A Textbook of Clinical Pharmacology and Therapeutics This page intentionally left blank A Textbook of Clinical Pharmacology and Therapeutics FIFTH EDITION JAMES M RITTER MA DPHIL FRCP FMedSci FBPHARMACOLS Professor of Clinical Pharmacology at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK LIONEL D LEWIS MA MB BCH MD FRCP Professor of Medicine, Pharmacology and Toxicology at Dartmouth Medical School and the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA TIMOTHY GK MANT BSC FFPM FRCP Senior Medical Advisor, Quintiles, Guy's Drug Research Unit, and Visiting Professor at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK ALBERT FERRO PHD FRCP FBPHARMACOLS Reader in Clinical Pharmacology and Honorary Consultant Physician at King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK PART OF HACHETTE LIVRE UK First published in Great Britain in 1981 Second edition 1986 Third edition 1995 Fourth edition 1999 This fifth edition published in Great Britain in 2008 by Hodder Arnold, an imprint of Hodden Education, part of Hachette Livre UK, 338 Euston Road, London NW1 3BH http://www.hoddereducation.com ©2008 James M Ritter, Lionel D Lewis, Timothy GK Mant and Albert Ferro All rights reserved. Apart from any use permitted under UK copyright law, this publication may only be reproduced, stored or transmitted, in any form, or by any means with prior permission in writing of the publishers or in the case of reprographic production in accordance with the terms of licences issued by the Copyright Licensing Agency. In the United Kingdom such licences are issued by the Copyright licensing Agency: Saffron House, 6–10 Kirby Street, London EC1N 8TS. Hachette Livre’s policy is to use papers that are natural, renewable and recyclable products and made from wood grown in sustainable forests. The logging and manufacturing processes are expected to conform to the environmental regulations of the country of origin. Whilst the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. In particular, (but without limiting the generality of the preceding disclaimer) every effort has been made to check drug dosages; however it is still possible that errors have been missed. Furthermore, dosage schedules are constantly being revised and new side-effects recognized. For these reasons the reader is strongly urged to consult the drug companies’ printed instructions before administering any of the drugs recommended in this book. British Library Cataloguing in Publication Data Acatalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data Acatalog record for this book is available from the Library of Congress ISBN 978-0-340-90046-8 1 2 3 4 5 6 7 8 9 10 Commissioning Editor: Sara Purdy Project Editor: Jane Tod Production Controller: Andre Sim Cover Design: Laura de Grasse Indexer: John Sampson Typeset in 9/12 pt palatino by Charon Tec Ltd (A Macmillan Company) www.charontec.com Printed and bound in Italy What do you think about this book? Or any other Hodder Arnold title? Please visit our website: www.hoddereducation.com This fifth edition is dedicated to the memory of Professors Howard Rogers and John Trounce, two of the three authors of this textbook’s first edition. COMPANION WEBSITE The fifth edition of ATextbook of Clinical Pharmacology and Therapeutics is accompanied by an exciting new website featuring the images from the book for you to download. To visit the book’s website, please go to www.hodderplus.com/clinicalpharmacology. Your username is: student009 Your password is: pharma CONTENTS FOREWORD viii PART V THE RESPIRATORY SYSTEM 231 PREFACE ix 33 Therapy of asthma, chronic obstructive pulmonary ACKNOWLEDGEMENTS x disease (COPD) and other respiratory disorders 233 PART I GENERAL PRINCIPLES 1 PART VI THE ALIMENTARY SYSTEM 245 1 Introduction to therapeutics 3 34 Alimentary system and liver 247 2 Mechanisms of drug action (pharmacodynamics) 6 35 Vitamins and trace elements 265 3 Pharmacokinetics 11 4 Drug absorption and routes of administration 17 PART VII FLUIDS AND ELECTROLYTES 271 5 Drug metabolism 24 36 Nephrological and related aspects 273 6 Renal excretion of drugs 31 7 Effects of disease on drug disposition 34 PART VIII THE ENDOCRINE SYSTEM 283 8 Therapeutic drug monitoring 41 9 Drugs in pregnancy 45 37 Diabetes mellitus 285 10 Drugs in infants and children 52 38 Thyroid 292 11 Drugs in the elderly 56 39 Calcium metabolism 297 12 Adverse drug reactions 62 40 Adrenal hormones 302 13 Drug interactions 71 41 Reproductive endocrinology 307 14 Pharmacogenetics 79 42 The pituitary hormones and related drugs 316 15 Introduction of new drugs and clinical trials 86 PART IX SELECTIVE TOXICITY 321 16 Cell-based and recombinant DNAtherapies 92 17 Alternative medicines: herbals and 43 Antibacterial drugs 323 nutraceuticals 97 44 Mycobacterial infections 334 45 Fungal and non-HIV viral infections 340 PART II THE NERVOUS SYSTEM 103 46 HIV and AIDS 351 18 Hypnotics and anxiolytics 105 47 Malaria and other parasitic infections 361 