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2015v1.0

MEDICAL

PHARMACOLOGY

&THERAPEUTICS

Fifth Edition

Dedication

To our families

Fifth Edition

Derek G. Waller

BSc (HONS), DM, MBBS (HONS), FRCP

Consultant Cardiovascular Physician, University Hospital Southampton,

Senior Clinical Lecturer, University of Southampton,

Southampton, United Kingdom

Senior Medical Adviser to the British National Formulary

Anthony P. Sampson

MA, PhD, FHEA, FBPhS

Associate Professor in Clinical Pharmacology, Faculty of Medicine,

University of Southampton, Southampton, United Kingdom

MEDICAL

PHARMACOLOGY

& THERAPEUTICS

Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2018

© 2018, Elsevier Limited. All rights reserved.

First edition 2001

Second edition 2005

Third edition 2010

Fourth edition 2014

Fifth edition 2018

The rights of Derek G. Waller and Anthony P. Sampson to be identified as authors of this work

have been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.

No part of this publication may be reproduced or transmitted in any form or by any means,

electronic or mechanical, including photocopying, recording, or any information storage and

retrieval system, without permission in writing from the publisher. Details on how to seek

permission, further information about the Publisher’s permissions policies and our arrangements

with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency,

can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the

Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience

broaden our understanding, changes in research methods, professional practices, or medical

treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in

evaluating and using any information, methods, compounds, or experiments described herein. In

using such information or methods they should be mindful of their own safety and the safety of

others, including parties for whom they have a professional responsibility.

With respect to any drug or pharmaceutical products identified, readers are advised to check

the most current information provided (i) on procedures featured or (ii) by the manufacturer of each

product to be administered, to verify the recommended dose or formula, the method and duration

of administration, and contraindications. It is the responsibility of practitioners, relying on their own

experience and knowledge of their patients, to make diagnoses, to determine dosages and the

best treatment for each individual patient, and to take all appropriate safety precautions.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors,

assume any liability for any injury and/or damage to persons or property as a matter of products

liability, negligence or otherwise, or from any use or operation of any methods, products,

instructions, or ideas contained in the material herein.

ISBN: 978-0-7020-7167-6

Printed in China

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Senior Content Strategist: Pauline Graham

Content Development Specialist: Carole McMurray

Project Manager: Dr. Atiyaah Muskaan

Design: Amy Buxton

Illustration Manager: Karen Giacomucci

Marketing Manager: Deborah Watkins

The

publisher’s

policy is to use

paper manufactured

from sustainable forests

Preface ...........................................................................vii

