Essentials of Medical Pharmacology Essentials of Medical Pharmacology Seventh Edition KD TRIPATHI MD Ex-Director-Professor and Head of Pharmacology Maulana Azad Medical College and associated LN and GB Pant Hospitals New Delhi, India ® JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi • London • Philadelphia • Panama ® Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 Email: [email protected] Overseas Offices J.P. Medical Ltd., Jaypee-Highlights Medical Publishers Inc. Jaypee Medical Inc. 83 Victoria Street London City of Knowledge, Bld. 237, Clayton The Bourse SW1H 0HW (UK) Panama City, Panama 111 South Independence Mall East Phone: +44-2031708910 Phone: +507-301-0496 Suite 835, Philadelphia, PA 19106, USA Fax: +02-03-0086180 Fax: +507-301-0499 Phone: + 267-519-9789 Email: [email protected] Email: [email protected] Email: [email protected] Jaypee Brothers Medical Publishers (P) Ltd Jaypee Brothers Medical Publishers (P) Ltd 17/1-B Babar Road, Block-B, Shaymali Shorakhute, Kathmandu Mohammadpur, Dhaka-1207 Nepal Bangladesh Phone: +00977-9841528578 Mobile: +08801912003485 Email: [email protected] Email: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2013, KD Tripathi Managing Editor: M. Tripathi Inquiries for bulk sales may be solicited at: [email protected] All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the author and the publisher. This book has been published in good faith that the material provided by author is original. Every effort is made to ensure accuracy of material, but the publisher, printer and author will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters to be settled under Delhi jurisdiction only. Essentials of Medical Pharmacology First Edition: 1985 Second Edition: 1988 Third Edition: 1994 Fourth Edition: 1999, Updated Reprint: 2001 Fifth Edition: 2003 Sixth Edition: 2008 Seventh Edition: 2013 ISBN: 978-93-5025-937-5 Printed at Ajanta Offset Preface Medical pharmacology is a unique synthesis of basic pharmacology with clinical pharmacology and pharmacotherapeutics. The subject is highly dynamic. Developments are occurring both in defining molecular targets for drug action and finding targeted drugs, as well as in accruing credible evidence regarding the impact of different treatment modalities on therapeutic outcomes. These efforts have begun to crystallize into evidence based medicine and clear cut therapeutic guidelines. The present edition endeavours to amalgamate the developments with the core content of the subject. While the primary theme of the book outlined in the preface to the first edition is maintained, the successive editions have become more descriptive and more comprehensive. In preparing this edition, all chapters have been revisited and extensively updated. Latest therapeutic guidelines from authoritative sources like WHO, British National Formulary, National Formulary of India, as well as from eminent professional bodies have been incorporated, especially in areas like hypertension, dyslipidaemias, acute coronary syndromes, surgical prophylaxis, tuberculosis (including MDR-TB), MAC-infection, leprosy, HIV-AIDS, malaria, kala-azar, etc. Recent innovations have been highlighted, notably in antidiabetic drugs, psychopharmacological agents, antiplatelet drugs, treatment of inflammatory bowel disease, drugs affecting renin-angiotensin system, anticoagulants, antiviral (including anti-HIV) drugs, targeted anticancer drugs, etc. New drugs released in India have been included. Infrequently used drugs and those not available in India are presented briefly in extract type. Important points are summarized in boxes. Use of distinctive headings in a hierarchical order makes the text highly systematic. Representative trade names of drugs with available dosage forms are mentioned. Due emphasis is given to diseases prevalent in India and similar tropical countries, alongwith their current drug therapy. The most important objective of medical pharmacology is to train medical students in therapeutic decision making according to specific clinical problems in individual patients. A new feature ‘problem directed study’ has been included at the end of majority of chapters to give an exercise in therapeutic decision making for a realistic clinical scenario. The solutions provided in Appendix-1 explain how rational decisions could be arrived at. I thank students and other readers of this text for their valuable feedback and suggestions. All credit for existence of this book, especially the present edition, goes to Mr. Jitendar Pal Vij, the untiring Group Chairman and Mr. Ankit Vij (Managing Director) of M/s Jaypee Brothers. Meticulous typesetting by Ms. Sunita Katla and proof reading by Ms. Geeta Srivastava deserves special mention. Credit for improving the illustrations goes to Mr. Manoj Pahuja. The cooperation and editorial management of my wife is acknowledged. New Delhi KD Tripathi May 2013 Extract from Preface to the First Edition Pharmacology is both a basic and an applied science. It forms the backbone of rational therapeutics. Whereas the medical student and the prescribing physician are primarily concerned with the applied aspects, correct and skilful application of drugs is impossible without a proper understanding of their basic pharmacology. Medical