Contents

Contributors

Preface

Acknowledgements

Part 1 Principles of Clinical Pharmacology

Chapter 1 Pharmacodynamics and pharmacokinetics

Introduction

Principles of drug action (pharmacodynamics)

Mechanism of drug action

Dose–response relationship

Principles of pharmacokinetics

Principles of drug elimination

Chapter 2 Clinical trials and drug development

Introduction

Drug development and regulation

Clinical trials

Phase IIIb and IV studies

Translational research

Part 2 Aspects of Therapeutics

Chapter 3 Drugs and gastrointestinal disease

Introduction

Gastro-oesophageal reflux disease

Peptic ulcer

Nausea and vomiting

Diarrhoea and constipation

Inflammatory bowel disease

Drugs adversely affecting gastrointestinal function

Chapter 4 Management of coronary artery disease and its complications

Introduction

Angina pectoris, myocardial infarction and ACS

Aims

Cardiac arrhythmia

Heart failure

General principles of management of heart failure

Chapter 5 Primary and secondary prevention of cardiovascular disease

Introduction

Hypertension

Cholesterol and lipids

Antiplatelet drugs

Chapter 6 Drugs used to treat respiratory disease

Introduction

Asthma

Chronic obstructive pulmonary disease

Management of asthma and COPD

Management of acute asthma

Management of acute exacerbations of COPD

Other therapy for airways diseases

Notes on other respiratory diseases

Chapter 7 Drugs used to treat neurological disease

Introduction

Epilepsy

Headache

Migraine

Cerebrovascular disease

Infections of the nervous system

Drug-induced neurological disorders

Neuroimmunology

Movement disorders

Chapter 8 Treatment of psychiatric disorders

Introduction

Antipsychotic drugs

Antidepressants

Mood stabilising agents

Anxiolytics

Hypnotic drugs and the treatment of insomnia

Drug-induced psychiatric disorder

Abuse of psychoactive drugs

Treatment of dementia

Chapter 9 Antimicrobial therapy

Aim

Principles of drug treatment

Antibacterial drugs

Antituberculous drugs

Antifungal drugs

Antiviral drugs

Chapter 10 HIV and antiretroviral treatment

Introduction

Overview of mechanisms of drug action

Drug classes and drugs

Nucleoside/nucleotide reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors

Protease inhibitors

Fusion and entry inhibitors

Integrase inhibitors

Combination therapy using HAART

HIV therapy in special situations

Chapter 11 Travel medicine and tropical disease

Introduction

Principles of immunisation

Vaccines used for preventing infection in travellers

Malaria prevention and treatment

Treatment of other common imported parasitic infections

Chapter 12 Drugs and endocrine disease

Diabetes mellitus

Introduction

Thyroid disease

Obesity

Bone metabolism

Pituitary and adrenal cortex disease

Chapter 13 Drugs and the reproductive system

Hormonal contraception

Hormonal contraception and breastfeeding

Hormone replacement therapy

Progestogens–non-contraceptive uses

Anti-progestogen

Drugs used to modify the pregnant uterus and cervix

Ovulation induction agents

Metformin

Danazol

Gonadotrophin-releasing hormone analogues

Anti-androgens

Chapter 14 Drugs and the urological system

Drugs for bladder outlet obstruction

Drugs for overactive bladder

Drugs for prostate cancer

Drugs for erectile dysfunction

Chapter 15 Cancer therapeutics

Introduction

Chemotherapy

Chemotherapy for metastatictesticular cancer

Adjuvant chemotherapy for breast cancer

Chapter 16 Immunopharmacology

Drugs that suppress immune responses

Small chemical agents that modify immune response

T-cell targeting agents

Combination of drugs in treatment of immune-mediated disorders

Other drugs that act by their effect on the immune system

Biological therapies

Immunostimulatory and immunomodulatory agents

Chapter 17 Corticosteroids

Introduction

Glucocorticoids

Clinical use and doses of commonly used steroids

Mineralocorticoids

Chapter 18 Drugs and the blood including anticoagulants and thrombolytic drugs

Introduction

Anticoagulant drugs

Thrombolytic agents

Anaemia and haematinics

Haemopoietic growth factors

Drug-induced blood conditions

Chapter 19 Drugs and inflammatory joint disease

Introduction

Principles of drug treatment

Symptom modifying antirheumatic therapies

Disease-controlling antirheumatic therapies

Drugs used in gout

Chapter 20 Anaesthesia and the relief of pain

Introduction

Relevant pathophysiology

Opioid analgesics

Local (regional) anaesthesia

General anaesthesia

Neuromuscular blocking drugs

Part 3 Practical Aspects of Prescribing

Chapter 21 Clinical pharmacokinetics: dosage individualisation

Introduction

Therapeutic drug monitoring

Clearance estimates

Interpretation of serum concentrations

Clinical examples of therapeutic drug monitoring

Gentamicin

Chapter 22 Influence of renal and hepatic disease on pharmacokinetics and pharmacodynamics