Drug dosage and nomenclature .....................................ix

SECTION 1 GENERAL

PRINCIPLES

1. Principles of pharmacology and

mechanisms of drug action.................................. 3

2. Pharmacokinetics................................................ 33

3. Drug discovery, safety and efficacy ................... 63

4. Neurotransmission and the peripheral

autonomic nervous system................................. 73

SECTION 2 THE

CARDIOVASCULAR SYSTEM

5. Ischaemic heart disease ..................................... 93

6. Systemic and pulmonary hypertension ............ 111

7. Heart failure....................................................... 131

8. Cardiac arrhythmias.......................................... 143

9. Cerebrovascular disease and dementia........... 161

10. Peripheral vascular disease.............................. 169

11. Haemostasis ..................................................... 175

SECTION 3 THE RESPIRATORY

SYSTEM

12. Asthma and chronic obstructive

pulmonary disease............................................ 193

13. Respiratory disorders: cough, respiratory

stimulants, cystic fibrosis, idiopathic

pulmonary fibrosis and neonatal respiratory

distress syndrome............................................. 211

SECTION 4 THE RENAL SYSTEM

14. Diuretics ............................................................ 219

15. Disorders of micturition .................................... 231

16. Erectile dysfunction........................................... 239

SECTION 5 THE NERVOUS

SYSTEM

17. General anaesthetics ........................................ 247

18. Local anaesthetics ............................................ 257

19. Opioid analgesics and the management

of pain ............................................................... 263

20. Anxiety, obsessive-compulsive disorder

and insomnia..................................................... 279

21. Schizophrenia and bipolar disorder.................. 287

22. Depression, attention deficit hyperactivity

disorder and narcolepsy ................................... 297

23. Epilepsy............................................................. 311

24. Extrapyramidal movement disorders

and spasticity.................................................... 325

25. Other neurological disorders: multiple

sclerosis, motor neuron disease and

Guillain–Barré syndrome................................... 337

26. Migraine and other headaches......................... 341

SECTION 6 THE

MUSCULOSKELETAL SYSTEM

27. The neuromuscular junction and

neuromuscular blockade .................................. 351

28. Myasthenia gravis ............................................. 359

29. Nonsteroidal antiinflammatory drugs................ 363

30. Rheumatoid arthritis, other inflammatory

arthritides and osteoarthritis............................. 373

31. Hyperuricaemia and gout ................................. 385

SECTION 7 THE

GASTROINTESTINAL SYSTEM

32. Nausea and vomiting........................................ 393

33. Dyspepsia and peptic ulcer disease ................ 401

34. Inflammatory bowel disease............................. 411

35. Constipation, diarrhoea and irritable

bowel syndrome................................................ 417

36. Liver disease ..................................................... 425

37. Obesity .............................................................. 433

Contents

vi Medical Pharmacology and Therapeutics

SECTION 8 THE IMMUNE

SYSTEM

38. The immune response and

immunosuppressant drugs ............................... 439

39. Antihistamines and allergic disease ................. 451

SECTION 9 THE ENDOCRINE

SYSTEM AND METABOLISM

40. Diabetes mellitus............................................... 459

41. The thyroid and control of metabolic rate........ 475

42. Calcium metabolism and metabolic

bone disease..................................................... 481

43. Pituitary and hypothalamic hormones.............. 491

44. Corticosteroids (glucocorticoids and

mineralocorticoids)............................................ 503

45. Female reproduction......................................... 513

46. Androgens, antiandrogens and

anabolic steroids............................................... 531

47. Anaemia and haematopoietic

colony-stimulating factors ................................ 537

48. Lipid disorders .................................................. 547

SECTION 10 THE SKIN AND

EYES

49. Skin disorders ................................................... 561

50. The eye ............................................................. 569

SECTION 11 CHEMOTHERAPY

51. Chemotherapy of infections.............................. 581

52. Chemotherapy of malignancy........................... 631

SECTION 12 GENERAL

FEATURES: DRUG TOXICITY

AND PRESCRIBING

53. Drug toxicity and overdose .............................. 659

54. Substance abuse and dependence.................. 675

55. Prescribing, adherence and information

about medicines ............................................... 689

56. Drug therapy in special situations .................... 695

Index............................................................................ 707

The fifth edition of Medical Pharmacology and Therapeutics

has been extensively revised and updated while preserving

the popular approach of the fourth edition. We particularly

wish to acknowledge here the contributions made to previous

editions of this book by Emeritus Professor Andrew Renwick

OBE BSc PhD DSc and Dr Keith Hillier BSc PhD DSc, Senior

Lecturer in Pharmacology, formerly our colleagues in the

University of Southampton Faculty of Medicine. As before,

a disease-based approach has been taken to explain clinical

pharmacology and therapeutics and the principles of drug

use for the management of common diseases. Medical

Pharmacology and Therapeutics provides key information on

basic pharmacology and other relevant disciplines sufficient to

underpin the clinical context. It provides information suitable

for all healthcare professionals who require a sound knowledge

of the basic science and clinical applications of drugs.

The text is structured to reflect the ways that drugs are

used in clinical practice. The chapters covering generic

concepts in pharmacology and therapeutics include sections

on how drugs work at a cellular level, drug metabolism and

pharmacokinetics, pharmacogenetics, drug development and

drug toxicity. The basic principles of prescribing have been

emphasized and new information provided on preparing for

the Prescribing Safety Assessment (PSA) in the UK. New

sections have been included on pharmacovigilance, on

so-called ‘legal highs’ and in all other areas, and the sections

on clinical management have been thoroughly revised and

updated.

Each chapter in this fifth edition retains the following

key features:

■ An up-to-date and succinct explanation of the major

pathogenic mechanisms of disease and consequent

clinical symptoms and signs, helping the reader to put

Preface

into context the actions of drugs and the consequences

of their therapeutic use.

■ A structured approach to the principles of disease

management, outlining core principles of drug choice

and planning a therapeutic regimen for many common

diseases.

■ A comprehensive review of major drug classes relevant to

the disease in question. Basic pharmacology is described

with clear identification of the molecular targets, clinical

characteristics, important pharmacokinetic properties

and unwanted effects associated with individual drug

classes. Example drugs are used to illustrate the common

pharmacological characteristics of their class and to

introduce the reader to drugs currently in widespread

clinical use.

■ To complement the information provided within each

chapter, a drug compendium is included describing the

main characteristics of all drugs in each class listed in

the British National Formulary.

■ A revised section of self-assessment questions for learning

and revision of the concepts and content in each chapter,

including one best answer (OBA), extended matching

items (EMI), true-false and case-based questions.

It is our intention that the fifth edition of this book will

encourage readers to develop a deeper understanding of the

principles of drug usage that will help them to become safe

and effective prescribers and to carry out basic and clinical

research and to teach. As medical science advances these

principles should underpin the life-long learning essential

for the maintenance of these skills.

