activ- ity. It provides effective and long-lasting Adverse effects include dyspepsia, gas- relief of pain and stiffness. Its convenient tric discomfort, nausea, vomiting, heartburn, once daily dosage provides round the clock dizziness, drowsiness, headache, fatigue, relief of symptoms. sweating, depression, ototoxicity, pruritus and thrombocytopenia. It acts peripherally by inhibiting the syn- thesis of prostaglandins by reversible inhi- It is indicated in osteoarthritis, rheuma- bition of cyclooxygenase. Inhibition of the toid arthritis, musculoskeletal disorders, migration of leukocytes to an inflammatory primary dysmenorrhoea, acute gout, pelvic site and inhibition of the release of lysoso- inflammation, ankylosing spondylitis, tooth mal enzymes may also be involved in the extraction, tendinitis, bursitis and juvenile antiinflammatory action. arthritis. It is well absorbed from the GIT. The rate, but not the extent of absorption is decreased ANTHRANILIC ACID DERIVATIVES by food and 99% plasma protein bound. MEFENAMIC ACID Piroxicam is metabolised in liver. Because of long half life single daily administration is It is an inhibitor of cyclooxygenase with an- sufficient. The half life may be especially pro- algesic, antiinflammatory and antipyretic longed in patients with renal function impair- properties. ment. Excretion of piroxicam is through re- It is readily absorbed from the GI tract, nal, fecal and as unmetabolised piroxicam. extensively bound to plasma proteins and Adverse effects include, nausea, vom- excreted mainly in the urine as unchanged iting, epigastric distress, skin rash, rarely drug or conjugated metabolites. haematuria, proteinuria, hepatitis and de- Adverse effects include drowsiness, di- pression. arrhoea, rashes (withdraw treatment), It is indicated in acute or long term use thrombocytopenia, haemolytic anaemia, in acute and chronic rheumatoid arthritis aplastic anaemia. Convulsions may occur in and other rheumatic disorders like osteoar- overdosage. thritis, ankylosing spondylitis, cervical It is indicated in muscle, joint and soft spondylosis, acute gouty arthritis and acute tissue pain, dysmenorrhoea, rheumatoid musculoskeletal disorders. and osteoarthritis, as antipyretic, in dental Tenoxicam is a congener of piroxicam pain, postoperative or postpartum pain. with similar properties and uses. 90 Section 2/ Drugs Acting on CNS

painful syndromes of the vertebral column, ARYL ACETIC ACID DERIVATIVES non-articular rheumatism and acute attacks of gout, DICLOFENAC Also used in posttraumatic and postop- It is a NSAID with pronounced antirheu- erative pain, inflammation and swelling e.g. matic, antiinflammatory, analgesic and an- following dental or orthopaedic surgery, tipyretic properties. Inhibition of prostag- painful and/or inflammatory conditions in landin biosynthesis is fundamental mecha- gynaecology e.g. primary dysmenorrhoea or nism of action. In rheumatic diseases, it leads adnexitis, in severe painful inflammatory to marked relief from pain at rest, pain on infections of the ear, nose or throat e.g. movement, morning stiffness and swelling pharyngotonsillitis, otitis etc. of the joints, as well as by an improvement in function. ACECLOFENAC In posttraumatic and postoperative in- It is newer COX-2 inhibitor and is a phe- flammatory conditions, diclofenac rapidly nylacetic acid derivative. It also inhibits syn- relieves both spontaneous pain and pain on thesis of IL-1b and TNF-a, thus inhibiting movement and reduces inflammatory swell- PGE2 production. It is rapidly and com- ing and wound oedema. pletely absorbed after oral administration, It also exerts a pronounced analgesic ef- highly protein bound and bioavailability is fect in moderate and severe pain of non- almost 100%. It is metabolized to a major rheumatic origin. metabolite 4'-hydroxyaceclofenac. After the passage of the tablet through It is indicated for the relief of pain and the stomach, it is completely absorbed. Due inflammation in osteoarthritis, rheumatoid to the enteric coating, onset of absorption is arthritis, ankylosing spondylitis and delayed. However, once the absorption sets musculo-skeletal trauma. in diclofenac is rapidly absorbed. Adverse effects include dyspepsia, ab- Diclofenac enters the synovial fluid, dominal pain, nausea and diarrhoea. where maximum concentrations are mea- sured two to four hours after peak plasma PARA-AMINOPHENOL DERIVATIVES values have been attained. Adverse effects include nausea, vomit- PARACETAMOL ing, epigastric discomfort, skin rash, peptic It is a para-amino derivative, acts on ulcer, fluid retention, edema and impair- CNS to produce analgesia and antipyretic ment of hepatic function rarely. effect. It has negligible antiinflammatory It is used in the treatment of inflamma- action peripherally in therapeutic uses. It is tory and degenerative forms of rheumatism, poor inhibitor of PG synthesis in peripheral rheumatoid arthritis, ankylosing spondyli- tissues, but more active on COX in brain. It tis, osteoarthritis and spondyloarthritis, also raises the pain threshold. Non-Narcotic Analgesics (NSAID’s) 91

Paracetamol is given orally and is well ab- similar to or greater than that of indometha- sorbed, peak plasma concentration is reached cin, diclofenac, piroxicam and ibuprofen in in 30 to 60 minutes. About 1/3rd is bound to standard animal models of inflammation. plasma proteins and the drug is inactivated in Oral drug absorption is nearly complete the liver, being conjugated to give the glucu- and concomitant administration of food may ronide or sulphate which are excreted in urine. decrease the rate, but not the extent of ab- Adverse effects include nausea, epigas- sorption. The drug is 99% bound to plasma tric distress. Rarely it can cause skin rash. proteins and metabolised (1 to 3% of a dose Acute toxicity may result in hepatic failure. is excreted unchanged in the urine) to sev- Paracetamol is used for the rapid relief eral metabolites which are excreted mainly of fever, pains and aches such as headache, in the urine or the faeces. earache, toothache, fibrositis, myalgia, neu- ralgia, arthralgia, osteoarthritis and postop- The adverse effects are gastrointestinal erative pain. disturbances (epigastralgia, heart burns, nausea, diarrhoea and vomiting). It can also NEWER COX-2 INHIBITORS lead to rash, pruritus, dizziness, somnolence and headache. KETOROLAC There were reports of hepatotoxicity es- Ketorolac is a NSAID chemically related pecially in children, due to which it should to indomethacin and tolmetin. not be used in children and in the presence Ketorolac has antiinflammatory and an- of hepatic dysfunction. tipyretic action that, together with its anal- It is indicated in the treatment of a vari- gesic effects. ety of painful inflammatory conditions, in- The absorption is rapid with maximum cluding osteoarthritis, oncology, postopera- plasma concentration being attained 30 to tively, trauma, sports injuries, ear, nose and 40 minutes after oral administration. Highly throat disorders, dental surgery, bursitis/ plasma protein bound and metabolised by tendinitis, thrombophlebitis, upper airways glucuronidation. 60% is excreted unchanged inflammation and gynaecological disorders. in urine. Nimesulide has shown to be well tolerated Adverse effects include, nausea, vom- even by aspirin sensitive asthmatic patients. iting, epigastric distress, diarrhoea, drowsi- CELECOXIB ness, dizziness, skin rash etc. It is indicated in short term management It is a NSAID which has COX-2 selec- of acute pain, pain associated with surgical tivity. It is a diaryl substituted pyrazole. procedures. It exhibits antiinflammatory, analgesic and antipyretic activities which are believed NIMESULIDE to be due to inhibition of COX-2. At thera- Nimesulide is a NSAID of the sulfonanilide peutic concentrations in humans, celecoxib class. Nimesulide has exhibited potency does not inhibit COX-1 enzyme. 92 Section 2/ Drugs Acting on CNS

After oral administration it is rapidly mal small joints of hand (usually) and large absorbed from the GI tract and undergoes joints as well. It is also associated with a predominantly hepatic metabolism with number of extra-articular and systemic fea- little unchanged drug recovered in the urine tures. There is joint inflammation, synovial and faeces. It is widely distributed into tis- proliferation and destruction of articular sues. All metabolites are inactive. cartilage by inflammatory cells. There is no Adverse effects include headache, diar- single treatment for RA and the principles rhoea, rhinitis, nausea, , dyspepsia, of treatment are directed towards relief of abdominal pain etc. symptoms and suppression of active and It is used in rheumatoid arthritis, osteo- progressive disease with conservation and arthritis and other conditions including maintenance of joint function. rheumatic pain, neuralgia, gout and Initial treatment consists of NSAIDs, low ankylosing spondylitis etc. dose corticosteroids. If the symptoms are not controlled then second line/disease modi- NABUMETONE fying drugs (DMDs) are added. Since it is a Nabumetone selectively inhibits COX- progressive disease, spontaneous remis- 2. It is metabolised into 6-methoxy-2- sions are rare and joint damage occurs early, naphthylacetic acid (MNA), that is a potent DMDs are started early and continued in- inhibitor of COX-2. It has no inhibitory ef- definitely with regular monitoring. fect on COX-1 which is responsible for pros- The disease modifying drugs (DMDs/ taglandin synthesis in gastric mucosa, DMARDs) used are gold, d-penicillamine, thereby minimising the risk of problems like hydroxychloroquine, sulfasalazine and ulcers and hypertension. After oral admin- immuno-suppressants like methotrexate, istration 80% of dose is excreted in the urine. azathioprine, cyclosporin etc. Peak plasma concentration is reached after 2.5 to 4 hours. GOLD COMPOUNDS Adverse effects include nausea, vomit- It appears to reduce immune respon- ing, heartburn, diarrhoea, constipation, siveness. It inhibits the migration of mono- headache and dizziness. nuclear cells in area of inflammation. It may also stabilise lysosomal membrane, hence It is indicated in osteoarthritis, rheuma- damage to cartilage is prevented. toid arthritis, inflammatory conditions and soft tissue injuries. It can be used orally and bioavailability is 25%. After administration it binds exten- sively to plasma albumin and is distributed DRUGS USED IN RHEUMATOID ARTHRITIS to inflamed synovium, liver and kidney. Rheumatoid arthritis (RA) is an autoim- Adverse effects include diarrhoea, der- mune chronic inflammatory joint disease. It matitis, stomatitis, glossitis, pharyngitis, is a progressive symmetrical, destructive pruritus, exfoliative dermatitis, alopecia, and deforming polyarthritis affecting proxi- blood dyscrasias including thrombocytope- Non-Narcotic Analgesics (NSAID’s) 93 nia, leucopenia, renal and hepatic damage (increased production) or is drug induced and encephalopathy. (due to reduced renal excretion by uric acid). Drugs used for gout can be divided into PENICILLAMINE two groups: The exact mechanisms of action of peni- cillamine in rheumatoid arthritis is not a. Drugs for acute attack of gout: NSAIDs, known. After oral administration it is partly colchicine, corticosteroids. metabolised and partly excreted unchanged. b. Drugs for chronic gout/hyperuricemia: Can be uric acid synthesis inhibitors Adverse effects include Gl upset, dose (allopurinol) and uricosurics (increase related impairment of taste, thrombocytope- renal excretion of uric acids) e.g. nia, aplastic anemia, allergic reactions, skin probenecid and sulfinpyrazone. rash, fever, SLE and proteinuria. NSAIDS SULFASALAZINE Drugs useful are indomethacin, When taken orally, it liberates 5-ASA (5- piroxicam or naproxen. Their usefulness is aminosalicylic acid) and sulfapyridine in due to strong antiinflammatory action and colon. 5-ASA acts locally by inhibiting PG can be continued for 3-4 weeks. They also synthesis and provide symptomatic relief in inhibit chemotactic migration of leukocytes ulcerative colitis. Sulfapyridine is absorbed into the affected joint. systemically and inhibits generation of su- peroxide radicals and cytokine elaboration CORTICOSTEROIDS by inflammatory cells and is responsible for Systemic/intraarticular steroids can be beneficial effects in RA. used in those cases not responding to or tol- METHOTREXATE erating NSAIDs/colchicine. It is a dihydrofolate reductase inhibitor COLCHICINE immuno-suppressant. Benefit in RA is due It is effective for treatment of acute at- to inhibition of cytokine production, chemo- tacks of gout. It has no effect on renal excre- taxis and cell mediated immune reaction. tion of uric acid. It binds to tubulin, it in- terferes with function of mitotic spindles, DRUGS FOR GOUT causes depolymerization and disappear- Gout results from hyperuricemia i.e. in- ance of fibrillar microtubules in granulo- creased serum uric acid levels. Normal se- cytes. In gout, the useful of colchicine is due rum uric acid level is 1-5 mg/dl. Uric acid to the inhibition of the release of glycopro- is formed in the metabolism of purine. When teins from granulocytes in inflamed joint the blood levels of uric acid are high, it pre- thus preventing precipitation of uric acid cipitates in joints, cartilage, kidney and sub- crystals and release of lysosomal enzymes. cutaneous tissues and leads to various signs After oral administration it is rapidly and symptoms. Hyperuricemia is also absorbed. A major part of the drug is ex- seen in various leukemias, lymphomas creted in faeces. 94 Section 2/ Drugs Acting on CNS

Adverse effects include nausea, vomit- PROBENECID ing, diarrhoea, abdominal pain, neuropathy, It increases the excretion of uric acid (by myopathy especially in patients with de- inhibiting its reabsorption from kidney tu- creased renal function. Prolonged therapy bules) and hence causes reduced serum lev- may lead to aplastic anaemia, agranulocy- els of uric acid. tosis, alopecia and myopathy. After oral administration it is completely It is used in the treatment of acute gout absorbed. It is 90% plasma protein bound. It and prophylaxis of gout. is partly metabolised and excreted in urine. ALLOPURINOL The metabolites also have uricosuric action. It inhibits the terminal steps in uric acid Adverse effects include skin rash, biosynthesis by inhibiting enzyme xan- gastro-intestinal irritation. Overdosage may thine oxidase. During therapy with allopu- result in convulsions and death due to res- rinol the uric acid plasma levels decline. piratory failure. After oral intake it is absorbed relatively It is used in chronic gout and secondary rapidly. It is converted to alloxanthine which hyperuricaemia. is active and non competitive inhibitor. SULFINPYRAZONE Adverse effects include hypersensitiv- ity reactions, maculopapular rash, urticaria, Pyrazolone derivative related to phe- myalgia, malaise fever, transient leucope- nylbutazone. It has uricosuric action. It also nia or leukocytosis, hepatic damage, nau- inhibits platelet aggregation. sea, vomiting, diarrhoea, headache and It is well absorbed orally and 98% drowsiness. plasma protein bound. It is excreted by ac- It is indicated in primary hyperuricaemia tive secretion in proximal renal tubule. of gout, secondary hyperuricaemia due to Adverse effects are gastric irritation myeloid metaplasia, radiation, cancer chemo- (most common), hypersensitivity reactions. therapy, thiazide diuretics. It is used in chronic gout.

 ChapterChapter PharmacodynamicsPharmacodynamicsPsychotropic 2.51. 4 (Mode Agentsof Action of Drugs)

Psychopharmacological agents may be clas- 3. Antidepressants for minor and major sified into three broad groups used in vari- depressive disorders and mood ous states of psychic disorders. stabilisers (antimanic drugs) for mania. 1. drugs or major tranquil- lizers used in all types of psychosis ANTIPSYCHOTIC DRUGS mainly schizophrenia. (MAJOR TRANQUILLIZERS) 2. Antianxiety drugs or minor tranquil- lizers used in anxiety. They are classified as in table 2.5.1.

Table 2.5.1: Classification of antipsychotic drugs. I. Phenothiazines Chlorpromazine (MEGATIL) 100-800 mg/day Triflupromazine (SIQUIL) 50-200 mg/day (NEOCALM) 5-15 mg BD II. Haloperidol (HEXIDOL) 5-10 mg/day Droperidol (DROPEROL) 10 mg IM, 5-15 mg/day IV (TRIPERIDOL) 0.5-8 mg/day III. Other newer compounds (LOXAPAC) 60-100 mg BD-QID (SIZOPIN) 25-50 mg/day (PIMODAC) 3-4 mg/day (CLOPIXOL) 20-40 mg IM repeated 2-4 week interval 20-200 mg/day 0.4-2 g/day 4-24 mg/day 96 Section 2/ Drugs Acting on CNS

c. Effect on endocrine system: They can PHENOTHIAZINES produce amenorrhoea and galactor- rhoea due to increase in serum prolac- PHARMACOLOGICAL ACTIONS tin level in females. It also blocks the a. Action on CNS: Effects differ in nor- release of growth hormone, ADH and mal and psychotic individuals. gonadotrophin secretion. 1. Sedation: They produce sedation d. Local anaesthetic: Chlorpromazine has which does not progress to anaesthesia. a potent local anaesthetic action. They decrease the agitation, anxiety and e. ANS: They have varying degree of a aggressiveness in psychotic patient without adrenergic blocking activity. They also affecting wakefulness. have weak anti-cholinergic, H1- antihistaminic and anti 5-HT actions as 2. Antipsychotic effect: In schizophrenic well. patients, they improve thought disorders, They also cause blockade of postsynap- blunted affect, withdrawal and self centered tic (including 5-HT, norad- behaviour. They also improve the halluci- renaline and dopamine) transmission in the nations and delusions. brain resulting in decrease in central sym- They produce neuroleptic syndrome pathetic activity. which consists of motor retardation and emotional quietening. Pharmacokinetics In animal studies, they reduce the spon- Phenothiazines are well absorbed after taneous motor activity and produce cata- oral and parenteral administration. They are lepsy (state of rigidity and immobility). distributed in all the body tissues and metabolised in liver by hydroxylation and 3. Action on CTZ: Chlorpromazine de- glucuronide conjugation and demethylation. presses the chemoreceptor trigger zone The metabolites are excreted in urine and bile (CTZ) and acts as a powerful antiemetic for long period of time even after discontinu- agent. ing the drug. 4. Effect on hypothalamus: They produce hypothermia by acting on temperature Adverse Reactions regulating centre. They also produce CNS side effects include lethargy, central sympathoplegia resulting in drowsiness, increase in REM sleep, restless- miosis and failure in ejaculation. ness, excitement and impaired psychomo- They produce parkinsonism like reac- tor functions. tion by increasing the spontaneous firing of The other side effects include epileptic neurons of basal ganglia. seizures, disturbances in body temperature b. Effect on CVS: Chlorpromazine may regulation. ANS side effects include tachy- produce orthostatic hypotension prob- cardia, difficulty in micturition, inhibition ably due to inhibition of centrally me- of ejaculation, postural hypotension, diated pressor reflexes. It also causes blurring of vision (with ), con- prolongation of QT interval in ECG. stipation, nasal stuffiness etc. Psychotropic Agents 97

Extrapyramidal reactions include par- is used in hallucination, delusions, agi- kinsonism, acute muscular dystonias, tation, withdrawal and other schizo- akathisia, tardive dyskinesia and malignant phrenic symptoms in schizophrenia, neuroleptic syndrome. They can also cause schizoaffective disorders, mania, hypo- hypersensitivity reaction including mania and panic anxiety. cholestatic jaundice, skin rash, urticaria, photosensitivity and contact dermatitis. BUTYROPHENONES There is also blue pigmentation of skin, len- ticular opacities on prolonged use of drug. HALOPERIDOL Therapeutic Uses It is a potent antipsychotic drug. It does not cause weight gain. Its pharmacological 1. Treatment of psychosis (schizophre- effects are similar to phenothiazines. nia): Schizophrenia is a split mind or splitting of perception from reality. Adverse effects include dystonia, hal- The patient of schizophrenia is dis- lucinations, restlessness, nausea, epigas- sociated from the world around him tric discomfort, anaemia, blurred vision, and lives in their own world which hypersensitivity reaction, blood dyscra- is characterized by aggression, anxi- sia, jaundice, galactorrhoea, gynecomas- ety, restlessness, hallucinations and tia and amenorrhoea. delusions. Phenothiazines reduce the It is indicated in acute and chronic hallucinations, aggression, anxiety schizophrenia, anxiety disorders, acute ma- and make them acceptable and coop- nia, hypomania and behavioural disorders erative. in children; antiemetic neuroleptanalgesia, 2. In the treatment of manic depressive Gilles de la Tourette’s syndrome and psychosis (treatment of mania). Huntington’s disease. 3. In alcoholic hallucinosis and Huntington’s disease. DROPERIDOL 4. As an antiemetic in drug and disease It is a short acting neuroleptic agent used induced vomiting. Also useful in morn- in anaesthesia. ing sickness but are ineffective in mo- tion sickness. TRIFLUPERIDOL 5. In the treatment of intractable hic- It exerts sedative and tranquillizing ef- cough. fect and it is postulated that it blocks dopam- 6. In the treatment of behavioural disor- ine receptors within CNS. It is used in acute ders in children. and chronic psychoses, anxiety disorders, 7. As preanaesthetic medication. mania and schizophrenia. 8. To produce hypothermia. Side effects include nausea, epigastric TRIFLUOPERAZINE distress, dry mouth, blurred vision, jaun- It is a phenothiazine derivative and dice, skin rash and photosensitivity. 98 Section 2/ Drugs Acting on CNS

ergic blocking activity. It has long duration NEWER COMPOUNDS of action (several days) after a single dose. LOXAPINE Adverse effects include mania, insomnia, nervousness, fatigue, drowsiness, nausea, It is the antipsychotic agent resembling extrapyramidal reactions and irritability. chlorpromazine in pharmacological actions. It is used in the treatment of acute and It is used in manifestation of psychotic chronic schizophrenia and manic excite- disorders, acute and chronic paranoid ment. schizophrenia. ZUCLOPENTHIXOL CLOZAPINE Zuclopenthixol is a of high It is an atypical neuroleptic drug. It in- potency with general property similar to the terferes with binding of dopamine at D1 and chlorpromazine. It has a side- D2 receptors in CNS. It produces few ex- chain. trapyramidal symptoms. Adverse effects include extrapyramidal After oral administration it is rapidly and symptoms and on prolonged administra- almost completely absorbed. The absorption tion, occasionally tardive dyskinesia, hypo- is not affected by food and it is almost com- thermia (occasionally pyrexia), drowsiness, pletely metabolised in liver. The metabolites apathy, pallor, nightmares, insomnia, de- are much less potent and less toxic. pression, agitation, EEG changes, endocrine Adverse effects include nausea, vomit- effects such as menstrual disturbances, ga- ing, heartburn, constipation, diarrhoea, lactorrhoea, gynaecomastia, impotence and agranulocytosis, eosinophilia, postural hy- weight gain, alterations in liver function. potension, tachycardia, angina, headache, It is used in the maintenance therapy of sedation, dizziness, syncope, seizures, hy- schizophrenia. perthermia, neuroleptic malignant syn- drome, weight gain and . ANTIANXIETY DRUGS May lead to myocarditis. (MINOR TRANQUILLIZERS) It is indicated in all types of schizophre- nia including resistant cases not responding Anxiety is a emotional feeling of fear along to conventional and chronic with discomfort and uneasiness. Antianxi- schizophrenia. ety drugs are used to control the symptoms of anxiety without affecting the other men- PIMOZIDE tal and physical functions of the body. They It is a diphenylbutylpiperidine deriva- are classified as in table 2.5.2. tive. Pimozide causes low incidence of dys- tonic reactions. BENZODIAZEPINES It acts by blocking dopaminergic recep- The detailed pharmacology of all the tors and has weak a-adrenergic and cholin- benzodiazepines used in anxiety disorders Psychotropic Agents 99

Table 2.5.2: Classification of antianxiety drugs. I. Benzodiazepines Diazepam, lorazepam, oxazepam, alprazolam. Details are already given in chapter ‘Sedative and hypnotics’ along with trade name and dose also. II. (BUSPIDAC) 5-15 BD-TDS III. Others Hydroxyzine (ATARAX) 25-100 mg TDS-QID Meprobamate Beta blockers e.g. propranolol. is discussed in chapter ‘Sedative and BP in patients on MAO inhibitors), nervous- hypnotics’. ness, dizziness, drowsiness, confusion, fa- tigue, sweating etc. They have selective action on limbic sys- tem and have little effect on other body sys- OTHER COMPOUNDS tems. They help in improving the anxiety and stress related symptoms. They are widely HYDROXYZINE used because of lower dependence produc- ing liability and wide margin of safety. It is antihistaminic agent having anti- emetic, sedative, anticholinergic and local anaesthetic property. Used in anxiety, pru- AZAPIRONES ritus and dermatoses; as an adjunct therapy in acute/ chronic alcoholism. BUSPIRONE Side effects include epigastric distress, It belongs to azapirones which is chemi- nausea and impaired alertness. cally and pharmacologically distinct class. It acts as a partial agonist at serotonin and BETA BLOCKERS dopamine receptors and having no hypnotic Beta blockers provide symptomatic re- and sedative action. It does not interact with lief by decreasing the symptoms due to sym- benzodiazepine receptor or modify GABA- pathetic overactivity e.g. palpitation, trem- ergic transmission. ors, rise in BP, etc. They may be used as ad- juvant to benzo-diazepines. It is rapidly absorbed and undergoes extensive first pass metabolism and excreted ANTIDEPRESSANTS through kidney and faeces. It is used in short-term management of They are classified into two main categories e.g. MAO inhibitors and tricyclic/tetracyclic anxiety disorders and relief of symptoms of antidepressants as in table 2.5.3. anxiety with or without accompanying de- pression. MAO INHIBITORS Adverse effects include headache, ex- Monoamine oxidase (MAO) is an intra- citement, tachycardia, palpitation (may raise cellular enzyme and metabolizes intracellu- 100 Section 2/ Drugs Acting on CNS

Table 2.5.3: Classification of antidepressant drugs.

I. MAO inhibitors i. Non-selective Phenelzine Isocarboxazid Pargyline ii. Selective Moclobemide (RIMAPREX) 150-600 mg/day II. Tricyclic and related compounds i. Tricyclic antidepressants Imipramine (DEPSONIL) 50-200 mg/day Amitriptyline (AMIXIDE) 150-225 mg/day (PRIMOX) 50-150 mg/day (SURMONTIL) 50-150 mg/day (DOXIN) 25-150 mg/day Dothiepin (EXODEP) 75-150 mg/day ii. Tetracyclic antidepressants (SERIDAC) 30-100 mg/day (MIRTAZ) 15-45 mg/day III. Serotonin reuptake inhibitors Sertraline (SERNATA) 50-200 mg/day Citalopram (CITADEP) 20-40 mg OD Paroxetine (PAROTIN) 20-50 mg/day (FLUDAC) 20-60 mg/day IV. Mood stabilizers (Antimania drugs) Lithium carbonate (LITHOSUN) 600-1000 mg/day lar catecholamines present in the non-granu- micturition, impotence, constipation. The lar cytoplasmic pool. It also causes oxida- serious side effects include peripheral neu- tive deamination of 5-hydroxytryptamine. ropathy and jaundice due to hepatocellular Their antidepressant action may be related injury. to increase in the brain catecholamines con- tent. Interaction with Other Drugs and Foods MAO inhibitors increase the catechola- 1. Hypertensive crisis: MAO inhibitors mine content of various organs so that more with ingestion of tyramine containing catecholamine is to be released by indirectly food e.g. cheese, beer, red wine or fer- acting sympathomimetic amines. mented food can cause intracranial haemorrhage due to hypertensive cri- Adverse effects include tremor, insom- sis because of release of noradrenaline nia, delirium, convulsion, postural hypoten- from adrenergic nerve endings by sion, dry mouth, constipation, difficulty in unmetabolised tyramine. Psychotropic Agents 101

2. MAO inhibitors along with barbitu- cardia. They also lead to postural hypoten- rates, alcohol, narcotic analgesic can en- sion due to a1 blockade and inhibition of hance and prolong the action of these cardiovascular reflexes. They also produce drugs. T wave suppression or inversion. Oral 3. Potentiate the toxic effects of tricyclic absorption is good and they are highly antidepressants. bound to plasma proteins. They are exten- 4. It’s use with anticholinergic antiparkin- sively metabolized in liver and metabo- sonian drugs can lead symptoms simi- lites are excreted in urine. lar to atropine poisoning. Because of their toxic effects and seri- IMIPRAMINE ous interactions, they are not commonly It is an efficacious drug in alleviating used. However, a new selective inhibitor is depression. When the drug is given to de- used clinically. pressed patients, elevation of mood occurs in about three weeks. Tolerance to anticho- MOCLOBEMIDE linergic effects occurs with continued use of It is a reversible and selective MAO-A imipramine. inhibitor used in the major depression. It is It is highly protein bound and is metabo- devoid of anticholinergic, sedative and car- lized to pharmacologically active metabo- diovascular effects of TCAs. lite. It crosses placental barrier. Side effects include sleep disturbances, Adverse effects include dry mouth, ta- dizziness, nausea, headache, restlessness, chycardia, palpitation, impotence, constipa- agitation, confusion state and nausea. tion, difficulty in accommodation, rarely hy- perpyrexia and paralytic ileus; lethargy, headache, drowsiness, tremors, ataxia, sweat- TRICYCLIC ANTIDEPRESSANTS ing, convulsion, urticaria, skin rash, pruritus, Tricyclic antidepressants are the most cholestatic jaundice, cardiac arrhythmias, commonly used drugs. They produce an- orthostatic hypotension, agranulocytosis, tidepressant effect by blocking the neu- gynaecomastia, galactorrhoea and depen- ronal uptake of noradrenaline and exert dence; loss of weight or gain. anti-cholinergic activity. They also inhibit It is indicated in all types of depression, neuronal uptake of 5HT and dopamine. nocturnal enuresis, intractable chronic pain, The exact mechanism of action is not narcolepsy, chorea, cachexia, mood distur- known. The antidepressant effect is no- bances and sleep apnoea syndrome. ticed after three to four weeks of drug ad- ministration. AMITRIPTYLINE TCAs lower seizure threshold and It causes sedation and after oral admin- overdose leads to convulsions. The side istration it is metabolised to nortriptyline effects are due to anticholinergic effect which is active form. leading to dry mouth, blurring of vision, Adverse effects include epigastric dis- constipation, urinary hesitancy and tachy- tress, sedation, drowsiness, orthostatic hy- 102 Section 2/ Drugs Acting on CNS potension, palpitation, dry mouth, urinary hyperpyrexia and paralytic ileus. Lethargy, retention, blurred vision, confusion and low- headache, drowsiness, tremors, ataxia, ering of seizure threshold. sweating, convulsion, urticaria, skin rash, It is indicated in depression, illness accom- pruritus, cholestatic jaundice, cardiac panied by anxiety, agitation, restlessness and arrhythmias, orthostatic hypotension, disturbances of sleep; masked depression; agranulocytosis, , galactor- dysphoria and depression in alcoholics; rhoea and dependence are also seen. childhood bed wetting. It is also useful for prophylaxis of migraine. TETRACYCLIC ANTIDEPRESSANTS

NORTRIPTYLINE MIANSERIN It is same as amitriptyline and its anti- It exerts potent presynaptic central a , adr- depressant effect may persist up to six 2 energic blocking activity which may cause weeks. increased noradrenaline release. It does not Adverse effects include dry mouth, con- effect noradrenaline or 5-HT uptake in stipation, nausea, epigastric discomfort, seda- CNS. tion, confusion, arrhythmias, altered vision, Adverse effects include hypersensitiv- skin rash, jaundice and impaired alertness. ity reaction, nausea, drowsiness, jaundice, It is indicated in neurotic, reactive, may precipitate seizures, blood dyscrasias, masked endogenous, recurrent depression; lethargy and tremors. depression with insomnia, depression, en- It is used in psychotic and neurotic uresis, panic disorder, neurogenic pain, ur- ticaria and nausea and vomiting during che- depression and obsessive compulsive neu- motherapy; maniac depressive psychosis in rosis. depressive phase. MIRTAZAPINE TRIMIPRAMINE It acts as an antagonist at central presyn- aptic a inhibitory adrenergic auto-receptors It has more sedative effect than other tri- 2 cyclic antidepressants and is suitable for and hetero-receptors. This results in an in- patients showing depression with agitation crease in central noradrenergic and seroton- and anxiety. ergic activity. Mirtazapine is a potent an-

tagonist of 5-HT2 and 5-HT3 receptors. DOTHIEPIN Adverse effects include asthenia, flu like The mechanism of action is same as of syndrome, back pain, dry mouth, increased and used in depres- appetite, constipation, weight gain, periph- sion and anxiety associated with depression. eral edema, myalgia, somnolence, dizziness, Adverse effects include dry mouth, ta- abnormal dreams, abnormal thinking, chycardia, palpitation, impotence, constipa- tremor, confusion, dyspnea and urinary tion, difficulty in accommodation, rarely frequency. Psychotropic Agents 103

gic activity in the CNS resulting from its in- SELECTIVE SEROTONIN hibition of CNS neuronal reuptake of sero- REUPTAKE INHIBITORS tonin (5-HT). Selective serotonin reuptake inhibitors Following a single oral dose of (SSRI) are currently used group of drug in citalopram, peak blood levels occur at about treatment of depression. These have a faster four hours. onset of action and are better tolerated. Adverse effects include activation of SERTRALINE mania/hypomania, dizziness, insomnia, agitation, nausea and vomiting, dry mouth, Sertraline is a potent and selective inhibi- diarrhoea, tachycardia, postural hypoten- tor of neuronal serotonin (5-HT) reuptake. sion, cardiac failure, MI, arthralgia, myal- It has only a weak effect on neuronal up- gia, arthritis, purpura, anaemia, leukocyto- take of and dopamine. sis, decreased or increased weight, thirst, Sertraline’s inhibition of serotonin reuptake ejaculation disorder, impotence, dysmenor- enhances transmission. rhoea, decreased or increased libido, cough- It has a wide therapeutic index and can ing, epistaxis, bronchitis, rash, pruritus, pho- be administered in elderly patients and tosensitivity reaction, urticaria, acne, abnor- those with underlying cardiovascular dis- mal accommodation, conjunctivitis, eye orders. pain, fatigue and fever. Adverse effects include nausea, head- It is indicated in the treatment of depres- ache, diarrhoea, insomnia, dry mouth, sion. tremor and fatigue. PAROXETINE It is indicated for the treatment of symp- toms of depressive illness including accom- It is an orally administered SSRI. panying symptoms of anxiety. It is also in- Paroxetine is readily absorbed from the dicated in preventing relapse of the initial GIT with peak plasma concentration occur- episode of depression or recurrence of fur- ring within about five hours. It is widely ther depressive episodes including accom- distributed throughout body tissues and is panying symptoms of anxiety. about 95% bound to plasma proteins. Excre- It is indicated in the treatment of obses- tion is via the urine and the faeces, mainly sions and compulsions in patients with ob- as metabolites. sessive compulsive disorder. Adverse effects include asthenia, sweat- It is also indicated for the treatment ing, nausea, decreased appetite, somno- of panic disorder with or without agorapho- lence, dizziness, insomnia, tremor, nervous- bia. ness, constipation, ejaculatory disturbance and impotence. CITALOPRAM It is indicated in the treatment of depres- It is orally active SSRI. The mechanism sion, obsessive compulsive disorder and of action is due to potentiation of serotoner- panic disorder. 104 Section 2/ Drugs Acting on CNS

FLUOXETINE of dopamine and noradrenaline and their A potent antidepressant drug, it does not synthesis. It increases the rate of 5-HT syn- cause sedation. In CNS it inhibits the neu- thesis in brain. On continuous therapy cy- ronal uptake of 5-HT. It shows negligible clic mood changes are prevented. α binding to histaminergic, muscarinic, 1 adr- It also inhibits ADH action on distal tu- energic receptors, so it is devoid of anticho- bules (diabetes insipidus like state), also has linergic and hypotensive side effects. insulin like action on glucose metabolism After oral administration the drug is con- and decreases thyroxine synthesis by inter- verted to norfluoxetine which has a very fering with iodination of thyroxine. long lasting biological activity. After oral administration it is well ab- Adverse effects include drowsiness, sorbed and is not protein bound. It not skin rash, insomnia, anxiety, weakness, fa- metabolised and is excreted mainly in urine tigue, nausea, anorexia, epigastric distress, and it inhibits the reabsorption of sodium diarrhoea, tremor and sweating. in renal tubules. It has narrow margin of It is used in the treatment of depression safety. where sedation is not required and for pro- Adverse effects include nausea, vomit- phylaxis of recurrent depression. ing, epigastric distress, polydipsia, polyuria, diarrhoea, dizziness, ataxia, nystagums, MOOD STABILIZERS (ANTIMANIC DRUGS) hyper-reflexia, arrhythmias, skin rash, gly- cosuria and blurred vision. LITHIUM CARBONATE It is indicated in acute hypomania, ma- It has narrow therapeutic index and treat- nia, recurrent mania, depression – cyclic ment requires facility for therapeutic moni- and recurring, unipolar depression, bipo- toring of serum lithium levels. lar depression, schizoaffective psychosis, Exact mechanism of action is unknown. mental depression, cluster headache, che- It brings the patient of mania towards nor- motherapy induced leukopenia and mal. Lithium decreases the neuronal uptake agranulocytosis.

 ChapterChapter PharmacodynamicsPharmacodynamicsAntiepileptic 1.2.6 4 (ModeAgents of Action of Drugs)

Epilepsy is a neurological disorder Phenobarbitone has long plasma half- characterized by short, recurrent and life but slow oral absorption, is metabolized periodic attacks of motor, sensory or in liver as well as excreted unchanged in psychological malfunction. It is associated urine. with paroxysmal abnormal electrical Phenobarbitone is useful in grandmal, discharge in the brain. According to Jackson, focal and temporal lobe epilepsy and epilepsy is due to sudden, excessive and sometimes petitmal also. It is also useful in rapid discharge in the grey matter of the the treatment of febrile convulsions. brain. Anti-epileptic drugs inhibit the spread Phenobarbitone is cheap and produces of abnormal electrical discharge in the brain less side effects which include sedation, with minimal general depressant action on behavioural abnormalities, mental confu- the central nervous system. sion, impairment of learning and memory The antiepileptic drugs belong to and hyperactivity in children. following groups as classified in table 2.6.1. MEPHOBARBITONE BARBITURATES It is N-methylphenobarbitone. It is more expensive than phenobarbitone and requires PHENOBARBITONE double dose compared to phenobarbitone. Phenobarbitone raises the threshold of It probably offers no advantage over electro-shock seizures and modifies phenobarbitone. maximal electro-shock seizures and abolish the tonic phase thus useful in the treatment PRIMIDONE of grandmal epilepsy. The threshold of Chemically it is deoxybarbiturate (carbo- pentylenetetrazol induced convulsion is nyl oxygen of urea moiety in phenobarbitone slightly raised and has less usefulness in the is changed by two hydrogen atoms) and is treatment of petitmal epilepsy. twice as active as phenobarbitone in modify- 106 Section 2/ Drugs Acting on CNS

Table 2.6.1: Classification of antiepileptic drugs I. Barbiturates Phenobarbitone (PHENOBARB) 60 mg OD-TDS Primidone (MYSOLINE) 250-500 mg BD II. Hydantoins Diphenylhydantoin (Phenytoin; EPTOIN) 100-200 mg BD Mephenytoin (MESANTOIN) 50-200 mg TDS III. Iminostilbene derivatives Carbamazepine (TEGRETAL) 200-400 mg. TDS Oxcarbazepine (OXYTEL) 600-1200 mg BD IV. Succinimides Ethosuximide (ZARONTIN) 250-500 mg TDS Methsuximide 300 mg OD-TDS V. Oxazolidinediones Trimethadione (TROXIDONE) 300-600 mg TDS VI. Aliphatic carboxylic acid Valproic acid (Sodium valproate; EPIVAL) 200-800 mg TDS VII. Benzodiazepines Clonazepam (EPITRIL) 0.5-4 mg TDS Diazepam (CALMPOSE) 0.2-0.5 mg/kg IV Clobazam (CLODUS) 20-60 mg OD-BD VIII. Phenyltriazine derivative Lamotrigine (LAMEPIL) 300-500 mg BD IX. Newer compounds Felbamate 2-4 g/day Topiramate (TOPEX) 200-400 mg BD Tiagabine 16-56 mg/day ing electroshock seizures in the rats. It is ef- HYDANTOINS fective against all type of seizures e.g. grandmal epilepsy, psychomotor epilepsy, DIPHENYLHYDANTOIN (PHENYTOIN) focal and myoclonic epilepsy. It is not effec- tive in petitmal epilepsy. In epileptic patients there is repetitive detonation of normal brain cells during the It is converted into phenobarbitone depolarisation shift and consists of synchronous and phenylethyl malonamide in the and unusually large depolarisation on which liver, which actually produces the action potentials are superimposed. Phenytoin antiepileptic actions. The common side prevents repetitive detonation of these normal effects are anorexia, drowsiness, nausea, brain cells as it has a stabilizing influence on leukopenia, osteomalacia and megalo- the neuronal membrane. It is achieved by blastic anaemia. prolonging the inactive state of voltage sensitive Antiepileptic Agents 107 neuronal Na+ channels & governs the refractory varieties of migraine (particularly period of a neurone. childhood, basilar artery and hemiplegic After oral administration peak plasma con- migraine) and in treatment of myotonia. centration of phenytoin usually takes 2 to 4 hours with a second peak at 10 to 12 hours. IMINOSTILBENE DERIVATIVES When administered intramuscularly, pheny- toin is eventually absorbed completely, the CARBAMAZEPINE drug first crystallises out at the injection site It is structurally and chemically related and then slowly redissolves in tissue fluids be- to tricyclic antidepressant drug imipramine fore entering into the circulation. As a result and pharmacologically it is similar to absorption of phenytoin by IM route is too slow diphenyl hydantoin sodium. It is effective to produce a reliable effect. In contrast a phos- in grandmal and psychomotor epilepsy and phate prodrug, fosphenytoin, is more soluble also in the treatment of trigeminal neuralgia and is well absorbed after IM administration. (a condition characterized by paroxysms of In liver it is extensively biotransformed intense pain of stabbing nature within the by oxidation, with less than 5 percent of the area of distribution of trigeminal nerve dose excreted unchanged in urine. Majority without sensory loss). of dose is excreted in urine with up to 15 It also exerts antidiuretic action by percent of the dose is eliminated in the faeces. enhancing ADH action on renal tubules. Adverse effects include gum hypertro- Carbamazepine, because of its poor phy, hirsutism, hypersensitivity reaction, water solubility has slow oral absorption. It megaloblastic anemia, osteomalacia and is metabolized in the liver to an active hyperglycemia. metabolite, (10-11 epoxy carbamazepine) by During pregnancy produces foetal oxidation as well as by hydrolysis and hydantoin syndrome. At higher conjugation to inactive forms. concentration produces ataxia, vertigo, Adverse effects include sedation, ataxia, diplopia, nystagmus, behavioural alteration dizziness and extrapyramidal side effects, dry and mental confusion. mouth, blurred vision and urinary retention; It is used in prophylactic treatment of hepatic damage, bone marrow depression, all varieties of partial epilepsy whether or hypertension, left ventricular failure and not seizure becomes secondarily cardiovascular collapse in toxic doses. generalised. It is also used in prophylactic treatment of generalised convulsive OXCARBAZEPINE seizures and treatment of status It is a keto analog of carbamazepine. It epilepticus; prophylactic management of produces blockade of voltage sensitive certain forms of supraventricular cardiac sodium channels, leading to stabilisation of arrhythmia as it has an ability to hyperexcited neural membranes, inhibition selectively inhibit high frequency firing; of repetitive neuronal firing and diminution prophylactic management of certain of propagation of synaptic impulses. 108 Section 2/ Drugs Acting on CNS

Oxcarbazepine is completely absorbed responses to GABA in the postsynaptic following oral administration and is exten- neurons. Also sodium valproate affects sively metabolised to its pharmacologically potassium flow across the neurons. The result active 10-monohydroxy metabolite. of these effects is inhibition of initiation as well Adverse reactions include dizziness, as spread of epileptic activity in the neurons. diplopia, fatigue, nausea, vomiting, Valproate has antiepileptic efficacy in dyspepsia, ataxia, abnormal vision, tremor different types of epilepsy. It is therefore etc. sometimes called the broad range antiepileptic drug. It has no significant hypnosedative SUCCINIMIDES effects nor does it have respiratory depressant activity. In addition it does not have ETHOSUXIMIDE undesirable effects on blood pressure, heart Ethosuximide is most commonly used rate, kidney function and body temperature. antiepileptic agent in the treatment of Absorption is rapid and complete. Protein petitmal epilepsy. It acts on thalamocortical binding is between 80 to 95 percent and the system by selectively suppressing T current elimination half life is 8 to 22 hours. It is without affecting other types of Ca2+ or Na+ metabolised in the liver and is excreted by the currents. It is completely absorbed from kidney. There is no presystemic metabolism. gastrointestinal tract and present in plasma Adverse effects include anorexia, in free form and approximately 20% is nausea, vomiting, diarrhoea and/or excreted unchanged in urine and remaining constipation, weight gain, skin rash; hair portion is metabolized in liver. loss, neutropenia, tremors and ataxia are Adverse effects include anorexia, nau- occasionally reported. Valproic acid is sea, vomiting, drowsiness, dizziness, agita- contraindicated in liver disease, especially tion, skin rashes and blood dyscrasias and cirrhosis, pregnancy and hypersensitivity. rarely cause systemic lupus erythematosus. BENZODIAZEPINES METHSUXIMIDE It is similar to ethosuximide and used CLONAZEPAM along with the other drugs in the treatment It is a benzodiazepine useful in the of temporal lobe epilepsy. treatment of petitmal epilepsy, myoclonic seizures and infantile spasms. It is used in ALIPHATIC CARBOXYLIC ACID the treatment of petitmal epilepsy not responding to ethosuximide and sodium SODIUM VALPROATE (VALPROIC valproate. Clonazepam and diazepam act by ACID) increasing the effectiveness of the Sodium valproate increases the levels of inhibitory neurotransmitter GABA, within GABA in the brain and increases the the central nervous system. Antiepileptic Agents 109

Clonazepam is well absorbed orally and Lamotrigine is almost completely approximately 85 percent is bound with absorbed after oral administration and plasma proteins, completely metabolized in metabolized completely in liver. liver and excreted through kidney. The adverse effects include headache, rash, Adverse effects include sedation, lack nausea, dizziness, somnolence and insomnia. of concentration, irritability, ataxia and It is mainly used as adjunctive therapy behavioural abnormalities. in patients for simple partial seizures, The detailed pharmacology of diazepam is complex partial seizures, secondary discussed in chapter ‘Sedative and hypnotics’. generalised tonic and clonic seizures.

CLOBAZAM NEWER COMPOUNDS It is 1, 5 benzodiazepine with a chemical structure slightly different from that of diaz- TOPIRAMATE epam and clonazepam. This change in struc- It is used as adjunctive treatment of ture results in less sedative and psychomo- seizures including refractory seizures, tor retardation. Though introduced as an simple and complex partial seizures. anxiolytic it has been found to be useful in It acts by reducing epileptiform treatment of patients with refractory epilepsy. discharges generated by blocking the Its antiepileptic activity results from its sensitive sodium channel and enhancing binding to one or more specific GABA recep- the activity of GABA receptors. tors increasing GABA mediated inhibition. It is rapidly absorbed after oral Adverse reactions include drowsiness, administration and is unaffected by hangover effects, dizziness, weight gain, presence of food and excreted mainly headache, dry mouth and orthostatic through kidney. hypotension etc. Adverse effects include abdominal pain, anorexia, weight loss, impaired concentra- PHENYLTRIAZINE DERIVATIVE tion, confusion, mood disorders, ataxia, diz- ziness, drowsiness, fatigue and psychotic LAMOTRIGINE symptoms. It is phenyltriazine compound, chemi- cally unrelated to existing antiepileptic GABAPENTIN drugs. It acts primarily via a dose depen- It is a new anticonvulsant drug and is a dent blockade of voltage sensitive sodium structural analogue of GABA. It increases channels in their slow inactivated state, the release of GABA by unknown mecha- thus stabilizing the presynaptic neuronal nism. It modifies maximal electroshock as membrane inhibiting release of excitatory well as inhibits pentylenetetrazol induced neurotransmitters mainly glutamate. convulsions. 110 Section 2/ Drugs Acting on CNS

After oral administration, it is rapidly VIGABATRIN absorbed and widely distributed into all It is an inhibitor of GABA transaminase tissues. It readily crosses blood brain which degrades GABA. It suppresses barrier and is not bound to plasma proteins. maximal electroshock and kindled seizures It is excreted unchanged in urine. It is and is used in partial seizure with or without mainly used as adjunctive therapy in generalization. treatment of partial seizures with or It is well absorbed after oral administra- without secondary generalization in adults. tion and excreted unchanged in urine. Adverse effects include sedation, Adverse effects include drowsiness, dizziness, diplopia, ataxia and fatigue. dizziness, agitation and amnesia.

 Muscle Relaxants 111

Muscle ChapterChapter PharmacodynamicsPharmacodynamics RelaxantsRelaxants 1.2.7 4 (Mode of Action of Drugs)

Skeletal muscle relaxants act peripherally at Chondrodendron tomentosum plant. It ini- the neuromuscular junction or centrally in tially produced motor weakness fol- the cerebrospinal axis to reduce muscle tone. lowed by flaccid paralysis after parenteral administration. The paralysis Skeletal muscle relaxation can be achieved occurs in following order e.g. paralysis by following group of drugs as in table 2.7.1. of fingers, toes, eyes, ears producing diplopia, speech slurring, difficulty in NEUROMUSCULAR BLOCKERS swallowing; the muscles of neck, limb, trunk, paralysis of diaphragm and death D-TUBOCURARINE occur due to hypoxia. It is an dextrorotatory quarternary In higher doses, d-tubocurarine can ammonium alkaloid obtained from produce blockade of autonomic ganglia. It

Table 2.7.1: Classification of skeletal muscle relaxants. I. Neuromuscular blockers d-Tubocurarine 0.2-0.4 mg IV Atracurium 10-15 mg IV Pancuronium 40-100 µg/kg IV Vecuronium 0.08-0.1 mg/Kg IV Succinylcholine 30-50 mg IV Benzoquinonium 10-15 mg IV Dantrolene 25 to 100 mg/day II. Centrally acting muscle relaxants Mephenesin Chlorzoxazone (MOBIZOX) 250 mg TDS Methocarbamol (FLEXINOL) 0.l5-1 g/day oral, 100-200 mg IM/IV Carisoprodol (CARISOMA) 350 mg TDS Orphenadrine (ORPHIPAL) 100-300 mg/day (CITANZ) 2-6 mg/day Baclofen (LIORESAL) 30-75 mg/day Metaxalone (FLEXURA) 400-800 mg TDS-QID 112 Section 2/ Drugs Acting on CNS can also produce release of histamine and cheal intubation, bronchoscopy, can cause bronchospasm and increase other esophagoscopy, laryngoscopy etc). body secretions. • Succinylcholine is used to avoid con- d-Tubocurarine is not absorbed orally vulsion and coma from electroconvul- and after intravascular administration, it is sive therapy. widely distributed in tissue. As it does not • In the treatment of tetanus and emer- cross blood brain barrier it has no effect on gency of epilepsy (status epilepticus). CNS. • As a diagnostic tool for myasthenia Adverse effects include hypoxia, respi- gravis. ratory paralysis, decreased blood pressure, bronchospasm etc. CENTRALLY ACTING MUSCLE RELAXANTS d-Tubocurarine is not used now due to These agents reduce skeletal muscle tone by its prominent histamine releasing and a selective action on cerebrospinal axis ganglionic blocking effect. without affecting consciousness. Mephenesin was the first drug used as PANCURONIUM muscle relaxant but due to its serious side Pancuronium is a synthetic steroidal effects e.g. haemolysis, hypotension and compounds and approximately five times thrombophlebitis, it is not clinically used potent than d-tubocurarine. Vecuronium is now. congener of pancuronium with short dura- tion of action. CHLORZOXAZONE Atracurium is bisquarternary competi- It is mephenesin related skeletal muscle tive blocker similar to pancuronium in prop- relaxant. After oral administration, it is erties and duration of action. rapidly and completely absorbed. It is metabolized in liver and excreted in urine SUCCINYLCHOLINE primarily as the glucuronide. Adverse It is a quarternary ammonium compound reactions include gastric irritation, nausea, with a structure similar to acetylcholine (De- lethargy, headache. tails are discussed in chapter ‘Cholinergic It is used in painful skeletal muscle agents’). spasm and is used in combination with paracetamol and diclofenac. Therapeutic uses • As a adjuvant to general anaesthesia METHOCARBAMOL (specially in major surgical procedures It causes skeletal muscle relaxation by e.g. abdominal and thoracic surgery, preferential blockade of polysynaptic spinal orthopaedic procedures, intubation etc). reflexes. • Succinylcholine is used for surgical It is rapidly absorbed from the GI tract, procedure of brief duration (endotra- metabolised in the liver and excreted in Muscle Relaxants 113 urine as the glucuronide and sulphate TIZANIDINE conjugates of its metabolites. Small amount α Tizanidine is an 2- is excreted in faeces. agonist at supraspinal and spinal levels. This Adverse effects include nausea, effect results in inhibition of spinal anorexia, skin rash, vertigo, drowsiness, polysynaptic reflex activity. It presumably headache and fever. reduces spasticity by increasing presynaptic It is indicated in skeletal muscle spasm, inhibition of motor neurons. Tizanidine has in surgery, orthopaedic procedures, no direct effect on skeletal muscle, the neurological diseases and tetanus. neuromuscular junction or on monosynaptic reflex activity. CARISOPRODOL In humans, tizanidine reduces It is used for the treatment of muscle pathologically increased muscle tone, spasm. It has antipyretic and weak including resistance to passive movements antiadrenergic activity. and alleviates painful spasms and clonus. It is absorbed from the GI tract, Adverse effects include nausea, seda- metabolised in the liver and excreted in urine tion, dry mouth, dizziness, hypotension, as metabolites including meprobamate. headache, palpitation. Other rarely pro- It is used in musculoskeletal disorders. duced side effects include hallucinations, Adverse reactions include nausea, rash, bradycardia etc. headache, drowsiness, constipation and It is indicated in spasticity due to dizziness. neurological disorders e.g., multiple sclerosis, chronic myelopathy, degenerative diseases of ORPHENADRINE the spinal cord, cerebrovascular accidents It is a centrally acting, anticholinergic and cerebral palsy; painful muscle spasm muscle relaxant drug. associated with static and functional With administration of 100 mg of disorders of the spine (cervical and lumbar orphenadrine, peak plasma concentration syndromes); painful muscle spasm following are achieved within two hours. Half-life is surgery e.g., for herniated intervertebral disc 14 hours for the parent drug and 2 to 25 or for osteoarthritis of the hip. hours for the metabolites. Excretion is via urine and faeces. BACLOFEN It is used in musculoskeletal disorders, It is beta-4 (chlorophenyl)-gamma trauma, sports injuries, low backache, aminobutyric acid. It is a powerful neuronal tension headache, sprains and strains, depressant. It reduces the release of excita- parkinsonism including the drug induced. tory transmitter and is antinociceptive in Adverse effects include dry mouth, animal studies. It inhibits monosynaptic and blurred vision, nausea, restlessness, polysynaptic reflex transmission at spinal dizziness etc. level, probably by stimulating the GABAB 114 Section 2/ Drugs Acting on CNS receptors which in turn inhibit the release culoskeletal conditions. Mechanism of ac- of glutamate and aspartate. tion is not known, however, it is thought that After oral administration, it is rapidly the skeletal muscle relaxation is due to its and completely absorbed and eliminated central nervous system depressant action. from the body by kidney in unchanged form. It probably acts by inhibiting polysynaptic pathways but has no effect on monosynap- Adverse effects include weakness, tic pathways. fatigue, dizziness, headache, insomnia, hypotension, confusion, skin rash, It is well absorbed from GIT and mostly constipation, nausea, anorexia, dry mouth metabolised in liver and excreted in urine. and taste disturbance etc. Peak plasma levels are reached at two hours and onset of action occurs within one hour. It is mainly used in the treatment of spasticity in multiple sclerosis, spastic spinal Adverse effects include blurred or paralysis etc. It is also used in the treatment double vision, dizziness, drowsiness, of trigeminal neuralgia. abdominal cramps, confusion, headache, hiccups, anaemia etc. METAXALONE It is mainly used to relieve pain and It is a skeletal muscle relaxant, discomfort caused by strains, sprains and oxazolidinone derivative used in conjunc- other painful muscular conditions in which tion with other therapeutic agents to treat muscles are in spasm i.e. fibromyalgia, and discomfort associated with acute mus- dislocations and fractures.

 Local Anaesthetics 115

Local ChapterChapter PharmacodynamicsPharmacodynamics Anaesthetics 1.2.8 4 (Mode of Action of Drugs)

Local anaesthetics reversibly block impulse Local anaesthetics are employed conduction in a restricted area of the body routinely in dentistry by nerve block or by where it is applied by topical application or infiltration and/or regional block techniques local injection. They are classified as in table to cary out varous operative procedures. 2.8.1. Local anaesthetics can also be classified into two categories based on their chemical All the local anaesthetics possess vary- structure: ing degree of water and lipid solubility. Both a. Ester linked local anaesthetics e.g. co- the properties are essential for a local anaes- caine, procaine, tetracaine, benzocaine, thetic, lipid solubility helps in migration of chloroprocaine. active drug into the neuronal fibre and wa- b. Amide linked local anaesthetics e.g. ter solubility is essential to get the drug to lidocaine, bupivacaine, dibucaine, site of action from the site of administration. prilocaine, ropivacaine.

Table 2.8.1: Classification of local anaesthetics. I. Used topically Lignocaine (XYLOCAINE) 1-5% (as ointment, jelly & topical solution) Benzocaine (MANDELAY) 5% ointment Tetracaine (ANETHANE) 0.25-0.5% (powder & ointment) Dibucaine (NUPERCAINAL) 1% ointment Oxethazaine (MUCAINE GEL) 2% suspension II. Used parenterally Procaine (NOVOCAINE) 0.5-2% inj Lignocaine (XYLOCAINE) 0.5-2% inj, 5% for spinal anaesthesia Tetracaine (ANETHANE) 0.25-0.5% Bupivacaine (SENSORCAINE) 0.25-0.5% inj, 0.5-0.75% for spinal anaesthesia Dibucaine (NUPERCAINE) 0.1-0.5%, 0.25-0.50% for spinal anaesthesia Newer compounds are prilocaine, ropivacaine, etidocaine etc. 116 Section 2/ Drugs Acting on CNS

Local anaesthetics block both the adrenaline 1 in 2,00,000. In dentistry, where generation and conduction of the nerve the total dose is small higher concentration impulse. such as 1 in 80,000 may be used.

Pharmacological Actions Adverse Effects Action on CNS: Local anaesthetics CNS side effects include dizziness, stimulate CNS and produce restlessness, mental confusion, tremors, twitching, tremor, mental confusion, convulsion. In visual disturbances, convulsion and toxic doses, it causes respiratory depression, respiratory depression. CVS toxicity coma and death. Cocaine is a powerful includes hypotension, cardiac arrhythmias stimulant while procaine and other agents and bradycardia. Other side effects include produce less CNS stimulant effect. allergic dermatitis, asthma, anaphylactic shock etc. Action on CVS: Local anaesthetics are myocardial depressant and decrease heart Therapeutic Uses rate and amplitude of myocardial Local anaesthetics are used for contraction. In high doses, they produce • Surface anaesthesia. changes in the ECG and may precipitate ventricular fibrillation. Bupivacaine is more • Spinal anaesthesia. cardiotoxic and can produce ventricular • Infiltration anaesthesia. tachycardia or fibrillation. • Nerve block or conduction block and Local anaesthetics also produce decrease • For systemic use in the treatment of cardiac arrhythmias (Details are given in blood pressure which may be due to in chapter ‘Antiarrhythmic agents’). sympathetic blockade. Only cocaine has the property to raise the BP due to its • Dental anaesthesia—The total amount of local anaesthetics injected sympathomimetic property. is much smaller (20-80 mg of Pharmacokinetics lignocaine) than that used for othr purpose. Lignocaine (2%) with Local anaesthetics are readily absorbed adrenaline (1:80,000) is the standard through mucous membranes and damaged local anaesthetic preparation used in skin. These are weak bases and at tissue pH dentistry which produces good soft diffuse through the connective tissue and tissue and pulpal anaesthasia and cellular membranes to reach the nerve fibres also reduce postextraction bleeding. where ionization can occur. Amide type local anaesthetics (lignocaine, bupivacaine) LIGNOCAINE are metabolised in the liver and in some Mechanism of Action cases the kidneys. These are considerably Lignocaine stabilizes the neuronal protein bound. For certain procedures the membrane by inhibiting ionic fluxes duration of action is prolonged by adding required for initiation and conduction of Local Anaesthetics 117 impulses thereby affecting local anaesthetic Indications action. Lignocaine injections are indicated for production of local or regional anaesthesia Pharmacokinetics by infiltration techniques such as percutane- Lignocaine is completely absorbed ous injection, peripheral nerve block, spinal following parenteral administration, its rate or subarachnoid block. of absorption depending upon various Lignocaine (2%) with adrenaline factors such as site of administration and the (1:80,000) is mostly used local anaesthetic in presence or absence of vasoconstrictor agent. dentistry which produces good soft tissue Lignocaine is metabolised rapidly by the and pulpal anaesthesia and also reduces post liver and metabolites and unchanged drug extraction bleeding. The pulpal anaesthesia are excreted by the kidneys. Approximately is obtained within 2-3 minutes after injection 90% of lignocaine administered is excreted and lasts for about on hour. in the form of various metabolites and less than 10% is excreted unchanged. BENZOCAINE The elimination half-life of lignocaine It is a local anaesthetic belonging to the following an intravenous bolus injection is ester group. It inhibits conduction of nerve 1.5 to 2.0 hours. impulses from sensory nerves. This action is a result of alteration of cell membrane Adverse Effects permeability to ions. It is poorly absorbed CNS manifestations are excitatory and/ from the intact epidermis. or depressant and may be characterised by Benzocaine has been termed by the FDA light-headedness, nervousness, apprehen- as ‘one of the most widely used and safest sion, euphoria, confusion, dizziness, drowsi- external analgesic and that the incidence of ness, tinnitus, blurred or double vision, sensitivity of benzocaine is quite low’. It’s male vomiting, sensation of heat, cold or numb- genital desensitizing product has been termed ness, twitching, tremors, convulsions, un- as premature ejaculation remedy. Benzocaine consciousness, respiratory depression. when applied on the penis aids in temporarily Drowsiness following the administration slowing the onset of ejaculation. of lignocaine is usually an early sign of a high blood level of the drug and may occur as a DIBUCAINE consequence of rapid absorption. It is another local anaesthetic with longer Cardiovascular manifestations are usu- action but most toxic. It is used for surface ally depressant and are characterised by anaesthesia. bradycardia, hypotension and cardiovascu- BUPIVACAINE lar collapse, which may lead to cardiac ar- rest. It is a potent and long acting local Allergic reactions are characterised by anaesthetic used for spinal, infiltration, cutaneous lesions, urticaria, edema or epidural anaesthesia and nerve block. anaphylactoid reactions may occur as a result Side effects include cardiac arrest, of sensitivity to local anaesthetic agent. cardiac arrhythmias and respiratory failure. 118 Section 2/ Drugs Acting on CNS

Bupivacaine (0.5%) with adrenaline anaesthetizing gastric mucosa. Along with (1:2,00,000) is less frequently used in dentistry antacid in suspension form it is used in because of its poor penetration into bone. gastritis, gastric irritation and gastroesophageal reflux. Side effects BENOXINATE include drowsiness and dizziness. It is a surface anaesthetic used in eye for producing corneal anaesthesia for ROPIVACAINE tonometry and does not cause mydriasis or Newer compound, long acting local an- any corneal damage. aesthetic which produces less . It is used mainly for nerve block and in post- OXETHAZAINE operative pain. It is occasionally used in A potent local anaesthetic used for dentistry.  CNS Stimulants 119

ChapterChapter PharmacodynamicsPharmacodynamicsCNSCNS 2.91. 4 StimulantsStimulants

These are the group of drugs which are used ANALEPTICS to stimulate the central nervous system. Some of them are also known as analeptics, These drugs stimulate respiration in coma or fainting but because of its narrow margin of but they are not much useful clinically due safety, they are occasionally used. Nikethamide to non-selectivity of action. is no longer used. Doxapram stimulates They are classified as in table 2.9.1. respiration and raises the blood pressure.

Table 2.9.1: Classification of CNS stimulants. I. Analeptics Nikethamide (CORAMINE) 25% solution oral/IM/IV Doxapram 40-80 mg IM/IV II. Psychostimulants Amphetamine, dexamphetamine, methamphetamine etc. Methylphenidate (RETALIN) 5-10 mg BD Methylxanthines: Theophylline, etc. III. Convulsants , picrotoxin, pentylenetetrazol etc. IV. Cerebroactive drugs Pyritinol (ENCEPHABOL) 100-200 mg TDS, 200-400 mg IV Piracetam (CERECETAM) 50 mg/kg TDS Dihydroergotoxine (HYDERGINE) 3-6 mg/day (SERMION) 30 mg OD-BD (TRIVASTAL) 50 mg OD-BD (NIMODIP) 2 mg/hr IV infusion 120 Section 2/ Drugs Acting on CNS

PSYCHOSTIMULANTS CEREBROACTIVE DRUGS

Amphetamines (dexamphetamine, meth- In this category, some of the compounds are amphetamine etc.) are central sympathomi- used in the treatment of dementia and other metics. These are drugs of abuse and re- related cerebral disorders. peated use can cause long lasting behavioural abnormalities and can precipi- PYRITINOL tate psychosis. The detail is discussed in It enhances cholinergic transmission and chapter ‘Adrenergic drugs’. improves cerebral microcirculation in Methylphenidate is chemically and ischemic regions. It protects the neurons pharmacologically similar to amphetamine. against hypoxia & disturbance of glucose Both act by releasing norepinephrine and metabolism. dopamine in brain. Both produce increased Adverse effects include anorexia, mental activity with little action on central epigastric distress, vomiting, fatigue, and peripheral functions. It is well absorbed headache, sleep disturbances, skin rash, orally, metabolized and excreted in urine. pruritus and increased excitement. It is indicated in organic brain CONVULSANTS syndrome, intellectual impairment of Strychnine (alkaloid obtained from the senility, encephalitis, alcohol with- seeds of Strychnos nux vomica) was used drawal state and perinatal distress, earlier due to its convulsant properties. It cerebrovascular accidents, and or- acts by blocking the postsynaptic inhibition ganic psychosyndrome. produced by inhibitory transmitter glycine. It acts at Renshaw cell-motor neurone PIRACETAM junction in spinal cord through which It improves the functioning of the brain inhibition of antagonistic muscles is involved in cognitive processes e.g. achieved. Picrotoxin (obtained from memory, thought, learning in normal and berries) is a potent convulsant. It acts by in subnormal conditions. It is categorized as blocking presynaptic inhibition mediated nootropic agent (cognition enhancers). through GABA by preventing Cl– channel The beneficial effects are due to im- opening. It is not used now-a-days. proved microcirculation, promotes the me- Bicuculline is a synthetic convulsant and tabolism and modulates neurotransmission. possessing picrotoxin like action. Pentylenetetrazol is a CNS stimulant, acting Adverse effects include nausea, by direct depolarization of central neurons. epigastric distress and skin rash. But none of these compounds are now It is indicated in mental retardation and used therapeutically and used in laborato- learning problems in children, confusional ries only as a research tool. state in old age, cerebrovascular accidents, CNS Stimulants 121 senile dementia, cerebral insufficiency and entry of extracellular calcium in smooth behavioural problem in elderly. muscle cells and neurons. The other drugs in this category are Adverse effects include nausea, aniracetam, oxiracetam, fosracetam, epigastric distress, hypotension and nefiracetam, nebracetam and pramiracetam. flushing. It is indicated in prevention and DIHYDROERGOTOXINE treatment of ischaemic neurological deficit It increases cerebral blood flow by following subarachnoid haemorrhage. blocking alpha adrenergic receptors. Some of the plant preparations Adverse effects include nausea, epi- containing Ginkgo biloba are used in cerebral gastric distress, headache, dizziness, impairment due to organic degeneration of nasal congestion, skin rash and orthostatic cortex, multiple vascular infarcts, in hypotension. psychobehavioural symptoms, certain It is indicated in arteriosclerotic demen- syndrome of vertigo, dizziness and tinnitus tia, primary progressive dementia, etc. Benefit is due to ginkgoflavin glycosides Alzheimer’s dementia, multiinfarct demen- which has PAF antagonistic action. tia and primary progressive dementia. DRUGS USED IN ALZHEIMER’S DISEASE NICERGOLINE (AD) It is an derivative with activity It is progressive neurodegenerative disorder similar to that of dihydroergotoxine. and mainly affects older individuals. It is the Adverse effects include GI disturbances, most common cause of dementia which is a malaise, dizziness, agitation and hot flushes. impairment of intellect, memory and It is indicated in cognitive, behavioural personality in the absence of gross clouding and somatic symptoms associated with of motor involvement. cerebral decay, parkinson’s disease, memory disorders, apathy, asthenia, anorexia, The drugs used in AD are: dizziness and tinnitus. • Centrally acting ChE inhibitor: , . PIRIBEDIL • ChE inhibitors: , It is a dopaminergic agonist and , epastigmine, . improves memory, concentration and • Cholinergic agonists: Milameline, vigilance in older individuals. xanomeline. NIMODIPINE TACRINE It is a calcium channel antagonist. It It is the first centrally acting anti-ChE enters the brain and acts by blocking the used in mild to moderate cases of AD. Side 122 Section 2/ Drugs Acting on CNS effects include diarrhoea, abdominal months and has been shown to improve cramps, polyuria etc. The major side effect cognitive functions in patients of AD and it is rise in serum transaminase and has central ChE inhibitory action. hepatitis. GALANTAMINE DONEPEZIL It acts by dual mechanism i.e. inhibition It is another predominant centrally acting of central ChE and as an agonist on central ChE inhibitor and does not cause hepatotox- acetylcholine nicotinic receptors. icity. It is given in dose of 5-10 mg OD HS. Other drugs which may have beneficial property in the AD are , beta RIVASTIGMINE blockers and drugs from natural origin e.g. It is given in a dose 6-12 mg/day for six Ginkgo biloba.

 Drugs used in Parkinsonism 123

ChapterChapter PharmacodynamicsPharmacodynamicsDrugsDrugs UsedUsed inin 2.101. 4 ParkinsonismParkinsonism(Mode of Action of Drugs)

Parkinsonism is an extrapyramidal motor and used in combination with peripheral disorder, characterized by akinesia, rigidity dopa decarboxylase inhibitors. Levodopa as and tremor with secondary manifestations such is inactive but it is the immediate such as excessive salivation, seborrhoea, precursor of the transmitter dopamine. mood changes (especially depression) and When administered orally, 95 percent of the in certain patients, liver damage has been dose is decarboxylated in the peripheral reported. It was first described by James tissues (mainly in liver). Dopamine thus Parkinson in 1817. formed in peripheral system act on CVS and In parkinsonism, there is a degeneration other peripheral tissues and produce the of dopaminergic nerve endings of the basal unwanted effects. Dopamine, as such, can ganglion (neurons in substantia nigra and not be used to treat parkinsonism as it does the nigrostriatal tract), which results in not cross the blood brain barrier. However, deficiency of dopamine and cholinergic the precursor of dopamine i.e. dopa crosses overactivity. This imbalance between the the blood brain barrier and is converted to dopamine deficiency and overactivity of dopamine in the brain and is released as a cholinergic system gives rise to this motor neurotransmitter. disorder. Thus, the rational approach to the Pharmacological Actions therapy of parkinsonism would be either to increase the central dopaminergic activity or 1. CNS: Levodopa does not produce any to decrease the central cholinergic activity. significant action in normal individual. In parkinsonism patient, it improves all The drugs used in the treatment of manifestations of parkinsonism. parkinsonism can be classified as in table 2.10.1. Akinesia responds first, followed by rigidity and tremor. Other symptoms LEVODOPA such as seborrhoea, sialorrhoea and Levodopa is the most effective drug aphonia also improve. The drug also available for the treatment of parkinsonism improves mood, memory and patients 124 Section 2/ Drugs Acting on CNS

Table 2.10.1: Classification of antiparkinsonism agents. I. Drug acting on central dopaminergic system i. Precursors of dopamine Levodopa (LEVOPA) 0.5-3.0 g/day ii. Dopaminergic agonists (PROCTINAL) 10-40 mg/day 2-5 mg/day 2-4 mg/day (ROPARK) 0.25 mg TDS, increased each week by 0.25 mg (max 24 mg/day) iii. Drugs facilitating dopaminergic transmission 100 mg BD Selegiline 5-10 mg/day iv. Peripheral dopa-decarboxylase inhibitors Carbidopa (used with levodopa; 25 mg carbidopa + 100 mg levodopa; TIDOMET PLUS) 20-100 mg/day Benserazide (used with levodopa; BENSPAR) 50-250 mg/day II. Drug acting on central cholinergic system i. Trihexyphenidyl (Benzhexol; PACITANE) 2 mg OD-QID Procyclidine (KEMADRIN) 2.5-5 mg OD-TDS Biperiden (DYSKINON) 1-4 mg TDS oral/IM/IV Benztropine (COGENTIN) 1-2 mg OD-TDS ii. Antihistaminics Promethazine (PHENERGAN) 10-25 mg TDS Orphenadrine (DISIPAL) 50-100 mg BD-TDS (BENADRYL) 50-100 mg/day

become more alert and interested in life 3. Endocrine system: Dopamine inhibits and surroundings. prolactin release in human being. It also 2. CVS: The levodopa produces its CVS acts on somatotrophs to increase effect by being converted into growth hormone release. dopamine. It acts by stimulating alpha 4. Miscellaneous actions: Peripherally adrenergic receptors in blood and formed dopamine (converted peripher- produce vasoconstriction and may ally after levodopa therapy) gains access raise the blood pressure. It also acts to the CTZ (chemoreceptor trigger zone) by stimulating betaadrenergic causing nausea and vomiting. receptors in heart and produce tachycardia and increase force of Pharmacokinetics myocardial contraction (positive Levodopa is rapidly absorbed when inotropic action). given orally and peak plasma level is Drugs used in Parkinsonism 125 reached at 30 minutes to 2 hrs and adrenaline and isoprenaline) should be plasma half life is 1 to 3 hours. More avoided in patients on levodopa than 95 percent of oral dose is rapidly therapy. decarboxylated peripherally mainly in • Pyridoxine accelerates the peripheral GIT, liver and other tissues to dopam- dopadecarboxylation of levodopa. ine and very little (less than 5%) is left to enter the central nervous system. PERIPHERAL DECARBOXYLASE INHIBITORS Hence, levodopa is given along with peripheral dopa decarboxylase inhibi- CARBIDOPA AND BENSERAZIDE tors (i.e. carbidopa, benserazide) so that Carbidopa and benserazide are peripheral more and more levodopa enters into decarboxylase inhibitors used in combination CNS and is converted into dopamine in with levodopa. They do not penetrate blood- CNS. brain barrier and do not inhibit the conversion Levodopa is excreted in the urine as into dopamine from levodopa in brain. conjugated metabolites and its main They make more of levodopa available metabolite is homovanillic acid (HVA). to cross blood-brain barrier where levodopa is converted into dopamine and reach at the Adverse Effects site of action. Nausea and vomiting because of CTZ When used along with levodopa, the stimulation, which can be minimized by start- plasma half life of levodopa is prolonged ing with a lower dose. It also causes confu- and dose may be markedly reduced. Also sion, hallucinations, delusions and other the most common side effect i.e. nausea and behavioural effects. Certain cardiovascular vomiting are not prominent and cardiac effects such as palpitation, postural hypoten- complications are minimized. It has no effect sion, sinus tachycardia and ventricular on involuntary movements, behavioral arrhythmias have also been reported. abnormalities and postural hypotension. On prolonged administration, grimac- ing facial tics and choreoathetoid move- DOPAMINERGIC AGONISTS AND ments of limbs have been reported. OTHER DRUGS Drug Interaction with Levodopa BROMOCRIPTINE (Bromoergocriptine) • Levodopa with MAO inhibitors may It is an ergot preparation which has a precipitate severe rise in blood pressure specific agonist action (MAO inhibitors should be stopped at (acts mainly on D1 receptors) and capable least two weeks before levodopa of crossing the blood brain barrier. It is less therapy). active than levodopa and used only in late • Methyldopa intensifies the adverse cases as a supplement to levodopa. Adverse effects of levodopa. effects are vomiting hallucinations, • Pressor agents (catecholamines such as hypotension, nasal stuffiness. 126 Section 2/ Drugs Acting on CNS

AMANTADINE The central anticholinergic drugs having It is an antiviral compound and also a higher central versus peripheral improves akinesia, rigidity and tremor in cholinergic action ratio are useful. The drugs parkinsonism. It is more effective than like atropine are much less effective than atropine like drugs but it is less effective levodopa but they are used when levodopa than levodopa. Its effect on tremors is less is not tolerated or contraindicated or the than on rigidity. It acts by releasing patient is not benefitted by levodopa or drug dopamine from the neuronal storage sites. induced parkinsonism. The drug is well absorbed orally and Atropine like drugs antagonize the excreted unchanged in urine and drug is rigidity and akinesia and cause reduction tolerated well and cause fewer adverse in the intensity of tremors. They act by effects. In toxic dose, it causes convulsions reducing the unbalanced cholinergic and mania and should be used cautiously activity in parkinsonism. Benzhexol is in epileptic patients. most commonly used and effective drug among the atropine substitutes used in SELEGILINE parkinsonism. It is a selective MAO-B inhibitor, which Atropine like drugs cause several side is predominant in brain and blood platelets. effects such as dry mouth, blurred vision, It retards intracerebral degradation of urinary retention, mental confusion, dopamine. It is used with levodopa in early hallucinations etc. cases of parkinsonism. It prolongs levodopa Antihistaminics are better tolerated by action, attenuates motor fluctuations and elderly patients who do not tolerate decreases wearing off effect. But clinical anticholinergics. Antihistaminics do not benefits are short lived (6-24 months). cause blurring of vision and xerostomia and Adverse effects are postural hypotension, also possess some central anticholinergic nausea, confusion, increased levodopa in- properties. duced involuntary movements and confusion. NEWER DRUGS DRUGS ACTING ON CENTRAL ANTICHOLINERGIC SYSTEM ROPINIROLE The cholinergic neurons are immediately Ropinirole is a non-ergot dopamine distal to dopaminergic fibres in the cau- agonist with high relative specificity date nucleus in brain. They are excitatory and full intrinsic activity at the D2 and D3 and in parkinsonism, there is a degenera- dopamine receptor subtypes, binding with tion of inhibitory dopaminergic neurons higher affinity to D3 than to D2 or D4 receptor and thus, there is increased cholinergic ac- subtypes. Ropinirole is more specific than tivity (preponderance of cholinergic sys- dopamine agonists, bromocriptine and tem) which results in the symptoms of par- pergolide. The relevance of D3 receptor kinsonism. binding in Parkinson’s disease is unknown. Drugs used in Parkinsonism 127

Ropinirole is rapidly and well absorbed pharyngitis, abnormal vision, confusion from the GIT with maximum plasma and hallucinations. concentration achieved within one to two It is indicated for the treatment of signs hours after single oral dose. and symptoms of idiopathic Parkinson’s Adverse effects include nausea, vom- disease. iting, drowsiness, fainting, fatigue, dys- has preferential affinity for pepsia, abdominal pain, constipation, D3 family of receptors.

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Drugs Acting on ANS This page intentionally left blank ChapterChapter SympathomimeticsSympathomimetics 1.3.1 4 (Adrenergic Agents)

The sympathomimetic or adrenergic or Alpha receptors: There are two major α α adrenomimetic drugs mimic the effects of groups of alpha receptors, 1 and 2. α adrenergic sympathetic nerve stimulation. Activation of postsynaptic 1 receptors These are the important group of increases the intracellular concentration of therapeutic agents which may be used to calcium by activation of a phospholipase C α maintain blood pressure and in certain cases in the cell membrane via . 2 of severe bronchial asthma. receptor is responsible for inhibition of renin The sympathomimetics are classified as release from the kidney and for central a- in table 3.1.1. adrenergically mediated blood pressure depression. Mechanism of Action and Adrenoceptors Beta receptors: On the basis of the The catecholamines produce their action by relative selectivity and potency of both direct combination with receptors located on agonists and antagonists, three types of beta the cell membrane. In 1948, Ahlquist divided receptors can be distinguished. the adrenergic receptors into two main groups a. Beta1 receptors have approximately – alpha and beta. The alpha receptor stimulation equal affinity for adrenaline and produces excitatory effect and beta receptor noradrenaline and are responsible for stimulation usually produces inhibitory effect. myocardial stimulation and renin Adrenergic receptors: These are release. membrane bound G-protein coupled b. Beta2 receptors have a higher affinity receptors which function primarily by for adrenaline than for noradrenaline increasing or decreasing the intracellular and are responsible for bronchial production of second messengers cAMP or muscle relaxation, skeletal muscle inositol triphosphate (IP3)/diacylglycerol vasodilatation and uterine relaxation.

(DAG). Adrenergic receptors are classified Dopamine receptors: The D1 receptor is into two main groups α and β. typically associated with the stimulation of 132 Section 3/ Drugs Acting on ANS

Table 3.1.1: Classification for sympathomimetics (adrenergic drugs). I. Pressor agents Noradrenaline (Norepinephrine) 2-4 µg/min IV infusion Ephedrine 30-60 mg oral, 15-30 mg IM/IV Dopamine (DOPAT) 2-50 µg/kg/min IV infusion (FRENIN) 0.5-1 mg IV, 5-10 mg IM II. Cardiac stimulants Adrenaline (EPINEPHRINE) 0.2-0.5 mg SC/IM Isoprenaline (Isoproterenol; ISOPRIN) 10-20 mg SL, 1-2 mg IM III. Bronchodilators Adrenaline 0.2-0.5 mg SC/IM, 0.5% aerosol Salbutamol (ASTHALIN) 2-4 mg TID-QID oral, 0.25-0.50 mg IM/SC, 100-200 mcg (1-2 puffs) TDS-QID aerosol inhalation Isoprenaline (ISOPRIN) 10-20 mg SL, 1-2 mg IM, 0.4-0.8 mg aerosol (AUTOHALER) (ALUPENT) 20 mg Q1D, 0.75-1.5 mg (1-2 puffs; max. of 9 mg daily) (BRICANYL) 2.5-5.0 mg TDS, 250-500 µg QID SC/IM, 250-500 µg (1-2 puffs) TDS-QID (ROBUROL) 10-20 mg OD (SEROBID) 25 µg BD (aerosol) Other agents are isoetharine, , rimeterol etc. IV. Nasal decongestants Ephedrine 0.5-2% topical solution, 0.75% nasal drops Phenylephrine (ANDRE) 0.125-5% topical, 5-10% eye drops, 0.25% nasal drops (SUDAFED) 60 mg oral (NASIVION) 0.025-0.05% nasal drops (OTRIVIN) 0.05-0.1% nasal drops (PRIVINE) 0.1% nasal drops V. CNS stimulants Ephedrine 30-60 mg oral Dexamphetamine (DEXEDRINE) 5-10 mg oral VI. Uterine relaxants and vasodilators (DUVADILAN) 5-10 mg oral/IM 4-6 hourly Nylidrin (ARLIDIN) 3-12 mg oral, 5-10 mg IM 0.1-0.35 mg /min IV infusion Orciprenaline 2-8 µg/min IV infusion Terbutaline 1-8 µg/min IV infusion VII.Anorectics Fenfluramine (FLABOLIN) 20-40 mg/day (ISOMERIDE) 15 mg BD Sibutramine (OBESTAT) 10-15 mg OD Sympathomimetics (Adrenergic Agents) 133 adenylyl cyclase. The important agonist of blood vessels of the skeletal muscles on β dopamine receptors is (D1) and account of the preponderance of 2 bromocriptine (D2) and antagonist is receptors. clozapine (D4). Blood pressure: Because of vasocon- α β These receptors are distinct from alpha striction ( 1) and vasodilatation ( 2) action and beta receptors and are particularly of adrenaline, the net result is decrease in important in the brain. total peripheral resistance. Although Adrenergic drugs can also be classified adrenaline increases the systolic blood pres- into: sure but simultaneously lowers the blood pressure by its peripheral action. The rise in a. Direct sympathomimetics: These act systolic blood pressure is often followed by directly on a or/and b adrenoceptors decrease in blood pressure, adrenaline in e.g. adrenaline, noradrenaline, isopre- such doses activates both a and b receptors. naline, phenylephrine, , But mean blood pressure rises with increase salbutamol etc. in pulse pressure. b. Indirect sympathomimetics: They act Noradrenaline causes rise in systolic, on adrenergic neurones to release diastolic and mean blood pressure and does noradrenaline e.g. tyramine. not cause vasodilatation (because of no c. Mixed action sympathomimetics: They β action on 2 receptors) and increase in act directly as well as indirectly e.g. ephe- peripheral resistance due to its a action. drine, amphetamine, mephentermine Isoprenaline causes rise in systolic blood etc. β pressure (because of 1 cardiac stimulant Pharmacological Action of action) but marked fall in diastolic blood

Sympathomimetics (Particularly pressure (because of b2 vasodilatation action) adrenaline and noradrenaline) but mean blood pressure generally falls. Heart: Direct effects on the heart are GIT: Adrenaline causes relaxation of β smooth muscles of GIT and reduce its determined largely by 1 receptors. Adrenaline increases the heart rate, force of motility. Relaxation of smooth muscles of myocardial contraction and cardiac output GIT can be brought about by both alpha and which is associated with increased beta stimulants. It decreases the tone, metabolism by the myocardium, increased frequency and amplitude of contraction of oxygen consumption and thus decreasing smooth muscles. β cardiac efficiency. Respiratory system: The presence of 2 Blood vessels: Adrenaline and receptors in bronchial smooth muscle causes noradrenaline constrict the blood vessels of relaxation and activation of these receptors β skin and mucous membranes. Constriction by 2 agonists cause bronchodilatation. predominates in cutaneous and mucous Among catecholamines, adrenaline and membranes which occur through both α isoprenaline are potent bronchodilators due α 1 β and 2 receptors. Adrenaline also dilates the to its 2 action but not noradrenaline. 134 Section 3/ Drugs Acting on ANS

Uterus: The response of the uterus to the f. Adrenaline produces leucocytosis and catecholamines varies according to species eosinopenia and accelerates blood and absence or presence of pregnancy. In coagulation and also stimulates platelet rats both pregnant and nonpregnant uterus, aggregation. relaxation is produced while in rabbits both Action on CNS: Catecholamines do not pregnant and nonpregnant uterus is produce any marked CNS effects because contracted. In human beings, nonpregnant they do not cross blood brain barrier uterus is contracted while pregnant uterus satisfactorily. However, adrenaline may is relaxed in the last month of pregnancy. produce restlessness, apprehension, excitement and tremors on intravenous or Eye: Mydriasis occur due to contraction intracarotid injection. of radial muscles of iris, intraocular tension is lowered due to less production of the Pharmacokinetics aqueous humor secondary to vasoconstric- Catecholamines are absorbed from the tion and conjunctival ischemia due to con- intestines, but are rapidly degraded in gut striction of conjunctival blood vessels. and liver by enzymes MAO and COMT. Action on other smooth muscles & other Thus they are inactive on oral miscellaneous actions: administration. a. Urinary bladder: Detrusor is relaxed Adverse Effects (b) and trigone is constricted (a) and Restlessness, anxiety, tremor, head- both the actions tend to inhibit ache. Both adrenaline and noradrenaline micturition. cause sudden increase in blood pressure, b. Spleen: In animals, it causes precipitating sub-arachnoid haemorrhage contraction (due to its a action) of the and occasionally hemiplegia, and ven- splenic capsule resulting in increase in tricular arrhythmias. May produce angi- number of RBCs in circulation. nal pain in patients with ischemic heart c. It also cause contraction of retractor disease. penis, seminal vesicles and vas deferens. Contraindications d. Adrenaline causes lacrimation and a. In patients with hyperthyroidism. salivary glands are stimulated. b. Hypertension. e. Adrenaline increases the blood sugar c. During anaesthesia with halothane and level by enhancing hepatic glyco- cyclopropane. genolysis and also by decreasing the d. In angina pectoris. uptake of glucose by peripheral tissues. Adrenaline inhibits insulin release by Therapeutic Uses its a-receptor stimulant action whereas Allergic reaction: Adrenaline is drug of it stimulates glycogenolysis by its b choice in the treatment of various acute al- receptor stimulant action. lergic disorders by acting as a physiological Sympathomimetics (Adrenergic Agents) 135 antagonist of histamine (a known mediator c. Anoretic drugs can help the obese of many hypersensitivity reactions). It is people. used in bronchial asthma, acute angion- d. Amphetamine may be useful in eurotic edema, acute hypersensitivity reac- nocturnal enuresis in children. tion to drugs and in the treatment of ana- e. Isoxsuprine (uterine relaxant) has been phylactic shock. used in threatened abortion and Bronchial asthma: When given dysmenorrhoea. subcutaneously or by inhalation, adrenaline is a potent drug in the treatment of status DOPAMINE asthmaticus. It is an immediate metabolic precursor of

Cardiac uses: Adrenaline may be used noradrenaline. It activates D1 receptors in to stimulate the heart in cardiac arrest. several vascular beds, which causes Adrenaline can also be used in Stokes-Adam vasodilatation. It acts on dopaminergic and α β syndrome, which is a cardiac arrest other adrenergic receptors ( & 1). occurring at the transition of partial to complete heart block. Isoprenaline or Pharmacological Actions of Dopamine orciprenaline may be used for the temporary The actions of particular sympathomi- treatment of partial or complete AV block. metic amine depend on its relative activity Vascular uses: Pressor agents like at different types of adrenergic receptors. adrenaline (more appropriate dopamine or The overall actions are: ) may be useful in hypotensive crisis. Cardiovascular system:

Adrenaline along with local anaesthetics a. Blood vessels: D1 receptors promote may be used for infiltration, nerve block and vasodilatation of renal, splanchnic, spinal anaesthesia for prolonging the action coronary and cerebral arteries. and to reduce the systemic toxicity of local Activation of the D1 receptors in the anaesthetics. renal vasculature may play a major role in the natriuresis induced by Adrenaline may be useful in control of pharmacologic administration of haemorrhage from the skin and mucous dopamine. membrane such as epistaxis and after tooth b. Heart: In the heart, intraventricular extraction. pressure rises and falls more rapidly, Also used as nasal decongestant. and ejection time is decreased. These direct effects are easily demonstrated Miscellaneous uses: in the absence of reflexes evoked by a. Phenylephrine is used in fundus changes in blood pressure, e.g. in examination as mydriatic agent. isolated myocardial preparations and b. Amphetamines are sometime used as in patients with ganglionic blockade. In adjuvant and to counteract sedation the presence of normal reflex activity, caused by antiepileptics. the direct effects on heart rate may be 136 Section 3/ Drugs Acting on ANS

dominated by a reflex response to It is indicated in shock syndrome due blood pressure changes. to MI, trauma, septicaemia, heart surgery, c. Blood pressure: The enhanced arterial renal failure and chronic cardiac failure. constriction may lead to a marked rise DOBUTAMINE in blood pressure. In the presence of normal cardiovascular reflexes, the rise It is a derivative of dopamine and has β in BP elicits a baroreceptor mediated relatively 1-selective action and it also α increase in vagal tone with slowing of activates 1 receptors and do not have D1 or D receptor agonistic property. It the heart rate. 2 Eye: The radial pupillary dilator muscle increases the force of myocardial of the iris contains alpha-receptors; activation contraction and cardiac output without significant change in heart rate, blood by drugs causes mydriasis. pressure and peripheral resistance. It is Respiratory tract: The blood vessels of used as inotropic agent and for short term the upper respiratory tract mucosa contain management of CHF and also in patients α 1-receptors; the decongestant action of who are unresponsive to digitalis. alpha stimulants is clinically useful. Gastrointestinal tract: Relaxation of GIT EPHEDRINE smooth muscle can be brought about by both Ephedrine is an alkaloid obtained from α and β stimulant agents. Alpha stimulants ‘Ephedra vulgaris’ plant. It act indirectly and α directly on α and β receptors. It increases especially 2 selective agonists, decrease muscle activity indirectly by presynaptically blood pressure both by peripheral α vasoconstriction and by increasing the reducing the release of catecholamines. 2- receptors may also decrease salt and water cardiac output. Ephedrine also relaxes the flux into the lumen of the intestine. bronchial smooth muscles. Effect on endocrine function: Catechola- Ephedrine stimulates CNS and produces mines are important endogenous regulators restlessness, insomnia, anxiety and tremors. of hormone secretion from a number of Ephedrine produces mydriasis on local as glands. Insulin secretion is stimulated by well as systemic administration. α Ephedrine is useful for the treatment of beta receptors and inhibited by 2-receptors. Similarly, renin secretion is stimulated by chronic and moderate type of bronchial β α asthma, used as nasal decongestant and as 1 and inhibited by 2 receptors; indeed, beta-receptor antagonists may lower plasma a mydriatic without cycloplegia. It is also renin at least part by this mechanism. useful in preventing ventricular asystole in Stokes Adams syndrome. It is also used in Adverse effects of dopamine include narcolepsy, however amphetamines are the nausea, vomiting, ectopic beats, anginal pain, drug of choice. tachycardia, palpitation and widened QRS. Contraindications are atrial or ventricu- PSEUDOEPHEDRINE lar tachyarrhythmias, hyperthyroidism and Pseudoephedrine appears to have less pheochromocytoma. pressor activity and weaker central nervous Sympathomimetics (Adrenergic Agents) 137 system effects than ephedrine. It has agonist administration. Oxymetazoline enters β β tissues rapidly and is released slowly. The activity at both 1 and 2 adrenoceptors, leading to increased cardiac output and plasma half life is 5-8 days. 30% of absorbed relaxation of bronchial smooth muscle. drug is eliminated in the urine and approximately 10% in the faeces. It is readily and completely absorbed from the GIT following oral administration It is used: with no presystemic metabolism. 1. As a nasal decongestant in allergic Pseudoephedrine is rapidly absorbed rhinitis, with or without the addition of throughout the body. It is eliminated largely antazoline or sodium chromoglycate. unchanged in urine by N-demethylation. 2. As a nasal decongestant in sinusitis, in It is excreted in breast milk at otitis media where there is evidence of concentration constantly higher than those in obstruction of the eustachian tube especially in subacute serous otitis maternal plasma. The elimination of media and otitic barotrauma. pseudoephedrine is reduced in renal 3. As an ocular decongestant in allergic impairment. Hepatic dysfunction is unlikely conjunctivitis. to affect the pharmacokinetics of the drug. 4. To ‘whiten’ an inflamed (red) eye Adverse effects include excessive caused by a local irritant such as dust tiredness, restlessness, nervousness, or following the removal of a foreign tremors, headache, palpitation, elevation in body. BP, vomiting, anorexia, constipation, nausea Adverse effects include local stinging or and convulsions. burning, sneezing, dryness of mouth and It is contraindicated in cardiovascular throat. Prolonged use may cause rebound disease causing hypertension, angina pectoris congestion and drug induced rhinitis, headache, tachycardia may occur. etc., endocrine disorders like hyperthyroidism, diabetes mellitus, enlargement and Compounds like naphazoline and xylometazoline are relatively selective α concurrent use of MAO inhibitors. 2 agonists, which on topical application It is indicated in symptomatic relief from produce local vasoconstriction. They are stuffed nose, respiratory tract congestion, used as nasal decongestants and have bronchospasm associated with asthma, longer duration of action. Prolonged use bronchitis and other similar disorders. can produce atrophic rhinitis and anosmia.