Influence of impaired renal function

Influence of liver disease

Chapter 23 Prescribing at extremes of age

Influence of ageing

Considerations when prescribing for infants and children

Chapter 24 Drugs in pregnant and breastfeeding women

Drugs in pregnancy

Introduction

Effect of pregnancy on drug absorption, distribution and elimination

Drug treatment of common medical problems during pregnancy

Drug use in breastfeeding

Chapter 25 Pharmacoeconomics: the economic evaluation of new drugs

Introduction – why do we need economic evaluations?

Economic evaluation

Perspective

Costs

Linking costs to benefits

Cost-minimisation analysis

Cost-effectiveness analysis

Cost-benefit analysis

Cost-utility analysis

Why use CUA and QALYs?

How are the constituent parts of QALYs estimated?

How is cost-effectiveness then assessed?

Sensitivity analysis

Pharmacoeconomics and decision-making

References

Chapter 26 Poisoning and drug overdose

Introduction

General approach to the poisoned patient

The management of specific complications

Features of common drug overdose

Chapter 27 Drugs you may need in a hurry

Adrenaline (epinephrine) for anaphylaxis

Chlorphenamine for anaphylaxis

Adrenaline (epinephrine) for cardiac arrest

Amiodarone for cardiac arrest

Atropine for cardiac arrest

Adenosine for supraventricular tachycardia

Loop diuretic for acute left ventricular failure

Morphine for acute LVF

Lorazepam for status epilepticus

Rectal diazepam for status epilepticus

Naloxone for opioid poisoning

Glucagon for hypoglycaemic coma

Chapter 28 Prescribing and its pitfalls

Good prescribing: questions to ask yourself before picking up the pen

Writing the prescription: practical aspects

General pointers on good prescribing

When prescribing goes wrong

Genetic factors

Idiosyncratic drug reactions

Drug interactions

What can we do to minimise drug-related harm to patients?

Compliance, concordance and adherence

Is good adherence important?

Factors that reduce adherence

Means of improving adherence

Index

This edition first published 2010, © 2010 by Gerard McKay, John Reid and Matthew Walters

Previous editions 1982, 1985, 1989, 1992, 1996, 2001, 2006

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Library of Congress Cataloging-in-Publication Data

McKay, Gerard A. Lecture notes. Clinical pharmacology and therapeutics/Gerard A. McKay, John L. Reid, Matthew R. Walters. – 8th ed.

p.; cm.

Other title: Clinical pharmacology and therapeutics

Rev. ed. of: Lecture notes. Clinical pharmacology & therapeutics/John L. Reid, Peter C. Rubin, Matthew R. Walters. 7th ed. 2006.

Includes bibliographical references and index.

ISBN 978-1-4051-9778-6

1. Clinical pharmacology. I. Walters, Matthew R. II. Reid, John L. Lecture notes. Clinical pharmacology & therapeutics. III. Title. IV. Title: Clinical pharmacology and therapeutics.

[DNLM: 1. Pharmacology, Clinical. 2. Drug Therapy. QV 38 M457L 2010]

RM301.28.R45 2010

615’.1–dc22

2010019097

Contributors

The following have contributed substantially to the writing, revision and rewriting of the chapters in the eighth edition of Lecture Notes in Clinical Pharmacology and Therapeutics.

Ailsa Brown Scottish Medicines Consortium,
Glasgow
(Chapter 25)

Andrew Gallagher Diabetes Centre, Southern
General Hospital, Glasgow
(Chapter 1)

Derek Gillen Gastroenterology unit, Gartnavel
General Hospital, Glasgow
(Chapter 3)

Charles Gourlay Cancer Research Centre,
University of Edinburgh
(Chapter 15)

Claire Higgins Developmental Medicine,
University of Glasgow
(Chapter 13)

Shazya Huda Developmental Medicine,
University of Glasgow
(Chapter 24)

Nicholas Kennedy Consultant in Infectious
Disease, NHS Lanarkshire
(Chapter 10)

Hing Leung Cancer Sciences, University of
Glasgow
(Chapter 14)

Alisdair Macconnachie Brownlee Centre,
Gartnavel General Hospital,
Glasgow (Chapter 11)

Frances Macdonald Scottish Medicines
Consortium, Glasgow
(Chapter 2)

Scott Nelson Developmental Medicine,
University of Glasgow
(Chapters 13 and 24)