DGW

APS

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DRUG NOMENCLATURE

In the past, the nonproprietary (generic) names of some drugs

have varied from country to country, leading to potential

confusion. Progressively, international agreement has been

reached to rationalise these variations in names and a single

recommended International Non-proprietary Name (INN) given

to all drugs. Where the previously given British Approved

Name (BAN) and the INN have differed, the INN is now the

accepted name and is used throughout this book.

A special case has been made for two medicinal sub-

stances: adrenaline (INN: epinephrine) and noradrenaline (INN:

norepinephrine). Because of the clinical importance of these

substances and the widespread European use and understand-

ing of the terms adrenaline and noradrenaline, manufacturers

have been asked to continue to dual-label products adrenaline

(epinephrine) and noradrenaline (norepinephrine). In this book,

where the use of these agents as administered drugs is being

described, dual names are given. In keeping with European

convention, however, adrenaline and noradrenaline alone are

used when referring to the physiological effects of the naturally

occurring substances.

DRUG DOSAGES

Medical knowledge is constantly changing. As new information

becomes available, changes in treatment, procedures,

equipment and the use of drugs become necessary. The

authors and the publishers have taken care to ensure that

the information given in the text is accurate and up to date.

However, readers are strongly advised to confirm that the

information, especially with regard to drug usage, complies

with the latest legislation and standards of practice.

Drug dosage and nomenclature

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General principles

1

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1

Studying pharmacology 3

Finding drug information 4

Receptors and receptor-mediated

mechanisms 4

Actions of drugs at binding sites (receptors) 4

Major types of receptors 5

Other sites of drug action 12

Properties of receptors 13

Properties of drug action 15

Dose–response relationships 16

Types of drug action 17

Agonists 17

Antagonists 18

Partial agonists 18

Inverse agonists 18

Allosteric modulators 19

Enzyme inhibitors and activators 19

Nonspecific actions 19

Physiological antagonists 19

Tolerance to drug effects 19

Genetic variation in drug responses 20

Summary 21

Self-assessment 21

Answers 22

Further reading 22

Appendix: student formulary 28

STUDYING PHARMACOLOGY

Drugs are defined as active substances administered to prevent,

diagnose or treat disease, to alleviate pain and suffering, or to

extend life. Pharmacology is the study of the effects of drugs

on biological systems, with medical (or clinical) pharmacology

concerned with the drugs that doctors, and some other

healthcare professionals, prescribe for their patients. The

prescribing of drugs has a central role in therapeutics, and

gaining a good knowledge of pharmacology is essential for

health professionals to become safe and effective prescribers.

Drugs may be chemically synthesised or purified from

natural sources with or without further modification, but

their development and clinical use are based on rational

evidence of efficacy and safety derived from controlled

experiments and randomised clinical trials. Drugs can be

contrasted with placebos (placebo is Latin for ‘I will please’),

defined as inactive substances administered as though they

are drugs, but which have no therapeutic effects other than

potentially pleasing the patient, providing a sense of security

and progress. Pharmacology evolved on the principle of

studying known quantities of purified, active substances to

identify their specific mechanisms of action and to quantify

their effects in a reproducible manner, usually compared

with a placebo or other control substance.

Much of the success of modern medicine is based

on pharmacological science and its contribution to the

development of safe and effective pharmaceuticals. This

book is confined to pharmacology as it relates to human

medicine and aims to develop knowledge and understanding

of medical pharmacology and its application to therapeutics.

The objectives of learning about medical pharmacology and

therapeutics are:

■ to understand the ways that drugs work to affect human

systems, as a basis for safe and effective prescribing;

■ to appreciate that pharmacology must be understood

in parallel with related biological and clinical sciences,

including biochemistry, physiology and pathology;

■ to develop numerical skills for calculating drug doses

and dilutions, and to enable accurate comparison of the

relative benefits and risks of different drugs;

■ to comprehend and participate in pharmacological

research advancing the better treatment of patients.

The answer to the frequently asked question ‘What do I

need to know?’ will depend upon the individual requirements

of the programme of study being undertaken and the

examinations that will be taken. The depth and type of

Principles of pharmacology

and mechanisms of

drug action

1 4 Medical Pharmacology and Therapeutics

RECEPTORS AND

RECEPTOR-MEDIATED

MECHANISMS

Pharmacology describes how the physical interaction of drug

molecules with their macromolecular targets (‘receptors’)

modifies biochemical, immunological, physiological and

pathological processes to generate desired responses in

cells, tissues and organs. Drugs have been designed to

interact with many different types of macromolecules that

evolved to facilitate endogenous signalling between cells,

tissue and organs, or to play key roles in the normal cellular

and physiological processes that maintain controlled condi-

tions (homeostasis). Drugs may also target macromolecules

produced by pathogens, including viruses and bacteria. While

the term ‘receptor’ was originally applied in pharmacology to

describe any such drug target, more commonly a receptor

is now defined in biochemical terms as a molecule on the

surface of a cell (or inside it) that receives an external signal

and produces some type of cellular response.