OXYMETAZOLINE ISOPRENALINE It is a directly acting sympathomimetic It is beta-receptor stimulant, which amine used in symptomatic relief in nasal stimulates the heart and causes tachycardia. congestion which increases mucosal It relaxes the smooth muscles particularly secretion. the bronchial and GIT. It is mainly used in Local vasoconstriction is normally bronchial asthma, in the treatment of shock achieved within 5 to 10 minute of intranasal and as a cardiac stimulant in heart block. 138 Section 3/ Drugs Acting on ANS

ORCIPRENALINE AMPHETAMINE Is a potent β-adrenergic agonist. It is a synthetic compound with Receptor sites in the bronchi and bronchioles structural similarity to ephedrine and is are more sensitive to the drug than those in available in racemic and dextro isomers. It the heart and blood vessels. increases the systolic and diastolic blood pressure. Amphetamine is a potent CNS It decreases reversible bronchospasm stimulant and causes alertness, insomnia, associated with chronic bronchitis, increased concentration, euphoria or pulmonary emphysema, bronchial asthma, dysphoria and increased work capacity. silicosis, tuberculosis and sarcoidosis. The Amphetamine produces wakefulness and resultant decrease in airway obstruction improved physical performance. It contracts may relieve the dyspnea associated with the sphincter of the bladder and relaxes the bronchospasm. bronchial smooth muscle in large doses. It is effective both by oral route as well Amphetamines are drugs of abuse and can as inhalation. produce behavioural abnormalities and can precipitate psychosis. It can produce There is more rapid onset of action psychological but no physical dependence. following inhalation administration. Because of its misuse especially by Absorption via the bile is 45 percent of teenagers, its use is limited to the treatment renal excretion. Bioavailability of the active of Attention Deficit Hyperactivity Disorder substance is 33% owing to a first pass effect. (ADHD) and narcolepsy. It is indicated in bronchial asthma and PHENYLEPHRINE reversible bronchospasm associated with chronic bronchitis and pulmonary emphy- It is a vasopressor agent with some struc- sema, including bronchospasm due to the tural similarity to adrenaline and has a power- ful alpha receptor stimulant action. The pres- use of b-blocking agents. 1 sor response is accompanied by reflex brady- Can be used as a supportive therapy cardia. It is used as a nasal decongestant and with antibiotics, secretomucolytics, mydriatic agent and also in the treatment of corticosteroids, physiological saline and paroxysmal supraventricular tachycardia. disodium chromoglycate. Side effects such as palpitation, restless- UTERINE RELAXANTS (TOCOLYTICS) ness and finger tremor may occur; in iso- These are the agents which decrease uterine lated cases, flushing, headache, sleep distur- motility and have been used to delay or postpone bances, nausea, ventricular disturbances or labour and to arrest threatened abortion which angina pectoris and allergic skin reactions is needed to allow to mature. have been observed. The injection or infusion of high doses ISOXSUPRINE may also cause tachycardia, arrhythmia and Both nylidrin and isoxsuprine have got a decrease in blood pressure. beta receptor stimulant action and is used Sympathomimetics (Adrenergic Agents) 139 in the treatment of peripheral vascular should not be used if mother has a history of diseases. But nylidrin is not used clinically. diabetes, heart disease or is on β-blocker or Isoxsuprine has a potent inhibitory steroid therapy. effect on vascular and uterine smooth Certain other drugs also having uterine muscle and has been used in the treatment relaxant property are calcium channel of dysmenorrhoea, threatened abortion, blockers, prostaglandin synthesis inhibitors, premature labour and peripheral vascular , nitrites, anticholinergics, diseases. Adverse effects include nausea, ethyl alcohol etc. tachycardia, flushing and dizziness. FENFLURAMINE RITODRINE It is a sympathomimetic amine. the mechanism of action is related to brain It is β selective agonist with uterine 2 levels (or turnover rates) of serotonin or relaxant property and preferred to suppress to increase glucose utilization. Its premature labour and delay delivery of fetus. antiappetite effect is suppressed by But, use of ritodrine in suppressing labour has serotonin blocking drugs. Its use in clinical been found to increase maternal morbidity and practice is recently banned in ‘India’ neonate may develop hyperglycemia. So it because of severe toxicity.

 This page intentionally left blank TreatmentTreatment ofof ShockShock ChapterChapter PharmacodynamicsPharmacodynamics&& 3.21. 4 VasopressorVasopressor AgentsAgents

Shock is a clinical syndrome in which pathetic nerve endings. profound and widespread reduction in – Release of vasopressin. the effective delivery of oxygen and – Release of vasodilators, including kinin other nutrients to the tissues. In shock and prostaglandins. condition, the individual is weak, anx- – Two activity of renin-angiolension sys- ious with coldness of extremeties, sweet- tem ing and marked fall in arterial pressure. All these mechanism can affect the Physiologic mechanisms can effect the arterial pressure by altering the vascular arterial pressure by acting on one or resistance and/or cardiac output. more of two variables i.e. preload, FORMS OF SHOCK impedance to blood flow (after load) and myocardral contractility. These macha- The classification of shock is based on nisms include: the cause which is as under: – Local release of vasodilater metabolits I Cardiogenic shock e.g. adenosine – Myopathic – Release form the endothelium of – Arrhythmic substances that relax (e.g. endothelium – Mechanical derived relax factor, nitric oxide) or contract (e.g. endothelium) II Oligemic shock or hypovolaemic shock – Activity of autonomic nervous system – Haemorrhage and the modulation of this activity by – Fluid depletion baroreceptor reflexes and vasomotor III Extracardiac obstructive shock centre in the brainstem. – The release of epinephrine or norepi- – Constrictive pericarditis nephrine by adrenal medulla and sym- – Pulmonary embolism 142 Section 3/ Drugs Acting on ANS

– Severe pulmonary hypertension mechanical causes have been excluded), the – Percardial tamponade therapy should be directed toward reducing – Coarctation of aorta ischemia and salvaging severely, ischemic but reversibly damaged myocardium at the IV Distributive shock infart border. This may also be supported – Anaphylaxis by administration of oxygen and nitrates, – Septic shock intraaortic balloon pumping and depending – Neurogenic shock upon the specific condition, thrombolytic – Endocrinologic shock agents may be added. – Due to toxic products e.g. overdose The repaired myocardium may be treated by combination of intraaoritc balloon TREATMENT couterpulsation and sympathomimetics amines e.g. dopamine, dobutamine, etc. CARDIOGENIC SHOCK In other conditions of cardrogenic shock It is characterized by severe, persisting (due to mechanical abnormalities) e.g. acute pain, shock and hypotension with possible mitral regurgitation or ventricular septal development of arrhythmias and is due to defect, surgical correction is usually severe depression of systolic cardiac required. performance, systolic arterial pressure is below 80 mm Hg, low cardiac index, OLIGEMIC OR HYPOVOLEMIC SHOCK ventricular filling pressure is elevated and pulmonary edema may or may not be It occur due to haemorrhage or a large evident. The most frequent cause is loss of body fluids secondary to diarrhoea, infarction involving more than fourty vomiting, burn or dehydration leads to percent of the left ventricular myocardiam, inadequate ventricular filling i.e. to decreased leading to a severe reduction in left preload severely, decreased right and left ventricular contractility contradictively and ventricular end-diastolic volumes and failure of the left ventricular pump. pressures. These changes leads to oligemic Acute myocarditis and depression of shock by causing an inadequate stroke myocardial contractility following cardiac volume and inadequate cardiac output. arrest and prologed cardiac surgery also the Oligemic shock may be managed by causes of cardiogenic shock. rapid infusion of or plasma Cardiogenic shock is also caused by substitutes/expanders and simultaneously mechanical abnormalities of the ventricle. Acute mitral or ventricular aneurysm, the source of blood / fluid loss in identified usually caused by acute myocardial and corrected. infarction, can cause a severe reduction in forward cardiac output and thereby result EXTRACARDIAC OBSTRUCTIVE in cardiogenic shock. SHOCK The management of cardiogenic shock Pericardial temponade is the main cause when it is due to myocardial infarction (after of extracardric obstructive shock, which is Treatment of Shock & Vasopressor Agents 143 the inability of the ventricle of fill during in severe vasomotor collapse. Septic shock is diastole markedly limiting the stroke characterized by a low systemic vascular volume and cardiac output. Another cause resistance and an elevated cardiac output and is massive pulmonary embolism it usually begins with a nidus of infection that In pericardial temponade, administra- releases microbes and/or one or more tion of sympathomimetic amines e.g. nore- mediators e.g. histamine, kinine, pinephrine and/or dopamine may improve prostaglandins, endorphins, TNF, interlukin haemodynamics temporarily and surgical 1 & 2 etc. into the blood stream which pericardial drainage is the only effective produce vascular dilatation and treatment. vasoconstriction (some PG’s & leukotrienes). The peripheral vasodilatation result in a DISTRIBUTIVE SHOCK reduced systemic vascular resistance and Anaphylactic, septic and neurogenic high cardric output. shock are the examples of distributive shock Management of septic shock may be and all of which usually cause profound carried out in three simultaneous ways, decrease in periperal vascular resistance. firstly, the nidus of infection must be In anaphylactic shock, when a sensitized identified and eliminated, using surgical person is re-exposed to the specific antigen drainage and antimicrobial therapy. and due to antigen-antibody reaction there Sacondly, using cardiovascular monitoring is large amount of histamine release along and support, adequate organ system with other mediators of anaphylaxis, perfusion and function must be maintained. resulting in fall in blood pressure with savere Thirdly, to interrupt the pathogenic allergic reaction and bronchospasm. sequence leading to septic shock. Penicillin is the common example of Neurogenic shock is generally occur in anaphylactic shock in sensitized individuals. abdominal trauma, spinal anasthesia, spinal Epinephrine is a life saving drug of choice cord injury and is managed by vasopressor in this type of case. Dopamine may be given agents e.g. dopamine.

 This page intentionally left blank Chapter Chapter PharmacodynamicsPharmacodynamicsSympatholytics 3.31. 4 (Antiadrenergic Agents)

These are the agents, which block the action GENERAL CHARACTERISTICS OF of adrenaline and noradrenaline. They block ALPHA BLOCKERS either alpha or beta or both adrenergic receptors. They are classified as in table 3.3.1 Alpha blockers are the drugs which block and 3.3.2. the pressor response to noradrenaline and

Table 3.3.1: Classification for alpha adrenergic blocking agents.

A. Non-equilibrium (FENOXENE) 20-60 mg orally, 1 mg/kg IV infusion B. Equilibrium ααα ααα I. Nonselective ( 1+ 2 blockers) i. Ergot alkaloids (GYNERGEN) 1-3 mg oral, 0.25-0.5 mg IM/SC 2-6 mg oral, 0.5-1 mg IM Dihydroergotoxine (HYDERGINE) 1.5 mg oral TDS, 0.15-0.6 mg IM ii. Imidazolines mesylate (FENTANOR) 50 mg QID (PRISCOL) 25-50 mg TDS iii. Phenothiazines Chlorpromazine (LARGECTIL) 25-50 mg oral/IM ααα II 1 Selective (MINIPRESS) 0.5-1.0 mg TDS (OLYSTER) 2-10 mg/day, 1 mg HS Triamazosin 25-200 mg TDS (DOXACARD) 1-4 mg/day (DYNAPRES) 0.4-0.8 mg OD ααα III. 2 Selective 2-4 mg TDS 146 Section 3/ Drugs Acting on ANS convert adrenaline induced stimulation PHENOXYBENZAMINE response to depressor response. Blockage of It is a potent alpha-adrenergic blocking vasoconstrictor receptors reduces peripheral agent and only haloalkylamine used resistance, venous return and cardiac output clinically. It effectively prevents the leading to fall in blood pressure. The responses mediated by alpha receptors and decrease in blood pressure by alpha blockers diastolic blood pressure tends to decrease. can reduce renal blood flow, which can lead It interferes with the reflex adjustment of to reduction of glomerular filtration rate and blood pressure and produces postural more reabsorption of sodium and water in the tubules and ultimately sodium retention hypotension. It increases the cardiac output and increase in blood volume. and decreases the total peripheral resistance. It also antagonizes cardiac arrhythmias Positive inotropic and chronotropic provoked by catecholamines. Apart from effects of catecholamines are not blocked by these effects, phenoxybenzamine has other alpha blockers, but these drugs can block actions also e.g. antagonism of acetylcholine, catecholamine induced cardiac arrhythmias. histamine, 5-hydroxytryptamine (serotonin). Certain stimulant actions of However, the vasodilatation produced by catecholamines on various smooth muscles phenoxybenzamine is because of alpha are blocked by alpha blockers such as blockage. Adverse reactions are miosis, uterine contraction of certain species, dryness of mouth, inhibition of ejaculation, contraction of vas deferens and retractor palpitation, nasal stuffiness and in higher penis, stimulation of seminal vesicles and doses, postural hypotension and reflex vas deferens. Alpha blockers can inhibit bradycardia. ejaculation and produce impotence. Salivary secretion and sweat formation induced by It is used in the management of catecholamines is blocked by alpha blockers. pheochromocytoma and also to treat Alpha blockers also produce certain peripheral vasospastic conditions e.g. metabolic effects such as inhibitory action Raynaud’s disease and shock syndrome. of adrenaline on insulin secretion is blocked Phentolamine, another is and adrenaline induced rise in blood exclusively used for the diagnosis of potassium level is also blocked. pheochromocytoma and for the prevention Miosis and nasal stuffiness can occur of abrupt rise in blood pressure during with alpha blockers by acting on radial surgical removal of adrenal medulla tumors. muscles of iris and nasal blood vessels. Diarrhoea may occur due to increase in ERGOT ALKALOIDS intestinal motility. Ergot is a parasitic fungus (Claviceps The common adverse effects with alpha purpurea). It contains different alkaloids of blockers are palpitation, nasal stuffiness, complex chemical structure. The amino acid postural hypotension, retention of fluid, ergot alkaloids are ergotamine, , diarrhoea, inhibition of ejaculation and , , and their impotence. dehydrogenated derivatives can block the Sympatholytics (Antiadrenergic Agents) 147

alpha receptors. Ergotamine is an important subtype of 5-HT1 receptor at very high alkaloid that possesses both vasoconstrictor concentration. and alpha-receptor blocking activity. Both Oral bioavailability is only 15% but af- ergotamine and dihydroergotamine are used ter SC injection absorption is rapid and com- in the treatment of migraine. plete. It is metabolized by MAO-A isoen- zyme and metabolites are excreted in urine. MIGRAINE Adverse effects include tightness in head and chest, paresthesia in limb, dizziness, rise Migraine is a severe episodic throbbing or in BP and bradycardia. Rarely seizures and dull pain in head, may be lateralized or hypersensitivity reactions occur. generalised associated with anorexia, nausea, vomiting, photophobia and blur- Dose: SUMINAT; 25-100 mg/day, 6 mg SC. ring of vision. The pain of migraine and Drugs useful in prophylaxis of migraine vascular are associated with va- are β-adrenergic blockers (usually sodilatation, edema and visible pulsations propranolol), , calcium of the extracranial blood vessels. The 5-HT channel blockers. plays a pivotal role in pathophysiology of migraine. OTHER ααα-INHIBITORS

DRUG THERAPY OF MIGRAINE PRAZOSIN a. Simple analgesics (aspirin or It is an piperazinyl quinazoline effective in paracetamol), NSAIDs and antiemetics are the management of hypertension. It is highly useful in mild attacks of migraine. α selective for 1 receptors. It also reduces the b. Moderate and severe attacks of venous return and cardiac output. It is used migraine besides NSAIDs need specific in essential hypertension, benign prostatic drugs like ergot alkaloids, and hypertrophy and in Raynaud’s syndrome. methysergide along with antiemetics. Prazosin lowers blood pressure in human beings by relaxing both veins and resistance METHYSERGIDE vessels but it dilates arterioles more than It is a 5-hydroxytryptamine antagonist veins.

(5HT2A/). It is effective in preventing an It has variable absorption from GIT and attack of migraine. Adverse effects include has about 50% hepatic first pass metabolism. nausea, abdominal pain, diarrhoea and ner- It is highly bound to plasma proteins. vousness. Adverse effects include orthostatic hypotension, dizziness, headache, drowsiness, SUMATRIPTAN weakness, palpitation and impotence.

It is a potent selective 5-HT1D receptor agonist used in the treatment of migraine. TERAZOSIN

The 5HT1D receptor is found dominantly in It is similar to prazosin but has higher cranial blood vessel. It activates other bioavailability and longer plasma t½. 148 Section 3/ Drugs Acting on ANS

α α It is another 1-selective blocker used in 2. Hypertension: The selective 1 blockers hypertension and benign prostatic such as prazosin, terazosin, doxazosin hypertrophy. etc. are used in the management of essential hypertension. DOXAZOSIN 3. Congestive heart failure: The selective α α It is another potent and selective 1- 1 blocker affords symptomatic relief adrenoceptor antagonist and quinazoline in congestive heart failure in short derivative. It’s antihypertensive effect is term. produced by a reduction in smooth muscle 4. Peripheral vascular disease: In tone of peripheral vascular beds. Raynaud’s phenomenon, the drugs like Doxazosin is well absorbed after oral prazosin, phenoxybenzamine produce administration and approximately two third a symptomatic relief. of the dose is bioavailable. 5. Alpha blockers can be used in secondary shock due to any blood/ TAMSULOSIN fluid loss accompanied by reflex α vasoconstriction. It is uroselective 1A blocker and has been found effective in improving BPH 6. Benign prostate hypertrophy: Alpha symptoms. receptor blockers increase urinary flow rate and causing more complete Adverse effects include dizziness and emptying of urinary bladder in benign retrograde ejaculation. prostate hypertrophy patients. YOHIMBINE 7. Migraine: Ergotamine is used in the treatment of migraine. It is an alkaloid obtained from an African plant Yohimbehe. Chemically it is 8. Erectile dysfunction: Injection of papav- erine with or without phentolamine in an indolealkylamine related to reserpine. the corpus cavernosum has been found It has selective α blocking property with 2 to be effective in erectile dysfunction of short duration of action and also blocks 5- penis. hydroxytryptamine receptors. It produces increase in heart rate and blood pressure Other drugs used for erectile dysfunction due to increase in noradrenaline release. Sildenafil: It is orally active selective in- It does not have any role in clinical hibitor of phosphodiesterase type 5 useful in practice. treatment of erectile dysfunction. It results in reduced breakdown of cyclic guanosine Therapeutic Uses of Alpha Blockers monophosphate (cGMP) which is responsible 1. Diagnosis and treatment of for nitric acid (NO) mediated vasodilatation pheochromocytoma: Phenoxybenzamine in corpora cavernosa. Thus inducing an erec- is used in the treatment of inoperable tile response to sexual stimulation. It has no pheochromocytoma. Phentolamine direct relaxant effect on smooth muscle of test is used for the diagnosis of corpus cavernosa and has no effect in absence pheochromocytoma. of sexual stimulation. Sympatholytics (Antiadrenergic Agents) 149

It is rapidly absorbed after oral recently introduced for erectile dysfunction administration with 40% bioavailability. It with proven efficacy and safety, given is metabolised in liver by sublingually and acts within 20 minutes in to a less active metabolite which is a dose of 2-3 mg. predominantly excreted in faeces (80%) and in urine (13%). BETA ADRENERGIC BLOCKERS It is useful in erectile dysfunction of any These are the agents which block the action etiology. of sympathetic nerve stimulation and Adverse effects include headache, circulating sympathomimetic amines on the flushing, dyspepsia, nasal congestion, beta adrenergic receptors. At the cellular abnormal vision (mild and transient), level, they inhibit the activity of the diarrhoea, dizziness, angina pectoris, AV membrane cAMP. The main effect is to block, palpitation, postural hypotension, β reduce cardiac activity by diminishing 1 priapism etc. receptor stimulation in the heart. This Dose: VIAGRA; 25-100 mg/day. decreases the rate and force of myocardial The newer drug of same category are contraction of the heart, and decreases the alprostadil, vardenafil and tadalafil which rate of conduction of impulses through the are recently introduced for erectile conduction system. They are classified as in dysfunction in man. Apomorphine is table 3.3.2.

Table 3.3.2: Classification for beta adrenergic blocking agents. βββ βββ A. Non-selective ( 1+ 2) Propranolol (CIPLAR) 10-80 mg TDS, 2-8 mg IV (SOTAGARD) 80-480 mg/day 40-240 mg OD (TIMOPRESS) 5-20 mg BD, 0.25-0.5% topical (eye) 200-800 mg/day (VISKEN) 10-30 mg/day With additional alpha blocking activity Labetalol (LOBATE) 100-200 mg TDS, 50 mg IV (CARDIVAS) 12.5-50 mg BD βββ B. 1 Selective (cardioselective) (BETALOC) 100-450 mg/day Atenolol (BETACARD) 50-100 mg/day (CONCOR) 5 mg OD-BD (CELIPRESS) 100-200 mg/day βββ C. 2 Selective Butoxamine 150 Section 3/ Drugs Acting on ANS

PROPRANOLOL Therapeutic Uses Propranolol is an optically active 1. Hypertension: Propranolol is antihy- compound. The β-adrenergic receptor pertensive. Propranolol suppresses the β blocking activity resides entirely in the L- activation of heart by blocking the 1 isomer, although the D-isomer has equivalent receptor. They reduce the work of heart membrane stabilising activity. L-propranolol by decreasing the cardiac output and β β causing a slight decrease in blood is a competitive antagonist at both 1 and 2 receptor. It is not cardioselective although it pressure. β 2. Glaucoma: Timolol and other ocular β- has slightly greater activity at the 1 than at β blockers are used to treat glaucoma. 2 receptor. It has no agonist activity but has membrane stabilizing activity at Propranolol is effective in diminishing concentration exceeding 1 to 3 mg, though intraocular pressure in glaucoma. This such concentrations are rarely achieved occurs by decreasing the secretion of during oral therapy. aqueous humor by ciliary epithelium. It neither affects the ability of eye to If adrenaline is administered to an focus for near vision, nor changes pupil animal which has been pretreated with size. Used in chronic cases only. propranolol the pressor action is potentiated 3. Migraine: Effective in reducing because the α-adrenergic vasoconstriction is migraine episodes due to blockade of not affected but the β vasodilator action is 2 catecholamine induced vasodilatation blocked. in the brain vasculature. Propranolol Pharmacokinetics decreases the incidence and severity of the attack. Propranolol is well absorbed after oral 4. Hyperthyroidism: Propranolol blocks administration. Peak concentration occurs the peripheral conversion of thyroxine after 1-3 hrs after administration. to triiodothyronine. It controls Propranolol undergoes extensive hepatic palpitation, nervousness, tremor & first pass metabolism. The proportion of sweating etc. drug, reaching the systemic circulation 5. Angina pectoris: Propranolol decreases increases as the dose is increased when the O2 requirement and work of heart hepatic circulation may become saturated. muscle and therefore is effective in It is rapidly distributed because it is lipid reducing the chest pain on exertion soluble. It can readily cross blood brain which occurs in angina. barrier (BBB). 6. Myocardial infarction: It blocks the It is highly bound to plasma protein action of circulating catecholamines (90% to 95%). The major binding protein is which would increase the oxygen α 1-acid glycoprotein. Plasma half life is 3 to demand in already ischemic heart 6 hrs, and excreted through urine (95%) muscle thereby limiting the infarct size. breast milk & 5% in faeces as glucuronide 7. Anxiety: Exerts an antianxiety effect metabolites. during nervousness and panic attacks. Sympatholytics (Antiadrenergic Agents) 151

8. Cardiac arrhythmias: It is life saving 10. Metabolic acidosis. in protecting against serious cardiac 11. Cold hand & feet. arrhythmias. It suppresses tachycardia. 12. Severe haemorrhage. 9. Pheochromocytoma: Propranolol is 13. Tiredness & reduced exercise capacity. used. 14. Can precipitate CHF by blocking 10. Hypertrophic obstructive cardiomy- sympathetic support to the heart. opathy: Propranolol inhibits the inotro- pic effect of sympathetic stimulation OTHER BETA BLOCKERS and may reduce intraventricular pres- sure gradient. SOTALOL β β β 11. Essential tremor: Non selective It is nonselective ( 1+ 2) blocking agent blockers are useful. with lower lipid solubility with additional blocking activity. Adverse Reactions & Contraindications 1. II or III degree heart block: Cardiac NADOLOL arrest may occur. It is another nonselective 2. Bronchial asthma: An immediate with longer duration of action and mainly contraction of bronchiolar smooth used in hypertension. It is excreted largely muscle prevents air from entering the in urine and does not cross blood-brain lungs. Bronchospasm may occur in barrier and has no central side effects. patient with obstructive pulmonary TIMOLOL diseases. It is nonselective agent with no local 3. Bradycardia: If it taken, resting heart anaesthetic activity and having excellent rate reduces to 60/min or less. ocular hypotensive effect preferred for 4. In digitalis and verapamil therapy: ophthalmic use. It is useful in chronic wide- Severe bradycardia may occur. Both angle and aphakic glaucoma. verapamil and propranolol are and are other agents used as negative inotropic agents. ophthalmic preparation used in glaucoma. 5. Cardiac failure: Beta blockers depress PINDOLOL myocardial contractility and may precipitate cardiac failure & bradycardia. It is a nonselective beta blocker with 6. Cardiogenic shock. marked intrinsic sympathomimetic activity. It has advantage over propranolol that it 7. Carbohydrate tolerance may be produces less bradycardia and rebound impaired in prediabetics. hypertension. resembles 8. Hypoglycemia. propranolol and is short acting with mild 9. Rebound hypertension & angina can intrinsic sympathomimetic activity. occur on abrupt withdrawal of Alprenolol is similar to pindolol and propranolol. oxprenolol. 152 Section 3/ Drugs Acting on ANS

of carvedilol or its active metabolites is BETA BLOCKERS WITH ADDITIONAL ALPHA unlikely in patients with renal impairment. BLOCKING ACTIVITY Carvedilol is indicated for the management LABETALOL of essential hypertension. It can be used alone or in combination with other anti-hypertensive It is a adrenergic antagonist which can agents. It is effective also in CHF. block both alpha and beta receptors. It is Carvedilol may be used in patients unable non-selective (β +β ) and selective (α ) 1 2 1 to tolerate an ACE inhibitor. Carvedilol may receptor blocker. Labetalol is five times more be used in patients who are not receiving potent in blocking beta than alpha receptors. digitalis, hydralazine and nitrate therapy. Both alpha and beta blocking actions of labetalol contribute to a decrease in blood Adverse effects include symptomatic pos- pressure in hypertensive patients. It is tural hypotension, dizziness, headache, fa- effective in mild to moderate hypertension, tigue, gastrointestinal upset and bradycardia. pheochromocytoma and clonidine with- CARDIOSELECTIVE/βββ BLOCKERS drawal hypertension. The most serious side 1 effect is postural hypotension because of alpha blocking activity. Other side effects METOPROLOL include sexual dysfunction, failure of It is cardioselective beta blocking agent ejaculation, depression etc. and is devoid of intrinsic sympathomimetic activity. It reduces plasma renin activity in CARVEDILOL hypertensive patients. Metoprolol may be βββ βββ ααα preferred to a nonselective agent in It is beta ( 1+ 2) and alpha ( 1) blocking agent with additional property. asthmatics and patients prone to develop It is mainly used in hypertension and in CHF hypoglycemia. Its antianginal action is as cardioprotective agent. comparable to that of propranolol. It is metabolised by hydroxylation and excreted. Carvedilol significantly reduces systemic blood pressure, pulmonary artery ATENOLOL pressure, right atrial pressure, systemic It is cardioselective beta blocking agent vascular resistance, and heart rate, while 1 with low lipid solubility, generally stroke volume index is increased. administered once daily because of its longer Carvedilol is a dualaction cardiovascular duration of action. Most commonly used in agent with non selective beta blocking, α 1 hypertension and angina pectoris. antagonistic vasodilating properties and is devoid of intrinsic sympathomimetic activity. BISOPROLOL

Carvedilol is well absorbed after oral Another cardioselective beta1 blocking administration with peak serum levels agent devoid of intrinsic sympathomimetic occurring after one hour. Excretion is activity given once daily in the treatment of primarily in bile and significant accumulation hypertension and angina pectoris. Sympatholytics (Antiadrenergic Agents) 153

CELIPROLOL βββ ELECTIVE LOCKERS 2 S B

It is beta1 selective blocker with a modest capacity to activate beta2 receptors BUTOXAMINE also. It is used in treating hypertension and It is selective beta2 blocker, but does not angina pectoris. have any efficacious role in clinical practice.

NEBIVOLOL THERAPEUTIC USES OF BETA β BLOCKERS is a new selective 1- adrenergic blocking agent that possesses a 1. Hypertension. unique pharmacodynamic profile, by which 2. Ischemic heart disease, angina pectoris. it differs from traditional β -blockers. 1 3. Cardiac arrhythmias. Nebivolol is quite safe and is well 4. Hypertrophic cardiomyopathy. tolerated. The most common adverse effects 5. Congestive heart failure. are dizziness, headache and fatigue. Owing 6. Myocardial infarction. to its combined dual mechanism of action, 7. Pheochromocytoma. nebivolol leads to a unique haemodynamic and therapeutic profile by which it may be 8. Hyperthyroidism. advantageous in essential hypertension, 9. Neurologic diseases: Migraine, anxiety, ischemic heart disease and congestive heart essential tremor. failure. 10. Glaucoma.

 This page intentionally left blank ChapterChapter Parasympathomimetics 3.41. 4 (Cholinergic Agents)

These are the drugs which stimulate the inhibitors together comprise a large group parasympathetic system and mimic the of drugs that initiate the action of action of acetylcholine. The acetylcholine acetylcholine. They belong to the various receptor stimulants and cholinesterase groups (Table 3.4.1).

Table 3.4.1: Classification of cholinergic agents. I. Choline esters Acetylcholine Methacholine (Acetyl-β-methylcholine) 5-10 mg SC Carbachol (Carbamocholine) 1-4 mg oral, 0.25-0.5 mg SC and 0.75-3.0% topical (eye). Bethanechol (Carbamoyl-β-methylcholine; UROCONTIN) 10-40 mg oral, 2.5-5.0 mg SC II. Naturally occurring alkaloids Pilocarpine (PILOCAR) 1, 2, 4% topical (eye) III. Anticholinesterases (Cholinesterase inhibitors) i. Reversible Physostigmine (BIO-MIOTIC) 0.5-1 mg oral/IM, 0.1-1.0% topical (eye) Neostigmine (PROSTIGMIN) 15-30 mg TDS oral, 0.5-5.0 mg IM/SC, 3-5% topical (eye) (MYESTIN) 60-180 mg oral, 1-5 mg IM/SC 1-10 mg IV 5 mg oral, 0.5 mg IM Rivastigmine, Donepezil, Tacrine etc. (used in Alzheimer’s disease). ii. Irreversible Diisopropyl fluorophosphate (DFP; DYFLOS) 0.025% topical (eye) (HETP) Certain insecticides such as and . 156 Section 3/ Drugs Acting on ANS

ACETYLCHOLINE muscarinic action of acetylcholine are Acetylcholine (ACh) is an ester of stimulated by muscarine and are blocked by choline and acetic acid available in powder atropine. Second, by its nicotinic action on form as chloride or bromide salt. It is autonomic ganglia, motor end plates of extremely hygroscopic and rapidly skeletal muscles and adrenal medulla etc. undergoes hydrolysis in a neutral or alkaline The action of acetylcholine on autonomic medium. ganglia can be blocked by ganglion blocking agents such as hexamethonium and action It is synthesized within the cholinergic on myoneural junction can be antagonised neurons by the transfer of an acetyl group by d-tubocurarine. from acetyl coenzyme A to the organic base choline. The specific enzyme ‘choline Muscarinic Actions acetylase’ is essential for this reaction. Coenzyme A is widely distributed in the Cardiovascular system: Acetylcholine body and choline acetylase is synthesized decreases the contractility (negative in the cell bodies of the cholinergic neurons. inotropy) and decreases the conduction velocity (negative dromotropy) of the atria. ACh is produced throughout the It depresses the sinoauricular node, neurone and is stored in synaptic vesicles decreases the heart rate (negative at the nerve endings. chronotropy) and may cause cardiac arrest. There are two types of esterases found in In isolated heart preparation, animal tissues. True cholinesterase which is acetylcholine reduces the cardiac rate and found in neural structures, RBC and placenta in the presence of atropine, it can stimulate and is concerned with destruction of the heart causing ventricular arrhythmias. acetylcholine released at the nerve endings. The second type is ‘pseudocholinesterase’ Acetylcholine dilates all blood vessels (non-specific cholinesterase) is found in causing flushing and fall in blood pressure. The blood serum, intestines, liver and skin and is vasodilatation is mediated through the release responsible for the hydrolysis of of endothelium dependent relaxing factor benzoylcholine and does not hydrolyse (EDRF). The fall in blood pressure is because methacholine. Cholinesterase hydrolyses of decrease in total peripheral resistance and acetylcholine into choline and acetic acid. cardiac output in anaesthetized animals. Effect on smooth muscles: Acetylcholine Pharmacological Actions causes increase in tone, amplitude of Stimulation of the parasympathetic contractions, peristalsis and secretory activity nervous system modifies the organ functions of the gastrointestinal tract. It causes by two main pathways. Firstly, the contraction of smooth muscles of gall bladder acetylcholine released from parasympathetic and relaxation of sphincters of gastrointestinal nerves can activate muscarinic receptors and biliary tract. which are present in gland cells (sweat It also causes contraction of detrusor glands), smooth muscles and heart. The resulting in decrease in the capacity of the Parasympathomimetics (Cholinergic Agents) 157 bladder and increase in the frequency of CHOLINOMIMETIC DRUGS ureteral peristaltic waves. Acetylcholine causes bronchoconstriction METHACHOLINE and increase in bronchial secretion and can It is effective orally and resistant to precipitate the bronchial asthma. pseudo-cholinesterase and possesses longer Effect on secretions: Acetylcholine duration of action. Its nicotinic action is less increases the salivary, sweat, lacrimal, than acetylcholine and actions are more nasopharyngeal, gastric and bronchial marked on CVS as compared to GIT and secretions. All these secretory effects urinary system. Earlier it was used for CVS are blocked by atropine and enhanced disorders such as peripheral vascular by cholinesterase inhibitors e.g. phys- disease and paroxysmal supraventricular ostigmine. tachycardia. But now, it is rarely used in Effect on eye: After intraconjunctival therapeutics. instillation, acetylcholine causes miosis, due to contraction of circular muscles of the iris CARBACHOL and fall in intraocular tension. It is resistant to both true and pseudo- cholinesterase and is more potent than Nicotinic Actions methacholine and action is more prolonged. Effect on autonomic ganglia: It can It is used topically for ophthalmic purpose. cause stimulation of sympathetic and parasympathetic ganglia and stimulation of BETHANECHOL adrenal medulla, which leads to rise in It is resistant to hydrolysis by both true arterial blood pressure due to peripheral and pseudocholinesterase and has mainly vasoconstriction. muscarinic actions. It has been used in Effect on myoneural junction: postoperative and postpartum non- Acetylcholine cause stimulation of skeletal obstructive urinary retention and muscles and in larger concentration at the gastroesophageal reflux. myoneural junction can produce paralysis of skeletal muscles. PILOCARPINE Effect on CNS: Acetylcholine when It is a natural alkaloid obtained from leaves injected parenterally does not cross blood of Pilocarpus microphyllus and Pilocarpus brain barrier being a quarternary jaborandi. Pilocarpine is direct acting ammonium compound and does not have muscarinic agonist. It acts on M3 receptor. It any central action. produces contraction of iris to produce miosis. It also stimulates ciliary muscle resulting in Therapeutic Uses increased accommodation and improved Because of nonselective actions, outflow of aqueous humor. As a result of acetylcholine can not be used for any miosis the pressure on canal of Schlemm is therapeutic purpose. reduced and hence improves drainage and 158 Section 3/ Drugs Acting on ANS thus reduces intraocular pressure. Thus it is retinal detachment has occurred. useful in treatment of glaucoma. 4. Symptomatic adverse effects: Topical Pilocarpine when given IV increases the pilocarpine therapy produces blurred flow from salivary gland and other exocrine vision or myopia, poor vision in dim glands. Bronchial smooth muscle and light or sometime painful spasm. Many intestinal smooth muscle contract. Small patients on pilocarpine may experience ciliary or conjunctival congestion, doses generally cause fall in BP, but higher headache, photophobia. Some patient doses elicit rise in BP and tachycardia (which may develop pupillary dilatation is due to ganglionic stimulation). following use of pilocarpine. Therapeutic Uses (2% eye drop) is recently a. Open angle glaucoma. introduced newer compound, producing dose b. Angle closure glaucoma. dependent mydriasis endowed with very interesting characteristics: rapid onset, marked c. Ocular surgery. pupil dilatation and rapid return to normal d. To counteract mydriasis. pupillary diameter. This rapid return to normal e. Diagnosis of Adie’s tonic pupil. pupillary diameter after its diagnostic f. Accommodative esotropia. application in eye offers significant advantages Adverse Reactions compared to other currently available mydriatics. Ibopamine is well absorbed 1. Potentially life threatening effects: Some through the cornea, it is rapidly hydrolyzed by commercially available preparation of pilocarpine contain sodium bisulphite esterases to epinine and the mydriatic effect is which may cause allergic reactions correlated with the concentration of epinine in including anaphylaxis and severe the aqueous humor. asthmatic episode. It is approved for mydriasis in ocular 2. Acute overdosage: The clinical examination and surgery and for the early symptoms may include nausea, diagnosis of glaucoma. vomiting, diarrhoea, abdominal pain. In addition frequent urination, ARECOLINE excessive salivation, lacrimation, It is obtained from the betel nut ‘Areca sweating, bronchoconstriction, nasal catechu’ and has got muscarinic and weak congestion. Severe pilocarpine toxicity nicotinic actions. It has no therapeutic value may produce tremors, muscle except for chewing to promote salivary weakness, bradycardia, cardiac secretion and in pan masala etc. arrhythmia, hypotension etc.

3. Severe or irreversible adverse effect: ANTICHOLINESTERASES Some patient with peripheral retinal degeneration may develop retinal These are the drugs which act by inhibiting detachment. A sudden drop of the enzymes true and pseudocholinesterase intraocular pressure indicates that and thereby produce an accumulation of Parasympathomimetics (Cholinergic Agents) 159 acetylcholine at the various cholinergic sites. is indigenous to tropical west . The released acetylcholine from the nerve The pharmacological actions of endings is quickly destroyed by the enzyme physostigmine are similar to those of cholinesterase. Anticholinesterase inhibit cholinergic drugs. Topical instillation into the this enzyme which results in accumulation eye produces miosis, spasm of accommo- of acetylcholine and continuous stimulation dation and decrease in intraocular pressure. of muscarinic and nicotinic receptors. Physostigmine is well absorbed after oral as As given in classification, these agents well as parenteral administration and also are of two type e.g. reversible and irrevers- produces central cholinergic actions because ible. The reversible anticholinesterases of penetration into blood brain barrier. have a structural resemblance to acetylcho- The main therapeutic use of line, are capable of combining with anionic physostigmine is as miotic to treat glaucoma and esteratic sites of cholinesterase as well and also to reverse the mydriatic effect of as with acetylcholine receptor. The complex atropine and its analogues used in refraction formed with the esteratic site of cholinest- of the eye. It is also used in the treatment of erase is less readily hydrolyzed than the atropine intoxication and poisoning with acetyl esteratic site complex formed with phenothiazines. It is also used in primary acetylcholine. Edrophonium forms revers- stages of Alzheimer’s disease. ible complex with the anionic site and has shorter duration of action. Also, neostigmine NEOSTIGMINE and edrophonium have a direct stimulating It is a synthetic quarternary ammonium action at cholinergic sites. compound, similar to physostigmine and Irreversible cholinesterases are mostly rapid onset of action and can inhibit both organophosphorus compounds and combine true and pseudocholinesterases. only with esteratic site of cholinesterase and It increases the tone and motility of the that site gets phosphorylated. The hydrolysis gut and enhances the gastric juice of phosphorylated site produces irreversible production and also promotes the inhibition of cholinesterase. And, because, of propulsion of intestinal contents. this property, the therapeutic usefulness is At the neuromuscular junction, it very limited. Most of the compounds are produces the contraction of skeletal muscle used as insecticides e.g. parathion, malathion by its direct action and by inactivation of and war gases e.g. , , etc. anticholinesterase and has got anticurare action. By virtue of its structural similarity REVERSIBLE ANTICHOLINESTERASE to acetylcholine, it acts as partial agonist on motor end plate. PHYSOSTIGMINE Neostigmine, by its peripheral It is a tertiary ammonium alkaloid vasodilatation action reduces the blood obtained from the Calabar bean, the dried pressure and heart rate. ripe seed of ‘Physostigma venenosum’, which On local ophthalmic administration, it 160 Section 3/ Drugs Acting on ANS produces miosis, spasm of accommodation activity as compared to neostigmine. It is and reduction in intraocular tension. mainly useful as diagnostic agent for myas- Neostigmine does not cross blood-brain thenia gravis and for postoperative barrier, hence has no significant central action. decurarization. Neostigmine is a drug of choice in the DISTIGMINE treatment of myasthenia gravis, a chronic It is a longer acting neostigmine disease characterized by muscular weakness and rapid fatiguability of the skeletal muscles analogue and is used to treat atony of the due to impaired neuromuscular transmission. bladder and intestine and its action lasts for The defect may be presynaptic or postsynaptic. 24 hours. It is given daily before breakfast. Apart from neostigmine, pyridostigmine IRREVERSIBLE ANTICHOLINESTERASES and ambenonium are the other standard drugs used in the treatment of myasthenia gravis. The organophosphorus cholinesterase Neostigmine preceded by atropine to inhibitors like diisopropyl fluorophosphate, block muscarinic effects rapidly reverses phospholine, parathion, malathion etc. are muscle paralysis induced by competitive highly toxic compound and cause neuromuscular blockers (decurarization). irreversible inhibition of both true and Neostigmine is also useful in pseudocholinesterases. They are highly lipid postoperative paralytic ileus/urinary soluble compound and can easily cross the retention. blood-brain barrier.

PYRIDOSTIGMINE DIISOPROPYL FLUOROPHOSPHATE (DFP) It structurally and pharmacologically resembles neostigmine but has longer The pharmacological effects are those of duration of action and less potent than acetylcholine. It produces prolonged neostigmine and better tolerated by inhibition of true and pseudocholinesterases. myasthenia gravis patients. They are inactivated in the body completely by oxidation and hydrolysis and excreted in EDROPHONIUM urine. It is a quarternary ammonium anticho- The are mainly used for the treatment linesterase and structurally related to neostig- of glaucoma, especially when other miotic mine but has got weak anticholinesterase agents fail.

 Parasympatholytics (Anticholinergic Agents) 161

ChapterChapter PharmacodynamicsPharmacodynamicsParasympatholytics 3.51. 4 (Anticholinergic(Mode of Action ofAgents) Drugs)

Anticholinergic or cholinergic blocking ATROPINE agents are the agents which block the action The alkaloids namely atropine, of acetylcholine at the postganglionic and are obtained parasympathetic nerve endings. They are from Atropa belladonna. Atropine is dl- also termed as antimuscarinic or muscarinic hyoscyamine, and, l-isomer is more potent blockers and atropine is the classical than d-form both peripherally and centrally. antagonist which blocks the effect of Atropine blocks the muscarinic effects of acetylcholine on muscarinic receptors. The acetylcholine, the antagonism between nicotinic antagonists also block certain acetylcholine and atropine is of competitive actions of acetylcholine and are termed as type. ganglion blocking agents. Pharmacological Actions The anticholinergics can be classified as in table 3.5.1. Pharmacological actions of atropine are due to equal blockade of M1, M2 and M3 The cholinergic blocking agents which muscarinic receptors. mainly include atropine and related al- Effect on cardiovascular system: kaloid are obtained from the plant Atropa Atropine initially decrease the heart rate due belladonna (deadly nightshade), Atropa to stimulation of vagal centre followed by acuminata, Hyoscyamus niger (black hen- tachycardia due to peripheral vagal block bane) and Datura stramonium (datura) and on SA node. It also shortens effective semisynthetic atropine/hyoscine ana- refractory period of AV node and facilitates logues and synthetic compounds. AV conduction. In therapeutic doses, The two important alkaloids of atropine completely blocks the peripheral belladonna are atropine and hyoscine vasodilatation and decrease in blood (scopolamine). pressure produced by cholinergic agents. 162 Section 3/ Drugs Acting on ANS

Table 3.5.1: Classification of anticholinergic agents. I. Natural alkaloids Atropine (used as sulphate; ATRO) 0.5-2 mg IM/IV, 1-2% topical (eye) Hyoscine (Scopolamine; BELLADENAL) 0.3-0.5 mg oral/IM II. Semisynthetic compounds Homatropine (HOMARIN FORTE) 1-3% topical (eye) Atropine methonitrate (SPASMOLYSIN) 2.5-10 mg oral/IM as inhalant (BROVON INHALANT) 0.1-0.2% inhalation Hyoscine methylbromide 2.5 mg oral/IM Ipratropium bromide (IPRAVENT) 40-80 µg inhalation III. Synthetic compounds i. Used as mydriatics Cyclopentolate (CYCLATE) 0.5-2% topical (eye) Tropicamide (ITROP PLUS) 0.5-1% topical (eye) ii. Used as antisecretory-antispasmodics Glycopyrrolate (GLYCO) 1-2 mg oral, 0.1-0.3 mg IM Pipenzolate methylbromide (PIPTAL) 5-10 mg/day (STELABID) 5 mg/day methylbromide 30-60 mg/day Dicyclomine (CATASPA) 10-20 mg/day TDS Pirenzepine 100-150 mg/day Flavoxate (URIPAS) 100-200 mg/day TDS-QID (COLOSPA) 135 mg TDS-QID before meals (DOVERIN) 40-80 mg TDS Valethamate (VALOSIN) 10-20 mg BD-TDS iii. Used as antiparkinsonian agents Trihexyphenidyl (PACITANE) 2 mg OD-QID Procyclidine (KEMADRIN) 2.5-5 mg TDS Biperiden (DYSKINON) 2-10 mg oral/IM/IV Benztropine (COGENTIN) 1-2 mg oral/IM OD-TDS Cycrimine (PAGITANE) 2.5-5 mg OD-TDS

In higher doses, atropine produces dilatation by blocking relative cholinergic overactivity of the cutaneous blood vessels which may in basal ganglia. Scopolamine also stimulates be due to paralysis of vasomotor centre. the respiratory and vagal centres. Toxic doses Effect on central nervous system: In of atropine may lead to CNS excitatory ef- therapeutic doses, atropine causes stimula- fects e.g. restlessness, anxiety, insomnia, de- tion of medullary vagal nuclei and higher lusions and hallucinations etc. It also cause cerebral centres and may produce bradycar- medullary paralysis (respiratory paralysis) in dia and increase in rate & depth of respira- still higher dose. tion. By depressing vestibular excitation, it Both atropine and scopolamine induce has antimotion sickness property. It also de- sleep like pattern of EEG, it also cause rise in creases tremors and rigidity in parkinsonism body temperature due to its action on Parasympatholytics (Anticholinergic Agents) 163 temperature regulating centre in hypothalamus clearly only at a long distance and can not and also inhibits sweating. constrict the pupil for viewing the near Effect on gastrointestinal system: objects clearly). Atropine induced mydriasis Atropine decreases the tone and motility of can be distinguished from the mydriasis all parts of gastrointestinal tract. It also produced by sympathomimetic amines as decreases the amplitude of contraction and the latter do not produce cycloplegia. frequency of peristaltic wave of stomach and Pharmacokinetics intestines. Atropine also exerts a weak antispasmodic action on biliary tract and All the belladonna alkaloids are well gall bladder. absorbed from the GIT, from the site of injection and the mucous membrane. They Effect on other smooth muscles: are distributed throughout the body and Atropine relaxes the smooth muscles of cross the blood-brain barrier. About 50% of bronchi and bronchioles which results in the atropine is metabolized in liver and widening of the airways. It is effective in remaining portion is excreted unchanged in relieving bronchospasm produced by urine. Atropine cross the placental barrier cholinergic agents. and is secreted in milk and saliva. Atropine also produces reduction in normal and drug induced ureteral Adverse Reactions peristalsis. It also tends to reduce the tone The adverse reactions are due to the of the fundus of urinary bladder and peripheral muscarinic blockade and cen- enhances the tone of trigonal sphincter and tral actions. The general side effects may cause of retention of urine. include dry mouth, difficulty is swallow- Effect on secretions: Atropine reduces ing, thirst, dry skin, skin rash, flushed skin the various body secretions e.g. sweat, etc. It also produces constipation, urinary salivary, bronchial and lacrimal etc. It also retention, impotence, difficulty in mictu- reduces the volume and total acidity of rition, tachycardia, palpitation, postural gastric secretion and, reduce the secretion hypotension, dilatation of pupil, photo- of and enzymes in the gastric phobia, blurred vision, dizziness, fatigue, secretions induced by cholinergic drugs. anxiety and tremors etc. It has no significant effect on intestinal Toxic doses can gives rise to acute bella- and pancreatic secretions. donna poisoning which is characterized by Effect on eye: Atropine produces depression of vasomotor centre, vasomotor mydriasis by blocking the cholinergic nerves collapse, coma and depression of respiratory supplying the smooth muscles of sphincter centre. of the iris on local administration into the Acute belladonna poisoning can be treated eye. It also produces paralysis of by administering universal antidote before accommodation or cycloplegia (the gastric lavage, physostigmine in the dose of condition in which, one can see things 1-4 mg SC can be administered after a interval 164 Section 3/ Drugs Acting on ANS of one to two hours until a satisfactory heart block in some patients of response is obtained. For urinary retention myocardial infarction. catheterization can be done and patients is 6. As mydriatic and cycloplegic kept in dark room to alleviate photophobia. agent: Atropine is used to produce mydriasis and cycloplegia for test- Therapeutic Uses ing errors of refraction. Mydriasis is 1. Gastrointestinal colic (as antispas- required for fundoscopic examina- modic): Belladonna alkaloids relax the tion and in the treatment of iritis spasm of smooth muscles of intestinal, and keratitis. urinary and biliary tract. They are also effective in functional and drug ANTIMUSCARINICS (SEMISYNTHETIC AND induced diarrhoea, to relieve urinary urgency and frequency and enuresis in SYNTHETIC) children. They are also used to reduce gastric secretion in peptic ulcer HOMATROPINE patients. Also, used to reduce the More potent than atropine. Used in excessive sweating in tuberculosis and eye and onset of mydriasis and sweating and salivation in parkinso- cycloplegia is similar to that of atropine nian patients. but homatropine is not much used for 2. CNS disorders: Scopolamine and producing cycloplegia. hyoscine are effectively used in the treatment of nausea, vomiting and motion CYCLOPENTOLATE sickness. Centrally acting anticholinergic/ It is more potent and rapidly acting as antihistaminics e.g. trihexyphenidyl are compared to homatropine for producing used in parkinsonism. mydriasis and cycloplegia especially in 3. Pre-anaesthetic medication: These children. It is also used in iritis. agents reduce the salivary and respi- ratory secretion and are administered TROPICAMIDE half an hour before general anaesthe- sia. They also prevent laryngospasm. It is used for refraction testing in adults Atropine is given in combination with and as mydriating agent for fundoscopy. It morphine as a preanaesthetic medi- has quickest and briefest action. cation to antagonize the central depressant action of morphine on ATROPINE METHONITRATE respiration. It is used for abdominal colic and in 4. In organophosphorus poisoning: aerosol form it is used in bronchial asthma. Atropine is used in mushroom poisoning due to muscarine. IPRATROPIUM BROMIDE 5. On CVS: Atropine is used for It is a valuable drug used in the treatment counteracting bradycardia and partial of chronic obstructive pulmonary disease Parasympatholytics (Anticholinergic Agents) 165

(COPD) by inhalation route. Titropium bro- MEBEVERINE mide is congener of ipratropium bromide It shows effect on colonic muscle producing long lasting bronchodilatation. activity. It is indicated in smooth muscle spasm. DICYCLOMINE It has got antispasmodic with direct PIRENZEPINE smooth muscle relaxant action. It is used in Selective M1 muscarinic receptor morning and motion sickness. blocker. It inhibits gastric secretion. Thus is effective in peptic ulcer patients and GLYCOPYRROLATE promotes ulcer healing. It does not produce Rapidly acting antimuscarinic lacking atropinic side effect (due to blockade of M2 central effects. Used for preanaesthetic and M3 receptors). medication. Only 20-30% oral bioavailability and is ISOPROPAMIDE excreted unchanged in urine. Indicated in hyperacidity, dyspepsia, FLAVOXATE . It produces direct relaxant action on Propantheline, oxyphenonium, smooth muscle with analgesic and panthienate are useful in peptic ulcer and anaesthetic action and used in the treatment gastrointestinal hypermotility. of dysuria, nocturia and urinary urgency Pipenzolate and mephenzolate are and frequency associated with cystitis and useful in dyspepsia and infantile colics. urethritis.

 This page intentionally left blank Section 4 Drugs Acting on Cardiovascular & Urinary System This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsCardiotonics 1.44.1 (Cardiac(Mode ofGlycosides) Action of Drugs)

Congestive heart failure (CHF) is a clinical physician and botanist identified digitalis syndrome with multiple causes and involve and other ingredients, which was found the right or left ventricle or both and in CHF, useful in the treatment of dropsy. In 1911, cardiac output is usually below the normal Mackenzie and Cushney studied the effect range. This ventricular dysfunction may be of digitalis on heart and its use in congestive systolic, which leads to inadequate force heart failure. generation to eject blood normally and The important cardiac glycosides are diastolic, which leads to inadequate listed in table 4.1.1. relaxation to permit normal filling. Systolic dysfunction, with decreased cardiac output Pharmacological Actions and significantly reduced ejection fraction Effect on Heart is typical of acute heart failure, especially that resulting from myocardial infarction. Contractility: Digitalis increases the force of myocardial contraction without causing CARDIAC GLYCOSIDES corresponding increase in the oxygen consumption. This pharmacological action There are the drugs having cardiac inotropic forms the basis of its use in treatment of property. They increase myocardial CHF. In a patient of CHF, force of contractility and cardiac output in a contraction of the heart at a given fibre hypodynamic heart without increase in length is decreased, thus the stroke volume oxygen consumption and overall is decreased. As digitalis increases the force myocardial efficiency is increased. of contraction of the heart and subsequently, The cardiac glycosides are mainly it increases the cardiac output, increase in obtained from plants e.g. digitalis, circulating velocity, residual volume is stropanthus and squill species and also decreased, diastolic volume is decreased present in certain other plants and animals. and size of heart is decreased but these In 1776, William Withering, a Birmingham effects are noticed secondary to increase in 170 Section 4/ Drugs Acting on Cardiovascular & Urinary System

Table 4.1.1: Classification of cardiac glycosides. I Natural glycosides Digitoxin (DIGITALIN) 0.05-0.2 mg/day Digoxin (LANOXIN) 0.125-0.5 mg/day oral 0.25-1.0 mg slow IV Lanatoside-C (CEDILANID) 0.25-1.0 mg/day Stropanthin-K (STROPHOSID) 0.25-0.5 mg IV Stropanthin-G (OVABAIN) 0.25-0.5 mg IV Proscillaridin-A 0.3-1.0 ml (Tr. Scilla) Cavallotoxin Thevetin Bufotoxin II. Semisynthetic Acetyl digoxin (ACYLANID) 0.2-0.5 mg/day oral/IV Desacetyl lanatoside-C (DESLANOSIDE) 0.25-1 mg IV Acetyl stropanthidin (diagnostic use) 0.25 mg IV contractility and are not the primary effects sympathetic tone and thus reducing the of digitalis. heart rate. Cardiac output: Digitalis increases the Refractory period: It is a period after onset cardiac output in CHF patients by increasing of depolarization during which a stimulus can the force of myocardial contraction. It also not evoke a propagated action potential. In increases the contractility of normal heart atrium, refractory period is shortened by vagal but cardiac output remains unchanged or is action and increased by direct action. slightly decreased. In normal individuals, it SA node: Digitalis sensitizes the SA node increases the tone of arteries as well as that to normal vagal impulse resulting in of the veins. bradycardia. In a patient suffering from Heart rate: In CHF patients, the heart paroxysmal supraventricular tachycardia, it rate is decreased. Digitalis produce a decreases the heart rate due to vagal action on decrease in heart rate by stimulation of SA node which is associated with decrease in vagus. The ‘vagal effect’ is probably evoked the slope of slow diastolic depolarisation and by sensitization of carotid baroreceptors, increase in the transmembrane negativity and, and by direct stimulation of vagal centre. also lower the SA rate by antiadrenergic action. The vagal action can be blocked by atropine Automaticity: It is the ability to generate but after full digitalising dose the effect can propagated impulse. Digitalis increases the not be blocked by atropine and it is due to ability of the Purkinje cell and the its direct cardiac action. In CHF patients, ventricular muscle to initiate impulses. the sympathetic activity is increased as a Conductivity: Conduction through AV compensatory phenomenon which leads to node is depressed whereas conduction is tachycardia. Digitalis decreases the slightly increased in the auricle and ventricles. Cardiotonics (Cardiac Glycosides) 171

ECG changes: Digitalis, in therapeutic may probably explain reversal of toxic effects doses causes inversion of T wave, sagging of digitalis by potassium. Inhibition of the Na+ of S-T segment and shortening of Q-T K+-ATPase leads to increase in intracellular internal (shortening of systole). In toxic dose, sodium and decrease in potassium. it causes prolongation of P-R interval Calcium also forms a link between the (slowing of AV conduction), atrial electrical events in the membrane and arrhythmias (atrial tachycardia and atrial contractile proteins. Digitalis makes more fibrillation) with AV block and ventricular calcium available for excitation-contraction arrhythmias. coupling and increasing cardiac contractility. Extracardiac Actions Digitalis also exerts some indirect action on heart mainly by increase in vagal activity • Digitalis produces diuresis in CHF which ultimately influences activity of AV patients, it increases excretion of node, SA node and auricles. sodium and water by the kidney which may be due to decrease in the Pharmacokinetics venous pressure bringing about Among the cardiac glycosides, digitoxin is shifting of edema fluid into the absorbed rapidly and completely from the circulation and also improves the gastrointestinal tract with oral absorption of renal circulation. approximately 90 to 100 percent with plasma • Digitalis can produce nausea and protein binding of approx. 95 percent with vomiting which is probably due to the plasma half life of 5 to 7 days. It enters the liver chemoreceptor trigger zone (CTZ) cells where it is metabolised to epidigitoxigenin stimulation. and is excreted in bile and urine. • Digitalis has mild vasoconstrictor action increasing the peripheral resistance. But Adverse Effects in CHF patients peripheral resistance It includes anorexia, vomiting which decreases due to withdrawal of reflex may be of central origin. Headache, visual sympathetic overactivity. Venous tone disturbance, xanthopsia (yellow vision), improves in normal as well as CHF white vision, diplopia, drowsiness, patients. It has no significant effect on disorientation, delirium and psychotic coronary circulation. behaviour. Cardiac related effects include Mechanism of Action of Digitalis cardiac arrhythmias e.g. tachyarrhythmias, Digitalis acts by interfering with the ventricular arrhythmias, supraventricular sodium and potassium transport across the arrhythmia, AV block and bradycardia. cell membrane and by increasing the Treatment of Digitalis Induced amount of coupling calcium i.e. making Arrhythmias more calcium available for excitation- contraction coupling. Tachyarrhythmias Cardiac glycosides inhibit Na+ K+- K+ tends to antagonise digitalis induced ATPase by competing with potassium and enhanced automaticity and decreases bind- 172 Section 4/ Drugs Acting on Cardiovascular & Urinary System ing of the cardiac glycosides to Na+ K+-AT- and is equal to the amount eliminated Pase. Infuse KCl 20 mmol/hr intravenously during the day. or orally depending upon the case. Methods of Digitalization Supraventricular Arrhythmias 1. Intravenous digitalization is done in Can be treated by beta blockers e.g. emergency conditions of CHF or in atrial propranolol 10-40 mg every 6 hourly orally fibrillation. Digoxin 0.25 mg followed by or 0.5-1 mg IV. 0.1 mg hourly be given by slow IV route with close monitoring of cardiac function. Ventricular Arrhythmias 2. Oral digitalization: Digoxin 0.5-1.0 mg Lignocaine (1-2 mg/kg IV) is the drug stat and followed by 0.25 mg 6 hourly of choice. Phenytoin is also useful (250 mg with monitoring of toxicity. IV) and has the added advantage of • Digitoxin 1.2 mg is administered as countering the depression of AV conduction a single dose. This can be given in by digitalis. divided dose also, in 8 hours interval. AV Block and Bradycardia 3. Maintenance dose method: Administration Can be treated by atropine (0.6-1.2 mg IM). of a daily maintenance dose (0.5 mg) of digoxin will digitalise the patient within Therapeutic Uses a week. Digitalis is used therapeutically in the Atrial Fibrillation treatment of: Digitalis is the drug of choice in atrial Congestive Heart Failure fibrillation for controlling ventricular rate. Digitalis increases stroke volume and Its effect is due to the prolongation of the cardiac output. Digitalis by increasing the refractory period of the conducting tissue. cardiac output, brings about more complete The dose in so adjusted as to maintain the emptying of the ventricles during systole. ventricular rate of 60 to 80 beats per minute This reduces the pulmonary congestion and at rest and approximately 100 beats per edema and decrease in systemic venous minute during light exercise. pressure. The cardiac glycosides primarily correct systolic dysfunction. Atrial Flutter The dosing schedule is dependent on the The reversal to normal rhythm is desired speed of action and urgency. Like because digitalis converts flutter into other drugs having a longer duration of ac- fibrillation. Digitalis enhances the AV block tion the treatment is initiated with a load- and reduces the ventricular rate. ing dose which is followed by maintenance dose for achieving a rapid onset of action Paroxysmal Supraventricular and to avoid cumulative toxicity. Tachycardia The maintenance dose is the amount Its effects is due to vagomimetic activity, required to maintain the therapeutic effect generally one fourth total IV digitalizing Cardiotonics (Cardiac Glycosides) 173 dose in given. In this condition, drugs like Side effects include nausea, abdominal verapamil is more effective. pain, diarrhoea, fever, thrombocytopenia (tran- sient and dose related) and hepatotoxicity. Left Ventricular Failure Digitalis is used in chronic pure, left MILRINONE ventricular failure with hypertension and It is relatively selective inhibitor of ischemic heart disease. peak III cyclic AMP phosphodiesterase isoenzyme in cardiac and vascular OTHER POSITIVE INOTROPIC muscle. In patients with CHF, it produces DRUGS USED IN CHF dose related and plasma concentration related increase in the maximum rate of BIPYRIDINE COMPOUNDS increase of left ventricular pressure. Milrinone has a direct inotropic and AMRINONE direct arterial vasodilator activity. It is administrated by IV infusion 0.50 mg/kg It is a relatively selective inhibitor of cyclic over 10 min with a maximum daily dose GMP, cyclic AMP-PDE (phosphodiesterase) of 1.13 mg/kg. type III family. It causes vasodilatation with a consequent decrease in systemic vascular Side effects include ventricular resistance. It increases both the force of arrhythmias, sustained ventricular tachycar- contraction and velocity of relaxation of dia, angina, ventricular fibrillation, head- cardiac muscles. It is administered IV 0.75 ache and hypokalemia. mg/kg/min as a bolus dose followed by 5- Both the compounds are indicated in short 10 µg/kg/min IV infusion and total dose not term management of CHF in patents unre- to exceed 10 mg/kg. sponsive to digitalis, diuretics or vasodilators.

 This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsAntihypertensive 4.21. 4 (ModeAgents of Action of Drugs)

Hypertension is the most common cardiovas- mmHg with low diastolic blood pressure is cular disease and pathophysiologically hyper- termed as ‘isolated systolic hypertension’ tension can be classified into two main groups. commonly seen in elderly person. a. Essential or primary hypertension, The blood pressure is mainly con- where the cause for rise in blood trolled by two systems. Firstly through the pressure is not known. Responsible for baro-receptors and the adrenergic nervous majority of cases. system. The baroreceptor reflexes protect b. Secondary hypertension, where rise is the circulation against stresses which due to renal disease e.g. chronic diffuse shows the changes in the arterial blood glomerulonephritis, pyelonephritis; pressure. Secondly through renin angio- due to some vascular disease e.g. renal tensin system, which is involved in the artery disease or due to some pathogenesis of some forms of secondary endocrinal disorders e.g. pheochro- hypertension. Renin is a proteolytic en- mocytoma, Cushing’s syndrome and zyme released from the juxtaglomerular primary aldosteronism. cells of kidneys. The reaction between re- Systemic arterial blood pressure is de- nin and plasma protein, serum termined by cardiac output and total periph- (angiotensinogen) forms an inactive com- eral resistance. In most of the cases, rise in BP pound ‘ I’ (decapeptide), is due to increase in total peripheral resistance. which further changed into ‘angiotensin II’ (octapeptide) by the action of angio- Clinically, hypertension can be divided tensin converting enzyme (ACE) and is the into three stages e.g. mild, moderate and most powerful vasoconstrictor agent. An- severe hypertension. The diastolic blood giotensin II also stimulates the synthesis pressure between 90-104 mmHg is graded as mild, 105-114 mmHg is graded as and release of aldosterone from adrenal moderate and above 115 mmHg is graded cortex of adrenal gland. as severe hypertension. The person having The drugs used in the treatment of systolic blood pressure more than 160 hypertension can be classified as in table 4.2.1. 176 Section 4/ Drugs Acting on Cardiovascular & Urinary System

Table 4.2.1: Classification of antihypertensive agents.

I. Centrally acting sympathetic inhibitors Clonidine (ARKAMIN) 75-225 µg/day Methyldopa (ALPHADOPA) 0.5-2 g/day II. Adrenergic neurone blocking agents Reserpine (ADELPHANE) 0.25-0.5 mg OD Guanethidine (ISMELIN) 10-50 mg OD III. Adrenergic receptor antagonists i. Alpha blockers Prazosin (PRAZOPRESS) 0.5 mg BD, maintained at 3-20 mg BD Terazosin (OLYSTER) 2-10 mg/day Doxazosin (DOXACARD) 2-8 mg/day Phentolamine (FENTANOR) 2-5 mg IV Phenoxybenzamine (FENOXENE) 20-60 mg/day oral, 1 mg/kg IV ii. Beta blockers Propranolol (CIPLAR) 10-80 mg TDS, 2-8 mg IV Metoprolol (BETALOC) 100-450 mg/day Atenolol (BETACARD) 50-100 mg/day Sotalol (SOTAGARD) 80-480 mg/day Pindolol (PINADOL) 10-30 mg/day Celiprolol (CELIPRESS) 100-200 mg/BD-TDS iii. Alpha & beta blockers Carvedilol (CARDIVAS) 12.5-50 mg OD Labetalol (NORMADATE) 100-200 mg TDS, 50 mg IV IV. Angiotensin converting enzyme (ACE) inhibitors Captopril (CAPOTRIL) 25-100 mg TDS Enalapril (ENCARDIL) 10-20 mg OD-BD Lisinopril (BIDPRIL) 5-20 mg/day Ramipril (RAMIPRESS) 2.5-10 mg OD Perindopril (PERIGARD) 4-8 mg OD Benzapril (BENACE) 10-40 mg OD-BD Also available omapatrilat, Quinapril, Trandolapril

V. Angiotensin II receptor (type AT1) antagonist Losartan potassium (LOSACAR) 25-100 mg OD Irbesartan (IROVEL) 150-300 mg OD VI. Calcium channel blockers Verapamil (VASOPTEN) 40-160 mg TDS Diltiazem (DILZEM) 30-60 mg TDS-QID Nifedipine (CALCIGARD) 5-20 mg TDS, oral/SL (AMLODAC) 5-10 mg OD Also available , Lacidipine, , NiImodipine VII. Direct vasodilators Hydralazine (NEPRESOL) 2-50 mg BD Sodium nitroprusside (NIPRESS) 0.1-0.3 mg/min IV infusion Nicorandil (ZYMCOR) 5-20 mg BD VIII.Diuretics (For details see chapter ‘Diuretics’) Antihypertensive Agents 177

is partly metabolized and partly excreted CENTRALLY ACTING DRUGS unchanged in urine. CLONIDINE Adverse effects include dizziness, pos- tural hypotension, sedation, dry mouth, It is an imidazoline derivative with a par- headache, sleep disturbances, depression, tial agonist action. It stimulates presynap- anxiety, impotence, blurred vision, consti- tic, α receptors in vasomotor centre of brain 2 pation, skin rash, arthralgia, fatigue, anor- causing decreased sympathetic outflow exia, haemolytic anemia, parkinsonian which results in fall of blood pressure and signs, drug fever and hepatitis. bradycardia. It is indicated in mild to moderate After oral administration the absorption hypertension. is almost complete and rapid. It penetrates easily into CNS. Half to two third of oral dose is excreted unchanged in urine. ADRENERGIC NEURONE BLOCKERS Adverse effects include drowsiness, dry RESERPINE mouth, sedation, restlessness, anxiety, nightmares, dizziness, sleep disturbances, It is an alkaloid obtained from the roots of skin rash, urticaria, nausea, constipation, ‘Rauwolfia serpentina.’ It is known to deplete indigestion and impotence. the catecholamines – adrenaline, noradrenaline and dopamine from the Abrupt withdrawal may result in severe various sites in the body. It also depletes 5- rebound hypertension, hepatic dysfunction hydroxytryptamine (serotonin). and renal dysfunction. Hypotension develops gradually and is It is indicated in hypertension of all grades due to depletion of noradrenaline from except pheochromocytoma, glaucoma and peripheral adrenergic nerve endings. migraine. It is also useful in , alcohol and nicotine withdrawal. It also attenuates vaso- Adverse effects include nasal motor symptoms of menopausal syndrome. congestion, flushing, bradycardia, postural hypotension, water and salt retention and METHYLDOPA CHF may be precipitated. It is α-methyl analogue of DOPA, the It also causes miosis, salivation, precursor of dopamine and noradrenaline. increased gastric acid secretion. CNS side It is converted to alpha methyl effects include lethargy, apathy, psychic noradrenaline which stimulates central depression which may result in suicidal tendencies and weight gain. alpha2 adrenergic receptors in brain thereby decreasing sympathetic outflow. It Endocrinal disturbances include decreases peripheral resistance more than gynecomastia and impotence. heart rate or cardiac output. Because of its serious side effects and After oral administration bioavailability limited efficacy, it is not much used now is low because of extensive metabolism. It clinically. 178 Section 4/ Drugs Acting on Cardiovascular & Urinary System

Guanethidine is another agent which plasma proteins and is metabolised in liver. inhibits release of noradrenaline. Causes About 10% terazosin is excreted unchanged sodium and water retention and may in urine. It crosses the placenta. precipitate CHF. Endocrinal side effects are Adverse effects include marked hy- more common e.g. impotence and inhibition potension with first dose of terazosin, drowsi- of ejaculation. It is also not used now ness, dizziness, nausea, blurred vision, nasal clinically. congestion, peripheral edema, syncopal epi- sodes and headache. In patients with BPH ADRENERGIC RECEPTOR ANTAGONISTS postural hypotension has been reported more The detailed pharmacology of alpha and than in those with hypertension. beta blockers is already discussed in chapter It is indicated in mild to moderate ‘Adrenergic blocking agents’. Only hypertension, symptomatic relief of urinary adrenergic blockers used in hypertension obstruction in patients of benign prostatic are discussed here. hypertrophy.

PRAZOSIN DOXAZOSIN It selectively blocks post synaptic α adr- 1 It effectively controls blood pressure energic receptors due to which vasodilata- over 24 hours suppressing early morning BP tion occurs. The haemodynamic effects are rise. It increases insulin sensitivity, improves decreased arterial pressure and reduction in lipid profile. venous and arterial tone. It is extensively metabolised in the liver It shows first pass metabolism in liver and it is highly bound to plasma proteins. mainly by O-demethylation or hydroxyla- tion. Approximately 4.8% is excreted in the Adverse effects include postural faeces as unchanged drug. hypotension, dizziness, tachycardia, palpitation, headache, weight gain, dry Adverse effects include postural hy- mouth, nausea, diarrhoea, constipation, potension (rarely associated with fainting), nasal stuffiness, priapism and skin rash. dizziness, headache, fatigue/malaise, ver- tigo, edema, asthenia, somnolence, nausea TERAZOSIN and rhinitis. ααα It is an 1 adrenoceptor antagonist and It is indicated in mild to moderate, is a close structural analog of prazosin. It has hypertension, treatment of both urinary a long duration of action. outflow obstruction, obstructive and α It selectively blocks 1 adrenoceptors irritative symptoms associated with BPH. due to which vasodilatation occurs and the blood pressure is reduced. PROPRANOLOL βββ βββ After oral administration it is almost It is 1, 2 adrenergic receptor blocker completely absorbed. It is highly bound to with membrane stabilising activity. Antihypertensive Agents 179

It selectively and competitively ness, nausea, vomiting, skin rash, diarrhoea, antagonises the action of catecholamines nightmares, hypotension and bradycardia. mediated through adrenergic receptors. It It is indicated in hypertension, angina decreases heart rate, force of cardiac contrac- pectoris, cardiac arrhythmia, post MI tion. During longterm therapy, the blood patients, adjunctive management of pressure falls in patients of hypertension. thyrotoxicosis and prophylaxis of migraine. The renin secretion is inhibited. After oral administration it is absorbed ATENOLOL βββ almost completely but a large portion of the It is a cardioselective 1 blocker with dose is metabolised in liver before reaching insignificant intrinsic sympathomimetic systemic circulation as a result the activity. bioavailability of propranolol is reduced. It After oral administration it is is highly bound to plasma proteins. incompletely absorbed, excreted largely in Adverse effects include fatigue, urine as unchanged drug. tiredness, skin rash, fever, depression, Adverse effects include bradycardia, nightmares, sexual dysfunction, nausea, nausea, vomiting, epigastric discomfort, epigastric distress, cold extremities and dizziness, fatigue, tiredness, skin rash, leg hypoglycaemia. pain, cold extremities because of peripheral It is indicated in hypertension, cardiac arterial insufficiency. arrhythmias, longterm management of MI, It is indicated in hypertension, angina hypertrophic subaortic stenosis, pheochro- pectoris and acute MI. mocytoma, migraine prophylaxis, angina pec- toris, essential tremors. PINDOLOL βββ The detailed pharmacology of propra- It is a non-selective adrenergic nolol is discussed in chapter ‘Adrenergic blocker with partial agonist activity. blocking agents.’ It is absorbed efficiently after oral administration and is metabolised in liver. METOPROLOL Adverse effects include dizziness, nausea, βββ It is a relatively selective 1 adrenergic vomiting, headache and sleep disturbances. antagonist with no agonist activity. It reduces plasma renin activity in CARVEDILOL βββ βββ ααα hypertensive patients. It competitively blocks 1, 2 and 1 adreno-receptors. It lacks sympathomi- After oral administration its absorption metic activity and has vasodilating prop- is good and rapid. It is metabolised erties which are exerted mainly through extensively in body and shows first pass β blockade. It reduces both systolic and metabolism in liver (less than propranolol). 1 diastolic blood pressure without reflex Adverse effects include headache, dizzi- tachycardia. 180 Section 4/ Drugs Acting on Cardiovascular & Urinary System

After oral administration it is rapidly diseases. They reduce cardiovascular and extensively absorbed. Metabolism is morbidity and mortality by improving primarily hepatic. coronary perfusion, reducing ventricular Adverse effects include postural hypertrophy and remodeling and preventing hypotension, dizziness, headache, fatigue, progression of coronary atherosclerosis. Gl disturbances and dry eyes. However, the cellular mechanisms underlying the beneficial effects of ACE LABETALOL inhibitor are not fully understood. ααα It is a mixed antagonist ( 1 and non- They are now first line drug in all grades selective βββ-receptor antagonist). It has of hypertension. They can be safely intrinsic sympathomimetic activity which is combined with diuretics and β blockers. β largely confined to 2 adrenergic receptors. It is more potent in blocking β than a CAPTOPRIL receptors. It is a potent hypotensive agent After oral administration it is absorbed especially useful in pheochro-mocytoma. rapidly, the drug is partly metabolised and After oral administration it is well partly excreted unchanged in urine. The absorbed and extensively metabolised in excretion is impaired in renal dysfunction. liver. Adverse effects include dry cough, skin rash, loss of taste, hyperkalemia, vertigo, ACE INHIBITORS headache, nausea, vomiting, hypotension, fatigue, neutropenia (rare), proteinuria and These drugs act primarily by suppressing anaemia. renin-angiotensin-aldosterone system. It is indicated in all grades of The main action of all ACE inhibitors is hypertension, CHF and scleroderma crisis. to inhibit conversion of angiotensin I (inactive) to angiotensin II (active). They ENALAPRIL inhibit the angiotensin converting enzyme Enalapril maleate is an orally active (ACE). Hence, angiotensin II production is angiotensin converting enzyme (ACE) inhibited. Decrease in angiotensin II results inhibitor, it lowers peripheral vascular in dilatation of peripheral vessels leading to resistance without causing an increase in a reduction in systemic vascular resistance heart rate. The maleate salt (enalapril) and a decreased aldosterone secretion. They allows better absorption after oral can be administered safely in patients of administration. It is an ideal drug for hypertension with diabetes mellitus or hypertensive patients who are intolerant to bronchial asthma. ACE inhibitors are beta-blocker therapy. It also shows promise efficacious drugs, are well tolerated and are in the treatment of congestive heart failure. useful antihypertensive drugs. ACE Following oral administration, enalapril is inhibitors are also used in coronary artery rapidly absorbed and hydrolysed to Antihypertensive Agents 181 enalaprilat – a highly specific, long acting, ANGIOTENSIN ANTAGONISTS non-sulphydryl angiotensin converting enzyme (ACE) inhibitor. LOSARTAN indicated It is in all grades of essential Angiotensin II is a potent vasoconstrictor, hypertension and renovascular hyperten- stimulant of aldosterone secretion and an sion where standard therapy is ineffective important component in the pathophysiol- or inappropriate because of adverse effects ogy of hypertension. Both losartan and its and in congestive heart failure. It should be principal active carboxylic acid metabolite. used as an adjunctive therapy with digitalis (10-40 times more potent than losartan) and/or diuretics. block the vasoconstrictor and aldosterone Enalapril is well tolerated in most secreting effects of angiotensin II by selec- patients. The most common side effects tively blocking the binding of angiotensin include dizziness, headache, nausea, II to the AT1 receptor found in many tis- diarrhoea, fatigue, muscle cramps, rash and sues (e.g. vascular smooth muscle, adrenals). cough. Other side effects are angioneurotic Losartan does not inhibit ACE (kininase II), edema, hypotension, urticaria which are rare. the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin. LISINOPRIL Losartan potassium is well tolerated. It is derivative of enalaprilat. Bioavailability is 33% due to hepatic first Mechanism of action is same as other ACE pass metabolism. It is 98% plasma protein inhibitors. After oral administration it is bound. It is activated in liver. Both parent absorbed incompletely and slowly. compound and active compound are Adverse effects include dizziness, excreted in urine. cough, hyperkalemia, headache, hypoten- Adverse effects seen most often are sion and angioedema. dizziness or light-headedness and rash. Angioedema (involving swelling of face, lips RAMIPRIL and/or tongue) have been rarely reported. Ramipril is a long acting ACE inhibitor There is also headache, asthenia, fatigue and and is converted to active metabolite – dizziness. ramiprilat. IRBESARTAN Ramipril in patients with mild to mod- erate hypertension results in a reduction of It is a specific antagonist of AT1 both supine and standing blood pressure. receptors with a much greater affinity (more

In patients of acute myocardial infarction that 8,500 fold) for the AT1 receptor than for with CHF, ramipril reduced total mortality, the AT2 receptor and no agonist activity. progression of heart failure and CHF-related Irbesartan is an orally active agent that hospitalizations. does not require biotransformation into an active form. It is rapidly absorbed from the 182 Section 4/ Drugs Acting on Cardiovascular & Urinary System

GIT and undergoes metabolism in liver to atrial fibrillation/flutter with tachya- inactive metabolites. It is about 90% bound to rrhythmia, extra systoles, hypertensive cri- plasma proteins. It is excreted as unchanged sis, acute coronary insufficiency (spasm), drug and metabolites in the bile and urine. angina pectoris, vasospastic angina, myocar- Adverse effects are headache, sinus dial infarction and hypertension. abnormality, cough, pharyngitis, diarrhoea, rhinitis, urinary tract infection, rash, anxiety/ DILTIAZEM nervousness, and muscle cramp. However, Diltiazem is a calcium influx inhibi- most side effects have been mild and tor which inhibits the transmembrane in- transient in nature. Rare cases of flux of calcium ions into cardiac muscle hypersensitivity reaction, occasionally severe and smooth muscle without changing (e.g. anaphylaxis), have been reported. serum calcium concentration. It is indicated in mild to moderate Diltiazem is well absorbed from gastro- hypertension, either alone or in combina- intestinal tract and is subject to extensive tion with other antihypertensive agents. first pass metabolism. It is 70% bound to plasma proteins. It is excreted as metabolites CALCIUM CHANNEL BLOCKERS in bile and urine. Calcium channel blockers interfere with the Adverse effects include headache ankle calcium entry into the myocardial and vascu- edema, hypotension, dizziness, flushing, lar smooth muscles and thereby decreasing the weight gain, nausea, GI disturbances includ- availability of the intracellular calcium. ing anorexia, nausea, vomiting, constipation diarrhoea and taste disturbances. Occasionally Calcium channel blockers depress the there is gingival hyperplasia, skin rash and contractility of the myocardium and decrease transient elevation in liver enzyme values. the cardiac work and the requirement of oxygen. This effect proves to be beneficial in It is indicated in the treatment of mild the treatment of angina pectoris. to moderate essential hypertension and in the management of chronic stable angina VERAPAMIL and angina due to coronary artery spasm. It increases coronary blood flow and causes vasodilatation. It has anti- NIFEDIPINE arrhythmic action also and it decreases It causes coronary vasodilatation and peripheral vascular resistance. increases coronary blood flow. It reduces the After oral administration it is bound to total peripheral vascular resistance and plasma proteins and it is metabolised to systolic and diastolic blood pressure is biologically active metabolite. reduced. It causes reflex tachycardia. Adverse effects include nausea, constipa- Adverse effects include headache, flushing, tion, hypotension, flushing, dizziness, vertigo, palpitation, nausea, vomiting and edema. pedal edema, nervousness and paraesthesias. It is indicated in vasospastic angina, It is indicated in tachycardias, such as chronic stable angina, hypertension, hyper- paroxysmal supraventricular tachycardia, tensive emergency, hypertrophic cardiomy- Antihypertensive Agents 183 opathy, peripheral vascular disorders, con- pressure more than systolic blood pressure gestive heart failure, acute myocardial inf- by lowering peripheral vascular resistance. arction, myocardial preservation during Due to preferential arteriolar dilatation, pos- surgery, migraine, oesophageal spasm and tural hypotension is uncommon. It increases exercise induced bronchial asthma. heart rate and cardiac output. After oral administration its absorption AMLODIPINE is almost complete and rapid. It is subject to Amlodipine is a long-acting calcium significant first pass metabolism in liver. channel blocker that inhibits the transmem- Adverse effects include nausea, vomiting, brane influx of calcium ions into vascular tachycardia, dizziness, fatigue, weakness, pal- smooth muscle and cardiac muscle. By in- pitations, headache, paresthesia, tremor, con- hibiting calcium ion influx it directly dilates vascular smooth muscle. stipation, anxiety, nasal congestion, lupus like syndrome and sleep disturbances. After oral administration of S- amlodipine besylate, bioavailability is 65- It is indicated in hypertension (moderate 80%. Approximately 93% drug is bound to or severe) and hypertension with renal plasma proteins. It is extensively converted involvement. to inactive metabolites via hepatic SODIUM NITROPRUSSIDE metabolism. It is excreted in urine as 10% parent drug and 60% of the metabolites. It has a brief duration of action. It relaxes directly arteriolar and venous smooth Amlodipine is generally well tolerated. muscle. It decreases both preload and The most commonly observed side effects afterload thus both cardiac output and are headache, edema, fatigue, flushing and dizziness. peripheral resistance are reduced. Other side effects include nausea, It is given parenterally and onset of ac- abdominal pain, somnolence, palpitations, tion occurs quickly (within 1 minute). On muscle cramps, frequency of micturition or stopping IV infusion, the effect dissipates nocturia, cough, breathlessness, epistaxis, rapidly. It is converted to NO by endothe- impotence, nervousness and conjunctivitis. lial cells and RBCs which relaxes vascular smooth muscle. It is converted to thiocyan- It is indicated in the treatment of ate in liver which is excreted slowly. essential hypertension and angina pectoris. Adverse effects include nausea, vomiting, DIRECT VASODILATORS nervousness, palpitation, sweating, headache, disorientation, methaemoglobinaemia. HYDRALAZINE It is indicated in hypertensive crisis, It acts directly on arteriolar smooth muscle congestive heart failure and acute mitral to cause relaxation. It decreases diastolic regurgitation.

 This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsAntianginal Agents 4.31. 4 (Mode of Action of Drugs)

Angina pectoris is a symptom of ischaemic NO by enzymatic step involving reaction heart disease. It develops as a result of an with tissue sulphydryl (–SH) groups in imbalance between the oxygen supply and vascular smooth muscles. oxygen demand of the myocardium. There NO released by GTN activates soluble, is a paroxysmal chest pain which occurs cytosolic form of guanylyl cyclase in vascular when coronary blood flow is inadequate to smooth muscles by interacting with haem supply required amount of oxygen to group in the enzyme. This converts GTP to myocardium. There is a characteristic radi- cGMP. cGMP dephosphorylates myosin light ating pain in distribution in left arm, chest, chain kinase and prevent myosin interaction jaw and neck region. This pain is mainly with actin leading to relaxation. brought about by exertion/excitement when Pharmacodynamics oxygen demand of heart increases and myo- cardial perfusion is decreased. Decrease in Action is almost exclusively on smooth myocardial perfusion is due to deposition muscle cells. of atherosclerotic plaques in blood vessels. Effect on vascular smooth muscles: These plaques are due to accumulation of Both large arteries and veins relax in re- cholesterol and other lipid compounds sponse to GTN. But in small doses, marked which develop as patches on inner side of venorelaxation is seen leading to reduced tunica intima of blood vessels i.e. subinti- preload. This causes decrease in stroke mal layer. volume which is compensated with reflex tachycardia. The drugs used in the treatment of an- Arterioles relax less than venules because gina pectoris are classified as in table 4.3.1. GTN evokes reflexes by baroreceptors which respond to decreased arterial pressure GLYCERYL TRINITRATE leading to reflex sympathetic discharge Glyceryl trinitrate (GTN) releases nitrite causing tachycardia and increased cardiac – ion (NO2 ) which is further metabolised to contractility. 186 Section 4/ Drugs Acting on Cardiovascular & Urinary System

Table 4.3.1: Classification of antianginal agents. I. Nitrates Glyceryl trinitrate (Nitroglycerine; ANGISED) 2.5-15 mg BD-TDS, 0.5 mg SL, 2.5-6.5 mg SR Amyl nitrate (VAPOROLE) 0.3 ml capsule inhalation Isosorbide dinitrate (SORBITRATE) 5-10 mg TDS-QID SL, 40-80 mg SR BD Isosorbide 5-mononitrate (MONOTRATE) 10-20 mg/day, 40 mg SR Erythrityl tetranitrate (CARDILATE) (30-60 mg/day oral, 5-10 mg SL) Pentaerythritol tetranitrate (PERITRATE) 30 mg/day II. Beta blockers Propranolol, atenolol etc. (For details see chapter on ‘Antihypertensive drugs’). III. Calcium channel blockers Verapamil, nifedipine etc. (For details see chapter on ‘Antihypertensive drugs’). IV. Potassium channel openers Nicorandil, diazoxide etc. (For details see chapter on ‘Antihypertensive drugs’). V. Miscellaneous Dipyridamole (PERSANTIN) 25-100 mg TDS Nicotinyl xanthinate (COMPLAMINA) 300-600 mg TDS

Effect on coronary blood of flow: Myo- Adverse Effects cardial oxygen extraction is nearly maxi- 1. Throbbing headache: It is due to arte- mum at rest, so, there is little reserve to meet riolar dilatation of meningeal arteries. increased demands. So, increased myocar- It usually decreases over a few days if dial demand for O2 can only be met by in- treatment is continued and can be con- creased coronary blood flow which depends trolled by decreasing the dose. on diastolic pressure and duration of dias- 2. Weakness and dizziness: It may arise due tole because coronary blood flow is negli- to postural hypotension especially if pa- gible during systole. tient is standing in a single position for a while. This is because, venodilatation re- Pharmacokinetics sults in ‘venous pooling’ i.e. accumulation They are administered through buccal, of blood in peripheral vessels leads to sublingual and parenteral routes. Skin oint- postural hypotension. ments are also available. GTN is rapidly in- 3. Flushing: It is due to arteriolar dilata- activated by hepatic first pass metabolism. tion in face and neck region. So, oral tablets which are swallowed are in- 4. Sweating: Arteriolar dilatation in arter- effective. ies beneath the skin tends to warm up Excretion is primarily as glucuronide and sweating is the body’s mechanism derivatives of the denitrated metabolite via to dispel heat. kidney. IV infusion has rapid onset of ac- 5. Tachycardia and palpitation: In small tion but effects are quickly reversed on stop- doses of GTN, arteriolar dilatation re- ping the infusion. So, it is used only in treat- sults in decreased arterial pressure. ment of severe, recurrent angina at rest. This leads to reflex sympathetic dis- Antianginal Agents 187

charge causing tachycardia and in- ISOSORBIDE-5-MONONITRATE creased cardiac contractility. So, palpi- It has a longer duration of action and tation are felt. mechanism of action is same as nitrates. 6. Methaemoglobinemia: Its a rare ad- verse effect. After oral administration hepatic first pass Methaemoglobin has very low affinity metabolism is less than isosorbide dinitrate, for oxygen, so large doses of nitrites can hence, systemic bioavailability is more.

result in pseudocyanosis (reduced O2 It is indicated in pulmonary hyperten- carrying capacity), tissue hypoxia and sion, prophylaxis of angina pectoris, post death. myocardial infarction therapy, CHF and Usually, even large doses of GTN and acute LVF. It is not recommended for acute other organic nitrates do not raise attacks of angina. plasma levels of nitrite dangerously high. ERYTHRITYL TETRANITRATE 7. Fainting: Venodilatation leads to increased capacity (venous pooling) It is used for chronic prophylaxis of an- leading to marked hypotension. This gina pectoris. Tolerance may develop to can cause syncope/temporary loss of pharmacological actions. consciousness. Adverse effects include flushing, head- Indications ache, dizziness, methaemoglobinaemia and drug rash. Sublingual tablet: Angina pectoris. Intravenous: Unstable angina, coronary It is indicated in treatment and prophy- vaso-spasm, left ventricular failure accom- laxis of exertional and vasospastic angina. panying MI, hypertension and during car- diac surgery. PENTAERYTHRITOL TETRANITRATE Ointment/transdermal patch: Prevention of angina pectoris. It is used for chronic prophylaxis of an- gina pectoris. Tolerance may develop to ISOSORBIDE DINITRATE pharmacological actions. It can be given sublingually and orally Beta blockers, calcium channel blockers for treatment of angina. Mechanism of action and potassium channel openers detailed is same as nitrates. pharmacology is given in chapter ‘Antihy- Adverse effects include throbbing head- pertensive drugs’. ache, sweating, skin rash, palpitation, flush- ing, weakness and dizziness. OTHER ANTIANGINAL DRUGS It is indicated in acute attacks (sublingually) and chronic prophylaxis DIPYRIDAMOLE (orally) of angina pectoris and coronary in- sufficiency. In acute myocardial infarction, It is a coronary dilator and claimed to di- CHF and acute LVF. late coronary resistance vessels. It probably 188 Section 4/ Drugs Acting on Cardiovascular & Urinary System act by inhibiting the uptake and degrada- Adverse effects include nausea, dizzi- tion of adenosine (a local mediator involved ness, skin rash and headache. Though it is in auto regulation of coronary flow in re- not useful as an antianginal drug, but it has sponse to ischemia). It has also weak plate- been employed for prophylaxis of coronary let inhibiting action. It reversibly inhibits and cerebral thrombosis in post MI and platelet phosphodiesterase hence cAMP post stroke patients, as well as to prevent concentration is increased and there is re- thrombosis in patients with prosthetic heart duction of platelet reactivity. valves.