Edward Newman Clinical Neurosciences,
University of Glasgow
(Chapter 7)

Manish Patel Respiratory Unit, Wishaw General
Hospital, Glasgow
(Chapter 6)

Kenneth Paterson Scottish Medicines
Consortium, Glasgow
(Chapter 25)

Prabhakar Rajan Cancer Sciences, University of
Glasgow
(Chapter 14)

Andrew Seaton Brownlee Centre, Gartnavel
General Hospital, Glasgow
(Chapter 9)

Katy Teo Cancer Sciences, University of Glasgow
(Chapter 14)

Stephen Waring York Hospital NHS Trust, York
(Chapter 26

Preface

Clinical pharmacology is the science of medicine discovery, development, regulation and utilisation in the context of the effects of drugs on humans. As such, some knowledge of clinical pharmacology is essential for all professionals involved in the treatment of patients with medicines. We live in an era of intensive research which drives new discoveries and maintains the field of therapeutics in a state of constant evolution: keeping this knowledge up to date can be a challenge. The discovery of new medicines increases the complexity of drug treatment regimens, and the ability to use drugs in a safe, appropriate and effective fashion needs to be taught and maintained.

The pace of change and the growing recognition of the challenges of safe prescribing are reflected in the eighth edition of Lecture Notes: Clinical Pharmacology and Therapeutics. This edition sees very significant changes to the content and structure of the text. Each chapter has been revised, updated and in some cases re-written, with particular focus upon the clinical relevance of the subject matter. New clinical chapters covering the treatment of Human Immunodeficiency Virus and the management of urological disease have been added, together with an overview of medicines regulation. In each chapter we have moved away from more abstract concepts and placed greater emphasis upon the practical aspects of clinical pharmacology and the application of the knowledge this book contains. We have also restructured the sections to strengthen the links between the basic principles of clinical pharmacology and their use in a clinical context. Although many aspects of the book have changed, our overall goal remains as stated in the preface to the first edition: ‘to describe with brevity and clarity the scientific background of rational prescribing while giving an insight into practical aspects of therapeutics’.

In the pursuit of this goal we have sought to equip the reader with skills essential for the modern healthcare professional. We hope to encourage a thoughtful and holistic approach to drug prescribing, incorporating consideration and clear understanding 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. We have taken steps in this edition further to instill a sense of familiarity with the emerging concepts of pharmacogenetics and personalised medicine.

In the nearly 30 years since the first edition of Lecture Notes in Clinical Pharmacology, there has been only one change to the editorial team. The eighth edition sees a second change: Peter Rubin has stepped down from his role as an author and editor. Peter has been replaced by Gerard McKay, a consultant in Clinical Pharmacology at the Glasgow Royal Infirmary.

We are grateful to Peter for his immeasurable contributions since the first edition, and to the expert colleagues who have reviewed and extensively revised the text of the eighth edition. In our view this new volume maintains the tradition of the lecture notes series, providing a clearly written and up-to-date review of a dynamic and evolving field. For those who use it, we hope this book will provide a clear understanding not only of how but also when to use drugs.

Gerard A. McKay

John L. Reid

Matthew R. Walters

Acknowledgements

We acknowledge the help and assistance freely given by many colleagues, commenting, reviewing and updating chapters related to their specialist interest and expertise. We particularly acknowledge the input and contribution of Jonathan Cavanagh, Derek Connolly,

Gordon Lowe, David McCarey, Brian McCreath, Robert Lindsay, John McMurray, Brian Murphy, Roger Sturrock and Simon Thomas.

We are grateful to Laura McMichael for her role in collecting, collating and coordinating the text and revisions.

Part 1

Principles of Clinical Pharmacology

Chapter 1

Pharmacodynamics and pharmacokinetics

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 antihypertensives, 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?

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 profile against time is termed pharmacokinetics.

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

Clinical pharmacology seeks to explore the factors that underlie variability in pharmacodynamics and pharmacokinetics for the optimisation of drug therapy in individual patients.

Introduction

A basic knowledge of the mechanism of action of drugs and how the body deals with drugs allows the clinician to prescribe them safely and effectively. Prior to the twentieth century, prescribing medication was based on intelligent observation and folklore with medical practices depending largely on the administration of mixtures of natural plant or animal substances. These 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 understanding has developed for biochemical and pathophysiological factors that influence disease. The chemical synthesis of agents with wellcharacterised and specific actions on cellular mechanisms has led to the introduction of many powerful and effective drugs. Additionally, advances in the detection of these compounds in body fluids have facilitated investigation into the relationships between the dosage regimen, the profile of drug concentration against time in body fluids, notably the plasma, and corresponding profiles of clinical effect. Knowledge of this concentration-effect relationship, and the factors that influence drug concentrations, underpin early stages of the drug development process.

