CLINICAL PHARMACOLOGY AND THERAPEUTICSLecture Notes

Gerard A. McKayMatthew R. Walters

9th Edition LNwith extended material online'

Clinical Pharmacology and TherapeuticsLecture Notes

Clinical Pharmacology and TherapeuticsLecture Notes

Edited by

Gerard A. McKayBSc (Hons) FRCP

Consultant Physician and Honorary Clinical Associate Professor

Glasgow Royal Infi rmary and University of Glasgow

Matthew R. WaltersMD FRCP MSc

Professor of Clinical Pharmacology

Director, Clinical Pharmacology and Therapeutics

Institute of Cardiovascular and Medical Sciences

University of Glasgow

Ninth Edition

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Library of Congress Cataloging-in-Publication DataLecture notes. Clinical pharmacology and therapeutics / edited by Gerard A. McKay, Matthew R. Walters.—9th ed. p. ; cm. Clinical pharmacology and therapeutics Includes bibliographical references and index. ISBN 978-1-118-34481-1 (pbk. : alk. paper) I. McKay, Gerard A. II. Walters, Matthew R. III. Title: Clinical pharmacology and therapeutics. [DNLM: 1. Pharmacological Phenomena. 2. Drug Th erapy. 3. Pharmacology, Clinical. QV 37] 615’.1—dc23

2012044843

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Set in 8.5/11pt Utopia Std by Aptara® Inc., New Delhi, India

1 2013

Contents

Contributors, vi

Preface, vii

Foreword, ix

Part 1 Principles of clinical pharmacology

1 Pharmacodynamics and pharmacokinetics, 3

2 Clinical trials and drug development, 11

Part 2 Aspects of therapeutics

3 Drugs and gastrointestinal disease, 19

4 Management of coronary artery disease and its

complications, 29

5 Primary and secondary prevention of cardiovascular

disease, 52

6 Drugs used to treat respiratory disease, 71

7 Drugs used to treat neurological disease, 81

8 Treatment of psychiatric disorders, 97

9 Antimicrobial therapy, 111

10 HIV and antiretroviral treatment, 132

11 Travel medicine and tropical disease, 143

12 Drugs and endocrine disease, 153

13 Drugs and the reproductive system, 169

14 Drugs and the urological system, 178

15 Cancer therapeutics, 185

16 Drugs and infl ammatory joint disease, 197

17 Immunopharmacology, 204

18 Drugs and the blood including anticoagulants and

thrombolytic drugs, 215

19 Drugs used for pain relief and anaesthesia, 228

Part 3 Practical aspects of prescribing

20 Clinical pharmacokinetics: dosage

individualisation, 241

21 Infl uence of renal and hepatic disease on

pharmacokinetics and pharmacodynamics, 247

22 Prescribing for the young and the elderly, 252

23 Drugs in pregnant and breastfeeding

women, 255

24 Pharmacoeconomics: the economic evaluation of

new drugs, 262

25 Poisoning and drug overdose, 269

26 Drugs you may need in a hurry, 283

27 Prescribing and its pitfalls, 287

Self assessment questions, 294

Self assessment answers, 299

Index, 302

Contributors

Th e following have contributed substantially to the writing, revision and rewriting of the chapters for this ninth edition.

Peter Higgins Institute of Cardiovascular and Medi-cal Sciences, University of GlasgowChapter 1, Pharmacodynamics and pharmacoki-netics

Jesse Dawson Institute of Cardiovascular and Medi-cal Sciences, University of Glasgow Chapter 2, Clinical trials and drug development

Beth Reed NHS Greater Glasgow and ClydeChapter 3, Drugs and gastrointestinal disease

Shona Jenkins NHS Greater Glasgow and ClydeChapter 4, Management of coronary artery disease and its complicationsChapter 5, Primary and secondary prevention of cardiovascular disease

Manish Patel NHS LanarkshireChapter 6, Drugs used to treat respiratory disease

Edward Newman Institute of Neuroscience and Psy-chology, University of GlasgowChapter 7, Drugs used to treat neurological disease

Tom McPhee NHS Greater Glasgow and ClydeChapter 8, Treatment of psychiatric disorders

Andrew Seaton Brownlee Centre, Gartnavel General Hospital, GlasgowChapter 9, Antimicrobial therapy

Nick Kennedy NHS LanarkshireChapter 10, HIV and antiretroviral treatment

Alisdair MacConnachie Brownlee Centre, Gartnavel General Hospital, Glasgow Chapter 11, Travel medicine and tropical disease

David Carty Institute of Cardiovascular and Medical Sciences, University of Glasgow Chapter 12, Drugs and endocrine disease

Claire Higgins School of Medicine, University of GlasgowChapter 13, Drugs and the reproductive system