 ChapterChapter PharmacodynamicsPharmacodynamicsAntiarrhythmicAntiarrhythmic 4.41. 4 (ModeAgentsAgents of Action of Drugs)

CARDIAC ARRHYTHMIAS Antiarrhythmic drugs can be classified Cardiac arrhythmias is a group of dis- as in table 4.4.1. order characterized by an abnormal cardiac rhythm and arise as a result of disorders of SODIUM CHANNEL BLOCKERS impulse formation or conduction or both. By limiting the conductance of Na+ (and K+) Tachyarrhythmias (sinus rate more across cell membrane, they interfere with than 100 per minute) are produced by a depolarization and decrease responsiveness disturbances of impulse generation or of to excitation thereby reducing rate of phase impulse conduction in the heart. of phase 4 depolarisation in automatic cells. Tachyarrhythmias due to disturbed im- pulse formation are associated with ir- QUINIDINE regular and rhythmic discharge from ec- It is an alkaloid obtained from the topic pacemaker activity in areas of the bark of cinchona and is a dextro isomer heart other than the SA node. The charac- of anti-malarial drug ‘quinine’. Its so- teristic of myocardial cells, which enables dium channel blocking property results them to generate spontaneous depolariza- in an increased threshold for excitability tion, is called automaticity. and decreased automaticity. As a conse- Bradycardia can be due to depressed quence of its potassium channel blocking sinus automaticity and AV block. properties, it prolongs action potential in Bradyarrhythmias manifest as slow heart most cardiac cells. rate (less than 50 to 60 beats per minute in sleep). Depressed SA nodal automaticity Pharmacological Actions lead to missing beats and bradycardia. AV Cardiac actions: block can be due to high vagal activity and side effect of certain drugs e.g. digitalis and a. Excitability: Quinidine depresses the β-blockers. excitability of cardiac tissues. 190 Section 4/ Drugs Acting on Cardiovascular & Urinary System

Table 4.4.1: Classification of antiarrhythmic agents. I. Class I: Sodium channel blockers Quinidine (NATCARDINE) 200-400 mg TDS-QID Procainamide (PRONESTYL) 50 mg/kg/day oral, 50 mg/min slow IV Disopyramide (NORPACE) 100-200 mg TDS-QID, 2 mg/kg slow IV Lignocaine (XYLOCARD) 1 mg/kg slow IV (bolus) then 1-3 mg/min IV infusion Phenytoin sodium (DILANTIN) 100-400 mg/day oral, 100 mg IV (max 600 mg/day) II. Class II: Beta adrenergic blockers Propranolol, etc. (Detailed pharmacology is discussed in chapter ‘Antihypertensive agents’ and Adrenergic blocking agents’). III. Class III: Drugs that prolong effective refractory period by prolonging action potential Amiodarone (ALDARONE) 200 mg TDS Bretylium 5-10 mg/kg bolus IV then 0.5-2 mg/min IV infusion IV. Class IV: Calcium channel blockers Verapamil, diltiazem etc. (Detailed pharmacology is discussed in chapter ‘Antihypertensive agents’). V. Miscellaneous Adenosine (ADENOCOR) 6-12 mg IV bolus. Atropine 0.6-2 mg IM (Used for AV block) Sympathomimetics (e.g. adrenaline, isoprenaline and orciprenaline are also used for AV block). Digitalis (DIGOXIN) 0.25-0.5 mg IV for paroxysmal supraventricular tachycardia (PSVT), atrial flutter and atrial fibrillation

b. Automaticity: Quinidine decreases the Its antivagal action prolongs the re- slope of slow diastolic depolarisation fractory period of atrium and short- (phase 4 of action potential) and thus ens that of AV node. The antivagal decreases the spontaneous rate of fir- action on the AV node causes para- ing of pacemakers. By depressing the doxical tachycardia in a patient of entry of sodium into the cell during atrium fibrillation. depolarization, quinidine depresses e. Contractility: Quinidine produces a diastolic depolarization and ultimately negative inotropic action on the heart automaticity. and contractility is depressed with c. Conductivity: Quinidine depresses in- toxic doses. terventricular and atrioventricular con- f. AV conduction: Quinidine depresses ductivity. PR and QRS intervals are the conduction in atrium and Purkinje also prolonged. Also decreases the rate system. of rise of action potential. g. Electrophysiological effect (effect on d. Effective refractory period: Quini- ECG): dine depresses the potassium efflux 1. It reduces the rate of rise of action during repolarization and prolongs potential i.e. phase zero of action repolarization. The refractory period potential which is due to increases due to its antivagal action. depolarisation. Antiarrhythmic Agents 191

2. Increase in the duration of ventricu- It decreases the rate of rise of action po- lar systole (QT interval). tential and prolongs the effective refractory 3. Decrease in amplitude of T waves. period. 4. Depression of ST segment. After oral administration it is absorbed 5. Reduction in conduction velocity quickly, about 20% is bound to plasma pro- (widening of QRS complex). tein up to and 70% of a dose is excreted in urine in unchanged form. Extracardiac actions: Adverse effects include renal failure, a. Quinidine in normal individuals pro- hypotension (when given IV), anorexia, nau- duce a decrease in blood pressure af- ter oral and IV administration. sea, vomiting, Q-T prolongation. Rarely there is diarrhoea, giddiness, psychosis, hallucina- b. Quinidine has got antimalarial, anti- tion, mental depression, hypersensitivity, pyretic, oxytocic and skeletal muscle relaxant activity also. agranulocytosis, myalgia, angioedema, skin It is well absorbed orally, undergoes ex- rash, digital vasculitis. Procainamide can tensive hepatic oxidative metabolism. 90% cause syndrome that resembles SLE, which quinidine is bound to plasma protein. The is reversible on discontinuation of drug is distributed to most tissues except procainamide; leukopenia and thrombocy- brain. About 20% is excreted unchanged by topenia. the kidney. It is indicated in ventricular arrhyth- Adverse effects include SA block or ar- mia, ventricular premature depolarization rest, high grade AV block, ventricular tachy- and paroxysmal ventricular tachycardia, cardia, arrhythmia or ventricular asystole, supra-ventricular tachycardia and atrial ar- polymorphic ventricular tachyarrhythmia, rhythmia. hypotension (particularly when given IV), cinchonism, tinnitus, loss of hearing, gas- DISOPYRAMIDE trointestinal upset, severe headache, diplo- It has got anticholinergic and mem- pia, photophobia, etc. brane depressant properties and like qui- It is indicated in prevention of atrial ar- nidine, it is effective against most of the rhythmia, atrial fibrillation or flutter, par- atrial and ventricular arrhythmias. It has no oxysmal supraventricular tachycardia, ven- effect on sinus rate. tricular premature beats and ventricular ta- Adverse effects include dry mouth, con- chycardia. stipation, blurred vision, urinary urgency PROCAINAMIDE and occasional urinary retention, nausea, vomiting, diarrhoea, abdominal pain, It has got quinidine like cardiac prop- erty. It depresses the excitability of both hypoglycaemia, jaundice, coronary heart atria and ventricles. Contractility and con- failure and hypotension. ductivity are also depressed. It has got mini- It is indicated in atrial and ventricular mal vagolytic action. arrhythmias in digitalised and non- 192 Section 4/ Drugs Acting on Cardiovascular & Urinary System digitalised patients, arrhythmias associated It is also used in digitalis induced ven- with Wolff-Parkinson-White (WPW) syn- tricular arrhythmia as it reverse the conduc- drome. tion block while accentuating the depression of automaticity (The detailed pharmacology LIGNOCAINE is discussed in chapter ‘Antiepileptic agents’). It is an amide local anaesthetic and has rapid onset of action. It depresses diastolic BETA-ADRENEGIC BLOCKERS depolarization and automaticity in ectopic The detailed pharmacology of beta blockers foci in ventricular tissue. Phase 4 depolar- is discussed in chapter ‘Adrenergic block- ization in partially depressed Purkinje fibres ing agents’ and ‘Antihypertensive agents’. and after depolarizations are antagonised. The antiarrhythmic action is due to It does not depress AV conduction and de- cardiac adrenergic blockade. It decreases the creases action potential duration, effective slope of phase 4 depolarization and refractory period. It has no effect on BP. automaticity in SA node, Purkinje fibres and Adverse effects include ventricular fi- other ectopic foci. It also prolongs the brillation, hypotension or massive cardiac effective refractory period of AV node and arrest due to overdose, dizziness, paraesthe- impedes AV conduction. ECG shows sia, drowsiness, seizures, disorientation, res- prolonged PR interval. It is useful in sinus piratory arrest, nausea, vomiting, circulatory tachycardia, atrial and nodal extrasystoles. collapse and blurred vision. It is also useful in sympathetically mediated It is indicated in prophylaxis or treat- arrhythmias in pheochromocytoma and halothane anaesthesia. ment of ventricular arrhythmias associated with Ml, digitalis intoxication, ventricular tachyarrhythmia, in patients predisposed to DRUGS PROLONGING ACTION POTENTIAL ventricular arrhythmias during general ana- By prolonging repolarization, AP is wid- esthesia. ened and ERP is increased, so the tissues remain refractory even after full PHENYTOIN SODIUM repolarization. It is a anticonvulsant drug and de- presses the ventricular automaticity and AMIODARONE accelerates the AV conduction. It also re- It is a long acting antiarrhythmic drug. duces the duration of action potential like It contains iodine and may cause disorders quinidine. It also shortens the QT interval. of thyroid function. It mainly blocks inactivated Na+ channels. It blocks inactivated sodium channels. It is used for the suppression of ectopic It also decreases calcium current and tran- beats and for prophylaxis of recurrent par- sient outward, delayed rectifier and inward oxysmal tachycardia and also for the treat- rectifier potassium currents. It is a potent ment of rapid supraventricular or ven- inhibitor of abnormal automaticity. It pro- tricular tachycardia. longs duration of action potential, refracto- Antiarrhythmic Agents 193 riness in Purkinje and ventricular muscle echolamines and has direct antiarrhythmic fibers. property. Bretylium may reverse the short- Amiodarone is slowly and poorly absorbed ening of action potential duration caused by after oral administration. It is metabolised ischemia. It acts due to K+ channel blockade. slowly in liver to active metabolite. It is used in the treatment of ventricular Adverse effects include hypotension tachycardia and ventricular fibrillation. due to vasodilatation and depression of myocardial performance is frequent with the CALCIUM CHANNEL BLOCKERS IV route. Heart block, bradycardia, corneal The detailed pharmacology is discussed in microdeposits, photosensitivity, hepatitis, gastrointestinal upset may occur. chapter ‘Antihypertensive agents’. These drugs inhibit Ca2+ mediated slow It is indicated in tachyarrhythmias asso- 2+ ciated with WPW syndrome, atrial flutter and channel inward current, thus inhibiting Ca fibrillation, paroxysmal tachyarrhythmias mediated depolarization. Phase 4 depolar- not responding to other agents. Ventricular ization in SA node and Purkinje fibres is re- tachycardia and ventricular arrhythmia re- duced. They also prolong AV nodal effec- fractory to other treatment. tive refractory period thus AV conduction is slowed. There is also negative inotropic BRETYLIUM action. It has direct action on myocardium and It is indicated in PSVT, to control ventricu- interferes with the neuronal release of cat- lar rate in atrial flutter or atrial fibrillation.

 This page intentionally left blank ChapterChapter AntihyperlipidemicPharmacodynamicsPharmacodynamics 1.4.5 4 (ModeAgents of Action of Drugs)

These drugs are used for treatment of Atherosclerosis is main cause of cardio- hyperlipidemia. They lower the levels of vascular deaths. It is characterized by a lipoproteins and lipids in blood. The plasma localised plaque in the intima and is lipids are present in lipoproteins after composed of cholesterol esters, deposition combining with apoproteins. They are high of fibrous proteins and calcification. These density lipoproteins (HDL), low density plaques may narrow the arterial lumen and lipoproteins (LDL), very low density can cause distalischemia. The coronary and lipoproteins (VLDL) and intermediate density cerebral circulation are main sites of lipoproteins (IDL). atherosclerosis. Raised levels of VLDL, LDL

Table 4.5.1: Classification for antihyperlipidemic agents.

I. HMG CoA reductase inhibitors Lovastatin (LOVASTROL) 10-40 mg/day Simvastatin (SIMCARD) 5-20 mg/day Atorvastatin (ATOCOR) 10-80 mg/day Pravastatin (PRASTATIN) 40 mg/day II. Fibric acid derivatives Clofibrate (ATROMID) 0.5-1 g BD Gemfibrozil (GEMPAR) 600 mg before meals III. Agents inhibiting production of VLDL and lipolysis in adipose tissue Nicotinic acid 100 mg TDS, increased to 2-6 g/day IV. Interferes with intestinal absorption of cholesterol Cholestyramine 4 g TDS Colestipol 5-10 g TDS V. Inhibit synthesis of LDL Probucol 500 mg BD after meals VI. Miscellaneous Gugulipid (GUGLIP) 25 mg TDS 196 Section 4/ Drugs Acting on Cardiovascular & Urinary System and IDL are atherogenic, while HDL is SIMVASTATIN protective because it facilitates removal of Simvastatin, is twice as potent as cholesterol from tissues. lovastatin. The drugs used in the treatment of Simvastatin has been shown to reduce hyperlipidemia are classified as in table 4.5.1. both normal and elevated low-density lipoprotein (LDL) cholesterol concentrations. HMG CoA REDUCTASE INHIBITORS Apolipoprotein B, VLDL cholesterol and plasma triglycerides also reduce and can Also known as statins. HMG CoA reductase produce increase in HDL cholesterol. (Hydroxymethyl-Glutaryl Coenzyme A Simvastatin reduces total cholesterol, Reductase) inhibitors block the synthesis of LDL cholesterol and triglycerides by 25%, cholesterol in liver by competitively 35%, and 10% respectively. The increase in inhibiting HMG CoA reductase activity, also HDL is upto 12%. cause depletion of critical intracellular pools of sterols and increased transcription of LDL Adverse effects are flatulence, receptors leading to enhanced removal from diarrhoea, constipation, nausea, abdominal plasma of LDL cholesterol and LDL pain, cramps, heart burn and dysgeusia. Rarely myopathy, rhabdomyolysis with precursors. They also reduce hepatic acute renal failure may also occur. synthesis of VLDL, increase plasma HDL. Reduction of LDL occurs over 4-6 weeks. Other adverse effects include headache, dizziness, rashes/pruritus, impotence LOVASTATIN insomnia, blurring of vision and lens opacities. It is a potent HMG CoA reductase Simvastatin is indicated in patients with inhibitor. This enzyme catalyzes the coronary heart disease and conversion of HMG CoA to mevalonate in hypercholesteremia, for the reduction of liver which is an important early and rate elevated total and LDL cholesterol in limiting step in the cholesterol synthesis. It patients with primary hypercholesterolemia causes marked reduction in LDL (type IIa and IIb hyperlipoproteinemia), cholesterol and also raise HDL level and combined hypercholesterolemia and may lower the triglyceride level. After oral hypertriglyceridemia. administration it is extensively metabolised Simvastatin is also used in combination in liver and metabolites are excreted in bile. with nicotinic acid. It is found to be the most useful drug combination for the treatment of Adverse reactions include arthralgia, dyslipidemias associated with coronary myopathy, vertigo, tremor, memory loss, artery disease. It is particularly effective in alteration of taste, peripheral neuropathy, normalizing the lipid profiles of patients with anxiety, insomnia, depression, hepatitis familial combined dyslipidemia. cholestatic jaundice, abdominal pain, alopecia, blurred vision etc. ATORVASTATIN It is indicated in primary hypercholesterol- Atorvastatin reduces total cholesterol, emia and hyperglyceridemia. LDL-cholesterol and apolipoprotein B Antihyperlipidemic Agents 197 hypercholesterolemia and mixed peak plasma levels occurring 1 to 1.5 hours dyslipidemias. Atorvastatin also reduces after dosing. Pravastatin undergoes VLDL-cholesterol and TG and produces extensive first-pass extraction in the liver, variable increases in HDL-cholesterol and which is its primary site of action. It is 50% apolipoprotein A1. Atorvastatin reduces bound to plasma proteins. LDL-cholesterol in patients with familial Adverse effects include rash, myalgia, hyper-cholesterolemia (FH). headache, non-cardiac chest pain; rarely Atorvastatin is generally well tolerated. nausea/vomiting, diarrhoea and fatigue Adverse effects include constipation, may occur. flatulence, dyspepsia, abdominal pain, headache, nausea, myalgia, diarrhoea, Pravastatin is indicated as an adjunct to asthenia and insomnia. diet in patients with primary hypercholesterolemia, mixed dyslipidemia, Dose related and reversible elevated serum ALT levels have also been reported. elevated serum triglyceride levels and primary dysbetalipoproteinemia who do not Elevated serum CPK levels have been respond adequately to diet. reported in some patients but only rarely patients have concurrent muscle pain, tenderness or weakness. FIBRIC ACID DERIVATIVES It is indicated as an adjunct to diet to These activate lipoprotein lipase which is reduce elevated total cholesterol, LDL- a key enzyme in degradation of VLDL cholesterol and TG levels in patients with resulting in lower circulating triglycerides. primary hypercholesterolemia, diabetic These drugs lower triglyceride levels by 20- dyslipidaemia or mixed hyperlipidemia, 50% with 10-15% decrease in LDL hypertriglyceridemia, dysbetalipo- cholesterol and a 10-15% increase in HDL proteinemia and familial hypercholester- cholesterol. olemia. CLOFIBRATE PRAVASTATIN It has a specific action on type III Pravastatin sodium besides increasing hyperlipo-proteinemia and also reduces LDL cholesterol catabolism, also inhibits VLDL and LDL but because of its association LDL-cholesterol production by inhibiting hepatic synthesis of VLDL-cholesterol, the with a small increase in risk of gastrointestinal LDL-cholesterol precursor. These effects and hepatobiliary neoplasia, it is seldom used. result in a reduction of total cholesterol, GEMFIBROZIL LDL-cholesterol, VLDL-cholesterol, apolipoprotein B and trigly-cerides, whilst Gemfibrozil reduces plasma increasing (HDL-cholesterol) and triglycerides by 40 to 55% by decreasing the apolipoprotein A. It has little effect on concentration of VLDL. Its effectiveness is cholesterol synthesis in other tissues. less in lowering LDL. Pravastatin is administered orally in the It also decrease hepatic synthesis and active form and is rapidly absorbed, with secretion of VLDL. The lowering of 198 Section 4/ Drugs Acting on Cardiovascular & Urinary System triglyceride plasma levels may be due to HDL level and it is administered with HMG reduction in hepatic synthesis of VLDL and CoA reductase inhibitors e.g. simvastatin. increase in VLDL clearance. CHOLESTYRAMINE AND COLESTIPOL It is completely absorbed from gastro- intestinal tract and is excreted in urine. They are useful only in hyperlipopro- teinemias involving elevated levels of LDL Adverse effects include nausea, i.e. type IIa, IIb and V. They are basic ion diarrhoea, abdominal pain, dyspepsia, exchange resins. They are neither digested fatigue, skin rash, weight gain, leucopenia, nor absorbed in the gut. They bind bile ac- alopecia, blurred vision etc. ids in intestine and interrupt their entero- hepatic circulation, leading to increased NICOTINIC ACID faecal excretion of bile salts and cholester- Nicotinic acid and nicotinamide ol. There is increased hepatic conversion of together represent the essential vitamin choles-terol to bile acids. More LDL recep- niacin in the diet. Of these two, only nicotinic tors are expressed on liver cells leading to acid is active as a lipid modifying drug. increased clearance of IDL, LDL and indi- Nicotinic acid is preferred in patients with rectly of VLDL. triglyceride levels exceeding 200 mg/dl Adverse effects include nausea, heart because bile acid sequestrants tend to raise burn, constipation and acidosis etc. triglyceride levels. Nicotinic acid reduces production of VLDL by liver, thus its PROBUCOL degradation products IDL and LDL are It is cholesterol lowering agent with subsequently reduced. It inhibits lipolysis antioxidant property. It is only 1/10 in adipose tissue and increases activity of absorbed when given orally. It reduces the lipoprotein lipase. It has no effect on serum cholesterol levels without reduction cholesterol and bile acid metabolism. in serum triglycerides level and also reduces Combination drug therapy has been shown the HDL levels. It has no effect on VLDL and to decrease cholesterol levels in triglyceride levels. hyperlipidemic patients. Adverse effects include headache, dizzi- Adverse effects include, flushing, ness, diarrhoea and eosinophilia. itching, vomiting, diarrhoea and dyspepsia. It may also lead to hyperpigmentation of GUGULIPID skin, liver dysfunction, hyperglycaemia and Is an indigenous drug obtained from hyperuricaemia. gum guggul used for treatment of It is indicated in type III, IV & V hyper- hyperlipidemia, hypercholesterolemia and triglyceridemia. It lowers VLDL and raise hypertriglyceridemia.

 ChapterChapter PharmacodynamicsPharmacodynamicsPlasma Expanders 4.61. 4 (Mode of Action of Drugs)

Plasma substitutes/expanders are high blood can be arranged. These do not have molecular weight substances when infused O2 carrying capacity. intravenously into blood stream retain flu- The clinically used plasma expanders id in the vascular compartment and exert are classified as in table 4.6.1. oncotic pressure. But before infusing into the blood stream, the following requirement HUMAN ALBUMIN may be present. It is obtained from heat treated pooled human plasma. 100 ml of 20% human albu- • Should have same oncotic pressure min solution is osmotic equivalent of 800 ml with plasma. of whole blood. It draws and holds addi- • Should remain in blood stream for ad- tional fluid from tissues. It can used irrespec- equate period. tive of patient’s blood group. For optimum • Should not be disposed rapidly by benefit it should be used with electrolyte metabolic degradation or by excretion. solutions. It does not interfere with coagu- lation and there is no risk of sensitization. • Should remain stable on storage. Table 4.6.1: Classification of plasma substitutes/ • Should not interfere with blood group- expanders. ing and cross matching. I. Human albumin (20% solution; ALBUSAFE) • Should be compatible with other IV II. Dextran fluid and other drugs. Dextran 70 (Mol. wt. 70,000; 6% solution; • Should be easily sterilized. LOMODEX-70) • Should be pharmacologically inert and Dextran 40 (Mol. wt. 40,000; 10% solution; LOMODEX-40) have a viscosity suitable for infusion III. Degraded gelatin polymer – polygeline (3.5% in into blood stream. electrolyte solution; HAEMACCEL) They are used in conditions where IV. Hydroxyethyl starch (HES; Hetastarch; 6% blood plasma has been lost e.g. shock, burn solution; HESTAR) cases, severe trauma and extensive tissue V. Polyvinylpyrrolidone (PVP; 3.5% solution in damage as a temporary measure till the buffered normal saline; OSMOPLASMA) 200 Section 4/ Drugs Acting on Cardiovascular & Urinary System

It is used in burns, shock, in patients of Side effects include transient skin reac- acute liver failure and on dialysis. tions (urticaria, wheals), hypotension, tachy- cardia, bradycardia, nausea/vomiting, dysp- DEXTRAN noea, a rise in temperature and/or chills may They are most commonly used plasma ex- occasionally occur. In rare cases of severe hy- panders. It is polysaccharide isolated from beet persensitivity reactions leading to shock. sugar which is formed by the action of If side effects occur, the infusion should Leuconstec mesenteroides. It is available in mainly be discontinued at once. Anaphylactic reac- two forms depending upon the molecular tions associated with polygeline are due to weight. Dextran 70 (mol. wt. 70,000) available histamine release. in 6% solution and Dextran 40 (mol. wt. 40,000) available in 10% solution. They are infused in- It is indicated in hypovolaemic shock, travenously in the treatment of shock. Dextran loss of blood and plasma (e.g., trauma, 40 acts more rapidly than dextran 70. It de- burns, preoperative autologous blood or creases the blood viscosity and prevents the plasma donation), and for priming the heart- sludging of RBC’s. Dextran 70 remains in cir- lung machine. In addition, it can be used as culation for longer period (upto 24 hrs) and is a vehicle for various drugs. slowly excreted by glomerular filtration. HYDROXYETHYL STARCH It is commonly used cheap plasma ex- pander and can be stored for a longer period It is similar to glycogen, the starch mol- of time but it may interfere with blood group- ecule is substituted to a selected degree to ing and cross matching. It may trigger ana- achieve a distinct plasma retention and vol- phylactic reaction characterized by urticaria, ume effect. It improves haemodynamics, bronchospasm and decrease in blood pres- macrocirculation, microcirculation, organ sure etc. It can also prolong bleeding time by function, oxygen supply. interfering in coagulation of blood. After IV administration it is enzymatically metabolised by endogenous amylase. The DEGRADED GELATIN POLYMER – smaller fragments undergo rapid glomerular POLYGELINE filtration. The 6% iso-oncotic infusion solution It is a polypeptide and exerts oncotic allows precise blood volume control and leads pressure similar to albumin. It remains in to an effective stabilisation of blood volume, circulation for 12 hours and is slowly ex- whereas 10% hyperoncotic infusion solution creted by the kidney. It does not interfere has a greater expansive volume effect. It im- with blood grouping and cross matching. proves plasma volume for 24 hours or more. It is a plasma substitute which corrects Adverse effects include anaphylactoid circulatory insufficiency due to plasma/ reactions, manifesting as itching, chills, ur- blood volume deficiency, absolute (e.g., re- ticaria, shock and bronchospasm. In rising sulting from bleeding) or relative (e.g., re- doses it can influence coagulation mecha- sulting from a shift in the blood volume be- nism without triggering clinical haemor- tween the circulatory compartments). rhage. Plasma Expanders 201

POLYVINYLPYRROLIDONE (PVP) 6. To provide adequate calories to the It is a synthetic, water soluble polymer body. of molecular weight approximately 40,000. NORMAL SALINE It is 3-5% solution in buffered physiological It is indicated in: saline administered intravenously. It pro- duce agglutination of RBC’s and therefore 1. When alkalosis is present alongwith interferes with blood grouping and cross fluid loss. matching and also releases histamine. It also 2. In case of severe salt depletion when binds certain drugs i.e. insulin, penicillin etc. rapid electrolyte restoration is essen- Because of these drawbacks, it is less com- tial. monly used. 3. In the treatment of low salt syndrome Plasma expanders are not used in severe which may occur in presence of heart failure, renal impairment, during sur- anaemia, cardiac failure, pulmonary edema gery, etc. In these cases chloride loss and renal failure. frequently exceeds sodium loss. Apart from colloidal plasma expanders 4. In severe salt depletion resulting from crystalloid (electrolyte) fluids are used in excessive fluid loss due to sweating, certain clinical conditions. vomiting, diarrhoea, etc.

DEXTROSE (5%) SOLUTION RINGER LACTATE Ringer lactate (contain calcium chloride, 1. It is used in prevention of: potassium chloride, sodium chloride and • Dehydration of all types. sodium lactate) is indicated in: • Excessive tissue protein catabolism. • Depletion of liver glycogen. 1. For replacing the deficit of ECF due to decreased water intake or increased • As vehicle for IV administration of secretion of water even in absence of numerous drugs. marked acid base disturbance. 2. When oral intake of food and water is 2. In case of burns, infections, fractures, limited as in pre and postoperative pa- peritoneal irrigation etc. For the resto- tients or in the patients with severe ration of normal ECF balance during hepatic or cardiac or GIT disease. surgery. 3. Correction of deficit of water as in case 3. In moderate metabolic acidosis which of inadequate intake and excessive occurs in cases of mild renal insuffi- losses in urine and perspiration. ciency, infant diarrhoea, diabetic keto- 4. In the treatment of ketosis in starvation, sis etc. diarrhoea, vomiting or high fever. 4. In diabetes mellitus to provide potas- 5. In promotion of sodium excretion sium to ECF. when there is excess sodium in the 5. During or after giving anaesthesia, to body due to excessive use of electro- correct metabolic acidosis which results lyte solutions. from disturbed respiration.  This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsDiureticsDiuretics andand 1.4.7 4 (ModeAntidiureticsAntidiuretics of Action of Drugs)

Diuretics are the agents which increase the BENZOTHIAZIDES rate of urine formation by the kidneys, or which cause a net loss of sodium and The main action of thiazides is exerted on water in urine, i.e. the diuretics increase the early segment of distal tubule or cortical the urine output of ions and fluids from diluting segment. They inhibit reabsorption the kidneys. of sodium and chloride. The thiazides enter the tubule partly by glomerular filtration Clinically, diuretics are among the most and partly by active secretion into the widely prescribed drugs used in the proximal tubule. At usual therapeutic doses, management of hypertension and various the major portion of the diuresis is due to edematous states like congestive heart an inhibition of reabsorption in the more failure, nephrotic edema and in some cases distal parts of the nephron. of edema in pregnancy. Almost all diuretics exert their action Pharmacodynamics at the luminal surface of the renal tubule In maximal doses, chlorothiazide will cells. Their mechanism of action includes markedly increase excretion of water, Na+, + – – interaction with specific membrane K , Cl and HCO3 . Chlorothiazide due to its transport proteins like thiazides, weak carbonic anhydrase activity, can cause furosemide etc., osmotic effects which some loss of bicarbonate in therapeutic dose. prevent the water permeable segments of Because of the marked inhibitory action the nephron from absorbing water like on sodium reabsorption, a large amount of mannitol, and specific interaction with sodium is made available to the distal tubule enzyme like carbonic anhydrase where exchange of potassium with sodium inhibitors i.e. acetazolamide, and takes place, this causes potassium loss. hormone receptors in renal epithelial cells Thiazides, due to their direct action on like spironolactone. blood vessels and on sodium metabolism They are classified as in table 4.7.1. produce a mild hypotension. They also tend 204 Section 4/ Drugs Acting on Cardiovascular & Urinary System

Table 4.7.1: Classification of diuretics. I. Benzothiazides and related compounds a. Thiazides Chlorothiazide (DIURIL) 0.5-2 g/day Polythiazide (NEPHRIL) 1-3 mg/day Cyclopenthiazide (NAVIDREX) 0.5-1.5 mg/day Benzthiazide (FOVANE) 25-100 mg/day b. Thiazide like compounds Chlorthalidone (HYTHALTON) 50-200 mg/day Xipamide (XIPAMID) 20-60 mg/day Indapamide (LORVAS) 2.5 mg/day II. High ceiling or loop diuretics a. Sulphamoyl derivatives Furosemide (Frusemide; LASIX) 20-80 mg/day Bumetanide (BURINEX) 1-5 mg/day b. Phenoxyacetic acid derivatives Ethacrynic acid (EDECRIN) 50-150 mg/day III. Carbonic anhydrase inhibitors Acetazolamide (DIAMOX) 250-500 mg/day IV. Potassium - sparing diuretics a. Directly acting Triamterene (DYTIDE) 50-100 mg/day Amiloride (MIDAMOR) 5-10 mg/day b. Aldosterone antagonist Spironolactone (ALDACTONE) 25-200 mg/day V. Osmotic diuretic Mannitol (OSMITROL) 1-2 g/kg as 10 to 20% solution IV Isosorbide (ISMOTIC) 1.5 g/kg as oral solution Urea (sterile; UREAPHIL) 40-120 g IV in 4% or 30% solution VI. Organic mercurials Mersalyl sodium (SALYRGAN) 1-2 ml of 100 mg/ml solution IM twice weekly Meralluride (MERCUHYDRIN) 1-2 ml IM twice weekly VII.Miscellaneous or minor diuretics a. Acidifying or alkalinizing salts Ammonium chloride 2-4 g/day Potassium citrate 0.3-1 g TDS b. Xanthines Aminophylline 250-500 mg IV Diuretics and Antidiuretics 205 to reduce glomerular filtration rate by their therapy in controlling the edema asso- action to reduce blood volume, also decrease ciated with CHF and cirrhosis. positive free water formation. Although this 2. Hypertension: They are widely used in response is less than that seen with ADH- the treatment of hypertension with or deficient diabetes insipidus patients treated without edema and often serve as the with ADH, it is sufficient to reduce first drug of choice. significantly urinary frequency and water 3. Diabetes insipidus: They reduce urine consumption. volume in both pituitary and renal dia- betes insipidus. They are especially Pharmacokinetics valuable for the latter in which ADH is All thiazides and related compounds are ineffective. well absorbed from the GIT and begin to produce diuresis within one hour after oral HIGH-CEILING OR LOOP DIURETICS administration, but the duration is variable, These are the most efficacious agents which are due to variation in rates of renal available for inducing marked water and tubular secretion and clearance, metabolism, electrolyte excretion. The peak diuresis is far and enterohepatic circulation. Approximately greater than that observed maximally with 50 percent of an oral dose is excreted in urine other diuretics. The drugs in this group within 6 hours. Most of the agents undergo little include furosemide, bumetanide and hepatic metabolism and excreted as such. ethacrynic acid and the main site of action However indapamide is extensively is the thick ascending limb of loop of Henle, metabolized. thus they are often called ‘loop diuretics.’ Adverse Reactions The high-ceiling diuretics act primarily by inhibiting electrolyte reabsorption in the In the presence of severe renal and hepatic thick ascending limb of the loop of Henle. disease, these drugs may precipitate renal As much as 20% of the filtered Na+ may be failure or hepatic coma. The most important reabsorbed in the loop of Henle. toxic effect associated with thiazide therapy These agents bind to Cl– binding site of is hypokalemia and hypochloremic alkalosis. Na+-K+-2Cl– cotransporter glycoprotein and The thiazides may induce hyperglyce- inhibit its transport function in ascending mia and aggravate pre-existing diabetes limb of loop of Henle. mellitus, the pharmacological effect of oral These agents tend to increase renal blood hypoglycemic agents may also be reduced. flow without increasing filtration rate, which Occasionally, they can cause allergic reduces fluid and electrolyte reabsorption reactions like rashes, photosensitivity, in the proximal tubule and may augment the thrombocytopenic purpura, dermatitis etc. initial diuretic response.

Therapeutic Uses Pharmacodynamics 1. Edema: Thiazides are useful adjunctive After oral administration, the intense 206 Section 4/ Drugs Acting on Cardiovascular & Urinary System diuretic action starts within one hour and commonly in patients with renal lasts up to 4 to 6 hours. Furosemide produces insufficiency. more loss of chloride than sodium, potassium loss also occurs, which is probably an indirect Therapeutic Uses effect due to the large Na+ load reaching to Edema: The high ceiling diuretics are the distal tubules. In low doses, these drugs effective for the treatment of edema of – + do not appreciably effect HCO3 or H cardiac, hepatic or renal origin. They are the excretion. drug of choice in case of congestive heart failure. These are preferred initially in all Pharmacokinetics cases for rapid mobilization of edema fluid. All the loop diuretics are rapidly IV administration of furosemide absorbed from the GIT, usually within 30 produces prompt relief in acute pulmonary minutes after oral, and 5 minutes after IV edema (acute left ventricular failure, administration. The bio-availability of following myocardial infarction). This is due furosemide is about 60% while that of to the vasodilator action that precedes the bumetanide is nearly 100%. They are saluretic action. extensively bound to plasma proteins, but In the management of refractory edema, they are rapidly secreted by the organic acid the high ceiling diuretics may be used in transport system of the proximal tubule. They conjunction with other types of diuretics. produce a peak diuresis in about 2 hours with They are also useful for forced diuresis in a total duration of diuretic action of 6 to 8 hypnotic or other poisonings. hours. Furosemide is mainly excreted BUMETANIDE unchanged by glomerular filtration as well Bumetanide is chemically similar to as tubular secretion. furosemide. It induces very rapid diuresis. The site and mechanism of action is similar Adverse Reactions to furosemide but it is 40 times more potent Abnormalities of fluid and electolyte than furosemide. imbalance are the most common forms of It is highly effective in pulmonary clinical toxicity, overdose may result in rapid edema. Adverse effects such as reduction of blood volume, dizziness, hyperuricaemia, potassium loss and orthostatic hypotension, headache, ototoxicity are less than furosemide. hypokalemia. ETHACRYNIC ACID Gastrointestinal symptoms of nausea, Ethacrynic acid is chemically distinct vomiting, diarrhoea are common with from the thiazides and furosemide but ethacrynic acid. ceiling effect is similar. It is a phenoxyacetic Ototoxicity has been reported with all acid derivative that also contains an adjacent the three loop diuretics, which is seen more ketone and methylene group. Diuretics and Antidiuretics 207

It does not inhibit carbonic anhydrase. tion. Peak concentrations in plasma occur Loss of potassium is less marked but chance with in 2 hours and persists for 12 hours of hypochloremic alkalosis are greater. It is after a single dose. Acetazolamide is ex- an irritant and upon oral administration it creted unchanged in urine. Ethoxzolamide produces diarrhoea, gastrointestinal is similar to acetazolamide but more bleeding may occur at higher dose. Chances potent. of hearing loss are greater. So, due to their uniform toxicity, they are no longer used. Adverse Reactions Serious toxic reactions include acidosis, CARBONIC ANHYDRASE INHIBITORS hypokalemia, drowsiness and paresthesia are common with larger doses. ACETAZOLAMIDE Hypersensitivity reactions are rare, they It is a potent, noncompetitive reversible consists of fever, skin reactions, bone- carbonic anhydrase inhibitor. Carbonic marrow depression and sulfonamide like anhydrase is an enzyme which catalyses the renal lesions. reversible reaction Drug induced osteomalacia has been

H2O + CO2 H2CO3 reported with the simultaneous use of Carbonic anhydrase influences the phenytoin. tubular reabsorption of sodium in proximal tubule where biocarbonate absorption occurs Therapeutic Uses and in the distal tubule where sodium is Carbonic anhydrase inhibitors are rarely exchanged for potassium or hydrogen ion used as primary diuretics, because of self- and bicarbonate is formed as the limiting action, production of acidosis, and accompanying anion. The hydration of hypokalemia. They are used in: carbon dioxide takes place under the i. Glaucoma, as adjuvant to miotics. influence of enzyme carbonic anhydrase which forms carbonic acid which dissociates ii. In urinary tract infections or to and breaks into hydrogen and carbonate ions. alkalinise urine to promote the excre- tion of acidic drugs. Acetazolamide inhibits the enzyme iii. In petit mal epilepsy as adjuvant. carbonic anhydrase, and interferes with the ability of the renal tubules to produce and iv. In the management of periodic paraly- secrete hydrogen ions. And, the diuretic sis. action is due to the decreased sodium v. Effective in ameliorating the symptoms biocarbonate absorption in proximal tubules of acute mountain sickness. and diminished hydrogensodium exchange in the distal tubules. DIRECTLY ACTING DIURETICS

Pharmacokinetics TRIAMTERENE AND AMILORIDE All the carbonic anhydrase inhibitors Triamterene and amiloride are non-steroidal are well absorbed after oral administra- potassium sparing diuretics, which interfere 208 Section 4/ Drugs Acting on Cardiovascular & Urinary System with transport in the late segments of the POTASSIUM SPARING DIURETICS nephron by blocking the luminal Na+ channels thus indirectly inhibiting K+ excretion. They SPIRONOLACTONE slightly increase sodium excretion and decrease potassium excretion, particularly when it is high It is a steroid and aldosterone antagonist. due to high potassium intake or use of diuretics Aldosterone acts on the late distal tubules that enhances potassium loss. and collecting tubule cells by combining In addition to these effects, all the with an intracellular receptor which induces potassium sparing diuretics are capable of the formation of aldosterone induced inhibiting urinary H+ secretion in the distal protein, which promotes Na+ reabsorption tubule and cortical collecting duct. and K+ secretion. Spironolactone also increases Ca2+ Pharmacokinetics excretion through a direct effect on tubular About 50% of an oral dose of each agent transport. In relatively high concentrations, is absorbed. Triamterene is about 60 percent it can inhibit the biosynthesis of aldosterone. bound to plasma proteins, while amiloride is bound to a lesser extent. Both drugs are Pharmacokinetics secreted in the proximal tubule, presumably The oral bioavailability of spironolac- by the organic cation secretory mechanism. tone is about 70%. It is extensively bound to plasma proteins and is completely metabo- Adverse Reactions lized in liver. is a major active The serious toxic effect is hyperkalemia. metabolite of spironolactone, which can be Triamterene produces relatively few other converted enzymatically into canrenoate side effects which includes nausea, (hydrolytic product). Canrenoate has no vomiting, dizziness etc. Megaloblastic intrinsic activity, but it can exert their effects anaemia has been reported in patients with by virtue of its interconversion with alcoholic cirrhosis, which is probably due canrenone. to inhibition of dihydrofolate reductase in Adverse Reactions patients with reduced folic acid intake. In patients with renal insufficiency, Therapeutic Uses spironolactone may induce hyperkalemia. Both drugs are used in conjunction with Minor side effects include drowsiness con- other diuretics like thiazide or loop diuretics fusion, gastrointestinal upset, gynaecomastia to augment natriuresis and reduce loss of and menstrual irregularities. potassium. Triamterene may be used in the treatment of congestive heart failure, cirrhosis Therapeutic Uses and the edema caused by secondary Spironolactone is generally used in hyperaldosteronism. Amiloride is also useful combination with other, more efficacious in lithium induced diabetes insipidus. diuretics. Diuretics and Antidiuretics 209

i. It is widely used in the treatment of tubular fluid to exert an osmotic effect and hypertension and in the management thus continue urine formation. of refractory edema. It is also used to reduce intraocular ii. Hypokalemia: Potassium sparing di- pressure prior to eye surgery for glaucoma. uretics have been used in patients with Mannitol has been used to reduce cerebral low serum K+ resulting from other di- edema. uretics, like thiazide and loop diuretics. The adverse reactions associated with iii. Edema: It has been used in cirrhotic and mannitol administration are nausea, nephrotic edema. vomiting, headache and hypernatremia.

OSMOTIC DIURETICS UREA Osmotic diuretics are non-electrolytes, Urea is administered intravenously and freely filterable at the glomerulus, undergo useful for reducing a raised cerebrospinal limited reabsorption by the renal tubules. fluid pressure during neurosurgery and The amount of diuresis produced is cerebral edema after head injury. proportional to the quantity of osmotic Urea is contraindicated in patients with diuretic, therefore for more diuresis, a large quantity of osmotic diuretic should be given. severe impairment of renal, hepatic or The primary effect of osmotic diuretics cardiac function due to their potential effect involves an increased fluid loss caused by on expansion of the extracellular fluid osmotically active diuretic molecule. This volume. results in reduced reabsorption of sodium ISOSORBIDE and water in proximal tubule and since the tubule is permeable to water, there is a Isosorbide is an orally active diuretic, passive back diffusion of water, such a most commonly used in the emergency process keeps the tubular fluid isotonic. treatment of acute angle-closure glaucoma. They also tend to increase glomerular filtration rate. ORGANIC MERCURIALS

MANNITOL In earlier twenties, these agents were Mannitol is not absorbed from the GIT diuretics of choice, but after the introduc- and must be given IV and is osmotically tion of thiazides and loop diuretics, the more active than urea. organomercurials have been almost re- placed. Mannitol is useful in clinical conditions which are characterized by hypotension and Mercurials depress the tubular decreased glomerular filtration. It is useful reabsorption of sodium at several sites in maintaining kidney function under these including loop of Henle and some portions conditions, even at low rates of filtration a of proximal and distal tubules. They inhibit sufficient amount of mannitol may enter the the reabsorption of Cl– and Na+. 210 Section 4/ Drugs Acting on Cardiovascular & Urinary System

The mercury ion is capable of caus- ANTIDIURETICS ing local or systemic toxicity. For local irritation, they are combined with theo- Antidiuretic agents reduce urine volume phylline in an attempt to diminish the and are used in the treatment of diabetes irritative toxicity at the site of injection. insipidus. They are classified as in table 4.7.2. IV administration may lead to ventricu- VASOPRESSIN lar arrhythmias. They cause hepatocellu- lar damage and even precipitate hepatic The antidiuretic hormone is an failure. They can also lead to low salt octapeptide released from the posterior lobe syndrome, hypochloraemic alkalosis and of pituitary gland. It is used in the treatment potassium depletion. of diabetes insipidus. ADH reduces the total urine volume and absence of this hormone MISCELLANEOUS COMPOUNDS cause diabetes insipidus. ADH acts on collecting duct cells to increase their water Ammonium Chloride permeability. It acts on V2 receptors in collecting duct and regulate their water Ammonium chloride was used earlier along permeability through cAMP production. with mercurials, as they act best in acidosis, ADH in larger dose increases the blood but now-a-days, it is not used as diuretic. pressure by direct stimulation of vascular It is converted to urea in liver and free smooth muscle. It also stimulates the hydrogen ion are liberated in the body which smooth muscle of gastrointestinal tract and tilt the buffer system towards acidosis. increase the peristalsis. It is inactive orally because it is destroyed by trypsin. It can be Potassium Citrate administered by any parenteral route or by Potassium citrate alkalinises the urine nasal spray. Vasopressin is indicated in and increases its volume. They are used to diabetes insipidus and in treatment of change the pH of urine. postoperative abdominal varices.

Table 4.7.2: Classification of antidiuretics. I. Antidiuretic hormone (vasopressin) Vasopressin (VASOPIN) 5-20 U SC/IM Desmopressin (MINIRIN): 0.2-0.4 mg/day HS II. Thiazide diuretics Hydrochlorothiazide (Details are given in section 25-50 mg TDS on ‘Diuretics’) III. Miscellaneous agents Carbamazepine (Antiepileptic drug, MAZETOL) 200-600 mg BD Chlorpropamide (Oral hypoglycemic agent, DIABINESE) 100-50 mg OD Diuretics and Antidiuretics 211

Adverse effects include nausea, belching, reducing the volume of urine produced abdominal cramps, hypersensitivity without any pressor effects. reactions etc. Oral administration of 0.1-0.2 mg DESMOPRESSIN desmopressin provides an antidiuretic effect lasting for 8-12 hours. Desmopressin does not Desmopressin is a synthetic analogue cross blood brain barrier and maximal plasma of vasopressin. Two chemical changes have concentrations are reached within 2 hours. been made to natural hormone, namely After oral administration, t½ varies between dissemination of and substitution 2.0 hours and 3.2 hours. 65% of oral of 8-L-arginine by 8-D-arginine. These desmopressin absorbed is excreted unchanged structural changes result in a compound in the urine. It is also used as a nasal spray. with significantly increased antidiuretic potency, very little activity on the smooth Adverse effects include headache, muscles, hence the avoidance of nausea and stomach pain and in very rare undesirable pressor effects. Desmopressin cases epistaxis. Treatment without proved to be a highly selective diuretic concomitant restriction of water intake may agent with a ratio between antidiuretic and lead to water retention with accompanying vasopressor activity in excess of 2,000 : 1. (reduced serum Desmopressin is more stable than sodium, weight gain and in serious cases, vasopressin and this is reflected in its convulsions). prolonged duration of action. Therapeutic Uses Desmopressin is a pure V2 receptor agonist. When bound to V2 receptors in the • Nocturia in adults. kidney, it increases the permeability of the • Primary nocturnal enuresis. collecting ducts and tubules thereby • Central diabetes insipidus: Desmo- enhancing water reabsorption and pressin is preparation of choice.

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Histamine and ChapterChapter Pharmacodynamics PharmacodynamicsPharmacodynamicsAntihistaminic (Mode of Action of Drugs) 1.45.1 Agents

The term ‘autacoid’ is derived from Greek, Histamine is an imidazole compound, autos – self and akos – remedy. These are formed by decarboxylation of the amino acid formed in various tissues of the body and L-histidine, a reaction catalyzed by the generally act locally at the site of synthesis enzyme histidine decarboxylase. and release in the body. They have also been Histamine is found in most of the tissues, called ‘local hormones’ and differ from hormones which are secreted from present in various biological fluids. In most endocrine glands. The hormones are tissues, histamine exists in bound form in produced by specific cells (endocrine granules, in mast cells or basophils. These glands), and are transported through mast cells are especially rich at sites of circulation to the distant target organs while potential tissue injury i.e. skin, lungs, liver, autacoids are produced in tissues rather than GIT etc. and is unevenly distributed. It is in glands. also present in many (of bees & wasps), bacteria and plant tissues. The important autacoids include: • Histamine, Histamine Receptors • Hydroxytryptamine (5-HT, serotonin), The present evidence indicates that • Prostaglandins, histamine act on three types of receptors • Leukotrienes, and namely H1, H2 & H3. • Kinins. The contraction of smooth muscle, HISTAMINE increase in vascular permeability and mucus secretion are mediated by H1 receptors and is Histamine is a potent biogenic amine, occurs associated with increase in intracellular cyclic in tissues in almost all forms of life and GMP. These type of effects are competitively released in a free state in response to injury blocked by H1 receptor antagonists or to any antigenantibody reaction. (antihistaminics) like . 216 Section 5/ Autacoids

Table 5.1.1: Classification of antihistaminic agents. I. Ethanolamines Diphenhydramine (BENADRYL) 25-50 mg/day (DRAMAMINE) 25-50 mg/day, IM II. Ethylenediamines Pyrilamine maleate (DORANTAMIN) 25-50 mg/day Tripelennamine 25-50 mg/day III. Alkylamines Pheniramine maleate (AVIL) 25-50 mg/day, IM Chlorpheniramine maleate (PIRITON) 2-4 mg/day, IM Triprolidine (ACTIDIL) 2.5-5 mg/day IV. Phenothiazines Promethazine (PHENERGAN) 25-50 mg/day, IM Promethazine chlorotheophyllinate (AVOMINE) 25-75 mg/day V. hydrochloride (MAREZINE) 50 mg/day hydrochloride (ANCOLAN) 25-50 mg/day Buclizine (LONGIFENE) 25-50 mg/day VI. Piperidines: Loratidine (LORMEG) 10 mg OD Fexofenadine (ALLEGRA) 60-180 mg OD Astemizole (STEMIZ) 10 mg/day VII. Miscellaneous compounds Cetirizine (CETZINE) 10 mg/day Levocetirizine (TECZINE) 5 mg/day (Antihistaminic/antiserotonin; PERIACTIN) 4 mg/day (Antivertigo; STUGERON) 25-50 mg/day

ANTIHISTAMINICS mine. They antagonize the stimulant actions of histamine on various smooth Antihistaminics are classified in table 5.1.1. muscles of the respiratory system, gas- trointestinal tract, the uterus and the Pharmacological Actions blood vessels. They inhibit the hyperten- sive effect (in rabbits & guinea pigs) and Most of the antihistaminics (H1-receptor antagonists) have similar pharmacological hypotensive effect (in cat & dog) pro- duced by histamine. They also reduced actions and conventionally can be discussed the triple response induced by histamine together. injection. 1. Antihistaminic action: The antihista- Histamine induced bronchospasm in minics blocks histamine effects at a many animal species, especially in guinea variety of sites. They inhibit most re- pigs can easily be antagonized by antihis- sponses of smooth muscles to hista- taminics. Histamine and Antihistaminic Agents 217

2. Action on central nervous system: antagonists block sodium channels in Majority of antihistaminic drugs excitable membranes in the same way as produce variable degree of CNS procaine and lignocaine. The drugs like depression i.e. sedation, drowsiness and diphenhydramine and promethazine are sleep. Drugs like diphenhydramine, occassionally used to produce local promethazine are potent sedatives and anaesthesia in patients allergic to local is often accompanied by inability to anaesthetic drugs. concentrate. 8. Antiserotonin effect: Drugs, like The newer H -antagonists such as 1 cyproheptadine is promoted as an terfenadine and astemizole are claimed to antiserotonin agent. have little or no sedative action. Astemizole is also claimed to be free of autonomic Pharmacokinetics blocking effects. Loratidine is claimed to H1-antagonists are well absorbed from have little autonomic and CNS blocking the gastrointestinal tract. Following oral effects. administration, antihistaminic effect is 3. Antimotion sickness effect: Several manifested within 30 minutes, peak plasma concentration is achieved in 2 to 3 hours and H 1-antagonists have significant property in preventing motion effects usually last 4 to 6 hours. However, sickness. This effect was first observed drugs in piperazine subgroups especially with drug, dimenhydrinate and and meclizine, the actions subsequently with other drugs like persists for 8 to 12 and 12 to 24 hours diphenhydramine, promethazine and respectively. other piperazine derivatives. The drugs are mainly metabolized in the 4. Anticholinergic effects: Many of the liver by hydroxylation and glucuronide

H1-antagonists also tend to inhibit conjugation, widely distributed throughout responses to acetylcholine that are the body and excreted in the urine. mediated by muscarinic receptors. The newer agents, terfenadine and Adverse Reactions astemizole have no effect on The most common side effect, common muscarinic receptors. to all H1 antagonists other than terfenadine

5. Adrenergic blocking effect: H1- and astemizole is sedation. Other untoward antagonists, specially of phenothiazine reactions include fatigue, dizziness, tinnitus, subgroups have weak alpha-receptor lassitude, blurred vision, diplopia, euphoria, blocking effect. nervousness, tremor and insomnia. 6. Antiparkinsonism effects: Because of Side effects include loss of appetite,

anticholinergic property, some H1- nausea, vomiting, epigastric distress, antagonists have significant constipation or diarrhoea. Side effects due suppressant effect on the parkinsonism to antimuscarinic actions of H1-antagonists like symptoms. include dryness of mouth, bladder

7. Local anaesthesia: Most of the H1 disturbances. 218 Section 5/ Autacoids

Therapeutic Uses logically active doses and with additional antiallergic properties. It is a selective H H1 antagonists have a widespread value 1 in the symptomatic treatment of various antagonist with negligible effects on other disorders. receptors and is, therefore, virtually free 1. Hypersensitivity reactions: To prevent from anti-cholinergic and anti-serotonin ef- allergic reactions or to treat their fects. Cetirizine inhibits the histaminemedi- symptoms, in which histamine is the ated ‘early’ phase of the allergic reaction and

primary mediator, the H1-antagonists also reduces the migration of inflammatory are the drugs of choice and are often cells such as eosinophils and the release of quite effective. They are used primarily mediators associated with ‘late’ allergic to treat allergic reactions produced by response. the release of histamine e.g., edematous states, pruritus, allergic rhinitis and Cetirizine is indicated for the urticaria. They are generally more symptomatic treatment of perennial allergic effective in acute conditions and are rhinitis, seasonal allergic rhinitis, chronic used only for symptomatic relief. idiopathic urticaria, conjunctivitis and 2. Motion sickness: Drugs like promet- pruritus in adults and children above two hazine, promethazine chlorotheophyl- years of age. linate, diphenhydramine, dimenhydri- Side effects include headache, dizziness, nate, cyclizine and meclizine have drowsiness, dry mouth and gastrointestinal value in prophylaxis of motion sickness. discomfort. 3. Antivertigo: Drugs line cyclizine, cin- narizine, dimenhydrinate, diphenhy- LEVOCETIRIZINE dramine are used in the treatment of The second generation H -receptor an- vertigo. 1 4. Antiparkinsonism: Based on tagonist cetirizine is a reacemate consist- ing of equal quantities of 2 enantiomers, anticholinergic property, some H1- antagonists such as diphenhydramine levocetirizine [(R)-enantiomer] and can be used in the early stages of dextrocetirizine [(S)-enantiomer]. In vitro treatment of parkinsonism. and human pharmacodynamic studies 5. Local anaesthetics: In patients allergic have provided evidence that levocetirizine

to procaine H1-antagonists, such as is the more active enantiomer, accounting diphenhydramine and tripelennamine for most or all clinical antihistaminic activ- have been used successfully as local ity of racemic cetirizine; this activity of anaesthetic. levocetirizine is seen at half the dose of NEWER ANTIHISTAMINICS cetirizine. Levocetirizine exhibit a 2-fold higher CETIRIZINE affinity for human H1-receptors than Cetirizine is a potent antihistaminic with a cetirizine, and is about 10 fold more potent low potential for drowsiness at pharmaco- than the (S)-enantiomer. Levocetirizine Histamine and Antihistaminic Agents 219

dissociates more slowly from the H1- Fexofenadine hydrochloride is rapidly receptor than the (S)-enantiomer. absorbed into the body following oral It is well absorbed with an oral administration, with Tmax occurring at bioavailability of 85%. Onset of action occurs approximately 1-3 hours post dose. It is 60- within one hour. 70% plasma protein bound. Indications for levocetirizine remain the Side effects include headache, fatigue, same as those of cetirizine. drowsiness, nausea, tachycardia, palpita- tions, dry mouth, GIT disturbances, taste Adverse reactions include headache, disturbances, photosensitivity, dysmenor- fatigue etc. rhoea and menstrual disorders. FEXOFENADINE The newer antihistaminics agents e.g. Azelastine inhibits histamine release and also It is a pharmacologically active inflammatory reactions evoked by metabolite of terfenadine, is a non sedating leukotrienes and plasma activating factor antihistaminic with selective peripheral H 1 (PAF). It is used for seasonal and perennial receptor antagonist activity. allergic rhinitis in the form of nasal spray. Fexofenadine inhibited antigen-induced Mizolastine, a non-sedating antihistaminic is bronchospasm and histamine release from mast used in allergic rhinitis and urticaria. Ebastine, cells. No anticholinergic or alpha adrenergic- another non-sedating antihistaminic is used receptor blocking effects were observed. in nasal and skin allergies. Moreover, no sedative or other CNS effects were observed. Fexofenadine does not cross the H2-RECEPTOR ANTAGONISTS blood-brain barrier. It inhibits skin wheal and As discussed earlier, H2 receptors are flare responses produced by histamine responsible for histamine induced gastric injection. Following single and twice daily oral acid secretion. H2-receptors antagonists such administration, antihistaminic effects occurred as cimetidine, ranitidine, famotidine etc. are within 1 hour, achieved a maximum at 2-3 used in the treatment of peptic ulcer and are hours, and lasted a minimum of 12 hours. discussed in chapter ‘Antiulcer agents’.

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ChapterChapter PharmacodynamicsPharmacodynamicsSerotoninSerotonin andand itsits 1.45.2 (ModeAntagonistsAntagonists of Action of Drugs)

acts directly to constrict the arteries and 5-HYDROXYTRYPTAMINE (5-HT, SEROTONIN) increases the peripheral vascular resistance. 5-Hydroxytryptamine is widely distributed The released adrenaline from adrenal in plant and animal tissues, mast cells, medulla, affects ganglionic transmission and platelets, the enterochromaffin cells located evokes cardiovascular reflexes. throughout the gastrointestinal tract, and On heart, 5-HT has weakly direct in certain regions of the brain. It is also positive inotropic and chronotropic effects, present in the venoms and stings. Some that are mediated by 5-HT1 receptors. 5-HT3 fruits such as bananas, pineapples, receptors are also present on vagal nerve tomatoes and plums contain considerable endings in the coronary bed, which evoke amount of 5-HT. bradycardia and hypotension. It is an indole ethylamine formed in A characteristic ‘triphasic response’ is biological systems from the amino acid L- observed after intravenous injection. The by hydroxylation with early transient fall in blood pressure is due tryptophan hydroxylase enzyme, followed to stimulation of chemoreceptors. The by the decarboxylation by the nonspecific second phase, pressor effect is due to aromatic L-amino acid decarboxylase. 5-HT vasoconstriction. The final depressor phase is then taken up into secretory granules and is due to vasodilator action on the skeletal stored. muscle. Pharmacological Actions Smooth muscle: 5-HT stimulates Cardiovascular system: 5-HT can smooth muscles, it increases the motility of directly stimulate or relax smooth muscles the small intestine, stomach and also large intestine by which peristalsis is increased & via 5-HT1 & 5-HT2 receptors and can influence the release of noradrenaline from diarrhoea can occur. adrenergic nerves and stimulate endothelial It also constricts bronchial smooth cells to release EDRF and prostaglandins. It muscles, but is less potent than histamine. It 222 Section 5/ Autacoids

Table 5.2.1: Classification of 5-HT antagonists. I. Ergot alkaloids and derivatives Ergotamine 1-3 mg/day, 0.25-0.5 mg SC/IM diethylamide (LSD) 2-Bromolysergic acid amide (BOL) Methysergide (Congener of LSD; SANSERT) 2 mg BD-TDS II. Antihistaminics Cyproheptadine (PERIACTIN) 4 mg/day Cinnarizine (STUGERON) 25-50 mg/day III. Phenothiazines Chlorpromazine (LARGECTIL) 25-100 mg/day, IM IV. Selective 5-HT blockers (SUFREXAL) 10-30 mg/day (PIZOTYLINE) 0.5-1 mg/day can also stimulate the smooth muscles of uterus. It antagonises the vasoconstrictor and Nerve endings: 5-HT is less potent than pressor effect of 5-HT as well as the action histamine in releasing catecholamines from of the amine on a variety of extravascular smooth muscles. adrenal medulla. 5-HT3 receptors located on various sensory neurons mediate a It has been used for migraine prophy- depolarising response, which may cause laxis, vascular headaches, postgastrectomy pain & itching. dumping syndrome and also used to combat diarrhoea and malabsorption in car- 5-HT ANTAGONISTS cinoid patients. 5-HT antagonists are classified in table 5.2.1. Common side effects include nausea, vomiting, heartburn, diarrhoea. Central Many of the drugs are partial agonists effects include drowsiness, weakness, or antagonise certain action of 5-HT but stimulate others. The two drugs that are nervousness, insomnia, confusion, excite- usually classified as 5-HT antagonist namely ment and hallucinations. methysergide and cyproheptadine is used CYPROHEPTADINE as a potent 5-HT1 antagonist, while another drug, ketanserin is highly selective for Chemically, it is a phenothiazine derivative and has equal potency at both blocking 5HT2 receptors. H1-histamine and 5-HT receptors as an METHYSERGIDE antagonist. As H1-histamine antagonist it Chemically, methysergide is 1-methyl-d- has been used in various allergic lysergic acid butanolamide, congener of conditions. It increases the appetite and methylergonovine and of LSD. promotes weight gain. Serotonin and its Antagonists 223

As 5-HT antagonist it is used in 5-HT1 & 5-HT3 receptors. It blocks 5-HT controlling intestinal manifestations of induced vasoconstriction, platelet carcinoid and postgastrectomy dumping aggregation and contraction of airway syndrome. In addition, it has weak smooth muscle. anticholinergic and sedative properties In addition, it has adrenergic, H and also. 1 dopaminergic blocking activity also. Side effects include drowsiness, dry mouth, weight gain and confusion. Ketanserin is an effective antihyperten- sive, but the mechanism of action is not KETANSERIN clear.

Ketanserin is a highly selective 5-HT2 Side effects include dry mouth, antagonist and has no significant action on sedation, nausea, dizziness etc.

 This page intentionally left blank ProstaglandinsProstaglandins ChapterChapter Pharmacodynamics andand (Mode of Action of Drugs) 5.3 LeukotrienesLeukotrienes

EICOSANOIDS – PROSTAGLANDINS AND Inhibitors of Eicosanoid Biosynthesis LEUKOTRIENES Salicylates and related non-steroidal anti-inflammatory drugs inhibit In 1935, von Eular demonstrated a substance cyclooxygenase, thus all the PG’s formed by present in the extracts of human seminal this pathway i.e. PGG , PGE , PGD , PGF , fluid, which caused contraction of the isolated 2 2 2 2a TXA and prostacyclin can not be intestine and uterine muscle. This substance 2 synthesized. was named as ‘prostaglandin’ (PG) because of its probable origin from the prostate gland. Pharmacological Actions In 1962, the structure of two prostaglandins Uterus: Uterine smooth muscle from namely PGE1 & PGF2a were elucidated and pregnant women are uniformly contracted in 1964, PGE2 was biosynthesized. by PGF’s. PGI2 and high concentrations of Biosynthesis and Metabolism PGE2 produce relaxation. While, nonpreg- Prostaglandins (PG’s) and leukotrienes nant human uterus are contracted by PGF’s (LT’s) are biologically active derivatives of but relaxed by PGE’s. 20 carbon atom polyunsaturated essential Bronchial muscle: Bronchial and fatty acids, which contains 3, 4 or 5 double tracheal muscle are contracted by PGF’s & bonds (e.g. 5, 8, 11, 14-eicosatetraenoic acid PGD and relaxed by PGE’s. Asthmatic i.e., arachidonic acid). 2 patients are sensitive to PGF2a and PGE1 & In human being, arachidonic acid is the PGE2 causes bronchodilatation. LTC4 & most important precursor for the LTD are bronchoconstrictors. biosynthesis of eicosanoids. Arachidonic 4 acid is formed from linoleic acid in most Gastrointestinal tract: Longitudinal mammalians by desaturation and carbon muscle is contracted by PGE2 & PGF2a, while elongation to dihomog-linolenic acid and circular muscle is contracted by PGI2 & subsequent desaturation. PGF2a and relaxed by PGE2. 226 Section 5/ Autacoids

PGE’s & PGI2 also inhibit gastric acid renal blood flow and may serve to regulate secretion stimulated by gastrin or histamine. urine formation. It also plays a role in the regulation of the secretion of renin (PGI , Cardiovascular system: PGE’s are 2 PGE & PGD evoke release of renin). PGE potent vasodilators. However, PGF’s 2 2 2 and PGI cause renal vasodilatation while constricts arterioles and veins. PGI inhibits 2 2 TXA causes renal vasoconstriction. the aggregation of human platelets in vitro. 2 TXA is a very powerful inducer of platelet 2 Uses of Prostaglandins aggregation. LTB4 stimulates the aggregation of polymorphonuclear 1. Abortifacient: Intra-amniotic adminis- leukocytes. tration of PGF2a produced abortion with Endocrine system: Systemic less severe adverse effects. It is used to administration of PGE increases circulating induce second trimester abortion & usu- 2 ally administered as a single 40 mg in- concentration of ACTH, GH, prolactin & traamniotic injection. gonadotrophins. Synthetic PGE2 analogues are also used It has also been observed in experimental as suppositories for abortion. It directly animal that PG’s cause regression of corpus affects the collagenase of the cervix and luteum and reduction in secretion of also stimulates the contraction of the progesterone. uterus. Central & peripheral nervous system: 2. Induction of labour: PG’s do not have PGE & PGE increase body temperature. They 1 2 any advantage over oxytocin for the also contribute importantly to the genesis of induction of labour. The adverse effects the signs and symptoms of inflammation. of the prostaglandins are slightly higher When injected intracerebroventrically, PGE2 than that produced by oxytocin. PGF2a produces sedation, rigidity and increased has more gastrointestinal toxicity than body temperature. PGE2 and is a bronchoconstrictor also.

Kidney: PGE2 and PGI2 increases water, Oral PGE2 is superior to oral oxytocin. + + Na and K excretion and have a diuretic PGE2 & PGF2a is used in place of effect. Prostaglandins probably modulate oxytocin in renal failure patients.

Table 5.3.1: Classification of prostaglandin analogues.

PGE1 Misoprostol (CYTOTEC) 200 µg/day oral Rioprostil

PGE2 Enprostil Arbaprostil Trimoprostil

Dinoprostone (PROSTIN E2)

PGI2 Carbacyclin Iloprost

PGF2α Dinoprost (PROSTIN F2 ALPHA) Prostaglandins and Leukotrienes 227

15-methyl-PGF is used to control 2a 7. PGE1 (Alprostadil) is being used as IV postpartum haemorrhage when infusion in infants with congenital oxytocin and ergot alkaloids fail to heart defects, to maintain the patency control the bleeding. of ductus arteriosus. 3. Peripheral vascular diseases: Infusion or intraarterial injection of prostacyclin LEUKOTRIENES

(PGI2) improves potency of blood vessels in certain peripheral vascular The leukotrienes play a major role in the in- flammatory response to injury and are diseases. Infusion of PGI2 can also reduce the infarct size in immediate implicated in the pathogenesis of many postmyocardial infarction period. inflammatory diseases, most notably asthma,

4. Respiratory system: PGE2 is a powerful allergic rhinitis, cystic fibrosis, glomerulone- bronchodilator when given in aerosol phritis, rheumatoid arthritis, psoriasis, and form, but due to its irritant action on inflammatory bowel disease. Several highly bronchial mucosa its clinical utility is effective cysteinyl leukotriene receptor antag- limited. onists and synthesis inhibitors are now in late 5. Renal system: PGE , PGE & PGI 1 2 2 stage clinical development and are coming increase glomerular filtration through in to the market for the treatment of asthma. their vasodilatory effects and increase water & sodium excretion. There are indications that these new com- pounds are steroid sparing in their actions. 6. Gastric ulcer: PGE2 & PGI2 has been found to promote healing in gastric The development of leukotriene receptor an- ulcer. PGE’s are cytoprotective at low tagonists and synthesis inhibitors for the doses and inhibit gastric acid secretion treatment of other inflammatory conditions at higher doses. is currently a highly active area of research.

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ChapterChapter DrugsPharmacodynamicsPharmacodynamics Used in Cough 5.41. 4 (Modeand of Action Asthma of Drugs)

Cough is a protective reflex which helps in PHARYNGEAL DEMULCENTS expulsion of respiratory secretion or foreign particles which are irritant to respiratory These are the agents which are generally tract. Irritation to any part of respiratory administered in the form of lozenges, cough tract starting from pharynx to lungs carried drops and cough linctus. They produce the impulses by afferent fibres in vagus and soothing action on throat directly and by sympathetic nerve to the cough centre in the increasing the flow of saliva and provide symptomatic relief from dry cough. medulla oblongata. Cough may be dry (without sputum or unproductive) or pro- EXPECTORANT ductive (with sputum production). There are certain factors which are responsible for Expectorants are the drugs which increase production of cough e.g. the production of bronchial secretion and reduce its viscosity to facilitate its removal i. Environmental factors: Certain irritant by coughing. Expectorants can stimulate the pollutants, dust, smoking, automobile expulsion of respiratory secretion either smoke. directly or reflexly. Certain volatile oils of ii. Upper respiratory tract infection. plant origin such as oil of lemon, anise, iii. Acute lung infections, asthma and eucalyptus by steam inhalation route increase certain pleural diseases e.g. pleural the respiratory secretion by its direct action. effusion. Another compound, guaiacol, which is iv. Chronic pulmonary ailments e.g. obtained from wood or synthetically tuberculosis, chronic bronchitis & lung prepared, directly increase bronchial secretion and syrup tolu (Tolu balsum) act cancer etc. in same way. v. Drug induced cough. The second type is reflex expectorant, The various drugs and their combination which acts by stimulating the gastric reflex- used in cough are clasified as in table 5.1.1. es which help to increase the respiratory 230 Section 5/ Autacoids

Table 5.4.1: Classification for drugs used in cough. I. Pharyngeal demulcents Certain lozenges, linctus and cough drops containing glycerine, liquorice and syrups. II. Expectorants Sodium and potassium citrate  Sodium and potassium acetate  0.3-1 g TDS. Used in various preparations as Potassium iodide expectorant Ammonium chloride & carbonate  Acetylcysteine 3-5 ml of 10-20% (as aerosol) 8 mg TDS (used with and cetirizine also) Guaiphenesin 100-300 mg TDS Syrup of Vasaka 2-4 ml TDS Syrup of Tolu 0.3-0.6 g TDS III. Antitussive i. Opioids Codeine (as linctus) 10-30 mg/day Pholcodeine 10-15 mg/day ii. Non-opioids Noscapine 15-30 mg/day 10-20 mg/day Pipazethate 40-80 mg/day iii. Antihistaminics Chlorpheniramine (PIRITON) 2-5 mg/day Diphenhydramine (BENADRYL) 15-25 mg/day Promethazine (PHENARGAN) 15-25 mg/day secretions. Certain salts which are used as sensitive to iodine and chronic use can emetics, when used in subemetic dose, in- induce hypothyroidism and goitre. crease the bronchial secretion and expel it Sodium and potassium citrate and ace- out, they are known as saline expectorants. tate act by increasing bronchial secretion by Ammonium salts (as chloride and car- their salt actions. bonate) are gastric irritant in nature and re- Certain alkaloids such as vasicine flexly increase bronchial secretion. obtained from plant Adhatoda vasica act as Potassium salts (as iodide) act by both potent expectorant and mucolytic agent. direct action and reflexly to increase the Bromhexine, a derivative of vasicine respiratory secretions and decrease its depolymerises mucopolysaccharides directly viscosity thus they are easy to expel out. and by liberating lysosomal enzymes. Potassium iodide is generally used for cough Another compound acetylcysteine opens associated with chronic bronchitis and disulfide bonds in present in asthma but it interferes with thyroid sputum and decrease its viscosity. function tests, so it is dangerous in patients acts in same manner. Drugs Used in Cough and Asthma 231

Erdosteine is recently introduced mucolyt- ANTIHISTAMINICS ic with unique protective functions for the res- Many H antihistaminics have been added piratory tract. It is indicated in the treatment of 1 to antitussive/expectorant formulations. They acute and chronic airway diseases such as bron- do not act on cough centre but provide relief chitis, rhinitis, sinusitis, laryngopharyngitis and due to their sedative and anticholinergic action. exacerbations of chronic bronchitis. BRONCHODILATORS ANTITUSSIVES Bronchodilators are helpful in individ- They are central cough suppressants and act uals with cough and bronchoconstriction centrally to raise the threshold of cough due to bronchial hyperreactivity. They help centre and inhibit the cough reflex by by improving the effectiveness of cough in suppressing the coordinating cough centre clearing secretions. in the medulla oblongata. They are mainly used in dry (unproductive) cough and are ANTIASTHMATIC AGENTS ineffective in cough due to pleural disease. Codeine, which is an opium alkaloid is BRONCHIAL ASTHMA most commonly opiate used as antitussive Asthma is a disease characterized by an in- and more selective for cough centre. Like creased responsiveness of the trachea and morphine, it depresses cough centre but is bronchi to a variety of stimuli and mani- less constipating and abuse liability is low. fests as narrowing of the airways that It is relatively safe drug used in cough along changes in severity either spontaneously or with analgesic property and it’s only impor- as a result of therapy. The impairment of tant adverse effect is constipation. air flow in asthma is caused by three ab- Pholcodeine is similar to codeine in ef- normalities: ficacy and is longer acting. It has no analge- sic or addicting property. a. Constriction of bronchial smooth Noscapine is another opium alkaloid of muscle (bronchoconstriction). benzylisoquinoline group. It is used as b. Swelling of bronchiolar mucosa antitussive with no analgesic and drug abuse or (bronchial edema). drug dependence property. It is contraindicated c. Excessive bronchial secretions. in asthmatic patients as it releases histamine which can cause bronchoconstriction. The drugs used in management of bron- chial asthma can be classified as in table 5.4.1. Dextromethorphan is a synthetic compound and its dextroisomer is used as SYMPATHOMIMETICS antitussive and is as effective as codeine without any addiction liability. β 2-agonists are invariably used in the symp- Pipazethate is another synthetic compound tomatic treatment of asthma. Epinephrine of phenothiazine category used as antitussive and ephedrine are structurally related to the with little analgesic and sedative properties. catecholamine norepinephrine, a neu- 232 Section 5/ Autacoids

Table 5.4.2: Classification for antiasthmatic drugs. I. Bronchodilators i. Sympathomimetics (adrenergic receptor agonists) Adrenaline, ephedrine, isoprenaline, orciprenaline, salbutamol, terbutaline, salmeterol, bambuterol etc. ii. Methylxanthines (theophylline and its derivatives) Theophylline (THEOLONG) 200-400 mg TDS Hydroxyethyl theophylline (DERIPHYLLIN) 250-500 mg/day oral/IM/IV Theophylline ethanolate of piperazine (CADIPHYLLATE) 250-500 mg/day oral/IV iii. Anticholinergics Atropine methonitrate (BROVON INHALANT) 2.5-10 mg/day oral/IM, 1-2 mg (aerosol) Ipratropium bromide (IPRATOP) 40-80 µg day (aerosol) II. Mast cell stabilizer Sodium cromoglycate (CHROMOTOP) 2 mg by aerosol TDS-QID, 2% nasal spray (FINTAL) (AIRYFEN) 1-2 mg/day III. Corticosteroids Beclomethasone dipropionate (BACLATE INHALER) 100-200 µg TDS-QID Beclomethasone (200 µg) with salbutamol (AEROCORT ROTACAPS) 2 rotacaps TDS-QID IV. Leukotriene pathway inhibitors (newer compounds) Montelukast (MONTAIR) 10 mg HS Zafirlukast (ACCOLATE) 20 mg/day rotransmitter of the adrenergic nervous sys- terbutaline and salbutamol are invariably tem. They also protect effectively against the used as bronchodilators both oral as well as challenge with various bronchoconstrictor aerosol inhalants. Salmeterol is long-acting agents and may inhibit microvascular leak- analogue of salbutamol in which the amine β age into the airway. 2-agonists are the drug substituent is a long lipophilic chain, but of choice to relieve acute exacerbation of found to be slower in achieving the peak asthma and prevent bronchoconstriction bronchodilatation effect. The detailed phar- following exercise or other stimuli. After macology is discussed in chapter ‘Adrener- β inhalation the 2-agonists have rapid onset gic Agents’. of action (within minutes), but are active Specific agents used in bronchial asth- only for 4 to 6 hours. ma are discussed here. Their adverse effects are dose-related and are more common after oral than aero- SALBUTAMOL sol administration because of the manifold β It is highly selective 2-adrenergic stim- higher dose required for oral drugs. Some ulant having a prominent bronchodilator β of the important 2-agonists like salmeterol, action. It has poor cardiac action compared Drugs Used in Cough and Asthma 233 to isoprenaline. It is given by oral as well as Increased cAMP leads to bronchodilatation, inhalation route by nebulizer. Palpitation, cardiac stimulation and vasodilatation. restlessness, nervousness are the common side effects with salbutamol. Pharmacological Actions CNS: The caffeine and theophylline are TERBUTALINE pharmacologically CNS stimulants and pro- β It is highly selective 2 agonist similar duce alertness and cortical arousal, but in to salbutamol, useful by oral as well as in- higher doses causes restlessness, nervous- halational route. ness and insomnia. SALMETEROL CVS: Methylxanthines stimulate the heart and increase the force of myocardial It is newer long acting selective β adr- 2 contraction. Tachycardia is more common energic agonist with slow onset of action, with theophylline. Cardiac output is used for maintenance therapy in asthma, increased in CHF patients. nocturnal asthma and asthma induced by exercise. Smooth muscles: Methylxanthines relax smooth muscles especially bronchi in The β selective adrenergic agonists 2 asthmatic patients. Theophylline produces are most widely used drugs for the treat- sustained bronchodilator action. ment of asthma. They are effective after oral and inhaled administration and have Kidney: Methylxanthines exert mild a longer duration of action. Albuterol diuretic action by inhibiting tubular (salbutamol), salmeterol, , pir- reabsorption of sodium and water, In buterol are available as aerosol pack in addition, it increases renal blood flow and metered dose. glomerular filtration rate. Skeletal muscles: Methylxanthines BAMBUTEROL facilitate neuromuscular transmission by β It is a latest selective adrenergic 2 ago- increasing acetylcholine release. nist with long plasma half life and given Mast cells: Methylxanthines inhibit the once daily in a dose of 10-20 mg orally. release of histamine and other mediators from mast cells which indirectly help in the METHYLXANTHINES (THEOPHYLLINE AND ITS management of bronchial asthma. DERIVATIVES) THEOPHYLLINE Among the methylxanthines, aminophylline is most commonly used drug in the treat- Theophylline has two distinct action: ment of bronchial asthma. It is a stable mix- smooth muscle relaxation (i.e. bronchodi- ture of theophylline and ethylenediamine. latation) and suppression of the response These drugs inhibit the enzyme phosphod- of the airways to stimuli (i.e. non-bron- iesterase, this inhibition results in higher chodilator prophylactic effects). Bron- concentration of intracellular cyclic AMP. chodilatation is mediated by inhibition of 234 Section 5/ Autacoids two isozymes of phosphodiesterase (PDE III MAST CELL STABILIZERS and to a lesser extent, PDE IV) while non-bron- chodilator prophylactic actions are mediated SODIUM CROMOGLYCATE through one or more different molecular mech- It is a synthetic chromone derivative, highly anisms, that do not involve inhibition of PDE effective in preventing asthma attacks. It in- III or antagonism of adenosine receptors. Theo- hibits degranulation of mast cells by trig- phylline increases the force of contraction of ger stimuli. It also inhibits the release of diaphragmatic muscles. various asthma provoking mediators e.g. It is well absorbed orally. It is distribut- histamine, leukotrienes, platelet activating ed to all tissues and is 50% plasma protein factor (PAF) and interleukins (IL’s) from mast bound. It is extensively metabolized in cells. It prevents the late response and sub- liver by demethylation and oxidation. Only sequent bronchial hyperresponsiveness by 10% is excreted unchanged in urine. acting on inflammatory cells such as mac- rophages or eosinophils. It does not produce Adverse Effects bronchodilatation and also does not antago- Side effects are usually associated with nize the constrictor effect of histamine etc. the increasing serum concentration of therefore not found beneficial in acute attack theophylline and includes nausea, of asthma and used for prophylaxis only. vomiting, headache, insomnia, tachypnea, Sodium cromoglycate is not absorbed epigastric pain, palpitation, hypotension, orally and is to be administered by aerosol. irritability. Higher doses can cause Only a small fraction of inhaled drug is ab- persistent vomiting, cardiac arrhythmias, sorbed systemically and it is rapidly excret- intractable seizures, tachycardia. Other ed unchanged in urine and bile. side effects include alopecia, hyper- Adverse reactions reported are bron- glycemia, inappropriate ADH syndrome, chospasm, throat irritation and rarely head- rash. ache, dizziness, rashes and nasal congestion.

ANTICHOLINERGICS Therapeutic Uses 1. Bronchial asthma: It is used for pro- Anticholinergics, like atropine and its deriv- phylactic treatment of bronchial ative ipratropium bromide block cholin- asthma. ergic pathways that cause airway constric- 2. Allergic rhinitis: Two percent aqueous tion . They may provide added bronchodi- nasal spray (FINTAL nasal spray) is lator effect in patients who are receiving used for nasal decongestion although beta2-adrenergic agents for asthma. it is not a nasal decongestant. The detailed pharmacology is discussed 3. Allergic conjunctivitis: Two percent in chapter ‘Cholinergic blocking agents.’ aqueous eye solution (FINTAL eye Drugs Used in Cough and Asthma 235

drop) is used in allergic conjunctivitis and increase the peak expiratory flow rate in in chronic cases. asthmatic patients. They are not effective during an acute attack or in status KETOTIFEN asthmaticus. Side effects are sore throat, It is a cromolyn analogue. It is an hoarseness of voice, dysphonia, oropharyn- antihistaminic (H1 antagonist) and probably geal candidiasis. inhibits airway inflammation induced by platelet activating factor (PAF) in primate. LEUKOTRIENE PATHWAY INHIBITORS It is not a bronchodilator. It is used in asthma and symptomatic relief in atopic dermatitis, Apart from histamine, leukotrienes liberated rhinitis, conjunctivitis and urticaria. It is during inflammation are more powerful absorbed orally and well tolerated. bronchoconstrictor and longer acting. Bioavailability is 50% due to first pass Leukotrienes also increase bronchial mucus metabolism and is primarily metabolized. secretion and increase vascular permeability. The common side effects include dry All the leukotrienes are derived from 5- mouth, sedation, dizziness and nausea. lipoxygenase pathway of arachidonic acid and are synthesized by a variety of CORTICOSTEROIDS inflammatory cells in the airways e.g. eosinophils, mast cells, basophils and Like mast cell stabilizer, corticosteroids do macrophages. The LTB4, C4 & D4 exert many not relax airway smooth muscle directly but effects known to occur in bronchial asthma, reduce bronchial reactivity, increase air- including bronchoconstriction and increased way caliber, suppress inflammatory bronchial reactivity. The drug, montelukast response to antigen antibody reaction or (LTB4 antagonist) and zafirlukast (LTD4 trigger stimuli and reduce the frequency antagonist) have the advantage of being used of asthma exacerbations. They produce when taken orally in asthmatic patients. more sustained symptomatic relief than any bronchodilator and mast cell stabilizer. MONTELUKAST Systemic steroids are used in both se- It is a cysteinyl leukotriene receptor vere chronic asthma and in acute emergen- antagonist indicated for the management of cy of asthma (status asthmaticus). persistent asthma. It has been shown to have Among the inhaled steroids, substantial blockade of airway leukotriene beclomethasone is a halogenated corticoster- receptors 24 hours after oral dosing. Mon- oid ester used in aerosol form. It suppresses telukast appears to be a useful alternative asthma by a topical antiinflammatory action or adjunct to inhaled therapy without causing any systemic side effects. in adults and an alternative to sodium cro- They reduce the bronchial hyperreactivity moglycate in children.

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Drugs Acting On Blood This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsCoagulants and 1.46.1 Anticoagulants(Mode of Action of Drugs)

Thrombogenesis is an abnormal state of anism is essential to maintain life. In case of haemostasis leading to the formation of any damage to a blood vessel, the haemo- arterial and venous thrombus, also known static response must be: as white and red thrombus respectively. • Quick. Haemostasis is the spontaneous arrest of • Controlled & localised to region of bleeding from the damaged blood vessels. damage. The immediate haemostatic response to a Three basic measures taken by the body damaged blood vessel is vasospasm and, to reduce and stop blood loss are: after few seconds, platelets stick to the i. Vascular spasm. exposed collagen of the damaged endothelium (platelet adhesion) and to each ii. Platelet plug formation. other (platelet aggregation). Certain agents iii. Clotting or coagulation. Clotting: Normally, blood remains e.g. thromboxane A2 (from arachidonic acid metabolic pathway) is synthesized within liquid as long as it is flowing within intact platelets and induces thrombogenesis and smooth blood vessels. But on damage to the blood vessel and/or if blood is extracted vasoconstriction and prostacyclin I2 (PGI2) inhibits thrombogenesis. from the blood vessel, there is conversion of liquid to gel state. This gel, on Coagulation of blood comprises the solidification gives a clot. The process of formation of fibrin. There are thirteen factors conversion of liquid to gel is termed as (synthesized in liver) which are involved in coagulation. the coagulation of blood. Clotting involves several factors called Review of Clotting Mechanism clotting factors. These include calcium, several inactive enzymes synthesized by Haemostasis: Haemostasis refers to the hepatocytes and various molecules arrest of blood loss from a damaged blood associated with platelets and/or released by vessel i.e. stoppage of bleeding. The mech- the damaged tissue. The clotting factors are 240 Section 6/ Drug Acting on Blood denoted by Roman numeral, denoting the contact with the blood in the intact blood order of their discovery (Table 6.1.1). vessels. No outside tissue damage is Table 6.1.1: Clotting factors. required. Rough vessels with exposed collagen is sufficient. Contact with I. Fibrinogen. collagen activates factor XII. This in turn II. Prothrombin. activates factor IX. Factor IX joins factor III. Thromboplastin. VIII and this gives active factor X. Factor IV. Calcium. X joins with calcium to bring about the V. Proaccelerin. formation of prothrombinase. VI. Accelerin. VII. Serum prothrombin conversion accelerator. Once prothrombinase has been formed, VIII. Antihaemophilic factor. the common pathway is followed. In stage IX. Plasma thomboplastin component. 2, prothrombinase and calcium catalyze the X. Stuart Prower factor. conversion of prothrombin to thrombin. In XI. Plasma thromboplastin antecedent. stage 3, thrombin, in the presence of calcium XII. Hageman factor. converts soluble fibrinogen to insoluble XIII. Fibrin stabilizing factor. fibrin threads.