More recently the development of genomics and proteomics has provided additional insights and opportunities for drug development with new and more specific targets. Such knowledge will replace the concept of one drug and/or one dose fitting all.

Principles of drug action (pharmacodynamics)

Pharmacological agents are used in therapeutics to:

1 Alleviate symptoms, for example:

paracetamol for pain

glyceryl trinitrate spray for angina

2 Improve prognosis – this can be measured in number of different ways – usually measured as a reduction in morbidity or mortality, for example:

prevent or delay end-stage consequences of disease, e.g. anti-hypertensive medication and statins in cardiovascular disease, levodopa in Parkinson’s disease

replace deficiencies, e.g. levothyroxine in hypothyroid

cure disease, e.g. antibiotics, chemotherapy

Some drugs will both alleviate symptoms and improve prognosis, e.g. beta-blockers in ischaemic heart disease. If a prescribed drug is doing neither, one must question the need for its use and stop it. Even if there is a clear indication for use, the potential for side effects and interactions with any other drugs the patient is on also needs to be taken into account.

Mechanism of drug action

Action on a receptor

A receptor is a specific macromolecule, usually a protein, situated either in cell membranes or within the cell, to which a specific group of ligands, drugs or naturally occurring substances (such as neurotransmitters or hormones), can bind and produce pharmacological effects. There are three types of ligands: agonists, antagonists and partial agonists.

An agonist is a substance that stimulates or activates the receptor to produce an effect, e.g. salbutamol at the β₂-receptor.

An antagonist prevents the action of an agonist but does not have any effect itself, e.g. losartan at the angiotensin II receptor.

A partial agonist stimulates the receptor to a limited extent, while preventing any further stimulation by naturally occurring agonists, e.g. aripiprazole at the D2 and 5-HT1A receptors.

The biochemical events that result from an agonist–receptor interaction to produce an effect are complex. There are many types of receptors and in several cases subtypes have been identified which are also of therapeutic importance, e.g. α and β adrenoceptors, nicotinic and muscarinic cholinergic receptors.

Action on an enzyme

Enzymes, like receptors, are protein macromolecules with which substrates interact to produce activation or inhibition. Drugs in common clinical use, which exert their effect through enzyme action generally do so by inhibition, for example:

1 aspirin inhibits platelet cyclo-oxygenase

2 ramipril inhibits angiotensin-converting enzyme

Drug receptor antagonists and enzyme inhibitors can act as competitive, reversible antagonists or as non-competitive, irreversible antagonists. Effects of competitive antagonists can be overcome by increasing the dose of endogenous or exogenous agonists, while effects of irreversible antagonists cannot usually be overcome resulting in a longer duration of the effect.

Action on membrane ionic channels

The conduction of impulses in nerve tissues and electromechanical coupling in muscle depend on the movement of ions, particularly sodium, calcium and potassium, through membrane channels. Several groups of drugs interfere with these processes, for example:

1 nifedipine inhibits the transport of calcium through the slow channels of active cell membranes

2 furosemide inhibits Na/K/Cl co-transport in the ascending limb of the loop of Henle

Cytotoxic actions

Drugs used in cancer or in the treatment of infections may kill malignant cells or micro-organisms. Often the mechanisms have been defined in terms of effects on specific receptors or enzymes. In other cases chemical action (alkylation) damages DNA or other macromolecules and results in cell death or failure of cell division.

Dose–response relationship

Dose–response relationships may be steep or flat. A steep relationship implies that small changes in dose will produce large changes in clinical response or adverse effects, while flat relationships imply that increasing the dose will offer little clinical advantage (Fig. 1.1).

Figure 1.1 Schematic examples of a drug (a) with a steep dose– (or concentration–) response relationship in the therapeutic range, e.g. warfarin an oral anticoagulant; and (b) a flat dose– (or concentration–) response relationship within the therapeutic range, e.g. thiazide diuretics in hypertension.

Figure 1.2 Schematic diagram of the dose–response relationship for the desired effect (dose–therapeutic response) and for an undesired adverse effect. The therapeutic index is the extent of displacement of the two curves within the normal dose range.

In clinical practice the maximum therapeutic effect may often be unobtainable because of the appearance of adverse or unwanted effects: few, if any, drugs cause a single pharmacological effect.

The concentration–adverse response relationship is often different in shape and position to that of the concentration–therapeutic response relationship. The difference between the concentration that produces the desired effect and the concentration that causes adverse effects is called the therapeutic index and is a measure of the selectivity of a drug (Fig. 1.2).