Prabhakar Rajan Institute of Cancer Sciences, University of GlasgowChapter 14, Drugs and the urological system

Charles Gourlay University of EdinburghChapter 15, Cancer therapeutics

Islay Morrison NHS Greater Glasgow and ClydeChapter 16, Drugs and infl ammatory joint disease

Jagtar Nijjar Institute of Infection, Infl ammation and Immunity, University of GlasgowChapter 17, Immunopharmacology

Nick Heaney Beatson Oncology Centre, GlasgowChapter 18, Drugs and the blood including antico-agulants and thrombolytic drugs

Rachel Harrison NHS Greater Glasgow and ClydeChapter 19, Drugs used for pain relief and anaesthesia

Kathleen Collins NHS Greater Glasgow and ClydeChapter 22, Prescribing for the young and the elderly

Shazya Huda NHS Greater Glasgow and ClydeChapter 23, Drugs in pregnant and breastfeeding women

Ailsa Brown Scottish Medicines ConsortiumChapter 24, Pharmacoeconomics

Kenneth Paterson Scottish Medicines ConsortiumChapter 24, Pharmacoeconomics: the economic evaluation of new drugs

Iain Keith NHS Greater Glasgow and ClydeChapter 26, Drugs you may need in a hurry

Preface

Th e ability to use drugs safely and eff ectively is a defi ning characteristic of a good doctor. Th is ability is predicated upon an up-to-date knowledge of the ever-expanding pharmacopeia available to modern clinicians. In recent years the advent of translational and stratifi ed approaches to the development of new medicines has accelerated the pace of change and re-sulted in a profusion of new knowledge across a wide range of therapeutic areas.

Th e extensive changes made to the text of this the ninth edition of Clinical Pharmacology and Th era-peutics Lecture Notes refl ect the enormous progress made in recent years. Th e new edition has been extensively revised and updated with signifi cantly expanded sections covering areas which are devel-oping rapidly such as immunopharmacology and cancer therapeutics. A particular emphasis has been placed upon practical aspects and clinical relevance throughout each chapter. Although the content of the text has been revised and refreshed, the objec-tive of this book remains as set out in the preface to its fi rst edition more than 30 years ago: to provide a brief, clearly written and up-to-date review of clinical pharmacology. As in earlier editions we have not at-tempted to be comprehensive, but have tried to em-

phasise the principles of clinical pharmacology, and topics which are of particular clinical importance.

Recognition of the importance of prescribing skills has prompted a focus on their assessment in UK medical schools. Key prescribing points are empha-sised in each chapter, and a series of questions cover-ing commonly examined topics is included to allow self-assessment.

Th is is the fi rst edition of Clinical Pharmacology and Th erapeutics Lecture Notes to have been prepared without Professor John Reid, former Regius Professor of Medicine and Th erapeutics at the University of Glasgow. John’s immense contribution to Clinical Pharmacology extends far beyond his founding role and expert st ewardship of this textbook over decades. Both of the current Editors gratefully acknowledge his expert mentorship and guidance which continues to infl uence the preparation of this text. We hope that the ninth edition will continue to succeed in the pro-vision of a clear understanding not only of how but also when to use drugs.

Gerry McKayMatthew Walters

Glasgow

Foreword

Over 30 years ago we were (then) three young clini-cal academics responsible for teaching medical stu-dents to prescribe medicines at one of the UK’s larg-est medical schools.

Th e curriculum at the time consisted of two years of preclinical teaching – mainly anatomy, physi-ology, biochemistry and pharmacology – increas-ingly delivered by non-clinicians. From the third year, students were based in hospital and through a four-term course of weekly lectures and seminars were introduced to applied or clinical pharmacology and therapeutics.

By the late 1970s, in recognition of the dramatic developments and innovation in drugs available, our programme aimed to close the gap between the ba-sic scientifi c principles of drug action and practical therapeutics at the bedside or in the clinic. As we said in the Preface to the fi rst edition ‘… clinical pharma-cology has as its primary aim the promotion of safe and eff ective drug use: to optimise benefi ts and mini-mise risks’ – an update on the classical objective ‘pri-mum non nocere’ or ‘fi rstly do no harm’!

Th e second half of the twentieth century had been a bonanza period for drug discovery. Understanding of basic physiological mechanisms and insights into pathology led to screening and testing of small molecules which had specifi c (or relatively specifi c) interactions with cellular processes: beta blockers for heart disease, antibiotics and eff ective anticancer drugs became available.

It became easier to demonstrate effi cacy and poss-ible to confi rm profi les of adverse side eff ects.

Th e potential for serious harm (for example birth defects after thalidomide) led internationally to rigor-ous protocols to establish effi cacy and safety not only for new drugs but also long available remedies with little or no evidence of usefulness (or safety).