19 Schizophrenia and behavioural emergencies 110 48 Cancer chemotherapy 367 20 Mood disorders 116 PART X HAEMATOLOGY 387 21 Movement disorders and degenerative CNS disease 124 49 Anaemia and other haematological disorders 389 22 Anti-epileptics 133 23 Migraine 142 PART XI IMMUNOPHARMACOLOGY 397 24 Anaesthetics and muscle relaxants 145 50 Clinical immunopharmacology 399 25 Analgesics and the control of pain 155 PART XII THE SKIN 409 PART III THE MUSCULOSKELETAL SYSTEM 165 51 Drugs and the skin 411 26 Anti-inflammatory drugs and the treatment of arthritis 167 PART XIII THE EYE 421 PART IV THE CARDIOVASCULAR SYSTEM 175 52 Drugs and the eye 423 27 Prevention of atheroma: lowering plasma PART XIV CLINICAL TOXICOLOGY 431 cholesterol and other approaches 177 28 Hypertension 185 53Drugs and alcohol abuse 433 29 Ischaemic heart disease 196 54Drug overdose and poisoning 444 30 Anticoagulants and antiplatelet drugs 204 INDEX 451 31 Heart failure 211 32 Cardiac dysrhythmias 217 FOREWORD John Trounce, who was the senior author of the first edition of this textbook, died on the 16 April 2007. He considered a text in clinical pharmacology suitable for his undergraduate and postgradu- ate students to be an important part of the programme he developed in his department at Guy’s Hospital Medical School, London. It is difficult to imagine today how much resistance from the medical and pharmacological establishments Trounce had to overcome in order to set up an academic department, a focussed course in the medical curriculum and a separate exam in final MB in clinical pharmacology. In other words, he helped to change a ‘non-subject’ into one of the most important areas of study for medical students. He was also aware of the need for a high quality textbook in clinical pharmacology that could also be used by nurses, phar- macists, pharmacology science students and doctors preparing for higher qualifications. (For example, it has been said that nobody knows more about acute pharmacology than an anaesthetist.) The present edition of the textbook reflects the advances in therapeutics since the publica- tion of the fourth edition. It is interesting to follow in all the editions of the book, for example, how the treatment of tumours has progressed. It was about the time of the first edition that Trounce set up the first oncology clinic at Guy’s Hospital in which he investigated the value of combined radiation and chemotherapy and drug cocktails in the treatment of lymphomas. John Trounce was pleased to see his textbook (and his subject) in the expert hands of Professor Ritter and his colleagues. Roy Spector Professor Emeritus in Applied Pharmacology, University of London PREFACE Clinical pharmacology is the science of drug use in humans. Clinicians of all specialties pre- scribe drugs on a daily basis, and this is both one of the most useful but also one of the most dangerous activities of our professional lives. Understanding the principles of clinical pharma- cology is the basis of safe and effective therapeutic practice, which is why this subject forms an increasingly important part of the medical curriculum. This textbook is addressed primarily to medical students and junior doctors of all special- ties, but also to other professionals who increasingly prescribe medicines (including pharma- cists, nurses and some other allied professionals). Clinical pharmacology is a fast moving subject and the present edition has been completely revised and updated. It differs from the fourth edition in that it concentrates exclusively on aspects that students should know and understand, rather than including a lot of reference material. This has enabled us to keep its length down. Another feature has been to include many new illustrations to aid in grasping mechanisms and principles. The first section deals with general principles including pharmacodynamics, pharmaco- kinetics and the various factors that modify drug disposition and drug interaction. We have kept algebraic formulations to a minimum. Drug metabolism is approached from a practical viewpoint, with discussion of the exciting new concept of personalized medicine. Adverse drug reactions and the use of drugs at the extremes of age and in pregnancy are covered, and the introduction of new drugs is discussed from the viewpoint of students who will see many new treatments introduced during their professional careers. Many patients use herbal or other alternative medicines and there is a new chapter on this important topic. There is a chap- ter on gene and cell-based therapies, which are just beginning to enter clinical practice. The remaining sections of the book deal comprehensively with major systems (nervous, musculo- skeletal, cardiovascular, respiratory, alimentary, renal, endocrine, blood, skin and eye) and with multi-system issues including treatment of infections, malignancies, immune disease, addiction and poisoning. JAMESM RITTER LIONELD LEWIS TIMOTHYGK MANT ALBERTFERRO