Stages of Clotting COAGULANTS Formation of prothrombinase: It can be formed by extrinsic pathway and intrinsic These are the agents which promote pathway. coagulation and are mainly used in any haemorrhagic condition. They are classified Extrinsic pathway: This pathway has as in table 6.1.2. fewer steps than the intrinsic pathway and occurs rapidly, within a matter of seconds if VITAMIN K the trauma is severe. It is called the extrinsic Vitamin K is a fat soluble vitamin pathway because a protein tissue factor, also found primarily in leafy green veg- called thromboplastin or coagulation factor etables. There are two normal forms ex- III, takes into the blood stream from outside ist, K1 found in food (called phytona- and initiates the formation of dione), K2 found in human tissue (syn- prothrombinase. Tissue factor is released thesized by intestinal bacteria) known as from the surface of the damaged cells. It menaquinone. The synthetic compound activates factor VII. Factor VII combines with is known as K3. Synthetic analogues of factor X, activating it. Factor X in the presence natural vitamin also show biological ac- of Ca++ combines with factor V to give active tivity. Most of the vitamin K is synthe- enzyme prothrombinase. sized by intestinal microorganisms and Intrinsic pathway: This pathway is there is a risk of vitamin K deficiency in more complex and is much slower. It is so new born infants. named as the activators are in direct Vitamin K is necessary for final stage of Coagulants and Anticoagulants 241

Table 6.1.2: Classification of coagulants. I. Vitamin K (along with other vitamins available) 0.66 mg OD-BD Vitamin K analogues Menapthone (KAPLIN) 5-20 mg/day Menadione (STYPINDON) 10-30 mg TDS Phytomenadione 10 mg/ml IM/day Botropase 1 ml BD-TDS IM Ethamsylate (ALSTAT) 250-500 mg TDS Adenochrome monosemicarbazone (STYPTOCID) 10-30 mg BD-TDS Feracrylum (HEMOLOK) Applied locally on affected surface Aprotinin (APROTIN) Upto 2 million KIU IV injection II. Other Tranexamic acid (TEXID) 15-25 mg/kg BD-QID oral, 10-15 mg/kg slow IV TDS Polidocanol (SCLEROL) Local application Sodium tetradecyl (SETROL) 1-3% solution synthesis of coagulation factors (mainly (phytomenadione is most effective as it acts factor II, VII, IX and X) in liver. In synthesis most rapidly). of coagulant proteins vitamins K is converted to an epoxide which is subsequently reduced BOTROPASE to vitamin K. Vitamin K is metabolised in It is a aqueous solution of haemocoagulase liver and metabolites are excreted in bile and isolated from venom of Bothrops jararaca and urine. B. atorox containing normal saline. It is The deficiency of vitamin K occur due indicated in primary and secondary post- to liver disease, jaundice, malabsorption operative internal and external haemorrhage. syndromes and chronic use of antimicrobial agents. ETHAMSYLATE Adverse effects include haemolysis It inhibits prostacyclin synthetase especially in infants and person with G-6- enzyme resulting in the prevention of PD deficiency. Menadione can cause prostacyclin induced vasodilatation and jaundice, and haemolysis in infants. corrects abnormal platelet function. It is Therapeutically, vitamin K is used in mainly used to control haemorrhage in prophylaxis and treatment of deficiency of epistaxis, haemoptysis, haematemesis, clotting factor due to dietary deficiency of menorrhagia and postsurgical conditions. vitamin K, chronic antimicrobial therapy, malabsorption syndrome, obstructive jaun- ADENOCHROME dice, liver diseases such as cirrhosis and MONOSEMICARBAZONE hepatitis, in neonates to prevent or treat It exerts its haemostatic action by haemorrhagic disease of new born; to coun- reducing capillary fragility, and is teract the overdosing of oral anticoagulants indicated in epistaxis, haematuria, retinal 242 Section 6/ Drug Acting on Blood haemorrhage and secondary haemorrhage Adverse effects include local thrombo- from wounds. phlebitis, hypersensitivity reactions (skin eruptions, tachycardia, pallor/cyanosis, FERACRYLUM dyspnoea, nausea or anaphylactic shock) It is a local haemostatic and antiseptic may occur. agent. The haemostatic effect of feracrylum It is indicated in patients at high risk of is based on the formation of synthetic blood loss following open heart surgery with complex consisting of its adduct with extracorporeal circulation, life threatening plasma proteins principally albumin. Like haemorrhage due to hyperplasminaemia, other biodegradable polymers, the hyperfibrinolytic haemorrhage occurring feracrylum-albumin complex formed gets post-traumatically and postoperatively e.g. broken down over a period of time. in obstetrics and gynaecology. Adverse effects include burning TRANEXAMIC ACID sensation. Tranexamic acid produces an It is indicated as adjunct to conventional antifibrinolytic effect by blocking the lysine haemostatic procedures in capillary and binding site on plasminogen which is venule oozing in various surgical and essential for binding to fibrin and thereby diagnostic procedures, dental extraction and prevents the activation of plasminogen on oral surgeries. the surface of fibrin. APROTININ Tranexamic acid is absorbed from the GIT with peak plasma concentration at It is a naturally occurring proteolytic about three hours. Bioavailability is about acting on and 30 to 50 percent. It is widely distributed kallikrein. throughout the body and has very low It inhibits plasmin and kallikrein, thus protein binding. It diffuses across the directly affecting fibrinolysis. It also placenta and is distributed into breast milk. inhibits the contact phase activation of It has a plasma half life of about two hours. coagulation which both initiates coagulation It is excreted in the urine mainly as and promotes fibrinolysis. unchanged drug. After IV injection rapid distribution of Adverse effects include dose related aprotinin occurs into the total extracellular gastrointestinal disturbances, hypotension space leading to a rapid initial decrease in particularly after rapid IV administration plasma concentration. It has a plasma half- and transient disturbance in colour vision life of 2.5 hours. After a single IV dose 25- rarely. 40% is excreted in the urine over 48 hours. It is used for prophylaxis and control of It is accumulated primarily in the kidney (it bleeding in gynaecological and obstetric is actively absorbed by the proximal surgery, haemorrhage associated with IUCD tubules). insertion, conisation of the cervix, intra- and Coagulants and Anticoagulants 243 postoperative haemorrhage (cardiac surgery forming equimolar stable complexes with with cardiopulmonary bypass, coronary them. artery bypass grafting), total knee It acts by activating plasma replacement, gastrointestinal bleeding, local III which rapidly inhibits activated coagulation and general fibrinolysis, epistaxis, prosta factors IXa, Xa, XIa and XIIa, plasmin, kallikrein tectomy, haemoptysis and haemorrhage and thrombin, thus inhibiting conversion of after dental extraction. fibrinogen to fibrin. Heparin is well absorbed after subcuta- POLIDOCANOL neous administration and is not effective It is a sclerosing agent for bleeding orally, and metabolized mainly in liver. It is oesophageal varices, varicose veins, not secreted in milk and does not cross pla- bleeding gastroduodenal ulcers etc. cental barrier. Adverse effects include bleeding, SODIUM TETRADECYL alopecia (reversible), bleeding from gums, IV injection causes intimal inflammation unexplained bruising, osteoporosis and and thrombus formation occluding the rarely hypersensitivity, thrombocytopenia injected vein. Subsequent formation of and hyperkalemia. fibrous tissue results in partial or complete It is indicated in the prophylaxis and vein obliteration. treatment of deep vein thrombosis in major It is indicated in the treatment of small, surgery and pulmonary embolism, uncomplicated varicose veins of the lower treatment of atrial fibrillation with extremities, haemangioma, ganglionoma, embolisation, prophylaxis and treatment of oesophageal varices. peripheral arterial embolism. LOW MOLECULAR WEIGHT ANTICOAGULANTS HEPARINS (LMWH) These are the drugs used to reduce the These are prepared by enzymatic or coagulability of blood. They can be classified chemical hydrolysis of conventional heparin, as in table 6.1.3. their molecular weight varies from 3,000 to 7,000. They are absorbed more completely HEPARIN than the conventional heparin preparation Heparin is a heterogenous mixture of and having longer duration of action. sulfated mucopolysaccharides and quick It is obtained as fragments of commercial acting anticoagulant which shows efficacy grade heparin which is produced by both in vitro and in vivo and having a chemical or enzymatic depolymerisation. It molecular weight from 4,000 to 40,000 contains less pentasaccharide sequences depending upon the type of preparations. with a high affinity for antithrombin III. Its biological activity is dependent upon the LMWH exerts its action mostly by anti- plasma protease inhibitor antithrombin III, thrombin mediated inhibition of factor Xa. which inhibits clotting factor proteases by But some thrombin inhibition by LMWH is 244 Section 6/ Drug Acting on Blood

Table 6.1.3: Classification of anticoagulants. I. Parenteral anticoagulants  Heparin (INHEP) 5,000-10,000 U IV stat and maintained at 5,000 U 4-6 hourly  Low molecular weight heparin (LMWH) Nadroparin (FRAXIPARINE) 3075-4100 IU OD SC Enoxaparin (CLEXANE) 20-40 mg OD SC Reviparin (CLIVARINE) 13.8 mg OD SC Dalteparin (FRAGMIN) 100-200 U/kg OD Pamparin (FLUXUM) 6400 IU OD SC Ardeparin (INDEPARIN) 2500-5000 IU OD SC  Semisynthetic heparinoids Ancrod 2 U/kg IV infusion Danaparoid Lepirudin II. Oral anticoagulants Warfarin (WARF) 30 mg (loading) & maintained on 2.5-10 mg/day (usual dose is 10-15 mg/day) Bishydroxycoumarin (DICUMAROL) 200 mg × 2 days (loading), maintained on 50-100 mg/ day Acenocoumarol (ACITROM) 8-28 mg/day (loading), maintained on 2-10 mg/day Phenindione (DINDEVAN) 200 mg/day (loading), maintained on 50-150 mg/day III. Fibrinolytics Streptokinase (PROKINASE) 7,50,000-1.5 million IU in 1 hr IV infusion Urokinase (URIDAN) 50,000-2.5 lac IV infusion Alteplase (ACTILYSE) 10 mg IV (bolus) upto 100 mg in 3 hrs retained and is of importance for the It is indicated in prevention and treatment antithrombotic effect. of deep vein thrombosis and pulmonary em- LMWH have higher bioavailability bolism in surgical patients, prevention of ex- after subcutaneous injection than tracorporeal thrombosis during haemodialysis. standard, heparin. LMWH binds less than The clinically used low molecular heparin to plasma proteins. The clearance weight heparins are enoxaparin, reviparin, of LMWH is mainly renal, independent of dalteparin, nadroparin, ardeparin and dose and slower than metabolic clearance tinzaparin etc. of heparin. Adverse effects include thrombocytopenia, HEPARINOIDS haemorrhage, injection site ecchymoses, Ancrod is an enzyme obtained from osteoporosis, sensitivity phenomenon. Malayan pit viper venom. It produces Coagulants and Anticoagulants 245 heparin like effect by degrading fibrinogen highly bound to plasma proteins and it into an unstable form of fibrin. crosses the placental barrier. Danaparoid containing mainly heparan Adverse effects include haemorrhage, sulfate isolated from porcine intestinal rash, alopecia, diarrhoea, hepatic dysfunction, mucosa and is used in heparin induced nausea, vomiting and pancreatitis. thrombocytopenia and deep venous It is used in venous thromboembolism, thrombosis. pulmonary embolism, atrial fibrillation and Lepirudin is a recombinant derivative for prophylaxis after insertion of prosthetic of hirudin (direct thrombin inhibitor heart valves. secreted by salivary glands of leech). It WARFARIN inhibits thrombin directly and is mainly It is most commonly used oral anticoagulants used in heparin induced thrombocytopenia. employed for long term anticoagulant therapy HEPARIN ANTAGONISTS and having less toxic effects including alopecia and dermatitis. It is rapidly and completely The agents like protamine sulfate react absorbed from intestines and is 99% plasma with the strongly acidic groups of heparin protein bound. It crosses the placental barrier and and can abolish its anticoagulant activity. is secreted in milk. The other properties are same Approximately 1 mg of protamine sulfate as acenocoumarol. neutralizes 80 to 100 units of heparin. It is used only in severe bleeding or when PHENINDIONE heparin action needs to be terminated The mechanism of action and adverse rapidly e.g. after cardiac or vascular effects are same as acenocoumarol. It surgery. produces more serious nonhaemorrhagic toxic effects, their use is now very limited. ORAL ANTICOAGULANTS FIBRINOLYTICS They act by interfering with synthesis of vitamin K dependent clotting factors in liver. These are agents used to lyse clot to They act as competitive antagonists of vitamin recanalise occluded blood vessels, mainly K and reduce plasma levels of clotting factors used in coronary arteries. in a dose dependent manner. They act by interfering with regeneration of active form STREPTOKINASE of vitamin K. Factor VII levels are reduced first It is a purified preparation of bacterial followed by factor IX, X and II. protein obtained from β hemolytic streptococci. ACENOCOUMAROL It acts by forming a complex with circulating plasminogen that binds loosely It takes at least 48 to 72 hours for the to fibrin and it converts plasminogen to anticoagulant effect to develop fully. plasmin. It has no intrinsic activity. It is Acenocoumarol is absorbed nearly given by parenteral route and has a short completely after oral administration. It is plasma half life. 246 Section 6/ Drug Acting on Blood

Adverse effects include fever, allergic thromboembolic disorders. Thromboxane reactions, bleeding from different sites, rarely A2 (TXA2) from platelets promote and anaphylaxis, arrhythmias, bronchospasm. prostacyclin (PGI2) from vessel wall inhibit It is indicated in acute myocardial infarction, platelet aggregation. pulmonary embolism, deep vein thrombosis, arterial thrombosis, acute thrombosis of central ABCIXIMAB retinal vessels, extensive coronary emboli and It binds to the intact glycoprotein severe iliofemoral thrombophlebitis. IIb/IIIa receptor of human platelets, which is a member of the integrin family UROKINASE of adhesion receptors and the major It is obtained from cultures of human renal platelet surface receptor involved in cells in tissue culture and it is a proteolytic platelet aggregation. The drug inhibits enzyme. It activates plasminogen directly. platelet aggregation by preventing the Plasmin acts on fibrin and fibrinolysis occurs. binding of fibrinogen, von Willebrand It is non antigenic. factor and other adhesive molecules to Adverse effects include drug fever and GP IIb/IIIa receptor sites on activated haemorrhage. platelets. It is used for myocardial infarction, for Adverse effects include bleeding, thrombo- venous thrombosis and pulmonary embolism. cytopenia, human antichimeric antibody deve- ALTEPLASE lopment, atrial fibrillation/flutter, complete AV Also known as recombinant tissue block, palpitation, SVT, constipation, ileus, Plasminogen Activator (rt-PA). It is produced abnormal thinking, dizziness. by recombinant DNA technology from It is indicated for platelet aggregation human tissue culture. It specifically activates inhibition as adjunct to percutaneous plasminogen bound to the fibrin clot. This transluminal coronary angioplasty or minimises the risk of systemic bleeding. atherectomy (PTCA). It is non antigenic and has a plasma t½ of 4-8 min. ASPIRIN Adverse effects are nausea, fever, mild In small doses aspirin inactivates irre- hypotension, rash, pruritus and localised versibly platelet enzyme cyclooxygenase, bleeding. hence thromboxane A2 is not synthesised. It is used in lysis of suspected occlusive The effect of enzyme inactivation lasts till coronary artery thrombi associated with the life of platelet. evolving MI in adults. It is indicated in prophylaxis in cases of increased risk of blood clotting, myocardial PLATELET INHIBITING DRUGS infarction, coronary bypass, transluminal These drugs interfere with platelet function angioplasty, stroke, transient ischaemic and may be useful in prophylaxis of attack and unstable angina.  (Drugs used in A

ChapterChapter PharmacodynamicsPharmacodynamicsHaematinics (Drugs Used in Anaemia) 1.46.2 (Drugs(Mode Usedof Action in Anaemia) of Drugs)

Anaemia is the decrease in number of red even if its mother has low stores, but blood cells or hemoglobin content caused mother becomes anaemic. by blood loss, deficient erythropoiesis, Anaemia may be classified into different excessive hemolysis, or combination of groups according to the pathophysiology. these changes. Iron deficiency anaemia is probably the most common nutritional 1. Dietary deficiency anaemia, which is due to deficient supply of various deficiency in the world. It is estimated that factors e.g. iron, folic acid, vitamin B , at least 500 million people are affected. Iron 12 vitamin C and pyridoxine which are deficiency anaemia is much more common essential for normal blood formation. in developing countries, as people are 2. Anaemia due to blood loss e.g. in consuming too little food or a limited severe gastric blood loss (ulcers), variety of food. protozoal or worm infestation. Infants and young children have higher 3. Anaemia due to excessive destruction, iron requirement. For the first six months of blood e.g. sickle cell anaemia and of life, these requirements are met by iron haemolytic anaemia. store in the infant’s body alone with 4. Anaemia due bone narrow depression supplementation from breast or formula e.g. aplastic and hypoplastic anaemia. milk. Iron requirement increases during adolescence because of growth, muscle IRON development and, for girls, at the start of The body iron is distributed mainly in two menstruation. Adult women have higher forms, one as haem in haemoglobin and iron requirement because of menstrual cytochrome oxidase enzyme and other as losses. During pregnancy it is not necessary iron bound to protein as storage compounds to have extra iron in the diet because ferritin and hemosiderin, and as transport absorption increases and menstruation iron bound to . The total body iron stops. The fetus is likely to get enough iron in human adult is approximately 3.5 g out 248 Section 6/ Drug Acting on Blood of which 66% is in haemoglobin and 25% is Iron is transported via transferrin. When stored as ferritin and hemosiderin and rest body stores of iron are high, ferric iron is in muscles and enzyme. combines with apoferritin to form ferritin. Iron absorption occurs predominantly in Ferritin is the protein of iron storage. About 80 percent iron in plasma goes to erythroid the duodenum and upper jejunum. The marrow. The excretion of iron is minimal. physical state of iron entering the duodenum Only little amount of iron is lost by exfoliation greatly influences its absorption. At of intestinal mucosal cells and trace amount physiological pH, ferrous iron is rapidly is excreted in urine, sweat and bile. oxidized to the insoluble ferric form. Gastric acid lowers the pH in the proximal duodenum, After confirmation of iron deficiency enhancing the solubility and uptake of ferric iron therapy can be given by oral or parenteral route. Generally oral iron therapy iron. When gastric acid production is is given unless the patient is suffering from impaired, iron absorption is reduced subs- severe anaemia, malabsorption syndrome, tantially. Ascorbic acid enhances iron gastrectomy or patient is showing adverse absorption. Ascorbic acid mobilizes iron from effects to oral iron therapy. iron-binding proteins in vivo, which in turn could catalyze lipid peroxidation. Iron Uses absorption is inhibited by antacids, phytates, Nutritional iron deficiency anaemia; other phosphates and tetracyclines. causes in which iron deficiency can occur are The iron is transferred by the mucosal pregnancy, lactation, infants, children. In epithelium to the body and is bound to plasma patients with malabsorption syndrome, transferrin in the ferric state. In the plasma, iron patients who are taking NSAIDs for long takes part in a dynamic transferrin-iron period, patients with chronic inflammatory equilibrium and is distributed into vascular and disease and in patients of gastrectomy. interstitial extravascular compartment. 50 to Preparations of iron alone or in 60% of transferrin is extravascular. The plasma combination with vitamin B12, folic acid or iron pool in adults is about 3 mg and has an other vitamins are available (see table 6.2.1). estimated turnover of 20 to 30 mg per 24 hours. Most of the oral formulations contain Daily and obligatory losses of iron in healthy one of the iron compound with many men are about 1 mg; in healthy menstruating vitamins, amino acids, liver extract, women these average 2 mg and in either case minerals, folic acid, appetite stimulants are compensated by a net absorption of 1 to 2 (cyproheptadine like compound). mg from the intestine, which enters the mobile pool of transferrin iron. Adverse Effects Oral administration can cause nausea, Pharmacokinetics vomiting, epigastric pain, metallic taste, After oral administration iron is absorbed staining of teeth, constipation and diarrhoea in ferrous form. The conversion of ferric iron both can occur, but constipation is more to ferrous iron is aided by hydrochloric acid. common. Haematinincs (Drugs Used in Anaemia) 249

Table 6.2.1: Classification for iron preparations. Ferrous sulphate (Hydrated salt 20% iron, exsiccated salt 30% iron; FERSOLATE). 200-600 mg/day Ferrous gluconate (12% iron; FERRONICUM). 300-1200 mg/day Ferrous fumarate (33% iron; AUTRIN). 100-300 mg/day Colloidal ferric hydroxide (50% iron; NEOFERUM). 200-800 mg/day Other forms of iron which are present in different pharmaceutical preparations are ferric ammonium citrate, ferrous succinate, iron choline citrate, ferrous amionate, iron calcium complex, carbonyl iron, ferric glycerophosphate, haemoglobin, elemental iron, ferrous glycine sulphate, glycerinated haemoglobin, and iron (III) hydroxide polymaltose complex (equivalent to elemental iron). Parenteral preparations: Iron dextran (IMFERON) & Iron-sorbitol citric acid complex (JECTOFER).

The parenteral administration can ERYTHROPOIETIN cause local pain at the site of injection. The It is produced primarily by peritubular other adverse effects include headache, cells in the proximal tubule of the kidney. fever, flushing, palpitation, dyspnoea, chest In anaemia renal secretion of erythropoi- pain, metallic taste and even disorientation etin increases rapidly manifold. Erythro- and temporary loss of taste. poietin levels are always detectable in IV administration can cause anaphylactic plasma. reaction characterized by circulatory collapse It exerts its action by binding to recep- and even deaths have been reported. tor on surface of erythroid precursor cells. Treatment of Acute Iron Poisoning There is increase in intracellular concentra- tion of calcium and arachidonate and 1. Gastric lavage with 1% sodium changes in intracellular phosphorylation. It bicarbonate solution to remove any stimulates proliferation, maturation and undissolved iron tablets. haemoglobin formation by committed 2. Administration of milk or egg yolk to erythroid progenitors. complex iron. Recombinant human erythropoietin is 3. Specific iron binding chelating agent available. It is given by parenteral route like desferrioxamine mesylate (5-10 g (IV or SC). in 100 ml isotonic saline) or calcium di- ethylene triamine pentaacetate (DTPA) It is used in the treatment of anaemia of 35-40 mg/kg or calcium disodium ac- chronic renal failure, in anaemia of patients etate (35-40 mg/kg). with AIDS who are being treated with 4. Electrolytes and other fluids to correct zidovudine and anaemia associated with metabolic acidosis and hypotension. cancer chemotherapy. 5. Supportive administration of various Adverse effects include exacerbation of agents e.g. anticonvulsants drugs to or new onset of hypertension and seizures control convulsions. in patients with renal disease.  This page intentionally left blank Section 7

Drugs Acting On GIT This page intentionally left blank (Drugs used in A

Laxatives and ChapterChapter PharmacodynamicsPharmacodynamics PharmacodynamicsAntidiarrhoeal (Mode of Action of Drugs) 1.47.1 Agents

LAXATIVES OSMOTIC LAXATIVES

These are the drugs which promote the These solutes are not absorbed in intestine. evacuation of bowels and used in constipation. They retain water osmotically in bowel lumen and distend the bowel thereby They are classified as in table 7.1.1. increasing peristalsis indirectly. These agents should be administered with plenty BULK FORMING AGENTS of water. The administration of sodium salts These contain natural or semisynthetic is to be avoided in patients of cardiac failure, hydrophilic colloidal derivatives of cellulose. renal failure and hepatic failure. These drugs act to increase the volume LACTULOSE of stool by absorbing water and as a result It is a semisynthetic disaccharide of softening of faeces occurs. These are safe fructose and lactose. It is not digested or drugs (except in patient with strictures when absorbed in small intestine thereby intestinal obstruction may be precipitated). withdrawing water into bowel lumen. It Adequate hydration of the patient is to be breaks down in colon to form more maintained. The onset of action occurs in 12- osmotically active products. It also causes 24 hours after oral intake. reduction in ammonia in hepatic coma.

Table 7.1.1: Classification of laxatives. I. Bulk forming agents Ispaghula, methylcellulose, psyllium II. Osmotic laxatives Magnesium salts, (sulphate, hydroxide), sodium salts (sulphate, phosphate), lactulose, glycerol suppositories III. Stool softener Liquid paraffin, docusate sodium IV. Stimulant laxatives Bisacodyl, senna, phenolphthalein, danthron, sodium picosulphate, castor oil 254 Section 7/ Drugs Acting on GIT

long term use may lead to hypokalemia. STOOL SOFTENER These drugs are to be avoided in pregnancy Docusate acts by its detergent action which and children. The onset of action occurs in 6- reduces the surface tension. 12 hours after oral administration.

LIQUID PARAFFIN BISACODYL It is a petroleum hydrocarbon, an inert It is stimulant laxative, when administered viscous liquid. It is a faecal softener and orally or as a rectal suppository it produces causes lubrication of hard scybali by coating increased peristalsis by direct action on the them. Paraffin lubricates the passage of mucosa of the colon, usually resulting in a soft, faeces. It is not absorbed and is safe. formed stool. It is indicated in postoperative constipation. It is indicated in all forms of Dose: CREMAFFIN 10-15 ml/day. constipation, e.g. in bedridden patients, due Adverse effects include aspiration to change of food or environment, illness or pneumonia, perianal pruritus, healing in digestive disorders; relief of evacuation in perianal region may be delayed, unpleasant painful conditions such as haemorrhoids; taste, the absorption of fat soluble vitamins pre and postoperatively; pre-paration for may be affected. Long-term administration barium enema; preparation of colon for is not recommended. proctosigmoidoscopy. Dose: DULCOLAX 5-15 mg HS oral and suppository (5-10 mg). DOCUSATES It is an anionic detergent which softens the SODIUM PICOSULPHATE stool by water accumulation in intestinal lumen In the colon, sodium picosulphate is and emulsifies the colon contents. It is indicated converted in to the active comound bis-(p- in obstetric, habitual, geriatric, paediatric hydroxy diphenyl) pyridyl methane constipation or when straining is to be avoided (BHPM) which stimulates propulsive (recent myocardial infarction, severe activity of the colon, prevents absorption of hypertension, post-operative cases, abdominal water in the colonic lumen and promotes hernia), fissures, haemorrhoids and bed ridden accumulation of water. Dose: patients. 100-200 mg/day. Following oral administration sodium Side effects include nausea, cramps and picosulphate is not absorbed. In colon it is abdominal pain. converted to the active metabolite BHPM, by the action of arylsulphatases secreted by STIMULANT LAXATIVES the colonic bacteria. These drugs exert their laxative action by Prolonged use or overdosage can increasing motility of colon. They mainly precipitate the onset of an atonic non- alter absorptive and secretory activity by functioning colon and hypokalemia. inhibiting Na+ K+ ATPase in mucosal cells, It is indicated in constipation e.g. in leading to water and electrolyte accumulation patients with cardiovascular disease, hernia in lumen. Colicky pain may occur and on the and anorectal disorders, the elderly and Laxatives and Antidiarrhoeal Agents 255 postoperatively; bowel clearance before ANTIDIARRHOEAL AGENTS radiography, endoscopy, labour or surgery. It is contraindicated in intestinal obs- Diarrhoea is defined as frequent passage of truction, undiagnosed abdominal symptoms. liquid faeces with or without blood and Dose: CREMALAX 5-10 mg HS. mucus. It occurs due to various causes, infective or non infective. SENNA The antidiarrhoeal agents can be It is an anthraquinone laxative. It is not classified as in table 7.1.2. active as such but after oral intake when it Antidiarrhoeals are given for reaches colon the bacteria liberate anthrones, symptomatic relief of diarrhoea. The first step which is the active form. Active form acts on in treatment of acute diarrhoea is replacement myenteric plexus to increase peristalsis. It also of fluid and electrolytes. If due to diarrhoea inhibits salt and water absorption in colon. there is severe dehydration, it requires It is indicated in intestinal evacuation immediate hospitalization for IV fluid and for radiological examination and atonic electrolyte replacement. Antidiarrhoeal constipation. drugs are administered for obtaining Adverse effects include vomiting, nausea, symptomatic relief in acute diarrhoea but fixed drug eruptions, skin rash. It is contrain- have untoward effects. Alongwith antidiar- dicated in spastic constipation, electrolyte rhoeal drugs, antispasmodics are imbalance, intestinal obstruction, lactation. administered in those patients who have Dose: As powder 0.6-10 gm. HS diarrhoea with abdominal pain.

Table 7.1.2: Classification of antidiarrhoeal agents.

I. Rehydrating solutions: Containing NaCl, KCl, NaHCO3 (for parenteral administration) and sodium chloride, potassium chloride, sodium citrate and glucose as oral formula (ORS). II. Absorbents & bulk forming agents Kaolin 2-4 g/day Pectin 100-300 mg/day Psyllium 8-16 g/day Ispaghula 8-16 g/day Methyl cellulose 4-6 g/day III. Antimotility & antisecretory drugs Codeine 30-60 mg TDS Loperamide (LOPAMIDE) 4-16 mg/day with atropine (LOMOFEN) 5 mg QID Sulfasalazine (SALAZOPYRIN) 1-3 g QID Mesalazine (MESACOL) 2-4 g/day IV. Antimicrobial drugs Details are given in chapter ‘Chemotherapeutic agents’. 256 Section 7/ Drugs Acting on GIT

ABSORBENTS AND BULK FORMING DRUGS may occur leading to abdominal obstruction. These are usually not prescribed for bacterial They are colloidal bulk forming agents which diarrhoea in children because by delaying the swell by absorbing water. They modify the passage of liquid faeces there is proliferation of consistency and frequency of stools. They are pathogens which is undesirable. used for functional bowel disease associated with diarrhoea. They are safe substances but SULFASALAZINE their effect occurs slowly. It is an antisecretory drug. It is 5-ami- nosalicylic acid with linked sulfapyridine ANTIMOTILITY AND ANTISECRETORY DRUGS through azo bond. The drug is poorly ab- sorbed from the intestine and the azo link- Antimotility drugs are opioid drugs. They age is broken down by the bacterial flora in increase small bowel smooth muscle tone and the distal ileum and colon to release 5-ami- segmentation activity. They also reduce nosalicylic acid (5-ASA) and sulfapyridine. propulsive movements and decrease intestinal secretions while increasing absorption. They 5-ASA inhibits locally prostaglandin synthe- mediate these actions through µ receptors. sis, decreases mucosal secretion. It is used in rheumatoid arthritis and ulcerative coli- LOPERAMIDE tis. Side effects include fever, rashes, blood dyscrasias, nausea, vomiting and headache. It has a direct action on intestinal muscu- lature and having a weak anticholinergic MESALAZINE property. It is used to treat acute and chronic diarrhoea. Adverse effects include 5-ASA is prepared as delayed release addominal cramps and skin rash. preparation by coating with acrylic polymer, which releases 5-ASA in distal ileum and colon. DIPHENOXYLATE It is used in ulcerative colitis to prevent relapses. Chemically it is an opioid, related to Olsalazine and balsalazine are the pethidine. It is used in acute and chronic newer compounds of 5-aminosalicylic acid diarrhoea but since it crosses the blood brain linked with azo bonds. barrier it can cause CNS effect similar to opioids. Atropine is added with diphenoxylate ANTIMICROBIAL THERAPY (LOMOFEN) to discourage abuse. Loperamide and codeine are preferred to Antimicrobials have a limited role in diphenoxylate in chronic diarrhoea, because treatment of diarrhoea because only a small they have less tendency to produce drug percentage of diarrhoeas are caused by dependence. Long-term use of these drugs may bacterial infection. Majority of cases are due aggravate irritable bowel syndrome. These to non infective causes, Rota virus and food drugs are used cautiously in attacks of colitis poisoning in which antimicrobial therapy because there is increased risk of toxic has no role. megacolon. Also all these drugs should be used Specific antimicrobial drugs are discussed with caution in elderly because faecal impaction in chapter ‘Chemotherapeutic agents.’  (Drugs used in A

ChapterChapter EmeticsPharmacodynamicsPharmacodynamics & Antiemetic 1.47.2 (Mode ofAgents Action of Drugs)

EMETICS given by subcuta-neous/IM route in the dose of 6 mg and it produces vomiting within 15 Vomiting or emesis occurs due to stimulation minutes. Apomorphine induced vomiting of vomiting/emetic centre in medulla oblon- can be antagonized by chlorpromazine. gata. The chemoreceptor trigger zone (CTZ) Side effects include tremors, restless- and nucleus tractus solitarius (NTS) are relays ness and in toxic doses it may cause convul- for the afferent impulses arising from GIT, sions and respiratory depression. throat and other viscera. There are different drugs e.g. morphine, digitalis glycosides, apo- IPECACUANHA morphine etc. which stimulate the CTZ. While certain agents e.g. chlorpromazine and certain It is used as tincture and syrup containing antihistaminics depress it. Vomiting due to ir- alkaloid obtained from plant ritants in the GIT especially upper region does Cephaelis ipeca-cuanha. It act on both gastric not involve CTZ and is mediated directly by mucosa and CTZ. the vomiting centre. Histamine (H1), seroto- The emetics are used mainly in poisoning nin (5-HT3), dopamine (D2) cholinergic (M) when gastric lavage facilities are not and opioid (µ) receptors on CTZ and NTS are available. But in certain poisoning e.g. involved in inducing vomiting. Impulses from kerosene poisoning, corrosive acid or alkali vestibular centre also lead to stimulation of poisoning, emetics are contraindicated. They vomiting centre via H1 and M receptors. are also not advisable in unconscious patients The drugs that produce or evoke as they may aspirate vomitus. vomiting are known as emetics. The most common compounds used are apomorphine ANTIEMETICS and ipecacuanha. These are the drugs which are used to prevent APOMORPHINE vomiting. They are classified in table 7.2.1. It is a semisynthetic opioid and act as The detailed pharmacology of phe- dopami-nergic agonist on the CTZ. It is nothiazines e.g. chlorpromazine, triflupro- 258 Section 7/ Drugs Acting on GIT

Table 7.2.1: Classification of antiemetics. I. Anticholinergics Dicyclomine, hyoscine etc. Details are given in chapter ‘Anticholinergic agents’ II. Antihistaminics Promethazine Promethazine theoclate (AVOMINE) Diphenhydrinate Diphenhydramine succinate etc. Details are given in chapter ‘Antihistaminic agents’. III. Dopamine antagonists Chlorpromazine 10-25 mg/day oral/IM Triflupromazine 10 mg/day oral/IM (STEMETIL) 5-10 mg/day oral/IM (DOMSTAL) 10-40 mg TDS Metoclopramide (PERINORM) 10 mg TDS oral/IM

IV. 5-HT3 antagonists (EMSETRON) Dose depends upon the patient’s requirement and stage. (GRANICIP) V. Prokinetic agents (CIZA) 10-20 mg TDS (MOZA) 2.5-10 mg BD-TDS (ITZA) 150 mg TDS

mazine and is discussed in chapter ‘Psy- DOMPERIDONE chopharmacological agents’. Only remain- It causes antiemetic action by block- ing compounds used as antiemetics are dis- ing dopamine (D ) receptors and it also cussed here. 2 increases gastric motility. It is absorbed DOPAMINE ANTAGONISTS orally but bioavailability is 15% due to first pass metabolism. It is completely PROCHLORPERAZINE biotransformed and metabolites are ex- creted in urine. It is used in nausea and It blocks dopaminergic neurotransmission in brain and exerts its action by blocking vomiting in postoperative period, drug dopamine receptors in brain. It is used in induced, radiation, uraemia, hepatitis, nausea and vomiting. peptic ulcer. It is also useful in reflex oe- Side effects include drowsiness, dry sophagitis. mouth, skin rash, insomnia and other Side effects include galactorrhoea, skin cholinergic effects. rash and gynaecomastia. Emetics & Antiemetic Agents 259

METOCLOPRAMIDE Side effects include headache, It is a centrally acting constipation, dizziness and allergic reactions. and acts on CTZ by blocking D receptors 2 GRANISETRON thereby preventing emesis. It also acts peripherally in GIT to enhance ACh release It is newer compound. Mechanism of action is similar to ondansetron but can from muscarinic receptors, leading to cause elevation of liver enzyme level e.g. increased gastric peristalsis and relaxing the SGOT, SGPT etc. It is mainly used in the pylorus and first part of duodenum. Thus it management of nausea and vomiting increases gastric emptying. It also increases induced by cytotoxic chemotherapy and tone of lower esophageal sphincter and radiotherapy. prevents gastroesophageal reflux. is a new compound of the It is absorbed orally, partly conjugated similar category acting by blocking 5-HT3 in liver and excreted in urine. receptor. It is used as antiemetic, for gastroesoph- ageal reflux disease, dyspepsia and as gas- PROKINETIC AGENTS trokinetic. Adverse effects include drowsiness, CISAPRIDE diarrhoea, facial spasm, trismus, oculogyric It is a selective 5-HT4 agonist. It restores crisis seen commonly in children and young and increases motility throughout adults. gastrointestinal tract. It appears to increase On prolonged use leads to tardive the release of acetylcholine from myenteric plexus of the gut. dyskinesia in elderly, gynaecomastia, galactorrhoea and parkinsonism. It is absorbed orally (bioavailability 33%) and is metabolised in liver. 5-HT3 ANTAGONISTS Adverse effects include abdominal cramps, diarrhoea, headache, convulsions ONDANSETRON and extrapyramidal effects. When used with imidazole antifungals/macrolide It causes antiemetic effect by blocking antibiotics, it may lead to Q-T prolongation 5-HT receptor in brain and periphery. 3 and ventricular arrhythmias. Absorbed orally and bioavailability is It is indicated in non-ulcer dyspepsia 60-70% due to first pass metabolism. and gastroesophageal reflux disease and not Metabolised by hydroxylation and mainly used as antiemetic. metabolites are excreted in urine and faeces. It is used in nausea and vomiting MOSAPRIDE induced by cytotoxic chemotherapy and Mosapride is a selective 5-HT4 receptor radiotherapy and for the prevention of agonist which is free from the extrapyrami- postoperative vomiting. dal and proarrhythmic effects. It stimulates 260 Section 7/ Drugs Acting on GIT

the 5-HT4 receptor in the presynaptic nerve thetic nerve endings and thereby increas- endings in the myenteric plexus promoting es the release of acetylcholine. It decreases the release of acetylcholine at the neuro- the metabolism of acetylcholine by inhibit- muscular junction, strengthening tone and ing the enzyme . contractions of the gut wall, in particular the It is highly protein bound (approx. 96%), tone of the lower oesophageal sphincter. metabolised in the liver by N-oxidation to Adverse effects include nausea and inactive metabolites by the enzyme flavin- diarrhoea. containing monooxygenase. It is excreted It is indicated in gastroesophageal reflux mainly by the kidneys in the form of disease and functional dyspepsia, diabetic metabolites and as unchanged drug. gastropathy. Adverse effects include rash, itching sensation, tremor, increase in SGOT, SGPT is also a selective 5-HT4 receptor agonist. levels, diarrhoea, abdominal pain, gyneco- mastia etc. ITOPRIDE It is indicated in upper abdominal It is a novel , it inhibits digestive symptoms associated with chronic dopamine D2 receptors at the parasympa- gastritis.

 (Drugs used in A

ChapterChapter PharmacodynamicsPharmacodynamicsAntacids and 1.47. 3 Antiulcer(Mode of Action Agents of Drugs)

not suitable for the treatment of peptic ulcer ANTACIDS because of risk of ulcer perforation due to Antacids are basic compounds that production of carbon dioxide in the stomach. neutralise acid in gastric lumen, have no Systemic absorption lead to alkalosis, may effect on gastric acid secretion. They are worsen edema and CHF because of quantitatively compared in terms of their increased Na+ load. acid neutralizing capacity (ANC), which is defined as the quantity of 1 N HCl (in MEq) NON-SYSTEMIC ANTACIDS that can be brought to pH 3.5 in 15 minutes by a unit dose of antacid preparation. An They are insoluble and poorly absorbed ideal antacid should be potent in compounds. neutralizing acid, inexpensive, not absorbed MAGNESIUM SALTS from GIT and contain negligible amounts of sodium, should be sufficiently palatable to Magnesium carbonate is most water be readily tolerated with repeated dosage soluble and reacts with hydrochloric acid at a and should be free of side effects. An ideal slow rate. Magnesium hydroxide has low antacid is yet to be developed. water solubility. It reacts with hydrochloric acid promptly. Magnesium trisilicate has low Role of antacids: solubility and has the power to adsorb and 1. Is primarily in pain relief. inactivate pepsin and to protect the ulcer base. 2. Higher dose given continuously can promote ulcer healing. ALUMINIUM HYDROXIDE

3. Are superior to H2 blockers in bleeding It is weak and slow reacting antacid. The peptic ulcer. aluminium ion relaxes smooth muscles, thus delays gastric emptying and causes SYSTEMIC ANTACIDS constipation. It can also adsorb pepsin at Systemic antacids e.g. sodium carbonate is pH > 3 but releases it at lower pH. It also water soluble and potent neutralizer, but is prevents phosphate absorption. 262 Section 7/ Drugs Acting on GIT

MAGALDRATE Gastric ulcer patients have a low to It is hydrated complex of hydroxy normal levels of gastric acid, but never true magnesium aluminate. It initially reacts with achlorhydria. Some primary defect in gastric mucosal resistance is seen and also an acid and releases Al(OH)3 which then reacts more slowly. It is a good antacid, with increased tendency to back diffusion of H+ prompt and sustained neutralizing action. ion. Other influences are thought to be decreased production of bicarbonate buffer, CALCIUM CARBONATE decreased blood flow which permits acid It is a potent antacid with rapid acid ions to accumulate. neutralizing capacity, but on long term use, it The various drugs used in peptic ulcer can cause hypercalcemia, hypercalciuria and are classified as in table 7.3.1. formation of calcium stones in the kidney.

Every single compound among the H RECEPTOR ANTAGONISTS antacids have some serious side effects 2 especially when used for longer period or The H2 antagonists in clinical use are analogs used in elderly patients. To avoid these, the of histamine that competitively inhibit the antacids combinations are used such as: interaction of histamine with H2 receptors i. Magnesium salts produce laxative and are highly selective. They inhibit gastric action while aluminium salts are acid secretion elicited by histamine and

constipating in nature, so combination other H2 agonists in a dose dependent

of these two counteract their effect and manner. H2 antagonists inhibit gastric acid are used commonly. secretion by food and fundic distension and ii. Fast acting antacid e.g. magnesium also inhibit fasting and nocturnal acid hydroxide and slow acting antacid e.g. secretion and they reduce both the volume aluminium hydroxide are used and H+ ion concentration of gastric juice. together for sustained action. iii. For reducing the systemic toxicity of Pharmacokinetics

individual compounds. The H2 antagonists are well absorbed orally (60-80%) and its absorption is not ANTIULCER AGENTS affected with the presence of food in the stomach. They cross the placental barrier and PATHOGENESIS OF PEPTIC ULCERS secreted mostly in mother’s milk. They are Peptic ulcers are chronic, most often solitary excreted in urine mostly in unchanged form. lesions that occur in any part of GIT exposed to the aggressive action of acid-peptic juices. Adverse Reactions Duodenal ulcer patients have an They produces headache, dizziness, dry increased capacity to secrete acid and mouth, rashes. CNS effects include pepsin, increased responsiveness to stimuli restlessness, delirium, hallucinations, of acid secretion and more rapid gastric convulsion and coma. Intravenous bolus emptying. injection cause bradycardia, arrhythmia and Antacids and Antiulcer Agents 263

Table 7.3.1: Classification of drugs used in peptic ulcer. I. Drugs which reduce gastric acid secretion

i. H2-receptor antagonists Cimetidine (CIMETIN) 200-400 mg TDS-QID, 400 mg HS, 200-400 mg/day IM/IV Ranitidine (HISTAC) 150 mg BD/HS, 50-100 mg/day IM/IV Famotidine (FACID) 40 mg HS, 20 mg BD Roxatidine (ZORPEX) 75-150 mg HS Also available Nizatidine, Loxatidine. ii. Proton pump inhibitor Omeprazole (OMIZAC) 20-60 mg OD (PANTOCID) 40 mg OD (VELOZ) 20 mg OD Also available Esomeprazole, Lansoprazole iii. Prostaglandin analogues Misoprostol (CYTOTEC) 200 µg QID Enprostil 35-140 µg/day Also available Rioprostil, Arbaprostil, Trimoprostil. II. Ulcer healing agents Carbenoxolone sodium (GASTRIULCER) 100 mg TDS III. Ulcer protective agents Sucralfate (SUCRASE) 1 g one hr before each (3) meals and at bed time IV. Antacids (Neutralize gastric acid) Systemic antacids Sodium bicarbonate 0.3-1.5 g TDS-QID Nonsystemic antacids Magnesium carbonate 0.5-2 g/day Magnesium hydroxide (MILK OF MAGNESIA) 0.3-1 g/day Magnesium trisilicate 0.5-1 g/day Aluminium hydroxide gel (ALUDROX) 0.5-1 g/day Magaldrate (STACID) 400-800 mg/day Calcium carbonate 0.5-1 g/day cardiac arrest due to histamine release. The • Zollinger-Ellison syndrome (ZES). cimetidine has antiandrogenic action and • Gastroesophageal reflux. can cause gynaecomastia, loss of libido and • NSAID’s induced ulcers. impotence, otherwise all other H blockers 2 • Prophylaxis of aspiration pneumonia. are devoid of these side effects. CIMETIDINE Therapeutic Uses Low potency, short duration of action. H blockers are used in the treatment of: 2 Oral bioavailability is 60% and 2/3 is • Duodenal ulcer. excreted unchanged in urine and bile. • Gastric ulcer. Incidence of adverse effects is 5%. 264 Section 7/ Drugs Acting on GIT

It has poor CNS entry but in elderly ROXATIDINE and in patients with impaired renal Roxatidine inhibit H2 induced gastric functions, CNS symptoms may occur. It secretion with a potency greater than displaces from cimetidine and in the same range as cytoplasmic receptors (antiandrogenic ranitidine. Its acetate salt is more than 95% action) and inhibits degrada- absorbed after oral administration and tion by liver. High doses given for rapidly converted to roxatidine by esterases longer periods produce gynaecomastia, in small intestine and liver. Plasma t½ is 6 decreased libido and impotence. It hours. Peak plasma levels occur about 8 inhibits cytochrome P450 catalyzed hours after dosing. Effects of the drug persist hydroxylation of estradiol in men, also for about 12 hours. slowing metabolism of many drugs and It has use in prophylaxis of acid concurrent administration of cimetidine aspiration syndrome after induction of will prolong the half life of many drugs anaesthesia. In a dose of 150 mg HS as (warfarin, phenytoin, theophylline, premedication affords reliable protection phenobarbital, benzodiazepines, against the consequences of acid aspiration propranolol, nifedipine, digitoxin, until 11 AM the next day and decreases the quinidine, mexiletine, tricyclic antide- danger of aspiration by reducing the high pressants). volumes of gastric juice. RANITIDINE PROTON PUMP INHIBITOR 5 to 8 times more potent than cimetidine. Produces higher suppression of gastric acid and action lasts longer than cimetidine. No OMEPRAZOLE clinically significant drug interaction and Omeprazole is gastric proton pump side effects are seen. inhibitor which reduces gastric acid secretion. It inhibits the enzyme FAMOTIDINE H+K+ATPase in the parietal cells of gastric On a weight basis 20 times more mucosa. It effectively inhibits both basal and potent than cimetidine and 7.5 times more stimulated acid secretion irrespective of the potent than ranitidine in inhibiting basal stimulus. It has quick onset of action and and pentagastrin stimulated gastric acid effective control of gastric acid secretion is secretion. It is a competitive-noncompeti- achieved with once daily dosing. It has no tive inhibitor of H2 receptors. It has a long- effect on pepsin, , juice er duration of action. Oral bioavailability volume and gastric motility. Proton pump is 40-50% and is excreted unchanged (70%) inhibitors do not exhibit anticholinergic or in urine. Incidence of adverse effects is H2 receptor antagonistic properties. low. Omeprazole distributes widely and is It is more useful in ZE syndrome and rapidly eliminated from plasma by prophylaxis of aspiration pneumonia. metabolism in liver. The antisecretory effect Antacids and Antiulcer Agents 265 persists for much longer as it strongly binds Adverse effects include nausea, diarr- to H+ K+ ATPase. The disposition is not hoea, skin eruptions, headache and dizziness. altered in patients with renal disease or in Other proton pump inhibitors e.g., lanso- those undergoing haemodialysis. Increased prazole is more potent than omeprazole and age and liver disease delays plasma clearance has higher bioavailability, rapid onset of ac- of the drug but this does not necessitate tion and longer duration of action. dosage adjustment in these patients. Pantoprazole is the new H+K+ATPase inhibi- It is indicated in: tor with similar properties and action to omeprazole. • Treatment of duodenal ulcer. • Treatment of gastric ulcer. PROSTAGLANDIN ANALOGUES • Treatment of reflux oesophagitis.

• For control of acid secretion in patients PGE2 and PGI2 are the main prostaglandins of Zollinger-Ellison syndrome. synthesized by gastric mucosa. They decrease It is well tolerated. Nausea, headache, acid secretion and improve mucosal defense diarrhoea, constipation and flatulence have mechanism by: been reported occasionally, Rarely skin rash • Stimulation of synthesis and release of has occurred in few patients. mucus. • Enhance bicarbonate production. RABEPRAZOLE • Enhancement of tight junctions of cell Rabeprazole belongs to substituted ben- membrane architecture. zimidazole proton-pump inhibitors. In • Inhibit gastrin production. gastric parietal cells, rabeprazole is proto- • Stimulation of a number of cellular nated, accumulates and is transformed to transport processes. an active sulfenamide. • Stimulation of DNA content in Following oral administration of 20 mg, damaged gastric mucosa by a process rabeprazole is absorbed and can be detected termed as cytoprotection. in plasma by one hour. Rabeprazole is 96.3% The important use of prostaglandin bound to plasma proteins. analogues is in the arthritic patients who are Rabeprazole is extensively metabolized. on chronic use of NSAID’s and are not The thioether and sulfone are the primary responding to H2 receptor antagonists. inactive metabolites. 90% of the drug is eliminated in the urine, primarily as MISOPROSTOL thioether carboxylic acid, its glucuronide 200 µg QID was of similar efficacy to and mercapturic acid metabolites. cimetidine 300 mg TDS in healing duodenal It is indicated in erosive and ulcerative and gastric ulcer. Pain relief occurred more gastroesophageal reflux disease, healing of slowly than with cimetidine. Shown to heal duodenal ulcers and Zollinger Ellison syndrome. erosions, ulcers due to NSAIDs. 266 Section 7/ Drugs Acting on GIT

ENPROSTIL electrostatic interaction of the drug with 35-140 µg day heal duodenal and gastric proteins at ulcer site. It also binds to basic fibroblast growth factor preventing its ulcer but are less effective than H2 receptor antagonists. degradation and thereby promotes healing. It also protects from intracellular enzymes released from damaged cells. It also helps in ULCER HEALING DRUGS formation of new blood vessels (angiogenesis) and helps in cell division (mitogenic). CARBENOXOLONE SODIUM Sucralfate also inhibits release of cytokines It is a steroid like triterpenoid synthetic (immunomodulator). It also has antibacterial derivative of glycyrrhizic acid (obtained activity. from liquorice) and has been found to be It precipitates surface proteins at ulcer effective in healing both gastric and base and act as a physical barrier, preventing duodenal ulcer without affecting volume or acid, pepsin and bile from coming in contact acidity of gastric juice. with ulcer base. It also augments gastric It acts by increasing mucus production, mucosal PG synthesis thereby enhancing slowing turnover of gastric cells and protective action. It has no acid neutralizing increasing regeneration of cells around ulcer. action. It also enhances pyloric tone preventing bile It promotes healing of both gastric and reflux. It retards PG’s degradation in gastric duodenal ulcers and also prevents ulcer mucosa. Its mineralocorticoid side effects lead recurrence. + + to Na and water retention and K loss Topical sucralfate (4-10%) is also preclude its use on large scale. useful in management of decubitus ulcer, diabetic ulcers, chemical and thermal ULCER PROTECTIVE AGENTS burns, radiation induced skin damage, vaginal ulceration, oral and genital SUCRALFATE ulceration. It is a basic aluminium salt of sucrose Side effects include dry mouth, octasulfate. It polymerizes at pH < 4 to form a constipation, nausea, vomiting, rash, pruritus, sticky, viscid yellow white gel which adheres dizziness. It adsorbs and interferes with to ulcer base. The gel acts as a strong absorption of tetracycline, cimetidine, digoxin mechanical barrier because of a strong and phenytoin.

 Section 8

Drugs Acting on Endocrine System This page intentionally left blank (Drugs used in A

ChapterChapter PharmacodynamicsPharmacodynamicsAnterior Pituitary 1.48.1 (ModeHormones of Action of Drugs)

The pituitary gland is situated in sella turcica 1. Growth hormone or somatotrophic or hypophyseal fossa of the sphenoid bone hormone (GH & STH). attached to the brain by a stalk which is 2. Thyroid stimulating hormone (TSH) or continuous with the part of brain i.e. thyrotrophic hormone. hypothalamus and there is a communication 3. Adrenocorticotrophic hormone (ACTH). between the hypothalamus and the pituitary 4. Follicle stimulating hormone (FSH). gland by means of nerve fibres and a complex 5. Luteinising hormone (LH) or of blood vessels. Pituitary gland consists of interstitial cell stimulating hormone three parts – anterior lobe or adenohypophysis, (ICSH). posterior lobe or neurohypophysis and middle 6. Lactogenic hormone or prolactin. lobe or pars intermedia. The anterior lobe secretes various trophic GROWTH HORMONE hormones, the posterior lobe is responsible It is secreted by acidophil cells. Human for the secretion of oxytocin and antidiuretic growth hormone has a single straight chain hormone (vasopressin) and middle lobe polypeptide structure containing two secretes melanocyte-stimulating hormone intramolecular disulphide bridges and is (MSH) which may affect the synthesis of composed of 188 amino acids. melanin. It stimulates growth directly and in conjunction with other hormones. It stim- ANTERIOR PITUITARY HORMONES ulates the multiplication of the cells of epiphyseal cartilage and thus increases the Anterior lobe of pituitary is the master gland length of the cartilage bone. After admin- of the endocrine system as a whole because istration, there is an increased body it produces peptide trophic hormones which growth due to its direct effect on the affect the other ductless/endocrine glands. tissues. It stimulates the growth of mus- The anterior lobe secretes the following cles. It also increases the secretion of milk hormones: during lactation. 270 Section 8/ Drugs Acting on Endocrine System

Growth hormone promotes protein Hypersecretion during adult life leads metabolism. It increases nucleic acid and to ‘acromegaly’ and is characterized by protein synthesis, decreases nitrogen excessive growth of facial bones, hands excretion in the urine. It diminishes the become large and spade like, thickening of amino acid content of the plasma by facial and hand’s skin etc. transferring it into the tissues and helps in the growth of tissue. In fat metabolism, it Clinical Preparations causes mobilisation of peripheral fat depot Human growth hormone is produced by to the liver. In carbohydrate metabolism, its recombinant DNA technique. The primary effect is to stimulate its storage. preparation available are: Administration of growth hormone produces hyperglycemia and glycosuria. In Sometrem (PROTROPIN) 5 mg (13 IU) inj. mineral metabolism, it increases intestinal Somatropin (GENOTROPIN) (12 & 16 IU per vial inj. absorption of calcium as well as its secretion. and 1 mg contains 2.6 IU) The secretion of growth hormone by acidophil cells is regulated by the The main use of growth hormone is in hypothalamic hormone, the growth the treatment of dwarfism. hormone-releasing factor (GHRF). GHRF Side effects include allergic reaction, levels in the hypothalamus are reduced by pain at the site of injection, hypothyroidism corticosteroids and increased by thyroxine. and glucose intolerance. Water retention Certain stimuli which can increase growth may also occur. hormone secretion are insulin-induced hypoglycemia, fasting, physical exercise, amino acid administration. Stress and sleep also stimulate growth hormone release. It is a peptide containing 14 amino acids Various hormones i.e., thyroxine and ACTH and inhibits the release of growth hormone, also stimulate growth. TSH and prolactin from the pituitary and insulin and glucagon in pancreas. It has a Hyposecretion of pituitary during childhood leads to ‘dwarfism’ which is of very short plasma half-life. Because of its two type, Lorain type and Frohlich’s type shorter duration of action and lack of and is characterized by stunted growth of specificity in inhibiting only GH secretion, the skeleton with resultant ‘dwarfism.’ its use in the treatment of acromegaly is Hyposecretion during adult life leads limited. to ‘Simmond’s disease’ and is characterized Another newer synthetic compound, by dry and wrinkled skin, grey hair and octerotride is a longer acting analogue of there is a atrophy of the sexual organs and somatostatin and is used in acromegaly. cessation of menstrual cycle in the female. Hypersecretion during childhood THYROID STIMULATING HORMONE leads to ‘gigantism’ and is characterized by This hormone controls the growth and excessive skeletal growth. activity of the thyroid gland. It influences Anterior Pituitary Hormones 271 the uptake of iodine, synthesis of thyroxine which stimulates the reabsorption of sodium

(T4) and triiodothyronine (T3) by the thyroid by the renal tubules and when the amount gland and their release into the blood of sodium reabsorbed is increased the stream. amount of potassium excreted is increased. Details are discussed in chapter ‘Thyroid Angiotensin (vasopressor agent) produced & antithyroid agents’. by the renin (from kidneys) stimulates the secretion of aldosterone. ADRENOCORTICOTROPHIC HORMONE (ACTH) Sex Hormones It is a polypeptide of 39 amino acid The secretion of estrogens in females and residues of molecular weight approximately androgens in males by the adrenal cortex is 4,500. It is secreted by basophil cells under controlled by ACTH. They are responsible the control of CRF (corticotropin releasing for the development and maintenance of factor) from the hypothalamus. ACTH secondary sexual characters in both males controls the growth of adrenal cortex and the and females. They also increase the synthesis of corticosteroids and is essential deposition of protein in muscles and reduce to life. The action of ACTH on adrenal cortex the excretion of nitrogen in males. is mediated through cyclic AMP. Hyposecretion of hormones from the This hormone stimulates the cortex of adrenal cortex leads to development of adrenal gland to produce its hormones. The ‘Addison’s disease’ which is characterized by amount of ACTH secreted depends upon loss of appetite, muscular weakness, loss of the concentration in the blood of the weight due to loss of water, hypoglycemia, hormones from the adrenal cortex and on subnormal body temperature, decreased stimulation by hypothalamus. basal metabolic rate, increased blood The cortex of adrenal gland produces potassium, decreased blood sodium and three types of hormones – the glucocorticoids, inability to maintain the normal protein mineralocorticoids and the sex hormones. deposition in the muscles. Hypersecretion from the adrenal Glucocorticoids cortex leads to condition known as The secretion is stimulated by ACTH ‘Cushing’s syndrome’ which leads to from the anterior lobe of pituitary gland. ‘feminism’ in males, which is the tendency Cortisone and hydrocortisone are the main to develop female sex characters and in glucocorticoids and their main function is females ‘virilism’ develops, which is the to regulate carbohydrate metabolism. tendency to develop male sex characters such as excess growth of hair on chest and Mineralocorticoids pubic region, increase and darkening of It is associated with the maintenance of facial hair, atrophy of mammary glands the electrolyte balance in the body. (breasts) and cessation of menstrual cycle Aldosterone is the main mineralocorticoid (amenorrhoea). 272 Section 8/ Drugs Acting on Endocrine System

ACTH is available as lyophilized In males, the same hormone under the powder which on reconstitution gives 40 name of ICSH stimulates the development IU/ml solution and is used mainly for the and functional activity of interstitial cells diagnosis of pituitary adrenal axis disorders. and ultimately the production of testicular , testosterone. GONADOTROPHIC HORMONES Gonadotrophin secretion is under the (GTH) OR GONADOTROPHINS control of hypothalamus and sex hormones. The basophil cells secrete gonadotro- The hypothalamic nuclei secrete a specific phins which control the growth and ac- releasing factor for the release of both FSH tivity of the gonads and indirectly other & LH. processes connected with it. There are This single releasing factor is a two gonadotrophins: decapeptide and is designated as GnRH or • Follicle stimulating hormone (FSH), gonadorelin. Frequency and amplitude of • Luteinising hormone (LH) or intersti- GnRH release pulses determine whether LH tial cell stimulating hormone (ICSH). or FSH or both will be secreted as well the Both of them are glycoprotein in nature. amount of each. Gonadal hormones from ovary and testis regulate the FSH and LH FSH secretion by direct action on pituitary as well In females, the target organs are the as through hypothalamus. ovaries where it increases the number and Gonadotrophins are used in the size (maturation, development and treatment of amenorrhoea, infertility, ripening) of Graafian follicles and prepare cryptorchidism and hypogonadotrophic them for . During its development, in males. It is also useful in the ovarian follicles secrete its own hormone in vitro fertilization. . In males, it stimulates There are two types of gonadotrophins spermatogenesis. Under the influence of this available: hormone, seminiferous tubules produce spermatozoa. • Obtained from urine of pregnant women, chorionic gonadotrophin as LH 1,000-10,000 IU (powder form, can be In females, it is responsible for: used after reconstitution by parenteral route). • Complete development of the ovarian follicles to secretory stage and secretion • Obtained from urine of menopausal of estrogen. women, menotrophin (combination of FSH 75 to 150 IU and LH 75 to 150 IU). • Promotes the final maturation of ova- rian follicles and ovulation and the for- Preparations of gonadotrophins have mation of corpus luteum which se- been used to treat infertility for the last cretes progesterone. several years. Anterior Pituitary Hormones 273

MENOTROPHIN Nasal mucosal irritation, migraine may also Purified extract of human post- occur. Naferelin therapy for six to nine menopausal urine containing follicle months may lead to three to five percent stimulating hormone (FSH) and luteinising bone loss. hormone (LH) is known as human It is indicated in endometriosis, menopausal gonadotrophin. The relative in . vivo activity is designated as a ratio, the 1:1 In infertile women choosing in vitro ratio is also known as menotrophin. fertilization, naferelin in combination with Adverse reactions include polycystic gonadotrophins can be used for stimulating ovary, edema, pain in lower abdomen and ovulation. It is also useful in management of uterine leiomyoma, benign prostatic allergic reactions. hypertrophy, hirsutism and polycystic It is used in amenorrhoea and infertility, ovarian syndrome. hypogonadism in males and females, follicle stimulation in IVH and cryptorchidism. PROLACTIN OR LACTOGENIC HORMONE NAFARELIN ACETATE It is a single chain , It is potent analogue (200 times more isolated in pure form and contains potent) of gonadotrophin releasing hormones tyrosine, tryptophan, cystine, arginine, (GnRH). methionine of approximately 25,000 molecular weight. It has a direct effect It is rapidly absorbed into the systemic upon the breasts immediately after the circulation following intranasal delivery. It delivery of baby and in conjunction with stimulates the release of LH and FSH from other hormones, it stimulates the breast to the anterior pituitary resulting in a temporary secrete milk. increase of ovarian steroidogenesis. After 2 to It also stimulates the proliferation of the 3 days of daily administration, the pituitary glandular elements of the mammary glands becomes refractory to further stimulation. LH/ during pregnancy and helps in complete FSH release is inhibited within 10 days and is development of breasts. followed by a decrease in secretion of gonadal Prolactin secretion is under the steroids within 2 to 6 weeks. inhibitory control of hypothalamus through After intranasal administration prolactin inhibiting hormone (PRIH) which maximum serum concentration are achieved is a dopamine and acts on pituitary within 10 to 45 minutes. It is 80% bound to lactotrope D2 receptor. plasma proteins. BROMOCRIPTINE (Bromoergocriptine) Adverse effects include hot flushes, change in libido, vaginal dryness, headache. It is a semisynthetic ergot alkaloid and Incidents of emotional lability and dopamine receptor agonist. depression are higher in infertile patients. It acts on pituitary lactotrophic cells to 274 Section 8/ Drugs Acting on Endocrine System inhibit the synthesis and release of prolactin axons into the posterior lobe of pituitary. by agonist action on dopaminergic receptors. It promotes contraction of the uterine Adverse effects are nausea, vomiting, muscle. It also causes contraction of the postural hypotension, behavioral alterations, myoepithelial cells of the lactating breast mental confusion, psychosis. and squeezing milk into the large ducts It is used in hyperprolactinemia and for situated behind the nipple of the mammary suppression of lactation and breast gland. engorgement. It is also useful in Oxytocin takes part in the onset of parkinsonism because it has levodopa like parturition, expulsion of the foetus and actions and in the treatment of acromegaly. placenta. It also facilitates the transport of Dose: PROCTINAL 1.25 mg BD. sperm in the female genital tract. Oxytocin is used in induction of labour, POSTERIOR LOBE OF PITUITARY GLAND in postpartum haemorrhage, abortion and The posterior lobe secretes two hormone in breast engorgement. It is used by IM/IV namely oxytocin and antidiuretic hormone route (PITOCIN, 2-5 IU/ml inj). (ADH or vasopressin). ADH OR VASOPRESSIN It increase force, frequency and duration Discussed in detail in chapter ‘Diuretics of uterine contractions. It is used to control and antidiuretics’. and prevent postpartum haemorrhage. It is also used to prevent uterine atony after UTERINE STIMULANTS cesarean or instrumental delivery. (OXYTOCICS, ABORTIFACIENTS) PROSTAGLANDINS OXYTOCIN PGE2, PGF2α and 15-methyl PGF2α are Oxytocin is an octapeptide synthesized potent uterine stimulant (Other details are in hypothalamus and transported down the given in chapter 5.3).

 (Drugs used in A

ChapterChapter PharmacodynamicsPharmacodynamicsAntidiabetic Agents 1.48.2 (Mode of Action of Drugs)

Diabetes mellitus (DM) is a chronic crystallized by Abel and it’s amino acid disorder characterized by altered sequence was established by Sanger in 1960. metabolism of carbohydrates, proteins and It’s formed from proteolysis of proinsulin fats. Epidemiological survey conducted in to give rise to two peptide chains (A with 21 several developing countries show that amino acid residues and B with 30) which prevalence rates of diabetes mellitus vary are interconnected by disulphide bond. from two to four percent in different population groups. Roughly two percent of Mechanism of Insulin Action the world population suffers from diabetes Insulin acts by binding to insulin mellitus. receptors on cell membrane. The insulin receptor complex is internalized. By Types of Diabetes Mellitus phosphorylation and dephosphorylation • Insulin dependent or type I diabetes reactions there is stimulation or inhibition of (IDDM). Formerly called juvenile onset, enzymes involved in metabolic actions of or ketone prone diabetes. It is an insulin. Second messengers like phosphatidyl autoimmune disease of pancreatic β- inositol glycan and DAG also mediate the cells. Arises due to insulin insufficiency. action of insulin on metabolic enzymes. • Non-insulin dependent or type II Normally, insulin stimulates storage of diabetes (NIDDM). Formerly called glucose in liver as glycogen and in adipose non ketotic or maturity onset diabetes. tissues as triglycerides and storage of amino It arises due to insulin resistance in acids in muscle as protein. It also promotes peripheral tissues. utilization of glucose in muscle for energy. Insulin inhibits the breakdown of INSULIN triglycerides, glycogen, and protein and Insulin (MW 5,800) a polypeptide conversion of amino acids to glucose hormone secreted from β-cells of islets of (gluconeogenesis). Conversion of amino Langerhans in pancreas was discovered by acids to glucose and glucose to fatty acids Banting and Best in 1921. It was purified and occur mainly in liver. 276 Section 8/ Drugs Acting on Endocrine System

Table 8.2.1: Classification of insulin preparations. I. Conventional preparations Regular (soluble) insulin (HUMINSULIN-R) 40, 80 IU/ml; SC/IV Insulin zinc suspension ‘prompt’ (Semilente) 40, 80 IU/ml; SC Insulin zinc suspension (Lente insulin; HUMINSULIN-L) 40-80 IU/ml; SC Isophane or Neutral Protamine Hagedorn (NPH) insulin 40 IU/ml; SC (HUMINSULIN-N) Globin zinc insulin 40 IU/ml; SC Insulin zinc suspension ‘extended’ (Ultralente; HUMINSULIN-U) 40 IU/ml; SC Protamine zinc insulin (PZI) 40 IU/ml; SC II. Newer purified insulin preparations i. Regular-ILETIN (Purified by gel filtration) ii. Regular-ILETIN-II (Purified by gel filtration and ion exchange chromatography) iii. Single peak insulins (Purified by gel filtration and then recrystallization) Pork regular insulin (ACTRAPID) 40 U/ml Pork lente insulin (LENTARD) 40 U/ml Pork regular and isophane insulin (in a ratio of 30:70; RAPIMIX) 40 U/ml iv. Monocomponent insulin (Purified by gel filtration and then by ion exchange chromatography; ACTRAPID MC and MONOTRAD MC) 40 U/ml III. Biosynthetic human insulins (by recombinant DNA technique) Human soluble insulin (HUMAN ACTRAPHANE) 40 U/ml Human regular insulin (HUMAN ACTRAPID) 40 & 100 U/ml Human lente insulin (HUMAN MONOTRAD) 40 & 100 U/ml

In diabetes mellitus, there is either insulin reaction is hypoglycemia. It can occur in any deficiency or insulin resistance in peripheral diabetic patient due to heavy dose of insulin, tissues which lead to hyperglycemia and failure to eat or missing a meal, performing glycosuria. Insulin corrects the various extensive exercise or by consuming alcohol. abnormalities of carbohydrate metabolism by The hypoglycemia caused by insulin is its action on various tissues. characterized by neuroglucopenic symptoms that include confusion, dizziness, Pharmacokinetics behavioural changes, visual disturbances, Insulin is not given orally. After IV or SC fatigue, muscle incoordination and may be injection, it circulates as free, monomer in blood fall in blood pressure. and has a short plasma half life. Insulin is The other side effects include insulin degraded mainly in liver, muscle and kidney. allergy which consists of local itching, swelling, redness at the site of injection. Adverse Reactions Urticaria and anaphylactic reactions are rarely The most frequent and serious adverse seen. Other rare side effects include insulin Antidiabetic Agents 277 lipodystrophy (atrophy at the site of injection), experience redness, swelling, and itching at insulin neuropathy and weight gain (obesity). the site of injection of insulin. Systemic allergy: Less common, but Therapeutic Uses potentially more serious, is generalized Insulin is used in: allergy to insulin, which may cause rash • Insulin dependent diabetes mellitus over the whole body, , (IDDM). wheezing, reduction in blood pressure, fast pulse, or sweating. Severe cases may be life • Diabetic ketoacidosis or diabetic coma. threatening. HUMINSULIN ORAL ANTIDIABETIC AGENTS Huminsulin 30/70 [biphasic isophane insulin injection (30% soluble insulin and 70% These are the agents which are effective isophane insulin)] is a mixture of soluble orally and lower the elevated blood glucose human insulin injection, a short acting blood levels. They are classified as in table 8.2.2. glucose lowering agent and isophane insulin human suspension, an intermediate acting SULFONYLUREAS blood glucose lowering agent. These drugs stimulate insulin secretion from pancreatic βββ-cells (so called Adverse Effects ‘sulfonylurea receptors’) which cause Local allergy: Patients occasionally depolarisation by reducing conductance of

Table 8.2.2: Classification of oral antidiabetic agents. I. Sulfonylureas i. First generation Tolbutamide (RASTINON) 0.5-2 g/day Chlorpropamide (COPAMIDE) 100-500 mg/day Tolazamide 0.125-1.0 g/day ii. Second generation Glibenclamide (BETANASE) 5-20 mg/day Glipizide (DIBIZIDE) 5-20 mg/day Gliclazide (GLIZID) 160-320 mg BD Glimepiride (GLIMER) 1-6 mg OD II. Biguanides Metformin (GLYCOMET) 250 mg to 3.0 g/day III. Meglitinides Repaglinide (RAPILIN) 0.25-4 mg/day Nateglinide (GLINATE) 60 mg/day IV. Thiazolidinediones Rosiglitazone (ENSELIN) 4-8 mg OD-BD Pioglitazone (GLIZONE) 15-45 mg OD V. ααα-Glucosidase inhibitors Acarbose (GLUBOSE) 50-200 mg TDS 278 Section 8/ Drugs Acting on Endocrine System

ATP sensitive K+ channels. They lower 1. The pancreatic effect, in the case of down the blood sugar level in type II failure of β-cell function together with diabetics and non-diabetic individuals. They an existing but inadequate insulin also decrease the elevated plasma free fatty secretion, gives rise to an intensified acid levels. They also sensitize the target insulin secretion as a result of a greater tissues to action of insulin by increasing the response of the β-cells to glucose. number of insulin receptors. 2. The extrapancreatic effect, in the case Sulfonylureas inhibit neoglucogenesis of resistance to insulin due to a reduced and glycogenolysis. Sulfonylureas are sensitivity of the peripheral tissue to rapidly absorbed from the gastrointestinal insulin, there is intensification of the tract after oral administration and are more insulin effect as a result of: than 90 percent bound to plasma proteins Adverse reactions include visual dis- and excreted unchanged in urine. turbances (transient, at the beginning of therapy), nausea and epigastric bloating CHLORPROPAMIDE (rare) and diarrhoea. Hypersensitivity in- After oral administration, it is rapidly cluding allergic skin reactions, thrombocy- absorbed and has long plasma half life and topenia, leucopenia, agranulocytosis, excreted by kidney slowly. haemolytic anaemia, vasculitis, cholestatic Adverse effects include nausea, vomiting, jaundice and hepatitis. cholestatic jaundice, skin rash, anaemia, It is indicated in non-insulin dependent leucopenia, hypoglycemia and intolerance to diabetes mellitus (type II, maturityonset alcohol (disulfiram like reaction). diabetes) whenever treatment by diet alone It is indicated in the treatment of proves to be inadequate. maturity onset non ketotic diabetes mellitus unresponsive to diet and neurogenic GLIPIZIDE diabetes insipidus. It is an oral blood glucose lowering drug of sulfonylurea class. TOLBUTAMIDE It is fast acting and post prandial It is a short acting, less potent oral insulinemic action persists even after hypoglycemic agent and after administration prolonged use. it is readily metabolized in liver. Glipizide is completely and rapidly Adverse effects include, nausea, absorbed ensuring prompt and constant vomiting, skin rash and epigastric distress. activity. It is mainly used in maturity onset diabetes mellitus. It is indicated in management of type II diabetes where diet control alone is not GLIBENCLAMIDE effective in controlling the hyperglycemia. Glibenclamide is a second generation Adverse effects include hypoglycemia, sulfonylurea. There are two mechanisms of GIT disturbances, allergic reactions include action for the lowering of the blood glucose: urticaria and erythema. Antidiabetic Agents 279

GLICLAZIDE absorption of carbohydrates in gut and sup- Gliclazide reduces blood glucose levels presses hepatic gluconeogenesis. by correcting both defective insulin Metformin improves glucose tolerance secretion and peripheral insulin resistance. in NIDDM subjects by lowering both basal Gliclazide also has been reported to reduce and postprandial plasma glucose. Metformin plasma cholesterol and triglyceride levels decreases hepatic glucose production, after repeated administration. decreases intestinal absorption of glucose and Adverse effects include nausea, improves insulin sensitivity (increases diarrhoea, gastric pain, vomiting, skin rash, peripheral glucose uptake and utilization). pruritus, flushing, erythema, headache and They are rapidly absorbed from gastro- dizziness with low incidence of hypoglycemia. intestinal tract and show adequate plasma It is indicated in non-insulin dependent levels and excreted unchanged in urine. diabetes mellitus, diabetes with or without Adverse effects include anorexia, nausea, obesity in adults, diabetes in the elderly and bitter or metallic taste in mouth, abdominal diabetes with vascular complications. discomfort, tolerance and lactic acidosis which is the most serious complication and GLIMEPIRIDE more common with phenformin. It is a very potent sulfonylurea with long They are indicated in maturity onset non- duration of action indicated in non-insulin insulin dependent diabetes mellitus and dependent (type II) diabetes, whenever diabetes mellitus not responding adequately blood sugar levels can not be controlled with dietary restrictions or with sulfonylureas. adequately by diet, physical exercise or Biguanides are contraindicated in reduction in body weight. hypotension, alcoholics (can precipitate Adverse effects include hypoglycemia, lactic acidosis), respiratory, hepatic, temporary visual impairment, gastrointestinal cardiovascular and renal diseases. disturbances. Rarely leucopenia, haemolytic anaemia. Occasionally allergic or pseudoallergic MEGLITINIDES reactions like itching, urticaria or rashes. In isolated cases allergic vasculitis, photosensitivity REPAGLINIDE or a decrease in serum sodium may occur. Repaglinide is a novel insulin secreta- gogue. It lowers postprandial blood glucose BIGUANIDES as well as fasting blood glucose in patients They lower the blood sugar levels in all types with type II diabetes mellitus by acting on of diabetes mellitus but like sulfonylureas the beta cells of pancreas. It stimulates insu- they do not lower the blood sugar level in lin release only during meal time. It is taken normal individuals. They act by increasing with or just before each meal, thus introduc- peripheral anaerobic glycolysis (stimulate ing the concept of ‘one meal one dose, no peripheral utilization of glucose), inhibit meal no dose’ and flexibility of meal times. 280 Section 8/ Drugs Acting on Endocrine System

Adverse effects include mild or It is indicated in the management of type moderate hypoglycemia. Other adverse II diabetes mellitus as monotherapy or in effects are nausea, vomiting, arthralgia, back combination. pain, and headache. It is indicated in the management of type PIOGLITAZONE II diabetes mellitus in patients who are not Pioglitazone hydrochloride, a thiazo- responding to diet and exercise. lidinedione, acts primarily by decreasing insulin resistance. It improves sensitivity NATEGLINIDE to insulin in muscle and adipose tissue and Nateglinide is a novel drug designed for inhibits hepatic gluconeogenesis. It also im- the management of postprandial hypergly- proves glycemic control while reducing cir- cemia in type II diabetes. Nateglinide culating insulin levels. belongs to the meglitinide class of oral hypoglycemic agents. It restores the first ααα-GLUCOSIDASE INHIBITORS phase of insulin secretion in type II diabe- tes. It is well tolerated and appears to have a significantly lower likelihood of inducing ACARBOSE hypoglycemia than sulfonylureas. It is a pseudo-tetrasaccharide derived Adverse reactions include dizziness, from the fermentation process of the fungus URTI, back pain, flu-like symptoms, Actinoplanes utahensis. bronchitis, cough and hypoglycemia. It acts by competitively inhibiting It is mainly indicated in the manage- pancreatic alphaamylase and intestinal ment of postprandial hyperglycemia in type alpha glucosidase hydrolase enzymes. II diabetes mellitus. Thus, it delays carbohydrate digestion, prolongs digestion time and reduces the rate THIAZOLIDINEDIONES of glucose absorption thereby lowering postprandial hyperglycemia. ROSIGLITAZONE Given orally less than 2% is absorbed as Rosiglitazone, a member of the the oral drug. It is metabolised in the GI tract thiazolidinedione class of antidiabetic primarily by intestinal bacteria and to a agents, improves glycemic control by lesser degree by digestive enzymes. improving insulin sensitivity. Adverse effects include flatulence, soft The oral bioavailability of rosiglitazone is 99%. Peak plasma concentrations are stools, diarrhoea, abdominal distention and observed about one hour after dosing. pain, rarely abnormal liver function tests Rosiglitazone plasma concentration and skin reactions. increases in a dose-proportional manner It is used as first line therapy in NIDDM over the therapeutic dose range. inadequately controlled by diet and as Adverse reactions include weight gain, adjunct to existing conventional oral edema, increase of total cholesterol and hypoglycemic agents where hypoglycemic reduction in haemoglobin content. control is inadequate.  ChapterChapter GlucocorticoidsPharmacodynamicsPharmacodynamics & Sex 1.48.3 (ModeHormonesHormones of Action of Drugs)

GLUCOCORTICOIDS mineralocorticoids and sex hormones. The glucocorticoids and mineralocorticoids are As discussed in previous chapters, twenty one carbon compounds having a secretion of adrenocortical steroids is cyclopentanoperhydro-phenanthrene controlled by the pituitary release of nucleus. Both these hormones are corticotrophin (ACTH). The adrenal synthesised in the adrenal cortex from gland has two main parts, adrenal cholesterol (see Fig. 8.3.1). medulla, which is responsible for the The important secreted in release of catecholamines and adrenal human being is hydrocortisone (10 mg/ cortex which secretes glucocorticoids, day). They are listed in table 8.3.1.

Cholesterol    Progesterone 17α-Hydroxy-  Dehydroepiandro-  pregnenolone sterone  Desoxy-    17α-Hydroxy-   progesterone Corticosterone   Desoxyhydro- Testosterone  cortisone Aldosterone   Hydrocortisone Estrogens Fig. 8.3.1: Biosynthesis of various steroid hormones. 282 Section 8/ Drugs Acting on Endocrine System

Table 8.3.1: Classification of glucocorticoids and mineralocorticoids. Glucocorticoids Hydrocortisone (Cortisol; HYCOSON) 100 mg IM used as hydrocortisone sodium succinate injection. Also used as intraarticular inj. as hydrocortisone acetate & 1-2.5% topical (skin, ear & eye; WYCORT) Prednisolone (EMSOLONE) 5-60 mg/day oral, 10-40 mg intramuscular/intra articular inj. and 0.25% topical (skin, eye) (TRICORT) 8-32 mg/day oral, intraarticular (2.5-15 mg), intradermal and deep intramuscular injection. 0.1% topical cream (as acetonide; LEDERCORT) Dexamethasone (DEXONA) 0.5-5 mg/day oral, 4-20 mg/day IM/IV, 0.1% topical (skin cream) as dexamethasone sodium phosphate and trimethyl acetate (BETNESOL) 0.5-5 mg/day oral, 4-20 mg/day IM/IV, 0.1 topical cream as betamethesone benzoate (TOPICASONE) and betamethasone valerate (BETNOVATE) Beclomethasone (as dipropionate; BECLATE) 0.025% topical (cream) (as acetonide; FLUCORT) 0.025% topical (ointment) Mineralocorticoids Desoxycorticosterone acetate (DOCA) 10-20 mg IM (once or twice in a week), 0.25 mg SL. Flurdocortisone (FLORICORT) 0.2-2 mg/day Aldosterone: It is a mineralocorticoid. Its actions are retention of sodium and reduction of serum potassium. It acts on distal tubules of kidney to increase sodium reabsorption (details are discussed in chapter ‘Diuretics and antidiuretics’).

Pharmacological Actions conversion into glucose (neoglucogenesis) in Corticosteroids are synthesized in the the liver. adrenal cortex under the influence of ACTH. Glucocorticoids inhibit the uptake of glucose Glucocorticoids affect the metabolism of by fat cells, resulting in increased lipolysis. The carbohydrates, proteins, fats, calcium and increased insulin secretion in response to electrolytes. hyperglycaemia also stimulates lipogenesis and Metabolic effects: Glucocorticoids ultimately increase in fat deposition. promote glycogen deposition in liver by The catabolic effect on bone can cause stimulating glycogen synthetase activity and osteoporosis in Cushing’s syndrome. increasing glucose production from protein. Glucocorticoids maintain normal They also inhibit peripheral utilization of glomerular filtration rate. The glucose and increase glucose release from adrenalectomized animal can not excrete a liver. It produces resistance to insulin. water load and tend to develop water Glucocorticoids also cause breakdown of intoxication and this can be treated by protein and amino acid mobilization from glucocorticoids. peripheral tissues. They stimulate the Glucocorticoids also inhibit calcium Glucocorticoids & Sex Hormones 283 absorption from intestine and enhance renal Effect on kidney: In deficiency of excretion of Ca2+. glucocorticoids, the glomerular filtration Antiinflammatory and immuno- rate is impaired. suppressive effects: Glucocorticoids suppress Effect on endocrine system: all types of inflammation, hypersensitization Glucocorticoids suppress the pituitary and allergic reactions. They suppress the edema, release of ACTH and betalipotropin and capillary dilatation, migration of leukocytes, reduce secretion of FSH and TSH. capillary permeability in the inflamed area. Glucocorticoids inhibit the functions of Mechanism of Action leukocytes and tissues macrophages. They Most of the established pharmacological also stabilize lysosomal membranes, thereby effects of glucocorticoids are mediated by reducing the concentration of proteolytic cytoplasmic glucocorticoid receptors. After enzymes at the site of inflammation. binding to the receptor, the steroid-receptor Glucocorticoids also inhibit the complex binds to chromatin and stimulate the production of plasminogen activator by formation of mRNA. The mRNA stimulates neutrophils. the synthesis of enzymes which produce They also influence the inflammatory various pharmacological actions. response by reducing the prostaglandin and Pharmacokinetics leukotriene synthesis that results from They are given by oral, parenteral and activation of enzyme phospholipase A2. topical route. Oral bioavailability of synthetic Effect on CNS: Large doses of cortico-steroids is high. Hydrocortisone after glucocorticoids cause euphoria, mood oral administration undergoes extensive first elevation, nervousness, restlessness, which pass metabolism in liver. are reversible type of actions. They often produce behavioural disturbances in human They are metabolised in liver and after being and also increase intracranial pressure. conjugation are excreted in urine. The synthetic derivatives are metabolised slowly Effect on CVS and blood: Glucocorticoids and have longer duration of action. inhibit capillary permeability and maintain myocardial contractility and also the tone of Adverse Reactions arterioles. GIT: Acute erosive gastritis and Glucocorticoids cause decrease in haemorrhage. Peptic ulcer risk is increased. number of circulating lymphocytes, basophils and eosinophils in blood. They Endocrine system: Cushing’s habitus, increase the number of neutrophils, platelets hirsutism, retardation of growth, suppression and erythrocytes. of hypothalamopituitary-adrenal axis. Effect on GIT: Glucocorticoids stimulate Metabolic disorders: Hyperglycemia, production of acid and pepsin in the glycosuria and diabetes mellitus may be stomach and facilitate the development of precipitated, osteoporosis, peptic ulcer. Eye: Glaucoma, cataract may develop. 284 Section 8/ Drugs Acting on Endocrine System

CNS: Psychiatric disturbances, euphoria. a. Allergic rhinitis, nasal polyposis. Other side effects include muscular b. Allergic sinusitis. weakness, delayed healing of wounds, c. Cicatrizing lesions of the middle ear. alopecia, hyperglycemia, susceptibility to 7. Dermatology: Topical steroids are useful infections etc. in keloids, hypertrophic scars, other Therapeutic Uses of Glucocorticoids localised hypertrophic, infiltrated, inflammatory lesions of lichen planus, Glucocorticoids are used in the psoriatic plaques, granuloma annulare following physiological and clinical and lichen simplex chronicus; discoid conditions: lupus erythematosus, necrobiosis 1. Adrenocortical insufficiency: lipoidica diabeticorum and alopecia • Acute: Hydrocortisone/dexametha- areata. sone IV inj. 8. Neurology: Lumbago, sciatica, • Chronic: Addison’s disease; congen- cervicobrachial neuralgia and other ital adrenal hyperplasia (genetic painful radiculopathies; selected cases disorder due to deficiency of ste- of inflammatory disorders such as roidogenic enzymes). tuberculous meningitis and multiple sclerosis. 2. Rheumatology: a. Intraarticular injection: Rheuma- 9. GIT: Ulcerative colitis, Crohn’s disease toid arthritis, osteoarthritis, gouty etc. arthritis, joint sequelae of fractures 10. Malignant diseases: Corticoids are and dislocations. used in combination with other therapy b. Periarticular/soft tissue injection: in the treatment of Hodgkin’s disease, Scapulohumeral periarthritis, peri- acute lymphatic leukemia and other lymphomas. arthritis of hip, bursitis, tendinitis, synovitis, tenosynovitis, tarsalgia, 11. Miscellaneous uses: Corticoids in metatarsalgia, epicondylitis, Du- higher dose can be given along with puytren’s contracture, Peyronie’s other immunosuppressants in certain disease, cystic tumors of aponeuro- organ transplantation cases to prevent rejection reaction. sis or tendon (ganglia). 3. Severe allergic reactions such as PREDNISOLONE urticaria, serum sickness, anaphylaxis. It is more potent (4 times) than 4. Bronchial asthma, in acute and severe hydrocortisone. It has intermediate duration chronic asthma, aspiration pneumonia of action. and pulmonary edema. Adverse effects include peptic 5. Autoimmune haemolytic anaemia, ulceration, myopathy, steroid psychosis. On thrombocytopenia etc. prolonged use posterior subcapsular cataract, 6. Ear disorders: glaucoma, osteoporosis, hyperglycemia, Glucocorticoids & Sex Hormones 285 increased susceptibility to infection, delayed reactions, anaphylactic reaction to drugs, severe wound healing and Cushing habitus. shock arising from surgical or accidental trauma It is indicated in suppression of or overwhelming infection; Addison’s disease, inflammatory and allergic disorders, Simmond’s disease, hypopituitarism following inflammatory bowel disease, asthma, adrenalectomy, tennis elbow, tenosynovitis immunosuppression and rheumatic disease. and bursitis; rheumatological disease, ulcerative colitis, regional enteritis, TB TRIAMCINOLONE meningitis and subarachnoid bleed. It is a highly, selective glucocorticoid used in asthma, allergic disorders, rheuma- SEX HORMONES toid arthritis and dermatoses. ESTROGENS DEXAMETHASONE Estrogens are produced mainly by the It is a selective and very potent long act- ovary and the placenta and the synthesis of ing glucocorticoid. It causes suppression of estrogens takes place from cholesterol (as pituitary adrenal axis. Used in shock due to discussed in section on ‘glucocorticoids’). Estrogens are classified into two main trauma, allergic emergencies, rheumatoid groups (see table 8.3.2). arthritis, asthma, nephrotic syndrome and Estradiol is the major secretory product suppression of inflammation in eye and skin of ovary. Estrogens are required for normal disorders. maturation of the female. They stimulate the development of secondary sexual characters BETAMETHASONE e.g. stimulate stromal development, ductal It is a glucocorticoid similar to growth in the breast, growth of axillary and dexamethasone. Used in status asthmaticus, pubic hair and alter the distribution of body acute allergic reactions, anaphylactic allergic fat to produce typical female body contours.

Table 8.3.2: Classification of estrogens and . I. Natural Estradiol (as benzoate/cypionate/ 2.5-10 mg IM enanthate/valerate; ESTRADERM) II. Synthetic Ethinyl estradiol (EVALON) 0.1-1 mg/day Mestranol 0.1-0.2 mg/day 0.5-5 mg/day, oral/IM (LIVIAL) 2.5 mg/day III. Antiestrogens Clomiphene citrate (CLOMID) 50 mg/day × 5 days citrate (TAMODEX) 20-40 mg/day 286 Section 8/ Drugs Acting on Endocrine System

It also stimulates the development of skin estrogen are metabolized very slowly and pigmentation particularly in the region of the are more potent. nipples and areolae and in the genital regions. Adverse effects include breast discomfort, Estrogens also play a role in stimulation pruritus, exanthema, thrombophlebitis and of the proliferative or preovulatory phase local skin irritation, increased risk of gall stones. of endometrium and vasodilatation of endometrial capillaries. Therapeutic Uses Estrogens are anabolic but weaker than The most common use of estrogen are testosterone. Estrogens also cause retention as oral/parenteral contraceptive and for of nitrogen, sodium and fluid in tissues. hormone replacement therapy. Estrogens also protect from osteoporosis in • Primary hypogonadism: Estrogens postmenopausal women, which occur as a have been used for replacement result of estrogen deficiency. therapy in estrogen deficient patients (treatment of amenorrhoea). Pharmacological Actions • In post menopausal hormonal Estrogens act by interacting with the therapy: specific estradiol receptors in the cytoplasm  Estrogen have been used in preven- of the target cells and mediate the tion and treatment of osteoporosis. transcription of the relevant mRNA by  Improve the general physical, attaching itself to the appropriate . mental and also sexual activity. Estrogens produce proliferative changes in  Maintain calcium balance. the endometrium. On chronic administration,  Decreases the risk of cardiovascular estrogen suppresses the secretion of FSH and (coronary artery) disease. somewhat LH resulting in inhibition of Transdermal estradiol is equally ovulation. In testes it may reduce the secretion effective: of androgens and inhibit spermatogenesis. • In atrophic vaginitis. Estrogens suppress lactation without • In atrophic urethritis. affecting the prolactin level in plasma. • For the treatment of vaginal complaints On chronic administration it may inhibit such as dyspareunia, dryness and itching. the growth of epiphyseal cartilage. • Pre and postoperative therapy in postmenopausal women undergoing Pharmacokinetics vaginal surgery. Natural estrogens are inactive orally due • Infertility due to cervical hostility. to rapid metabolism in liver. Synthetic • As a diagnostic aid in case of doubtful estrogens are well absorbed after oral atrophic cervical smear. administration as well as by transdermal application. Estradiol is metabolized to TIBOLONE estrone and estriol. All these are conjugated It is a synthetic steroid which combines and excreted in urine and bile. Synthetic oestrogenic and progestogenic activity with Glucocorticoids & Sex Hormones 287 weak androgenic activity. It needs to be overstimulation and can also lead to rupture given continuously without cyclical and bleeding. . Clomiphene is mainly used in the treatment It restores plasma endorphin level in of female infertility due to ovulatory failure and postmenopausal women and act centrally to is also found useful to aid in vitro fertilization. affect the thermoregulatory system. It is also used to promote spermatogenesis in male due to oligospermia and asthenosper- Adverse effects include weight changes, mia. ankle edema, dizziness, headache, abdominal pain, GI disturbances, vaginal bleeding, TAMOXIFEN arthralgia, myalgia, migraine, visual It is a competitive partial agonist inhibitor disturbances, liver function changes, of estradiol at the and is increased facial hair, depression, skin rash used mainly in the treatment of advanced and pruritus. breast cancer in postmenopausal women. It It is indicated in vasomotor symptoms is also used in male infertility due to its in estrogen deficiency and osteoporosis weaker estrogen effect and lesser side effects. prophylaxis. It is effective on oral administration and is excreted in bile. ANTIESTROGENS Adverse effects include hot flushes, vaginal bleeding, menstrual irregularities, Also known as estrogen antagonists or anorexia, depression and dermatitis. ovulation inducing agents. They act by binding to estrogen receptors. PROGESTINS CLOMIPHENE CITRATE Progesterone is naturally secreted by the It is a triphenyl ethylene compound and corpus luteum and placenta and functions a competitive partial agonist inhibitor of to maintain pregnancy after conception. endogenous estrogen. It can produce Their derivatives are of two types, which are regression of estrogen induced proliferative classified as in table 8.3.3. endometrium. It can also prolong the luteal PROGESTERONE phase in normal menstruating women. The physiological functions of Due to its probable direct effect on progesterone include: ovaries, it may increase the gonadotrophin secretion. It also exerts a weak estrogenic • Induction of secretory phase of the action on endometrium. menstrual cycle. It is well absorbed after oral • Development of alveolar system of administration, metabolized and excreted in breasts. bile and main side effects include hot • Preparation of endometrium for the flushes, ovarian enlargement and cyst implantation of fertilized ovum for formation which may be due to further pregnancy. 288 Section 8/ Drugs Acting on Endocrine System

Table 8.3.3: Classification of progestins and antiprogestin. I. Progesterone derivatives Progesterone (MICROGEST) 10-50 mg OD/wk IM (PROVERA) 5-20 mg oral, 50-400 mg IM II. 19-Nortestosterone derivatives (NORGEST) 5-10 mg OD Lynoestrenol (Ethinylestrenol) 5-10 mg OD (NIDAGEST) 10-40 mg/day (OVRAL-G) 0.5-1 mg OD III. Antiprogestin 600 mg single dose

• Induction of certain changes in the liver to pregnanediol, which is conjugated and vaginal epithelium and secretion. excreted in urine. It has a short plasma half life. • Increases the basal body temperature and Adverse effects include acne, urticaria, inhibit uterine contractions by decreasing fluid retention, weight changes, GI sensitivity of myometrium to oxytocin. disturbances, change in libido, breast Pharmacological Actions discomfort, premenstrual symptoms, irregular menstrual cycles, chloasma, Progesterone prolongs the luteal phase depression, pyrexia, insomnia, somnolence, and induce decidual changes in the alopecia, hirsutism and rarely jaundice. endometrial stroma. It prevents the Injection may be painful. cornification of the vaginal epithelium and brings about increased glycogen deposition. It is indicated as contraceptive, in hor- It changes the watery cervical secretion to mone replacement therapy, primary and viscid, thick and scanty secretion for sperm secondary amenorrhoea, dysfunctional penetration. uterine bleeding, endometriosis, post- ponement of menstruation, premenstrual Progesterone causes proliferation of syndrome, uterine hypoplasia, threatened acini in the breasts and with the help of or habitual abortion and premenstrual ten- estrogen, prepare them for lactation. sion. It is also useful in endometrial carci- It causes slight rise in body temperature noma. and this is seen during the luteal phase. Administration during follicular phase MEDROXYPROGESTERONE suppresses the preovulation LH and It is a synthetic progestogen structurally prevents ovulation. related to progesterone given orally or by After reaching cell nucleus it binds to IM injection. progesterone receptors and influences the Adverse effects include skin rash, transcription of a limited set of genes. urticaria, pruritus, depression, nausea, After oral administration progesterone alopecia, acne, hirsutism, galactorrhoea, undergoes extensive first-pass metabolism in anaphylaxis, thromboembolic disorders, Glucocorticoids & Sex Hormones 289 insomnia, fatigue, dizziness, headache, ANTIPROGESTIN tenderness of breast and somnolence. It is used in dysfunctional uterine bleeding, MIFEPRISTONE secondary amenorrhoea and endometriosis. It is 19-norsteroid partial agonist that binds NORETHISTERONE to the and inhibits the activity of progesterone. If given during the Norethisterone and its acetate and follicular phase it slows down the follicular enanthate esters are synthetic development and failure of ovulation. It also given orally in the treatment of abnormal stimulates uterine contraction and induces uterine bleeding and endometriosis. menstruation. Oral bioavailability is 25%. It is Adverse effects include breakthrough metabolized in liver and excreted in bile. Its bleeding, amenorrhoea, spotting, exacerbation major use is to terminate pregnancy. It can be of epilepsy and migraine. used alone or in combination with vaginal

It is indicated in primary and secondary pessary of prostaglandin E1 (1 mg) or oral amenorrhoea of long duration, metropathia misoprostol to terminate the pregnancy. haemorrhagica, menorrhagia, dysmenorrhoea, It is also used as contragestational agent polymenorrhoea and . and for induction of labour. LYNOESTRENOL ANDROGENS AND ANABOLIC STEROIDS It is an oral synthetic progestogen. Androgens are substances which cause Adverse effects include nausea, vomit- development of secondary sex characters in ing and epigastric discomfort, breakthrough males. The most important androgen secreted bleeding or spotting, headache, nervousness, by testes is testosterone. Testosterone is migraine, dizziness, edema and breast pain. synthesized from the cholesterol in testes It is indicated in dysfunctional uterine mainly, under the influence of LH from bleeding, amenorrhoea, dysmenorrhoea, hypo pituitary. In peripheral tissues testosterone is and hypermenorrhoea, delay of menstrual partly converted into more active period, oligo and polymenorrhoea, benign dihydrotestosterone. breast disease, endometriosis, metrorrhagia Adrenal cortex also produces small and endometrial carcinoma. quantities of weak androgens (androstenedione ALLYLESTRENOL and ) which are partially converted to testosterone in It stimulates placental progesterone peripheral tissues. In females, ovaries also synthesis and increases the secretion of secrete small quantities of testosterone. placental hormones. Follicle stimulating hormone is responsible Adverse effects include nausea, for the growth of testes. It promotes vomiting and epigastric discomfort. spermatogenesis. Along with LH, FSH plays It is indicated in habitual abortion, an essential role in maintaining the normal failure of nidation, threatened abortion, testicular functions such as development of male premenstrual tension, metrorrhagia and sex organs e.g. penis, scrotum; development of threatened premature labour. secondary sexual characters e.g. growth of facial, 290 Section 8/ Drugs Acting on Endocrine System

Table 8.3.4: Classification of androgens, anabolic steroids and . I. Natural Testosterone (as propionate, cypionate Propionate 25-200 mg IM per day to bimonthly; undecanoate, enanthate; NUVIR) undecanoate 40 mg OD-TDS II. Synthetic Methyltestosterone 25 mg/day SL III. Anabolic steroids (as decanoate, phenyl 10-100 mg IM once a wk to every 3 wks propionate; DURABOLIN) (NEURABOL) 2-6 mg/day (PROVIRONUM) 25-50 mg/day IV. Antiandrogens (DANOGEN) 200-800 mg/day acetate (PROSTAMID) 250 mg TDS

axilla, chest and pubic hair and change in voice; Pharmacokinetics development of accessory sexual organs e.g. seminal vesicles, prostate and epididymis and Testosterone is not given orally as it is development of male skeletal musculature. extensively metabolised in liver and the Androgens and anabolic steroids are bioavailability is low. Testosterone is classified as in table 8.3.4. converted by 5a-reductase in target tissues to more potent dihydrotestosterone. TESTOSTERONE It is metabolized in liver to glucuronic acid It is a natural androgen secreted by and sulfate conjugates and excreted in urine. testis. The secretion is regulated by LH Adverse effects include menstrual hormone secreted by pituitary gland. irregularities, deepening of voice in women, It is responsible for development of sex edema, cholestatic jaundice, virilization, organs and secondary sex characters in priapism, increased libido, acne, precocious males at puberty. It leads to growth of puberty, premature epiphyseal closure, genitals, growth of hair (pubic, axillary, gynaecomastia and hepatic carcinoma and beard, moustache, body hair), thickening reduction in spermatogenesis. of skin, larynx grows and voice deepens The capacity of androgens to enhance the and also behavioural changes. It is also epiphyseal closure in children may persist for needed for normal spermatogenesis and as long as several months after discontinuation maturation of spermatozoa. It is also of the drug. In children androgens should be responsible for pubertal spurt of growth in used with great caution. boys leading to increased bony and skeletal It is indicated in replacement therapy to muscles growth. maintain sex characteristics in adults with Glucocorticoids & Sex Hormones 291 testicular failure, accidental ; in progestational and androgenic activities used hereditary angioneurotic edema, infertility to inhibit ovarian and testicular function. due to defective spermatogenesis, osteoporosis, refractory anaemia, breast car- It inhibits gonadotrophin secretion from cinoma, menopausal syndrome, en- pituitary in both men and women thus dometriosis; to improve nitrogen balance in inhibiting both testicular/ovarian function. catabolic states; certain types of infertility It is used in menorrhagia, gynaecomastia, due to disorders of spermatogenesis. fibrocystic breast disease, treatment of NANDROLONE visually proven endometriosis or It is closely related to androgen symptomatic control when surgery is testosterone having both lower androgenic contraindicated. It is also used in infertility and higher anabolic properties. in women and precocious puberty in boys. Adverse effects include virilism, edema Adverse effects include skin rash, nausea, and hypercalcaemia. flushing, headache, weight gain, acne, It is used in debilitating illness, postmeno- hirsutism, loss of libido and amenorrhoea. pausal osteoporosis, burn or major illness, postmenopausal metastatic mammary carci- noma, haemolytic, hypoplastic or malignancy It has a potent and mild associated anaemias. progestional activity. It can also inhibit STANOZOLOL gonadotropin secretion in larger dose It is a synthetic steroid with anabolic and and also suppresses spermatogenesis androgenic properties. Used in prophylactic and Leydig cell function. It is used in treatment of hereditary angioedema, vascular precocious puberty in males, acne, manifestations of Behcet’s syndrome. carcinoma prostate and hirsutism and Adverse effects include liver damage, virilization in women. virilism, nausea, skin rash, headache and epigastric discomfort. FLUTAMIDE MESTEROLONE Non-steroidal drug having specific It provides oral therapy and does not antiandrogen activity. Active metabolite, cause liver damage. It is indicated in 2- competitively blocks hypogonadism and male infertility. Adverse androgen action on accessory sex organs effects include frequent erection of penis and pituitary. It leads to increased LH and priapism. secretion by blocking feedback inhibition. It is used in advanced carcinoma prostate, ANTIANDROGENS female hirsutism. DANAZOL is a congener of It is an isoxazole derivative of flutamide, causing less hepatotoxicity and (17α-ethinyl testosterone) with weak can be given once daily.  This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsThyroidThyroid HormoneHormone && 1.48.4 AntithyroidAntithyroid(Mode of Action ofAgentsAgents Drugs)

Thyroid gland secretes two important • In the treatment of non-toxic goitre. hormones, thyroxine (T4) and triiodothyronine • Papillary thyroid carcinoma: It is often

(T3). The third hormone, calcitonin secreted responsive to TSH. from interstitial cells is physiologically different Adverse reactions include palpitation, and is responsible for the regulation of calcium angina, tremors, thyrotoxicosis, allergic metabolism. reactions, headache, tachycardia, diarrhoea, Thyroid hormones exert their effect sweating, restlessness, loss of weight and by binding to nuclear receptors in target muscle weakness. organs. Both the thyroid hormones are well absorbed after oral administration. They are ANTITHYROID AGENTS conjugated with sulfuric acid in liver and excreted in bile. These are used to inhibit the functional activity of hypersecretive thyroid The various preparation used are: gland. The hypersecretion leads to the Thyroxine (l-thyroxine sodium) development of thyrotoxicosis. The (ELTROXIN) 50-300 µg/day antithyroid agents acts by interfering Liothyronine sodium 20-60 µg/day with the synthesis and release of thyroid (TETROXIN) hormones. They are classified as in table (PROLOID) 32.5-195 mg/day 8.4.1.

