A Textbook of Clinical Pharmacology and …

1 A Textbook of Clinical Pharmacology and TherapeuticsThis page intentionally left blank A Textbook ofClinical Pharmacology and TherapeuticsFIFTH EDITIONJAMES M RITTERMA DPHIL FRCP FMedSciFBPHARMACOLSP rofessor of Clinical Pharmacology at King s College London School of Medicine, Guy s, King s and St Thomas Hospitals, London, UKLIONEL D LEWISMA MB BCH MD FRCPP rofessor of Medicine, Pharmacology and Toxicology at Dartmouth Medical School andthe Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USATIMOTHY GK MANTBSCFFPM FRCPS enior Medical Advisor, Quintiles, Guy's Drug Research Unit, and Visiting Professor atKing s College London School of Medicine, Guy s, King s and St Thomas Hospitals,London, UKALBERT FERROPHD FRCP FBPHARMACOLSR eader in Clinical Pharmacology and Honorary Consultant Physician at King s CollegeLondon School of Medicine, Guy s, King s and St Thomas Hospitals, London, UKPART OF HACHETTE LIVRE UKFirst published in Great Britain in 1981 Second edition 1986 Third edition 1995 Fourth edition 1999 This fifth edition published in Great Britain in 2008 byHodder Arnold, an imprint of Hodden Education, part of Hachette Livre UK,338 Euston Road, London NW1 3 2008 James M Ritter, Lionel D Lewis.

2 Timothy GK Mant and Albert FerroAll rights reserved. Apart from any use permitted under UK copyright law, this publication mayonly be reproduced, stored or transmitted, in any form, or by any means with prior permission inwriting of the publishers or in the case of reprographic production in accordance with the termsof licences issued by the Copyright Licensing Agency. In the United Kingdom such licences areissued by the Copyright licensing Agency: Saffron House, 6 10 Kirby Street, London EC1N Livre s policy is to use papers that are natural, renewable and recyclable products andmade from wood grown in sustainable forests. The logging and manufacturing processes areexpected to conform to the environmental regulations of the country of the advice and information in this book are believed to be true and accurate at the date ofgoing to press, neither the authors nor the publisher can accept any legal responsibility or liabilityfor any errors or omissions that may be made.

3 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 beingrevised and new side-effects recognized. For these reasons the reader is strongly urged to consultthe drug companies printed instructions before administering any of the drugs recommended inthis Library Cataloguing in Publication DataA catalogue record for this book is available from the British LibraryLibrary of Congress Cataloging-in-Publication DataA catalog record for this book is available from the Library of CongressISBN978-0-340-90046-81 2 3 4 5 6 7 8 9 10 Commissioning Editor: Sara PurdyProject Editor:Jane TodProduction Controller:Andre SimCover Design:Laura de GrasseIndexer.

4 John SampsonTypeset in 9/12 pt palatino by Charon Tec Ltd (A Macmillan Company) and bound in ItalyWhat do you think about this book? Or any other Hodder Arnold title?Please visit our website: fifth edition is dedicated to the memory of Professors Howard Rogers and John Trounce, two of the three authors of this Textbook s first WEBSITEThe fifth edition of A Textbook of Clinical Pharmacology and Therapeuticsis accompanied by anexciting new website featuring the images from the book for you to download. To visit thebook s website, please go to username is: student009 Your password is: pharmaCONTENTSFOREWORD viiiPREFACEixACKNOWLEDGEMENTSxPART I GENERAL PRINCIPLES11 Introduction to therapeutics 32 Mechanisms of drug action (pharmacodynamics)

5 63 Pharmacokinetics 114 Drug absorption and routes of administration 175 Drug metabolism 246 Renal excretion of drugs 317 Effects of disease on drug disposition 348 Therapeutic drug monitoring 419 Drugs in pregnancy 4510 Drugs in infants and children 5211 Drugs in the elderly 5612 Adverse drug reactions 6213 Drug interactions 7114 Pharmacogenetics 7915 Introduction of new drugs and Clinical trials 8616 Cell-based and recombinant DNA therapies9217 Alternative medicines: herbals and nutraceuticals 97 PART II THE NERVOUS SYSTEM10318 Hypnotics and anxiolytics 10519 Schizophrenia and behavioural emergencies 11020 Mood disorders 11621 Movement disorders and degenerative CNS disease 12422 Anti-epileptics13323 Migraine 14224 Anaesthetics and muscle relaxants 14525 Analgesics and the control of pain 155 PART III THE MUSCULOSKELETAL SYSTEM16526 Anti-inflammatory drugs and the

6 Treatment of arthritis 167 PART IV THE CARDIOVASCULAR SYSTEM17527 Prevention of atheroma: lowering plasma cholesterol and other approaches 17728 Hypertension 18529 Ischaemic heart disease 19630 Anticoagulants and antiplatelet drugs 20431 Heart failure 21132 Cardiac dysrhythmias217 PART V THE RESPIRATORY SYSTEM23133 Therapy of asthma, chronic obstructive pulmonarydisease (COPD) and other respiratory disorders233 PART VI THE ALIMENTARY SYSTEM24534 Alimentary system and liver 24735 Vitamins and trace elements265 PART VII FLUIDS AND ELECTROLYTES27136 Nephrological and related aspects273 PART VIII THE ENDOCRINE SYSTEM28337 Diabetes mellitus 28538 Thyroid 29239 Calcium metabolism 29740 Adrenal hormones 30241 Reproductive endocrinology 30742 The pituitary hormones and related drugs 316 PART IX SELECTIVE TOXICITY32143 Antibacterial drugs 32344 Mycobacterial infections 33445 Fungal and non-HIV viral infections 34046 HIV and AIDS 35147

7 Malaria and other parasitic infections 36148 Cancer chemotherapy 367 PART X HAEMATOLOGY38749 Anaemia and other haematological disorders 389 PART XI IMMUNOPHARMACOLOGY39750 Clinical immunopharmacology 399 PART XII THE SKIN40951 Drugs and the skin411 PART XIII THE EYE42152 Drugs and the eye 423 PART XIV Clinical TOXICOLOGY43153 Drugs and alcohol abuse43354 Drug overdose and poisoning444 INDEX451 John Trounce, who was the senior author of the first edition of this Textbook , died on the 16 April 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 atGuy s Hospital Medical School, London.

8 It is difficult to imagine today how much resistancefrom the medical and pharmacological establishments Trounce had to overcome in order to setup an academic department, a focussed course in the medical curriculum and a separate examin final MB in Clinical Pharmacology . In other words, he helped to change a non-subject intoone of the most important areas of study for medical students. He was also aware of the needfor 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. (Forexample, it has been said that nobody knows more about acute Pharmacology than an anaesthetist.)

9 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 thatTrounce set up the first oncology clinic at Guy s Hospital in which he investigated the value ofcombined radiation and chemotherapy and drug cocktails in the treatment of Trounce was pleased to see his Textbook (and his subject) in the expert hands of ProfessorRitter and his SpectorProfessor Emeritus in Applied Pharmacology , University of LondonFOREWORDC linical Pharmacology is the science of drug use in humans.

10 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 mostdangerous 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 anincreasingly important part of the medical 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 movingsubject and the present edition has been completely revised and updated.