In the 1970s, we felt that the available textbooks to support student learning were less than optimal. In Glasgow, staff had been preparing their own ‘lecture notes’ for individual lectures. Th ese were generally very popular with the students and largely replaced textbooks in this area. Th ese notes were usually two or three pages of summary information but were in-dividually prepared by lecturers and varied greatly in quality as well as length. In addition, the prep-aration and copying of several pages of notes for over

200 students – before the widespread availability of photocopiers – was a major task for the secretarial support staff !

Following encouragement from our students we explored alternative means of making the notes available. Th e obvious approach was to publish and the most obvious vehicle to us was the already existing and popular series of Lecture Notes pub-lished by Blackwell Scientifi c Publications, a series which already included a successful Lecture Notes on Pharmacology by J.H. Burn. We were encouraged by Blackwell to prepare a book based on the notes for students prepared by us and our colleagues. Th is manuscript became the fi rst edition of Lecture Notes in Clinical Pharmacology in 1981

We have been very fortunate in the enormous help and support we have had over the years. In the early days most of the contributions both in writing specialist chapters and reviewing draft texts came from colleagues in Glasgow, often those individuals who gave the lectures to our students. As time has passed, with retirements and promotions/transfers, we have broadened the specialties and locations of our collaborators.

Time has also taken a toll on the editorial team. For this edition, although none of the original team is directly involved, we have all taken a close interest in the contents, particularly the newer styles and ap-proaches to learning in the electronic age.

As we noted in the Prefaces to earlier editions ‘whether learning is problem based or more tra-ditional, it must be underpinned by a clear under-standing of the principles of the pathophysiology of disease, the molecular mechanisms of drug action in humans and an appreciation of drug therapy in the context of overall health care’ Th e style and inno-vative layout of this book provides the core infor-mation and encourages self learning.

We strongly believe that the book now named Clini-cal Pharmacology and Th erapeutics Lecture Notes continues, as we have believed for over 30 years, to ‘provide a clear understanding not only of how but also when to use drugs’.

John ReidPeter Rubin

Brian Whiting

Part 1Principles of clinical

pharmacology

Clinical Pharmacology and Th erapeutics Lecture Notes, Ninth Edition. Edited by Gerard A. McKay and Matthew R. Walters. © 2013 John Wiley & Sons, Ltd. Published 2013 by John Wiley & Sons, Ltd.

physiological factors that infl uence disease. Th e chemical synthesis of agents with well-characterised and specifi c actions on cellular mechanisms has led to the introduction of many powerful and eff ec-tive drugs. Additionally, advances in the detection of these compounds in body fl uids have facilitated investigation into the relationships between the dos-age regimen, the profi le of drug concentration against time in body fl uids, notably the plasma, and corre-sponding profi les of clinical eff ect. Knowledge of this concentration–eff ect relationship, and the factors that infl uence drug concentrations, underpin early stages of the drug development process.

Clinical scenario

A 50-year-old obese man with type 2 diabetes, hypertension and hyperlipidaemia has made arrangements to see his general practitioner to review his medications. He is on three different drugs for his diabetes, four different anti-hypertensives, a statin for his cholesterol and a dispersible aspirin. These medications have been added over a period of 2 years despite him not having any symptoms and he feels that if anything they are giving him symptoms of fatigue and muscle ache. He has also read recently that aspirin may actually be bad for patients with diabetes. He is keen to know why he is on so many medications, if the way he is feeling is due to the medications and whether they are interfering with the action of each other. What knowledge might help the general practitioner deal with this?

1Pharmacodynamics and pharmacokinetics

KEY POINTS – WHAT IS PHARMACODYNAMICS AND PHARMACOKINETICS?

• The variability in the relationship between dose and response is a measure of the sensitivity of a patient to a drug. This has two components: dose – concentration and concentration – effect

• The latter is termed pharmacodynamics. The description of a drug concentration profi le against time is termed pharmacokinetics

• In simple terms pharmacodynamics is what the drug does to the individual taking it and pharmacokinetics what the individual does to the drug

• Clinical pharmacology seeks to explore the factors that underlie variability in pharmacodynamics and pharmacokinetics for the optimization of drug therapy in individual patientsIntroduction

A basic knowledge of the mechanism of action of drugs and how the body deals with drugs allows the clinician to prescribe safely and eff ectively. Prior to the twentieth century prescribing medication was based on intelligent observation and folklore with medical practices depending largely on the admin-istration of mixtures of natural plant or animal sub-stances. Th ese preparations contained a number of pharmacologically active agents in variable amounts (e.g. powdered bark from the cinchona tree, now known to contain quinine, being used by natives of Peru to treat ‘fevers’ caused by malaria).

During the last 100 years an increased under-standing has developed of biochemical and patho-