The shape and position of dose–response curves for a group of patients is variable because of genetic, environmental and disease factors. However, this variability is not solely an expression of differences in response to drugs. It has two important components: the dose–plasma concentration relationship and the plasma concentration–effect relationship.

Dose → Concentration → Effect

With the development of specific and sensitive chemical assays for drugs in body fluids, it has been possible to characterise dose–plasma concentration relationships so that this component of the variability in response can be taken into account when drugs are prescribed for patients with various disease states. For drugs with a narrow therapeutic index it may be necessary to measure plasma concentrations to assess the relationship between dose and concentration in individual patients (see Chapter 21, section ‘Therapeutic drug monitoring’).

Principles of pharmacokinetics

Absorption

Drug absorption after oral administration has two major components: absorption rate and bioavailability. Absorption rate is controlled partially by the physicochemical characteristics of the drug but in many cases it is modified by the formulation. A reduction in absorption rate can lead to a smoother concentration–time profile with a lower potential for concentration-dependent adverse effects and may allow less frequent dosing.

Bioavailability is the term used to describe the fraction of the dose that is absorbed into the systemic circulation. It can range from 0 to 100% and depends on a number of physicochemical and clinical factors. Low bioavailability may occur if the drug has low solubility or is destroyed by the acid in the stomach. Changing the formulation can affect the bioavailability of a drug and it can also be altered by food or the co-administration of other drugs. For example, antacids can reduce the absorption of quinolone antibiotics, such as ciprofloxacin, by binding them in the gut. Other factors influencing bioavailability include metabolism by gut flora, the intestinal wall or the liver.

First-pass metabolism refers to metabolism of a drug that occurs en route from the gut lumen to the systemic circulation. For the majority of drugs given orally, absorption occurs across the portion of gastrointestinal epithelium that is drained by veins forming part of the hepatoportal system. Consequently, even if they are well absorbed, drugs must pass through the liver before reaching the systemic circulation. For drugs that are susceptible to extensive hepatic metabolism, a substantial proportion of an orally administered dose can be metabolised before it ever reaches its site of pharmacological action, e.g. insulin metabolism in the gut lumen is so extensive that it renders oral therapy impossible.

The importance of first-pass metabolism is twofold:

1 It is one of the reasons for apparent differences in drug bioavailability between individuals. Even healthy people show considerable variation in liver metabolising capacity.

2 In patients with severe liver disease first-pass metabolism may be dramatically reduced, leading to the appearance of greater amounts of active drug in the systemic circulation.

Distribution

Once a drug has gained access to the bloodstream it begins to distribute to the tissues. The extent of this distribution depends on a number of factors including plasma protein binding, lipid solubility and regional blood flow. The volume of distribution, VD, is the apparent volume of fluid into which a drug distributes on the basis of the amount of drug in the body and the measured concentration in the plasma or serum. If a drug was wholly confined to the plasma, VD would equal the plasma volume – approximately 3 L in an adult. If, on the contrary, the drug was distributed throughout the body water, VD would be approximately 42 L. In reality, drugs are rarely distributed into physiologically relevant volumes. If most of the drug is bound to tissues, the plasma concentration will be low and the apparent VD will be high, while high plasma protein binding will tend to maintain high concentrations in the blood and a low VD will result. For the majority of drugs, VD depends on the balance between plasma binding and sequestration or binding by various body tissues, for example, muscle and fat. Volume of distribution can therefore vary considerably.

Clinical relevance of volume of distribution

Knowledge of volume of distribution (VD) can be used to determine the size of a loading dose if an immediate response to treatment is required. This assumes that therapeutic success is closely related to the plasma concentration and that there are no adverse effects if a relatively large dose is suddenly administered. It is sometimes employed when drug response would take many hours or days to develop if the regular maintenance dose was given from the outset, e.g. digoxin.

Figure 1.3 Steady-state concentration–time profile for an oral dose (—) and 0 a constant rate intravenous infusion 0 5 (− − − – -).

In practice, weight is the main determinant to calculating the dose of a drug where there is a narrow therapeutic index.

Plasma protein binding

In the blood, a proportion of a drug is bound to plasma proteins – mainly albumin (acidic drugs) and α₁-acid glycoprotein (basic drugs). Only the unbound, or free, fraction distributes because the protein-bound complex is too large to pass through membranes. It is the unbound portion that is generally responsible for clinical effects – both the target response and the unwanted adverse effects. Changes in protein binding (e.g. resulting from displacement interactions) generally lead to a transient increase in free concentration but are rarely clinically relevant. However, a lower total concentration will be present and the measurement might be misinterpreted if the higher free fraction is not taken into account. This is a common problem with the interpretation of phenytoin concentrations, where free fraction can range from 10% in a normal patient to 40% in a patient with hypoalbuminaemia and renal impairment.