Therapeutic Uses of Thyroid Hormones Drugs Inhibiting Hormone Synthesis • Infant hypothyroidism (cretinism). The thioamides which include propyl • Adult hypothyroidism (myxoedema). thiouracil and methimazole are the major • Myxoedema coma: It is an emergency. drugs for the treatment of thyrotoxicosis. In Liothyronine 100 µg IV can be used and India carbimazole is most commonly used maintained by thyroxine 500 µg IV. drug. They bind to thyroid peroxidase and 294 Section 8/ Drugs Acting on Endocrine System

Table 8.4.1: Classification of antithyroid agents. I. Agents which inhibit hormone synthesis Propyl thiouracil 50-100 mg/day (initial) and maintained at 20-30 mg/day Carbimazole (THYROZOLE) 5-15 mg/day (initial) and maintained at 2.5-20 mg/day Methimazole 5-10 mg/day (initial) maintained at 2.5-15 mg/day II. Agents which inhibit iodide trapping Thiocyanates, perchlorates and nitrates III. Agents which inhibit hormone release Iodine (Lugol’s solution: 5% iodine in 10% KI; Colloid iodine: 10% solution) Sodium and potassium iodide Organic iodide IV. Agents which destroy thyroid gland tissue Radioactive iodine (131I) 3-5 mcurie. prevent the oxidation of iodide and uptake of iodide by the gland through iodotyrosyl residue which subsequently competitive inhibition of iodide transport inhibits the formation of tyrosine residue in mechanism. But it requires higher dose thyroglobulin and coupling of iodotyrosine which can cause aplastic anaemia and due to this major drawback they are not used residues to T3 and T4. clinically. CARBIMAZOLE It inhibits oxidation of iodide, inhibits Agents Which Inhibit Hormone iodination of tyrosine residue and inhibits Release the coupling of iodotyrosine residue. After Iodine inhibits hormone release. They oral administration, it is rapidly absorbed inhibit organification and hormone release and metabolised to methimazole which is and also decrease the size and vascularity active form and crosses the placental barrier. of hyperplastic gland on regular Adverse reactions include agranulocytosis, administration. Peak antithyroid affect is transient leucopenia, arthralgia, nausea, fever, seen in two weeks after which thyrotoxicosis loss of hair and hepatic damage. may reoccur. It is well absorbed orally and It is used in hyperthyroidism due to crosses the placental barrier. Graves’ disease, prior to surgical treatment Adverse effects include angioedema, of hyperthyroidism i.e., thyroidectomy. It is fever, thrombocytopenia, arthralgia, also used in the treatment of paroxysmal lymphadenopathy, salivation, sneezing and tachycardia and intractable congestive swelling of lips and eyelids. cardiac failure. Iodine is used in thyroid storm, hyperthyroidism, preoperatively before Agents Which Inhibit Iodide Trapping thyroidectomy and prophylaxis of endemic Monovalent anions such as thiocyanates, goitre. Iodine is also useful as antiseptic and perchlorates and pertechnetate can block the in expectorants. Thyroid Hormone & Antithyroid Agents 295

The iodinated contrast agents, ipodate concentrated by the thyroid and incorporat- and iopanic acid are used in the treatment ed into the storage follicles. Beta radiation of hyperthyroidism. These drugs rapidly penetrates up to 3 to 5 mm into the soft inhibit the conversion of T4 to T3 in the liver, tissue, they destroy some of the thyroid kidney, brain and pituitary gland. follicles and produce fibrosis. Adverse reactions include hypothyroid- Agents Which Destroy Thyroid Gland ism, thyroid carcinoma, damage to foetal Tissue thyroid and possibility of genetic damage, so 131I is the only radioisotope of iodine contraindicated during pregnancy. used in the treatment of thyrotoxicosis. The Radioactive iodine is indicated in other isotopes 123I and 125I are used only in hyperthyroidism due to Graves’ disease or diagnosis. 131I emits gamma and beta radia- toxic nodular goitre and also used as tions. It is available as sodium solution. palliative therapy after thyroidectomy for When taken orally, it is rapidly absorbed, papillary carcinoma of thyroid.

 This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsHormonal 8.51. 4 Contraceptives(Mode of Action of Drugs)

Hormonal contraceptive are the most this is considered the first day of cycle). The effective spacing methods of contraception. pill is to be taken everyday at a fixed time, They are used for reversible suppression of preferably before going to bed at night. fertility. PHASED PILLS

ORAL CONTRACEPTIVES This is a combined pill but biphasic or triphasic in nature e.g. the estrogen level is The oral hormonal contraceptive can be kept constant but the progestin amount is classified as in table 8.5.1. low in early phase and increasing in subsequent phases of menstrual cycle. COMBINED PILLS Fifth day to tenth day menstrual cycle It is a combination of estrogen and (ethinyl estradiol 30 µg + levonorgestrel 50 progestin given together for remarkable µg), eleventh to fifteenth day (ethinyl efficacy, safety and ease in administration. It estradiol 30 µg + levonorgestrel 75 µg), has total 21 pills, each pill is given orally for sixteenth to twenty fifth day (ethinyl 21 consecutive days beginning on the 5th day estradiol 30 µg + levonorgestrel 125 µg). of menstrual cycle (when the bleeding occurs They are supplied in one pack of different

Table 8.5.1: Classification of oral contraceptives. Estrogen Progestins Ethinyl estradiol (20, 50 µg) + Norethindrone (1, 3 and 4 mg) (ANOVLAR) Ethinyl estradiol (50 µg) + (0.5 mg) (OVRAL-G) Ethinyl estradiol (30 µg) + Norgestrel (0.5 mg) (PRIMOVLAR-30) Ethinyl estradiol (30 µg) + L-Norgestrel (0.3 mg) (OVRAL-L) Mestranol (100 µg) + Ethynodiol diacetate (1 mg) (OVULEN) Mestranol (50 µg) + Ethynodiol diacetate (1 mg) (OVULEN-50) Ethinyl estradiol (50 µg) + (1 mg) (LYNDIOL) 298 Section 8/ Drugs Acting on Endocrine System coloured pills starting from fifth day of in 3 month and 400 mg given once in 6 menstrual cycle to twenty-fifth day and next month. pack can be started after a gap of seven days Some subcutaneous and intrauterine as in case of combined pills. implants of progesterone have also been used which are prepared in biodegradable MINIPILL polymeric matrices. It is also known as progestin only pill (POP). It contains only progestins, which is Mechanism of Action of Oral given in small amount throughout the men- Contraceptives strual cycle (without interruption) but because The oral contraceptives act by the dif- of lower efficacy rate, it is not much popular. ferent mechanisms. Norgestrel (OVRETTE) 0.075 mg • Inhibiting ovulation by blocking the Norethindrone (MICRONOR) 0.35 mg release of follicle stimulating hormone POSTCOITAL CONTRACEPTION and luteinising hormone from the anterior lobe of pituitary gland. The postcoital (morning after) • Increasing the thickness of cervical contraception is recommended within 48 mucus due to progestins and producing hours after an unprotected intercourse, rape an unfavourable environment for pen- or contraceptive failure. etration of sperm and further conception. Diethylstilbestrol 5 mg per day is given • Inducing other changes in the uterine for five days. mucosa which may be unfavourable for Other regimens used are combination of the implantation of fertilized ovum. ethinyl estradiol 0.1 mg + levonorgestrel 0.5 to This action is important in minipills 1 mg. Two tablets are taken 12 hours apart and postcoital pills. within three days of intercourse. Levonorgestrel 0.75 mg (1 tablet) is also used and is taken as Adverse Effects early as possible (within 72 hrs) and second The most common side effects are nausea, tablet after 12-24 hours of first tablet. vomiting, headache, dizziness, fatigue, weight Withdrawal bleeding occur within 3-7 days. gain and breast fullness. The other side effects which appear after sometime of therapy are INJECTABLE FORMULATIONS acne, increased body hair, pigmentation of cheeks, nose and forehead (chloasma). They are usually given by IM route. They The other serious side effects include lead to higher incidence of menstrual high blood pressure, increased risk of myo- irregularities and amenorrhoea. cardial infarction, thromboembolic diseas- • Norethindrone enanthate es like thrombophlebitis, venous thrombo- (NORISTERAT) 200 mg given once in sis, cerebral thrombosis. two months. They were suspected to lead to increased • Depot medroxyprogesterone acetate risk of cancer of breast and carcinoma of (DEPOT PROVERA) 150 mg given once cervix and endometrium. Hormonal Contraceptives 299

CENTCHROMAN age and maturation and preventing sperm Its a nonsteroidal estrogen antagonist, transport in vas deferens. But the which acts by preventing implantation due hormones which suppress sperm produc- to embryouterine asynchrony, accelerated tion tend to lower testosterone and affect tubal transport and suppression of the potency and libido. . It has no effect on pituitary The one product obtained from cotton- or ovarian functions. It is taken 30 mg twice seed oil, Gossypol which is categorized as weekly for 12 weeks followed by once a non-hormonal selective spermatogenesis week as long as fertility is to be suppressed. suppressant, is effective in producing azoospermia or severe oligospermia but it MALE CONTRACEPTIVE is not widely used as male contraceptive. The main research focus is different Mechanism of action is not known. Adverse approaches e.g. agent which prevent sper- effects are edema, diarrhoea, hypokalemia, matogenesis, interfering with sperm stor- neuritis.

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Chemotherapy This page intentionally left blank Sulfonamides, ChapterChapter PharmacodynamicsPharmacodynamicsNitrofuransNitrofurans andand (Mode of Action of Drugs) 1.9.1 4 QuinolonesQuinolones

CHEMOTHERAPY The general mechanism of action of Chemotherapy is the use of chemical antimicrobial agents is listed in table 9.1.1. compounds for the treatment of infectious Antimicrobials can be classified according diseases by killing or inhibiting the growth to type of action into: of causative organisms without damaging a. Primarily bactericidal: Penicillin, the host tissues or cells. cephalosporins, aminoglycosides, Paul Ehrlich demonstrated the effective vancomycin, polypeptides, INH, use of methylene blue in the treatment of cotrimoxazole, rifampicin, fluoro- malaria. He also synthesized arsenical quinolones, nalidixic acid. compounds (neoarsphenamine) effective in b. Primarily bacteriostatic: Ethambutol, the treatment of syphilis. The synthesis of erythromycin, chloramphenicol, tetra- newer and powerful antibacterial substances cyclines, sulfonamides. gave the recognition to Paul Ehrlich as ‘the Beta lactam antibiotics having a β-lactam father of modern chemotherapy’ and ring, which includes penicillin, in which a awarded the Nobel prize of medicine in 1909. thiazolidine ring is attached to a betalactam In 1928, Sir Alexander Fleming found ring that carries a secondary amino group. that a diffusible substance was elaborated Other similar compounds are cephalosporins, by Penicillium notatum (a fungus) which monobactams and carbapenems. prevented the growth of surrounding bacterial colonies in culture plate. He named ANTIMICROBIALS USED IN DENTISTRY this as ‘penicillin’ but this discovery remained a scientific curiosity for more than Various antimicrobials agents is used in a decade. This work was followed up by dentistry for prevention of local oral wound Chain, Falk and Florey who established the infection and prevention of distant infection efficacy of penicillin in 1941 and in 1945, i.e., bacterial endocarditis. Generally, Fleming, Chain and Florey were awarded prophylaxis by the use of antibiotics is not the Nobel Prize. required for routine type of dental surgery 304 Section 9/ Chemotherapy

Table 9.1.1: Mechanism of action of antimicrobial agents. 1. Inhibit cell wall synthesis Penicillins, cephalosporins, bacitracin, vancomycin and cycloserine. 2. Damage to the cytoplasmic membrane Polypeptides Polymyxin, bacitracin, colistin. Polycines Nystatin, amphotericin B, hamycin. 3. Inhibit protein synthesis & impairment of Tetracyclines, chloramphenicol, aminoglycosides, functions of ribosomes erythromycin, clindamycin and other macrolide antibiotics. 4. Inhibit DNA gyrase Fluoroquinolones i.e. ciprofloxacin, ofloxacin. 5. Interfere with DNA function Rifampicin, metronidazole. 6. Interfere with DNA synthesis Acyclovir, idoxuridine, zidovudine. 7. Antimetabolite action Sulfonamides, sulfones, INH, ethambutol, trimethoprim, PAS, pyrimethamine. as simple extraction and other minor (p-aminobenzene sulfonamide). Sulfona- peridental procedures are associated with mides were the first antimicrobial agents very low risk of any wound infection. effective against pyogenic bacterial infec- Prophylaxis is recommended when the tions. The antimicrobial compounds con- procedure in which a prosthesis is inserted into taining a sulfonamido (SO2 NH2) group are bone or soft tissue (e.g., dental implants), or called sulfonamides and a free amino group in other extensive reconstructive surgery. at the para position is required for its anti- bacterial activity. The same sulfonamido In dentistry, the antimicrobials agents group is also present in other non-bacterial which should be active against gram compounds such as tolbutamide (oral anti- positive cocci and oral anaerobes and which diabetic drug), chlorothiazide, furosemide yields peak blood levels higher than and acetazolamide (diuretics) etc. minimum inhibitry concentration for the common oral pathogens is recommended. The sulfonamides can be classified Amoxycillin, safe & bactericidal in nature is according to their therapeutic utility and generally the drug of choice. Antiseptic rinse pharmacokinetic parameters (table 9.1.2). However, because of bacterial resistance and (chlorhexidine 0.2%) is also used as an discovery of many safer and more effective adjuvant to reduce the bacteraemia antibiotics, the utility of sulfonamides is following dental extraction. The detail limited to few infections which are of clinical pharmacology of antimicrobial agents are interest. given in individual chapters. Pharmacological Actions SULFONAMIDES The most important pharmacological ac- Chemically, all sulfonamides may be con- tion of sulfonamides is its antibacterial ac- sidered to be derivatives of sulfanilamide tivity against variety of gram positive and Sulfonamides, Nitrofurans and Quinolones 305

Table 9.1.2: Classification of sulfonamides. I. Highly absorbed sulfonamides a. Short acting Sulfadiazine 2 g initially then 1 g 4-6 hourly Sulfadimidine 2 g initially then 0.5 g 6-8 hourly Sulfafurazole (GANTRISIN) 2 g initially then 1 g 4-6 hourly Sulfamethizole (UROLUCOSIL) 1.0-2 g 4-6 hourly b. Intermediate acting Sulfamethoxazole (used in combination with 160 mg of trimethoprim & 800 mg of trimethoprim; SEPTRAN: Sulfamethoxazole sulfamethoxazole every 12 hourly 400 mg + Trimethoprim 80 mg) c. Long acting Sulfadimethoxine (MADRIBON) 1 g initially then 0.5 g OD Sulfamethoxine (SULFADOXINE) 1 g initially then 0.5 g OD Sulfamethoxypyridazine (LEDERKYN) 1 g initially then 0.5 g OD Sulfamethopyrazine (used in malaria; METAKELFIN) II. Poorly absorbed sulfonamides (for GIT local action) Phthalyl sulfathiazole (THALAZOLE) 3-6 g/day Succinyl sulfathiazole (SULFASUXIDINE) 3-6 g/day Sulfaguanidine 3-6 g/day III. Special purpose sulfonamides Sulfacetamide (ALBUCID) 10-30% eye drops Sulfacetamide (NEBASULF) 6% powder used externally Sulfasalazine (for autoimmune bowel disease; 1-2 g QID initially then 0.5 g TDS-QID SALAZOPYRIN) Silver sulfadiazine (burn etc. local application; SILVIRIN) 1% local cream Mafenide propionate (MARFANIL) 1% local cream gram negative organisms (mainly bacterio- Mechanism of Action static) and certain species of chlamydia in- The compound sulfanilamide exhibits a fections such as: structural similarity to para-amino benzoic • Streptococci, staphylococci, pneumococci, acid (PABA). Woods and Fields proposed gonococci, meningococci, Haemophilus the theory that sulfonamides, being influenzae, H. ducreyi, Calymmatobacterium structurally similar to PABA, inhibit granulomatis, Vibrio comma, Vibrio cholerae, bacterial folate synthetase so that folic acid E. coli, Pasteurella pestis, Shigella. is not formed which is needed for a number • Actinomyces, Nocardia and Toxoplasma. of metabolic reactions. Folic acid derived • Chlamydia causing lymphogranuloma from PABA is essential for bacterial venereum, psittacosis, trachoma and metabolism. Sulfonamides inhibit the inclusion conjunctivitis. enzyme folic acid synthetase which is 306 Section 9/ Chemotherapy involved in the conversion of PABA to folic Therapeutic Uses acid, which causes folic acid deficiency and Because of development of resistance ultimately cause injury to the bacterial cell. and availability of more advanced antimi- crobial agents, the use of sulfonamides is Pharmacokinetics limited. However they are used in combi- After oral administration, sulfonamides nation with trimethoprim. The important are rapidly and completely absorbed from therapeutic uses are: gastrointestinal tract and approximately 70 i. Urinary tract infection: Used in chronic to 90 percent of oral dose reaches to the suppressive therapy in various UTI blood stream, but the binding with plasma conditions e.g. acute cystitis. proteins differ considerably among different ii. Acute bacillary dysentery. groups. The highly plasma protein bound iii. Ulcerative colitis, mainly sulfasalazine sulfonamides have longer action. The main (a chemical combination of sulfapyri- site of absorption is small intestine. dine and 5-amino salicylic acid) is used in the treatment of ulcerative colitis. Adverse Reactions iv. Streptococcal pharyngitis, prophylaxis The common side effects are nausea and of rheumatic fever and tonsillitis. vomiting. The others are allergic symptoms v. Trachoma and inclusion conjunctivitis: including drug fever, skin rash, urticaria, Sulphacetamide (10-30%) local eye eosinophilia, photosensitization reactions, drops are used. serum sickness like syndrome. Stevens- vi. Chancroid: Sulfadimidine may be Johnson syndrome and exfoliative dermatitis used. are also common with longer acting agents. vii. In the treatment of meningococcal meningitis. The uncommon allergic reactions include acute toxic hepatitis, toxic nephrosis viii. Sulfonamides in combination with py- rimethamine are used in the treatment and acute haemolytic anaemia. of chloroquine resistant malaria. Sulfonamides also cause renal irritation ix. Toxoplasmosis: Sulfadiazine and and may precipitate renal colic. Crystalluria, pyrimethamine combination is used. haematuria and albuminuria can also occur x. Burns: Topical silver sulfadiazine or which may lead to the development of mafenide is used. oliguria and anuria. TRIMETHOPRIM The hematopoietic toxicity includes agranulocytosis, thrombocytopenia and Trimethoprim is a derivative (diaminopyrimidine) related to antimalarial rarely aplastic anaemia and in patients with drug pyrimethamine, which selectively inhib- glucose-6-phosphate dehydrogenase (G-6- its bacterial dihydrofolate reductase, neces- PD) deficiency, sulfonamides may cause sary for the conversion of dihydrofolate to intravascular haemolysis. tetrahydrofolic acid. Sulfonamides act by in- The other CNS effects include depression, hibiting the incorporation of PABA into confusion, tinnitus, fatigue etc. dihydrofolate by bacteria. A combination of Sulfonamides, Nitrofurans and Quinolones 307 trimethoprim and sulfamethoxazole indications. The combination is cheaper than (cotrimoxazole) act sequentially in the same newer antibiotics. metabolic pathway in the synthesis of nucle- otides. NITROFURANS Adverse Effects It possesses antimicrobial action against All those side effects seen with sulfona- gram positive and negative organisms mides. including staphylococci, streptococci, E. coli, Salmonella and Shigella species. Therapeutic Uses NITROFURANTOIN Used in all types of infection caused by Salmonella typhi, Klebsiella, Enterobacter, Bacteriostatic drug. It is effective against Pneumocystis carinii etc. and many other a variety of gram positive and negative sulfonamide resistant stains of S. aureus, organisms including E. coli and Aerobacter. Strep. pyogenes, Shigella, E. coli, H. It is most commonly used as urinary influenzae, meningococci and gonococci antiseptic for prophylaxis and treatment of etc. It is particularly effective as a second urinary tract infections. line agent in penicillin allergic patients Adverse effects are nausea, diarrhoea, and also in patients where newer haemolytic anaemia in persons with G-6-PD antibiotics are contraindicated or can’t be deficiency and peripheral neuritis (on long- used. term use). The common indications are: Dose: FURADANTIN; 50-100 mg TDS-QID. i. Urinary tract infection: Acute cystitis. ii. Bacterial diarrhoea and dysentery. NITROFURAZONE iii. Respiratory tract infection such as Bactericidal drug for both gram positive chronic bronchitis and otitis media etc. and negative bacteria. Acts by inhibiting iv. In the treatment of typhoid. enzymes necessary for carbohydrate v. Chancroid. metabolism in bacteria. It is available as vi. Sexually transmitted diseases. ointment. Used for the topical treatment of vii. Prophylaxis and treatment of certain superficial wounds and skin infections. HIV associated infections. FURACIN; 0.2% ointment/cream. viii. For the prophylaxis of certain concurrent FURAZOLIDONE bacterial infections e.g. organ transplan- tation patients receiving immunosup- This is mainly employed for the pressants. treatment of gastrointestinal infections e.g. ix. Nosocomial infections. bacillary dysentery, giardiasis, bacterial Despite development of resistance to enteritis etc. this combination in certain microorganisms, Dose: FUROXONE; 100-200 mg TDS- it has been used widely for several clinical QID. 308 Section 9/ Chemotherapy

QUINOLONES rarely against Pseudomonas. Acts by inhibiting bacterial DNA gyrase. Quinolones, are synthetic antimicrobial It is mainly used as urinary antiseptic agents effective against gram negative and in diarrhoea caused by E. coli, Shigella, bacteria. Although newer compounds Salmonella. (second generation quinolones – the The main side effects are GIT upset, fluoroquinolones) are also effective against headache, drowsiness, vertigo, visual gram positive bacteria. disturbances and on prolonged use can The important quinolones are synthetic produce parkinsonism like symptoms. In fluorinated analogs of nalidixic acid (which individuals with G-6-PD deficiency can was introduced in mid 1960s and had cause haemolysis. limited use in UTI and GIT infections). They are active against a variety of gram positive FLUOROQUINOLONES and gram negative bacteria. Quinolones These are quinolone antimicrobial block bacterial DNA synthesis by agents having one or more fluorine inhibiting bacterial topoisomerase II substitutions, relatively broad spectrum of (DNA gyrase) and topoisomerase IV. action and effective against gram positive Inhibition of DNA gyrase prevents the and gram negative organisms. They are relaxation of positively supercoiled DNA highly effective against E. coli, Klebsiella, that is required for normal transcription and Proteus mirabilis, Shigella, Salmonella species, replication. H. ducreyi etc. The fluoroquinolones inhibit The important quinolones are listed in bacterial enzyme DNA gyrase. table 9.1.3. The presence of a 6-fluoro and 7- piperazine substitution greatly enhances NALIDIXIC ACID their antimicrobial efficacy as compared to It is 4-quinolone derivative effective nalidixic acid. The fluorine atom is against gram negative bacteria mainly E. coli responsible for increased potency against and Shigella. It is less effective against gram negative organisms and broadens the Klebsiella and Aerobacter species and very spectrum of their activity including gram

Table 9.1.3: Classification of quinolones. Nalidixic acid (GRAMONEG) 0.5-1.0 g QID Ciprofloxacin (CIPLOX) 250-750 mg BD Norfloxacin (NORFLOX) 400 mg BD Pefloxacin (QUCIN) 400 mg BD Sparfloxacin (SPARFLOX) 200-400 mg OD Ofloxacin (OFLIN) 200-400 mg BD Levofloxacin (LOXOF) 500 mg OD Gatifloxacin (GATILOX) 400 mg OD, eye drop (0.3%) Sulfonamides, Nitrofurans and Quinolones 309 positive organism. The piperazine moiety CIPROFLOXACIN imparts antipseudomonal activity. It is the most potent first generation After oral administration, the fluoroqui- fluoroquinolone, effective against a broad nolones are well absorbed with the bioavail- range of microorganisms. The most ability of 80 to 95 % and distributed widely in susceptible one are the aerobic gram body fluids and tissues. Depending upon the negative bacilli. newer compound, the different dose regimen It attains several times higher have been adopted. The fluoroquinolones are concentration in the urine than plasma. excreted mainly by tubular secretion and by Ciprofloxacin produces rapid and glomerular filtration. complete clinical relief in nosocomial Fluoroquinolones are well tolerated. The bronchopneumonia patients. It has been most common adverse effects are nausea, successfully used prior to cardiac surgery vomiting, diarrhoea, headache, insomnia, and has attained levels higher than MICs for skin rash and occasionally abnormal liver the commonly susceptible pathogens for at function tests (with trovafloxacin). least 8 hours. The bone, soft tissue and skin Phototoxicity has been particularly reported infections, bacterial gastroenteritis, severe/ with pefloxacin, lomefloxacin, sparfloxacin complicated UTI will respond to and ofloxacin. Tendinitis is a serious side ciprofloxacin. It has been used widely as a effect rarely reported in adults. Because of drug of first choice for typhoid fever, cartilage damage in children it must be used however, resistance has also been reported. under close supervision. It is also useful in respiratory infections due Therapeutic Uses to Mycoplasma, Legionella, multidrug resistant tuberculosis and as topical agent The most common conditions in which in conjunctivitis. fluoroquinolones may be useful is: The drug has been used alone as well as • Urinary tract infections. in combination. • Bacterial gastroenteritis. • Typhoid fever. NORFLOXACIN • In septicemia. It is less potent than ciprofloxacin and • In otitis media. is primarily used in genitourinary tract • Respiratory infections e.g. acute infections. It is relatively more potent than pneumonia etc. ciprofloxacin in above condition. It is not • Ocular infections and useful in respiratory and systemic infections • Other infections caused by E. coli, K. due to gram positive cocci. pneumoniae, Enterobacter, Salmonella PEFLOXACIN typhi, N. gonorrhoeae, N. meningitidis, H. influenzae, H. ducreyi, Shilgella, Vibrio It is a methyl derivative of norfloxacin cholerae, Pseudomonas aeruginosa, Staph. which penetrates tissues better and attains aureus etc. higher plasma concentration. Concentration 310 Section 9/ Chemotherapy in CSF is higher than other fluoroquinolones, respond well to ofloxacin in vitro. It does not therefore is preferred drug for meningeal inhibit the cytochrome P450. infections. It is used in the treatment of gonorrhoea and typhoid. Genotoxicity has LEVOFLOXACIN been reported at higher concentration of It is the levoisomer of ofloxacin and pefloxacin. having better activity than ciprofloxacin and ofloxacin against S. pneumoniae. It is also SPARFLOXACIN used in chronic bronchitis, sinusitis, It is difluorinated quinolone effective pyelonephritis, and other related infections against gram positive bacteria, anaerobes of soft tissues. Due to high oral and mycobacteria. It is used in the treatment bioavailability, patient can be shifted from of pneumonia, chronic bronchitis, sinusitis IV to oral therapy. It can be administered etc. just once a day regimen as an alternate to other fluoroquinolones in the treatment of OFLOXACIN respiratory infections. It is more potent than ciprofloxacin for GATIFLOXACIN gram positive organisms. It also inhibits Mycobacterium tuberculosis and The antibacterial action of gatifloxacin Mycobacterium leprae and used as alternative result from inhibition of DNA gyrase and in multidrug resistant therapeutic regimens. topoisomerase IV. DNA gyrase is an It is also used in the treatment of chronic essential enzyme that is involved in the bronchitis and other ENT infections. Also replication, transcription and repair of used in gonorrhoea, gonococcal urethritis bacterial DNA. Topoisomerase IV is an and urinary tract infections due to E. coli, K. enzyme known to play a key role in the pneumoniae, P. mirabilis, Citrobacter diversus partitioning of the chromosomal DNA or paeruginosa. Mycoplasma pneumoniae, U. during bacterial cell division. urealyticum are also susceptible. The Gatifloxacin ophthalmic solution is the anaerobes like Bacteroides fragilis, first FDA approved fourth generation perfringens, B. intermedium, C. welchii, fluoroquinolone and is available in Indian Peptococcus niger, Peptostreptococcus sp. market.

 Tetracyclines, ChapterChapter PharmacodynamicsPharmacodynamicsChloramphenicol and(Mode Chemotherapy of Action of Drugs) 9.21. 4 of UTI

TETRACYCLINES antimicrobial spectrum of activity against a wide range of gram positive and negative The tetracyclines are a group of drugs with a organisms. Cross-resistance of these common basic chemical structure and organisms to tetracyclines is common. pharmacological activity. The first tetracycline, chlortetracycline was isolated from Antimicrobial Spectrum of Activity Streptomyces aureofaciens, then oxytetracycline Tetracyclines has one of the widest was derived from Streptomyces rimosus and spectrum amongst antimicrobials. The then tetracycline was obtained by catalytic microbes that are sensitive to tetracycline dehalogenation of chlortetracycline. They are include Staph. aureus, Staph. epidermidis, classified as in table 9.2.1. Strep. pyogenes, Strep. viridans, Strep. pneumoniae, Strep. faecalis (UTI), Listeria Mechanism of Action monocytogenes, Bacillus anthracis, Clostridium The tetracyclines are primarily sp., Actinomyces sp., T. pallidum, T. pertenue, bacteriostatic and are thought to exert their Borrelia recurrentis, Fusobacterium fusiforme, antimicrobial effect by the inhibition of Brucella sp. and bacteroides sp. Commonly protein synthesis. The tetracyclines, occurring gram negative organisms e.g. H. including doxycycline, have a similar influenzae, H. ducreyi, Neisseria gonorrhoeae,

Table 9.2.1: Classification of tetracyclines. Tetracycline (SUBAMYCIN) 250-500 mg/day, 1-3% topical (eye/ear drop, skin oint) Oxytetracycline (TERRAMYCIN) 250-500 mg/day, 1-3% topical (skin, eye ointment) Chlortetracycline (AUREOMYCIN) 250-500 mg/day, 1-3% topical (skin, eye ointment) Demeclocycline (LEDERMYCIN) 300 mg BD, 0.5% skin oint. Doxycycline (BIODOXI) 200 mg OD Minocycline (CANOMYCIN) 100 mg BD 312 Section 9/ Chemotherapy

V. cholerae, E. coli, Enterobacter aerogenes, diarrhoea have been infrequent. The Shigella sp. are also highly sensitive. Atypical following side effects have been observed bacteria e.g. Chlamydia sp., Mycoplasma sp., with the use of tetracycline including Ureaplasma urealyticum as well as Rickettsia doxycycline. are extremely sensitive to tetracycline. Anorexia, nausea, vomiting, diarrhoea, Besides being highly effective against a wide glossitis, dysphagia, maculopapular and range of gram positive and negative erythematous rashes and photosensitivity; organisms, tetracycline is effective against hypersensitivity reactions including all bacteria responsible for sexually urticaria, angioneurotic edema, anaphylaxis, transmitted diseases viz. syphilis, anaphylactoid reactions. They also cause gonorrhoea, chancroid and nongonococcal discoloration of deciduous teeth. urethritis. It is effective/synergistic with specific drugs against even protozoa and Therapeutic Use fungi. Though effective against a number of 1. Orodental infection caused by mixed anaerobes it can not be relied upon as sole aerobic, anaerobic bacteria including therapy of anaerobic infections. Tetracycline Vincent’s infection caused by Fusobac- is not effective against viruses, Pseudomonas, terium. Tetracycline also prove to be Proteus and Klebsiella. beneficial in peridontal inflammation by scavenging free radicals. Its use in Pharmacokinetics pregnancy, lactation and in children is The absorption of tetracycline contraindicated. Its use in dentistry is administered orally is variable and depend very much restricted due to its chelat- upon the type of tetracycline used. The ing effect on teeth and bones. tetracycline form insoluble complexes i.e. 1. Respiratory tract infection: Bronchitis, chelation with calcium, magnesium, milk pneumonia and other lower respiratory and antacids reduce their absorption. tract infections due to susceptible strains Administration of iron also interferes with of Strep. pneumoniae, H. influenzae, K. the absorption of tetracycline. Doxycycline pneumoniae and other organisms is rapidly and virtually completely absorbed including Mycoplasma pneumoniae. after oral administration and its absorption Upper respiratory tract infections is not affected by presence of food or milk. including sinusitis, otitis, mastoiditis. 2. Urinary tract infection: Caused by The tetracyclines are widely distributed susceptible strains of Klebsiella sp., in the body and diffuse into various body Enterobacter sp., Strep. faecalis and other fluids. organisms. Adverse Effects 3. Sexually transmitted diseases: Uncomplicated urethral, endocervical Because of virtually complete absorption and rectal infections. Non gonococcal of doxycycline and minocycline side effects urethritis (NGU) caused by Ureaplasma pertaining to the lower bowel, particularly urealyticum, chancroid caused by H. Tetracyclines, Chloramphenicol and Chemotherapy of UTI 313

ducreyi, granuloma inguinale caused by binding reversibly to the 50S submit of the Calymmatobacterium granulomatis. bacterial ribosome. It inhibits the peptidyl As an alternative drug in the treatment transferase step of protein synthesis. It is of gonorrhoea and syphilis in patients bacteriostatic broad-spectrum allergic to penicillin. active against gram positive and negative 4. Dermatological infections: Acne organisms, Rickettsia, the Chlamydia of the vulgaris, when antibiotic therapy is psittacosis, lymphogranuloma group and considered necessary. Mycoplasma pneumoniae. The other organisms 5. Ophthalmic infections: Due to suscep- sensitive to chloramphenicol are E. coli, K. tible strains of N. gonorrhoeae, staphy- pneumoniae, Shigella, and certain strains of lococci, H. influenzae and in the treat- Brucella, Pasteurella, Proteus and Vibrio comma. ment of trachoma. It exerts bactericidal against H. influenzae, 6. Prophylaxis and treatment of Traveller’s Strep. pneumoniae and N. meningitidis. diarrhoea. 7. Miscellaneous infections caused by Pharmacokinetics susceptible strains of bacteria causing Chloramphenicol is completely absorbed psittacosis, cholera, melioidosis, lep- after oral administration, bound to plasma tospirosis, brucellosis, bartonellosis, protein (approximately 60%) and widely plague, tularemia, Campylobacter fetus distributed in body. It crosses the blood-brain infection, rickettsial infections including and placental barrier and shows its presence typhus and Q fever, relapsing fever due in CSF, bile and milk. It is conjugated with to Borrelia recurrentis and actinomyco- glucuronic acid in liver and excreted in urine. sis in penicillin allergic patients. Small amount is excreted in urine in unchanged form. 9. As an adjunct in acute intestinal amoebiasis. Adverse Effects 10. Prophylaxis of malaria due to P. Allergic reaction includes skin rashes, falciparum. drug fever, dermatitis, angioneurotic CHLORAMPHENICOL edema. Bone marrow depression includes It is a broad spectrum antibiotic originally aplastic anaemia, leukopenia, agranulocy- derived from Streptomyces venezuelae and later tosis, thrombocytopenia. on became the first completely synthetic Gray baby syndrome: Premature babies antibiotic. It is used as palmitate and sodium develop vomiting, hypothermia, abdominal succinate salt in given dosage. distension, shallow irregular respiration and Dose: 250-500 mg QID oral, 1-2 g IM further leading to gray cyanosis, vascular injection, 0.5-1.0% topical (eye ointment/ collapse, shock and death. drops/applicap and ear drops). CNS toxicity includes headache, mental Chloramphenicol is a potent inhibitor of confusion, internal ophthalmoplegia, periph- microbial protein synthesis. It acts by eral neuritis, depression, optical neuritis. 314 Section 9/ Chemotherapy

Other adverse effects include superin- antagonizes the action of nalidixic acid and fection, hepatotoxicity and typhoid shock. its activity is enhanced by lower pH. After oral administration it is rapidly and Therapeutic Uses completely absorbed from GIT, Because of bone marrow toxicity of metabolized in liver and less than half is chloramphenicol, its use is restricted to the excreted unchanged in urine. treatment of infection caused by S. typhi and It is used exclusively for urinary tract paratyphi (treatment of typhoid fever). infections. The side effects include nausea, Other indications in which chlorampheni- vomiting, diarrhoea, anorexia, leukopenia, col can be used are H. influenzae meningitis, haemolytic anaemia, jaundice, dizziness and urinary tract infections, anaerobic infections headache. On chronic use can lead to periph- caused by Bacteroides fragilis and locally in eye eral neuritis and interstitial pulmonary fi- and external ear infections. brosis.

CHEMOTHERAPY OF URINARY METHENAMINE TRACT INFECTIONS Methenamine mandelate is a salt of mandelic acid and methenamine and both of URINARY ANTISEPTICS these possess property of urinary antiseptic. Urinary antiseptics are orally administered It is rapidly absorbed in gastrointestinal tract agents that exert antibacterial activity in the and excreted unchanged in urine, where it urine but have no systemic antibacterial broken down in acidic pH (< 5) of urine and activity. Urinary antiseptics are listed as in formaldehyde is released, which inhibits most table 9.2.2. of the bacteria. It is administered with sodium biphosphate, mandelic acid or ascorbic acid NITROFURANTOIN to keep the urinary pH below 6. Its use is It is bacteriostatic and but bactericidal restricted to chronic, resistant type of UTI. against many gram positive and negative Adverse effects are gastritis, hematuria, organisms in higher concentration and chemical cystitis and skin rash. It is acidic urine. Pseudomonas aeruginosa and contraindicated in renal failure and hepatic various strains of Proteus are resistant. It insufficiency.

Table 9.2.2: Classification of urinary antiseptics. Nitrofurantoin (FURADANTIN) 50-100 mg QID Methenamine (as mendelate & hippurate) 1 g TDS-QID Phenazopyridine (PYRIDIUM) 200-400 mg TDS Other antimicrobial agents used in urinary tract infection e.g. sulfonamides, quinolones, penicillins, cephalosporins etc. (details are discussed in respective sections). Tetracyclines, Chloramphenicol and Chemotherapy of UTI 315

PHENAZOPYRIDINE moxazole act better in alkaline medium. In It is used for symptomatic relief of specific cases, where urine of desired reac- urinary burning sensation and urgency due tion (acidic or alkaline), some acidifying or to cystitis. It is a orange dye and excreted in alkalinizing agents is sometimes used to urine. It has no antibacterial property. get a desired clinical result. Urinary pH can be increased by carbonic anhydrase URINARY ALKALINIZERS AND ACIDIFIERS inhibitors (e.g. acetazolamide) and prolonged therapy requires bicarbonate Certain antimicrobial agents used to treat administration. In treatment of drug poi- urinary tract infections act better in acidic soning, the excretion of some drugs can pH i.e. nitrofurantoin, tetracycline, be hastened by acidification and alkalin- methenamine, cloxacillin. Certain other an- ization of the urine. Ammonium chloride timicrobial agents such as gentamicin, is used to acidify urine and potassium ac- cephalosporins, fluoroquinolones, cotri- etate/citrate is used to alkalinize urine.

 This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsBeta Lactam 1.9.3 4 (ModeAntibioticsAntibiotics of Action of Drugs)

PENICILLINS Penicillin is effective against gram posi- tive and negative cocci and some gram Penicillin was originally extracted from the positive bacilli. Among the cocci, strepto- mould Penicillium notatum but now it is cocci are highly sensitive. Gonococci, pneu- extracted from its related mould Penicillium mococci and meningococci are sensitive to chrysogenum due to its high yield. Penicillin penicillin. consists of thiazolidine ring fused with a Among the bacilli, gram positive Bacillus beta lactam ring which is essential for its anthracis, Corynebacterium diphtheriae, antibacterial activity. These two rings forms Clostridium species are highly sensitive. a nucleus named as 6-aminopenicillanic Among the spirochetes, Treponema pallidum acid. is highly sensitive to penicillin. Mechanism of Action Gram negative bacilli, fungi, protozoa, rickettsiae, chlamydiae, viruses and The bacterial cell wall is a rigid outer Mycobacterium tuberculosis are totally layer that completely surrounds the insensitive to penicillin. cytoplasmic membrane. Penicillin and other betalactam antibiotics inhibit bacterial Pharmacokinetics growth by interfering with a specific step in bacterial cell wall synthesis. Penicillins After oral administration, benzyl are classified as in table 9.3.1. penicillin is destroyed by gastric acid. It is mainly absorbed from the duodenum. BENZYL PENICILLIN It is absorbed in aqueous solution rapidly It is the most potent β-lactam antibiotic after intramuscular or subcutaneous and inhibits the growth of susceptible administration. Penicillin is widely microorganism in vitro in lowest distributed in the body after absorption concentration and is available in water and approximately 60% of plasma soluble sodium and potassium salts. penicillin is bound to albumin. The major 318 Section 9/ Chemotherapy

Table 9.3.1: Classification of penicillins. I. Penicillinase sensitive penicillins Benzyl penicillin (Penicillin G; sodium and potassium salt) 0.5-5 MU* IM/IV Procaine penicillin G 0.5-1 MU IM Benzathine penicillin G (PENIDURE) 0.6-2.4 MU IM Phenoxymethyl penicillin (Penicillin V; KAYPEN) 250-500 mg/day II. Penicillinase resistant penicillin Cloxacillin (BIOCLOX) 250-500 mg 6 hourly oral/IM/slow IV III. Broad spectrum penicillins Ampicillin (BIOCILIN) 0.25-2 g 6 hourly, oral/IM/slow IV Amoxycillin (NOVAMOX) 0.25-1 g/day IV. βββ-Lactamase Inhibitors Clavulanic acid 125-250 mg/day oral, IV Sulbactam 0.25-1 g/day IM/IV V. Antipseudomonal penicillins Carbenicillin (BIOPENCE) 1-2 g/day IM, 1-5 g IV 4-6 hourly Piperacillin (PIPRACIL) 25-50 mg/kg IM/IV 6 hourly Ticarcillin 200-300 mg/kg/day IV 4-6 hourly * IU of crystalline sod. benzyl penicillin = 0.6 mg of standard preparation (1 MU = 0.6 g or 1 g = 1.6 million units). portion is rapidly excreted by the kidney rash, pruritus, serum sickness like syndrome, mainly by tubular secretion and small eosinophilia, angioneurotic edema, asthma, amounts appear in bile, saliva, and milk. haematuria, albuminuria, haemolytic anemia, granulocytopenia and anaphylaxis. Adverse Effects To avoid that, a skin test using a 10,000 The penicillins are nontoxic and U of benzyl penicillin per ml is to be done remarkably safe drug. The hypersensitivity and if any local edema or wheal occurs reaction leading to anaphylaxis is only major within 15 minutes, it is considered to be as a problem which is seen in approximately 5 positive test and in that person penicillin to 10% of the patients taking penicillin. should not be used. The minor adverse effects include nausea, vomiting, pain and inflammation at Therapeutic Uses the site of injection after intramuscular Penicillin G is the drug of choice for the administration has been reported. After following categories of infection: intrathecal administration (which is a • Dental infections: Penicillin G is contraindication) it may lead to convulsions, effective in majority of infections arachnoiditis and encephalopathy. caused by both aerobic and anaerobic The major side effect is allergic reactions and bacteria in dentistry. It is used in acute anaphylaxis which is characterized by skin suppurative pulpits, pericoronitis, oral Beta Lactam Antibiotics 319

cellulitis, necrorotizing ulcerative PHENOXYMETHYL PENICILLIN gingivitis etc. But due to penicillin It has an antibacterial spectrum similar resistance, its use in dentistry is to benzyl penicillin but is less active. It is restricted. gastric acid stable and effective on oral • Streptococcal infections: Pharyngitis, administration. rheumatic fever, otitis media and even Adverse effects include urticaria, fever, for subacute bacterial endocarditis. rashes, angioedema, anaphylaxis, haemolytic • Staphylococcal infections: Penicillinase anemia, neutropenia, thrombocytopenia, resistant penicillin can be used. coagulation disorders, diarrhoea etc. • Meningococcal infections: Meningitis It is used in tonsillitis, otitis media, & other infections caused by meningo- erysipelas, prophylaxis of rheumatic fever cocci. and pneumococcal infections. • Pneumococcal infections: Pneumonia and meningitis. PENICILLINASE RESISTANT PENICILLIN • Gonococcal infection: Procaine It is resistant to degradation by penicillinase. penicillin along with probenecid can be Mainly it exhibits activity against gram used. positive microorganisms and is useful • Sexually transmitted diseases: against penicillinase producing Staph. Penicillin is a drug of choice in the aureus. treatment of syphilis. • In the treatment of actinomycosis and CLOXACILLIN anthrax. It has an isoxzalyl side chain and has • In the treatment of diphtheria, tetanus weaker antibacterial activity than benzyl and gas gangrene. penicillin. It is absorbed after oral • Penicillins are also used in the administration partially and elimination prophylaxis of rheumatic fever, occurs mainly by kidney and partly by liver. sexually transmitted diseases e.g. It is devoid of any serious side effect but can gonorrhoea and syphilis and bacterial cause hypersensitivity reaction in some endocarditis. patients. Other analogs of cloxacillin are SEMISYNTHETIC PENICILLINS dicloxacillin and flucloxacillin. They are relatively less protein bound, however, Semisynthetic penicillins are produced by dicloxacillin gives approximately double the combining the specific side chains in place blood level than cloxacillin. of benzyl side chain. They have been produced to overcome the shortcomings of BROAD SPECTRUM PENICILLINS benzyl penicillin like poor bioavailability, susceptibility to penicillinase and narrow They have broad antibacterial spectrum and spectrum of activity. are effective against both gram positive and 320 Section 9/ Chemotherapy gram negative organisms. They are Adverse effects include nausea, hydrolysed by penicillinase. epigastric distress, diarrhoea, skin rash, urticaria, serum sickness, thrombocytopenia, AMPICILLIN leucopenia, eosinophilia etc. It is a broad spectrum penicillin which It is used in respiratory, genitourinary, is not destroyed by gastric acid but is skin and soft tissue, ENT infections caused penicillinase susceptible. It is more effective by pneumococci, streptococci, staphylo- than benzyl penicillin against a variety of cocci, H. influenzae, E. coli and other suscep- gram negative microorganisms. tible organisms. Also useful in Chlamydia After oral administration it is readily but trachomatis in pregnancy, meningitis due to incompletely absorbed and food interferes susceptible strains of gram negative micro- with its absorption. Peak plasma level are organisms, enteric fever, gonococcal urethri- reached within two hours after oral tis, bacteriaemia and septicaemia. administration and one hour after IM Amoxycillin is also used in chemoprophy- administration. It is excreted in urine in laxis during dental procedures. unchanged form and high amount is also Amoxycillin is also used in combina- present in the bile. tion with clavulanate potassium. The for- Adverse effects include skin rash, mulation of amoxycillin with clavulanic acid nausea, epigastric distress, diarrhoea, drug protects amoxycillin from degradation by fever, urticaria etc. beta lactamase enzymes and effectively ex- tends the antibiotic spectrum of amoxycillin It is used in infection caused by to include β lactamase producing bacteria susceptible gram positive and gram normally resistant to amoxycillin and other negative organisms (respiratory tract, soft betalactam antibiotics. tissue, gonococcal, GI and genitourinary infections), septicaemia, meningitis, chronic Amoxycillin along with bromhexine bronchitis, otitis media, sinusitis, invasive and carbocisteine is used in bronchitis, salmonellosis and cholecystitis. bronchopneumonia, , sinusitis and otitis media. AMOXYCILLIN Amoxycillin along with cloxacillin is Amoxycillin is a semisynthetic used in lower respiratory tract, skin and soft penicillin, a close congener of ampicillin and tissue, urinary tract and postoperative active against gram positive and negative infections, osteomyelitis, gynaecological organisms. Its absorption is more complete infections, septicaemia, bacterial endocarditis than ampicillin. Food does not interfere with and bacterial meningitis. its absorption. Its absorption after oral Amoxycillin along with probenecid is administration is complete hence less used in bacterial septicaemia, skin and soft incidence of diarrhoea. It is eliminated in tissue infection, acute and chronic urine in unchanged form. respiratory tract infections. Beta Lactam Antibiotics 321

It is indicated in bacteriaemia, septicae- βββ-LACTAMASE INHIBITORS mia, genitourinary and respiratory tract in- fections, endocarditis and postoperative in- CLAVULANIC ACID fections caused by pseudomonas or proteus. It ‘progressively’ inhibits a wide variety of β-lactamases produced by gram positive PIPERACILLIN and negative organisms and is obtained The unique advantages of piperacillin from Streptomyces clavuligerus. It has no anti- are broad spectrum of antibacterial activity bacterial activity of its own. and excellent antipseudomonal activity. It is used along with amoxycillin in They have a synergistic effect with various infections as discussed above. aminoglycosides (e.g. gentamicin or netilmicin) and hence should be given con- SULBACTAM comitantly in pseudomonas septicaemia. β It is another semisynthetic -lactamase They should however, not be mixed in the inhibitor used along with ampicillin. It is same syringe. Owing to the sodium content, related to clavulanic acid both chemically high doses may lead to hypernatremia. and in activity. Adverse effects include platelet dys- Adverse effects include diarrhoea, rash, function leading to bleeding, superinfec- pain at site of injection and thrombophlebitis tion, local pain and thrombophlebitis. of injected vein. It is indicated in systemic and local It is indicated in gynaecological, intra- infections, gynaecological infections, UTI, abdominal, skin and soft tissue infections. RTI, neonatal and lifethreatening paediatric infections, burns and septicaemia caused by ANTIPSEUDOMONAL PENICILLINS susceptible organisms.

These are indicated mainly to treat gram TICARCILLIN negative bacilli infection by pseudomonas, proteus and enterobacter. It is derived from penicillin nucleus 6- aminopenicillanic acid. It has broad spectrum CARBENICILLIN of activity against both gram positive and It is a penicillinase susceptible and is negative organisms. It is more potent than principally indicated for serious infection carbenicillin against Pseudomonas. caused by Pseudomonas aeruginosa. It is Adverse effects include hypersensitiv- effective against certain other gram negative ity, thrombocytopenia, neutropenia, leu- bacilli including Proteus species and copenia, pain at the site of injection and GI Bacteroides fragilis. disturbances. Adverse effects include platelet dys- It is indicated in bacterial septicaemia, function, hypokalemia and hypersensitiv- skin and soft tissue infections, acute and ity reaction. chronic respiratory tract infections. 322 Section 9/ Chemotherapy

CEPHALOSPORINS Antibacterial activity: Cephalosporins are active against a wide range of gram Cephalosporins are important bactericidal positive and negative bacteria which broad spectrum β-lactam antibiotics used for includes pneumococci, C. diphtheriae, E. the treatment of septicaemia, pneumonia, coli, N. gonorrhoeae, Proteus mirabilis, S. meningitis, urinary tract infections, peritonitis typhi and paratyphi. The newer and biliary tract infections. They are obtained cephalosporins are effective against from fungus Cephalosporium acremonium and are Pseudomonas aeruginosa. In dentistry, chemically related to penicillin. It consists of cephalosporins is used only as alternative beta lactam ring fused to a dihydrothiazine ring. to penicillin or amoxycillin in patients All cephalosporins act by inhibiting bac- who are allergic to penicillins. The second terial cell wall synthesis and are bacteri- generation cephalosporins are having cidal. Also the autolytic enzymes in cell wall good activity against oral anaerobes and may be activated leading to bacterial death. are generally preferred in dentistry. They are widely distributed after administration throughout body fluids. Pharmacokinetics Cephalosporins are mainly excreted by the Cephalosporins are distributed in the kidneys and dose should be altered in body after oral or parenteral administration patients with renal disease. in same manner as penicillin is distributed. Cephalosporins are classified as in table The majority are not metabolized and are 9.3.2. eliminated by kidney.

Table 9.3.2: Classification of cephalosporins. I. First generation cephalosporins Cephalexin (SPORIDEX) 1-4 g QID Cefazolin (AZOLIN) 1-4 g/d IM/IV Cefadroxil (ODOXIL) 0.5-1 g BD II. Second generation cephalosporins Cefuroxime (CEFTUM) 250-500 mg BD Cefaclor (KEFLOR) 250-500 mg TDS Cefoxitin 1-2 g/day IM/IV III. Third generation cephalosporins Cefotaxime (OMNATAX) 1-2 g TDS, IM/IV Ceftriaxone (CEFAXONE) 0.5-2 g OD IM/IV Ceftizoxime (CEFIZOX) 1-3 g BD-TDS Cefixime (BIOTAX-O) 200-400 mg OD-BD Cefoperazone (CEFOMYCIN) 1-2 g TDS IM/IV IV. Fourth generation (Newer) cephalosporins Cefpirome (FORGEN) 1-2 g BD Cefepime (KEFAGE) 1-2 g BD-TDS IV Beta Lactam Antibiotics 323

Adverse Reactions CEFADROXIL Cephalosporins are generally well tol- It has good tissue penetration. Excreted erated and various side effects include pain unchanged in urine. Used in soft tissue and at the site of injection and can also cause skin infection caused by staphylococci or thrombophlebitis. Allergic reactions include streptococci, pharyngitis, tonsillitis, ENT skin rash, fever, serum sickness, eosino- infections and urinary tract infections. philia, neutropenia and rarely anaphylactic reaction. SECOND GENERATION CEPHALOSPORINS CNS side effects include nystagmus and hallucinations and some of the newer CEFUROXIME compounds can cause disulfiram like reaction. It is effective against a wide range of Larger doses can cause nephrotoxicity. gram positive and negative organisms. It is indicated in:

FIRST GENERATION CEPHALOSPORINS • Lower respiratory tract infections e.g., pneumonia, acute bronchitis and acute Highly active against gram positive but exacerbations of chronic bronchitis. weaker against gram negative bacteria. • ENT infections, such as otitis media, CEPHALEXIN sinusitis, tonsillitis and pharyngitis. It is orally active first generation • Genitourinary tract infections e.g., cephalosporin and less active against pyelonephritis, cystitis and urethritis. penicillinase producing staphylococci. • Skin and soft tissue infections e.g., furunculosis, pyoderma and impetigo. Adverse effects include skin rash, urticaria, nausea, vomiting, diarrhoea and • Enteric fever. neutropenia. • Gonorrhoea, acute uncomplicated gonococcal urethritis, and cervicitis. It is excreted unchanged in urine. It is Adverse reactions to cefuroxime have indicated in respiratory, genitourinary, skin and soft tissue infections, bone and joint been generally mild and transient in nature. infections, dental and ENT infections. As with other cephalosporins there have been rare reports of erythema multiforme, CEFAZOLIN Steven-Johnson syndrome, toxic epidermal It is a semisynthetic potent cephalosporin necrolysis (exanthematic necrolysis) and for parenteral administration. It can be hypersensitivity reactions including skin administered less frequently because of its rashes, urticaria, pruritus, drug fever, serum long half life. It is used in infections of sickness and very rarely anaphylaxis. genitourinary tract, bone, joint and soft tissue infections, septicaemia, endocarditis, CEFACLOR gonorrhoea, postoperative chest infections, The antibacterial spectrum of cefaclor in- biliary tract infection and surgical prophylaxis. cludes the following organisms: Staphylo- 324 Section 9/ Chemotherapy cocci (coagulase-positive, coagulase-nega- CEFTAZIDIME tive and penicillinase producing strains), It is a broad spectrum cephalosporin Streptococcus pyogenes, Streptococcus having anti-pseudomonal activity. Used pneumoniae, Moraxella catarrhalis, H. in serious infections of respiratory tract, influenzae including beta-lactamase produc- ENT and soft tissue infection, septicae- ing strains, E. coli, P. mirabilis, Klebsiella sp., mia, meningitis, GI and biliary tract in- N. gonorrhoeae. fections. Cefaclor is well absorbed after oral administration. The presence of food may CEFOXITIN delay the absorption of cefaclor but the total It is produced by an Actinomyces. Used amount absorbed remains unchanged. in the treatment of anaerobic and mixed About 25 percent of the drug is protein surgical infections and lung abscess. bound. Cefaclor is widely distributed in the body. It is rapidly excreted by the kidneys, THIRD GENERATION CEPHALOSPORINS up to 85% appears unchanged in the urine within two hours. CEFOTAXIME It is indicated in: A broad spectrum cephalosporin, • Pneumonia, acute bronchitis and acute effective against staphylococci, Haemophilus exacerbation of chronic bronchitis. influenzae, Salmonella, Shigella, Serratia, • Otitis media, pharyngitis, tonsillitis Citrobacter, Neisseria and Proteus. and sinusitis. The drug is given by parenteral route • Urinary tract infections. and is deacetylated in body to active • Skin and soft tissue infections. metabolite which acts synergistically with Cefaclor is generally well tolerated. parent drug. However the reported adverse effects in- Adverse effects include skin rash, clude mild gastrointestinal reactions (nau- drug fever, anaphylaxis, nausea, vomiting, sea, vomiting, abdominal cramps and di- diarrhoea, thrombocytopenia and leu- arrhoea). Symptoms of pseudomembra- copenia. Local reaction and pain at injec- nous colitis may appear either during or tion site, pseudomembranous colitis and after antibiotic treatment. The other side headache. effects are allergic in nature viz. skin rash, itching, bronchospasm, hypotension, It is used in respiratory, genitourinary erythema multiforme, Steven-Johnson infections including gonorrhoea, septicemia, syndrome. Other side effects viz. meningitis, endocarditis; surgical, abdomi- haemolytic anaemia, hypoprothrombine- nal, bone and joint infections; preoperative mia, seizures and thrombophlebitis have prophylaxis in those at increased risk of in- been rarely reported. fection and CNS infections. Beta Lactam Antibiotics 325

CEFTRIAXONE Adverse effects include diarrhoea, It is a broad spectrum cephalosporin nausea, vomiting, skin rash, urticaria, drug having a long half life and administered fever, pruritus, dizziness, hypersensitivity once daily and indicated in meningitis, reactions, hematological disorders. septicaemia, typhoid, urinary tract It is indicated in respiratory tract infections, prophylaxis in surgical infections, infections, gonorrhoea, otitis media, urinary pneumonia, STD, bacteremia and pelvic tract infection and typhoid fever. inflammatory disease. CEFOPERAZONE CEFTIZOXIME It is broad spectrum cephalosporin with It is a parenteral, semisynthetic third anti-pseudomonal activity. It is more generation cephalosporin. It is not susceptible to β-lactamases and is primarily metabolised and approximately 90 percent excreted in bile. Used in severe susceptible of drug is excreted by the kidney in infections of respiratory, urinary, GIT, skin unchanged form. It is indicated in lower and soft tissues, meningitis, septicaemia, respiratory tract, skin and soft tissue gonorrhoea, bacteremia and peritonitis. infection, septicaemia, urinary tract infection Cefoperazone is also used in combina- and gonorrhoea. tion with sulbactam.

CEFIXIME FOURTH GENERATION CEPHALOSPORINS Cefixime is an orally active third- generation cephalosporin antibiotic which CEFPIROME has marked in-vitro bactericidal activity It is fourth generation cephalosporin against a wide variety of gram positive and used mainly in serious infections including negative organisms. It is indicated for the septicaemia and respiratory tract infections treatment of urinary tract, infection, and infections acquired from hospitals. It is respiratory tract infection and biliary tract resistant to many β-lactamases. infection etc. CEFEPIME Cefixime given orally is about 40 to 50 percent absorbed whether administered Its antibacterial spectrum is similar to with or without food. However, time to that of third generation cephalosporins. It β maximum absorption is increased approxi- is highly resistant to -lactamases. mately 0.8 hours when administered with It is indicated in bacteremia, septicae- food. It is excreted unchanged in the urine mia, febrile neutropenia and hospital ac- in 24 hours. quired infections.

 This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsAminoglycosidesAminoglycosides 9.41. 4 (ModeAntibioticsAntibiotics of Action of Drugs)

Aminoglycosides are group of bactericidal excretion is principally via the kidney, antibiotics originally obtained from various accumulation occurs in renal impairment. Streptomyces species. All the aminoglycosides produce All aminoglycosides act by inhibiting cochlear and vestibular damage (ototoxicity) protein synthesis of bacteria by directly which is a dose and duration of treatment combining with ribosomes. They penetrate related side effect. Another serious side the outer cytoplasmic membrane and inhibit effect is nephrotoxicity. Aminoglycosides protein synthesis. Streptomycin combines also reduce the acetylcholine release from with the bacterial 30S ribosomes and the motor nerve endings and cause inteferes with the mRNA-ribosome neuromuscular blockade. combination. Other aminoglycosides bind Aminoglycoside antibiotics are to additional sites on 50S subunit as well as classified as in table 9.4.1. to 30S-50S interface. All aminoglycosides are poorly STREPTOMYCIN absorbed after oral administration, are more The aminoglycoside antibiotic, obtained active in alkaline pH and are excreted from Streptomyces griseus is the first unchanged by glomerular filtration. Since antitubercular drug.

Table 9.4.1: Classification of aminoglycoside antibiotics. Streptomycin (AMBISTRYN-S) 0.75-1 g/day IM Gentamicin (TAMIACIN) 3-5 mg/kg/day IM; 0.1-0.3% topical (eye drop, skin ointment/cream) Tobramycin (TOBACIN) 3-5 mg/kg/day IM/IV Amikacin (NOVACIN) 15 mg/kg/day IM Kanamycin (KANSIN) 0.5-1 g/day IM Neomycin (as sulphate) 0.3-0.5% topical (eye/ear drop, ointment/powder) Framycetin (SOFRAMYCIN) 0.5-1.0% topical (eye drop/ointment, skin cream) 328 Section 9/ Chemotherapy

It is bactericidal drug and exerts its It is valuable in critically ill patients action by combining with bacterial with impaired host defence; Pseudomonas ribosome and induces misreading of or Proteus infections in burns, urinary tract mRNA codons. Also in sensitive bacteria, infections, lung abscesses, osteomyelitis, disruption of cytoplasmic membrane occurs middle ear infection, septicaemia; menin- resulting in leakage of amino acids, ions, gitis caused by gram negative bacilli, peri- leading to bacterial death. tonitis, in skin and soft tissue infections and postoperative infection. After oral administration it is not Topical administration in the form of absorbed. After IM injection the absorption drop and ointment have been used for the is rapid. It is excreted unchanged in urine. treatment of infected burns, wounds and Half life is prolonged in patients of renal the prevention of intravenous catheter failure. infections and in the treatment of ocular Adverse effects include pain at infections. injection site, ototoxicity, nephrotoxicity, Adverse effects include ototoxicity (in- skin rash, fever, exfoliative dermatitis and cidence is related to dose and duration of eosinophilia. Anaphylaxis is rarely seen. therapy), nephrotoxicity, hypersensitivity Optic nerve dysfunction. reactions, skin itching, headache, neuromus- It is used in all forms of tuberculosis cular junction blockade, anorexia, nausea, along with other antitubercular drugs. vomiting, superinfection, photosensitivity, drowsiness, weakness, thrombocytopenia, Other indications are tularemia, plague, agranulocytosis. brucellosis, bacterial endocarditis, entero- coccal endocarditis. Used concomitantly TOBRAMYCIN with penicillin G for synergistic effect in the It belongs to family nebramycins, is treatment of enterococcal endocarditis isolated from Streptomyces tenebrarius. Its when other antibiotics are ineffective or antibacterial activity is similar to contraindicated. gentamicin and slightly more active than gentamicin against Pseudomonas aeruginosa GENTAMICIN and Proteus. It is obtained from Micromonospora It is used in the treatment of infection pupurea. It has broader spectrum of action of gastrointestinal and respiratory tract, and is effective against Pseudomonas skin and soft tissue infections, septicaemia aeruginosa, E. coli, Klebsiella, Enterobacter and urinary tract infection. and Proteus. Streptococci and enterococci Adverse effects include skin rash, are relatively resistant to it owing to failure ototoxicity, nephrotoxicity, phlebitis, of the drug to penetrate into the cell. nausea, vomiting, urticaria and headache. Following parenteral administration, it Ototoxicity and nephrotoxicity is lower defuses mainly into extracellular fluids. than gentamicin. Aminoglycosides Antibiotics 329

AMIKACIN nas, but due to severe ototoxicity and neph- It is semisynthetic derivative of rotoxicity, it is replaced by other kanamycin. It is active against gentamicin aminoglycosides and occasionally used in resistant organisms e.g. Pseudomonas multidrug resistant cases of tuberculosis. aeruginosa, Klebsiella, E. coli and Proteus. It is resistant to bacterial aminoglycoside NEOMYCIN inactivating enzymes. It is isolated from Streptomyces fradiae It is indicated in bacteriaemia, septicae- and is effective against most gram negative mia; respiratory tract, bones and joints, CNS bacilli and some gram positive cocci. (including meningitis), skin, soft tissue, Because of its high ototoxicity and intraabdominal infections (including perito- nephrotoxicity, it is not used systemically nitis); burns and postoperative infections. and used locally in various skin and eye infections. Adverse effects include hypersensitivity reactions, nausea, vomiting, nephrotoxicity, oto- FRAMYCETIN toxicity, headache and neuromuscular blockade. It is derived from Streptomyces lavendule. KANAMYCIN It is similar to neomycin and used locally in It is derived from Streptomyces various skin infections and eye/ear kanamyceticus. It is active against Pseudomo- infections.

 This page intentionally left blank Macrolide and ChapterChapter PharmacodynamicsPharmacodynamicsPolypeptide (Mode of Action of Drugs) 1.9.5 4 Antibiotics

MACROLIDE ANTIBIOTICS It is a narrow spectrum antibiotic, low concentration are bacteriostatic, Macrolides, as their name indicates are however high concentrations are bacte- characterized by a large or macrocyclic ricidal. The spectrum of activity also de- lactone ring with attached sugar residue(s). They are classified as in table pends on the concentration of drug at 9.5.1 the desired site and sensitivity of the tar- get microorganisms. It is more active in ERYTHROMYCIN alkaline medium. Erythromycin was the first macrocyclic Erythromycin is effective against gram antibiotic which was isolated from positive and few gram negative organisms Streptomyces erythreus. Erythromycin is widely used antibiotic both in children as which mainly includes pneumococci, well as in adults. streptococci, staphylococci, Neisseria and It acts by binding with 50S ribosomal some strains of C. diphtheriae, H. influenzae, subunit of bacteria and inhibit protein Rickettsiae and Treponema. It is also effective synthesis. against penicillin resistant staphylococci,

Table 9.5.1: Classification of macrolide antibiotics. Erythromycin 250-500 mg QID as stearate (RESTOMYCIN) as estolate (ALTHROCIN) also as ethyl succinate, 0.4-0.6 g every 6 hourly (drop & syrup) and gluceptate 0.5-1.0 g IV 6 hourly Roxithromycin (ROXID) 150 mg BD Azithromycin (ZATHRIN) 500 mg OD Clarithromycin (CLAMYCIN) 250-500 mg BD Clindamycin (DALACIN-C) 150-300 mg QID oral, 200-600 mg TDS IV Lincomycin (LYNX) 500 mg TDS-QID oral, 600 mg IV 6-12 hourly Vancomycin (FORSTAF) 250-500 mg 6 hourly 332 Section 9/ Chemotherapy

Mycoplasma, Campylobacter, Legionella, in the serum after 15 minutes of Gardnerella vaginalis are also highly administration. It is more than 90% plasma sensitive. protein bound and more than half the dose is excreted unchanged in urine and faeces. Adverse effects include gastrointesti- nal side effects like nausea, epigastric pain Adverse effects include gastrointesti- are common. Diarrhoea occurs occasion- nal symptoms like nausea, vomiting, epi- gastric pain, diarrhoea, hypersensitivity ally. Skin rashes, hypersensitivity reaction, reactions like rash, urticaria, angioedema, hepatotoxicity (hepatitis alongwith exceptionally bronchospasm, anaphylactic cholestatic jaundice, especially with shock; dizzy sensations (caution in driving estolate ester), oral candidiasis, throm- or use of machinery); moderate increase in bophlebitis and fever have been reported. ASAT, ALAT and/or alkaline phos- Erythromycin is used as a substitute to phatases; cholestatic or more rarely acute penicillin in allergic patients for upper liver injury. respiratory tract infections, e.g. tonsillitis, AZITHROMYCIN pharyngitis and mastoiditis, pneumococcal infection and prophylaxis of rheumatic Azithromycin is an azalide antibiotic, fever. It is drug of choice in treatment of a sub-class of the macrolides. Azithromycin atypical pneumonia due to Mycoplasma differs chemically from erythromycin in that a methyl substituted nitrogen atom is pneumoniae, Legionnaire’s pneumonia and incorporated into the lactone ring. whooping cough. It is also useful in wound and burn infections and severe impetigo not Following oral administration, responding to topical antibiotics. azithromycin is rapidly absorbed and widely distributed throughout the body. ROXITHROMYCIN Rapid distribution into tissues and high concentration within cells result in signifi- Roxithromycin is a semisynthetic cantly higher azithromycin concentration macrolide antibiotic. is tissues than in plasma or serum. It is effective against Streptococcus Azithromycin is indicated for the pyogenes, Streptococcus viridans, Streptococcus treatment of following infections caused by pneumoniae, mitis, S. aureus and sensitive organisms: coagulase negative staphylococci, Neisseria 1. Lower respiratory tract infections: meningitidis, Bordetella pertussis, Moraxella Community-acquired pneumonia, catarrhalis, Corynebacterium diphtheriae, List- acute bacterial exacerbations of eria monocytogenes, Clostridium, Mycoplasma chronic obstructive pulmonary pneumoniae, Pasteurella multocida, Chlamydia disease, acute bronchitis due to trachomatis/psittaci/pneumoniae, Ureaplasma Haemophilus influenzae, Moraxella urealyticum, Legionella pneumophila, catarrhalis or Streptococcus pneumoniae. Helicobacter pylori, Gardnerella vaginalis. 2. Ear, nose and throat infections like It is more stable in acid media than tonsillitis, sinusitis, otitis media and other macrolides. Roxithromycin is found pharyngitis. Macrolide and Polypeptide Antibiotics 333

3. Skin/skin structure infections: Fu- bosomes and hence suppresses protein runculosis, pyoderma and impetigo synthesis. It is 7-chloro-7-deoxylincomycin, due to Staphylococcus aureus, S. a semisynthetic derivative of lincomycin. pyogenes or S. agalactiae. It inhibits most of the gram positive Adverse reactions include vomiting, cocci e.g. streptococci, staphylococci and dyspepsia, flatulence, jaundice, palpita- pneumococci, C. diphtheriae, Actinomyces, tions, chest pain. Allergic reactions include Nocardia and Toxoplasma. rash, photosensitivity and angioedema. CNS side effects are headache, dizziness, It is used in the treatment of severe vertigo and fatigue. anaerobic infections caused by bacteroides and other anaerobes. It is also used in CLARITHROMYCIN combination with aminoglycoside in the It is a macrolide antibiotic obtained by treatment of abdomen and GIT wounds, infections of female genital tract, pelvic substitution of hydroxyl group by a CH3O group in the erythromycin lactone ring. It abscesses, aspiration pneumonia and septic is found to be 2 to 10 times more active than abortion. It is also used for prophylaxis of erythromycin. endocarditis. It is also used along with Clarithromycin is readily and rapidly primaquine in Pneumocystis carinii absorbed after oral administration and is pneumonia in AIDS patients and with metabolized significantly in liver. Active pyrimethamine for toxoplasmosis. metabolite is excreted by kidney and other Oral absorption is good. It is largely routes. metabolized and metabolites are excreted It is indicated in the treatment of lower in urine and bile. respiratory tract infection e.g. bronchitis Adverse effects include pain at and pneumonia, upper respiratory tract injection site, stomatitis, glossitis, infections e.g. pharyngitis and sinusitis, angioneurotic edema, serum sickness, infections due to chlamydia, legionella and vertigo, tinnitus, aplastic anaemia. mycoplasma, skin and soft tissue infections Hypotension and cardiac arrest after rapid and eradication of H. pylori with acid IV use. Anorexia, metallic taste, suppressants. oesophagitis, abdominal pain. The most frequently reported side effects are GI-related complaints i.e. LINCOMYCIN nausea, dyspepsia, abdominal pain and It is mainly bacteriostatic and inhibits diarrhoea. Other side effects include the growth of gram positive organisms headache, skin rash and transient elevation which includes staphylococci, streptococci, of liver enzymes, hepatic dysfunction with or without jaundice and psychosis. pneumococci, C. diphtheriae and B. anthracis. Like erythromycin it act by CLINDAMYCIN interfering with protein synthesis. It is a lincosamide and act by binding ex- Adverse effects include nausea, clusively to 50S submit of the bacterial ri- vomiting, diarrhoea, abdominal pain, 334 Section 9/ Chemotherapy pseudomembranous colitis, dizziness, rash, POLYPEPTIDE ANTIBIOTICS headache, pruritus, jaundice, leucopenia etc. It is indicated in upper and lower respi- They have bactericidal activity against ratory tract infections, skin infections, septi- gram negative bacteria only and are low caemia, bone and joint infection including molecular cationic polypeptide antibiotics. acute haematogenous osteomyelitis. They are listed in table 9.5.2.

VANCOMYCIN POLYMYXIN B It is a antibiotic and Has detergent like action on cell primarily active against gram positive membrane and have high affinity for bacteria, strains of Staph. aureus which are phospholipids. They penetrate into and resistant to methicillin are inhibited by vancomycin. It is also effective against disrupt the structure of cell membranes, Strep. viridans, enterococcus, Clostridium as a result of which amino acids and ions difficile and diphtheroids. leak out. It is bactericidal drug and it exerts it After oral administration negligible or action by inhibiting the synthesis of the no absorption occurs. cell wall in sensitive bacteria. It is used systemically in enteric After oral administration it is poorly infections caused by gram negative absorbed. It is given by parenteral route organisms and topically for pseudomonal and high concentration of drug may infections of conjunctiva and cornea, burns accumulate when renal function is and skin. impaired. Adverse effects include nausea, vom- It is indicated in serious life threatening iting, diarrhoea after oral administration. staphylococcal infections resistant to other Parenteral administration (IM) cause pain, antibiotics, in severe staphylococcal flushing, ototoxicity, nephrotoxicity and infections in patients who are allergic to penicillin and cephalosporin. neurotoxicity. Adverse effects include skin rash, ana- COLISTIN phylaxis, nephrotoxicity, ototoxicity like other aminoglycosides. Other side effects are Also known as polymyxin E, is also a local pain and phlebitis at the site of injec- cationic detergent used only orally. Side tion, fever, eosinophilia and hypotension. effects and uses are similar to polymyxin B.

Table 9.5.2: Classification of polypeptide antibiotics. Polymyxin B (AEROSPORIN) 15,000-25,000 U/kg daily for 7-10 days Colistin (as sulphate) (WALAMYCIN) 25-100 mg TDS Bacitracin 250 µ/g powder, skin/eye ointment Tyrothricin (0.5 mg/kg skin cream, 0.2 mg/ml solution (topical), 0.05% as otic solution with benzocaine Macrolide and Polypeptide Antibiotics 335

BACITRACIN TYROTHRICIN This antibiotic is obtained from Bacillus It is obtained from Bacillus bravis and subtilis. It is effective against gram positive effective against gram positive and some (cocci and bacilli), Neisseria and H. influenzae. gram negative organisms. It acts on bacte- It is used only topically as antibacterial pow- rial cell membrane causing leakage and der, skin and eye ointment and acts by inhib- uncoupling of oxidative phosphorylation. iting the cell wall synthesis. It is bactericidal. Used topically as skin cream and solution.

 This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsAntiviral Agents 9.61. 4 (Mode of Action of Drugs)

Viruses have no cell wall and made up of It prevents the replication of DNA nucleic acid core enclosed in a protein coat viruses and its clinical use is limited to which consists of identical subunits. herpes simplex keratitis. Viruses are of two types, DNA Toxicity includes alopecia, leucopenia, (deoxyribonucleic acid) viruses and RNA thrombocytopenia and liver damage. (ribonucleic acid) viruses. DNA viruses are It is used in herpes simplex keratocon- herpes simplex, small pox, hepatitis B, junctivitis in 0.1 to 0.5% solution/eye oint- varicellazoster etc. and RNA viruses are ment applied one to two hourly. rabies, measles, dengue, rubella, yellow fever, poliomyelitis and HIV etc. ACYCLOVIR In viral infections, replication of viruses Acyclovir is a synthetic purine are at peak, at or before the manifestation nucleoside analogue with in vitro and in of clinical symptoms. So, the treatment vivo inhibitory activity against human generally depends either on early initiation herpes viruses. of therapy or prevention of infection i.e. Acyclovir triphosphate interferes with chemoprophylaxis. the viral DNA polymerase and inhibits The various antiviral agents are viral DNA replication with resultant chain classified as under (the doses for specific termination following its incorporation into infections is given in text) in table 9.6.1. the viral DNA. Acyclovir is only partially (20%) ANTI-HERPES AGENTS absorbed from the gut. Most of the drug is excreted un- IDOXURIDINE changed by the kidney by tubular secre- It is chemically related to thymidine and tion and glomerular filtration.9- acts by competing with it in the Carboxymethoxymethylguanine is the synthesis of DNA and ultimately only significant metabolite of acyclovir re- preventing the utilization of thymidine. covered from the urine. 338 Section 9/ Chemotherapy

Adverse reactions include nausea, vom- • For the prevention of recurrences of iting, fatigue, diarrhoea and abdominal pain, herpes simplex infection in immuno- rashes including photosensitivity, urticaria, competent patients. pruritus, increase in blood urea and creatinine, • Prophylaxis of herpes simplex infection reversible rise in bilirubin and liverrelated en- in immunocompromised patients. zymes. Neurological adverse effects are • Treatment of varicella (chickenpox) and headache, dizziness, confusional state, hallu- herpes zoster (shingles) infections. Early cinations, somnolence and convulsions. treatment of shingles with acyclovir can reduce the incidence of post-herpetic Indications neuralgia (zosterassociated pain). • Treatment of herpes simplex virus infection of the skin and mucous Dosage membrane, including initial and For treatment of herpes simplex in recurrent genital herpes. adults: 200 mg five times daily for five days.

Table 9.6.1: Classification of antiviral agents. I. Antiherpes agents Idoxuridine (RIDINOX) Acyclovir (ZOVIRAX) Famciclovir (FAMTRAX) Valacyclovir Ganciclovir II. Antiretroviral agents a. Nucleoside reverse transcriptase inhibitors Zidovudine (RETROVIR) Lamivudine (HEPITEC) Stavudine (STAVIR) Didanosine (DINEX) b. Nonnucleoside reverse transcriptase inhibitors Nevirapine (NEVIMUNE) (EFAVIR) c. Retroviral protease inhibitors Indinavir (INDIVIR) Saquinanir Nelfinavir III. Antiinfluenza virus agents Amantadine Zanamavir Ribavarin (RIBAVIN) Interferons Antiviral Agents 339

In severely immunocompromised DOSAGE AND ADMINISTRATION patients or in patients with impaired absorption from the gut the dose can be Herpes Zoster doubled to 400 mg or IV dose can be given. • Immunocompetent patients: 750 mg Dosage for suppression of herpes once daily for 7 days or 250 mg every simplex in adults: In immunocompetent 8 hours for 7 days. patients, 200 mg four times daily six hourly. • Immunocompromised patients: 500 mg three times daily for 10 days. Dosage for prophylaxis of herpes Famciclovir should be initiated simplex in adults : 200 mg four times daily immediately upon diagnosis of herpes at six hourly intervals. zoster, preferably within 48 hours of In severely immunocompromised the onset of the rash. patients or in patients with impaired Genital Herpes absorption from the gut the dose can be doubled to 400 mg or IV dosing can be First episode of genital herpes: given. • Immunocompetent patients: 250 mg famciclovir three times daily for 5 Dosage for treatment of varicella and days, initiated as soon as possible after herpes zoster in adults: 800 mg five times lesion onset. daily four hourly intervals for seven days. • Immunocompromised patients: 500 mg IV dose can be given in severely twice daily for 7 days. immunocompromised patients or in patients Episodic treatment of recurrent genital herpes: with impaired absorption from the gut. • Immunocompromised patients: 125 mg Dosage for management of severely twice a day for 5 days. immunocompromised patients: 800 mg Acute recurrent genital herpes infection: four times daily at six hourly intervals. • Immunocompromised patients: 500 mg twice daily for 7 days. FAMCICLOVIR Suppressive treatment of recurrent genital Famciclovir is an orally administered herpes: prodrug of the antiviral agent penciclovir. • Immunocompetent patients: 250 mg BD Famciclovir is indicated for the treatment for up to one year. of acute herpes zoster (shingles), treatment • In HIV-infected patients: Famciclovir is or suppression of recurrent genital herpes to be given 500 mg BD orally. in immunocompetent patients, treatment VALACYCLOVIR of recurrent mucocutaneous herpes It is the L-valyl ester of acyclovir and simplex infections in HIV-infected patients. rapidly converted into acyclovir after oral Adverse reactions are headache, admnistration. Its mechanism of action and paresthesia, migraine, nausea, diarrhoea, pharmacokinetics are similar to acyclovir. vomiting, flatulence, abdominal pain, In genital herpes dose required is 1 g BD fatigue, pruritus, rash and dysmenorrhoea. for 10 days and on recurrence 500 mg BD 340 Section 9/ Chemotherapy for 5 days. For herpes zoster infection 1 g TDS HIV infected patients. However, it does not for 7 days is required. Dose of 2 g QID has protect individuals from contracting HIV also been used in preventing cytomegalovirus infection even if started soon after (CMV) disease after organ transplantation. inoculation. Thus, it can not be used as a prophylactic in health care workers who GANCICLOVIR are accidently exposed to HIV infection. It is an acyclic guanosine analog which require triphosphorylation for activation LAMIVUDINE prior to inhibition of viral DNA polymerase. It is synthetic nucleoside analogue It is active against cytomegalovirus (CMV), active against HIV. It is phosphorylated to varicellazoster virus, Epstein-Barr virus and its active 5’-triphosphate metabolite (L-TP). human herpes virus-8. It is almost 100 times Lamivudine triphosphate inhibit HIV more potent than acyclovir against CMV. reverse transcription via viral DNA chain Its use is restricted in severe CMV termination. infections in immunocompromised especially It is rapidly absorbed after oral CMV retinitis, CMV pneumonia or colitis. administration. The major part of the dose is excreted in unchanged form in urine. ANTI-RETROVIRAL AGENTS Adverse effects include pancreatitis with symptoms of nausea, vomiting, severe ZIDOVUDINE abdominal or stomach pain and is more It is a thymidine analogue. After frequent in children. Paresthesia and phosphorylation in body zidovudine peripheral neuropathy with tingling, triphosphate selectively inhibits viral burning, numbness or pain in the hands reverse transcriptase i.e. RNA dependent and feet are also more frequent in children. DNA polymerase. It is effective against Lamivudine may be used prophylactically retrovirus only. in health care workers at risk of acquiring HIV It has rapid oral absorption and 65% infection after occupational exposure to the bioavailability. It can cross the placenta. It virus and in combination with zidovudine for is eliminated primarily by renal excretion treatment of HIV infection. following glucuronidation in the liver. It is to be given in a dose of 150 mg BD Adverse effects include anorexia, nau- in combination with zidovudine (in sea, headache, abdominal pain, myalgia, children 4 mg/kg BD, max 150 mg BD). anaemia insomnia, neutropenia, convul- sions and encephalopathy. STAVUDINE It is used in asymptomatic and It is synthetic thymidine nucleoside symptomatic HIV disease in a dose range analogue, active against HIV. of 200 mg six times a day on initial basis Stavudine rapidly enters cells by diffu- and thereafter upto 500 to 1500 mg daily sion. Stavudine triphosphate acts as a com- in four to five divided doses. petitive inhibitor of reverse transcriptase It decreases the rate of clinical with respect to deoxythmidine triphos- progression and prolongs the survival in phate and incorporation causes termina- Antiviral Agents 341 tion of DNA chain elongation. It inhibits life (40-55 hrs) and administered once daily. replication of HIV in human cells. It is metabolised by CYP3A4 and CYP2B6 It is rapidly absorbed after oral to inactive hydroxylated metabolites and administration. Approximately 40 percent of eliminated in feces. It is used in stavudine appears unchanged in the urine combination with other retroviral drugs for through tubular secretion and glomerular the treatment of HIV infection in a dose of filtration. Nonrenal clearance mechanisms 600 mg once daily. account for about 50 percent of elimination of Adverse effects include drowsiness, a dose. insomnia, dizziness, agitation, confusion, Adverse effects include peripheral depression, delusions, vomiting, diarrhoea, neuropathy which is a major clinical tox- crystalluria, elevation in liver enzyme and icity. Other side effects include pancreati- total serum cholesterol. Serious side effect tis, anaemia, arthralgia, headache, fever, is skin rash including Stevens Johnson rash, nausea, vomiting, diarrhoea, elevated syndrome as in case of nevirapine. transaminase values. INDINAVIR It is indicated in the treatment of advanced HIV infection in a dose range 30 It is an inhibitor of the enzyme HIV to 40 mg BD. protease which is required for the pro- teolytic cleavage of the viral polyprotein NEVIRAPINE precursors into the individual functional It is non-nucleotide reverse proteins found in infectious HIV. transcriptase inhibitor extensively Indinavir binds to the protease active metabolized by the CYP3A P450 isoform to site and inhibits the activity of the hydroxylated metabolites and excreted in enzyme HIV protease preventing urine. It is indicated in combination with cleavage of the viral polyproteins resulting other anti-retroviral agents in a dose of 200 in the formation of immature noninfectious mg OD-BD for first 14 days. It is also been shown to be effective in the prevention of viral particles. transmission of HIV from mother to new Adverse effects include nausea, born. vomiting, diarrhoea, abdominal discomfort, The serious side effect is life threaten- dry mouth, taste disturbances; headache, ing rash including Stevens Johnson syn- dizziness, insomnia; myalgia, rash, pruritus, drome and rarely toxic epidermal dry skin, hyperpigmentation, nephrolithiasis, necrolysis. Other side effects are hepatitis, dysuria, haematuria, crystalluria, proteinuria; nausea, vomiting, fatigue, fever, headache, elevated liver enzymes and bilirubin, hypersensitivity reactions, urticaria, an- hepatitis; neutropenia, haemolytic anaemia gioedema and anaphylactic shock. and hyperglycaemia etc. It is indicated in treatment of HIV EFAVIRENZ infection and is used in combination with It is also an non-nucleotide reverse other anti-retroviral agents in a dose 800 transcriptase inhibitor having long half- mg every eight hourly. 342 Section 9/ Chemotherapy

RITONAVIR It is active against influenza A and B, It is inhibitor of HIV-1 and 2 proteases. measles, paramyxoviruses, respiratory The common adverse effects include GIT syncytial virus, HCV and HIV-1 in a dose disturbances, hypertriglyceridemia and of 200 mg four times per day. elevation of serum aminotransferase. INTERFERONS ANTI-INFLEUNZA VIRUS AGENTS Interferons are cellular AMANTADINE AND ITS DERIVATIVES produced by the host cells which exert It exerts its action by inhibiting the complex antiviral, immunoregulatory and replication of influenza virus, by antiproliferative activities. After binding to inhibiting uncoating of viral RNA of interferon receptors it acts through cellular influenza A within infected host cells. It is metabolic processes which involves used in a dose of 200 mg/day in prevention synthesis of viral RNA and proteins. of influenza A virus infection. Interferon receptors are tyrosine protein After oral administration, it is excreted kinase receptors which on activation unchanged in urine. phosphorylate cellular proteins. These then Adverse effects include confusion, induce transcription of ‘interferon induced insomnia, anxiety, hallucinations, skin rash proteins’ which exert antiviral effects. and retention of urine. There are three type of interferons – alpha, It is used in prophylaxis of influenza A beta and gamma. virus, idiopathic parkinsonism and drug- Interferons are indicated in chronic induced extrapyramidal reactions. hepatitis B and C in a dose of 10 MU Rimanditine is a more potent and injection three times a week for six months. longer acting congener of amantadine. Alpha interferon is also effective in the RIBAVIRIN treatment of hairy cell leukaemia, condy- It is a guanosine analog which loma acuminata (caused by papilloma vi- probably interferes with the synthesis of rus), chronic myelogenous leukaemia and guanosine triphosphate, inhibiting AIDS related Kaposi’s sarcoma. capping of viral mRNA and to inhibit the viral RNA-dependent RNA polymerase. Interferons are not effective orally and is used only by IM or SC injection. Orally absorbed and bioavailability is about 50%. It is partly metabolized and Adverse effects include fever, leucopenia, eliminated in a multiexponential manner. thrombocytopenia, alopecia, neurotoxicity Adverse reactions include anaemia, and elevated aminotransferase levels. Other gastrointestinal disturbances, headache less common side effects include hypotension, and haemolysis. cardiomyopathy and hyperglycaemia.