pharmacology, therefore, must include both fundamental back- ground and clinical pharmacological information. Objective and quantitative data on the use of drugs in man, i.e., relationship between plasma concentration and intensity of therapeutic/toxic actions, plasma half lives, relative efficacy of different medications and incidence of adverse effects etc., are being obtained with the aim of optimising drug therapy. The concepts regarding mechanism of action of drugs are changing. In addition, new drugs are being introduced in different countries at an explosive pace. A plethora of information thus appears to be important. However, trying to impart all this to a medical student would be counter-productive. One of the important aims of this book is to delineate the essential information about drugs. The opening sentence in each chapter defines the class of drugs considered. A ‘prototype’ approach has been followed by describing the representative drug of a class followed by features by which individual members differ from it. Leading trade names have been included. Clinically relevant drug interactions have been mentioned. Clear-cut guidelines on selection of drugs and their clinical status have been outlined on the basis of current information. Original, simple and self-explanatory illustrations, tables and flow charts have been used with impunity. Selected chemical structures are depicted. Recent developments have been incorporated. However, discretion has been used in including only few of the multitude of new drugs not yet available in India. This is based on their likelihood of being marketed soon. The information and views have been arranged in an orderly sequence of distinct statements. I hope this manageable volume book would serve to dispel awe towards pharmacology from the minds of medical students and provide a concise and uptodate information source for prescribers who wish to remain informed of the current concepts and developments concerning drugs. My sincere thanks are due to my colleagues for their valuable comments and suggestions. New Delhi KD Tripathi 1st Jan., 1985 Contents 1 Section General Pharmacological Principles 1. Introduction, Routes of Drug Administration 1 2. Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs 10 3. Pharmacokinetics: Metabolism and Excretion of Drugs, Kinetics of Elimination 22 4. Pharmacodynamics: Mechanism of Drug Action; Receptor Pharmacology 37 5. Aspects of Pharmacotherapy, Clinical Pharmacology and Drug Development 61 6. Adverse Drug Effects 82 2 Section Drugs Acting on Autonomic Nervous System 7a. Autonomic Nervous System: General Considerations 92 7b. Cholinergic System and Drugs 99 8. Anticholinergic Drugs and Drugs Acting on Autonomic Ganglia 113 9. Adrenergic System and Drugs 124 10. Antiadrenergic Drugs (Adrenergic Receptor Antagonists) and Drugs for Glaucoma 140 3 Section Autacoids and Related Drugs 11. Histamine and Antihistaminics 159 12. 5-Hydroxytryptamine, its Antagonists and Drug Therapy of Migraine 170 13. Prostaglandins, Leukotrienes (Eicosanoids) and Platelet Activating Factor 181 14. Nonsteroidal Antiinflammatory Drugs and Antipyretic-Analgesics 192 15. Antirheumatoid and Antigout Drugs 210 viii CONTENTS 4 Section Respiratory System Drugs 16. Drugs for Cough and Bronchial Asthma 218 5 Section Hormones and Related Drugs 17a. Introduction 234 17b. Anterior Pituitary Hormones 236 18. Thyroid Hormone and Thyroid Inhibitors 245 19. Insulin, Oral Hypoglycaemic Drugs and Glucagon 258 20. Corticosteroids 282 21. Androgens and Drugs for Erectile Dysfunction 296 22. Estrogens, Progestins and Contraceptives 306 23. Oxytocin and Other Drugs Acting on Uterus 329 24. Drugs Affecting Calcium Balance 335 6 Section Drugs Acting on Peripheral (Somatic) Nervous System 25. Skeletal Muscle Relaxants 347 26. Local Anaesthetics 360 7 Section Drugs Acting on Central Nervous System 27. General Anaesthetics 372 28. Ethyl and Methyl Alcohols 388 29. Sedative-Hypnotics 397 30. Antiepileptic Drugs 411 31. Antiparkinsonian Drugs 425 32. Drugs Used in Mental Illness: Antipsychotic and Antimanic Drugs 435 33. Drugs Used in Mental Illness: Antidepressant and Antianxiety Drugs 454 34. Opioid Analgesics and Antagonists 469 35. CNS Stimulants and Cognition Enhancers 486 CONTENTS ix 8 Section Cardiovascular Drugs 36a. Cardiac Electrophysiological Considerations 492 36b. Drugs Affecting Renin-Angiotensin System and Plasma Kinins 495 37. Cardiac Glycosides and Drugs for Heart Failure 512 38. Antiarrhythmic Drugs 526 39. Antianginal and Other Anti-ischaemic Drugs 539 40. Antihypertensive Drugs 558 9 Section Drugs Acting on Kidney 41a. Relevant Physiology of Urine Formation 575 41b. Diuretics 579 42. Antidiuretics 593 10 Section Drugs Affecting Blood and Blood Formation 43. Haematinics and Erythropoietin 599 44. Drugs Affecting Coagulation, Bleeding and Thrombosis 613 45. Hypolipidaemic Drugs and Plasma Expanders 634 11 Section Gastrointestinal Drugs 46. Drugs for Peptic Ulcer and Gastroesophageal Reflux Disease 647 47. Antiemetic, Prokinetic and Digestant Drugs 661 48. Drugs for Constipation and Diarrhoea 672 12 Section Antimicrobial Drugs 49. Antimicrobial Drugs: General Considerations 688 50. Sulfonamides, Cotrimoxazole and Quinolones 704 51. Beta-Lactam Antibiotics 716