Clearance

Clearance is the sum of all drug-eliminating processes, principally determined by hepatic metabolism and renal excretion. It can be defined as the theoretical volume of fluid from which a drug is completely removed in a given period of time.

When a drug is administered continuously by intravenous infusion or repetitively by mouth, a balance is eventually achieved between its input (dosing rate) and its output (the amount eliminated over a given period of time). This balance gives rise to a constant amount of drug in the body which depends on the dosing rate and clearance. This amount is reflected in the plasma or serum as a steady-state concentration (Css). A constant rate intravenous infusion will yield a constant Css, while a drug administered orally at regular intervals will result in fluctuation between peak and trough concentrations (Fig. 1.3).

Clearance depends critically on the efficiency with which the liver and/or kidneys can eliminate a drug; it will vary in disease states that affect these organs, or that affect the blood flow to these organs. In stable clinical conditions, clearance remains constant and is directly proportional to dose rate. The important implication is that if the dose rate is doubled, the Cssaverage doubles: if the dose rate is halved, the Cssaverage is halved for most drugs. In pharmacokinetic terms this is referred to as a first-order or linear process, and results from the fact that the rate of elimination is proportional to the amount of drug present in the body.

Single intravenous bolus dose

A number of other important pharmacokinetic principles can be appreciated by considering the concentrations that result following a single intravenous bolus dose (see Fig. 1.4) and through a number of complex equations the time at which steady state will be achieved after starting a regular treatment schedule or after any change in dose can be predicted.

As a rule, in the absence of a loading dose, steady state is attained after four to five half-lives (Fig. 1.5).

Furthermore, when toxic drug levels have been inadvertently produced, it is very useful to estimate how long it will take for such levels to reach the therapeutic range, or how long it will take for the entire drug to be eliminated once the drug has been stopped. Usually, elimination is effectively complete after four to five half-lives (Fig. 1.6).

The elimination half-life can also be used to determine dosage intervals to achieve a target concentration–time profile. For example, in order to obtain a gentamicin peak of 8 mg/L and a trough of 0.5 mg/L in a patient with an elimination halflife of 3 hours, the dosage interval should be 12 hours. (The concentration will fall from 8–4 mg/L in 3 hours to 2 mg/L in 6 hours, to 1 mg/L in 9 hours and to 0.5 mg/L in 12 hours.) However, for many drugs, dosage regimens should be designed to maintain concentrations within a range that avoids high (potentially toxic) peaks or low, ineffective troughs. Excessive fluctuations in the concentration-time profile can be prevented by giving the drug at intervals of less than one halflife or by using a slow-release formulation.

Figure 1.4 Plot of concentration versus time after a bolus intravenous injection. The intercept on the y- (concentration) axis, C₀, is the concentration resulting from the instantaneous injection of the bolus dose.

Figure 1.5 Plot of concentration versus time illustrating the accumulation to steady state when a drug is administered by regular oral doses.

Figure 1.6 Semi-logarithmic plot of concentration versus time after a bolus intravenous injection. The slope of this line is −k; the elimination rate constant and the elimination half-life of the drug can be determined from such a plot by noting the time at which the concentration has fallen to half its original value.

Linear versus non-linear kinetics

In the discussion on clearance, it was pointed out that the hallmark of linear pharmacokinetics is the proportionality between dose rate and steady-state concentration. This arises because the rate of elimination is proportional to the amount of drug in the body, while the clearance remains constant. This is not, however, always the case for a few drugs such as phenytoin, alcohol and heparin. When the enzymes responsible for metabolism reach a point of saturation, the rate of elimination, in terms of amount of drug eliminated in a given period of time, does not increase in response to an increase in concentration (or an increase in the amount of drug in the body) but becomes constant. This gives rise to non-linear or zero-order kinetics.

The clinical relevance of non-linear kinetics is that a small increase in dose can lead to a large increase in concentration. This is particularly important when toxic side effects are closely related to concentration, as with phenytoin.