 ChapterChapter PharmacodynamicsPharmacodynamicsAntifungal Agents 9.71. 4 (Mode of Action of Drugs)

Antifungal agents are used in the treatment Histoplasma capsulatum, Cryptococcus of topical and systemic fungal infection. neoformans, Candida albicans, Sporotrichum They can be classified as systemic or topical schenkii, Blastomyces brasiliensis, Coccidioides antifungal agents and some are used both immitis, Rhodotorula, Aspergillus etc. It is systemically as well as topically in the form fungicidal at high and fungistatic at low of powder, ointment and vaginal tablets etc. concentration. They are classified as in table 9.7.1. It is poorly absorbed from GIT and topically. After IV administration it is widely ANTIFUNGAL ANTIBIOTICS distributed in tissues. About 60% drug is metabolized in liver and excretion occurs AMPHOTERICIN B slowly both in urine and bile. It is an antifungal antibiotic obtained from Adverse effects include nausea, Streptomyces nodosus and chemically it is an vomiting, headache, fever, breathlessness, amphoteric polyene macrolide. It has a highly anaemia, thrombophlebitis on IV double bonded structure. The cell membrane administration. On long term use, dose sterol ‘ergosterol’ is found in the cell related nephrotoxicity and anaemia occurs. membrane of fungi and the predominant It is used orally for intestinal sterol of bacteria and human cell is cholesterol. candidiasis, topically for oral, vaginal and This antifungal antibiotic binds to ergosterol cutaneous candidiasis and hospital which alters the permeability of the cells by treatment of progressive and potentially forming amphotericin-B associated pores in fatal systemic fungal infections. It is the cell membrane, which allows the leakage gold standard of antifungal therapy. of intracellular ions and macromolecules Flucytosine has supraadditive action with which can lead to cell death. amphotericin B if the fungi is sensitive to Amphotericin B has a wide spectrum both. It is also potentiated by rifampicin of antifungal activity. It is active against and minocycline. 344 Section 9/ Chemotherapy

Table 9.7.1: Classification of antifungal agents. I. Antifungal antibiotics Amphotericin-B (FUNGIZONE) 50-100 mg QID, 200 µg to 1.5 mg/kg daily or on alternate days IV infusion, 3% topical (ear drops) Nystatin (MYCOSTATIN) 5 lac U orally TDS, 1 lac U topical (ointment vaginal tablet) Griseofulvin (DERMONORM) 0.5-1.0 g/day Pimaricin Topical (2% cream, 25 mg vaginal tablet, 5% ophthalmic ointment) Hamycin 2-5 lac U (suspension & topically as vaginal tablet and ointment) II. Antimetabolite Flucytosine (ALCOBON) 100-150 mg/kg/day III. Imidazoles & triazoles Clotrimazole (CLOTRIN) 100 mg vaginal tablet, 1% topical (lotion, cream and powder) Ketoconazole (NIZRAL) 200 mg OD-BD orally, topical 2% ointment and shampoo (DAKTARIN) 3-15 mg/kg with glucose & saline IV infusion, 1-2% topical (powder, lotion, vaginal gel, ointment & vaginal ovules) Econazole 150 mg vaginal tablet, 1% topical (cream & ointment) Itraconazole (CANDITRAL) 100-200 mg/day (the number of days depend upon the type of infection) Fluconazole (FLUZON) 400 mg on 1st day, then 200-400 mg OD, for 28 days, Also used with (AZOSTAT) Terbinafine (LAMISIL) 250 mg OD for 6-12 wks. IV. Miscellaneous agents (used topically) Tolnaftate (TINADERM) 1% solution cream Selenium sulfide (SELSUN) Shampoo Cyclopirox olamine 1% solution, skin cream & vaginal cream Benzoic acid 3-5% skin ointment Sodium thiosulfate 20% solution Quiniodochlor 3-8% skin cream

NYSTATIN monilial vaginitis, conjunctival, cutaneous It is obtained from Streptomyces noursei. and corneal candidiasis. It has similar antifungal action as GRISEOFULVIN amphotericin but is highly toxic and used topically only. It is effective against Candida, It is isolated from Penicillium griseofulvium. Histoplasma, Trichophyton, Blastomyces, It is active against Epidermophyton, Trichophy- Microsporum audouini etc. It is indicated in ton and Microsporum causing superficial in- Candida albicans especially oral moniliasis, fection or dermatophytosis. Antifungal Agents 345

It is not effective against fungi causing ANTIMETABOLITES deep/systemic infection. It interferes with mitosis and also FLUCYTOSINE causes abnormal metaphase configura- It is a synthetic fluorinated pyrimidine tions . Griseofulvin gets deposited in kera- anti-metabolite which acts by its conversion tin and persists for weeks. As it is fungi- to anti-metabolite 5-fluorouracil which static the newly formed keratin is not in- inhibit DNA synthesis. vaded by the fungus but fungus persists in It is effective against Cryptococcus already infected keratin, till it is shed off. neoformans and some Candida strains and Oral absorption is irregular. It is largely dermatiaceous moulds which cause metabolised by methylation and excreted chromoblastomycosis. in urine. It is ineffective topically. Adverse effects include anaemia, Adverse effects include nausea, epigas- leukopenia, thrombocytopenia, diarrhoea, tric distress, vomiting, headache, peripheral GIT disturbances and liver dysfunction. neuritis, skin rash, photosensitivity, drowsi- It is mainly used as an adjuvant drug ness and transient leucopenia. It can cause to amphotericin. disulfiram like reaction.

It is indicated in fungal infections of IMIDAZOLES & TRIAZOLES skin, scalp and nails, tinea of hand and beard and athlete’s foot. CLOTRIMAZOLE PIMARICIN Clotrimazole, is an imidazole derivative and has a broad antimycotic spectrum of It is obtained from Streptomyces notalensis action in vivo, which includes dermato- and it is found effective against Trichophyton phytes, yeasts, moulds etc. violaceum, Trichomonas vaginalis and Clotrimazole acts against fungi by in- Aspergillus fumigatus. It is used as eye ointment hibiting ergosterol synthesis. Inhibition in keratitis due to Fusarium and Cephalosporium of ergosterol synthesis leads to structural and as an inhalation in bronchopulmonary and functional impairment of the cytoplas- aspergillosis and candidiasis. mic membrane. HAMYCIN In addition, it also acts on Trichomonas vaginalis, gram positive microorganisms It is obtained from Streptomyces pimprina (streptococci/staphylococci) and gram and effective against blastomycosis, negative microorganisms (Bacteroides/ cryptococcosis, vaginal and cutaneous Gardnerella vaginalis). candidiasis, Trichomonas vaginitis and It is useful as topical application. It is Aspergillus otomycosis. indicated in infections of the genital region Adverse effects include diarrhoea, (vaginitis) caused by fungi (mostly Candida) eosinophilia, nephrotoxicity and rise in and superinfections caused by clotrimazole SGOT levels after oral administration in the sensitive bacteria; infectious leucorrhoea treatment of blastomycosis in man. caused by yeast fungi. 346 Section 9/ Chemotherapy

It is well tolerated but some patients of superficial and deep seated fungal reported skin reactions including burning, infections. stinging or redness. It impairs the synthesis of ergosterol KETOCONAZOLE in fungi. It is orally effective broad spectrum After oral administration, it is widely imidazole antifungal drug. It is useful in both distributed in the body. CSF and saliva dermatophytosis and deep mycosis. Oral contain negligible amounts of the drug. It absorption is facilitated by gastric acidity. It is is extensively metabolised in liver and the highly protein bound, metabolised in liver and metabolites are excreted in urine. metabolites are excreted in urine and faeces. It is indicated in dermatophytoses, tinea Its spectrum is similar to that of miconazole versicolor, onychomycoses, oropharyngeal and is more active against Coccidioides. candidiasis, cutaneous candidiasis, chronic Adverse effects include gastric mucocutaneous candidiasis, oculomycoses; irritation, nausea, vomiting, headache, systemic mycoses like cryptococcosis, candidi- paresthesia, rash, hair loss, allergic reaction asis and aspergillosis; subcutaneous mycoses and gynecomastia. like sporotrichosis and chromomycosis. MICONAZOLE Adverse effects include nausea, vomiting, skin rash, depression, dizziness, It has broad spectrum antifungal and vertigo and loss of libido, hypokalemia and antibacterial activity and is effective against hypertriglyceridemia. Cryptococcus, Blastomyces, dermatophytes, Microsporum, Coccidioides and Candida. FLUCONAZOLE Used topically as ointment, lotion, gel, ear It has broad range of antifungal drop and vaginal gel. Adverse effects activity. It is well absorbed orally (94%). It include fever, chills, allergic reaction and is primarily excreted unchanged in urine. even anaphylaxis. Fungicidal concentration is achieved in It is indicated in vulvovaginal nail, saliva and vagina and also penetrates candidiasis, Trichomonas vaginitis, brain. Adverse effects include nausea, otomycosis, tinea and Pityriasis versicolor. vomiting, headache, abdominal pain, ECONAZOLE and skin rash. It is similar to clotrimazole and is It is indicated in mucosal candidiasis, effective in dermatophytosis, otomycosis systemic candidiasis, crypttococcosis, and oral thrush. It causes local irritation. prophylaxis of fungal infections following cytotoxic chemotherapy or radiotherapy; ITRACONAZOLE maintenance to prevent relapse of It is a triazole antifungal drug closely cryptococcal meningitis in patients with related to ketoconazole and is meant for AIDS; sporotrichosis, histoplasmosis and oral use. It is very effective in a wide range vaginal candidiasis. Antifungal Agents 347

TERBINAFINE and cream used topically. Not useful in It is a synthetic allylamine derivative, candidiasis and other types of superficial which exerts its antifungal effect by inhib- mycoses. Adverse reaction includes local iting squalene epoxidase leading to de- irritation. ficiency of ergosterol and corresponding Selenium sulfide is used as shampoo accumulation of squalene which causes and used in the treatment of scalp fungal fungal cell death. infection. It is well absorbed from the GI tract, Cyclopirox olamine is used in the treat- widely distributed in body. It is strongly ment of tinea infections, dermal and vaginal plasma protein bound. It is metabolised in the liver to inactive metabolites which are candidiasis. excreted in the urine. Benzoic acid has got antifungal and Adverse effects are irritation, burning, anti-bacterial activity and used in itching and dryness on topical application. combination with salicylic acid (Whitfield’s Oral intake causes gastric upset, rash, taste ointment). Salicylic acid by its keratolytic disturbance and hepatic dysfunction. action helps to remove the infected tissue Terbinafine is used in the treatment of and promotes the penetration of benzoic dermatophytoses especially onchomycosis acid into the lesion. by oral therapy. Also useful in tinea and Sodium thiosulfate is effective against pityriasis versicolor. Malassezia furfur. Quiniodochlor is found effective MISCELLANEOUS AGENTS against dermatophytosis, infected eczema Tolnaftate is effective in tinea cruris and and seborrhoeic dermatitis. Orally it is used tinea corporis. Used in the form of solution as luminal amoebicide.

 This page intentionally left blank ChapterChapter Pharmacodynamics PharmacodynamicsPharmacodynamicsAntimalarial Agents 9.81.4 (Mode of Action of Drugs)

Human malaria is caused by four species has antiinflammatory and local irritant of Plasmodium namely Plasmodium properties. falciparum, P. vivax, P. malariae and P. ovale. It probably influences haemoglobin P. vivax is mainly responsible for most of degradation by parasitic lysosomes by the infections (70%) which results in raising intravesicular pH in malarial benign tertian malaria. In P. falciparum parasite cells. It also interferes with and P. vivax infections, the patient has fever synthesis of nucleoproteins by the parasite. with rigors every third day and termed as It is well absorbed (about 90%) from tertian. The other two, P. ovale and P. gastrointestinal tract. After IM injection malariae are mild in nature in which fever absorption is rapid. Elimination is very slow develops every fourth day and termed as and it may persist in tissue for months or benign quartan. Symptoms and years after discontinuation of therapy complications in P. falciparum malaria are Adverse reactions include nausea, more severe than P. vivax malaria. vomiting, epigastric distress, headache, anorexia, difficulty in accommodation and The antimalarial drugs can be classified chronic therapy may cause loss of vision as in table 9.8.1. due to retinal damage. On prolonged use it may also cause skin rash, photoallergy, 4-AMINOQUINOLINE DERIVATIVES myopathy, loss of hearing, greying of hair and mental disturbances. CHLOROQUINE Parenteral administration may cause Chloroquine is a 4-aminoquinoline hypotension, arrhythmia and CNS toxicity. antimalarial agent used for the suppression and clinical cure of malaria. It is an Therapeutic Uses excellent erythrocytic schizontocide. It It is a drug of choice for clinical cure does not prevent relapse in P. vivax and P. and suppressive prophylaxis of acute ma- ovale malaria. It has no effect on pre and laria but not for the resistant cases of P. exoerythrocytic phase of the parasite. It also falciparum. It can be safely used in preg- 350 Section 9/ Chemotherapy

Table 9.8.1: Classification of antimalarial drugs. I. 4-aminoquinoline derivative Chloroquine (LARIAGO) Initially 600 mg, after 6 hr 300 mg followed by 300 mg daily for 3 days, 200-400 mg IM 6 hourly Amodiaquine (CAMOQUIN) 25-35 mg/kg for 3 days II. 8-aminoquinolines Primaquine (MALIRID) 15 mg daily for 14 days III. -methanol derivatives Mefloquine (MEFLOC) 15 mg/kg single dose (for treatment, maximum 1 g); 5 mg/kg, up to 250 mg per wk (for prophylaxis in areas with multidrug resistance) Bulaquine (AABLAQUIN) 125 mg (used with chloroquine 500 mg) IV. Acridine derivative (MALADIN) 900 mg 1st day, 600 mg on 2nd & 3rd day, 300 mg on 4th, 5th and 6th day in divided doses; 600 mg/wk for prophylaxis V. Cinchona alkaloids Quinine (as sulphate) 600 mg/day, oral TDS or 10 mg/kg with 5% glucose IV infusion TDS (for cerebral malaria) for 7 days VI. Biguanides Proguanil (Chloroguanide; LAVERAN) 100 mg daily during exposure and continued for 6 weeks after exposure VII. Diaminopyrimidine & Sulfonamides Pyrimethamine (DARAPRIM) 25 mg (for prophylaxis) Pyrimethamine 25 mg + sulfadoxine Once a week 3 tablets single dose 500 mg (MALARPRIM) Pyrimethamine 25 mg + sulfamethopyrazine 3 tablets single dose 500 mg (METAKELFIN) VIII. Artemisinin derivatives Artesunate (FALCIGO) 100 mg BD on 1st day, followed by 50 mg BD for next four days (for cerebral malaria, chloroquine- resistant malaria & P. falciparum malaria). Artether (EMAL) 150 mg daily for 3 days IM Artemether (LARITHER) 160 mg BD on first day and 80 mg OD for next four days orally; 80 mg BD IM on first day and 80 mg OD IM for next four days IM nancy. Apart from malaria, chloroquine in • Lepra reactions. also used in: • Hepatic amoebic abscess (used along • Rheumatoid arthritis. with metronidazole). • Giardiasis. AMODIAQUINE • Discoid lupus erythematosus. Another 4-aminoquinoline and pos- • Infectious mononucleosis. sesses antimalarial activity similar to that • Taeniasis. of chloroquine. It is useful in uncompli- Antimalarial Agents 351 cated falciparum malaria but is not recom- It is absorbed after oral administration mended for prophylaxis. and presence of food may enhance the absorption. It is extensively metabolised in 8-AMINOQUINOLINES liver and primarily secreted in bile. Adverse reactions include nausea, PRIMAQUINE vomiting, dizziness, diarrhoea, abdominal Primaquine, a 8-aminoquinoline, is a pain, anxiety disorder, sinus bradycardia, poor erythrocytic schizontocide. It is ataxia. It is reported that mefloquine is highly effective against gametocytes and teratogenic in nature so should not be given exoerythrocytic stages. in first trimester of pregnancy. It disrupts the parasites mitochondria It is used in multiresistant P. falciparum and binds to native DNA, resulting in malaria. It is not useful in complicated/ inhibition of gametocytes and exoeryth- cerebral malaria. rocytic forms. BULAQUINE Adverse effects include nausea, vom- Bulaquine is a mixture of 3{-1-4-6(- iting, weakness, abdominal pain and methoxy-8-quinolinyl) aminopentyl} methaemoglobinaemia. Haemolytic ethylidenedihydro-2-(3H) furanone and it’s anaemia in patients with G-6-PD defi- tautomers. ciency. Passage of dark urine is indica- tion of haemolysis. In larger dose it can The exact action is not fully eluci- cause leucopenia. dated. However, bulaquine inhibits protein synthesis in protozoa and It is effective in radical cure of P. vivax indirectly inhibits polymerisation of and P. ovale malaria. amino acids by the plasmodia. Treat- ment prevents emergence of either QUINOLINE-METHANOL DERIVATIVES primary or secondary liver stage para- sitaemia and the disease. MEFLOQUINE Since bulaquine is a tissue schizonto- It is a highly effective erythrocytic cide it is effective against the dormant schizonticide especially against mature hepatic stages of P. vivax only. It has to be trophozoite and schizont forms of malarial combined with chloroquine which acts on parasite. the erythrocytic stage of the plasmodium. It behaves like quinine in many ways For convenience bulaquine is available but does not inhibit haem polymerase. It along with chloroquine as an anti-relapse probably acts by forming toxic complexes treatment pack. with free haem that damages membranes It is an erythrocytic schizontocide used and interacts with other plasmodial in the treatment and prevention of P. vivax components. malaria relapse. 352 Section 9/ Chemotherapy

Adverse effects ACRIDINE DERIVATIVE include nausea, vomiting, epigastric discomfort, skin rash, MEPACRINE itching, hypotension, haemolysis, blurred vision, vertigo, tinnitus and cinchonism. It is an erythrocytic schizontocide It is used in the treatment of cerebral related to its ready intercalation into DNA. falciparum malaria and multidrug resistant Readily absorbed from the GI tract even strains of cerebral malaria. It is also used in the presence of severe diarrhoea. It is along with clindamycin in the treatment widely distributed in the tissues and is of babesiosis. It is also effective in myotonia eliminated very slowly. congenita and nocturnal muscle cramps. Adverse effects include urticaria, exfoliative dermatitis, GI disturbances, BIGUANIDES dizziness and yellow discoloration of the skin on prolonged use. PROGUANIL It is indicated in drug resistant P. It is an effective erythrocytic falciparum malaria and in the treatment of schizontocide against P. falciparum and P. giardiasis. vivax but slower acting than chloroquine. The active triazine metabolite, inhibits CINCHONA ALKALOIDS plasmodial dihydrofolate reductase and thus disrupts the synthesis of nucleic QUININE acids in the parasite. Quinine is a natural alkaloid obtained It is slowly but adequately absorbed from cinchona bark. from the GI tract. It is metabolised in the It is erythrocytic schizontocide and is liver to the active metabolite cycloguanil. effective against all species of plasmodia. Adverse effects include gastrointesti- It has no effect on preerythrocytic stage and nal disturbances, nausea, vomiting, diar- on hypnozoites of relapsing malaria. It kills rhoea, abdominal pain and haematuria. the gametes of P. vivax. It is mainly used in prophylaxis of It also has anaesthetic, local irritant malaria in combination with chloroquine action. Quinine causes hypotension, in areas with low chloroquine resistance cardiac depression (IV injection), stimulates among P. falciparum. It can be safely used myometrium and rapid IV injection causes in pregnancy. hypoglycaemia. It is highly concentrated in the acidic DIAMINOPYRIMIDINE & SULFONAMIDES food vacuoles of the parasite where it inhibits haem polymerase leading to the PYRIMETHAMINE accumulation of haem which is cytotoxic. It is an inhibitor of plasmodial Antimalarial Agents 353 dihydrofolate reductase. It is slow acting isolated from plant Artemisia annua, active erythrocytic schizontocide. It can eliminate against P. falciparum resistant strains. preerythrocytic phase of P. falciparum and the secondary tissue phase of P. vivax. ARTESUNATE Absorption of pyrimethamine from GIT is It is a new, potent antimalarial drug slow but good. It is concentrated in liver, and is a water soluble synthetic analogue spleen, kidney and lungs. It is metabolised of artemisinin. and excreted in urine. If it is employed alone It is concentrated in parasitized development of resistance occurs fast. Pyrimethamine alone is used for prophylaxis erythrocytes, where it is activated by occasionally. parasite haem, generating free radicals. Hence it causes increase in oxidant PYRIMETHAMINE-SULFONAMIDE stress on the infected red cells pro- COMBINATION moting cytotoxicity and death of para- Ultra long acting sulfonamides in sites. It rapidly clears parasitaemia, combination with pyrimethamine are used. faster than any other antimalarial drug. The effect is supraadditive due to sequential After administration it is rapidly block. It may be employed as a clinical absorbed and distributed in tissue e.g. liver, curative. Another advantage of the drug intestine and kidneys. It is metabolised in combination is that the development of liver and converted to active metabolite resistance is retarded. dihydroartemisinin. Its action is based on differential Adverse effects include nausea, vom- requirement between host and parasite for iting, dizziness, anorexia, gastrointestinal nucleic acid precursors involved in growth disturbances and convulsions. as it selectively inhibits plasmodial dihydrofolate reductase. It is indicated in acute attack of multi- drug resistant P. falciparum malaria where It is very well absorbed after oral use quinine is not effective. and is metabolised in the liver. Pyrimethamine is a safe drug and cause ARTETHER only nausea, vomiting, skin reaction e.g. skin It is an ethyl ether derivative of rash, pruritus and higher dose can cause dihydroartemisinin in sterile arachis oil. megaloblastic anaemia and granulocytopenia. A racemic mixture of a, β-artether The combination is indicated in chloro- (30:70 ratio) has greater solubility and quine resistant malaria and prophylaxis. Py- stability than artemisinin and is more rimethamine-sulfadiazine combination is cost-effective. used for treatment of toxoplasmosis. It shows rapid schizonticidal action and brings about quick clinical improvement in ARTEMISININ DERIVATIVES falciparum malaria with low recrudescence Artemisinin is the active plant principle rate. It has some gametocidal action too. 354 Section 9/ Chemotherapy

It is used in the treatment of chloroquine cerebral and falciparum malaria. It is a resistant malaria and cerebral malaria. effective drug against all strains resistant to other antimalarial agents. ARTEMETHER It is a schizonticidal drug and leads to It is derivative of artemisinin. These destruction of asexual erythrocytic forms agents produce a more rapid clearance of P. falciparum and P. vivax. There is of parasites than quinine, chloroquine inhibition of protein synthesis during and mefloquine in treatment of severe growth of trophozoites.

 Antiamoebic and ChapterChapter Pharmacodynamics PharmacodynamicsPharmacodynamicsother Antiprotozoal (Mode of Action of Drugs) 9.91. 4 Drugs

After oral administration it is rapidly AMOEBIASIS and completely absorbed. It penetrates well Amoebiasis is an infectious disease caused into body tissues and fluids. It is by Entamoeba histolytica. It can cause metabolised in liver by oxidation and asymptomatic intestinal infection, colitis glucuronide conjugation and is excreted in (mild to moderate), dysentery (severe urine. intestinal infection), ameboma, liver abscess Adverse effects include nausea, etc. The drugs used in chemotherapy of metallic taste, headache, dry mouth, amoebiasis are classified as in table 9.9.1. abdominal distress, vomiting, diarrhoea, glossitis, stomatitis, vertigo, dizziness, METRONIDAZOLE ataxia, thrombophlebitis and very rarely It is a . It has a broad convulsions. It shows disulfiram like effect. spectrum of protozoal and antimicrobial It is drug of choice for all forms of activity. It shows antibacterial action amoebic infections used in trichomonas against all anaerobic cocci, anaerobic gram vaginitis, anaerobic postoperative negative bacilli including bacteroides infections, giardiasis, acute ulcerative gin- species and anaerobic spore forming gram givitis, H. pylori infection, pseudomem- positive bacilli. It is very effective in branous enterocolitis and anaerobic vaginosis. infections due to Entamoeba histolytica, Giardia lamblia and Trichomoniasis. It also TINIDAZOLE causes radio-sensitization. It is similar to metronidazole and has In shows selective toxicity to anaerobic long plasma half life and given once daily. microorganisms, where it is converted to It is well absorbed after oral active form by reduction of its nitro group administration and penetrates well into the and this gets bound to DNA and prevent body tissues and fluids. Incidence of side nucleic acid formation. effects in lower. 356 Section 9/ Chemotherapy

Table 9.9.1: Classification of drugs used in amoebiasis. I. Imidazole derivatives Metronidazole (FLAGYL) Amoebiasis 400-800 mg TDS for 5-10 days; 7.5-15 mg/kg IV infusion BD-QID Trichomonas vaginitis 400 mg TDS × 7 days Giardiasis 200 mg TDS × 3 days Tinidazole (TINIBA) Amoebiasis 2 g OD × 3 days Trichomoniasis and giardiasis 2 g OD (SECNIL) 2 g single dose (DAZOLIC) 500 mg BD × 5-7 days II. Quinoline derivative Iodochlorohydroxyquin (ENTEROQUINOL) 250-500 mg TDS Diiodohydroxyquin (DIODOQUIN) 650 mg TDS Chloroquine 600 mg × 2 days then 300 mg OD × 2-3 wks III. Emetine derivatives (TILEMETIN) 10-20 mg TDS × 6-10 days Emetine, emetine bismuth iodide IV. Miscellaneous furoate (FURAMIDE) 500 mg TDS × 5-10 days Furazolidone (FUROXONE) 100 mg TDS-QID × 5-7 days 500 mg TDS × 5 days Tetracycline 250 mg QID

Side effects include nausea, epigastric having longer plasma half life and discomfort, metallic taste, furred tongue, administered orally as single dose. It is used skin rash, urticaria and leucopenia. in intestinal amoebiasis, hepatic amoebiasis, It is indicated in giardiasis, amoebic liver giardiasis and trichomonal vaginitis. abscess, intestinal amoebiasis, trichomoniasis, Side effects include nausea, anorexia, ulcerative gingivitis, treatment and epigastric pain, diarrhoea, skin rash, prophylaxis of anaerobic infections. urticaria, headache and leucopenia. It is also used in combination with diloxanide furoate and dicyclomine to ORNIDAZOLE eradicate intestinal and extraintestinal It is a 5-nitroimidazole derivative with amoebiasis and also asymptomatic cyst the same antimicrobial profile as that of passers. metronidazole, except that it has a much SECNIDAZOLE longer half-life. It is 5-nitroimidazole derivative with Readily absorbed from the GI tract, properties similar to metronidazole and widely distributed in body tissues and fluids Antiamoebic and other Antiprotozoal Drugs 357 including the CSF and metabolised in the liver, it is used in the treatment of hepatic liver. It is excreted mainly in the urine as amoebiasis concurrently or immediately conjugates and to a lesser extent in faeces. after metronidazole for complete cure. It is Adverse effects include nausea, skin not effective in amoebic dysentery and in rash, abdominal pain and headache. cyst passers. It is indicated in giardiasis, severe EMETINE DERIVATIVES hepatic and intestinal amoebiasis, Emetine and dehydroemetine are trichomoniasis of urogenital tract and natural alkaloid obtained from Cephaelis bacterial vaginosis. ipecacuanha and synthetic analog respective- ly. They are effective against tissue tropho- 8-HYDROXYQUINOLINES zoites of E. histolytica. It has no effect on cysts , iodochloro- but effective in amoebic liver abscess also. It hydroxyquin are effective against E. acts by inhibiting protein synthesis by histolytica, Trichomonas and Giardia. arresting intraribosome translocation of Diiodohydroxyquinoline is directly tRNA-amino acid complex. Dehydroemet- ine is less toxic than emetine and very effec- amoebicidal. It has activity against motile tive drug for tissue amoebiasis. It is more rap- and cystic forms. It kills cyst forming idly eliminated from the body than trophozoites in intestine but has no tissue emetine. amoebicidal action. It is ineffective in extraintestinal amoebiasis. It is also effective Adverse effects include nausea, vomiting, diarrhoea, myalgias and because in cyst passing patients. of its serious side effects including cardiac Diiodohydroxyquinoline is partly and arrhythmia, CHF and hypotension, they irregularly absorbed from the GI tract. have been almost completely replaced by Metabolised in liver and excreted in urine metronidazole. as glucuronide and sulfate conjugates. Adverse effects include nausea, diar- DILOXANIDE FUROATE rhoea, abdominal discomfort, headache It is a dichloroacetamide derivative, and goitre (so contraindicated in patients very effective luminal amoebicide. Used with intolerance to iodine). Prolonged use alone for cyst passers or usually with of iodochlorohydroxyquin causes subacute metronidazole for other forms of amoebic myelooptic neuropathy (SMON). They are infections. indicated in giardiasis, trichomonas It directly kills trophozoites. It has no vaginitis, intestinal amoebiasis and amoe- antibacterial activity. bic colitis. After oral administration it is rapidly absorbed and excreted rapidly in urine as CHLOROQUINE glucuronide conjugate. It kills trophozoites of E. histolytica and Adverse effects include flatulence, because of its selective concentration in nausea, vomiting, anorexia and pruritus. 358 Section 9/ Chemotherapy

It is mainly indicated in mild intestinal PENTAMIDINE amoebiasis and asymptomatic cyst passers. Pentamidine is an aromatic diamidine It is also used in combination with formulated as an isoethionate salt used tinidazole (TINIBA DF) and metronidazole parenterally (4 mg/kg IM or slow IV injec- (ENTAMIZOLE) in the treatment of tion). It has activity against trypanosomatid intestinal amoebiasis, hepatic amoebiasis protozoans and against Pneumocystis and other systemic diseases due to E. carinii. It probably interacts with kineto- histolytica. plast DNA and inhibits topoisomerase II. It is used in the treatment of pneumocys- FURAZOLIDONE tosis (pulmonary and extrapulmonary It is effective against gram negative disease caused by P. carinii), African trypa- bacilli e.g. Shigella, Salmonella and also nosomiasis (disease caused by Trypanosoma effective against Trichomonas and Giardia. brucei) and leishmaniasis. Systemic pentami- It is indicated in bacterial enteritis, dine is highly toxic and can lead to severe diarrhoea, giardiasis and bacillary dysentery. hypotension, tachycardia, dyspnea, dizzi- Adverse effects include nausea, ness, hypoglycemia. Other adverse effects vomiting, headache and dizziness. are skin rash, metallic taste, gastrointestinal symptoms, thrombocytopenia and cardiac PAROMOMYCIN arrhythmias. It is an aminoglycoside antibiotic used SODIUM STIBOGLUCONATE only as luminal amoebicide and has no effect against extra intestinal amoebic It is pentavalent antimonial. It inhibits infections. It is less toxic than other agents, –SH dependent enzymes and block but it should be used cautiously in patients glycolytic & fatty acid oxidation with significant renal disease and with pathways. It is rapidly absorbed after IM gastrointestinal ulcer. injection and excreted unchanged in urine. Used in cutaneous and visceral LEISHMANIASIS leishmaniasis. It is given parenterally (20 mg/kg/day IM/IV) for three weeks in Visceral leishmaniasis (kalaazar) is caused cutaneous leishmaniasis and for four weeks by Leishmania donovani and transmitted by in visceral and mucocutaneous disease. Phlebotomus sandfly. In human being, it is Adverse effects include metallic taste found intracellularly within macrophages headache, fever, rash, myalgia and ECG in the nonflagellate form. The important changes. drugs used in leishmaniasis are pentamidine, sodium stibogluconate, anti- TRYPANOSOMIASIS fungal antibiotics (amphotericin B and ketoconazole) and antigout agent It is caused by genus Trypanosoma which (allopurinol). is characterized by skin eruptions, sus- Antiamoebic and other Antiprotozoal Drugs 359 tained fever, lethargy and lymphadenitis, disease and encephalopathy characterized progressive brain dysfunction. by cerebral edema, seizures, coma (even death). Apart from imidazole derivative e.g. metronidazole, tinidazole, etc. EFLORNITHINE and other agents such as hydroxyquinolines, It is an inhibitor of ornithine decarboxylase iodine preparation (povidoneiodine) and and is used as second line therapy for antifungal antibiotics e.g. clotrimazole (used advanced CNS African trypanosomiasis. mainly as vaginal pessaries), there are some After oral or IV administration, peak plasma other compounds which are mainly used in level is reached rapidly and elimination half the treatment of trypanosomiasis. They are: life is approximately three hours. 1 g each wk for 5 wks IV or 1 g on It is effective against advanced T. day 1, 3, 7, 14, 21 brucei gambiense infection. Melarsoprol 3.6 mg/kg/day IV for 3-4 days Adverse effects include vomiting, Eflornithine 100 mg/kg IV every 6 hrs for 14 diarrhoea, leukopenia, thrombocytopenia, days anaemia and seizures. Nifurtimox 8-10 mg/kg orally 3-4 months. SURAMIN NIFURTIMOX It is a sulfated napthylamine and used Chemically it is nitrofuran, used for American trypanosomiasis which is as first line therapy for early commonly known as ‘Chagas disease.’ hemolymphatic African trypanosomiasis After oral administration, it is well T. brucei gambiense (caused by ). It has very absorbed and plasma half life is about three tight protein binding and having short hours. initial half life but terminal half life is about Adverse effects 50 days and is excreted by kidney. It is also include nausea, vomiting, fever, rash, abdominal pain, used for chemoprophylaxis against African neuropathies and seizures. trypanosomiasis.

Adverse effects include nausea, TRICHOMONIASIS vomiting, fatigue, dermatitis, fever, photophobia, haemolytic anaemia, It is caused by Trichomonas vaginalis and is albuminuria and hematuria. mainly associated with vulvovaginitis which is characterized by greenish yellow MELARSOPROL and cheesy vaginal discharge. Chemically it is trivalent arsenical used The various agents used in trichomo- for advanced CNS African trypanosomiasis. niasis are metronidazole, tinidazole and It is administered IV in propylene glycol and secnidazole which are already described after administration it is rapidly excreted. It earlier. They produce 100% cure. is highly toxic and used only in advanced Other protozoal infection is giardiasis trypanosomiasis when no alternative is there. which is caused by Giardia lamblia and the Adverse effects include vomiting, drug of choice in its treatment are fever, abdominal pain, renal and cardiac imidazole derivatives.  This page intentionally left blank ChapterChapter AnthelminticPharmacodynamicsPharmacodynamics Agents 9.101. 4 (Mode of Action of Drugs)

Anthelmintic agents are used to eradicate Poorly absorbed from the GI tract, oral (either kill or expel) the infesting helminths. bioavailability being enhanced when given The important anthelmintic agents with a fatty meal (up to 5 fold). Its active along with their specific uses and dosage sulphoxide metabolite is widely distributed are listed in table 9.10.1. throughout the body and is excreted in urine. MEBENDAZOLE Adverse effects include nausea, It is a synthetic having vomiting, epigastric distress, abnormal a wide spectrum of anthelmintic activity. LFTs, reversible alopecia. After administration it is poorly absorbed and approximately 90 percent of the drug THIABENDAZOLE is passed in faeces. Complete clearance of Apart from anthelmintic property, thia- the parasites from the GIT may take up to bendazole also possesses antiinflammatory, three days. analgesic and antipyretic actions. It also in- Mebendazole binds to microtubular hibits development of eggs of worms and protein ‘βββ tubulin’ of parasite and inhibits kills the larvae. its polymerization, thus irreversibly It is rapidly absorbed, metabolised by impairing glucose uptake. hydroxylation and conjugation to inactive Adverse effects include nausea, metabolites and excreted through kidney. diarrhoea, abdominal pain. Alopecia and Adverse effects include nausea, vomiting, granulocytopenia may occur at high skin rash, anorexia, giddiness, abdominal doses. pain, diarrhoea, fever and headache.

ALBENDAZOLE Congener of mebendazole. It is given It is a synthetic imidazothiazole only as single dose. derivative and is highly effective in 362 Section 9/ Chemotherapy

Table 9.10.1: Classification of anthelmintic agents. Drug(s) Uses and Dose 1. Mebendazole (MEBEX) Ascariasis, ankylostomiasis: 100 mg BD × 3 days; Trichu- riasis: 400 mg single dose; Pinworm: 100 mg OD & repeat after 2 & 4 weeks; Intestinal capillariasis: 400 mg/d × 21 days; Taeniasis: 300 mg BD × 3 days. 2. (ZENTEL) Ascariasis, ankylostomiasis and trichuriasis: 400 mg single dose; Taeniasis & strongyloidosis: 400 mg × 3 days; Neurocysticercosis: 15 mg/kg/daily × 1 month; Hydatid disease: 400 mg BD × 1 month (if required repeat after 2 wks). 3. Thiabendazole (MINTEZOL) Trichinosis and strongyloidosis: 25 mg/kg/day in two divided doses × 2 days after meal (if required repeat after 2 days) 4. Levamisole (DECARIS) Ascariasis and hook worm infestation: 50-150 mg single dose. 5. (NICLOSAN) Taeniasis: 0.5-2 g (After breakfast 1 g to be chewed and swallowed with water followed by 1 g after 1 hr); For H. nana infestation: 2 g dose is repeated daily for 5 days. 6. Piperazine (as citrate) Ascariasis: 4.5 g OD × 2 days; in children 0.75 g/year of age (max 4.5 g); Enterobiasis: 4.5 g OD, repeat after 3 weeks. 7. pamoate For Ascaris, enterobius & ancylostoma: 10-15 mg/kg (max 1 g) single dose; Necator and strongyloides: 3 day course. 8. Diethyl carbamazine (HETRAZAN) Tropical eosinophilia: 4-6 mg/kg BD-TDS × 7-10 days; Filariasis: 6-12 mg/kg OD-BD × 21 days; Also used in prophylaxis of filaria. 9. (IVERMECTOL) Onchocerciasis: 150 µg/kg single dose. Also used in intestinal nematode infection and enterobiasis. For scabies and strongyloidiasis: 200 µg/kg single dose. 10. (CYSTICIDE) Taeniasis: 10 mg/kg single dose; H. nana: 15-25 mg/kg single dose; Neurocysticercosis: 50 mg/kg in 3 divided doses × 15 days; Schistosome and other flukes except Fasciola hepatica: 75 mg/kg/day, can be repeated if needed.

eradicating ascariasis and ancylostomiasis. inhibiting anaerobic phosphorylation of It acts by stimulating ganglia of the worm ADP by the mitochondria of the parasite. which results in tonic paralysis, which are It is devoid of any major toxicity except subsequently eliminated from the intestines. minor gastrointestinal disturbances. Adverse effects include nausea, epigastric PIPERAZINE CITRATE discomfort, insomnia, dizziness, weakness and It is an alternative drug for treatment drowsiness. of ascariasis and pinworms. If taken along with alcohol, it may It possibly exerts its action by produce disulfiram like reaction. antagonizing the action of acetylcholine thus blocking neuromuscular transmission. NICLOSAMIDE Hence, flaccid paralysis occurs. It is It is salicylamide derivative, act by considerably absorbed, partly metabolized Anthelmintic Agents 363 in liver and excreted in urine. It can be Ivermectin binds selectively and with safely used in pregnancy. high affinity to glutamate gated chloride Adverse effects include nausea, ion channels in nerve and vomiting, epigastric distress, skin rash, muscle cells. This leads to an increase in urticaria, headache and seizures. the permeability of cell membrane to PYRANTEL PAMOATE chloride ions with hyperpolarization of nerve of muscle cell, resulting in paralysis It is a broad spectrum anthelmintic effective in pinworm, ascariasis and hook worm and death of the parasite. infestation. It exerts its action by producing Following the oral administration of persistent nicotinic receptor activation which ivermectin, peak plasma concentration is results in spastic paralysis of worms. achieved in four hours. Ivermectin is It is poorly absorbed from GIT and is absorbed well on an empty stomach. The active against luminal organisms. It is bioavailability is 50 to 60%. It is mainly excreted in urine as metabolites and in metabolized in the liver and the tissue unchanged form. Adverse reactions concentration is maximum in liver and fat. include rash, nausea, vomiting, headache, Ivermectin and its metabolites are excreted dizziness, anorexia and elevation of SGOT levels. mainly in faeces. Adverse effects include nausea, vomiting, abdominal pain, constipation and It is the drug of choice for filariasis. It is fatigue. effective against W. malayi, W. bancrofti, Loa loa and Onchocerca volvulus. It is mainly indicated in scabies, ascariasis trichuriasis, strongyloidiasis, It has a dual action. Hyperpolarization effect of piperazine moiety causes enterobiasis, filariasis, onchocerciasis (River paralysis of the worms and alteration in blindness) and elephantiasis. It is drug of microfilarial surface membrane makes choice for onchocerciasis producing long them susceptible to destruction by host lasting reduction in microfilaria without defence mechanism. affecting adult worm. It is absorbed after oral administration, distributed all over body, metabolized in PRAZIQUANTEL liver and excreted in urine. Effective against schistosomes, other Adverse effects include anorexia, trematodes, cestodes and their larval forms nausea, vomiting, skin rash, urticaria, but not against nematodes. fatigue, dizziness and headache. It causes spastic paralysis of worms It is indicated in filariasis and due to leakage of intracellular calcium tropical eosinophilia. from membranes. At high concentration IVERMECTIN it causes vacuolization of tegument and Semisynthetic derivative of drug release of contents of worms and their obtained from Streptomyces avermitilis. destruction by host defence mechanism. 364 Section 9/ Chemotherapy

It is rapidly absorbed from intestine, MELARSOPROL undergoes high hepatic first pass Chemically it is trivalent arsenical used metabolism. It readily crosses the blood for advanced CNS African trypanosomia- brain barrier. sis. It is administered intravenously in pro- Adverse effects are nausea, abdominal pylene glycol and after administration it pain, headache, dizziness. rapidly excreted. It is highly toxic and used only in advanced trypanosomiasis when Suramin (1 gm. each wk for 5 wk. IV or 1 no alternative is there, these effects include gm. on day 1, 3, 7, 14, 21) vomiting, fever, abdominal pain, renal and Melarsoprol 3.6 mg/kg/day IV for 3-4 days cardiac disease and encephalopathy char- Eflornithine 100 mg/kg IV every 6 hrs. for 14 days acterized by cerebral edema, seizures, coma Nifurtimox 8-10 mg/kg orally 3-4 months. (even death).

SURAMIN EFLORNITHINE It is a sulfated napthylamine and used in It is an inhibitor of ornithine first line therapy for early hemolymphatic decarboxylase and is used as second African trypanosomiasis. (caused by T. brucei therapy for advanced CNS African gambiense). It is very tight protein binding and trypanosomiasis. After oral or intravenous having short initial half life but terminal half administration, peak plasma level reached life is about 50 days and is excreted by kidney. rapidly and elimination half life is It is also used for chemoprophylaxis against approximately 3 hours. African trypanosomiasis. Adverse effects It is effective against advanced T. brucei include nausea, vomiting, fatigue, dermatitis, gambiense infection. Adverse effect includes fever, photophobia, haemolytic anaemia, vomiting, diarrhoea, leukopenia, thrombocy- albuminuria and hematuria. topenia, anemia and seizures.

 ChapterChapter PharmacodynamicsPharmacodynamicsChemotherapyChemotherapy ofof 9.111. 4 (ModeTuberculosisTuberculosis of Action of Drugs)

Tuberculosis is a chronic infectious disease lation is infected with tuberculosis. Due to caused by various species of mycobacteria. spread of HIV virus, there is increased The important human mycobacterium prevalence of tuberculosis, infection with pathogens are Mycobacterium tuberculosis Mycobacterium avium complex and and Mycobacterium bovis. According to multidrug resistant tuberculosis. The che- WHO, about one third of the world’s popu- motherapeutic agents used in the treatment

Table 9.11.1: Classification of antitubercular drugs. I. First line or standard drugs Isoniazid (Isonicotinic acid hydrazide – INH; ISONEX) 300-450 mg/day Rifampicin (R-CIN) 450-600 mg/day Streptomycin (AMBISTRYN-S) 0.75-1 g IM Pyrazinamide (PZA-CIBA) 1.5-2 g/day Ethambutol (MYCOBUTOL) 15-25 mg/kg/day Combination of rifampicin & isoniazid (R-CINEX), combination of rifampicin, INH & pyrazinamide (MYCOCOX-Z) II. Second line or reserved drugs Ethionamide (MYCOTUF) 0.5-1.0 g/day Para-amino salicylic acid (PAS; INAPAS) 10-12 g/day Cycloserine (CYCLORINE) 0.5-1.0 g/day Thiacetazone 150 mg/day Kanamycin (KANSIN) 0.75-1 g/day IM Capreomycin (KAPOCIN) 0.75-1 g/day IM Amikacin (AMICIN) 0.75-1 g/day IM Fluoroquinolones like ciprofloxacin, ofloxacin; Macrolide antibiotics like clarithromycin, azithromycin. Newer drugs Rifabutin (Ansamycin) 450 mg/day Rifapentine 600 mg once or twice in a wk 366 Section 9/ Chemotherapy of tuberculosis are classified as in table ranei. It is bactericidal against Mycobacteri- 9.11.1. um tuberculosis and also against many gram positive and negative organisms such FIRST LINE OR STANDARD DRUGS as Staph. aureus, pneumococci, Bacillus an- thracis, N. gonorrhoeae, C. diphtheriae, men- ISONIAZID ingococci, H. influenzae and Streptococcus It is the most active drug used in the faecalis. treatment of tuberculosis. It is a hydrazide of It acts by inhibiting DNA-dependent isonicotinic acid. It is a bactericidal drug, RNA polymerase and stopping the effective against Mycobacterium tuberculosis expression of bacterial genes. and ineffective against atypical mycobacteria. After oral administration, it is absorbed Isoniazid possibly exerts its action by well and distributed to different body inhibiting the synthesis of mycolic acid tissues and penetrates meninges, caseous which is an essential component of masses and placental barrier. It is mycobacterial cell wall. It is also postulated metabolized in liver to active deacylated that the ability of isoniazid to suppress the metabolite and induces the microsomal formation of DNA and RNA and also enzymes in liver. It is excreted mainly in bile inhibition of various oxidative mechanisms and urine. may be responsible for its action. Adverse effects include skin rash, drug Isoniazid is completely absorbed on oral fever, nausea, vomiting, peripheral neuropathy, administration and penetrates all tissues of the fatigue, hepatitis and jaundice, haemolytic body. Peak plasma levels are reached within anaemia, diarrhoea, drowsiness, ataxia, one hour and persists for 24 hours. It penetrates headache, flu like syndrome and stomatitis. intracellularly and diffuses into macrophages Apart from its main use in tuberculosis, and the necrotic centres. It is metabolized in it is also used in leprosy and prophylaxis liver by acetylation and isoniazid metabolites of meningitis due to H. influenzae and and a small amount of unchanged drug is meningococci. It is also used with excreted mainly by kidney. doxycycline in treatment of brucellosis. Adverse effects include skin rash, fe- ver, peripheral neuritis, nausea, vomiting, STREPTOMYCIN weakness, dizziness, lethargy, slurred Detailed pharmacology is discussed in speech, blurred vision, agranulocytosis, chapter ‘Aminoglycoside antibiotics’. hepatitis (which is dose related, common in old people but rare in children), optic PYRAZINAMIDE neuritis, optic atrophy and convulsions. It is chemically related to nicotinamide and thiosemicarbazone. It is bactericidal. RIFAMPICIN It is effective against Mycobacterium tuber- It is a semisynthetic derivative of rifa- culosis resistant to INH and streptomycin. mycin isolated from Streptomyces mediter- It is converted to pyrazinoic acid (active Chemotherapy of Tuberculosis 367 form) by mycobacterial pyrazinamidase. is completely metabolised and less than one Pyrazinamide is a first line drug. Resistance percent of the drug is excreted in urine. develops fast, if given alone, hence it is used The common side effects are nausea, in conjunction with isoniazid and rifampi- vomiting and anorexia. Other effects cin for shortcourse therapy. include hepatotoxicity, drowsiness, It is absorbed after oral administration depression, peripheral neuritis, skin rash, and has good penetration in CSF and is acne, alopecia and hypertension. metabolised in liver and excreted in urine. Adverse effects include nausea, vomit- PARA-AMINOSALICYLIC ACID (PAS) ing, myalgia, arthralgia, hyperuricaemia and It is a tuberculostatic and very less hepatotoxicity. Hypersensitivity reactions active drug in the treatment of tuberculosis. have also been reported. It is used as sodium salt and its larger dose can cause sodium overload in the body. ETHAMBUTOL Bacteriostatic against Mycobacterium It is tuberculostatic drug effective tuberculosis. It inhibits the onset of against many atypical mycobacteria also. bacterial resistance to streptomycin and It acts mainly against rapidly multiplying INH. organisms in the cavities walls. Readily absorbed from GI tract. Ethambutol is well absorbed from the Concentrated in pleural and caseous tissue. GIT after oral administration, distributed widely and excreted in urine by glomerular Does not enter CSF. 50% metabolised by filtration and tubular secretion. acetylation. Adverse effects include optic neuritis, Adverse effects include nausea, visual disturbance, colour blindness, vomiting, diarrhoea, abdominal pain, skin hyperuricaemia, skin rash, drug fever, rashes, goitre, fever and blood dyscrasias. malaise, confusion, disorientation, head- ache, nausea, anorexia, vomiting and ab- CYCLOSERINE dominal pain. It is an antibiotic obtained from S. orchidaceus. It is a chemical analogue of D- SECOND LINE OR RESERVED DRUGS alanine. It is a second line tuberculostatic antitubercular drug and inhibitor of cell ETHIONAMIDE wall synthesis. It is chemically related to isoniazid and After oral administration, it is rapidly inhibit the synthesis of mycolic acids. It absorbed and is distributed in various body is effective against tubercle bacilli resistant tissues including CSF. It is excreted largely to other drugs and atypical mycobacteria. unchanged in urine by glomerular filtration. After oral administration it is well It is used for treatment of multidrug resistant absorbed from gastrointestinal tract and tuberculosis with other primary drugs. It is widely distributed throughout body tissues also used in acute urinary tract infections and CSF. It crosses the placental barrier and caused by susceptible microorganisms. 368 Section 9/ Chemotherapy

Adverse effects include skin rash, chapter ‘Sulfonamides, nitrofurans and nervousness, dizziness, drowsiness, vertigo, quinolones’ and the pharmacology of tremors, convulsions and psychotic state. macrolide antibiotics e.g. clarithromycin and azithromycin is discussed in chapter CAPREOMYCIN ‘Macrolide and polypeptide antibiotics.’ It is a peptide protein synthesis inhibitor antibiotic isolated from Streptomyces RIFABUTIN capreolus. It is second line antimycobacterial It is similar to rifampicin and shows drug which exhibits activity against human significant activity against M. tuberculo- strains of Mycobacterium tuberculosis. sis, M. avium complex and M. fortuitum. After oral administration, it is Rifabutin is both substrate and cyto- insignificantly absorbed. It is administered chrome 450 enzyme inducer. Because it parenterally and is excreted unchanged by is less potent inducer, rifabutin is used (in glomerular filtration. place of rifampicin) for the treatment of Adverse effects include tinnitus, tuberculosis in HIV-infected patients, vertigo, leucopenia, hypokalemia, skin rash, who are on concurrent antiretroviral urticaria, fever, pain and induration at therapy with a protease inhibitor. It is injection site, excessive bleeding at injection used alone or in combination with pyrazi- site and abnormalities in liver function. namide. KANAMYCIN RIFAPENTINE It is used in the treatment of It is an analog of rifampicin active against tuberculosis caused by streptomycin M. tuberculosis and M. avium. It inhibits bac- resistant strains but since agents with lesser terial RNA polymerase and it is a potent toxicity e.g. capreomycin and amikacin are inducer of cytochrome P450 enzymes. available, its use is obsolete. It is indicated in the treatment of tu- The pharmacology of quinolones e.g. berculosis caused by rifampicin susceptible ciprofloxacin and ofloxacin is discussed in strains.

 ChapterChapter PharmacodynamicsPharmacodynamicsChemotherapyChemotherapy ofof 9.12 (ModeLeprosyLeprosy of Action of Drugs)

Leprosy is caused by Mycobacterium leprae. (PABA) incorporation into folic acid (in- The various drugs used in the treatment of hibition of folate synthesis). In large leprosy are classified as in table 9.12.1. proportion of Mycobacterium leprae infec- tions e.g. in lepromatous leprosy, SULFONES resistance can develop, so combination of dapsone, rifampicin and clofazimine is DAPSONE used in initial therapy. It is diamino diphenyl sulfone (DDS), After oral administration, it is chemically related to sulfonamides, have completely absorbed and is concentrated in been used effectively in the long term treat- lepromatous skin, liver, kidney and muscles. ment of leprosy. Its mechanism of action It is metabolized in liver and excreted in is same as that of sulfonamides i.e. inhi- urine as glucuronic acid and sulfate bition of paraamino benzoic acid conjugates.

Table 9.12.1: Classification of drugs used in leprosy. I. Sulfones Dapsone (DDS) 100 mg daily II. Phenazine derivative Clofazimine (CLOFOZINE) 100 mg TDS III. Antitubercular drugs Rifampicin 600 mg monthly/daily Ethionamide 250 mg daily IV. Other antimicrobial agents Quinolones e.g. ofloxacin; 400 mg/day Others include pefloxacin, sparfloxacin Macrolides e.g. clarithromycin 500 mg/day Minocycline 100 mg/day 370 Section 9/ Chemotherapy

Adverse effects include haemolysis The detailed pharmacology is discussed which is most common and dose related. in chapter ‘Chemotherapy of Tuberculosis’. Patients with G-6-PD deficiency are more susceptible. Nausea, vomiting, anorexia, ETHIONAMIDE headache, methaemoglobinaemia, drug It is antitubercular drug used as an fever, allergic skin reactions, insomnia and alternative to clofazimine in the treatment paresthesia. Rarely hepatitis and of leprosy. But due to its hepatotoxicity, its agranulocytosis. use in leprosy is very limited. It is also used with pyrimethamine in chloroquine resistant malaria. OTHER ANTIMICROBIAL AGENTS Among fluoroquinolones, ofloxacin, PHENAZINE DERIVATIVES pefloxacin and sparfloxacin can be used in alternative regimen, when drugs like CLOFAZIMINE rifampicin can not be used. Detailed Clofazimine is phenazine dye and used pharmacology of quinolones is discussed in as alternative to dapsone in dapsone chapter ‘Sulfonamides, nitrofurans and intolerant/resistant cases and in quinolones’. combination with dapsone and rifampicin Among macrolide antibiotics, in the multidrug treatment of leprosy. It’s clarithromycin is effective against M. leprae probable mechanism of action is its as an alternative multidrug therapy (MDT) involvement in DNA binding, it may regimen (detailed pharmacology is interfere with template function of DNA. discussed in ‘Macrolide antibiotics’). After oral administration, it is slowly absorbed, stored widely in reticuloendot- MINOCYCLINE helial system and fatty tissues. It has long It is a tetracycline which is active elimination half life. against M. leprae and its bactericidal Adverse effects include discolouration activity is higher than that of of skin (red brown to black) and skin lesion clarithromycin. Used in alternative persists for month after discontinuation of multidrug treatment regimen (MDT). therapy. Other side effects include dry skin, itching, phototoxicity, nausea, abdominal CLARITHROMYCIN pain, anorexia and diarrhoea. Only macrolide antibiotic useful in leprosy. It is used in alternative MDT regimen. ANTITUBERCULAR DRUGS Recently, thalidomide (50-100 mg capsule form, approved by FDA), an RIFAMPICIN immunomodulatory agent is used in It is bactericidal and highly effective in erythema nodosum leprosum (ENL) which leprosy. A single monthly dose of 600 mg is a complication of leprosy occurring in may be used in combination with other approximately one half of borderline antileprosy drugs to avoid any probable lepromatous and lepromatous leprosy risk of rifampicin resistant M. leprae. patients.  ChapterChapter PharmacodynamicsPharmacodynamicsChemotherapy of (Mode of Action of Drugs) 9.13 Malignancy

Cancer is a disease of cells characterized cells or modify their growth. The various by a shift in the control mechanism which anticancer agents are classified according govern cell proliferation and differentiation to their mode of action as in table 9.13.1. and the anticancer agents either kill cancer

Table 9.13.1: Classification of anticancer agents. I. Alkylating agents Cyclophosphamide (CYCLOXAN) 2-3 mg/kg/day oral; 10-15 mg/kg IV every 7-10 days (UROMITEXAN) 20% of a dose of anticancer agent IV Chlorambucil (LEUKERAN) 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily for maintenance Busulfan (MYLERAN) 4-8 mg/day, 1-3 mg/day for maintenance Lomustine (LUSTIN) 120-130 mg/m2 BSA single dose orally every 6 weeks Thio-TEPA (THIOTEPA) 0.3-0.4 mg/kg IV every 1-4 week interval II. Antimetabolites Methotrexate (ONCOTRAX) 15-30 daily for 5 days orally repeat after one week or 20-40 mg/m2 BSA IM/IV twice weekly. 6-Mercaptopurine (ZYPURIN) 2.5 mg/kg daily 5-Fluorouracil (FLURACIL) 12 mg/kg OD for 4 successive days IV, 10-15 mg/ kg/week maintenance Cytarabine (Cytosine arabinoside; CYTABIN) 1.5-3.0 mg/kg IV BD for 5-10 days III. Cytotoxic antibiotics Dactinomycin (Actinomycin-D) (COSMEGEN) 15 µg/kg IV daily for 5 days Doxorubicin (ONCODRIA) 60-75 mg/m2 BSA every 3 wks slow IV Bleomycin (ONCOBLEO) 30 mg twice weekly IV/IM Mitomycin-C (MITODUS) 2-10 mg/m2 BSA IV twice weekly

Contd.… 372 Section 9/ Chemotherapy

…Contd. IV. Vinca alkaloids Vincristine (Oncovin; BIOCRISTINE) 1.5 mg/m2 BSA IV weekly Vinblastine (CYTOBLASTIN) 0.1-0.15 mg/kg IV weekly (total 3 doses) Vinorelbine (VINELBINE) 30 mg/m2 BSA IV weekly V. Taxanes Paclitaxel (MITOTAX) 175 mg/m2 BSA IV infusion repeated every 3 weeks Docetaxel (DOXOTEL) VI. Topoisomerase-I inhibitors Irinotecan (IRINOTECAN) 125 mg/m2 BSA weekly IV Topotecan (TOPOTEL) 1.5 mg/m2 BSA IV infusion for five consecutive days VII. Hormone & hormone antagonists Fosfestrol (Stilboestrol) 40-80 mg IM every 2-4 weeks Ethinyl estradiol (LYNORAL) 1-3 mg daily Tamoxifen (ONCOTAM) 10-20 mg BD VIII. Radioactive isotopes Radioactive iodine (131I) 3-6 mci oral/IV Radioactive phosphorus (32P) 2.5-5.0 mci IV Radioactive gold (198AU) 35-150 mci IP IX. Miscellaneous agents Hydroxyurea (CYTODROX) 20-30 mg/kg daily or 80 mg/kg every 3rd day Procarbazine 100-300 mg/day L-Asparaginase (LEUNASE) 50-200 KU/kg daily IV infusion for 2-4 weeks Cisplatin 50-100 mg/m2 BSA single IV dose every 3-4 wks Interferon alfa (ALFERON) 3-36 million IU daily SC/IM (depending upon the X. Immunosuppressants type of cancer) Azathioprine Cyclosporine

* BSA = Body surface area

DNA synthesis and also interfere with cell ALKYLATING AGENTS replication. Alkylating agents has got cytotoxic The alkylating agents can transfer an alkyl action and damage the nuclei of growing and radical to a suitable receptor site. Alkylation multiplying cells. They have got of DNA within the nucleus represent the immunosuppressant action also and suppress major interactions which will lead to cell antibody production. They also have death. These agents react chemically with radiomimetic (like ionizing radiation) actions. sulfhydryl, carboxyl, amino and phosphate groups of other cellular nucleophiles in the CYCLOPHOSPHAMIDE cells which make them unavailable for the It is an alkylating agent given orally or normal metabolic reactions. Alkylating by intravenous route. It exerts its action agents react with nucleic acid and inhibit by alkylation of DNA. Chemotherapy of Malignancy 373

After oral administration it is well (Waldenstrom’s) macroglobulinaemia, absorbed. It is a prodrug and converted in advanced ovarian adenocarcinoma, breast the blood and liver to its active form cancer, certain forms of nonHodgkin’s (metabolites) namely hydroxyphosphamide lymphoma and Hodgkin’s disease. and aldophosphamide. It is excreted in urine. Adverse effects include nausea, Adverse effects include nausea, vomiting, pulmonary fibrosis, dermatitis, vomiting, visual blurring, facial burning hepatotoxicity, seizures, amenorrhoea, with IV administration, teratogenic effect, azoospermia, peripheral neuropathy and haemorrhagic cystitis, bone marrow bone marrow depression. depression, hyponatremia, sterility, inappropriate secretion of ADH, alopecia BUSULFAN and increased skin pigmentation. After oral administration, it is well It is indicated in leukaemias, absorbed and excreted in urine as lymphogranulomatosis, lymphosarcoma, methanesulfonic acid. It is mainly used in reticulum cell sarcoma, Hodgkin’s disease, chronic myeloid leukaemia, polycythemia multiple myeloma, retinoblastoma, vera, essential thrombocythemia and carcinoma of the breast, adenocarcinoma myelofibrosis. of the ovary, inoperable solid malignancies. Adverse effects include, thrombocy- It is used in combination with surgery, topenia, amenorrhoea, azoospermia, skin radiation and other therapeutic measures. pigmentation, nausea, vomiting, cataract, MESNA gynaecomastia, pulmonary fibrosis and hyperuricaemia. Cyclophosphamide and ifosfamide cause urothelial toxicity (haemorrhagic LOMUSTINE cystitis) which is caused by metabolite ‘ac- It is rapidly absorbed from GIT after rolein’. Mesna reacts with this metabo- oral administration and is completely and lites in the urinary tract to prevent toxic- rapidly metabolised. It is indicated in ity and is used in prevention of toxicity Hodgkin’s disease, brain tumour, lung to the urinary passage caused by carcinoma, solid tumours and malignant oxazaphosphorins e.g. ifosfamide and cyclophosphamide. melanoma. Adverse effects include nausea, vom- CHLORAMBUCIL iting, delayed bone marrow depression It is a slow acting alkylating agent. (four to six weeks), leucopenia, thrombocy- After oral administration, it shows topenia and pulmonary fibrosis. adequate and reliable absorption and almost completely metabolised. THIO-TEPA It is indicated in chronic lymphocytic Chemically it is ethylenimine and leukaemia (drug of choice), primary because of high toxicity, it is rarely used. 374 Section 9/ Chemotherapy

ANTIMETABOLITES lymphocyte proliferation, rheumatoid factor production and interferes with the Antimetabolites are analogues of normal release of inflammatory cytokines. DNA components or of coenzymes involved in nucleic acid synthesis. They get 6-MERCAPTOPURINE incorporated or competitively inhibit It is an antimetabolite antineoplastic, utilization of normal substrate to form which being an analogue of hypoxanthine dysfunctional nucleic acid molecules. and adenine inhibits purine metabolism. After oral administration absorption is METHOTREXATE incomplete and drug is metabolised in liver. It is a broad spectrum antineoplastic The active metabolites have longer half life drug which act as an antimetabolite of folic than parent drug. acid. Adverse effects include nausea, It acts by inhibiting dihydrofolate vomiting, diarrhoea, cholestasis, bone reductase. It inhibits conversion of marrow depression, pancreatitis, oral and dihydrofolic acid to tetrahydrofolic which intestinal ulcers. Rarely hepatic necrosis. is essential for purine synthesis and amino It is used in acute leukaemia, acid interconversions. It primarily affects choriocarcinoma and chronic granulocytic DNA synthesis but also RNA and protein leukaemia. synthesis. It has cell cycle specific action and kills cells in S phase. It is readily absorbed FLUOROURACIL from gastrointestinal tract but larger doses It is fluorinated analogue of pyrimidine, are absorbed incompletely, little drug is act by binding the enzyme thymidylate metabolised and it is excreted largely synthetase and preventing the production unchanged in urine. of basic component of DNA-thymine. It Adverse effects include nausea, is converted into 5-fluorouridine vomiting, diarrhoea, anaphylaxis, hepatic triphosphate and is incorporated into RNA necrosis, fever, bone marrow depression, where it interferes with RNA processing osteoporosis, menstrual dysfunction, and function. cirrhosis, pulmonary infiltrates and fibrosis, It is used in the treatment of carcinoma renal toxicity and depigmentation. of breast, colon, urinary bladder, stomach It is indicated in lymphoblastic leukemia liver, rectum and ovaries. and choriocarcinoma, psoriasis, adjuvant The major toxicity includes myelosup- therapy of non-metastatic osteosarcoma and pression and mucositis. to reduce corticosteroid requirement in patients with severe steroid dependent asthma. CYTARABINE It is also used as ‘disease modifying Cytarabine or cytosine arabinoside drug’ in rheumatoid arthritis as it reduces competitively inhibits DNA polymerase Chemotherapy of Malignancy 375 and blocks generation of cytidylic acid DNA intercalator and it generates free and is a drug of choice for acute myeloid radicals. leukaemia. It is usually administered by It is indicated in acute myelocytic intravenous route. It does not cross blood leukaemia, acute lymphocytic leukaemia, brain barrier. chronic myeloid leukaemia (blast phase), Adverse effects include nausea, vom- non-Hodgkin’s lymphoma in children, iting, diarrhoea, fever, red urine (harmless), treatment and maintenance of meningeal ventricular arrhythmia, severe local tissue neoplasms, erythroleukaemia. damage on extravasation, cardiotoxicity, Adverse effects include depression of bone marrow depression, anorexia, stoma- bone marrow which gives rise to leukopenia, titis, alopecia, conjunctivitis. thrombocytopenia, reticulocytopenia. GI It is indicated in GI tract carcinoma, disturbances, oral and anal ulceration, acute myeloblastic leukaemia, bronchogenic, hepatic and renal dysfunction and breast and ovarian carcinoma, soft tissue peripheral neurotoxicity with high doses. and bone sarcomas, malignant lymphoma; primary management of nonmetastatic CYTOTOXIC ANTIBIOTICS bladder carcinoma (intravesical administra- tion), Wilm’s tumor and neuroblastoma. These drugs are obtained from various microorganisms and have antitumor activity. Epirubicin (FARMORUBICIN) is They act by binding to double stranded DNA structurally similar to doxorubicin and is and interfere with its functions. similarly effective in the treatment of breast cancer, lung cancer and lymphoma. DACTINOMYCIN (ACTINOMYCIN D) BLEOMYCIN It is a potent antitumor antibiotic isolated from Streptomyces organism. It It is a mixture of cytotoxic glycopeptide binds tightly to double stranded DNA antibiotic isolated from a strain of Streptomyces verticillus. through intercalation between adjacent guanine cytosine and inhibit all It exerts its cytotoxic action by causing forms of DNA dependent RNA synthesis. fragmentation of DNA and it generates free radicals. It is used in choriocarcinoma, Hodgkin’s disease and Wilm’s tumour in It is usually administered by parenteral combination with irradiation. route. It does not cross blood brain barrier. Adverse effects include damage of Adverse effects include nausea, vom- skin, alopecia, bone marrow depression, iting, allergic reactions, fever, anaphylaxis, vomiting and diarrhoea. skin rash, Raynaud’s phenomenon, stoma- titis, pulmonary fibrosis, hyperpigmenta- DOXORUBICIN tion, renal and hepatic toxicity. It is a cytotoxic anthracycline antibiotic Bleomycin is used as palliative and ad- isolated from Streptomyces pneuceticus. It is juvant to surgery and radiation therapy in 376 Section 9/ Chemotherapy testicular tumour, squamous cell carcinoma After oral administration the absorp- of skin, neck and head, genitourinary tract tion is unpredictable. It is metabolised in and oesophagus neoplasm, malignancy of liver. cervix, Hodgkin’s and non Hodgkin’s lym- Adverse effects include local reaction phoma, choriocarcinoma and embryonal if extravasation occurs, constipation, para- cell carcinoma of testis, brain tumour and lytic ileus, jaw pain, alopecia, bone mar- glioma. row depression, peripheral neuropathy, inappropriate ADH secretion, shortness of MITOMYCIN-C breath and bronchospasm. It is a highly toxic antibiotic with It is indicated in acute leukaemias, lym- antitumour activity isolated from phomas, Ewing’s sarcoma, neuroblastoma, Streptomyces caespitosus. Wilm’s tumour and idiopathic thrombocy- It inhibits DNA synthesis and cross topenic purpura. links DNA. VINBLASTINE After oral administration it exhibits inconsistent absorption. Hence it is It interferes with metabolic pathways administered by IV route and is metabolised of amino acids leading from glutamic acid in liver. to the citric acid (Krebs) cycle and urea. It is used in the treatment of adenocar- Vinblastine has an effect on cell energy production required for mitosis and cinoma, lymphosarcoma and seminoma. It interferes with nucleic acid synthesis. is also used in squamous cell carcinoma of Reversal of antitumour effect by glutamic cervix. acid or tryptophan has occurred. Adverse effects include nausea, It undergoes rapid distribution and vomiting, alopecia, pulmonary fibrosis, extensive tissue binding following IV bone marrow depression, sterility, injection. It is metabolised in liver. amenorrhoea and renal toxicity. Adverse effects include hepatic function impairment, leucopenia, VINCA ALKALOIDS aspermia, nausea, vomiting, hypertension and alopecia. The vinca alkaloids are isolated from plant Vinca rosea. They are cell cycle specific and It is indicated in Hodgkin’s and non Hodgkin’s lymphoma, testicular mitotic inhibitors. carcinoma, mycosis fungoides and Kaposi’s VINCRISTINE sarcoma. It blocks mitosis and produces VINORELBINE metaphase arrest by binding to microtu- It is semisynthetic vinca alkaloid. It bular protein ‘tubulin’, preventing its interferes with microtubules, in miotic polymerization. spindle fibres leading to cell cycle arrest Chemotherapy of Malignancy 377 in metaphase. It is used in the treatment of metastatic It is used for the treatment of non small carcinoma of colon or rectum. cell lung carcinoma, breast carcinoma, Adverse effects include vomiting, di- Hodgkin’s disease, ovarian carcinoma, arrhoea, abdominal discomfort, leukopenia, squamous cell carcinoma of the head and anemia, neutropenia, haemorrhage, insom- neck, cervical squamous cell carcinoma, nia and dizziness. renal cell cancer and Kaposi’s sarcoma. TOPOTECAN TAXANES Topotecan also inhibits topoisomerase I. Adverse effects include abdominal dis- PACLITAXEL comfort, vomiting, diarrhoea, intestinal It is an alkaloid ester derived from the obstruction, nausea, stomatitis, anorexia, western yew Taxus brevifolia. bone marrow suppression (primarily neu- It is a diterpenoid compound and is a tropenia, anaemia and thrombocytopenia). natural product with antitumour activity. It is valuable in control of metastatic It binds specifically to the βββ-tubulin ovarian cancer, including cisplatinresistant subunit of microtubule and appears to neoplasms. antagonise the disassembly of this cytoskeletal protein i.e. enhances HORMONE AND HORMONE ANTAGONISTS polymerization of tubulin. Arrest in mitosis These are not cytotoxic drugs. They act by follows. The cell killing is dependent on modifying the growth of hormone both drug concentration and duration of dependent tumours. cell exposure. It is indicated in metastatic ovarian and FOSFESTROL (STILBOESTROL) breast cancer. Fosfestrol is a synthetic non-steroidal Adverse effects include bone marrow estrogen which is activated by the enzyme depression, hypersensitivity reactions, chest acid phosphatase to produce stilboestrol. pain, bradycardia, sensory neuropathy, Metabolism occurs primarily in the liver. nausea, vomiting, diarrhoea, alopecia and It is used as palliative treatment of dissemi- impaired liver function tests. nated mammary or prostatic carcinoma. Docetaxel (DOXOTEL), a related drug, Adverse effects include hepatic cuta- used in metastatic breast cancer. neous porphyria, perineal pain, erythema and feminising effects in man. TOPOISOMERASE-I INHIBITORS ETHINYL ESTRADIOL IRINOTECAN It is also indicated in palliative treat- It inhibits topoisomerase-I, the enzyme ment of disseminated mammary or pros- which is involved in DNA replication. tatic carcinoma. The detailed pharmacol- 378 Section 9/ Chemotherapy ogy is discussed in chapter ‘Oral Contra- metastatic or inoperable carcinoma of ceptives.’ ovary. In combination with radiotherapy in carcinoma of cervix, head, neck and ACETATE lung. It belongs to group of progesterone which are mainly used as second or third Adverse effects include nausea, vom- line therapy in breast and endometrial iting, rash. Bone marrow depression is the cancer. major toxic effect. Alopecia, stomatitis, Adverse effects include nausea, acne, dysuria; inflammation and increased pig- fluid retention, GI disturbances and weight mentation may occur in areas exposed to changes. radiation. Rarely neurological distur- bances occur. TAMOXIFEN It exerts its action by binding to PROCARBAZINE estrogen receptors. Tumours with estrogen After metabolic activation, it depoly- receptors respond. merizes DNA and causes chromosomal It is given orally, the drug has biphasic damage and also nucleic acid synthesis half life and is primarily excreted in bile. inhibition. It is found to be effective in Adverse effects include nausea, Hodgkin’s disease and carcinoma of vomiting, hot flushes, vaginal bleeding, lungs. pruritus vulvae and menstrual Adverse effects include drowsiness, irregularities. restlessness, anaemia, leucopenia, throm- It is used as palliative treatment of bocytopenia, bone marrow toxicity and estrogen receptor positive advanced or disulfiram like reaction with alcohol. metastatic carcinoma of breast. L-ASPARAGINASE MISCELLANEOUS AGENTS It destroys essential amino acid (asparagine) hence leukaemic cells are HYDROXYUREA deprived of amino acid and leads to cell The primary action is inhibition of death. It is given by parenteral route. enzyme ribonucleoside diphosphate reductase. The drug is specific for S phase Adverse effects include nausea, vom- of the cell cycle and causes cell to arrest iting, headache, fever, abdominal pain, hyperglycemia leading to coma, hypersen- at the G1-S interface. After oral administration it is readily sitivity, renal damage, coagulation defects, absorbed from GI tract. Hydroxyurea thrombosis, CNS depression or hyperex- readily crosses blood brain barrier. citability and acute haemorrhagic pancre- It is indicated in treatment of chronic atitis. granulocytic leukaemia, polycythemia It is used in the treatment of malignant vera, essential thrombocytosis, melanoma, lymphoma and acute leukaemia. Chemotherapy of Malignancy 379

CISPLATIN IMMUNOSUPPRESSANTS It acts by cross-linking of DNA. It also has radiomimetic property. It is bound to The drugs like azathioprine and plasma proteins and is excreted slowly cyclosporine A are used chiefly to prevent unchanged in urine. It is effective in transplant rejection and in the treatment metastatic testicular and ovarian of autoimmune diseases. They are used to carcinoma, advanced bladder carcinoma prevent graft rejection after kidney, liver, and refractory squamous cell head and neck lung, pancreas transplant or bone marrow carcinoma. transplantation. Adverse effects include nausea, vomit- ing, fever, anaphylactic reactions, hypokale- AZATHIOPRINE mia, hypomagnesaemia, haemolysis, renal It is a purine antimetabolite which has damage, sterility, teratogenesis, ototoxicity, marked effect on T-lymphocytes, suppresses peripheral neuropathy, Raynaud’s disease cell mediated immunity (CMI). It selectively and bone marrow depression. affects differentiation and functions of T INTERFERON ALFA cells and inhibits cytolytic lymphocytes. It is used primarily as immunosuppressant in It is highly purified protein containing organ transplantation, progressive rheuma- 165 amino acids and is manufactured by recombinant DNA technology. toid arthritis and some other autoimmune diseases. Mechanism of action is not clearly understood but direct antiproliferative CYCLOSPORINE action against tumour cells and modulation of the host immune response may play It is a cyclic polypeptide with 11 amino important roles. acids. It selectively inhibits T-lymphocytes proliferation, IL-2 and other cytokine pro- It exhibits half life of 3.7-8.5 hours. Alpha interferons are filtered through the duction. It is the most effective drug for glomeruli and undergo rapid proteolytic prevention and treatment of graft rejec- degradation during tubular reabsorption. tion reaction. It is used in cardiac, hepatic, renal, bone marrow transplantation and It is indicated in hairy cell leukemia, as second line drug in rheumatoid arthri- AIDS related Kaposi’s sarcoma (the detailed pharmacology and its use as tis, inflammatory bowel disease, dermato- antiviral agent is discussed in chapter myositis, bronchial asthma and certain ‘Antiviral agents’). other autoimmune diseases. Adverse effects include GI haemor- Mycophenolate mofetil, a semisynthetic rhage, leukopenia and elevation in liver derivative of mycophenolic acid, isolated enzyme levels. from the mould Penicillium glaucum is used Recently introduced interferon a-2b is in kidney and liver transplant patient. used in chronic myeloid leukaemia, chronic Another newer compound mizoribine is hepatitis B and C. used in kidney transplantation.  This page intentionally left blank Section 10

Vitamins and Trace Elements This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsVitamins and Trace 10.11. 4 (ModeElements of Action of Drugs)

Vitamins are exogenous chemical soluble vitamins can cause toxicity, while substance required by the body in very small water soluble vitamins are rapidly excreted amount for the various metabolic functions in the urine and cause very less toxicity. of the body and categorized as essential The different market preparation nutrients. They do not yield energy but available for vitamins are given in table enable the body to use other nutrients and 10.1.1 and the deficiency diseases which are primarily used in the prevention and occur with deficient supply of various treatment of certain deficiency diseases. vitamins are listed in table 10.1.2. Vitamins are vital for normal metabo- lism in body. They vary in their chemical Table 10.1.1: Classification of various preparations structure and are supplied in very small of vitamins. quantity in diet, because they are not syn- Vitamin A (ROVIGON) thesized in body or their rate of production Vitamin D (CALCIROL) is not sufficient for maintenance of health. Vitamin E (EVION) Vitamin deficiency leads to development of Alfacalcidol (ALCIDOL) deficiency symptoms. Different vitamin Vitamin B complex group Vitamin B (Thiamine; BENALGIS) preparations are available for treatment and 1 Vitamin B (Riboflavin; LIPABOL) prophylaxis. Most of the vitamins are non- 2 toxic but on chronic administration can Vitamin B5 (Calcium pantothenate; SIGMA cause toxicity especially vitamin A and D. PANTOTHENATE) Vitamin B (Pyridoxine; PYRICONTIN) Vitamins are classified into two main 6 Vitamin B12 (Cyanocobalamin/Mecobalamin; groups: METHYCOBAL) I. Fat soluble vitamins, includes Folic acid (FOLVITE) vitamin A, D, E and K. Vitamin C (Ascorbic acid; CELIN) II. Water soluble vitamins, includes B- Multivitamins preparations

complex group and vitamin C. B1 + B6 + B12 (NEUROBION)

The fat soluble vitamins are stored in the B complex (B1, B2, B3, B5, B6, B12 + folic acid; body and excessive administration of fat BECOSULE) 384 Section 10/ Vitamins and Trace Elements

Table 10.1.2: Diseases due to deficient supply of vitamins. Vitamins Deficiency 1. Vitamin A Night blindness (inability to see in dim light), conjunctival xerosis (dry and non-wettable conjunctiva), corneal xerosis (dry and non-wettable cornea and become opaque), kerato- malacia (cornea becomes soft and burst open and vision is lost), Bitot’s spots, growth retardation, dry and rough skin, sterility due to faulty spermatogenesis. 2. Vitamin D Rickets (reduced calcification of growing bones). 3. Vitamin E Axonal degeneration, ophthalmoplegia (however, vitamin E deficiency does not occur clinically). 4. Vitamin K Decreased prothrombin content of blood and blood clotting time is prolonged.

5. Vitamin B1 (Thiamine) Beriberi (characterized by nerve involvement – peripheral neu- ritis), Wernicke’s encephalopathy (characterized by ophthalmo- plegia, polyneuritis and mental disorientation).

6. Vitamin B2 (Riboflavin) Angular stomatitis (occurs in malnourished children).

7. Vitamin B3 (Niacin or Nicotinic acid) Pellagra (characterized by diarrhoea, dermatitis and dementia).

8. Vitamin B5 (Pantothenic acid) Clinical deficiency is not known (has role in biosynthesis of corticosteroids).

9. Vitamin B6 (Pyridoxine) Peripheral neuritis, mental confusion, impairs the optimal utilization of pyridoxine [INH (anti TB drug) is a recognised antagonist].

10. Vitamin B12 (Cyanocobalamin) Megaloblastic anaemia (pernicious anaemia), demyelinating neurological lesions in the spinal cord & infertility. 11. Vitamin C (Ascorbic acid) Scurvy 12. Folic acid Megaloblastic anaemia and gastrointestinal disturbances such as diarrhoea, distension and flatulence. Severe folate deficiency causes infertility or even sterility.

betacarotene which has the highest vitamin FAT SOLUBLE VITAMINS A percentage. Carotenes are converted to vitamin A in the small intestine. VITAMIN A In animal foods, vitamin A is present in Vitamin A is widely distributed in plant liver, eggs, butter, cheese, milk, fish and meat. and animal foods. In plants, the main Fish liver oil are the richest source of retinol. source of vitamin A is green leafy vegetables e.g. spinach and amaranth. The It is vital for the functioning of retina. darker the green leaves, the higher the Vitamin A is essential for differentiation carotene present. Vitamin A is also present and growth of epithelial tissue. It enhances in green & yellow vegetables and fruits e.g. function of immune system and protect pumpkin, papaya and mango, and in roots against development of certain malignan- e.g. carrots (richest source among plant cies. Different forms of vitamin A mediate source). The most important carotenoid is different functions. Vitamins and Trace Elements 385

Retinoids: They influence a wide variety VITAMIN D of biological activities including cellular The term vitamin D is used for a range proliferation, cellular differentiation, of compounds which possess the property immune function, inflammation. e.g. tretinoin, isotretinoin, etretinate. of preventing or curing rickets. They include ergocalciferol (calciferol, vitamin D ), chole- Isotretinoin is a retinoid, recently 2 calciferol (vitamin D3), dihydrotachysterol, approved for use in capsule form (10-20 mg). α It decreases the amount of sebum that alfacalcidol (1 -hydroxycholecalciferol) and sebaceous glands produce. Isotretinoin exhibits calcitriol (1,25-dihydroxycholecalciferol). antiproliferative and antiandrogenic effects on It plays an important role in calcium the sebaceous glands. It also interacts with the metabolism. It regulates calcium formation of androgens in sebaceous glands. homeostasis and maintains normal levels of It is indicated in the treatment of severe plasma calcium and phosphate. nodular acne, acne conglobata and recalcitrant acne. It is available in International market Deficiency symptoms: Rickets occurs under the brand name ‘ACCUTANE’ by in patients who are having deficiency of Roche pharmaceuticals. vitamin D. The bones are unusually soft Deficiency symptoms: Bitot’s spots, and due to stress and strain of weight xerosis, night blindness, keratomalacia, bearing produce characteristic deformities. diarrhoea, follicular hyperkeratosis, It is indicated in prophylaxis and papular eruptions, drying of epidermis, treatment of rickets, postmenopausal urinary calculi, degeneration of testis, osteoporosis, Fanconi syndrome and impaired spermatogenesis, sterility, hypoparathyroidism. abortion, impairment of smell and taste. Adverse effects include headache, It is indicated in night blindness, vitamin A deficiency (in infants, in pregnancy, weakness, nausea, vomiting, dry mouth, lactation, malabsorption syndrome), for muscle pain, constipation, somnolence, prophylaxis of vitamin A deficiency, acne, ectopic calcification, hypertension, ichthyosis, psoriasis, xerophthalmia, Bitot’s nephrocalcinosis and weight loss. spots (especially children). ALFACALCIDOL Dosage: It regulates calcium metabolism by Severe deficiency with increasing calcium and phosphate xerophthalmia: 50,000 IU per day for three absorption from the intestinal tract and also days followed by 50,000 IU per day for two weeks. mobilises minerals from the bone. Severe deficiency: 100,000 IU per day After oral administration it is absorbed for three days followed by 50,000 IU per in the small intestine and undergoes rapid day for two weeks. metabolism to 1,25 (OH)2 D3 in liver and Children: 5,000 to 10,000 IU per day further distribution to bone and intestine is for two weeks. nearly similar to its physiological distribution. 386 Section 10/ Vitamins and Trace Elements

Adverse effects include hypercalcae- including cardiovascular, reproductive and mia and hyperphosphataemia. haematopoietic. It is indicated in osteoporosis, hypo- The clinical manifestations are axonal parathyroidism, hyperparathyroidism degeneration, gait disturbances, ophthal- moplegia, hyporeflexia and necrotizing (with bone disease), renal osteodystrophy, myopathy. nutritional and malabsorptive rickets, hypophosphataemic vitamin D resistant Adverse effects include nausea, fatigue, headache, blurred vision, diarrhoea. rickets and osteomalacia. It is indicated in premature infants Dosage: exposed to high concentration of oxygen, Adults: Initially 1 mcg daily adjusted correction of established vitamin E defi- ciency, in patients at risk of developing according to response. Elderly: Initially 0.5 vitamin E deficiency, nocturnal muscle mcg daily adjusted according to response. cramps, intermittent claudication, Children: Over 20 kg: Initially 1 mcg fibrocystic breast disease, coronary artery daily adjusted according to response. disease and as an antioxidant. Under 20 kg: 0.05 mcg/kg body wt. daily. Dosage: VITAMIN E Adults: It is an antioxidant vitamin. It – Nocturnal muscle cramps: 400 mg daily presumably prevents oxidation of for 8 to 12 weeks. coenzyme Q and inhibits generation of – Intermittent claudication: 400 mg daily peroxidation products from unsaturated for 12 to 18 weeks. fatty acids. – Fibrocystic breast disease: 600 mg daily Vitamin E is a family of eight com- for 2 to 6 months. pounds, four tocopherols and four Children: 200 mg daily. tocotrienols. Tocotrienols appear to affect a key enzyme in the liver (HMG CoA re- WATER SOLUBLE VITAMINS ductase), which plays a key role in the syn- thesis of cholesterol. As such tocotrienols VITAMIN B GROUP help maintain good cardiovascular health. Vitamin B (Thiamine) Vitamin E is an antioxidant and prevents 1 Vitamin B1 is the first member of the B the oxidation of LDL (the bad cholesterol). complex. Vitamin E functions as anticoagulant, Thiamine pyrophosphate is a coenzyme which means it delays the clotting of the and the active form of vitamin B1. It func- blood. It can help prevent thrombosis, the tions as coenzyme in decarboxylation of α- formation of blood clots in the arteries. keto acid and in hexose monophosphate Deficiency symptoms: In vitamin E shunt. deficiency in experimental animals the Deficiency symptoms: In severe manifestations are seen in several systems vitamin B1 deficiency beriberi develops. Vitamins and Trace Elements 387

It is indicated in wet beriberi, dry features of this condition are diarrhoea, beriberi, Wernicke’s encephalopathy, dermatitis and dementia. Nausea, vomiting, prophylaxis of thiamine deficiency, stomatitis, dizziness, depression, insomnia, hyperemesis gravidarum, Korsakoff’s headache develops. In severe deficiency syndrome, chronic alcoholics, multiple hallucinations and dementia occurs. neuritis, toxic and confusional states, Adverse effects include flushing, delirium tremens and anorexia nervosa. activation of peptic ulcer, vomiting, Dosage: Mild chronic deficiency: 10-25 diarrhoea, pruritus, skin rash and transient mg daily; severe deficiency, 200-300 mg headache. daily. It is indicated in pellagra, for prophy- laxis, Hartnup disease, hyperlipoprotein-

VITAMIN B2 (RIBOFLAVIN) aemia. It carries its physiological function in VITAMIN B (CALCIUM its active forms, flavin mononucleotide 5 PANTOTHENATE) (FMN) and flavin adenine dinucleotide. These coenzymes are involved in various Pantothenic acid is traditionally biochemical reactions. considered to be vitamin B substance. It is widely distributed in meat, legume and Deficiency symptoms: It is character- whole grain cereals, egg, milk, vegetables ized by glossitis, dermatitis of trunk and and fruit. extremities, angular stomatitis, cheilosis, anaemia, neuropathy, cataract formation It is a component of coenzyme A which is essential in the metabolism of carbohy- and vascularization of cornea. drate, fat and protein. It is indicated in arteriosclerosis, as Deficiency symptoms: Deficiency of adjunct in treatment of hypertension, panthothenic acid is unlikely in man diabetes and obesity. because of its widespread distribution in food, though it has been administered by VITAMIN B (NIACIN) 3 mouth as a nutritional supplement as the Niacin was initially called pellagra calcium salt and usually in conjunction preventing factor. with other vitamins of the B group. It is converted to coenzymes, Dosage: 50 to 100 mg per day. nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide VITAMIN B6 (PYRIDOXINE) phosphate (NADP). These coenzymes are It is involved as a coenzyme (pyridoxal bound to hydrogenases, function as phosphate) in metabolism of tryptophan, oxidants by accepting hydrogen and in several metabolic transformations of electrons from substrates and become amino acids including transamination, reduced. decarboxylation and racemization. Deficiency symptoms: In niacin Deficiency symptoms: Peripheral deficiency, pellagra develops. The main neuritis, seizures, stomatitis, anaemia, 388 Section 10/ Vitamins and Trace Elements seborrhoea like lesions, mental confusion Clinical Applications and growth retardation. Bell’s palsy: It increases the recovery It is indicated to prevent and treat time for facial nerve function in Bell’s palsy. isoniazid, hydralazine, penicillamine Cancer: Experimental studies indicate and cycloserine induced neurological dis- that it inhibits the proliferation of malignant turbances, mental symptoms in women cells. on oral contraceptives, pyridoxine re- Diabetic neuropathy: Oral administra- sponsive anaemia and homocystinuria, tion of methylcobalamin (500 mcg three morning sickness and hyperemesis times daily for four months) resulted in gravidarum, convulsions in infants and subjective improvement in burning sensa- children. tion, numbness, loss of sensation and Dosage: Adults: 100 mg daily. In muscle cramps. suppression of lactation: 2 tablets thrice Immune system regulation: It has been daily followed by one tablet daily. suggested that vitamin B12 plays an important role in immune system CYANOCOBALAMIN regulation, but the details are still obscure. (METHYLCOBALAMIN) Rheumatoid arthritis: Vitamin B12 is a Methylcobalamin is the coenzyme potential agent in management of RA. It form of vitamin B . It is neurologically 12 mainly acts by correcting abnormalities in active, most bioavailable and best uti- RACD8+ T cells in autologous mixed lized. Unlike cyanocobalamin, it does lymphocyte reaction (AMLR). not require any conversion after ab- Eye function: It protects retinal neurons sorption by the body and is better re- against N-methyl-D-aspartate receptor tained by the liver and other tissues. It mediated glutamate neurotoxicity. has exhibited beneficial effects against Deterioration of accommodation following brain aging, irregular sleep patterns. It visual work has also been shown to improve supports immune function and pro- in individuals receiving methylcobalamin. mote normal cell growth. It represents Heart rate variability: Methylcobalamin one of the best values in nutritional produces improvement in several components products, given its comparably low of heart rate variability, suggesting a balancing cost and its wide range of potential effect on the nervous system. benefits. HIV: Under experimental conditions, Methyl B12 is the superior form of methylcobalamin inhibited HIV-1 infection vitamin B12. of normal human blood monocytes and Deficiency symptoms are glossitis, GIT lymphocytes. disturbances, megaloblastic anaemia, Homocysteinemia: Elevated levels of subacute combined degeneration of spinal homocysteine can be a metabolic indication cord, peripheral neuritis, poor memory, of decreased levels of the methylcobalamin mood changes and hallucinations. form of vitamin B12. Vitamins and Trace Elements 389

Male impotence: It is known to and nontropical sprue, alcoholism; increase sperm count in male patients with adjunctive therapy in nutritional anaemias impotence. and anaemias of pregnancy. Sleep disturbances: The use of Dosage: methylcobalamin in the treatment of a Adults: Therapeutic: 5 to 20 mg daily in variety of sleep-wake disorders is very divided doses. promising. Children: 5 to 10 mg daily in divided Vitamin B complex preparations are doses. indicated in vitamin deficiency states. Specific vitamin B preparations can be used VITAMIN C (ASCORBIC ACID) as per indications mentioned above in the It functions as a cofactor in number of pharmacological write up; as an adjuvant amidation and hydroxylation reactions. to antibiotic therapy; combination with The active form of vitamin C is ascorbic lactobacillus are indicated in aphthous acid itself. The main function of ascorbate is stomatitis, thrush. as a reducing agent in a number of different

Preparations of vitamin B1 + B6 + B12 reactions. Vitamin C has the potential to reduce are indicated to prevent and treat isoniazid, cytochrome a and c of the respiratory chain hydralazine and cycloserine induced neu- as well as molecular oxygen. The most rological disturbances, mental symptoms in important reaction requiring ascorbate as a women on oral contraceptives, pyridoxine cofactor is the hydroxylation of proline responsive anaemia and homocystinuria, residues in collagen. Vitamin C is, therefore, neuropathies, subacute combined degenera- required for the maintenance of normal tion, beriberi, anaemia, hepatitis, debility. connective tissue as well as for wound healing since synthesis of connective tissue is the first FOLIC ACID event in wound tissue remodeling. Vitamin C It plays a vital role in various is also necessary for bone remodeling due to intracellular reactions e.g. conversion of the presence of collagen in the organic matrix of bones. It is also required for conversion of serine to glycine, synthesis of thymidylate, folic acid to folinic acid, biosynthesis of adrenal synthesis of purines, histidine metabolism steroids, catecholamines, oxytocin and ADH; etc. Due to folic acid deficiency these metabolism of cyclic nucleotides and reactions are affected. prostaglandins. Deficiency symptoms: The character- Deficiency symptoms: In vitamin C istic feature of folic acid deficiency is mega- deficiency scurvy develops. It is character- loblastic anaemia. Deficiency also leads to ized by ecchymosis, petechiae, swollen and glossitis, enteritis, diarrhoea, general debil- bleeding gums, subperiosteal haemorrhage, ity, weight loss and sterility. bones are painful to touch, impaired It is indicated in folic acid deficiency wound healing, anaemia, loosening of teeth states e.g. megaloblastic anaemia, tropical and gingivitis. 390 Section 10/ Vitamins and Trace Elements

It is indicated for treatment of scurvy, intestinal absorption of calcium and for prophylaxis of vitamin C deficiency, to decreasing the renal excretion. acidify urine, anaemia of vitamin C Calcium play vital role in excitation deficiency, as antioxidant to protect natural - contraction coupling in myocardium. colour and flavour of many foods, dental Calcium mediates contraction in caries and increased capillary fragility. vascular and other smooth muscles. Dosage: Calcium is required for exocytosis and also involved in neurotransmitters Adults: Prophylaxis : 50-500 mg daily. release. Calcium also help in maintain- Pregnancy and lactation: 100-150 mg ing integrity of mucosal membranes and daily. mediating cell adhesions. Hypercalcemia CALCIUM may occur in hyperthyroidism, Calcium is the most abundant body vitamin D intoxication and renal constituent (approx. 2% of body weight). It insufficiency, which can be treated by controls excitability of nerves and muscles administration of calcitonin, edetate and regulates permeability of cell sodium, oral phosphate etc. Hypocal- membranes. It act as intracellular messenger cemia may occur in hypothyroidism, for hormones and autacoids and help in malabsorption, osteomalacia second- coagulation of blood. ary to leak of vitamin D or vitamin D resistance, pancreatitis and renal Plasma calcium level is precisely regu- failure. Hypocalcemia can be treated lated by three hormones e.g. parathormone, by chloride, gluconate, gluceptate, calcitonin and calciferol (which is a active form of vitamin D). They control its absorp- lactate and carbonate salts of calcium. tion, exchange with bone and excretion. TRACE ELEMENTS Calcium is present in three forms e.g., as free calcium ion, bound to plasma protein NICKEL albumin and in diffusable complexes. The endocrine system, through parathyroid It is an essential trace element for mam- hormone and calcitonin, helps in keeping mals, but little is known about its role or the concentration of ionized plasma requirement in human metabolism. In calcium in normal level. Decrease in plasma humans, serum levels of nickel are about levels of ionized calcium leads to increased 1.1 to 1.6 mcg/l. This level increases in parathyroid hormone secretion. conditions such as stroke and acute myo- Parathyroid hormone tends to increase cardial infarction. A dietary requirement plasma calcium level by increasing bone for adults is about 30 mcg/day. resorption, increasing intestinal absorption Nickel occurs mainly in plant foods, and increasing reabsorption of calcium in especially grains and vegetables with little kidney. Vitamin D acts by stimulating in animal food sources or fats. Vitamins and Trace Elements 391

CHROMIUM tions, other minerals sometimes can sub- Less than 6 mg of chromium is found in stitute for manganese. the body, with the highest concentrations MOLYBDENUM occurring in the adrenal glands, brain, skin, muscles and fat. Molybdenum is found primarily in the liver, kidneys, bone, skin and adrenal glands. The total body content of chromium is estimated to be 6 to 10 mg. The recommended Organ meats, legumes and grains are good sources. The adequate range of safe limit for daily chromium intake by adult molybdenum intake for adults is 75 to 250 is 0.05 to 0.2 mg. mcg/day. It is equally excreted in the urine MANGANESE and the faeces. The body contains only 20 mg of Because molybdenum is a copper manganese, found mostly in the bones and antagonist, high levels of copper decrease glands. The plasma level is low, about 2.5 the absorption of molybdenum. It is equally excreted in the urine and the faeces. mcg/dl. Molybdenum is a cofactor for enzymes The best sources of manganese are involved in protein synthesis. wheat bran, dried legumes, seeds, nuts and leafy green vegetables, other good sources SELENIUM are cereal grains, coffee and tea. The Selenium is an essential trace element adequate range in adult diet is 2.5 to 5.0 in the human body. This nutrient is an im- mg/day. portant part of antioxidant enzymes that Manganese is a cofactor of enzymes protect cells against the effects of free radi- involved in energy metabolism and is re- cals that are produced during normal oxy- quired for hemoglobin synthesis, thiamin gen metabolism. Selenium is also essential utilization and tendon and bone formation. for normal functioning of immune system Unlike nutrients that fulfil unique func- and thyroid gland.

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Chelating Agents and Treatment of Poisoning

Chelat ng Agents & Treatment of Po son ng This page intentionally left blank ChelatingChelating AgentsAgents && ChapterChapter PharmacodynamicsPharmacodynamics (ModeTreatmentTreatment of Action of Drugs) ofof 11.11.4 PoisoningPoisoning

Antidotes are used in life threatening iii. Systemic antidotes: They produce the situations and are administered for a short action which are opposite to that of treatment course. They can be divided into poison e.g. caffeine for morphine and three main categories: atropine for pilocarpine. • Antidotes that remove active poison iv. Universal antidotes: These antidotes from its site of action e.g. hydroxylamine can be given in all such conditions used in anticholinest- where nature of poison is not known erase poisoning. or where more than one poison is • Antidotes that act pharmacologically suspected to be taken e.g. charcoal as e.g. naloxone used in opioid poisoning. adsorbent of toxins and alkaloids, • Antidotes that antagonised other tannic acid for precipitating alkaloids, macromolecules e.g. carbon monoxide glycoside and many metals. produce poisonous condition by binding the haemoglobin and other CHELATING AGENTS cellular components. Chelating agents are widely used as specific The antidotes are classified into four antidotes for heavy metals. They form stable, main types. soluble, nontoxic complexes and in easily i. Mechanical antidotes: These sub- excreted form. They promote dissociation of stances interfere with the absorption of bound metal from tissue enzymes and other poison. They act by forming a coat over functional macromolecules. These metal mucous membrane of the stomach. e.g. chelates are water soluble. e.g. EDTA, BAL, fats, oils, albumin, activated charcoal desferrioxamine etc. is specifically used in adsorbing alka- loidal poisons. DIMERCAPROL (BRITISH ANTI ii. Chemical antidotes: They react with LEWISITE, BAL) poison to form harmless insoluble form It acts by forming chelation com- e.g. acids are neutralised by alkalis, plexes between its sulphydryl groups and

KMnO4 used in opium poisoning. metals. Its effectiveness is much more, if 396 Section 11/ Chelating Agents & Treatment of Poisoning given immediately after exposure to the Dose: CILAMIN; 0.5-1 g/day in metal. divided dose. It is given by parenteral route (deep IM injection) and has short plasma half life. DESFERRIOXAMINE Adverse effects include increased It is a iron chelating agent, available for blood pressure, burning sensation in lips, intramuscular, subcutaneous and mouth and throat; nausea, vomiting, intravenous administration. sweating, pain in chest, throat or hands; When injected, it forms a stable water- painful sterile abscess at site of injection; soluble iron complex (ferrioxamine) that haemolytic anaemia in patients with G-6- prevents the iron from entering into PD enzyme deficiency; hypertension, further chemical reactions and is readily tachycardia, salivation, lacrimation and excreted in the urine giving the urine a conjunctivitis. characteristic reddish colour. Some of it is It is indicated in metallic intoxication also excreted in the faeces via the bile. It due to arsenic, mercury, gold, bismuth, can also chelate aluminium and thus is lead, nickel, thallium and ; in conjunction with sodium calcium edetate useful in aluminium overload. It is for lead poisoning. It is also useful in primarily a chelator used in acute iron hepatolenticular degeneration (Wilson’s poisoning and chronic iron overload as in disease). It is contraindicated in iron and thalassemia patients needing multiple cadmium poisoning. transfusions. Dose: BAL; 2.5 to 5.0 mg/kg QID Adverse effects include flushing, depending upon the severity of the urticaria, hypotension, shock, tachypnoea, poisoning. hypoxaemia, tachycardia, cardiac arrhythmias, convulsions, erythema, D-PENICILLAMINE swelling, GIT disturbances, dysuria, fever, It is a monothiol, prepared by alkaline allergic skin rashes. Leg cramps on long term hydrolysis of benzyl penicillin and therapy and reversible ocular and auditory chemically it is beta-dimethylcysteine. disturbances have also been reported. It acts as a chelating agent which helps in elimination of heavy metal ions by DESFERAL forming stable soluble complexes which Acute iron intoxication: Initially 1 g IM can be easily excreted by the kidneys. followed by 500 mg every four hours for It is used in poisoning due to copper, two doses. Subsequent doses of 500 mg are mercury and lead; Wilson’s disease, given 4 to 12 hourly depending on response, cystinuria, scleroderma and rheumatoid arthritis. maximum 6 g in 24 hours. Adverse effects include skin rash, Patients with cardiovascular collapse: IV proteinuria, bone marrow depression, infusion 50 mg/kg/hour up to a maximum nausea and loss of taste sensation. of 80 mg/kg in 24 hours. Chelating Agents & Treatment of Poisoning 397

Chronic iron overload: 0.5 to 1 g IM are flushing, pulsating headache, nausea, daily. In addition 2 g IV infusion given vomiting, thirst, marked uneasiness, ver- separately with each unit of blood tigo, weakness, confusion, hypotension and transfused. circulatory collapse. After oral administration it is rapidly CALCIUM DISODIUM EDETATE absorbed from gastrointestinal tract. It is the calcium chelate of disodium Adverse effects include urticaria, edetate having high affinity for metals like allergic dermatitis, restlessness, tremor, lead, zinc, cadmium, copper, manganese dizziness, metallic taste, fatigue, decrease and some radioactive metals. Given by IV in sexual potency and lassitude. route, it is distributed extracellularly and excreted unchanged in urine by glomerular It is indicated in chronic alcoholism filtration carrying the toxic metal along. in a dose range of 1 g on 1st day, 0.75 g on 2nd day, 0.5 on 3rd day, decreasing to It is primarily indicated in lead 0.125-0.25 g/day. Sensitization to alcohol poisoning. It is also useful in iron, zinc, develops after two to three hours of first copper, manganese and radioactive metal dose and lasts for 7 to 14 days after but not mercury poisoning. stopping it. Adverse effects include nephrotoxic- ity, anaphylactoid reaction, chills, bodyache LEUCOVORIN and malaise. It is used as leucovorin calcium (calcium folinate). It is 5-formyl derivative DEFERIPRONE of tetrahydrofolic acid and it acts as an It is an orally active iron chelator. It is antidote to folic acid antagonists like useful in acute iron poisoning, iron methotrexate or pyrimethamine which overload in cirrhosis, transfusion siderosis inhibit the enzyme dihydrofolate in thalassemia patients. Adverse effects reductase. are anorexia, vomiting, altered taste, joint Well absorbed by the oral or IM route pain and neutropenia. and is rapidly converted to biologically DISULFIRAM (ESPERAL) active folate. Distribution occurs to all body tissues and it is concentrated in the CSF. It It is relatively nontoxic, used as an is excreted in the urine. adjunct in the treatment of chronic alcoholism. Adverse effects include pyrexia which occurs rarely. It exerts its action by inhibiting alde- hyde dehydrogenase enzyme. Disulfiram It is indicated in overdose of thus increases the concentration of acetal- methotrexate, folic acid antagonists and as dehyde in body when ethanol is ingested adjuvant treatment of colorectal carcinoma. by an individual pretreated with disul- Dose: NYRIN; 120 mg per day by IM firam. The symptoms and signs produced or IV infusion. 398 Section 11/ Chelating Agents & Treatment of Poisoning

PRALIDOXIME dopamine. In tissues from rat brain, It causes reactivation of the produced greater inhibition of phosphorylated acetylcholinesterase dopamine reuptake than noradrenaline reuptake; however in, in vivo models, enzyme. After administration, it is bupropion is a stronger inhibitor of no- metabolised in liver. radrenaline than dopamine reuptake. The Adverse effects include blurred vision, metabolites and dizziness, diplopia, headache, tachycardia, threohydrobupropion are pharmacologi- mild weakness and nausea. In high dose it cally active in vitro and in animal models can cause neuromuscular blockage. of depression and are expected to con- It is indicated as antidote for organo- tribute to the therapeutic effects of phosphorus poisoning like malathion, bupropion. TEPP, parathion etc. Adverse effects include abdominal pain, chest pain, facial edema, nausea, dry NICOTINE mouth, constipation, diarrhoea, anorexia, Nicotine is a tertiary amine compound mouth ulcer, thirst, myalgia, arthralgia, composed of a pyridine and a pyrrolidine anxiety, disturbed concentration, dizziness, ring. It binds selectively to acetylcholine nervousness, tremor, dysphoria, rhinitis, receptors at the autonomic ganglia in the increased cough, pharyngitis, sinusitis, dyspnea, epistaxis, agitation, insomnia and adrenal medulla at neuro-muscular headache. junction and in the brain. It exerts a stimulating effect in the cortex and a It is indicated in smoking cessation in ‘reward’ effect via the ‘pleasure system’ in the dose of 150 to 300 mg twice daily. the limbic system. TREATMENT OF POISONING Adverse effects include erythema, pru- ritus or burning at the site of application, The treatment of different drug poison- headache, somnolence, dizziness, arthral- ing is discussed in individual chapters. gia, myalgia, dyspepsia, dry mouth, diar- In this section, general treatment is rhoea, sweating, BP changes, angioneurotic discussed. edema, urticaria and dyspnea. The general principles of treatment are: It is used in the treatment of nicotine 1. Support ventilation. dependence and as an aid to stop smoking. 2. Maintain cardiovascular function. BUPROPION 3. Reverse hypothermia if present. 4. Treat convulsions. The mechanism by which bupropion acts as an aid in smoking cessation is un- 5. Correct fluid, acid-base and electrolyte known. Bupropion weakly inhibits neu- imbalance. ronal reuptake of noradrenaline and se- 6. Relieve pain. rotonin and inhibits the reuptake of 7. Good nursing care. Chelating Agents & Treatment of Poisoning 399

Prevention of Poison Absorption Frequent administration of activated The aim is to reduce the absorption of charcoal is effective for the following poison. substances: 1. Substances which form masses: Aspirin, 1. Gastric lavage may be useful for six iron, lithium, enteric-coated tablets, hours after ingestion of poison. The meprobamate. lavage should be done as early as possible but only if vital functions are 2. Substance which remain in the stomach adequate. for a long time: Barbital, aspirin, iron, alcohol, cholinergic blockers, narcotic 2. It is inappropriate to employ gastric drugs, phenytoin, antidepressants. lavage unless the lungs can be protected, either by virtue of patient 3. Substances which have a long half-life having an adequate cough reflex or by when present in large amounts: Theo- means of a cuffed endotracheal tube. phylline, aspirin, alcohol, phenytoin, chloral hydrate, acetaminophen. 3. Gastric lavage is contraindicated if 4. Substances which have active metabolites: corrosive or caustic substances have Benzodiazepines, chloral hydrate, been taken, because oesophageal and acetaminophen, antidepressants, gastric erosion and perforation may procainamide. occur. 5. Substances whose poisonous metabolites are 4. Activated charcoal is probably more eliminated slowly: Ethylene glycol, metha- effective than either emesis or lavage. nol, primidone, isopropyl alcohol, car- Accelerating Poison Elimination bon tetrachloride, levothyroxine. Alkalinisation of urine (alkaline 6. Substances which are reabsorbed from the diuresis) is effective for salicylates and urinary tubules in a pH dependent manner: phenoxyacetate herbicides. Phenobarbital, aspirin, amphetamine. 7. Substances with persistent tissue accumu- Repeated dose of activated charcoal lation: Iron, lithium. administered by oral route have been shown to enhance the non-renal elimi- 8. Substances which enter the enterohepatic nation of carbamazepine, salicylates, circulation: Carbamazepine, digoxin, phenobarbitone, phenytoin, digoxin, phenobarbital. The specific antidotes for various theophylline and meprobamate. In se- poisons are listed in table 11.1.1 vere cases activated charcoal is to be ad- ministered via a nasogastric tube. ORGANOPHOSPHORUS POISONING Haemoperfusion, using a cartridge These compounds are mainly used as containing charcoal or an uncharged resin agricultural and household insecticides. is effective in enhancing drug excretion in The poisoning may be occupational (for few selected cases of poisoning e.g. those who are involved professionally with theophylline, barbiturates, non-barbiturate these agents), accidental (accidental con- hypnotics, etc. (Also see Section I for the sumption) or suicidal due to intentional management of poisoning). ingestion of these compounds. 400 Section 11/ Chelating Agents & Treatment of Poisoning

Table 11.1.1 List of specific antidotes for various poisons. Poison Antidote 1. Arsenic Dimercaprol, BAL, D-penicillamine 2. Cyanide Oxygen (100%), dicobalt edetate, Amyl nitrite, sod. nitrite 3. Ethylene glycol, methanol Ethanol 4. Opioids Naloxone 5. Organophosphorus insecticides Atropine and mesylate 6. Iron Desferrioxamine 7. Beta-blockers Atropine for bradycardia, glucagon 8. Digoxin Digoxin specific antibody fragments (DIGIBIND) 9. Carbon monoxide Oxygen (100%) 10. Oral anticoagulants Vitamin K (phytomenadione) 11. Heparin Protamine sulfate 12. Lead (inorganic) Sodium calcium edetate, D-penicillamine 13. Mercury (inorganic) Dimercaprol, D-penicillamine, BAL 14. Methanol Ethanol 15. Paracetamol, gold N-acetylcysteine 16. Benzodiazepines Flumazenil 17. Atropine Physostigmine 18. Isoniazid Pyridoxine 19. Folic acid antagonists Folinic acid 20. Acetaminophen (Paracetamol) N-acetylcysteine 21. Copper BAL, EDTA D-penicillamine 22. Methotrexate Folic acid, Leucovorin 23. Snake bite Antisnake venom polyvalent 24. Hydroxzines Pyridoxine 25. Theophylline Esmolol 26. Curare compounds Neostigmine 27. Insulin Glucose

a. Local exposure produces miosis, 2. Maintenance of a patent airway. Use spasm of accommodation, headache, oropharyngeal or nasopharyngeal irritation of eye, lacrimation and airway or endotracheal intubation if blurring of vision. airway obstruction persists. b. On ingestion fall in blood pressure, ta- 3. Washing of skin, mucous membrane chycardia, cardiac arrhythmias, ataxia, and eye. convulsion, respiratory paralysis and 4. Supportive therapy: Maintenance of vasomotor collapse occurs. The death blood pressure, artificial respiration, is generally due to respiratory failure. rehydration (fluid/electrolyte therapy) Treatment and control of convulsions. 1. Gastric lavage, fresh air for 5. Antidote/Reactivators. termination of further exposure to a. Atropine is highly effective in compound. counteracting the muscarinic Chelating Agents & Treatment of Poisoning 401

symptoms. It is given in a dose of 2 and available in 200 mg tablet. The mg IV every 10 min till muscarinic treatment is initiated with 800 mg single effects are controlled. dose which is gradually reduced over 5 days b. The cholinesterase reactivators are used to a maintenance dose of 100 to 200 mg to restore neuromuscular transmission. daily and treatment may be continued up Pralidoxime (pyridine-2-aldoxime to one year. methiodide; 2-PAM) is an antidote and After a week’s therapy, if a small cholinesterase reactivator. It breaks the quantity of alcohol is consumed by the bond between the organophosphate patient, it produced unpleasant toxic poison and the molecular surface of reactions such as flushing, palpitation, acetylcholinesterase and the enzyme is nausea, vomiting throbbing headache, freed and reactivated to hydrolyse the uneasiness, dizziness, visual disturbances, excess of acetylcholine at the receptor fall in blood pressure and even collapse. sites. It is to be given in the dose of 1-2 The patient thus realizes that during the g IV infusion along with 100-200 mg treatment he can not tolerate even a small of atropine. amount of alcohol and would abstain from Other cholinesterase reactivators are alcohol drinking. diacetylmonoxime (DAM) which combines The drug disulfiram interferes with the with free organophosphate molecule in the oxidation of acetaldehyde formed during body fluids. It is administered 1-2 g IV slowly. the metabolism of alcohol. This increases the blood level of acetaldehyde which acts CHRONIC ALCOHOLISM directly on cardiovascular system and It is associated with development of produce these toxic reactions. Disulfiram psychic dependence, tolerance and physical also inhibits dopamine beta oxidase and dependence and sudden withdrawal of thus interferes with the synthesis of alcohol may lead to withdrawal syndrome. noradrenaline, which causes depletion of catecholamines. In addition, the alcohol addicts are li- able to other neuropsychiatric syndrome Disulfiram is slowly absorbed incom- (Korsakoff’s psychosis) which is associated pletely from the gut and is metabolised with hallucination, suicidal tendencies and slowly. encephalopathy. They may also suffer from METHYL ALCOHOL (METHANOL) hyperlipidemia, hyperuricemia, pancreati- tis and hepatitis. Methyl alcohol is only used to denature ethyl alcohol in 5 percent concentration. It Drug Treatment of Chronic Alcoholism is metabolised to formaldehyde and formic (Aldehyde Dehydrogenase Inhibitors) acid by alcohol and aldehyde dehydroge- nases. Its absorption and distribution are DISULFIRAM similar to ethyl alcohol. Chemically it is tetraethyl thiuram Ingestion of methyl alcohol produces disulphide, commonly known as antabuse the following signs and symptoms: 402 Section 11/ Chelating Agents & Treatment of Poisoning

• Nausea and vomiting. Generalised (Systemic) Symptoms & • Blurring of vision, hyperemia of optic Signs disc and blindness. • Nausea, vomiting, malaise, abdominal • Pancreatitis. pain weakness. • Albuminuria. • Visual disturbances, faintness, collapse, • Coma followed by death. shock, hypotension, pulmonary edema & conjunctival edema. Treatment of Methanol Poisoning • Bleeding & clotting disorders. • Gastric lavage, activated charcoal. • Skeletal muscle breakdown. • Hospitalization: Correction of • Acute pituitary/adrenal insufficiency. acidosis. First-aid Treatment • IV/oral ethyl alcohol. • First aid treatment is carried out • Maintenance of nutrition. immediately before hospitalisation. • Administration of folinic acid (1 mg/ • Immobilise the bitten limb with a splint kg, IV) together with folic acid (1 mg/ or sling. kg IV) to accelerate the metabolic • Consider pressure-immobilisation for degradation of formate. some elapid bites. • Administration of 4-methylpyrazole • Avoid any interference with the bite (inhibitor of alcohol dehydrogenase). wound as this may introduce infec- • In severe case: Haemodialysis. tion, increase absorption of the venom and increase local bleeding. TREATMENT OF SNAKE BITE • Tight (arterial) tourniquets are not Vipers, Cobras and Kraits are the common recommended. poisonous snakes and in India 40,000 to 50,000 deaths recorded per year due to Treatment in hospital snake bite. • Rapid clinical assessment and resuscitation. Local Signs & Symptoms in the Bitten • History (especially the snake identifi- Part cation). • Fang marks. • Physical examination. • Local pain & bleeding. • Investigation/laboratory tests: • Bruising. – 20 minute whole blood clotting test • Lymphangitis. (20 WBCT). • Inflammation (swelling, redness, – Haemoglobin concentration/ heat). haematocrit. • Blistering. – Platelet count. • Lymph node enlargement. – WBC count. • Local infection, abscess formation & – Biochemical abnormalities. necrosis. – Urine examination etc. Chelating Agents & Treatment of Poisoning 403

Supportive Therapy bulin purified from the serum or plasma of a Blood pressure, ECG, blood gas analysis, horse or sheep that has been immunised with urine output and respiration are to be the venoms of one or more species of snake. monitored. To correct coagulation Antivenom should be given by the intrave- parameters, blood transfusion may be nous route. Freeze dried (lyophilised) needed. antivenoms are reconstituted, usually with 10 ml of sterile water for injection per am- ANTISNAKE VENOM poule. Adrenaline should always be drawn Antivenom is the only specific antidote up in readiness before antivenom is adminis- to . Antivenom is immunoglo- tered for any possible anaphylactic reactions.

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Dental Pharmacology This page intentionally left blank ChapterChapter PharmacodynamicsPharmacodynamicsAntiseptics & 12.11. 4 (ModeDisinfectants of Action of Drugs)

These are the agents which inhibit or kill Factors which Modify the Activity of microbes on contact. Conventionally Germicides • Antiseptics are used on living 1. Temperature & pH. surfaces. 2. Period of contact with the microor- • Disinfectants are used for inanimate ganisms. objects. 3. Nature of microbes involved. The practical distinction of these two – Spectrum of activity of majority of agents is on the basis of a growth inhibiting antiseptic disinfectants is wide re- or direct lethal action. There are flecting non selectivity of action. concentration dependent. Germicide covers However, some are selective e.g. these two category. Potency of germicide is hexachlorophene, chlorhexidine, generally expressed by its “phenol quarternary ammonium antisep- coefficient or Rideal Walker (RW) tics, gentian violet, acriflavine are coefficient” – “which is the ratio of the more active for gram +ve than gram minimum concentration of the test drug –ve. Silver nitrate is highly active required to kill a 24 hour culture of B. typhosa against gonococci and benzoyl in 7.5 minutes at 37.5°C to that of phenol peroxide against P. acnes. (as standard) under similar conditions.” 4. Size of inoculum. In dentistry, they are used for sterilization of certain instruments and 5. Presence of blood, pus & other organic prevention and treatment of dental plaque matter. and peridental diseases. They are also used Mechanism of Action (Cidal or in root canal therapy (RCT), treatment of Inhibiting Action) acute necrotizing gingivitis and other infective oral conditions. Antiseptics and i. Oxidation of bacterial protoplasm. disinfectants are also used as ingredient in ii. Denaturation of bacterial proteins various dentifrices. including enzymes. 408 Section 12/ Dental Pharmacology

iii. Detergent like action increasing • Hexachlorophene: permeability of bacterial membrane. – Act by inhibiting bacterial enzyme and in high concentration cause Classification bacterial lysis. i. Phenol derivatives. – Incorporated in soap & other ii. Oxidizing agent. cleansing antiseptics. Also acts as iii. Halogens. deodorant. iv. Biguanides. – Highly active against gram +ve microorganisms. v. Quarternary ammonium compounds. Phenol is used to disinfect urine, faeces, vi. Acids. pus, sputum of patients and sometime vii. Metallic salts. included in antipruritic preparation viii. Dyes. because of its mild anaesthetic action. ix. Furan derivatives. x. Alcohol. OXIDIZING AGENTS xi. Aldehydes. 1. Potassium permanganate (KMnO4): xii. Soaps. lWater soluble purple crystals. • Liberates oxygen which oxidizes PHENOL DERIVATIVES bacterial protoplasm. • Potassium permanganate (KMnO ) is Used as disinfectants 4 used as Condy’s lotion (1 : 4,000 to 1 : • Phenol (carbolic acid): Acts by 10,000 solution). denaturing bacterial proteins. • As antiseptic: • Methylphenol (cresol; LYSOL): 3-10 – Used for gargels, irrigating cavities, times more active. urethra & wounds. • Resorcinol: 1/3 as potent as phenol – Higher concentration cause burns (used both as an antiseptic/ & blistering. disinfectant). Used as antiseptic. • As disinfectants: • Hexyl-resorcinol: More potent. Used – To disinfect water (well, ponds) & as mouth wash, lozenges & as anti- for stomach wash in alkaloidal fungal. poisoning (except atropine & • Chloroxylenol: cocaine which are not efficiently – 4.8% sol. (DETTOL): Used for oxidized). surgical antisepsis. – Not suitable for surgical – 1.0% sol. (DETTOLIN) used as instruments (promotes rusting).

mouth washes, 0.8% cream & soap; 2. Hydrogen peroxide (H2O2): 1.4% lubricating obstetric cream – Used as antiseptic. (for vaginal examination). – Removes slough, ear wax etc. Antiseptics & Disinfectants 409

– Used in cosmetic preparation. – More than 5% can cause burning – As gargels. & blistering of skin. – Potency loses on keeping and not • Iodophores: much used. – Are soluble complexes of iodine 3. Benzoyl peroxide (PERSOL 2.5, 5.0% with large molecular organic gel, 10% cream): compounds that serve as carrier – – Used in acne. release free iodine slowly. – Gradually liberates oxygen (in the Povidone (polyvinyl pyrrolidone): presence of water) which kills – BETADINE (5% sol.; 5% ointment; bacteria, specially anaerobic. 200 mg vag. pessaries). – Mild irritant to skin. – 1% mouth wash. – Can cause dryness of skin, edema etc. – 10% solution. – 10% cream. HALOGENS – 5% spray (aerosol) (RANVIDONE AEROSOL): Used in boils, burns, 1. Used as disinfectants: ulcers, non-specific vaginitis & all • Chlorine: surgical dressings. Also for disinfec- – Highly reactive element & potent tions of endoscopes and instruments. germicide. – 0.1-0.25 ppm kills most pathogens • Chlorophores: in 30 secs. – Compounds that slowly release – Used to disinfect urban water hypochlorous acid (HOCl). supplies. – Used in preference of gaseous – More active in acidic & neutral chlorine due to ease of handling. medium. • Chlorinated lime (bleaching 2. Used as antiseptic: powder): • Iodine: – Used as disinfectant for drinking – Act by iodinating and oxidizing water, swimming pools & sanitizer microbial protoplasm. for privies etc. – 1:20,000 solution kills most • Sodium hypochlorite solution (4-6% vegetative forms within 1 min. sod. hypochlorite): – Tr. iodine (2%) in alcohol: Used – Used as disinfectant in dairies for on cuts, for degerming skin before milk. surgery. – Used for root canal therapy in – Mandel’s paint (1.25%): Used in dentistry as antiseptic. sore throat. – Non-staining iodine ointment (4% • Chlorinated lime (1.25%) with boric – IODEX) used as counter irritant acid (1.25%) (EUSOL): & antiseptic. – Used to clean infected wounds. 410 Section 12/ Dental Pharmacology

• Chloramine-T and halazone: • Benzalkonium chloride: 1 : 5000-1 : – Used as sanitizer. 10,000 sol. used for douches, irrigation etc. BIGUANIDES – Used as preservative for eye/ear/ nasal drops. • Chlorhexidine: • Dequalinium chloride: – Having high antiplaque activity. – As an antiseptic used in gum paints – Used as antiseptic. & lozenges. – Nonirritating antiseptic that disrupts bacterial cell membrane. ACIDS – More active against gram +ve bacteria • Boric acid: – Used for surgical scrub, mouth- – Bacteriostatic & weak antiseptic. wash, neonatal bath & general skin – 4% sol.: Used for irrigating eyes, antiseptic. mouth washes, douche etc. – Boroglycerine paint (30%): Used QUARTERNARY AMMONIUM ANTISEPTICS for stomatitis & glossitis. (CATIONIC) – 10% ointment (BOROCIDE): Used for cuts & abrasion. – Act by altering permeability of cell • Acetic acid: membranes. – Weak antiseptic. – Soaps (being anionic) neutralise their – Bactericidal (>5%). action while alcohol potentiates. – Occasionally used for burn dressing. – Non-irritating & mild keratolytic.

• Cetrimide: METALLIC SALTS – 20% sol. (CETAVLON). – Chlorhexidine gluconate (1.5%) + a. Mercury compounds: Act by cetrimide (3%) [SAVLON LIQUID]. inactivating SH enzymes and acts as – SAVLON CREAM: Chlorhexidine bacteriostatic. (0.1%) + cetrimide (0.5%). • Ammoniated mercury: – SAVLON HOSPITAL CONCEN- – 5-10% ointment: Used for TRATE: Chlorhexidine (7.5%) + dermatophytosis & anal pruritus. cetrimide (15%). – Phenyl meruric nitrate: EPHYTOL – Also used in soaps, shaving creams. PAINT used for tinea. MEDITHANE – Used for cleansing action. – anorectal use. – Used as antiseptic & disinfectant – Merbromin 1-2% solution (MERCU- for surgical, instruments, utensils, ROCHROME): Used in first aid kit. baths etc. b. Silver compounds: • Cetylpyridinium chloride (similar to – Astringent action.

cetrimide): Used in mouth wash & in – React with SH, COOH, PO4 & NH2 lozenges. groups of proteins. Antiseptics & Disinfectants 411

• Silver nitrate: – Combination of gentian violet – Rapidly kills microbes, action per- (0.25%) + brilliant green (0.25%) + sisting for long periods because of acriflavine (0.1%) (TRIPLE DYE): slow release of Ag+ ions from silver Used for burns & for dressing proteinate formed by interaction umbilical stump in neonates. with tissue proteins. – Silver nitrate touch is used for FURAN DERIVATIVES hypertrophied tonsillitis and aphthous ulcers. • Nitrofurazone (FURACIN 0.2% – Highly active against gonococci cream, ointment, powder): (10% sol.). – Bactericidal to both gram +ve & – ve, aerobic & anaerobic bacteria. • Silver sulphadiazine (SILVEREX – Highly effective in burns & for skin 1%): grafting. – Highly active against Pseudomonas. – Act by inhibiting enzymes neces- – Used in burns. sary for carbohydrate metabolism c. Zinc salts: Astringent & mild in bacteria. antiseptic. • Zinc sulphate: ALCOHOLS (ETHANOL) – 0.1-1.0% solution used for eye wash and eye/ear drop (ZINCOSULFA – Act by precipitating bacterial proteins. eye drops). – Effective antiseptic & cleansing agent – Lotion containing zinc sulfate & at 40-90% concentration (above 70% saturated potash (THIOSOL 2.5% antiseptic & up to 90%). 24%): Used in acne. – Used for hypodermic inj. & on minor – Zinc oxide and calamine: Used as cuts. dermal protectives & adsorbants. – In open wounds it produces burning sensation DYES – Poor disinfectant for instruments (does not kill spores & promotes rusting). • Rosaniline dye: • Isopropanol: Used as substitute of – Gentian violet (0.5-1% alcoholic ethanol. solution): Effective against staphy- lococci, gram +ve bacteria & fungi. ALDEHYDES (FORMALDEHYDE) – Brilliant green: Rosaniline dye, similar to gentian violet. – It denatures proteins, general protoplasmic poison (but acts slowly). – Acriflavine & proflavine: Orange- yellow acridine dye. ACRINOL – Broad spectrum germicide. 0.1% cream. Effective against gram – Use as antiseptic is restricted because +ve bacteria & gonococci. Activity of its irritating nature & pungent odor. enhanced in alkaline medium. Used – 4% solution is used for hardening & in chronic ulcers & wounds preserving dead tissues. 412 Section 12/ Dental Pharmacology

– 37% sol. is called FORMALIN. SOAPS – Occasionally used to disinfect instruments & excreta. – Anionic detergent. – Weak antiseptic, mainly used for • Glutaraldehyde: cleansing action. – Less volatile, less pungent, less – Affect only gram +ve bacteria. irritating. 2% solution is used to – Medicated by other antiseptic & herbal disinfect surgical instruments & origin compounds (DETTOL, SAVLON, endoscopes. NEEM, MEDIMEX etc).

 ChapterChapter PharmacodynamicsPharmacodynamicsAstringentAstringent andand 12.21. 4 (ModeObtundentsObtundents of Action of Drugs)

ASTRINGENTS ZINC CHLORIDE It is a caustic astringent, used as 5-10% Astringents act by precipitating proteins in solution in ulcerative gingivitis, pyorrhoeal superficial layers of cells and are used to pockets and apthous ulcers. diminish the excretion or exudation of superficial cells. They are also used as local ZINC SULPHATE haemostatics and mummifying agents (discussed elsewhere). The different types It is used as astringent in 0.5-1% of astringents used in dentistry are: concentration in the form of mouthwash and lotion in mastoiditis, stomatitis and TANNIC ACID chronic alveolar abscess It is vegetable astringent obtained from nutgalls. It acts by precipitating protein COPPER SULPHATE and gelatin as tannates owing to its acid It is used as astringent mouth in 0.5- radical. While hardening the superficial 2% concentration in indolent ulcer of gums. cells it forms pellicle on them. Tannic acid glycerine (30% tannic acid) and mouth- ALUM washes/gumpaints containing 1-5% of It has an astringent, antiseptic and tannic acid are used to strengthen gums haemostatic properties and used in 1-2% and check bleeding. Its preparations are concentration to harden the gum or for used as astringent mouth wash, astringent dentrifices, local haemostatics, mummify- inflamed and ulcerated gums. ing agent and obtundent. Certain other metallic astringents e.g. Another astringent of vegetable origin ferric chloride solution, lead acetate, silver i.e. catechu is also used as an astringent nitrate, mercuric chloride etc. are used as mouthwash. astringents in dentistry. 414 Section 12/ Dental Pharmacology

OBTUNDENTS PHENOL On local application, it causes Obtundents are the agents which are used to irritation followed by numbness. It is used either diminish or eliminate the dentine alone and in combination with chloroform sensitivity to make the excavation painless. But and olive oil in a 2:4:10 ratio. It acts rapidly due to the availability of local anaesthetics e.g. but does not penetrate deeply and due to xylocaine for painless excavation, the use of its protoplasmic poisonous nature it obtundents is very limited. produces its obtundent action. An ideal obtundent should possess the CREOSOTE following characteristics Its characteristics and action is same as (i) It should remove dentive sensitivity that of phenol, in addition its penetrability and penetrate the dentine sufficiently. is relatively more. (ii) It should not stain the dentine. BENZYL ALCOHOL (iii) It should be free from any local Due to its local anaesthetic property it is irritation or pain. used as obtundent agent. It can be used Obtundents may be classified into three either alone or in combination of chloroform main categories according to their and ethyl alcohol in a 5:3:2 ratio. mechanism of action. I Act by destroying the nervous tissue CAMPHOR, THYMOL, – Absolute alcohol All three are volatile oils and are used in II Act by paralysing the sensory nerve a mixture in a ratio of 1:2:1 for rapid action. endings The mixture acts initially stimulating and – Phenol creosote then paralysing the sensory nerve endings. – Benzyl alcohol EUGENOL (CLOVE OIL) – Camphor Clove oil is used due to the presence of – Thymol eugenol as its main constituent. It acts by – Menthol paralysing the sensory never endings. It is – Eugenol (clove oil) non-irritating but stains the dentine yellow. III Act by precipitating proteins SILVER NITRATE – Silver nitrate It is an astringent and caues pain on – Zinc chloride application followed by desensitization. It acts by precipitating dentine proteins and ETHYL ALCOHOL liberating acid and stains the dentine black. Ethyl alcohol (70%) is painless and nontoxic to the pulp and penetrates rapidly. ZINC CHLORIDE It does not cause staining of the dentive. It Its action is similar to that of silver is to be applied locally, allow the alcohol to nitrate but it causes sharp pain and does evaporate and carry out the excavation. not stain the dentine.  ChapterChapter PharmacodynamicsPharmacodynamicsMummifying and 12.31. 4 Bleaching(Mode of Action Agents of Drugs)

MUMMIFYING AGENTS PARAFORM (PARAFORMALDEHYDE): It is a prodrug used in combination of In dentistry, when astringents and zinc oxide or zinc sulphate glycerine and antiseptics are used to harden and dry creosote and act by slow liberation of tissues of the pulp and root canal so that fomaldehyde. It is also used alone as the tissues are resistant to infection, they obtundents. Its main disadvantage is that are termed as mummifying agents. It is used formaldehyde may penetrate the pulp and in certain dental procedures when it is not can cause inflammation. possible to completely remove the pulp and Liquid formaldehyde is also used in the contents of root canal. For this, generally a form of paste with zinc oxide, glycerine combination of various mummifying agents along with local anaesthetic and it hardens are used in the form of paste or semi-liquid the tissue without causing the shrinkage. preparation like tannic acid glycerine. The following are mummifying agents IODOFORM used in dentistry. It acts by slow liberation of iodine and has both antiseptic and local anodyne TANNIC ACID properties. It is used in the form of paste It is an astringent which is yellowish which contains tannic acid, phenol, eugenol white to light brown amorphous powder (clove oil), cinnamon oil and glycerine. obtained from nutgalls (excrescences produced on the young twigs to Quercus TOOTHACHE DROPS infectoria which gradually darkens on These are the preparations used for tem- exposure to air and light. It is used along porary relief of toothache by application of with glycerine and it hardens the tissues a small pledget of cotton soaked with the and precipitates proteins and thereby product into the tooth cavity. Certain local avoids bacterial action. anaesthetic compounds. e.g. benzocaine, 416 Section 12/ Dental Pharmacology eugenol or clove oil, camphor, menthol, REDUCING AGENTS creosote and alcohol has been considered Saturated solution of sodium thio safe and effective for toothache but re- sulphate is used to remove superficial stains stricted its use only for first aid type or tem- with silver, iodine or permanganate. porary relief. CHLORINATED LIME BLEACHING AGENTS It is a chlorine compound, which acts Bleaching agents are used to remove by evolution of chlorine to remove the pigmentation of teeth. They are classified pigmentation of teeth. It is also used as clinically by packing into the cavity as a dry powder. (i) Oxidizing agents e.g. perhydrol, pyrozone, sodium peroxide ULTRAVIOLET RAYS (ii) Reducing agents e.g sodium thio To bleach the dentine from a carbon or sulphate mercury, arc lamp UV rays have been used. (iii) Chlorinated lime Other agents are also available, which (iv) Ultraviolet rays are used to remove pigmentation of teeth OXIDIZING AGENTS e.g. weak ammonia solution is used to Hyrdrogen peroxide in various remove iodine stains, hypochlorite or iodine solution are used to remove silver stains, percentages e.g. perhydrol (30% H2O2 in water) and sodium peroxide (50% aqueous hypochlorites are used to remove iron solution) are used as oxidizing agents to stains of teeth and for dye stains, remove pigmentation of teeth. chlorinated lime and acetic acid are used.

 Styptics (Local ChapterChapter PharmacodynamicsPharmacodynamics Haemostatics) and Haemostatics)(Mode of Action of Drugs) and 12.41. 4 DisclosingDisclosing AgentsAgents

STYPTICS (LOCAL HAEMOSTATICS) cavities or tooth socket after tooth extraction. The evenly porous foam After tooth extraction and many dental structure absorbs its own weight in procedures, bleeding occurs due to blood several time over, promotes disruption of arterioles and minute blood thrombocyte aggregation due to large vessels which can not be surgically repaired surface and fills the wound cavity. It or sutured. Styptics or local haemostatics remains in the wound and is are the agents used to arrest bleeding, or to completely absorbed within four control oozing of blood form minute blood weeks. The addition of colloid silver vessel, by the formation of an artificial clot, has an antimicrobial effect whilst or by providing a matrix which facilitates being nontoxic and these type of bleeding. After extraction of tooth, bleeding preparations can be easily gamma sterilised. from the tooth socket is generally controlled by a cotton guaze pressure pack which (ii) Fibrin foam- Fibrin foam or sheets are may be aided by use of local haemostatics. prepared from human plasma and these dried sheets are used to cover or They can be categorized as pack the bleeding surfaces where it (i) Gelatin sponge- It is used for packing gets absorbed in the body. It is applied wounds after moistening with normal directly to the bleeding area and it is saline or thrombin solution which is also combined with thrombin. completely absorbed in 2 to 4 weeks (iii) Human or bovine thrombin- Dry and generally cause no foreign body powder or freshly prepared solution reaction. Gelatin sponge is also of human or bovine thrombin can be available with 5% colloid silver applied on the oozing surfaces and it (GELATAMP). It facilitates optimum is employed in haemophilia, skin wound treatment when applied to a grafting and in neurosurgery. surgical cavity and can be cut to the Thrombin solution with fibrinogen is required size to fit smaller wound also used locally to induce clotting. 418 Section 12/ Dental Pharmacology

(iv) Oxidized cellulose- It is a surgical (vii) Astringents- Tannic acid (20% in gauze, specially treated to promote glycerine) is used for bleeding gums clotting by reaction between and bleeding piles. haemoglobin and cellulosic acid. Since Certain systemic haemostatics e.g. it is not well absorbed it is used only tranexamic acid, ethamsylate etc. are also for surface haemostatics. used in the prevention and treatment of (v) Russel’s Viper venom- It has a strong capillary bleeding in epistaxis, haematuria thromboplastin activity and used in and after tooth extraction. haemophilia cases by applying locally. (vi) Vasoconstrictors - Adnenaline (1% DISCLOSING AGENTS solution) is used in the form of cotton- gauze pack in the bleeding socket. It A dye used in dentistry as a diagnostic acid, stops bleeding by causing local vaso- applied to the teeth to reveal the presence constriction and useful in epistaxis. of dental plague.

 ChapterChapter PharmacodynamicsPharmacodynamicsDentifricesDentifrices andand 12.51.4 MouthMouth(Mode of Action WashesWashes of Drugs)

DENTIFRICES 6. Should help to reduce caries, maintain healthy gingiva, improve aesthetics These are the agents or mechanical aids and reduce mouth odours. which are available as tooth powder, For getting all these properties in one paste, or gel and used with tooth brush to single oral preparation, the following cleanse and polish natural teeth. They are ingredients/agents are used together. prepared in the form of bulk powder and containing soap or detergent and mild 1. Abrasive agents abrasive agent which should have These are fine dental preparations maximum cleansing efficiency with used to help the scouring action to minimum tooth abrasion. toothbrush mechanically. And, abrasion is defined as the wearing Properties of an Ideal Dentifrice away of a substance or structure 1. An ideal dentifrice should assist the through a mechanical process, such toothbrush to mechanically remove as grinding, rubbing or scrapping. debris, soft deposits and stains from The abrasives is made into a paste the teeth. and supplied in a tube. 2. It should be non-decalcifying and non- Abrasives used in dentistry can be overabrasive to the teeth. classified into three categories. 3. It should impart a polished surface to (i) Finishing abrasives- They are hard, the teeth. coarse abrasives which are used 4. It swallowed, it should be non- initially to develop contour and poisonous to the body as a whole and remove gross irregularities e.g. coarse also to the mucous membrane. stones. 5. Should have pleasant taste and odour (ii) Polishing abrasives- They have fine and having sufficient cleansing particle size and less hard than property. abrasive used for finishing. They are 420 Section 12/ Dental Pharmacology

used for smoothening the surfaces that 2. Humectants have been roughened by coarse stones These are the agents which are e.g. pumice, polishing cakes etc. used to keep paste from drying out (iii) Cleansing abrasives- They are soft e.g. glycerine, sorbitol, propylene materials with small particle size and glycol etc. are used to remove soft deposits that 3. Detergents and foaming agents adhere to enamel or restorative These are cleansing agents and de- material. creases surface tension of dentrifrice. Commonly used abrasives are: Most common detergent used in dentistry is sodium lauryl sulfate. (i) Pumice- It is a highly siliceous material They cause loosening of debris which of volcanic origin and is used either adhere to teeth and also dissolving as an abrasive or polishing agent fatty substances and mucous plaques. depending upon particle size. It They also act as an lubricant when consists of aluminium, potassium and scrubbed over the teeth. sodium chiefly. It is available as pumice with glycerine and its use 4. Binders ranges from smoothening dentures to Carboxy methyl cellulose is the polishing teeth in the mouth. most commonly used binder in the (ii) Emery- It consists of a natural oxide dental preparation. of aluminium called corundum. The 5. Sweetening agents different impurities e.g. iron oxide Artificial sweeteners such as sorbitol present in it also act as an abrasive. saccharin is used as synthetic (iii) Aluminium oxide- It can be replaced sweetening agent which is more by emery for abrasive purpose. Pure palatable having no food value and alumina which is manufactured from can be used by diabetic patients. bauxite (an impure aluminium oxide) 6. Antiseptics/therapeutic agents is also used as a polishing agent. Certain antiseptic and therapeutic (iv) Chalk/precipitated calcium carbon- agents (such as sodium fluoride, ate- Chalk is a calcium carbonate pre- stannous fluoride, chloride, pared by precipitation method. Vari- urea, dibasic ammonium phosphate, ous grades of precipitated calcium are used in dentrifrices for their carbonate is available depending anticarcinogenic, bacteriostatic and upon its fineness, weight and colour. bactericidal actions. It is mild abrasive and used to give fi- nal polish to silver amalgam fillings. 7. Coloring and flavoring agents The other abrasive agents used are tin Certain coloring agents (methylene oxide, chromic oxide, sand, carbides (silicon blue (0.001%), magenta (0.05%) and carbide and boron carbide), zirconium flavoring agents (peppermint, clove silicate, zinc oxide, garnet, rouge (fine red etc.) are also used to make the powder of iron oxide), kieselgurh, tripoli, preparation more attractive, magnesium oxide, hydrated silica etc. palatable and acceptable. Dentifrices and Mouth Washes 421

8. Preservatives fatty acid esters may be used over anionic To preserve the quality and stability, surfactant e.g. sodium lauryl sulfate. They certain preservative e.g. methyl aid in the solubilization of flavours and in paraben etc. are also used in dental the removal of debris by its foaming action. preparations. Certain other agents e.g. cetylpyridinium chloride (cationic surfactant) is used for its MOUTH WASHES antimicrobial property. Mouthwashes are aqueous concentrated Flavouring agents— Flavouring agents solutions containing one or more active e.g. peppermint, spearmint, menthol, ingredients and . They are used cinnamon, oil of wintergreen (methyl by swishing the liquid in the oral cavity. salicylate) are used in conjunction with Approximately 15–30 ml. of mouthwash are alcohol and humectants to overcome used for single mouthful of rinse for about a disagreeable taste. minute. Mouthwashes can be used for Colouring agents— Certain colouring therapeutic and cosmetic purpose. agents (e.g. methylene blue, magenta etc.) Therapeutic mouthwashes are used to are used in mouthwashes for pleasing reduce plaque, dental caries, gingivitis and colour. stomatitis while cosmetic mouthwashes are used to reduce bad breath and it contains Medicated mouthwashes—Mouth- used antimicrobial and/or flavoring agent. washes are also being used as a dosage Mouthwashes other than used for cosmetic form in certain specific conditions in oral purpose, should only be used under the cavity e.g. direction of physician/dentist since it (i) Mouthwashes containing a contains certain medicines. combination of antihistaminics, Mouthwashes contain the following corticosteroids, antimicrobial agent ingredients and excipients: (nystatin, tetracycline etc.) have Alcohols—It is used in the range of 10- been prepared from commercially 20%. Alcohol enhances the flavor, aids in available syrups, suspensions, masking the unpleasant taste of certain solutions, powders for the treatment ingredients and also serve as solubilizing of stomatitis. agent and preservative. (ii) Mouthwashers containing allopurinol for the treatment of stomatitis. Humectants—Humectants such as glycerine and sorbitol (5-20% of the (iii) Pilocarpine for dry mouth. mouthwashes) increase the viscosity of the (iv) Amphotericin B for oral candidiasis. preparation and enhance the sweetness of (v) Tranexamic acid for prevention of the final product. It also enhances the bleeding after oral surgery. preservative property of the product along (vi) Chlorhexidine gluconate for control of with alcohol. plaque. Surfactants—Non-anionic surfactant (vii) Hexetidine for its antibacterial and e.g. polyoxyethylene derivative of sorbitol, antifungal property.  This page intentionally left blank ChapterChapter CariesCaries andand PharmacodynamicsPharmacodynamics FluoridesFluorides 12.61.4 (Mode of Action of Drugs)

DENTAL CARIES Caries involves the actual demineralization and destruction of tooth structure. It is a degenerative condition which is characterized by decay of the hard and soft Treatment tissues of the teeth. Infection and decaying Dental caries can be treated by using food are the main causative factors of the following chemical agents. dental caries. Carbohydrates mainly act as Ammonium ions—To reduce the in- decaying food and acids are formed in the oral cavity due to fermentation of cidence of dental caries, ammonium ions carbohydrates. The acid thus formed then are applied locally in the oral cavity. Cer- react with the insoluble calcium salts of the tain dentifrices which contain ammonia teeth and convert them into soluble salts. or ammonium compounds e.g. dibasic am- Proteolytic enzyme (produced by the monium phosphate and urea carbamide bacteria present in the mouth) digest the which liberates ammonia in the mouth are organic enamel matrix and also enhances used. They decrease the number of acid the action of acids and digest the organic producing pathogen, decrease the acidity matter of dentine, and organic acids of the of the oral cavity and dissolve the dental oral cavity destroy the inorganic matter. In plaques. a later stage, pulp also affected with the Urea—It is used to treat dental caries advancing decay and infection may and is one of the oldest chemical used. In progress in the body. some dentifrices, urease is present. Urea is For dental caries, the preventive phase broken down to ammonia by urease. is probably the most important which include regular brushing, flossing and FLUORIDES periodic dental checkup. Regular brushing has been shown to be very effective at The role of fluoride in the control of dental controlling caries as well as gum problems. caries has been known for a long time. 424 Section 12/ Dental Pharmacology

Fluoride therapy and fluoridation of cleaning. The local application of fluoride drinking water has played a significant role leads to the absorption of fluorine on the in deccreasing the dental caries. The enamel surface as calcium fluoride. But, incidence of dental caries can be sodium fluoride must be used with caution significantly decreased by adding fluorides as it may cause nausea, vomiting and into the drinking water supply. Fluorides abdominal pain and on chronic ingestion prevent decalcification of the structure of it may lead to chronic fluoride poisoning tooth by inhibiting bacterial enzymes which and also affects enamel and dentine of produce lactic acid. Fluorides also increase developing teeth. the tooth resistance to acid decalcification. Antimicrobial agents— Certain Fluorides can be used prophylactically antimicrobial agents e.g. penicillin, as well as therapeutically. Prophylactically, bacitracin, aeuromycin etc. are being used fluoride (in the form of sodium fluoride) can to reduce the bacterial count which may be used in drinking water and one part of be beneficial in reducing the incidence of fluoride to one million part of drinking dental caries. water is sufficient for reducing the Certain other agents such as incidence of dental caries by 50%. hexachlorophene, silver nitrate, chlorophyll Therapeutically, 2% sodium fluoride are also used to clean debris and decaying solution is applied locally to the teeth after material and incidence of dental caries.

 Pharmacotherapy of Chapter Common Oral Conditions & Dental 12.7 Emergencies

The most common oral condition and irreversible pulpitis, root canal therapy dental emergency is dental caries, which is (RCT) becomes necessary. The contents of a destructive disease of the hard tissues of the pulp chamber and root canals are the teeth due to bacterial infection with removed, followed by thorough cleaning, Streptococcus mutans and other bacteria. It antisepsis and filling. Alternatively, is characterized by destruction of enamel extraction may be indicated. and dentine. Dental decay presents as Apical peridontitis- A severely opaque white areas of enamel with grey inflammed pulp will eventually necrose, undertones and in more advanced cases, causing apical peridontitis, which is the brownish discoloured cavitations. Dental inflammation around the apex of the caries is initially asymptomatic and pain tooth. It is characterised by severe does not occur until the decay impinges on spontaneous and persistent pain and the pulp, and an inflammation develops. regional lymphadenopathy can be present. Treatment of caries involves removal of the Management is root canal treatment or softened and infected hard tissues, sealing extraction. Antibiotics are generally not of exposed dentines and restoration of the necessary but patients should be advised lost tooth structure with porcelain, silver, to report back to dentist/physician, if amalgam, composite plastic, gold etc. swelling or other evidence of infection occurs. The common dental emergencies are: Periapical abscess- It is pulpal Pulpitis- If the caries lesion progresses, inflammation characterized by localized infection of the dental pulp may occur, pain and swelling. If the pulpitis is not causing acute pulpitis (Pulpal treated successfully, infection may spread inflammation). The tooth become sensitive beyond the tooth apex into the peridontal to hot or cold, and then severe continuous ligament. This infection causes acute throbbing pain ensues. In reversible inflammation with pain on chewing or on pulpitis, filling is an option but in case of percussion is present. The treatment of 426 Section 12/ Dental Pharmacology abscess is incision and drainage or RCT or untreated, the abscess may rupture or less extraction supported by antimicrobial and commonly, progress to cellulitis. NSAlD’s. The treatment is drainage and debride- Cellulitis- Proliferation of epithelial cell ment of the infected perdontal area sup- cysts may convert the granuloma into a ported with antibiotics. periapical cyst. The pus in the periapical Pericoronitis- It is the inflammation of abscess may track through the alveolar soft tissues surrounding the crown of a bone into soft tissues, causing cellulitis and partially erupted tooth and most bacteremia, or may discharge into the oral commonly, a wisdom tooth. It generally cavity, into the maxillary sinus, or through occurs when bacterial plaque and food the skin of the face or submandibular area. debris accumulate beneath the flap of gum Maxillary infection also may spread to the covering the partially erupted tooth. It is periorbital area, increasing the risk of other characterized by inflammation, often serious complications including loss of complicated by trauma from the opposing vision, carvernous sinus thrombosis and tooth, leads to swelling of the flap, CNS involvement. tenderness, pain and a bad taste due to pus Outpatient with localized cellulitis oozing from beneath the flap. should be treated by the physician with In localized pericoronitis, hot saline antistreptococcal oral antibiotics e.g. oral mouthwashes and irrigation under the flap penicillin and in case of penicillin allergy, can resolve symptoms in most of the cases. macrolide antibiotics may be substituted Severe disseminated cases with spreading with appropriate pain medication. cellulitis should be treated with penicillin Definitive theraphy is root canal treatment and appropriate medication for pain. or extraction. Dental trauma- Dental trauma is In severe infection, patients be extremely common in children with injuries hospitalized under the direct supervision to their primary or permanent teeth. of physician and treatment should be Examination of any injury should focus on started immediately with intravenous related soft tissue injuries and the need for broad- spectrum antibiotics and surgical suturing, signs of tooth loosening, drainage if abscess formation is detected. displacement or fracture or any other Peridontal disease- It is an inflammatory disturbance in the bite or other signs of destruction of the periodontal ligament and alveolar fracture. The complete diagnosis supporting alveolar bone and the main require dental radiograph (x-rays) and etiologic agent is bacterial plaque. Multiple need follow up with the dentist for bacteria are implicated but after progressing complete diagnosis, treatment and long- the disease, gram negative anaerobes term care. predominate. It is characterized by Tooth fracture may involve the crown, throbbing pain with erythema and swelling root or both and with or without the over the affected tissue. At this stage, if left exposure of the pulp. Fracture exposing the Pharmacotherapy of Common Oral Conditions and Dental Emergencies 427 pulp are often painful and immediately often coupled with root canal require referral to a dentist and definitive treatment. treatment may involve root canal treatment (iii) Avulsion (complete displacement of or extraction depending on the exact nature the tooth out of its socket- It is a true of the root fracture. dental emergency. Primary teeth are Injuries to teeth and their supporting never implanted. Permanent teeth structures can be classified as fractures. that are avulsed should be reimplanted as soon as possible and (i) Lateral or extrusive (loosening and care should be taken not to touch or displacement of the tooth)- It requires clean the root, which could remove immediate referral to dentist. Luxated periodontal ligament fibres and permanent teeth require repositioning, which ultimately reduce the chance splinting or root canal treatment and of successful re-implantation. The long term follow up. Any luxated patient should be immediately tooth that interferes with normal referred to dentist for splinting and occlusion requires immediate dental antibiotic prophylaxis. Antibiotic evaluation and treatment for pain and prophylaxis with penicillin should be other complications. given and tetanus toxoid vaccine (ii) Instrusion (displacement of the tooth should be administered vertically into the alveolar bone)- Dental caries and peridontal disease Teeth subject to intrusive luxation which can lead to certain dental have been intruded into the alveolar emergencies can be minimised by regular bone, which may occur at the point dental care i.e. regular tooth brushing, that the teeth are not visible. Dental appropriate fluoride use, decreasing referral is required for monitoring to ingestion of sugar containing confectionery determine if the teeth will re-erupt. For items and regular dental examination. permanent teeth, monitoring and Dental trauma especially in children and treatment is required to promote re- sport persons can be avoided by using eruption (surgical or orthodontic) and certain mouth guards and face shields.

 This page intentionally left blank Section 13

Miscellaneous This page intentionally left blank Vaccines, Sera and ChapterChapter PharmacodynamicsPharmacodynamics OtherPharmacodynamics Immunological (Mode of Action of Drugs) 13.11. 4 Agents

The immunological agents are the agents The active immunity may be acquired which produce active or passive immunity following clinical infection (chicken pox, and are used to prevent or to modify certain rubella, measles), following subclinical infectious disease. Immunity can be infection (polio and diphtheria) and defined as the ability of the body to following immunization with an antigen neutralize and eliminate the pathogens and which may be killed vaccine, live their toxic products. attenuated vaccine or a toxoid. The immunity can be divided into two When an antigen is administered for sub-groups: the first time in human body, the antibodies I. Active immunity: that is elicited first is entirely of the IgM Humoral immunity. type. The IgM antibody titres rise steadily Cellular immunity. during the next three to four days, reaches Combination of these two. a peak and then declines. Meanwhile if the antigenic stimulus was sufficient, IgG II. Passive immunity: antibody appears in a few days, reaches a Normal human Ig. peak in a week time and gradually falls over Specific human Ig. a period of weeks or months, this is called Animal antitoxins or antisera. as primary response. Active Immunity The secondary response is also known Active immunity depends upon the as booster response. It differs from primary humoral and cellular responses of the host. response and has a shorter latent period, It is the immunity which an individual production of antibodies is more rapid, develops as a result of infection and antibodies are more abundant, antibody production of antibodies or cells having a response is maintained at a higher level for specific action on the microorganisms a longer period and antibodies elicited tend concerned with a particular infectious to have a greater capacity to bind to the disease or on its . antigen. 432 Section 13/ Miscellaneous

Passive Immunity be administered in a person with immune When antibodies produced in one body deficiency disease or a person with are transferred to another to induce leukemia, lymphoma or are on cytotoxic protection against disease, it is known as chemotherapy, radiation or corticosteroid passive immunity. It can be acquired therapy because of malignancy. naturally i.e. in foetus receiving mother’s The examples of live vaccines are: antibodies through placenta or artificially by • Live (bacterial): BCG, typhoid oral. administration from outside in the form of • Live (viral): Polio oral vaccine, yellow antisera containing antibodies. fever, measles, rubella, mumps, influenza. Types of Immunizing Agents • Live (rickettsial): Epidemic typhus. The various preparations employed for conferring immunity are: Killed or Inactivated Vaccines These consist of microorganisms killed VACCINES by heat or chemicals. Killed vaccines It is an immunobiological substance for usually require a primary series of two- three doses of vaccine to produce an producing specific protection against a adequate antibody response and generally given disease. It stimulates the production booster dose is required. The duration of of protective antibodies and other immune immunity varies from months to years. (e.g. mechanisms. Vaccines may be prepared in case of polio vaccine) The examples are: from attenuated live organisms, inactivated or killed microorganisms, toxoids or • Killed (bacterial) vaccine: Typhoid, cholera, pertussis, plague, meningitis. combination of these and more recent one are recombinant vaccines. • Killed (viral) vaccine: Rabies, influenza, hepatitis B, encephalitis Live Vaccines (Japanese), polio. These are prepared from live organisms Toxoids e.g. BCG, measles and polio oral vaccine. These are produced by addition of The live vaccines are more potent formalin to the toxin of microorganisms and immunizing agent because live organisms incubating them at 37°C for three to four multiply in the host and the resulting weeks. Certain microorganisms produce antigenic dose is larger than what is endotoxins e.g. tetanus and diphtheria. The injected and live vaccines have all the major toxins produced by these organism are and minor antigenic components. Besides detoxicated and used for the preparation that live vaccines engage certain tissues of of vaccine. The toxoids have lost their the body e.g. intestinal mucosa by polio oral toxicity but antigenicity is retained. vaccine. Polysaccharides But there are some limitations with live Certain vaccines are prepared from vaccines, such as live vaccines should not extracted cellular fractions e.g. meningo- Vaccines, Sera and Other Immunological Agents 433 coccal vaccine from polysaccharide antigen VACCINATION PROGRAMMES of the cell wall, pneumococcal vaccine from The result of vaccination programmes polysaccharides contained in the capsule have been very impressive. The treatment of the organism and hepatitis B polysac- of certain infectious diseases have been charide vaccine. drastically reduced, with their virtual Combined Vaccines elimination from some countries where When more than one kind of immuniz- they formerly caused considerable disability ing agents are included in the vaccines, it and many deaths. Vaccination has also is known as mixed or combined vaccine. opened up the possibility of completely For example, DPT (diphtheriapertussistet- eradicating some diseases from the face of anus), MMR (measlesmumpsrubella), DT the earth e.g. small pox and polio. (diphtheriatetanus), DP (diphtheriapertus- The general schedule of vaccination sis) etc. age-wise is listed below in table 13.1.4. The various types of vaccines and the immunization schedule are listed in table VACCINE PREPARATIONS 13.1.1. TB (BCG VACCINE) IMMUNOGLOBULINS This vaccine is routinely given to infants There are five major classes IgG, IgM, and small children in countries where TB is IgA, IgD and IgE, which form human common. This vaccine contains a live immunoglobulin system. The various attenuated (weakened) strain of classes and sub-classes of immunoglobulin Mycobacterium tuberculosis, the bacterium represent different functional groups that which causes tuberculosis. The bacterium are required to meet different types of has been modified to produce a strain antigenic challenges (Table 13.1.2). known as Bacille Calmette-Guerin, named Normal human Ig: Normal human Ig is after its discoverer. Killed vaccines (strain) an antibody rich fraction and used to prevent can not be used to protect against measles in highly susceptible individuals and tuberculosis infection since they do not also provide protection against hepatitis A produce the necessary cellular immune & B, mumps, poliomyelitis and chicken pox. response. Specific human Ig: These preparation A single dose of vaccine is administered are made from the plasma of the patients intradermal into the skin over the upper who have recently recovered from infection. shoulder area. Protection lasts for several The specific human Ig are used for the years. prophylaxis of chicken pox and hepatitis B, rabies and tetanus. POLIO (OPV) The various immunoglobulins used for Poliomyelitis is caused by a highly passive immunization are listed in table 13.1.3. infectious virus known to affect only 434 Section 13/ Miscellaneous

Table 13.1.1. Vaccines for active immunization. Type of Agent type Route of Immunization dose (primary & booster) vaccine administration LIVE VIRUS Measles Live virus Subcutaneous Two doses at least 1 months apart and no booster. Measles-mumps- Live virus Subcutaneous 2 doses, first at 12-15 months & then 4-6 years. rubella (MMR) Varicella Live virus Subcutaneous Two doses, 4-8 weeks apart. Yellow fever Live virus Subcutaneous One dose 10 days to 10 years before travel and booster at every 10 yrs. Rubella Live virus Subcutaneous One dose & no booster. Mumps Live virus Subcutaneous One dose & no booster. Polio virus Live viruses of Oral 3 doses, 4-8 weeks apart and booster dosage vaccine, oral (OPV) all 3 serotypes at 18 months and 5 yrs.

INACTIVATED VIRUS Polio virus vaccine Inactivated Subcutaneous Two doses, 4 to 8 weeks apart and a third inactivated (IPV) viruses of all 3 dose 6 to 12 months after the second and serotypes one-time booster dose for travellers. Rabies Inactivated virus Intramuscular or Preexposure: 3 doses (IM or ID) at days 0, 7, intradermal and 21 or 28. Postexposure: 5 doses (IM only) at days 0, 3, 7, 14, and 28 and serologic testing every 6 months to 2 years in persons at high risk. Influenza Inactivated Intramuscular One dose (children ≤12 years of age should virus or viral receive split virus vaccine only; children < 9 yrs components who are receiving influenza vaccine for the first time should receive 2 doses, administered at least 1 month apart) and booster yearly with current vaccine. Hepatitis A Inactivated virus Intramuscular One dose (administer at least 2 to 4 weeks before travel to endemic areas) and booster at 6 to 12 months for long-term immunity. Hepatitis B Inactive viral Intramuscular Three doses at 0, 1, and 6 months. antigen

BACTERIA Typhoid, Ty 21a Live bacteria Oral Four doses given 2 days apart and booster 4 oral doses every 5 years. Typhoid, heat-phe- Inactivated Subcutaneous Two doses ≥ 4 weeks apart & booster every nol inactivated bacteria or intradermal 3 years. Cholera Inactivated Subcutaneous, Two doses given at least 1 week apart, prefer- bacteria intramuscular, ably 1 month apart & booster every 6 months. or intradermal Contd.… Vaccines, Sera and Other Immunological Agents 435

…Contd. BACTERIAL POLYSACCHARIDES Typhoid, Vi-capsular Bacterial Intramuscular One dose and booster at every 2 years. polysaccharide polysaccharide Haemophilus, Bacterial Intramuscular One dose influenzae type b polysaccharide conjugate (Hib) conjugated to protein Pneumococcal Bacterial poly- Intramuscular or One dose & booster after 6 years in patients saccharides subcutaneous at high risk. of 23 serotypes Meningococcal Bacterial poly- Subcutaneous One dose saccharides of serotypes A/C/Y/W-135

TOXOIDS Tetanus-diphth- Toxoid Intramuscular Two doses at least 4 weeks apart and a third eria (Td or DT) dose 6 to 12 months after the second and booster at every 10 years or at age 50. Diphtheria-tetanus- Toxoids and Intramuscular DTP at 2 months, 4 months, 6 months and at pertussis (DTP) inactivated 12 to 18 months then at 4 to 6 years. whole bacteria Diphtheria-tetanus- Toxoids and Intramuscular Same as DTP vaccine. acellular inactivated pertussis (DTaP) bacterial components DTP-Haemo- Toxoids, inac- Intramuscular Same as DTP vaccine. philus influenzae tivated whole type b conjugate bacteria and (DTP-Hib) bacterial poly- saccharide conjugated to protein.

Table 13.1.2: Types of immunoglobulin. Type of Characteristics immunoglobulin IgG 75 percent of the total serum immunoglobulin, small molecular wt. (1,60,000), diffuse into the intestinal mucosa. IgA 15 percent of the total serum immunoglobulin, found in all body secretions (internal & external). IgM 10 percent of total serum immunoglobulins. IgD Normal serum contains 0.3-40 mg/100 ml of IgD. IgE Normal serum level is 10 to 130 µg/100 ml. 436 Section 13/ Miscellaneous humans. The virus usually spreads by Polio is a highly contagious disease. By the contact with infected individuals via the time first case is detected in a family, all family water borne route, though mouth-to-mouth members may have probably been infected transmission is also possible. The disease due to the rapidity of viral spread. Viral spread typically affects very young children, with is enhanced by crowding and poor sanitation. 80 to 90 percent of cases occurring in The most prominent example of the children under three years of age. effectiveness of OPV is the success of the

Table 13.1.3: Immunoglobulins for passive immunization. Product Dosage Use Immune globulin Preexposure prophylaxis: 0.02 mL/kg IM for anticipated Hepatitis A (intramuscular) risk of <3 months, 0.06 mL/kg for anticipated risk of >3 months, repeated every 4 to 6 months for continued exposure. Postexposure: 0.02 mL/kg IM immediately after exposure up to 2 weeks. Hepatitis B 0.06 mL/kg IM immediately after exposure up to 1 week for Hepatitis B immune globulin percutaneous exposure or 2 weeks for sexual exposure. (HBIG) 0.5 mL IM within 12 hours after birth for perinatal exposure. Immune globulin 400 mg/kg IV daily for 2 to 5 consecutive days, depending Idiopathic thrombocyto- (intravenous) on platelet count and clinical response or 1 g/kg once daily penic purpura for 1 day or 2 consecutive days. Immune globulin 400 mg/kg IV daily for 4 consecutive days within 4 days Kawasaki disease (intravenous) after the onset of illness. A single dose of 2 g/kg IV over 10 hours is also effective. Immune globulin Normal hosts: 0.25 mL/kg IM Measles (intramuscular) Immunocompromised hosts: 0.5 mL/kg IM (maximum dose of 15 mL). Immune globulin Minimum effective dosage is 150 mg/kg every 3 to 4 weeks Primary immunodefici- (intravenous) (serum IgG concentration ≥ 400 mg/dL). ency disorders Rabies immune 20 IU/kg. Rabies globulin

RhO (D) immune The usual dose (1 vial) administered IM within 72 Rh isoimmunization globulin hours after delivery or termination of pregnancy. Immune globulin 0.55 mL/kg IM Rubella (intramuscular) Antivenin At least 3 to 5 vials (30-50 mL) IV initially within 4 hours Snake bite (coral snake) (Micrurus after the bite. Additional doses may be required. fulvius), equine Antivenin The entire dose should be given within 4 hours after Snake bite (pit vipers) (Crotalidae) the bite by the IV or IM route (1 vial = 10 mL); upto 15 polyvalent, equine vials can be used depending upon the degree of envenomation. Contd.… Vaccines, Sera and Other Immunological Agents 437

…Contd. Tetanus immune Postexposure prophylaxis: 250 units IM. Tetanus globulin Treatment: 3,000 to 6,000 units IM. Varicella-zoster 125 units/10 kg IM, up to 625 units. Higher doses may be Varicella immune globulin required. Immune globulin Initial dose of 400 mg/kg IV every 3 weeks. Dosage should Chronic lymphocytic (intravenous) be adjusted upward if bacterial infections occur. leukemia Cytomegalovirus Bone marrow transplantation: 1 g/kg weekly. Cytomegalovirus immune globulin Kidney transplantation: 150 mg/kg then 50 to 100 mg/kg (intravenous) every 2 weeks. Diphtheria 20,000 to 120,000 units IV or IM depending on the severity Diphtheria antitoxin, equine and duration of illness. Anti gas gangrene Prophylactic: 10, 000 IU; Gas gangrene serum Therapeutic: 30-75,000 IV SC/IM/IV

Table 13.1.4: General schedule of vaccination. Age Immunization Birth to 2 months Hepatitis B vaccine, BCG vaccine. 2 months Diphtheria and tetanus toxoid and pertussis vaccine (DTP), oral polio virus vaccine (OPV), Haemophilus influenzae type b conjugate vaccine (Hib). 2-4 months HBV and second dose after one month of first dose. 4 months DTP, Hib, OPV. 6 months DTP, Hib, OPV. 6-18 months HBV, OPV, oral polio vaccine at 6 months of age is more preferred. 12-15 months Measles-mumps-rubella vaccine (MMR), Hib. 12-18 months DTP or diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) at 15 months, varicella vaccine. 4-6 yrs DTP or DTaP, OPV. 4-6 yrs or 11-12 yrs MMR. 11-12 yrs Diphtheria and tetanus toxoids (Td). worldwide polio eradication programme. contributed substantially to the reduction Oral polio vaccine (OPV) is used for active in clinical pertussis. immunisation against poliomyelitis. It Children given three doses of this stimulates the formation of antibodies both remarkable vaccine get good protection in the blood and the mucosal tissues of the against three diseases namely diphtheria, GI tract. tetanus and pertussis. DTP (DIPHTHERIA, TETANUS, Diphtheria is an infection that attacks PERTUSSIS; TRIPLE ANTIGEN, the throat, mouth and nose. It is a highly TRIPVAC) contagious disease (easy to get), but has Combined DTP vaccines have been in become rare ever since the vaccine was use worldwide since the 1940s and have introduced. 438 Section 13/ Miscellaneous

Tetanus is an infection caused by a • It is less traumatic for children since bacteria found in dirt, gravel and rusty lesser number of injections have to be metal. It usually enters the body through a given. cut. Tetanus bacteria causes the muscles to • Combined vaccines invariably cost less spasm (move suddenly). If tetanus attacks than the sum of their component the jaw muscles it causes lockjaw, the individual vaccines. inability to open the mouth. Tetanus can • The overall number of adverse also cause spasm of the respiratory muscles, reactions is lower. which can be fatal. • The chance of compliance is increased Pertussis also called whooping cough benefitting the individual and the which is caused by a bacteria that clogs the community. lungs with mucus (a thick, slimy • There is more cost-effective use of substance). This can cause a severe cough health-care manpower and resources. that sounds like a ‘whoop.’ The cough can • The cost of purchase, transportation last for two months and allows the infection and storage of vaccines are by other bacteria which can cause substantially reduced. pneumonia and bronchitis (infection of • The administration of medical records lungs). and vaccine scheduling is simplified. Some examples of combination Diphtheria Antitoxin vaccines include DTP, MMR etc. Now, It is used for passive immunisation in newer combination vaccines are available suspected cases of diphtheria and should that provide prevention against four be given without waiting for bacteriological diseases (DTP + HB) or even five diseases confirmation of the infection and (DTP + HB/Hib) making it pentavalent antibacterial agent is usually given vaccine. concomitantly. A test dose of diphtheria antitoxin should always be given to test COMBINATION VACCINES WITH hypersensitivity. HAEMOPHILUS B CONJUGATE VAC- CINE (HIB TITER) COMBINATION VACCINE Each lyophilisate for one immunising dose A combination vaccine consists of two of diphtheria, tetanus toxoids and pertussis or more separate immunogens physically with Haemophilus b conjugate vaccine combined in a single preparation. A contains Haemophilus influenzae type b combination vaccine gives protection from polysaccharide conjugated to tetanus protein more than one disease. 10 mcg, purified diphtheria toxoid 1 immunising dose, purified tetanus toxoid 1 Advantages of Combination Vaccines immunising dose, Bordetella pertussis • It is more convenient for parents and minimum of 4.1 IU. medical staff since number of visits to It is indicated in all children from age the hospital are reduced. of two months onwards for the combined Vaccines, Sera and Other Immunological Agents 439 prevention of invasive infections such as infectious than HIV which causes AIDS. meningitis, septicaemia, epiglottitis etc. Hepatitis B kills more people in a day than caused by Haemophilus influenzae type b, AIDS kills in a whole year. diphtheria, tetanus and pertussis. Blood is the most important vehicle for Dosage: Three injections of 0.5 ml at transmission but other body fluids have one or two months interval followed by a also been implicated including semen, booster injection administered one year vaginal secretions and saliva. after the primary vaccination. HBV can spread in three ways: From DUAL ANTIGEN mother to child (MTC), at birth and from person to person. It is a uniform suspension of diphtheria Hepatitis B vaccine is used for active and tetanus toxoid adsorbed on aluminium phosphate and suspended in isotonic saline immunisation against hepatitis B infection. solution. Immunisation should be considered in persons at high risk of contracting hepatitis Adverse effects include mild local B. reactions like pain, redness, tenderness at the site of injection. Mild to moderate Adverse effects include mild transient transient fever and irritability. soreness and induration at injection site. Occasionally low grade fever, malaise, It is used for active immunisation of fatigue, headache, nausea and dizziness. children against diphtheria and tetanus in cases where it is decided not to immunize It is used for active immunization against pertussis also. against hepatitis B virus infection. Dosage: 3 IM injections of 0.5 ml to be Dosage: administered with an interval of four to • Adults: 1 ml by IM injection into the eight weeks between doses. A fourth deltoid muscle; repeated one month injection of 0.5 ml should be administered and six months later. one year after initial injection. • Children: 0.5 ml by IM injection into the HEPATITIS B (BEVAC) anterolateral aspect of thigh; repeated Hepatitis B is a worldwide disease one month and six months later. caused by the hepatitis B virus (HBV). HBV Administration: This is for IM use only. primarily affects the liver inducing an In adults the injection should be given in inflammatory reaction that destroys liver the deltoid region; in neonates and infants cells and often hinders liver function. The the injection should be given in consequences of infection are variable and anterolateral thigh. Dose for adults and unpredictable. They depend on the age and children above 10 years is 20 mcg and for immunity status of the patient. neonates, infants and children below 10 The hepatitis B virus is highly infectious. years the dose is 10 mcg. Three doses are It is estimated to be 100 times more given as above. For rapid immunization the 440 Section 13/ Miscellaneous third dose can be given two months after hepatitis A is an occupational hazard or in the first dose and a fourth booster dose at whom there is an increased risk of 12 months. transmission (persons working in a day care centre, nursing, medical and paramedical HEPATITIS A (AVAXIM) personnel especially gastroenterology and Hepatitis A is one of the most paediatric unit, sewage workers, widespread infectious diseases worldwide. homosexuals, haemophilia patients, abusers It is caused by the hepatitis A virus and is of injectable drug and persons with multiple common in places with poor standards of sexual partners. hygiene and sanitation. The virus attacks Adverse effects include injection site the liver and causes varying degrees of soreness, redness and swelling; mild illness in patients. headache, malaise, fatigue, fever, nausea The hepatitis A virus is excreted in the and loss of appetite. faeces. Direct contact with an infected person’s faeces or indirect contamination of Dosage: food, water, hands and cooking utensils may • Adults (19 years onwards): A single result in the virus being ingested, causing dose of hepatitis A adults vaccine (1 infection. ml suspension containing not less than 1,440 ELISA units of viral antigen) is Symptoms include nausea, vomiting, used for primary immunization. jaundice (yellowness of eyes, skin and urine), diarrhoea, pale stools, abdominal • Children and adolescents (from 1 year up to 18 years of age): A single dose pain, malaise, fatigue, fever, chills, lack of of hepatitis A junior vaccine (0.5 ml appetite, sore throat, etc. suspension containing not less than Hepatitis A is often confused with 720 ELISA units of viral antigen) is hepatitis B. What is important to remember used for primary immunization. is that hepatitis A is the single largest cause In both a booster dose is recommended of jaundice. Also vaccination against hepatitis any time between 6 to 12 months later to B does not protect from hepatitis A. ensure long time protection from hepatitis A. A vaccine is now available and is the Administration: By IM route only, in most practical means of protection against deltoid muscle. hepatitis A. A complete course of vaccine should be taken to get long term protection. TYPHOID (TYPHIVAX) Hepatitis A vaccination is indicated for Typhoid fever is a disease which starts active immunisation against hepatitis A virus as an infection of the gastrointestinal tract. (HAV) infection in subjects at risk of exposure It is caused by the bacterium Salmonella to HAV such as travellers to high prevalence typhi. It spreads by ingestion of areas, armed force personnel travelling to contaminated food or drink. Normally high endemic areas, person in whom Salmonella typhi bacterium is inactivated by Vaccines, Sera and Other Immunological Agents 441 acid in stomach. However, if a large Dosage: One capsule on day 1, 3 & 5 number of bacteria are ingested, a irrespective of age and weight. substantial number may reach the small intestine. Symptoms include periodic fever, HIB (H. INFLUENZAE TYPE B; VAXIGRIP) headache, tiredness and weakness, changes in behaviour and abdominal discomfort Haemophilus influenzae is a bacteria with constipation in the early stages of the which exists in many forms. The type B disease followed by diarrhoea later. form called Hib, commonly produces disease in humans by colonizing the upper Typhoid vaccines are used for active respiratory tract of up to 80 percent of the immunisation against typhoid fever. Two population and is major cause of infection types of vaccine, one injectable and other and mortality in children. oral are available. Almost all Hib disease occurs in Polysaccharide Typhoid Vaccine children younger than five years and It is prepared from Vi capsular mostly in children younger than one year. polysaccharide of Salmonella typhi. Transmission of Hib from one individual Immunity develops 7 to 15 days after to another primarily occurs via respiratory injection and protection lasts for three secretions from carriers. However, Hib can years. also be spread through direct contact with a person with Hib disease but this accounts Adverse effects include slight local for only two percent of cases in children pain, fever and rash. younger than four years old. It is indicated for prevention of typhoid The manifestations of Hib disease are fever in adults and children over five years. varied with the most serious being Dosage: Single dose of 0.5 ml SC or IM. meningitis and epiglottitis. Adverse effects include mild and Oral Typhoid Vaccine transient local erythema, swelling, fever, It contains the attenuated strain Ty21a irritability, sleepiness, GIT disturbances, of Salmonella typhi. The attenuation is due rashes and anorexia. to the absence of enzyme uridine It is indicated for immunisation of diphosphate galactose-4-epimerase which children against invasive disease caused by is essential for the production of the Haemophilus influenzae type b (meningitis, ‘O’ antigen. The septicemia, cellulitis, arthritis, epiglottitis). absence of this enzyme makes Ty21a highly immunogenic. The safety and efficacy of Hib vaccines have clearly been demonstrated in Adverse effects include fever and/or developed countries and their introduction mild GI effects. into the national vaccination programme It is indicated for prophylactic of developing countries in the future can immunization of adults and children over markedly reduce the incidence of Hib- six years against typhoid fever. related disease worldwide. 442 Section 13/ Miscellaneous

MMR (MEASLES, MUMPS & Rubella soon after birth is a disease which RUBELLA; TRESIVAC) is usually trivial and of short duration. Its most obvious sign is a mild rash. Rubella Measles virus infection during pregnancy can In developing countries, measles can be disrupt fetal growth and cause birth defects. a very severe disease, with mortality rates Approximately 25 to 50% of rubella in- as high as 10 percent. Hence, vaccination fections may go undetected. When symp- is recommended for all children at the toms do present, they are usually quite mild. earliest possible age. Currently, the WHO recommended nine months as the age for Adults who contract rubella present measles vaccination, taking into account with fever and loss of appetite for two days maternal antibody levels and vaccine intake, prior to the onset of the rash. as well as disease incidence. MMR Vaccination The signs and symptoms of measles Live attenuated virus vaccines for include fever, common cold-like symptoms, measles, mumps and rubella (MMR) have conjunctivitis, cough, spots inside the mouth been combined into a single vaccine known and a skin rash. Diarrhoea, stomach pain as MMR vaccine. The MMR vaccine is and loss of appetite may also be present. effective as the single-virus vaccine The severity of the symptoms of measles composed of the respective strains and has is greater in adolescents and adults than in been shown to be highly effective. The children. The incubation period is 10 to 12 immunity induced by MMR is long lasting days and during this period there is virtually and may be lifelong. no outward sign of illness. During this Adverse effects include hyperthermia, period the virus first causes a local infection rhinopharyngeal or respiratory symptoms of of the upper respiratory tract then spreads short duration. Hyperthermia convulsions to other parts of the body. The virus is then are rarely observed. Lymphadenopathies or disseminated throughout by bloodstream parotitis may be observed. causing a primary disease. It is indicated for joint prevention of Mumps measles, mumps and rubella, normally, given Mumps or infective parotitis is an acute from the age of 12 months, in infants of both infectious disease usually marked by a sexes. painful enlargement of one or both salivary CHICKENPOX (VARICELLA; OKAVAX) glands around the jaw. In addition, dryness of the mouth may often occur. Chickenpox or varicella is caused by the varicella zoster virus (VZV). Varicella Rubella vaccine is indicated for active immunisation Rubella or German measles, is a highly against varicella in healthy subjects and infectious disease, which mostly affects their susceptible healthy close contacts children, adolescents and young adults. from the age of 12 months onwards. Vaccines, Sera and Other Immunological Agents 443

Varicella vaccine is a lyophilized Adverse effects include low grade preparation of the Oka strain of live fever and pain at injection site. attenuated varicella virus obtained by It is indicated for prophylaxis against propagation of the virus in MRC human 5 cerebrospinal meningitis due to meningo- diploid cell culture. cocci A & C groups by SC or IM route in Varicella vaccine produces an attenu- single 0.5 ml dose. ated clinically inapparent varicella infec- tion in susceptible subjects. PNEUMOCOCCAL VACCINE Adverse effects include mild and (PNEUMO 23) transient reaction at the site of injection, This vaccine is recommended for those headache, fever, paraesthesia and fatigue. who are at risk of pneumococcal It is indicated for active immunisation pneumonia. A single dose of vaccine gives against varicella in healthy subjects from protection against infection. Revaccination the age of 12 months onwards. Susceptible is required at a later date. healthy close contacts (parents and siblings It is prepared from purified pneumo- of high-risk patients, medical, paramedical coccal capsular antigens and includes 23 personnel and other people who are in close serotypes which are responsible for at least contact with varicella patients) should be 85% of pneumococcal infections and has immunised in order to reduce the risk of greater than 90% coverage against sero- transmission of virus to high-risk patients. types that are penicillin resistant. FLU VACCINE (HIBERIX) Adverse effects include hypersensitiv- ity, redness, slight pain and induration at Influenza vaccine contains antigens the site of injection. Rarely fever may occur. from two or three of the currently circulating types of flu virus. It is indicated in prevention of Vaccination is recommended for elderly pneumococcal infections, particularly people particularly those with heart, lung those of respiratory origin in all subjects or kidney disease. Flu vaccination has to over the age of two years who are at risk of be repeated before each winter because of serious pneumococcal infection. the possible changes in virus types. RABIES VACCINE (RABIPUR) MENINGOCOCCAL VACCINE Commonly known as treatment for dog (MENCEVAX A & C) bite. Rabies is usually caused by the bite of This vaccine is recommended for both infected dog, monkey, cat, etc. and can lead adults and children to protect them from to hydrophobia (feeling of fear of water) Meningococcal meningitis. and death. A series of five injections need A single dose of vaccine provides good to be given. Usually rabies vaccine is given protection against infection caused by once the dog bite has already taken place. meningococci. Regular revaccinations are Rabies vaccines which are used for ac- required for long-term protection. tive immunisation against rabies may be 444 Section 13/ Miscellaneous used as part of postexposure treatment. It MEASLES VACCINE may also be used as preexposure prophy- It contains live attenuated Edmonston- laxis against rabies in high risk persons like Zagreb strain of measles virus propagated dog handlers etc. on human diploid cells. Rabies vaccines may be Adverse effects include fever which i. Purified chick embryo cell rabies may be accompanied by skin rash, malaise, vaccine. cough, headache and rarely febrile ii. Inactivated rabies vaccine prepared on convulsions. vero cells. This vaccine for the pre or It is indicated for active immunization postexposure immunization against of children and susceptible adults by SC rabies is obtained by culture on vero route in a dose of 0.5 ml. continuous cell lines. iii. Human diploid cell rabies vaccine. TETANUS TOXOID iv. Highly purified duck embryo rabies It is a sterile uniform suspension of vaccine. tetanus toxoid adsorbed on aluminium Adverse effects include pain, phosphate and suspended in isotonic saline reddening and swelling at injection site, used for active immunization against swollen lymph nodes, joint pains and GI tetanus. complaints. Adverse effects include mild local It is indicated for immunization against rabies after exposure and for reactions, tenderness and induration at the prophylactic vaccination against rabies site of injection. before exposure. Dosage: Dosage: Vaccine should be given For active primary immunization: Two intramuscular in the deltoid region only. doses of 0.5 ml each by IM route at an a. Preexposure: 3 dose IM injections on interval of four to six weeks. Reinforcing day 0, 7 and 28. A booster dose after dose should be given, six to eight months one year and one dose after every five later, to increase the level of immunity. years. In case of subsequent exposure, Booster dose: In previously immunized only two doses at day 0 and day 3 persons, a booster dose of 0.5 ml IM should provide protection, if proper previous vaccination status is available. be given every five years to maintain adequate level of immunity. The need for b. Postexposure: After exposure start immediately a full course of treatment tetanus vaccine in wound management for both adults and children consists depends both on the condition of the of 5 injections on days 0 (day of wound and immunisation history of the exposure), 3, 7, 14 and 30. A booster patient. For tetanus prone wound, tetanus dose on day 90 is optional. immunoglobulin may also be required. Vaccines, Sera and Other Immunological Agents 445

RUBELLA VACCINE (R-VAC) population. Specific immunoglobulins It is used for active immunisation contain minimum specified levels of one against rubella. It is administered to girls antibody. aged 10 to 14 years. It is also recommended Anti-D immunoglobulins are given to for women of child bearing age if they are prevent the formation of rhesus antibodies seronegative, women who are found to in rhesus-negative (Rh –ve) persons on seronegative during pregnancy should be exposure to rhesus positive red blood cells. vaccinated in the early postpartum period. Pregnancy should be avoided for at least TETANUS IMMUNOGLOBULIN (TIG; one month after vaccination. TETGLOB) It is a sterile solution of hyperimmuno- ANTISNAKE VENOM globulin prepared from the placenta of The venom of snake is a complex mixture healthy volunteers specifically immunised of protein which has enzymatic activity and against tetanus. may also provoke local inflammatory Adverse effects include local pain, reaction. The venom may have effect on fever, flushing, headache and chills. tissue, blood vessels, blood cell coagulation It is indicated in subjects already or neurotoxic effect with sensory, motor and sensitised with serums of animal origin, respiratory involvement. Management of existence of prior or present allergic snake bite involves general supportive care manifestations (asthma, eczema, etc.), and monitoring of vital functions but in a systemic snake bite poisoning, specific burns, injuries, open and compound antivenom is the most effective therapy. It fractures; unimmunized or inadequately is highly recommended to wait for clear immunised mothers. clinical evidence of systemic poisoning Dosage: before giving antivenom. Monospecific antivenoms are more effective and are less Prophylaxis: 250-500 IU intramuscular. likely to cause side effects than polyvalent Therapeutic: Tetanus neonatorum 500 antivenoms. to 10,000 IU intramuscular or 250 IU intrathecal. In adults and children 500 to IMMUNOGLOBULINS 10,000 IU intramuscular and/or 250 to 500 These are preparations containing IU intrathecally. antibodies against infectious microorganisms and are usually prepared RABIES IMMUNOGLOBULIN from human plasma or serum. (BERIRAB-P) Normal immunoglobulins are prepared It provides passive protection when from material from blood donors and given immediately to individuals exposed contain several antibodies against to rabies virus. This provides maximum infectious diseases prevalent in the general circulating antibody with minimum 446 Section 13/ Miscellaneous interference of active immunisation with (pipetting accident) involving HBsAg human diploid cell vaccine. positive material such as blood, plasma or Adverse effects include local serum. tenderness, muscle soreness or stiffness at For prophylaxis of hepatitis B in the injection site, low grade fever, neonates born to HBsAg positive mothers. sensitisation to repeated injections of Dosage: Following exposure to HBsAg. human globulin in immunoglobulin Adults: 1,000 to 2,000 IU IM. deficient patients. Children: 32 to 48 IU/kg body weight It is indicated in all injuries, even licks, This should be administered within seven on mucous membranes by wild animals (or days (preferably within 48 hrs) after even pet animals) suspected to be suffering exposure to HBsAg. from rabies. Neonates: Initial dose is 100 to 200 IU. The HEPATITIS B IMMUNOGLOBULIN first dose should be administered within five (HEPABIG) days after birth. The booster dose should HBIG provides immediate passive be 32 to 48 IU/kg of body wt. between two immunity for those individuals with acute to three months after initial dose. exposure to HBsAg positive blood/blood HUMAN NORMAL derivatives. Clinical trials have IMMUNOGLOBULIN (BHARGLOB) demonstrated reduction in attack rate of clinical hepatitis B following its use. After It is indicated for prophylaxis of administration of the usual recommended infectious diseases and immunotherapy. dose of the HBIG there is a detectable level Adverse effects include flushing with of circulating anti-HBsAg antibody which chills, nausea and headache. persist for three months. No case of GAMMAGLOBULIN (HISTOGLOB) transmission of hepatitis B has been associated with the use of this product. Intravenous preparations are available for replacement HBIG does not interfere with generation therapy for patients with congenital of antibody response to hepatitis B vaccine. agammaglobulinaemia and hypogammag- Ideally, persons exposed to blood which lobulinaemia, idiopathic thrombocytopenic contains hepatitis B virus should be given purpura and Kawasaki syndrome. It is also combined passive active immunization. used for prophylaxis of infection following Adverse effects include transient, mild bone marrow transplantation. pain at the site of injection and itching. It is indicated for prophylaxis of HUMAN ANTI-D hepatitis B after exposure to HBsAg e.g. by IMMUNOGLOBULIN (RHOCLONE) accidental ‘needle-stick’, contact by It is indicated for prevention of accidental splash or oral ingestion development of anti-D antibodies in Rh Vaccines, Sera and Other Immunological Agents 447 negative mothers after child birth, abortion IMMUNOSUPPRESSANTS beyond 13 weeks gestation, antepartum prophylaxis at 26 to 28 weeks gestation. These are the agents used to suppress the immunity. The drugs like azathioprine and Dosage: cyclosporin A are used chiefly to prevent Adults: Prophylaxis after delivery, abor- rejection in organ transplantation. They are tion, amniocentesis: 300 mcg IM within 72 also used for treatment of autoimmune hours. Massive transplacental haemor- disease. rhage: 25 mcg/ml of foetal erythrocytes. AZATHIOPRINE (IMURAN) HISTAGLOBULIN It is a purine antagonist, immunosup- pressant drug which suppresses cell medi- Histaglobulin is a lyophilised prepa- ated immunity. It acts by inhibiting DNA ration of histamine (as histamine dihydro- synthesis and hence prevents proliferation chloride) coupled with human normal of T-lymphocytes. immunoglobulin. After administration in body it is Histaglobulin is thoroughly screened for converted to mercaptopurine. hepatitis B surface antigen and anti HIV Adverse effects include skin rash, bone using third generation technique RIA and marrow depression, GI disturbances and ELISA and is found to be non-reactive. hepatotoxicity. As histamine by itself is not an It is indicated in renal transplantation, antigenic molecule, it is conjugated with severe active rheumatoid arthritis to form a complete antigen unresponsive to other therapy, certain wherein histamine acts as hapten when autoimmune diseases, chronic active injected into a living body, forming hepatitis, idiopathic thrombocytopenic antibodies to the hapten histamine purpura and acquired haemolytic complex. Antibodies thus formed increase anaemia. the histamine binding capacity of serum. It has been demonstrated that the histamine Dosage: binding capacity of normal plasma is 20 Renal transplantation: Initially 3 to 5 mg/ percent to 30 percent, whereas it is only kg/day followed by 1 to 3 mg/kg/day as zero to five percent in allergic patients. maintenance dose. Rheumatoid arthritis: Initially 1 mg/kg as Adverse effects include nausea, a single dose; if required increase after six to vomiting and vasodilatation in the facial eight weeks by 0.5 mg/kg/day at four weeks area. intervals up to a maximum of 2.5 mg/kg/day. It is indicated in bronchial asthma, migraine, urticaria, eczema, allergic CYCLOSPORINE A (SANDIMMUN) rhinitis, pruritus, neurodermatitis, atopic It inhibits early cellular response to dermatitis and other allergic disorders. antigenic and regulatory stimuli, mainly in 448 Section 13/ Miscellaneous helper T-cells. At molecular level it affects Dosage: cyclophilin proteins. Solid organ transplantation: Oral dose After oral administration it is absorbed should be initiated within 12 hours before and is highly concentrated in erythrocytes. surgery at a dose of 10 to 15 mg/kg in two After metabolism in liver most of the drug is divided doses, then continued for one to excreted in bile. Some metabolites are active two weeks postoperatively followed by and show immunosuppressive activity. maintenance dose of 2 to 6 mg/kg. Adverse effects include nephrotoxicity, Bone marrow transplantation: Start a hypertension, tremor, seizures, increased day before transplantation. IV infusion: incidence of infections, gingival hyperpla- 3 to 5 mg/kg/day, continue two weeks sia, hirsutism, flushing, paraesthesias, tin- postoperatively, then continue with oral nitus, headache, gynaecomastia and con- preparation in dose of 12.5 mg/kg in junctivitis. It has no toxic effects on bone marrow and RE system. two divided doses for six months to one year. It is used to prevent graft rejection after kidney, liver, heart, lung, pancreas transplant Psoriasis: Initial 2.5 mg/kg/day orally or bone marrow transplantation and psoria- in two divided doses. Maximum dose is 5 sis not responding to conventional therapy. mg/kg/day.