Principles of drug elimination

Drug metabolism

Drugs are eliminated from the body by two principal mechanisms: (i) liver metabolism and (ii) renal excretion. Drugs that are already water-soluble are generally excreted unchanged by the kidney. Lipid-soluble drugs are not easily excreted by the kidney because, following glomerular filtration, they are largely reabsorbed from the proximal tubule. The first step in the elimination of such lipid-soluble drugs is metabolism to more polar (water-soluble) compounds. This is achieved mainly in the liver, but can also occur in the gut and may contribute to first-pass elimination. Metabolism generally occurs in two phases:

Phase 1 – Mainly oxidation, but also reduction or hydrolysis to a more polar compound: Oxidation can occur in various ways at carbon, nitrogen or sulphur atoms and N- and O-dealkylation. These reactions are catalysed by the cytochrome P450 dependent system of the endoplasmic reticulum. Knowledge of P-450, which exists as a superfamily of similar enzymes (isoforms), has increased greatly recently and is divided into a number of families and subfamilies. Although numerous P-450 isoforms are present in human tissue, only a few of these have a major role in the metabolism of drugs. These enzymes, which display distinct but overlapping substrate specificity, include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Induction or inhibition of one or more of these enzymes may form the basis of clinically relevant drug interactions. Phase 1 metabolites usually have only minor structural differences from the parent drug, but may exhibit totally different pharmacological actions. For example, the metabolism of azathioprine produces the powerful antimetabolite 6-mercaptopurine.

Phase 2 – conjugation usually by glucoronidation or sulphation to make the compound more polar: This involves the addition of small endogenous molecules to the parent drug, or to its phase 1 metabolite, and this change almost always leads to abolition of pharmacological activity. Multiple forms of conjugating enzymes are also known to exist, although these have not been investigated to the same extent as the P-450 system.

Metabolic drug interactions

The wide range of drugs metabolised by the P-450 system provides the opportunity for interactions of two types, namely enzyme induction and inhibition.

Clinical scenario

A 24-year-old woman goes to a family planning clinic for advice about contraception. The patient has a history of epilepsy which is stable on carbamazepine 200 mg twice daily. What options are available to the general practitioner?

Induction

Enzyme induction, which may be defined as the increase in amount and activity of drugmetabolising enzymes, is a consequence of new protein synthesis resulting from prolonged exposure to the inducing drug. While a drug may induce its own metabolism, it can also accelerate the metabolism and clearance of unrelated compounds. Many compounds are known to act as enzyme inducers in animals at toxicological dose levels, but relatively few drugs produce clinically significant induction in humans when used at therapeutic dose levels. For practical purposes anticonvulsants (carbamazepine, phenytoin) and rifampacin are the most potent enzyme inducers in clinical use and have produced numerous clinically significant drug interactions, related primarily to increases in the metabolism of CYP2C9, CYP2C19 and CYP3A4 substrates (including, for example, oestrogen and progesterone the constituents of a combined oral contraceptive pill). Enzyme induction is not, however, limited to administration of prescription drugs. St John’s wort, a herbal remedy can also cause enzyme induction as can cigarette smoking (induction of CYP1A2 substrates, e.g. theophylline) and ethanol (induction of CYP2E1 but unlikely to be clinically relevant).

Key points – enzyme induction and inhibition

Enzyme induction produces clinical changes over days or weeks, but the effects of enzyme inhibition are usually observed immediately. In most circumstances, these changes are manifest as:

Therapeutic failure resulting from induction

Adverse effects resulting from inhibition

Clinical relevance occurs when drug therapy needs to be altered to avoid the consequences of the drug interaction and this is most common and most serious in compounds that have a narrow therapeutic index.

Clinical scenario

A 58-year-old man with chronic obstructive pulmonary disease is admitted to hospital with an infective exacerbation. He is on three different inhalers and additionally takes simvastatin for hypercholesterolaemia. He is allergic to penicillin. The admitting doctor prescribes nebulised salbutamol, prednisolone and clarithromycin along with the patient’s usual medications. The next day the patient complains of general aches and pains. Could this be due to a drug interaction?

Inhibition

Concurrently administered drugs can also lead to inhibition of enzyme activity, with many P-450 inhibitors showing considerable isoform selectivity. Some of the most clinically relevant inhibitors are listed in Table 1.1, together with the isoform inhibited. In some cases this can lead to potentially dangerous adverse events, e.g. ketoconazole decreases the metabolism of the CYP3A4 substrate, terfenadine, leading to QT interval prolongation and torsades de pointes.

As with induction, P-450 inhibition is not limited to drug administration. Grapefruit juice is an inhibitor of CYP3A4 activity and produces clinically significant interactions with a number of drugs, including midazolam, simvastatin and terfenadine. This type of information, together with some knowledge of the enzymes involved in a particular drug’s clearance, makes it much easier to understand and predict drug interactions.

Clearly, pronounced enzyme inhibition, which may result in plasma concentrations of the inhibited drug being many times higher than intended, can be a major safety issue. For example, co-administration of ketoconazole or ritonavir with the hypnotic drug midazolam increases the midazolam plasma exposure (AUC – area under the curve) by 15–20 times, a situation which should be avoided.