 ChapterChapter PharmacodynamicsDrugsPharmacodynamics Used in Skin 13.21. 4 (ModeDisorders of Action of Drugs)

For the treatment of various skin disorders, positive aerobic bacteria including methicil- local application of drugs in the form of lin resistant S. aureus are sensitive to cream, ointment, gel etc., appears to be the mupirocin. It inhibits in-vivo synthesis of ideal and convenient form of management. bacterial proteins by specific and reversible However, in severe conditions different binding to isoleucyl transfer-RNA syn- drugs can also be given by oral routes. The thetase bacterial enzyme. It is indicated in different agents used in various skin the treatment of impetigo (which is a com- disorders are classified as in table 13.2.1. mon skin disease, characterized by superfi- The detailed pharmacology of various cial bacterial infection caused by S. aureus agents listed in table are discussed in or streptococci. The primary lesion is a su- different chapters and only remaining perficial pustule crust, which may occur on agents are covered in this section. normal skin or superimposed upon another skin disease). ANTIBACTERIAL AGENTS Topical Antibiotics Used in Acne Topical antibacterial agents are used to Clindamycin is active against prevent infection and in the early treatment Propionibacterium acnes. Erythromycin alone of infected dermatoses and wounds. Various and in combination with benzoyl peroxide preparations contain corticosteroids in is used in the treatment of acne vulgaris. addition to antibacterial agents. Topical metronidazole is effective in the Detailed pharmacology of various treatment of acne rosacea. antibacterial agents is discussed in chapter Tetracycline hydrochloride and ‘Chemotherapeutic agents’. minocycline sulfosalicylate are used in the MUPIROCIN treatment of acne vulgaris. It is structurally unrelated to other topi- Topical sodium sulfacetamide is used in cal anti-bacterial agents. Most of the gram the form of lotion and in combination of 450 Section 13/ Miscellaneous

Table 13.2.1: Classification of drugs used in different skin disorders. I Antibacterial agents (used topically) Bacitracin, polymyxin B sulphate, neomycin, gentamicin, gramicidin, mupirocin (T-BACT) II. Antibiotics used in acne (topically) Erythromycin (ACNESOL), clindamycin (CLINDAC-A), tetracycline and minocycline sulfosalicylate, metronidazole, sodium sulfacetamide III. Antifungal agents (used orally) Griseofulvin, ketoconazole, fluconazole, itraconazole Used topically Miconazole, oxiconazole, ketoconazole, sulconazole, clotrimazole (along with betamethasone dipropionate), terbinafine (SEBIFIN), naftifine, butenafine, tolnaftate, nystatin, amphotericin B, cyclopirox olamine IV. Antiviral agents (used topically) Acyclovir, valacyclovir, penciclovir, famciclovir, imiquimod V. Steroid preparations (used topically as antiinflammatory agents) Beclomethasone dipropionate (BECLATE) Betamethasone valerate (BETNOVATE) with neomycin also valerate (TENOVATE) Dexamethasone sodium acetate (DECADRON) with neomycin (ULTRALAN) (LEDERCORT) Hydrocortisone acetate (WYCORT) VI. Ectoparasiticides , crotamiton, , sulphur, benzyl benzoate VII. Melanizing/demelanizing agents (agents affecting pigmentation) Hydroquinone, monobenzone (BENOQUIN), trioxsalen (NEOSORALEN), methoxsalen (MACSORALEN), VIII.Sunscreens Para-aminobenzoic acid (PABA) and its esters, benzophenones IX Acne preparations Retinoic acid, adapalene, isotretinoin (ADAFERIN), benzoyl peroxide, azelaic acid X. Agents for psoriasis Acitretin, tazarotene, calcipotriene XI. Keratolytic agents Salicylic acid, propylene glycol, podophyllum resin & podofilox, urea, cantharidin, fluorouracil, benzoic acid XII. Antipruritic agents Doxepin, pramoxine XIII. Drugs for alopecia (trichogenic agents) Minoxidil, , XIV.Antiseborrheic agents Coal tar compound, chloroxine, selenium sulfide (SELSUN) XV. Miscellaneous compounds Tacrolimus, sirolimus, antimetabolites e.g. methotrexate, antihistaminics for pruritus dermatitis, (DERMATOP), becaplermin, dapsone, thalidomide, cyclosporine, interferon Drugs used in Skin Disorders 451 sulfur for the treatment of acne vulgaris and CROTAMITON acne rosacea. It is scabicide, pediculocide and antipruritic used in the form of lotion and ANTIFUNGAL AGENTS cream. Detailed pharmacology of antifungal agents PERMETHRIN (oral & topical) is discussed in detail in chapter ‘Chemotherapeutic agents- It is neurotoxic to Pediculus humanus, Antifungal agents’. Pthirus pubis and Sarcoptes scabiei. It is used in the form of cream. Adverse ANTIVIRAL AGENTS effects include transient burning and stinging. Detailed pharmacology of acyclovir, valacyclovir, penciclovir and famciclovir is Sulphur is used as scabicide and benzyl discussed in detail in chapter ‘Chemothera- benzoate is effective as pediculicide and peutic agents- Antiviral agents’. scabicide.

IMIQUIMOD DEMELANIZING AGENTS It is an immunomodulator agent used locally in the treatment of external genital Hyperpigmentation is an aberration in perianal warts in adults. which dark spots on the skin, which often make it cosmetically undesirable. This Adverse effects include local inflamma- benign condition is attributed to an tory reaction, erythema, pruritus etc. overproduction of melanin, a dark-coloured pigment in the skin. The relative amount of STEROIDAL PREPARATIONS melanin as well as other skin pigments, Topical corticosteroids are used in the genetically determine an individual’s skin treatment of inflammatory dermatoses. The colour. Thus, people with innately dark skin general pharmacology are discussed in have more melanin than people with lighter chapter ‘Glucocorticoids’. skin colour. The production of melanin is dependent upon the activity of the enzyme ECTOPARASITICIDES tyrosinase. This enzyme is essential in catalyzing the reaction that produces LINDANE melanin. Thus drugs that block tyrosinase, It is a gamma isomer of hexachlorocycl- inhibit the overproduction of melanin. ohexane used as pediculicide and scabicide Post-inflammatory hyperpigmentation in the form of lotion, shampoo and cream. is the most common cause of hyperpigmen- Adverse effects include neurotoxicity, tation, which occurs after irritation or in- haematotoxicity and local irritation when it flammation of the skin for example after an comes in contact with eye and mucous episode of acne. This type of hyperpigmen- membrane. tation occurs more often in darker skinned 452 Section 13/ Miscellaneous people as a result of the increased level of benzophenones provide a broader spectrum melanin pigment in the skin. If the affected of absorption from 250 to 360 nm. area only extends into the skin epidermis, Various physical sunscreens such as this makes it easier to treat because the af- heavy petroleum jelly, zinc oxide, titanium fliction only involves the superficial layers oxide, calamine are also used, which can of the skin. Therefore, patients will respond stop and scatter ultraviolet rays faster to treatment. However, if the condi- tion affects deep layers of the skin, such as ACNE PREPARATIONS dermis, treatment may need to be prolonged or may require other alternatives. Acne is a common skin condition, which Hydroquinone and monobenzone are consists of blackheads, white heads, and used to reduce hyperpigmentation of the sometimes deeper boil-like lesions called skin. Trioxsalen and methoxsalen used for nodules or cysts. It occurs during the teen- repigmentation of depigmented macules of age years in boys and girls. vitiligo. Acne vulgaris affects the pilosebaceous Azelaic acid is a newer treatment for units to the skin, leading to their eventual hyperpigmentation, primarily for post- blockade and development of acne lesions. inflammatory hyperpigmentation. It works Abnormal desquamation, defective by blocking the activity of tyrosinase and keratinisation, blockade of the follicular ori- does not cause photosensitivity of the skin fice and collection and colonization of sebum or residual changes in the skin. There is lead to proliferation of Propionibacterium acnes. decreased incidence of allergic reactions associated with azelaic acid. Corticosteroids RETINOIC ACID also block the activity of tyrosinase. Retinoic acid is an effective treatment of Corticosteroids are used in combination acne vulgaris and is used topically. It with other drugs to minimize the side stabilizes lysosomes, increases ribonucleic effects. The combination of azelaic acid and acid polymerase activity, increases hydrocortisone acetate (10%) may also be prostaglandin E , cAMP and cGMP level. useful in the treatment of post-inflammatory 2 hyperpigmentation of skin Adapalene is a napthoic acid derivative with retinoid-like activity used for the topical treatment of acne vulgaris. Adverse SUNSCREENS effects include erythema, dryness of skin These are the agents which protect the skin and skin irritation. from harmful effects of exposure to sunlight Isotretinoin is a synthetic retinoid which by absorbing ultraviolet light. The most com- acts by inhibiting sebaceous gland size and monly used compounds are paraamino ben- function. zoic acid (PABA) and its esters and ben- zophenones include oxybenzone, Azelaic acid is also used in the treatment dioxybenzone and sulisobenzone. These of acne. Drugs used in Skin Disorders 453

PSORIASIS Propylene glycol is an effective kera- tolytic agent for the removal of hyperk- It is an autoimmune disease which is eratotic debris. It is also used in combi- characterized by marked increase in nation with salicylic acid in the treatment undifferentiated epidermal cell proliferation of ichthyosis, psoriasis, keratosis pilaris and can increase the number of superficial and hypertrophic lichen planus. cells having abnormal keratinization. Podophyllum resin, an alcoholic extract of Podophyllum palatum is used in the ACITRETIN treatment of condyloma acuminatum and It is a metabolite of the aromatic retinoid, other verrucae. etretinate used in the treatment of psoriasis. Urea is used in cream or ointment to Adverse effects include elevation of make it less greasy, it increases the water content of stratum corneum which may be cholesterol and triglycerides levels; because of its hygroscopic property. It also hepatotoxicity and raised liver enzyme possesses keratolytic property. levels has also been reported. Cantharidin is the active irritant isolated TAZAROTENE from cantharides. It is mainly used in the treatment of molluscum contagiosum and It is an acetylenic retinoid prodrug verruca vulgaris, particularly periungual which is hydrolysed to active metabolite warts. tazarotenic acid, binds to retinoic acid receptors resulting in modified gene Fluorouracil, a fluorinated pyrimidine expression. antimetabolite is used topically for the treatment of multiple actinic keratoses and CALCIPOTRIENE intralesionally for keratoacanthomas. Benzoic acid is a antifungal with mild It is a synthetic vitamin D3 derivative effective in the treatment of plaque type keratolytic action. psoriasis vulgaris. Adverse effects include itching and mild irritation. ANTIPRURITIC AGENTS Pruritus is a common symptom in skin along KERATOLYTIC AGENTS with itching. Antihistaminics and hydrocortisone are very effective in pruritus These are the agents used in the treat- due to inflammation. ment of disorders of keratin which cause mild peeling of superficial layers of the DOXEPIN skin. Topical doxepin in the form of cream is Salicylic acid is used to treat various used in the treatment of pruritus associated hyperkeratotic lesions like corns, warts, with atopic dermatitis or lichen chronicus. ring- worm, athlete’s foot, chronic dermatitis Adverse effects include marked burning etc. and stinging at the treatment site. 454 Section 13/ Miscellaneous

PRAMOXINE shampoo are used in dandruff which is most It is a topical anaesthetic which can common problem. Selenium sulfide also has provide temporary relief from pruritus with antikeratolytic and fungicidal properties. mild eczematous dermatoses. MISCELLANEOUS COMPOUNDS TRICHOGENIC AGENTS These are the agents which can be used in various skin disorders e.g., atopic MINOXIDIL dermatitis, seborrheic dermatitis and certain Topical minoxidil is effective in revers- types of psoriasis and other related ing the progressive miniaturization of scalp disorders. hairs associated with androgenic alopecia (male pattern baldness). It is a hereditary TACROLIMUS disorder due to excessive conversion of tes- It is an immunosuppressant macrolide tosterone to dehydrocorticosterone in the antibiotic produced by Streptomyces scalp skin in genetically susceptible men. tsukubaensis. Like cyclosporine, tacrolimus FINASTERIDE binds to a cytoplasmic immunophylin and the complex inhibits the activity of the It is a inhibitor of 5-alpha reductase and blocks the conversion of testosterone to calcium dependent phosphatase known as dehydrotesto-sterone. It prevents further calcineurin. This in turn, inhibits the hair loss in the significant proportion of men translocation of the transcription factor in the androgenic alopecia. NF-AT into the cell nucleus, blocking the initiation of NF-AT dependent T-cell Adverse effects include decreased responses. It is indicated in atopic libido, ejaculation disorders and erectile dysfunction. dermatitis. It is used in the treatment of benign It is recently approved for immunosup- prostatic hypertrophy in the dose of 5 mg pression in liver and kidney transplant pa- daily. In 1 mg dose it is used in the treatment tients. of androgenic alopecia. SIROLIMUS Dutasteride is newer compound similar to finasteride. It is a newer agent derived from Streptomyces hygroscopicus that binds immunophylin (same as in tacrolimus and ANTISEBORRHEIC AGENTS cyclosporine). It is indicated in the These agents are effective in seborrheic management of psoriasis and uveoretinitis. dermatitis which is characterized by erythematous scaling lesions. PREDNICARBATE The various agents, e.g. selenium sulfide It is a halogen free steroid and highly and imidazole antifungals lotion or active corticosteroid for topical application. Drugs used in Skin Disorders 455

It has pronounced antiinflammatory, skin disorders like antimalarials in lupus antiallergic, anti-exudative and antipruritic erythematosus, antimetabolites in psoriasis, properties. It is indicated in atopic dapsone in dermatitis herpetiformis and dermatitis, seborrheic dermatitis and certain erythema elevatum diutinum, interferon in types of psoriasis. viral warts and thalidomide in erythema Certain other agents are also used in other nodosum leprosum.

 This page intentionally left blank Appendices This page intentionally left blank List of Recently Approved AppendixChapter PharmacodynamicsPharmacodynamicsNew Drugs and Chapter PharmacodynamicsCombinations(Mode of Action ofin Drugs) India I (Mode(During of 1999-ActionJuly of Drugs) 2006) 1.1.4 4

Name of the drugs Pharmacological classification 1. Glimepiride Antidiabetic agent 2. Mycophenolate mofetil Immunosuppressant 3. Meloxicam NSAID 4. Pre-synaptic monoamine depleting agent 5. Doxazosin mesylate Antihypertensive agent 6. Nafarelin acetate Antiendometriotic agent; gonadotropin inhibitor 7. Milrinone lactate inj Cardiotonic 8. tartrate Alpha 2-adrenoreceptor agonist, adjunct in glaucoma 9. Nabumetone NSAID 10. Zolpidem Sedative-Hypnotic 11. Basiliximab inj Immunosuppressant 12. Topotecan hydrochloride Antineoplastic 13. Fludarabine phosphate IV inj Antineoplastic 14. Zuclopenthixol acetate Antimaniac and antischizophrenic 15. Piperacilin-Tazobactam inj Antibiotic 16. Topiramate Antiepileptic 17. Eptifibatide Platlet aggregation inhibitor 18. Atorvastatin Antihyperlipidemic; HMG-CoA reductase inhibitor 19. Sulpiride Antipsychotic 20. Bambuterol Bronchodilator 21. Bulaquine Antimalarial 22. Fenofibrate Lipid lowering agent 23. Sibutramine hydrochloride Appetite suppressant 24. Oxiconazole Antifungal 25. Temozolomide Antineoplastic 26. Antipsychotic Contd.… 460 Appendices

…Contd. 27. Fluvoxamine maleate Antidepressant 28. Celecoxib NSAID 29. Nevirapine Anti HIV 30. Repaglinide Antidiabetic 31. Ganciclovir Antiviral 32. Trapidil Adjunct in angioplasty 33. Cerivastatin Lipid lowering agent 34. Rofecoxib NSAID 35. Irbesartan Antihypertensive 36. Rosiglitazone maleate Antidiabetic 37. Granisetron Antiemetic 38. Rituximab Antineoplastic 39. Trastuzumab Antineoplastic 40. Rosiglitazone Antidiabetic 41. Moclobemide Antidepressant 42. Candesartan Antihypertensive 43. Venlafaxine hydrochloride Antidepressant 44. Paroxetine hydrochloride Antidepressant 45. Iomeprol Contrast medium 46. Capecitabine Antineoplastic 47. Daclizumab Immunosuppressive agent 48. Pioglitazone hydrochloride Antidiabetic 49. Didanosine Anti-HIV 50. OctyIonium bromide For irritable bowel syndrome 51. Pravastatin Lipid lowering agent 52. Sildenafil citrate Male erectile dysfunction 53. Triflusal Platelet aggregation inhibitor 54. Thymosin Alfa-1 inj Immunomodulator (for chronic hepatitis-B) 55. Vinorelbin tartrate inj Antineoplastic aggregation inhibitor 56. Broncho-Vaxom Antiasthmatic, immune boosting drug 57. Indinavir sulphate Antiviral (Anti-HIV) 58. Butenafine hydrochloride cream Antifungal 59. Mirtazapine Antidepressant 60. Clopidogrel Antithrombotic; platelet aggregation inhibitor 61. Mosapride Prokinetic agent 62. Donepezil hydrochloride For Alzheimer’s dementia 63. Bupropion SR Smoking cessation adjunct 64. Raloxifene hydrochloride Menopausal osteoporosis 65. Efavirenz Anti-HIV 66. Moxifloxacin Antibacterial 67. Misoprostol Antiulcer agent

Contd.… Appendix-I List of Recently Approved New Drugs and Combinations... 461

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68. Human Recombinant Haemopoietic stimulant, antineutropenic Granulocyte Colony Stimulating Factor inj 69. Nelfinavir mesylate Anti-HIV 70. Ciprofloxacin 1g SR Antibacterial 71. Tolterodine-L-tartrate For overactive bladder 72. Ebastine Antiallergic 73. Leflunomide Anti-rheumatoid arthritis 74. Citalopram hydrobromide Antidepressant 75. Gatifloxacin Antibacterial 76. Linezolid Antibacterial 77. Genirelix releasing hormone (fertility drug) 78. Racecadotril Antidiarrhoeal 79. Cefdinir Antibacterial 80. Iobitridol Contrast medium 81. Estemestane Antineoplastic 82. Decapeptide For vitiligo 83. Oxcarbazepine Antiepileptic 84. Desloratidine Antiallergic 85. Zolendronic acid For hypercalcaemia 86. Zafirlukast Antiasthmatic (leukotriene receptor antagonist) 87. Ropinirole (for parkinson’s disease) 88. Esomeprazole Antiulcer 89. Etanercept-Recombination Antirheumatic, receptor 90. Imatinib mesylate Anticancer 91. Valsartan Antihypertensive 92. Rabeprazole Antiulcer; proton pump inhibitor 93. Bimatoprost (ophthalmic sol) Anti-glaucoma 94. Meropenem inj Beta-lactum antibiotic 95. Fosinopril sodium Antihypertensive 96. Divalproax sodium Antiepileptic 97. Zaleplon Sedative-hypnotic 98. Tizanidine SR Multiple sclerosis 99. Thymogen inj Anticancer 100. Montelukast sodium Antiasthmatic (leukotriene receptor antagonist) 101. Mifepristone Progesterone antagonist 102. Dexarazoxane inj Cardioprotective agent 103. Tranexamic acid Antifibrinolytic 104. Bicalutamide Anticancer 105. etabonate (ophthalmic sol) Corticosteroid, ophthalmic anti-inflammatory 106. (ophthalmic sol) Alpha 2-adrenoreceptor agonist 107. Mizolastine Antiallergic

Contd.… 462 Appendices

…Contd. 108. Miltefosine For Kalaazar 109. hydrochloride For Schizophrenia 110. Abacavir Anti-HIV 111. Nadifloxacin cream Antibacterial; antiacne 112. Meloxicam inj (vet) NSAID 113. Mesalazine SR For bowel disease (inflammatory) 114. Tamsulosin hydrochloride For BPH (benign prostate hypertrophy) 115. Famciclovir Antiviral 116. Nateglinide Antidiabetic 117. Lercanidine hydrochloride Antihypertensive 118. Itopiride capsule Gastroprokinetic agent 119. Alprostadil inj For erectile dysfunction 120. Vimpocetine Vasodilator 121. fumarate Antipsychotic 122. Isotretinoin soft gel cap For Acne vulgaris 123. Nebivolol hydrochloride Antihypertensive 124. Sirolimus Immunosuppressant 125. Drotrecogin alpha For severe sepsis 126. Pygenum africum For BPH (benign prostate hypertrophy) 127. Valdecoxib NSAID 128. Thalidomide For leprosy 129. S (–) Amlodipine besylate Antihypertensive 130. For hyperproloactemia 131. Butarphenol tartarate Opoid analgesic 132. Gemtuzumab For myeloid leukemia 133. Quinapril antihypertensive 134. Valacyclovir Antiviral 135. Fosphenytoin sodium Anti-Epileptic 136. Ceftiofur sodium and hydrochloride Antibiotic (For veterinary use) 137. Metaxalone Muscle relaxant 138. Meglumine gadoteric Contrast media 139. Cafepine hydrochloride Antibiotic 140. Acamprosate calcium For alcohol dependency 141. Aztreonam Antibacterial 142. Tegasserod maleate For irritable bowel syndrome 143. Parecoxib inj NSAID 144. Balsalezide disodium For ulcerative colitis 145. Cefetemet-piroxil Antibacterial 146. Telmisartan Antihypertensive 147. Levocetrizine Antihistaminic 148. Poractant α For respiratory distress in preterm babies Contd.… Appendix-I List of Recently Approved New Drugs and Combinations... 463

…Contd.

149. Reboxetine Antidepressant 150. Cefprozil Antibiotic 151. Cilostazol For intermittent claudication 152. Escitalopram oxalate Antidepressant 153. Anastrazole Anticancer 154. Rizapriptan Antimigraine 155. Gadobenate (Dimeglumine IV injection) MRI contrast medium 156. Tacrolimus ointment Immunomodulator 157. Metolazone Diuretic 158. Tiotropium bromide Antiasthmatic 159. Gadoversetamide inj MRI contrast medium 160. Torsamide Diuretic 161. Cyproterone For prostatic cancer 162. Anti schizophrenia 163. Azelaic acid Antiacne 164. Bendrofluazide Diuretic 165. Vinpocetin Antipsychotic 166. Tirofiban hydrochloride IV Antiplatelet 167. Teriparatide For Osteoporosis 168. Cladribine Anticancer 169. Tadalafil For erectile dysfunction 170. S-Atenolol Antihypertensive 171. Rosuvastatin Lipid lowering agent 172. Tazarotene Antiacne 173. Aceclofenac NSAID 174. Ibopamine hydrochloride Ophthalmic 175. Trandolapril Antihypertensive 176. Dorzolamide Ophthalmic 177. Antispasmodic 178. Risedronate sodium For osteoporosis 179. Fondaparinax sodium LMWH (Low Molecular Weight Heparin) 180. For hepatic disorder 181. Valgancyclovir For CMV (Cyto Megalo virus) 182. Isopropyl Unoprostone Ophthalmic 183. Amorolfine Antifungal 184. Fluvastatin sodium Lipid lowering agent 185. For sleeping disorder 186. Sufentanil citrate Anaesthetic agent 187. Ezetimibe Lipid lowering agent 188. Dutasteride For BPH 189. Gefitinib Anti-cancer Contd.… 464 Appendices

…Contd.

190. Imidapril Anti-hypertensive 191. Adefovir Dipivoxil Anti-viral (Hepatitis-B) 192. Etoricoxib NSAID 193. Dicerein For osteoarthritis 194. Nitazoxanide Anti-diarrhoeal 195. Trolamine cream (0.67%) For topical use 196. Neotame Sweetening Agent 197. Oxybutynine For neurogenic bladder disorder 198. Cabergoline For parkinson’s disease 199. Rabeprazole Sodium Injection For gastric and Deudonal Ulcers & GERD 200. E.R. For BPH 201. Tiagabine HCl Anti-epileptic 202. Racecadotril Sachet Anti-diarrhoeal 203. Ibandronic Acid Inj Anti-cancer 204. Tacrolimus Capsule For organ rejection 205. Cefdinir Dispersible Antibiotic 206. Linezolid For osteomyelitis in adults 207. Cefprozil Dispersible tablet Antibiotic 208. Divalproex Sodium E.R. tablets Anti-epileptic 209. Lithium Carbonate ER tablet Anti-depressant 210. Nimesulide Injection For short-term treatment of post-operative pain 211. Tablet & Syrup For obstructive airway disease 212. HCl For dementia of Alzheimer’s type 213. Pimcrolimus cream For atopic dermatitis 214. Rebamipide For gastric ulcer 215. Cefetamet Pivoxil Suspension Antibiotic 216. Diclofenac Transdermal patch For osteoarthritis & soft tissue injury 217. Fluconazole Gel Anti-fungal 218. Miglitol Anti-diabetic 219. Citicholine Tablet & Injection Membrane permeability enhancer 220. Lamotrigine S.R. tablet Anti-epileptic 221. Moxifloxacin Eye drops For bacterial conjunctivitis 222. long-acting suspension for injection For schizophrenia 223. Everolimus Immunosuppressant 224. Gemcitabine Anti-cancer 225. b-arteether Injection Anti-malaria 226. Ziprasidone powder for injection Anti-psychotic 227. Voriconazole Tablet & Infusion Anti-fungal 228. Cefuroxime Axetil ER tablets Antibiotic

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229. Diclofenac Transdermal Patch For pain relief 230. Gatifloxacin Eye Ointment Ophthalmic use 231. Nimesulide Injection Veterinary use 232. Isotretinoin Gel For acne 233. Levosalbutamol rotacaps & inhaler For obstructive airway disease 234. Celecoxib Injection For acute pain 235. Orlistat Anti-obesity 236. Duloxetine HCl Anti-depressant 237. Delfazacort Anti-asthma, anti-arthritis 238. Atomoxetine HCl For ADHD 239. Ursodeoxycholic acid S.R. Capsule For dissolution of gall stones 240. Methylphenidate Hcl E.R. tablet For ADHD 241. Calcium Polycarbophil For constipation 242. Imiquimod Cream For warts in adults 243. Entacapone For Parkinson’s disease 244. Levocetirizine Syrup For allergic rhinitis & urticaria 245. Pitavastatin Lipid lowering agent 246. Bacillus calusii spores suspension For alteration of intestinal bacterial flora 247. Diacetate Cream For corticosteroid responsive dermatoses 248. Azelaic acid Cream For the treatment of inflammatory papules and pustules of mild to moderate rosacea 249. oral suspension For non-productive cough in adults 250. Duloxetine HCl Anti-depressant 251. Levofloxacin Ophthalmic Solution For susceptible bacterial conjunctivitis 252. Metformin Oral Solution For type-II diabetes mellitus 253. Tirofiban injection For acute coronary syndrome including patients undergoing PTCA or atherectomy 254. Stavudine powder for suspention For HIV-1 infusion 255. Erdosteine For chronic obstructive brochilits 256. Levetiracetam As adjunctive therapy in treatment of partial onset seizures in adults with epilepsy. 257. Esomeprazole Sodium for Injection For GERD in patients with esophagitis and/or severe symptoms of reflux as an alternative to oral therapy when oral intake is not appropriate 258. Rupatadine For perinial allergic rhinitis 259. Acesulfame Potassium As sweetener in pharmaceutical preparation 260. S(–) Metoprolol Succinate S.R. For hypertension 261. R(–) Ondansetron For chemotherapeutic induced nausea and vomiting 262. Balanced salt intraocular irrigating solution For intraocular irrigating during intraocular surgical enriched with glutathione dextrose, procedures bicarbonate Contd.… 466 Appendices

…Contd.

263. Intralipid For patients with essential fatty acid deficiencies 264. Montelukast Granules For prophylaxis and chronic treatment of asthma in adult and pediatric patients of 12 months age and older 265. Bortezomib for injection For the treatment of myeloma patients 266. Nelfinavir For HIV patients 267. Sevelamer For control of serum phosphorus in patients with chronic kidney disease and hemodialysis 268. S(–) Pantoprazole For gastric ulcer, duodenal ulcer & GERD 269. R(–) Ondansetron oral Solution For chemotherapy, induced nausea and vomiting 270. Emtricitabine For HIV infection in adults 271. For hypertension 272. Strontium Ranelate Granules For post-menopausal women with osteoporosis 273. Midazolam Maleate Bulk Anesthetic 274. Calcium Polycarbophil For IBS 275. Testosterone Gel For replacement therapy in male with testosterone deficiencies and hypogonadotropic hypoganadism 276. Erlotinib Hydrochloride For metastatic non-small cell lung cancer 277. Chloroquine Phosphate eye drops For dry eye syndrome 278. Mecobalamine E.R. tablet For neuropathic pain 279. Olmesartan Medoxomil Anti-hypertension 280. Ursodeoxycholic Acid S.R Tablet Addl. strength 281. Feropenem Sodium Anti-bacterial 282. Saquinavir (as mesylate) 500 mg. tablet Addl. strength 283. Pramipexole Di-hydrochloride For Parkinson’s disease 284. Phenytoin Sodium 300 mg. tablet Addl. strength 285. Tenofovir Disproxil Fumarate Anti-HIV 286. Bivalirudin Injection Anti-coagulant in PTCA 287. Efavirenz oral solution Anti-AIDS 288. Didanosine Powder for oral solution Anti-AIDS 289. Sodium Valproate C.R. Tablet (750/1000 mg) Addl. strength 290. Oxcarbazepine S.R. Tablet Anti-epileptic 291. Acitretin For sever psoriasis in adults 292. Dried IVY Leaf Extract (7.5 gm/100ml) Cough syrup 293. Ketorolac Tromethamine Eye drops Ophthalmic 294. Levetiracetam oral Solution Anti-epileptic 295. Zinc (Gluconate) oral solution For acute diarrhoea 296. Maleate For IBS 297. Oseltamivir (as phosphate) Capsule & oral suspension For influenzae 298. Cetrizine HCl drops Anti-histaminic

Contd.… Appendix-I List of Recently Approved New Drugs and Combinations... 467

…Contd.

299. Lanthanum Carbonate Chewable tablet For the treatment of hyperphosphatemia 300. Sodium Hyaluronate eye drops Ophthalmic use. 301. Voglibose anti-diabetic 302. Lactitol Sachet For the treatment of consipation. 303. Aspirin Bolus For Veterinary use 304. Pregabalin For neuropathic pain 305. Methotrexate Topical gel Psoriasis 306. Testosterone Spray For replacement therapy in males with testosterone deficiency 307. Omeprazole Powder for suspension Anti-ulcer 308. Doxazosin (as Mesylate) E.R. Tablet For hypertension 309. Phenylephrine Eye drops For ophthalmic use 310. Entecavir Tablet & oral solution For chronic Hepatitis-B infection 311. Travoprost Eye drops For glaucoma & ocular hypertension. 312. Atomoxetine (as HCl) Sachet For ADHD 313. Levofloxacin oph. solu. Ophthalmic 314. Zonisamide Anti-epileptic 315. Methimazole For hyperthyroidism 316. Caspofungin Acetate injection For invasive candidiasis fungal infection 317. Cefprozil Powder for oral suspension Antibiotic 318. Inhaler For persistent Asthma 319. Pegaptinib Sodium Injection For neovascular (wet) age related macular dege- neration 320. Dexibuprofen For OA, RA & ankylosing spondylitis 321. Moxifloxacin Eye Ointment For ophthalmic use 322. Erdosteine Powder for oral suspension For chronic obstructive bronchitis 323. Doxofylline For bronchila asthma & COPD 324. Zanamavir inhalation powder For influenzae 325. Testosterone Transdermal Spray For replacement therapy in males with testosterone deficiency. 326. Cefetamet Pivoxil HCl oral suspension Antibiotic 327. Voriconazole Powder for oral solution Anti-fungal 328. Aceclofenac S.R. tablet NSAID 329. Desflurane liquid for inhalation For induction & maintenance of anaesthesia 330. Levetiracetam Oral Solution Anti-epileptic 331. Atomoxetine For ADHD 332. Fluorescein Sodium Solution for Injection Ophthalmological diagnostic agent 333. Cefditeron (as pivoxil) Antibiotic 334. Sodium Hyaluronate Cream For leg ulcer, diabetic ulcer etc. 335. Saquinavir Anti-AIDS Contd.… 468 Appendices

…Contd.

336. Tobramycin Inhalation solution For chronic pulmonary infection cystic fibrosis. 337. Propionyl-L-Carnitine HCl Tablet & injection Chronic congestive heart failure 338. Eflornithine HCl Cream For reduction of unwanted facial hair in women. 339. Lactulose Enema For constipation & hepatic encephalopathy 340. Doxofylline Syrup For bronchial asthma & COPD. 341. Cholestyramine Powder for oral suspension For hypercholesterolaemia 342. Haloperidol As approved earlier (Antipsychotic) 343. Resperidone Tablet & Syrup Acute mania & mixed episode in bipolar-I disorder. 344. D-trans Fentantyl Transdermal patches For pain 345. Oseltamivir formulation (additional indication) For Prophylaxis of influenzae in adult and children > 14 years of age 346. Atazanavir Anti-HIV in adults. 347. Nicorandil E.R. Tablet Angina Pectoris 348. Nadifloxacin Gel 1% Acne vulgaris 349. Midazolam (as maleate) For insomnia 350. Olmesartan (as Medoxomil) 10 mg Anti-hypertensive (Addl. Strength) 351. Pregabalin capsule 25/50/100/200 mg Same as approved (Addl. Strength) 352. Oxcarbazepine S.R 450 mg/900 mg Anti-epileptic (Addl. Strength) 353. Ciclesonide rotacaps For Asthma 354. Itopride capsule (S.R) For GERD 355. Ibandronic Acid Tablet (150 mg) Same as approved. (Addl. Strength) 356. Zonisamide capsule 25/50 mg Same as approved (Addl. Strength) 357. Perflutren liquid microsphere injectable For diagnostic use suspension 358. Cyclosporin Eye drops (0.1%) (Addl. Strength) For Ophthalmic use 359. Bemiparin Sodium Solution For deep vein thrombosis 360. Icodextrin peritoneal dialysis solution For peritoneal dialysis 361. Lamotrigin 200 mg tablet (Addl. Strength) Anti-epileptic dispersible tablet 362. Olopathadine Ophthalmic solution For allergic conjunctivitis 363. Methyl Prednisolone Aceponate Cream For atopic dermatitis 364. Levofloxacin Ear drops For otitis media 365. Buclizine HCl tablet & syrup As appetite stimulant 366. Solifenacin Succinate Tablet For overactive bladder with urge urinary incontinence urgency & urinary frequency 367. Zolpidem Tartrate E.R. tablet For insomnia 368. Deferasirox dispersible tablet For chronic iron overload due to blood transfusion 369. Sodium Hyaluronate Injection For OA 370. Forskolin Eye drop For open angle glaucoma Appendix-I List of Recently Approved New Drugs and Combinations... 469

Fixed dose combinations 1. furoate + Terbinafine 2. Rosiglitazone + Metformin 3. Mosapride + MPS (Methyl polysiloxane) 4. Formeterol + 5. Butenafine+ Betamethasone 6. Amlodipine + Benazapril 7. Sucralfate + Metronidazole 8. Glycopyrrolate + Neostigmine 9. Betamethasone + Salicylic acid 10. Mefenamic acid + Tizanidine 11. Latanoprost + Timolol 12. Tobramycin + Fluromethalone 13. Betamethasone + Gentamicin 14. S-Amlodipine + Losartan 15. S-Amlodipine + Atenolol 16. Pioglitazone + Glimeperide 17. Glimeperide + Metformin 18. Rosiglitazone + Glimeperide 19. Tramadol + Paracetamol 20. Ramipril + s(-) Amlodipine 21. Olanzapine + Fluoxetine 22. Ciprofloxacin + Ornidazole 23. Quinapril + HCTZ (Hydrochlorothiazide) 24. Aspirin + Dipyridamole 25. Cyproterone + Ethinyl estradiol 26. S-Amlodipine + Lisinopril 27. Valsartan + HCTZ 28. Montelukast + Bambuterol 29. Adapeline + Clindamycin 30. Ramipril + Candisartan 31. Telmisartan + HCTZ 32. Rofecoxib + Tizanidine 33. Losartan + Ramipril 34. Rofecoxib + Paracetamol 35. Lamivudine + Zidovudine + Abacavir 36. Nadifloxacin + Clobetasol 37. Lercanidipine + Atenolol 38. S-Amlodipine + Valsartan 39. S-Atenolol + S-Amlodipine 40. Imipenem + Cilastatin

Contd.… 470 Appendices

…Contd.

41. Gatifloxacin + Dexamethasone Phos. Eye drops 42. Esomeprazole + Domperidone SR Capsule 43. Aceclofenac + Paracetamol 44. Lamivudine (E.R) + Zidovudine (E.R) + Nevirapine tablets 45. Rabeprazole + Masopride S.R. Tablet 46. Atorvastatin + Ezetimibe 47. Buprenorphin + Naloxone 48. Sucralfate + Metronidazole + Lignocaine cream 49. Glibenclamide + Metformin SR tablet 50. Escitalopram + Clonazepam 51. Dorzolamide + Timolol Eye drops 52. Nebivolol + S(–) Amlodipine 53. Valdecoxib + Paracetamol 54. Amlodipine + Ramipril 55. Rabeprazole Sodium + Domperidone S.R. Capsule 56. Epi-Growth Factor + Silversulphadiazine Cream 57. Amlodipine + Atorvastatin 58. Lovastatin + Nicacin ER tablet 59. Gatifloxacin + Ambroxol HCl 60. Nebivolol HCl + Hydrochlorothiazide 61. Atorvastatin Calcium + Finofibrate 62. Pantoprazole + Domeridone 63. Centbucridine + Feracrylem 64. Atenolol + HCTZ 65. Ofloxacin + Ornidazole 66. Lamivudine + Nevirapine + Stavudine powder for suspension 67. + Contraceptive rings 68. Metaxalone + Diclofenac Potassium 69. Tranexamic acid + Mefenamic acid 70. Fluconazole + Zinc Pyrethione suspension 71. Desloratadine + Ambroxol + Guiphenasine + Menthol Syrup 72. Omeprazole Enteric coated + Domeperidone (S.R.) capsule 73. Buprenorphine + Naloxone S/L tablet 74. Lamivudine +Stavudine reconstituted solution 75. Gliclazide M.R. + Metformin HCl ER tablets 76. Drosperinone + Ethinylestradiol 77. Simvastatin + Ezetimibe 78. Ramipril + Telmisartan 79. Tazarotene + Mometasone Furoate Cream 80. Gatifloxacin + Ornidazole Contd.… Appendix-I List of Recently Approved New Drugs and Combinations... 471

…Contd.

81. Combikit of 2 tablet of Stavudine + Lamivudine each & 1 tablet of Efavirenz 82. Aceclofenac gel 1.5% alongwith linseed oil, menthol, Salicylate, Capsaicin 83. Lamivudine + Stavudine + Nevirapine dispersible tablet 84. Nitazoxanide + Olfoxacin 85. Papain + Urea Ointment 86. Amlodipine + Bisoprolol 87. Ceftriaxone + Tazobatum Injection 88. Levodopa + Carbidopa + Entacapone 89. Atorvastatin + Niacin E.R. Capsule 90. Levocetirizine + Ambroxol S.R. Capsule 91. Gabapentin + Methylcobalamin 92. Calciprtriol + Betamethasone Dipro Ointment 93. Glimepiride + Pioglitazone + Metformin E.R. Tablet 94. Sucralfate + Povidone Iodine Ointment 95. Nimesulide + Methyl Salicylate Aerosol 96. Feracrylum + Metronidazole 97. Methylobalamin + Pyridoxine + Folic Acid 98. Enalapril + HCTZ 99. Ambroxol HCl + Desloratadine 100. S-Metoprolol Succinate Tartrate + HCTZ 101. Stavudine + Lamivudine + Nevirapine dispersible tablet 102. Domperidone + Activated dimethicone chewable tablet 103. Moxifloxacin + Dexamethasone Phosphate Eye drops 104. Brimonidine Tartrate + Timolol 105. Amlodipine (as besylate) + Bisoprolol 106. Olmesartan Medoxomil + HCTZ 107. Ketorolac Tromethamine + Ofloxacin Eye drops 108. Hyoscine-N-Butylbromide + Paracetamol 109. Amlodipine (as besylate) + Losartan Pot 110. Ceftriaxone (as sodium) + Sulbactam (as sodium) powder 111. Nebivolol (as HCl) + Valsartan 112. Combikit of Tamsulosin HCl & Dutasteride Soft Gelatin Capsule 113. Alendronate Sodium + Cholecalciferol 114. Atenolol + HCTZ 115. Tamsulosin HCl + Dutasteride 116. Metoprolol Succinate + Amlodipine 117. Aspirin + Clopidogrel (as bisulphate) 118. Tenofovir Disoproxil fumarate + Emtricitabine 119. Diclofenac Sodium + Misoprostol 120. Pantoprazole (as Sodium) (E.C) + Itopride S.R.

Contd.… 472 Appendices

…Contd.

121. Amlodipine (as besylate) + HCTZ 122. Fumarate + dry powder inhaler 123. Nevibolol (as HCl) + Amlodipine (as besylate) 124. Levocetrizine + Ambroxol Hydrochloride SR 125. Gatifloxacin + Prednisolne Acetate eye drops 126. Amlodipine (as besylate) + Metoprolol Succinate equivalent to Metoprolol Tartrate 50 mg. 127. Nadifloxacin + Miconazole Nitrate + Mometasone Furoate Cream 128. Amoxycillin + Clavulanate Potassium E.R. tablet 129. Lopinavir 200 mg + Ritonavir 50 mg Tablet (Addl. Strength) 130. Ferrous ascorbate + Folic acid 131. Aspirin + Clopidogrel (as bisulphate) 132. Olmesartan 40 mg + HCTZ 25 mg tablet (Addl. Strength) 133. Ceftriaxone (as sodium) 25 mg + Tazobactam 31.25 mg for injection (Addl. Strength) 134. Bimatoprost + Timolol (as maleate) eye drops 135. Mebeverine HCl + Isabgula husk sachet. 136. Vitamin C + Zinc Citrate + Selenium tablet. 137. Lamivudine + Stavudine dispersible tablet 138. Levocetrizine + Ambroxol syrup 139. Cefixime + Pot. Clavulanate tablet 140. ISMN SR 30 mg + Aspirin 75/150 mg tablet (Addl. Strength) 141. Clobestasol Propionate + Calcipotriol ointment

List of recently approved new drugs and combinations in Indian Market by Directorate General of Health Services, Min. of Health & Family Welfare, Govt. of India. List of Banned Drugs AppendixChapter PharmacodynamicsPharmacodynamicsand Fixed Dose Combinations(Mode of Action of in Drugs) India 1.II 4 (Updated till January 2007)

1. Amidopyrine 2. Fixed dose combinations of vitamins with antiinflammatory agents and tranquilizers. 3. Fixed dose combinations of atropine and analgesics and antipyretics. 4. Fixed dose combinations of strychnine and caffeine in tonics. 5. Fixed dose combinations of yohimbine and strychnine with testosterone and vitamins. 6. Fixed dose combinations of iron with strychnine, arsenic and yohimbine. 7. Fixed dose combinations of sodium bromide/chloral-hydrate with other drugs. 8. Phenacetin. 9. Fixed dose combinations of antihistaminics with antidiarrhoeals. 10. Fixed dose combinations of penicillin with sulphonamides. 11. Fixed dose combinations of vitamins with analgesics. 12. Fixed dose combinations of tetracyclines with vitamin C. 13. Fixed dose combinations of hydroxyquinoline group of drugs with any other drug except for preparations meant for external use only. 14. Fixed dose combinations of corticosteroids with any other drug for internal use. 15. Fixed dose combinations of chloramphenicol with any other drug for internal use. 16. Fixed dose combinations of crude ergot preparations except those containing ergotamine, caffeine, analgesics, for the treatment of migraine, headache. 17. Fixed dose combinations of vitamins with anti TB drugs except combination of isoniazid with pyridoxine

hydrochloride (vitamin B6). 18. Penicillin skin/eye ointment. 19. Tetracycline liquid oral preparations. 20. Nialamide. 21. . 22. Methapyrilene, its salts. 23. Methaqualone. 24. Oxytetracycline liquid oral preparations. 25. Demeclocycline liquid oral preparations.

Contd.… 474 Appendices

…Contd. 26. Combinations of anabolic steroids with other drugs. 27. Fixed dose combinations of estrogen and progestin (other than oral contraceptive) containing per tablet estrogen content of more than 50 mcg (equivalent to ethinyl estradiol) and of progestin content of more than 3 mg (equivalent to ) and all fixed dose combination injectable preparations containing synthetic estrogen and progesterone. 28. Fixed dose combination of sedatives/hypnotics/ anxiolytics with analgesics-antipyretics. 29. Fixed dose combination of pyrazinamide with other antitubercular drugs except combination of pyrazinamide with rifampicin and INH as per recommended daily dose given below: Drugs Minimum Maximum Rifampicin 450 mg 600 mg INH 300 mg 400 mg Pyrazinamide 1000 mg 1500 mg

30. Fixed dose combination of histamine H2-receptor antagonists with antacids except for those combinations approved by the Drugs Controller, India. 31. The patent and proprietary medicines of fixed dose combinations of essential oils with alcohol having percentage higher than 20% proof except preparations given in the Indian Pharmacopoeia. 32. All pharmaceutical preparations containing chloroform exceeding 0.5%, w/w or v/v whichever is appropriate. 33. Fixed dose combination of ethambutol with INH other than the following: INH Ethambutol 200 mg 600 mg 300 mg 800 mg 34. Fixed dose combination containing more than one antihistaminic. 35. Fixed dose combination of any anthelmintic with cathartic/purgative except piperazine. 36. Fixed dose combination of salbutamol or any other bronchodialator with centrally acting antitussive and/or antihistaminics. 37. Fixed dose combination of laxatives and/or anti-spasmodic drugs in enzyme preparations. 38. Fixed dose combination of metoclopramide with systemically absorbed drugs except fixed dose combination of metoclopramide with aspirin/paracetamol. 39. Fixed dose combination or centrally acting antitussive with antihistaminics having atropine like activity in expectorants. 40. Preparations claiming to combat cough associated with asthma containing centrally acting antitussive and/or antihistaminics. 41. Liquid oral tonic preparations containing glycerophosphates and/or other phosphates and/or central nervous system stimulant and such preparations containing alchohol more than 20 proof. 42. Fixed dose combination containing pectin and/or kaolin with any drug which is systemically absorbed from GI tract except for combination of pectin and/or kaolin with drugs not systemically absorbed. 43. Chloral Hydrate as a drug 44. Dover’s powder IP 45. Dover’s powder tablets IP 46. Antidiarrhoeal formulations containing kaolin or pectin or attapulgite or activated charcoal. 47. Antidiarrhoeal formulations containing phthalyl sulfathiazole or sulfaguanidine or succinyl sulphathiazole. Contd.… Appendix-II List of Banned Drugs and Fixed Dose Combinations in India 475

…Contd. 48. Antidiarrhoeal formulations containing neomycin or streptomycin or dihydrostreptomycin including their respective salts or esters. 49. Liquid oral antidiarrhoeals or any other dosage form for paediatric use containing diphenoxylate or atropine or belladonna including their salts and esters or metabolites, hyoscyamine or their extracts or their alkaloids. 50. Liquid oral antidiarrhoeals of any other dosage form for paediatric use containing halogenated hydroxyquinolines. 51. Fixed dose combination of anti-diarrhoeals with electrolytes. 52. Patent and proprietary oral rehydration salts other than those conforming to the specified parameters. 53. Fixed dose combination of oxphenbutazone or phenylbutazone with any other drug. 54. Fixed dose combination of analgin with any other drug. 55. Fixed dose combination of dextropropoxyphene with any other drug other than anti-spasmodics and/ or non-steroidal antiinflammatory drugs (NSAIDs). 56. Fixed dose combination of a drug, standards of which are prescribed in the Second Schedule to the said Act with an Ayurvedic, Siddha or Unani drug. 57. Mepacrine hydrochloride (Quinacrine and its salts) in any dosage form for female sterilization or contraception. 58. Fenfluramine and dexfenfluramine. 59. Fixed dose combination of diazepam and diphenhydramine hydrochloride. 60. Cosmetics licensed as toothpaste/tooth powder containing tobacco. 61. Parenteral preparations containing fixed dose combination of streptomycin with penicillin.

62. Fixed dose combination of vitamin B1, vitamin B6, and vitamin B12 for human use. 63. Fixed dose combination of haemoglobin in any form (natural or synthetic). 64. Fixed dose combination of pancreatin or pancrelipase containing amylase, protease and lipase with any other enzyme. 65. Fixed dose combination of nitrofurantoin and trimethoprim. 66. Fixed dose combination of phenobarbitone with any anti-asthamatic drugs. 67. Fixed dose combination of phenobarbitone with hyoscine and/or hyoscyamine. 68. Fixed dose combination of phenobarbitone with ergotamine and/or belladona. 69. Fixed dose combination of haloperidol with any anti-cholinergic agent including . 70. Fixed dose combination of nalidixic acid with any anti-amoebics including metronidazole. 71. Fixed dose combination of loperamide hydrochloride with furazolidone. 72. Fixed dose combination of cyproheptadine with lysine or peptone. 73. Astemizole 74. Terfenadine 75. Phenformin 76. Rofecoxib. 77. Valdecoxib & its formulation.

List of drugs and fixed dose combination prohibited for manufacturing and sale through Govt. of India (Ministry of Health & Family Welfare) Gazette notification GSR 578 (E) Dated 23-7-83 Amended from time to time. (Published in the Gazette of India, Extraordinary Part-II; Section 3 Subsection (i), Ministry or Health & Family Welfare, Govt. of India notification). This page intentionally left blank IndexIndexIndexIndex

Agonists 43 Amoxycillin 318, 320 A Albendazole 361, 362 Amphetamine 119, 138 Aldosterone 281, 282 Amphotericin-B 345 Ampicillin 318, 320 Abciximab 246 Aldosterone antagonist 204, Amrinone 173 Abrasions 12 208 Amyl nitrate 186 Absorption 25, 26 Alfacalcidol 383, 385 Anabolic steroids 289, 290 Acacia 5 Alkaloids 4 Anaemia 247, 388 Acarbose 277, 280 Alkylating agents 372 Analeptics 119 Accelerin 240 Allopurinol 84, 94 Anaphylactic reaction 48 Aceclofenac 84, 90 Allylestrenol 289 Androgens 289, 290 Acenocoumarol 244, 245 Alpha blockers 145, 148 Angina pectoris 185 Acetazolamide 204, 207, 304 Alpha receptors 131 Angiotensin antagonists 181 Acetyl salicyclic acid 84 Alphadone 66 Alprazolam 70, 73, 99 Antacids 261 Acetyl stropanthidin 171 Antagonism 54 Acetylcholine 112, 154, 156 Alprenolol 148, 151 Alprostadil 149 Anterior pituitary hormones Acetyl-CoA 32 269 Acetylcysteine 230, 231 Aluminium hydroxide gel 261, 263 Antiandrogens 290, 291 Acromegaly 270 Anticholinergics 68, 161, 234 Alzheimer’s disease 121 Acute barbiturate poisoning 71 Anticholinesterases 158 Amantadine 125, 126, 338 Acute iron poisoning 249 Anticoagulants 243 Amikacin 327, 329, 365 Acyclovir 337, 338 Antidepressents 95, 99 Addison’s disease 271, 284 Amiloride 204, 207 Antiemetics 68, 257 Adenochrome Aminophylline 204 Antiestrogens 285, 287 monosemicarbazone 241 Amiodarone 190, 192 Antihaemophilic factor 240 Adrenaline 125, 133, 190, 232 Amitriptyline 101 Antimetabolites 374 Adrenergic receptors 131 Amlodipine 176, 183 Antimuscarinics 164 Adrenocorticotrophic Ammonium chloride 204, Antiparkinsonism 218 hormone (ACTH) 269, 271 210, 231 Antiprogestin 289 Aerosols 6, 10, 14 Amodiaquine 350 Antisnake venom 6 Affinity 43 Amoebiasis 355 Antitussive 231 478 Index

Antiviral agents 338 Barbiturate poisoning 71 Bronchial asthma 231 Apolipoprotein B 196 Barbiturates 65, 69, 70 106 Bronchodilators 231 Apomorphine 149, 257 Beclomethasone dipropionate Buclizine 216 Applications 13 232, 282 Bufotoxin 171 Aqua 12 Belladona 4 Bulaquine 350, 351 Arbaprostil 226 β-endorphin 75 Bumetanide 204, 206 Ardeparin 244 Benoxinate 118 Bupivacaine 114, 117 Arecholine 158 Benserzide 125 Buprenorphine 80 Artemether 350, 354 Benzathine penicillin G 318 Buspirone 99 Artemisinin 353 Benzhexol 126 Busulfan 371, 373 Ardeparin 244 Benzocaine 114, 117 Butabarbitone 67, 70 Artesunate 350, 353 Benzodiazepines 70, 71, 98 Butorphanol 80, 81 Artether 350, 353 Benzoic acid 345, 347 Butoxamine 148, 153 Asafoetida 5 Benzoquinonium 111 Aspirin 246 Benzothiazides 203, 204 Astemizole 216 Benztropine 125, 163 Astringent 5 Benzyl penicillin 317, 318 C Atenolol 148, 152, 176, 179, Beta adrenergic blockers 149 186 Beta blockers 99 Cachets 12 Atherosclerosis 195 Beta lactam antibiotics 303 Caffeine 119 Atorvastatin 195, 196 Beta receptors 131 Calcitonin 293 Atracurium 111, 112 Betamethasone 282, 285 Calcium 240 Atrial fibrillation 172 Betaxolol 151 Calcium carbonate 263 Atrial flutter 172 Bethanechol 154, 157 Calcium channel blockers Atropine 68, 161, 163, 172, 190, Bicuculline 120 182, 193 254 Biguanides 279 Capreomycin 365, 368 Atropine methonitrate 163, Bioavailability 28 Capsules 10 164, 232 Biological half-life (t½) 36 Captopril 176, 180 AUC 29 Biopharmaceutics 25 Carbachol 154, 157 Auranofin 84 Biperiden 125, 163 Carbacyclin 226 Autacoid 215 Bisacodyl 253 Carbamazepine 106, 107, 211 Azathioprine 92, 372, 379 Bishydroxycoumarin 244 Carbenicillin 318, 321 Azelastine 219 Bisoprolol 148, 152 Carbenoxolone sodium 263, Azithromycin 331, 332, 365 β-lactamase inhibitors 321 266 Azoreductase 34 Bleomycin 371, 375 Carbidopa 125 Blood Brain Barrier (BBB) 30 Carbimazole 294 Botropase 241 Carbocisteine 230 Bougies 7, 12 Carbonic anhydrase B Bretylium 190, 193 inhibitors 204 ,207 British National Formulary 4 Carcinogenicity 47, 49 Bacillus subtilis 5 British Pharmaceutical Codex Cardiac arrhythmias 189 Bacitracin 335 4 Cardiac glycosides 169 Baclofen 111, 113 Broad spectrum penicillins Carisoprodol 111, 113 Bacterial 30S ribosomes 327 319 Carminative 4 Balsams 5 Bromhexine 231 Carvedilol 148, 152, 176, 179 Bambuterol 133, 232, 233 Bromocriptine 125, 273 Castor oil 4, 253 Index 479

Cavallotoxin 171 Chromium 391 Cough 229, 253 Cefaclor 322, 323 Cimetidine 263 COX-2 Inhibitors 91 Cefadroxil 322 Cinchona 4 Creams 6, 13 Cefazolin 322 Cinnarizine 216, 222 Cretinism 293 Cefepime 322, 325 Ciprofloxacin 308, 309, 365 Cross tolerance 42 Cefixime 322, 325 Cisapride 258, 259 Cushing’s syndrome 271 Cefoperazone 322, 325 Cisplatin 372, 379 Cyanocobalamin 388 Cefotaxime 322, 324 Citalopram 101, 103 Cyclazocine 80 Cefoxitin 322, 324 Clarithromycin 331, 333, 365, Cyclizine hydrochloride 216 369, 370 Cefpirome 322, 325 Cyclopenthiazide 204 Clavulanic acid 318, 321 Ceftazidime 324 Cyclopentolate 163, 164 Clearance 36 Ceftizoxime 322, 325 Cyclophosphamide 371, 372 Ceftriaxone 322, 325 Clindamycin 331, 333 Clobazam 106, 109 Cyclopirox olamine 345, 347 Cefuroxime 322 Cyclopropane 61, 62 Ceilling dose 45 Clofazimine 369, 370 Clofibrate 195, 197 Cycloserine 365, 367 Celecoxib 84, 91 Cyclosporin 92, 372, 379 Celiprolol 148, 153 Clomiphene citrate 285, 287 Clonazepam 70, 73, 106, 108 Cyproheptadine 216, 222 Cemetidine 263 Clonidine 176, 177 Cyproterone acetate 290, 291 Cephalexin 322, 323 Clotrimazole 345 Cytarabine 371, 374 Cetrizine 216, 218 Clotting factors 239, 240 Cytochrome P450 31 Chemoreceptor trigger zone Cloxacillin 318, 319 Cytokine receptors 43 (CTZ) 77, 257 Clozapine 95, 98 Chemotherapy 3, 303 Coagulants 240 Chewable tablets 11 Coagulation 239 Chlopromazine 68 Coca butter 4 D Chloral hydrate 67 Cocaine 115 Chlorambucil 371, 373 Cod liver oil 4, 6 Dactinomycin 375 Chloramphenicol 313 Codeine 76, 78, 231, 254, 256 Dalteprin 244 Chlordiazepoxide 70, 73 Colchicine 84, 93 Danaparoid 244, 245 Chloroquine 349, 350, Colestipol 195, 198 Danazol 290, 291 356, 357 Colistin 334 Danthron 253 Chlorothiazide 203, 204, 304 Collodions 12 Dantrolene 111 Chlorpheniramine maleate Colloid iodine 294 Deamination 31 216, 231 Colloidal ferric hydroxide Degraded gelatin polymer Chlorpromazine 95, 96, 145, 248 199 222, 258 Combined pills 297 Chlorpropamide 211, Competitive antagonism 44 Dehydroemetine 356 277, 278 Complexation 27 Delayed hypersensitivity 49 Chlortetracycline 311 Compressed pessaries 12 Demeclocycline 311 Chlorthalidone 204 Congestive heart failure Depot medroxyprogesterone Chlorzoxazone 112 (CHF) 169 acetate 298 Cholestyramine 195, 198 Conjugation reaction 32 Depot tablets 11 Cholinergic agents. 154 Convulsants 120 Dermojet 8 Cholinesterase 156 Corticosteroids 93, 235 Desacetyl lanatoside-C 171 Chorionic gonadotrophin 5, Corticotropin releasing factor Desflurane 64 272 271 Desmopressin 211 480 Index

Desoxycorticosterone acetate Distigmine 154, 160 Ebastine 219 282 Distribution of drug 29 Econazole 345, 346 Dexamethasone 282, 285 Diuretics 203 ED50 (median effective dose) Dexamphetamine 119, 133 DMARDs 92 46 Dextran 40 199 DNA gyrase 308 Edrophonium 154, 160 Dextran 70 199 Dobutamine 136 Efavirenz 338, 341 Dextromethorphan 231 Docetaxel 372, 377 Effervascent granules 10 Dextropropoxyphene 76, 79 Docusate sodium 253 Effervascent powder 11 Dextrose 201 Dolasetron 259 Eflornithine 359, 364 Diabetes insipidus 205, Domperidone 258 Eicosanoids 225 210, 211 Donepezil 122, 154 Elemental iron 248 Dopamine 133, 135 Diacetyl morphine 76 Elixirs 10, 12 Dopamine receptors 131 Diazepam 62, 66, 67, 70, 72, Emetics 257 Dosage interval 37 99, 106 Emetine 356, 357 Diazoxide 186 Dose-response Curve 45 Emetine bismuth iodide 356 Dibucaine 114, 117 Dothiepin 101, 102 Emulsions 10, 12 Diclofenac 84, 90 Doxapram 119 Enalapril 176, 180 Dicyclomine 163, 165, 258 Doxazosin 145, 148, 176, 178 Enema 7, 13 Diethyl carbamazine 362 Doxepin 101 Enfenamic acid 84 Diethylstilbestrol 285, 298 Doxorubicin 371, 375 Enoxaparin 244 Diflunisal 84 Doxycycline 311, 312 Enprostil 226, 263, 266 Digitalis 4, 169, 190 Doxylamine succinate 258 Enteric-coated 12 Digitalization 172 d-Penicillamine 84, 92 Digitoxin 171 Drogue 4 Enterohepatic circulation 35 Digoxin 171 Droperidol 62, 68, 95, 97 Epastigmine 121 76 Drops 10 Ephedrine 133, 136, 232 Dihydroergotamine 145 Drug antagonism 44 Epirubicin 375 Dihydroergotoxine 119, 121, Drug interactions 51 Epoxidation 31 Drug receptors 42 145 Erdosteine 231 Drug resistance 42 Diiodohydroxyquin 356 Erectile dysfunction 148 Drug withdrawal symptoms Diisopropyl fluorophosphate Ergot alkaloids 145, 146, 222 47 154, 160 Ergotamine 145, 222 Drug-receptor interaction 43 Diloxanide furoate 356 Erythirtyl tetranitrate 186 Drugs and Cosmetics Act, Diltiazem 176, 182, 190 Erythromycin 331 1940 21 Dinoprost 226 δ Erythropoietin 249 -Tubocurarine 111 Estradiol 285 Diphenhydramine 125, 216, Duodenal ulcer 262 Estrogens 281, 285 217, 231, 258 Dusting Powder 12 Ethacrynic acid 204, 206 Diphenhydrinate 258 Dwarfism 270 Diphenoxylate 254 Ethambutol 365, 367 Diphenylhydantoin Ethamsylate 241 (Phenytoin) 106 Ether (Diethyl ether) 62 Dipyridamole 186, 187 E Ethinyl estradiol 285, 297, Direct vasodilators 183 372 Disopyramide 190, 191 Ear cone 12 Ethionamide 365, 367, Dissolution rate 27 Ear/eye/nasal drops 13 369, 370 Index 481

Ethoheptazine 76, 79 Folic acid 383, 384, 389 Good Manufacturing Practice Ethosuximide 106, 108 Follicle stimulating hormone (GMP) 21 Etidocaine 114 (FSH) 269, 272 Gossypol 299 Etomidate 66 Fosfestrol 372, 377 Gout 93 Expectorant 229 Fosphenytoin 107 G-protein 43 Extrinsic pathway 240 Fosracetam 121 Granistetron 258 Eye applicaps 10 Framycetin 327, 329 Granules 10 Furazolidone 307, 356, 358 Graves’ disease 295 Furosemide 71, 204, 304 Grey baby syndrome 40 F Griseofulvin 345 Growth hormone 269 G Growth hormone- releasing 5-Fluorouracil 371 factor (GHRF) 270 Famciclovir 338, 339 G-6-PD deficiency 351 Guaiphenesin 231 Famotidine 263, 264 Guanethidine 176, 178 Fat soluble vitamins 383 Gabapentin 109 Galantamine 122 Gugulipid 195, 198 Felbamate 106 Gumresins 5 Feminism 271 Ganciclovir 338, 340 Fenoterol 133 Gargles 6, 11, 13 Fentanyl 62, 76, 79 Gastric ulcer 262 Feracrylum 241, 242 Gatifloxacin 308, 310 H Ferric ammonium citrate 248 Gels 10, 12 Ferric glycerophosphate 248 Gemfibrozil 195, 197 5-HT blockers 222 Ferritin 248 Gentamicin 327, 328 5-Hydroxytryptamine 221 Ferrous amionate 248 Giardiasis 359 Haemodialysis 50 Ferrous gluconate 248 Gigantism 270 Haemoglobin 248 Ferrous glycine sulphate 248 Ginkgo biloba 122 Ferrous succinate 248 Glibenclamide 277, 278 Haemolytic anaemia 247 Ferrous sulphate 248 Gliclazide 277, 279 Haemoperfusion 50 Fexofenadine 216, 219 Glimepiride 277, 279 Haemostasis 239 Fibrin stabilizing factor 240 Glipizide 277, 278 Haloperidol 68, 95, 97 Fibrinogen 240 Globin zinc insulin 276 Halothane 62, 63 Fibrinolysis 242 Glomerular filtration rate Hamycin 345 Fibrinolytics 245 (GFR) 34 Hard capsules 10 First order kinetics 36 Glucocorticoids 271, 281, 282 Hegeman factor 240 Fixed oils 4 Glucuronide conjugation 32 Hemosiderin 248 Flavouring agent 4 Glutathione conjugation 32 Heparin 243, 244 Flavoxate 163, 165 Gluthemide 67 Heparin antagonists 245 Fluconazole 345, 346 Glycerinated haemoglobin Heparinoids 244 Flucytosine 345 248 Hexaethyl tetraphosphate 154 Fluocinolone 282 Glycerine 231 Hexobaritone 62 Fluoroquinolones 308 Glycerol suppositories 253 High density lipoproteins Fluorouracil 374 Glyceryl trinitrate 185 (HDL) 195 Fluoxetine 101, 104 Glycine conjugation 33 Histamine 215 Flurbiprofen 84, 88 Glycopyrrolate 163, 165 HMG CoA reductase Flurdocortisone 282 Glycosides 4 inhibitors 196 Flutamide 290, 291 Gold compounds 84, 92 Homatropine 163, 164 482 Index

Human albumin 199 Indinavir 338, 341 Isopropamide 163, 165 Human lente insulin 276 Indomethacin 84, 88, 93 Isosorbide 5-mononitrate 186 Human regular insulin 276 Insufflations 12 Isosorbide dinitrate 4, 186, 187 Human soluble insulin 276 Insulin 6, 275 Isosorbide-5-mononitrate 187 Huminsulin 277 Insulin zinc suspension Isotretinoin 385 Hyaluronidase 6 (Lente insulin 276 Isoxsuprine 133, 138 Hydantoins 106 Insulin zinc suspension Ispaghula 253, 254 Hydralazine 176, 183 ‘extended’ (Ultralente 276 Itopride 258, 260 Hydrochlorthiazide 211 Insulin zinc suspension Itraconazole 345, 346 hydrocodone 76 ‘prompt’ (Semilente) 276 Ivermectin 362, 363 Hydrocortisone 282 Interferons 338, 342, 372, 379 Hydrolysis 31, 32 Intermediate density Hydromorphone 76 lipoproteins (IDL) 195 J Hydroxychloroquine 92 Interstitial cell stimulating Hydroxyethyl starch 199, 200 hormone (ICSH) 269, 272 Hydroxyethyl theophylline Jellies 6, 13 Intra-articular 9 232 Intracardiac 9 hydroxylation 31 Intracellular receptors 43 Hydroxyurea 372, 378 K Hydroxyzine 68, 99 Intradermal 9 Hyoscine 163, 258 Intramedullary 9 Intramuscular 8 Kanamycin 327, 329, 365, 368 Hyoscine methylbromide 163 Kaolin 254 Intraperitoneal 9 Hypercholesterolaemia 196 Ketamine 62, 66 Intrathecal 9 Hyperlipidemia 195 Ketanserin 222, 223 Intravenous 9 Hypersenstivity (Drug Ketoconazole 345, 346 Intrinsic pathway 240 Allergy) 48 Ketoprofen 88 Inverse agonist 43 Hypertensive crisis 100 Ketorolac tromethamine 84 Iodine (Lugol’s solution) 294 Hypertriglyceridaemia 197 Ketotifen 232, 235 Iodochlorohydroxyquin 356 Hypnotics 67, 69 Kinins 215 Ipecacuanha 257 Ipratropium bromide 163, 164, 232 I Irbesartan 176, 181 L Irinotecan 372 Iatrogenicity 47 Iron 247 Labetalol 148, 152, 176, 180 Ibopamine 158 Iron calcium complex 248 Lactogenic hormone 269, 273 Ibuprofen 84, 88 Iron choline citrate 248 Lactulose 253 IDDM 275 Iron dextran 248 Lamivudine 338, 340 Idiosyncrasy 50 Irrigation 6 Lamotrigine 106, 110 Idoxuridine 337, 338 Irrigators 13 Lanatoside-C 171 Iloprost 226 Isocarboxazid 101 L-Asparaginase 372, 378 Imipramine 101 isoetharine 133 Laxatives 253 Immunoglobulins 5, 48 Isoflurane 62, 64 LD50 () 46 Implants 11 Isoniazid 365 Leishmaniasis (kala-azar) Indapamide 204 Isoprenaline 125, 133, 137, 358 Indian pharmacopoeia 4 190, 232 Lemon oil 4 Index 483

Lepirudin 244, 245 Mestranol 285, 297 Leprosy 369 M Metaxalone 111, 114 Leukotriene pathway Metergoline 222 inhibitors 235 Metformin 277, 279 Leukotrienes 215, 225, 227 6-Mercaptopurine 371, 374 Macrolides 331 Methacholine 154, 157 Levallorphan 80 Methadone 76, 79 Levamisole 361, 362 Mafenide propionate 304 Magaldrate 262, 263 Methamphetamine 119 Levocetrizine 216, 218 Methenamine 314 Levodopa 123, 125 Magnesium carbonate Methimazole 294 Levofloxacin 308, 310 261, 263 Methocarbamol 111, 112 Levonorgestrel 289 Magnesium hydroxide 253, Ligand-gated channels 43 263 Methohexitone sodium 62, 65 Lignocaine 114, 116, 172, Magnesium trisilicate 263 Methotrexate 84, 92, 93, 190, 192 Malathion 154 371, 374 Lincomycin 331, 333 Male contraceptive 299 Methoxyflurane 62, 64 Linctus 10, 13 Manganese 391 Methsuximide 106, 108 Liniments 10, 13 Mannitol 71, 204, 209 Methyl cellulose 254 Liquid paraffin 253 MAO inhibitors 99, 101, 125 Methylcellulose 253 Liquorice 231 Mast cell stabilizer 232, 234 Methyldopa 125, 176, 177 Lisinopril 176, 181 Masterolone 291 Methylphenidate 119 Lisuride 125 Mebendazole 361, 362 Methyltestosterone 290 Lithium carbonate 101, 104 Methysergide 147, 222 Loading dose 37 Mebeverine 163, 165 Meclizine hydrocloride 216 Metoclopramide 258 Local anaesthetics 115, 218 Metoprolol 148, 152, 176, 179 Local haemostatic 242 Medroxyprogesterone Metrifonate 121 Local hormones 215 288, 289 Metronidazole 355, 356, 359 Log-dose response curve 45 Mefenamic acid 84, 89 Lomustine 371, 373 Mefloquine 350, 351 Mianserin 101, 102 Loop diuretics 205 Megaloblastic anemia 388 Miconazole 345, 346 Loop of Henle 205 Melanocyte-stimulating Midazolam 62, 70, 72 Loperamide 254, 256 hormone (MSH) 269 Mifepristone 289 Loratidine 216 Melarsoprol 359, 364 Migraine 147 Lorazepam 62, 70, 72, 99 Menadione 241 Milrinone 173 Losartan potassium 176 Menotrophin 273 Mineralocorticoids 282 Lotions 6, 14 Mepacrine 350, 352 Minimum effective Lovastatin 195, 196 Mepenzolate methylbromide concentration (MEC) 37 Low density lipoproteins Minipill 298 (LDL) 195 163 Minocycline 311, 369, 370 Low molecular weight Mephenesin 111, 112 Mirtazapine 101, 102 heparins 243 Mephenytoin 106 Loxapine 95, 98 Mephobarbitone 105 Misoprostol 226, 263, 265 Lozenges 6, 11 Meprobomate 99 Mitomycin-C 371, 376 Luteinising hormone (LH) Mepyramine 215 Mixtures 10 269, 272 Mersalyl sodium 204 Moclobemide 101 Lynestrenol 297 Merulluride 204 Molindone 95 Lysergic acid diethylamide Mesalazine 254, 256 Molybdenum 391 222 Mesna 371, 373 Montelucast 232, 235 484 Index

Mood stabilizers 104 Nicotinic acid 195, 196, 198 Olsalazine 256 Morphine 75, 76 Nicotinyl xanthinate 186 Omeprazole 263, 264 Mosapride 258, 259 NIDDM 275 Ondansetron 258, 259 Motion sickness 218 Nifedipine 176, 182, 186 Opioid agonists/antagonists Moulded passaries 12 Nifurtimox 359 80 Mouth washes 6, 14 Night blindness 385 Opioids 67, 75, 231 Multiple drug therapy 51 Nikethamide 119 Opium 4 Mycophenolate mofetil 379 Nimesulide 84, 91 Oral anticoagulants 245 Myxoedema 293 Nimodipine 119, 121 Oral contraceptives 297 Nitrates 294 Orciprenaline 133, 138, 190, Nitrazepam 70 232 Nitrofurans 307 Organic iodide 294 N Nitrofurantoin 307, 314 Organic mercurials 209 Nitrofurazone 307 Ornidazole 356 Nitroreductase 34 Nabumetone 84, 92 Orphenadrine 111, 113, 125 Nitrous oxide 62 N-acetyltransferases 32 Osmotic diuretic 204, 209 Nocturia 211 Nadolol 148, 151 OTC (over the counter) 47 Nadroparin 244 Non-competitive antagonism 45 Oxazepam 70, 72, 99 Nafarelin acetate 273 Oxcarbazepine 106, 107 Nalbuphine 80 Non-steroidal antiinflammatory drugs Oxethazaine 114, 118 Nalidixic acid 308 Oxiracetam 121 Nalmefene 80 (NSAIDs) 83 Noradrenaline 133 Oxprenolol 151 Nalorphine 80 Oxycodone 76 Naloxone 80, 81 Norethindrone 297, 298 Norethindrone enanthate Oxymetazoline 133, 137 Naltrexone 80, 81 Oxymorphone 76 Nandrolone 290, 291 298 Oxyphenbutazone 84, 87 Naphazoline 133 Norethisterone 289 Oxyphenonium 165 Naproxen 84, 88, 93 Norfloxacin 308, 309 Oxytetracycline 311 Nateglinide 277, 280 Norgestrel 297, 298 Oxytocin 274 National Formulary 4 Normal saline 201 Nebivolol 153 Nortriptyline 101, 102 Nebracetam 121 Noscapine 231 Nebulizers 14 N-oxidation 31 P Nefiracetam 121 Nylidrin 133 Nystatin 345 Negative antagonists 43 Paclitaxel 372, 377 Neomycin 327, 329 Paediatric drops 13 Neostigmine 154, 159 Paints 14 Nephron 34 O Pamparin 244 Neuroleptics 67 Pancuronium 111, 112 Neutral Protamine Hagedorn Panthienate 165 (NPH) insulin 276 Octerotride 270 Nevirapine 338, 341 Ofloxacin 308, 310, 365, 369 Pantoprazole 263, 265 New Drug Policy 24 Oils 4 Para-amino benzoic acid Nicergoline 119, 121 Ointments 6, 14 (PABA) 305 Nickel 390 Oleogum resin 5 Para-amino salicylic acid 365 Niclosamide 362 Oleoresins 5 Paracetamol 84, 90 Nicorandil 186 Olive oil 4 Paraldehyde 67 Index 485

Parathion 154 Phenylephrine 133, 138 Potassium - sparing diuretics Pargyline 101 Phenytoin sodium 190, 192 204 Parkinsonism 123, 217 Pheochromocytoma 148 Potassium acetate 231 Paromomycin 356, 358 Phenylbutazone 84 Potassium citrate 204, 210, Paroxetine 101, 103 Pholcodeine 76, 231 231 Partial agonists 43 Phthalyl sulfathiazole 304 Potassium iodide 231, 294 Passive diffusion 35 Physostigmine 154, 159 Potassium sparing diuretics Pastes 6, 10, 14, Phytomenadione 241 208 Pastilles 11, 13 Phytonadione 240 Poultices 10, 14 Pectin 254 Picrotoxin 119 Powders 6, 11 Pefloxacin 308, 309 Pilocarpine 4, 154, 157 Pramipexole 127 Pellagra 387 Pimaricin 345 Pramiracetam 121 Pellet implantation 8 Pimozide 95, 98 Pravastatin 195, 197 Penicillamine 93 Pindolol 148, 151, 176, 179 Praziquantel 362, 363 Penicillinase resistant Pioglitazone 277, 280 Prazosin 145, 147, 176, 178 penicillin 319 Pipazethate 231 Preanaesthetic medication 67 Penicillins 317 Pipenzolate methylbromide Prednisolone 282, 284 Pentaerythritol tetranitrate 163 Prescription 15 186, 187 Piperacillin 318, 321 Prienzepine 165 Pentamidine 358 Piperazine 362 Prilocaine 114 Pentazocine 80 Piracetam 119, 120 Primaquine 350 Pentobarbitone 67, 70 Pirenzepine 163 Pentylene tetrazol 119, 120 Primary hypertension 175 Piribedil 119, 121 Primary nocturnal enuresis Pepsin 6 Piroxicam 84, 89, 93 Perchlorates 294 211 Pizotifen 222 Primidone 105, 106 Pergolide 125 Placental extract 5 Pessaries 7, 12 Proaccelerin 240 Plasma protein binding 29 Probenecid 84, 93, 94 Pethidine 76, 78 Plasma substitutes/ Pharmacopoeia 4 Probucol 195, 198 expanders 199 Procainamide 190, 191 Pharyngeal demulcents 229 Plasma thomboplastin Phased pills 297 Procaine 114 component 240 Procaine penicillin G 318 Phenazopyridine 314, 315 Plasma thromboplastin Procarbazine 372, 378 Phenelzine 101 antecedent 240 Prochlorperazine 258 Phenindione 244, 245 Plasters 12 Procyclidine 125, 163 Pheniramine maleate 216 Platelet aggregation 239 Progesterone 287, 289 Phenobarbitone 70, 105, 106 Platelet inhibiting drugs 246 phenolphthalein 253 Poisoning 50 Progestins 287, 289 Phenothiazines 96 Polidocanol 241, 243 Proguanil 350, 352 Phenoxybenzamine 145, 146, Polymyxin B 334 Prolactin 269, 273 176 Polythiazide 204 Promethazine 67, 125, 216, Phenoxymethyl penicillin Polyvinylpyrrolidone 199 217, 231, 258 318 Polyvinylpyrrolidone (PVP) Promethazine Phentolamine 146, 148 201 chlorotheophyllinate 216 Phentolamine mesylate 145, Pork lente insulin 276 Promethazine theoclate 258 176 Pork regular insulin 276 Propanidid 62, 65 Phenylbutazone 87 Postcoital contraception 298 Propantheline 165 486 Index

Propranolol 99, 148, 150, 172, Rauwolfia serpentina 4 Secnidazole 356, 359 176, 178, 186, 190 Recombinant human Secobarbitone 67, 70 Propyl thiouracil 294 erythropoietin 249 Secondary hypertension 175 Proscillaridin-A 171 Reflex expectorant 229 Sedative 67 Regular (soluble) insulin 276 Prostacyclin I2 (PGI2) 239 Selective serotonin reuptake Rehydrating solutions 254 Prostaglandin analogues 226, inhibitors (SSRI) 103 Renin angiotensin system Selegiline 125, 126 265 175 Selenium 345, 347, 391 Prostaglandins 83, 215, 225 Renzapride 260 Senna 4, 253, 255 Protamine sulfate 245 Repaglinide 277, 279 Protamine zinc insulin 276 Reserpine 176, 177 Serotonin 221 Prothrombin 240 Resins 5 Sertindole 95 Prothrombinase 240 Retinoids 385 Sertraline 101, 103 Proton pump inhibitor 264 Reversible anticholinesterase Sevoflurane 65 Pseudocholinesterase 156 159 Sex hormones 285 Pseudoephedrine 133, 136 Reviparin 244 Shark liver oil 6 Psychostimulants 120 Rheumatoid arthritis 92 Sildenafil 148 Psyllium 253 Ribavarin 338, 342 Silver sulfadiazine 304 Purgative 11 Rifabutin 365, 368 Simmond’s disease 270 Pyrantel pamoate 362 Rifampicin 365, 366, 369, 370 Simvastatin 195, 196 Pyrazinamide 365, 366 Rifapantine 365, 368 Skeletal muscle relaxants 111 Pyridostigmine 154, 160 Rimeterol 133 Sodium biocarbonate 263 Pyridoxine 125 Ringer Lactate 201 Sodium channel blockers 189 Pyrilamine maleate 216 Rioprostil 226 Sodium cromoglycate 232, Pyrimethamine 350, 352 Ritodrine 133 234 Pyritinol 119, 120 Ritonavir 338, 342 Sodium nitroprusside 176, Pysllium 254 Rivastigmine 122, 154 183 Ropinirole 125, 126 Sodium phosphate 253 Ropivacaine 114, 118 Sodium picosulphate 253, Rosiglitazone 277, 280 254 Q Roxatidine 263, 264 Sodium salicylate 84 Roxithromycin 331, 332 Sodium stibogluconate 358 Quinidine 189, 190 Sodium thiosulfate 345, 347 Quinine 350, 352 Sodium valproate 108 Quiniodochlor 345, 347 S Soft capsules 10 Quinolones 308 Solid dosage form 12 Salbutamol 133, 232 Soluble tablets 11 Salicylamide 84 Solutions 10, 13 R Salicylate poisoning 86 Somatostatin 270 Salicylates 83 Sometrem 270 Rabeprazole 263, 265 Salicylism 86 Sotalol 148, 151, 176 Radioactive gold (198AU) Saline expectorants 230 Sparfloxacin 308, 310, 369 372 Salmeterol 133, 232, 233 Spironolactone 204, 208 Radioactive iodine 294, 372 Salt Form 27 Sprays 6, 10, 14 Radioactive phosphorus 372 Scopolamine 68 Stanozolol 290, 291 Ramipril 176, 181 Scored Tablets 11 Status asthmaticus 235 Ranitidine 263, 264 Scurvy 389 Stavudine 338, 340 Index 487

Stevens-Johnson syndrome 49 Thyroglobulin 293 Stimulant laxatives 254 T Thyroid extract/thyroxine 6 Stokes Adams syndrome 136 Thyroid stimulating hormone (TSH) 269 Stool softener 254 Tachyphylaxis 42 Streptokinase 244, 245 Tacrine 121, 154 Thyroxine (l-thyroxine Streptomyces aureofaciens 5 Tadalafil 149 sodium) 293 Streptomyces erythreus 5 Tamoxifen 285, 287, 372, 378 Thyroxine (T4) 271, 293 Streptomyces griseus 5 Tamsulosin 145, 148 Tiagabine 106 Streptomyces venezuelae 5 Tannins 5 Tibolone 285, 286 Streptomyces nouresi 5 Taxanes 377 Ticarcillin 318, 321 Streptomycin 327, 365, 366 Tenoxicam 84, 89 Timolol 148, 151 Stropanthin-G 171 Teratogenicity 47, 49 Tinctures 10, 13 Stropanthin-K 171 Terazosin 145, 147, 176, 178 Tinidazole 345, 355, 356, 359 Structure Activity Terbinafine 345, 347 Tinzaparin 244 Relationship (SAR) 42 Terbutaline 133, 232, 233 Tizanidine 111, 113 Strychnine 119, 120 Terfenadine 217 Succinyl sulfathiazole 304 Tobramycin 327, 328 Testosterone 290 Tolazamide 277 Succinylcholine 111, 112 Tetracaine 114 Tolazoline 145 Sucralfate 263, 266 Tetracyclines 311, 356 Tolbutamide 277, 278, 304 Sulbactam 318, 321 Thalidomide 370 Tolerance 42 Sulfacetamide 304 The Drugs & Magic Remedies Sulfadiazine 304 Act 24 Tolnaftate 345, 347 Sulfadimethoxine 304 The Drugs (Price Control) Topiramate 106, 109 Sulfadimidine 304 Order 24 Topotecan 372, 377 Sulfadoxime 350 The Medical Termination of Toxicology 3 Sulfafurazole 304 Pregnancy Act 24 Trace elements 390 Sulfaguanidine 304 The Medicinal & Toilet Tragacanth 5 Sulfamethaxazole 304 Preparations Act 23 Tramadol 76, 79 Sulfamethizole 304 The Poisons Act 24 Tranexamic acid 241, 242 Sulfamethopyrazine 304, 350 The Prevention of Food Transferrin 248 Sulfamethoxypyridazine 304 Adulterations Act 24 Triamazosin 145 Sulfasalazine 84, 92, 93, 254, Theophylline 119, 232, 233 Triamcinolone 282, 285 256, 304 Theophylline ethanolate of Triamterene 204, 207 Sulfinpyrazone 84, 93, 94 piperazine 232 Trichloroethylene 62, 63 Sulindac 84, 88 Therapeutic Index 46 Sumatriptan 147 Trichomoniasis 359 Thevetin 171 Trifluoperazine 95, 97 Suppositories 7, 12 Thiabendazole 361, 362 Trifluoperidol 95, 97 Supradditive 44 Thiacetazone 365 Triflupromazine 68, 95, 258 Suramin 359, 364 Thiazides 204 Trihexyphenidyl 125, 163 Surgical ligatures and Thiocyanates 294 sutures 6 Thiopentone sodium 62, 65 Triiodothyronine (T3) 271, Sympathomimetics 231 Thio-TEPA 371, 373 293 Synergism 43, 54 Throat paints 6, 14 Trimethadione 106 Syrup of Tolu 231 Thrombogenesis 239 Trimethoprim 304, 306 Syrup of Vasaka 231 Thromboplastin 240 Trimipramine 101, 102 Syrups 10, 13 Thromboxane A2 239 Trimoprostil 226 488 Index

Tripelennamine 216 Verapamil 176, 182, 186, 190 Water soluble vitamins 383 Triphala 5 Very low density lipoproteins Triprolidine 216 (VLDL) 195 Tropicamide 163, 164 Vigabatrin 110 True cholinesterase 156 Vinblastine 372, 376 X Trypanosomiasis 358 Vinca rosea 4 Turpentine oil 4 Vincristine 372, 376 Xipamide 204 Tyramine 100 Vinorelbine 372, 376 Xylometazoline 133 Tyrothricin 335 Virilism 271 Viscosity 27 Vitamin A 384 Y Vitamin B 383 U Vitamin C (Ascorbic acid) 384, 389 Yohimbine 145, 148 United States Pharmacopoeia Vitamin D 383, 384, 385 4 Vitamin E 383, 384, 386 Urea 204, 209 Vitamin K 240, 241, 384 Z Urinary antiseptics 314 Vitrellae 14 Urokinase 244, 246 Volatile oil 4 Zafirlukast 232, 235 Volume of distribution (Vd) Zaleplon 70, 74 36 Zero order kinetics 36 V Zidovudine 338, 340 Zolliger-Ellison syndrome Valacyclovir 338, 339 W (ZES) 263 Valproic acid 106 Zolpidem 70, 74 Vancomycin 331, 334 Warfarin 244, 245 Zopiclone 70, 74 Vasopressin 210, 211, 274 Water partition coefficient 25 Zuclopenthixol 95, 98