Table 1.1 P-450 inhibitors involved in drug interactions.

Major human P-450s | Typical inhibitors
CYP1A2 | Furafylline, fluvoxamine, ciprofloxacin
CYP2C9 | Fluconazole, ketoconazole, sulfaphenazole
CYP2C19 | Omeprazole, ketoconazole, cimetidine
CYP2D6 | Quinidine, fluoxetine, ritonavir
CYP2E1 | Disulfiram
CYP3A4 | Ketoconazole, itraconazole, ritonavir, clarithromycin, diltiazem

Table 1.2 Major enzymes displaying genetic polymorphism.

Enzyme | Typical substrates | Characteristics
CYP2C19 | (S)-Mephenytoin, diazepam omeprazole, | About 2–5% of white people are poor metabolisers, but 18–23% of Japanese people have this phenotype
CYP2D6 | Propafenone, flecainamide, desipramine | About 7% of white people are poor metabolisers, but this frequency is only about 2% in black Americans and <1% in Japanese/Chinese
N-acetyl-transferase | Hydralazine, sulphonamides, isoniazid, procainamide | About 50% of white people are slow acetylators

Genetic factors in metabolism

The rate at which healthy people metabolise drugs is variable. Although part of this variability is a consequence of environmental factors, including the influence of inducers and inhibitors, the main factor contributing to interindividual variability in metabolism is the underlying genetic basis of the drug-metabolising enzymes. Although there is probably a genetic component in the control of most P-450 enzymes, some enzymes (e.g. CYP2C19 and CYP2D6) actually show genetic polymorphism. This results in distinct subpopulations of poor and extensive metabolisers, where the poor metabolisers are deficient in that particular enzyme. There are a number of enzymes under polymorphic control and some clinically important examples are shown in Table 1.2. As with enzyme inhibition, genetic polymorphism is primarily a concern for drugs that have a narrow therapeutic index and that are metabolised largely by a single polymorphic enzyme. In such cases, the phenotype of the patient should be determined and lower doses of the drug used, or alternative therapy should be considered.

Renal excretion

Three processes are implicated in renal excretion of drugs:

1 Glomerular filtration: This is the most common route of renal elimination. The free drug is cleared by filtration and the protein-bound drug remains in the circulation where some of it dissociates to restore equilibrium.

2 Active secretion in the proximal tubule: Both weak acids and weak bases have specific secretory sites in proximal tubular cells. Penicillins are eliminated by this route, as is about 60% of procainamide.

3 Passive reabsorption in the distal tubule: This occurs only with un-ionised, i.e. lipid-soluble, drugs. Urine pH determines whether or not weak acids and bases are reabsorbed, which in turn determines the degree of ionisation.

If renal function is impaired, for example, by disease or old age, then the clearance of drugs that normally undergo renal excretion is decreased.

Chapter 2

Clinical trials and drug development

Clinical scenario

A chemist in a major pharmaceutical company has been doing some research into a compound that seems to have some benefit in neuronal protection in in vitro models. This discovery has caused some excitement – if it is shown to have efficacy in humans then it might be useful in patients with acute strokes. What are the various stages that this compound has to go through in development before it can be licensed as a drug to be used in patients?

Key points

Many compounds are screened as potential drugs but few make it through to being used in patients

Drug development is a lengthy process with high costs, particularly in the later stages

Rigorous regulatory requirements have to be met before a drug can be tested in humans

To get a license a drug has to be shown to be safe and efficacious

Introduction

Drug regulation in the UK and elsewhere came about as a result of the use of thalidomide in the late 1950s and early 1960s. Thalidomide was marketed as a sedative that had little hangover effect, and was also used in treatment of morning sickness in pregnancy. In 1961 it became clear that thalidomide use in early pregnancy resulted in the congenital defect phocomelia where the long bones of the fetus fail to develop properly. This resulted in the formation of the Committee on Safety of Drugs and the passing of the Medicines Act in 1968, providing for a system of licensing affecting manufacture, sale, supply and importation of medicinal products into the UK. Drug regulation in the UK was initially under the control of the Medicines Control Agency. This was merged in 2003 with the Medical Devices Agency to form the Medicines and Healthcare products Regulatory Agency (MHRA). Other countries in Europe had similar systems to regulate drug development and as early as 1965 there was a European directive to try and harmonise the processes within Europe. This has now evolved and European legislation now takes precedence over the Medicines Act. The MHRA contributes to the work of the European Medicines Evaluation Authority (EMEA). At a European level, new drugs can now either be reviewed and licensed across all members states simultaneously, i.e. in partnership, or the drug can get a license from one member state first, and undergo a shortened ‘mutual recognition’ review and approval in the other member states.

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