The function of such a receptor can be divided typically

into three main stages:

1. The generation of a biological signal. Homeostasis is

maintained by communication between cells, tissues and

organs to optimise bodily functions and responses to

external changes. Communication is usually by signals in

the form of chemical messengers, including neurotransmit-

ter molecules, local mediators or endocrine hormones.

The signal molecule is termed a ligand, because it ligates

(ties) to the specialised cellular macromolecule. The cellular

macromolecule is a receptor because it receives the ligand.

2. Cellular recognition sites (receptors). The signal is

recognised by responding cells by its interaction with a

site of action, binding site or receptor, which may be in the

cell membrane, the cytoplasm or the nucleus. Receptors

in the cell membrane react with extracellular ligands that

cannot readily cross the cell membrane (such as peptides).

Receptors in the cytoplasm often react with lipid-soluble

ligands that can cross the cell membrane.

3. Cellular changes. Interaction of the signal and its site of

action in responding cells results in functional changes

within the cell that give rise to an appropriate biochemical

or physiological response to the original homeostatic

stimulus. This response may be cell division, a change in

cellular metabolic activity or the production of substances

that are exported from the cell.

Each of these three stages provides important targets

for drug action, and this chapter will outline the principles

underlying drug action mainly in stages 2 and 3.

ACTIONS OF DRUGS AT BINDING

SITES (RECEPTORS)

For very many drugs, the first step in producing a biological

effect is by interaction of the drug with a receptor, either on

the cell membrane or inside the cell, and it is this binding

that triggers the cellular response. Drugs may be designed to

mimic, modify or block the actions of endogenous ligands at

that receptor. The classified list of receptors at the end of this

chapter shows that cell-membrane and cytosolic receptors

knowledge required in different areas and topics will vary

when progressing through the programme; for example,

early in the course it may be important to know whether a

drug has a narrow safety margin between its wanted and

unwanted effects, and in the later years this may translate into

detailed knowledge of how the drug’s effects are monitored

in clinical use. Personal enthusiasm for medical pharmacology

is important and should be driven by the recognition that

prescribing medicines is the most common intervention

doctors (and increasingly other health professionals) use

to improve the health of their patients.

FINDING DRUG INFORMATION

Learning about medical pharmacology is best approached

using a variety of resources in a range of learning scenarios

and preferably in the context of basic science and therapeu-

tics, not from memorising lists of drug names. The following

provides a useful structure to organise the types of information

that you should aim to encounter:

■ the nonproprietary (generic) drug name (not the proprietary

or trade name);

■ the class or group to which the drug belongs;

■ the way the drug works (its mechanism of action and

its clinical effects), usually shared to variable extents by

other drugs in the same class;

■ the main clinical reasons for using the drug (its

indications);

■ any reasons why the drug should not be used in a

particular situation (its contraindications);

■ whether the drug is a prescription-only medicine (PoM)

or is available without prescription (over-the-counter

[OTC]);

■ how the drug is given (routes of administration);

■ how its effects are quantified and its doses modified if

necessary (drug monitoring);

■ how the drug is absorbed, distributed, metabolised and

excreted (ADME; its pharmacokinetics), particularly where

these show unusual characteristics;

■ the drug’s unwanted effects, including any interactions

with other drugs or foods;

■ whether there are nonpharmacological treatments that are

effective alternatives to drug treatment or will complement

the effect of the drug.

The Appendix at the end of this chapter provides a

formulary of core members of each major drug class to

give students in the early stages of training a manageable

list of the drugs most likely to be encountered in clinical

practice. At the end of later chapters, the Compendium

provides a classified listing and key characteristics of those

drugs discussed within the main text of each chapter and

also other drugs listed in the corresponding section of the

British National Formulary (BNF).

The BNF (www.evidence.nhs.uk) contains monographs

for nearly all drugs licensed for use in the United Kingdom

and is the key drug reference for UK prescribers. Students

should become familiar at an early stage with using the

BNF for reference. More detailed information on individual

drugs (the Summary of Product Characteristics [SPC]),

patient information leaflets (PIL) and contact details for

pharmaceutical companies is available from the electronic

Medicines Compendium (eMC; www.medicines.org.uk/emc/).

Principles of pharmacology and mechanisms of drug action 5

■ ion pumps and transporters, which transport specific

ions from one side of the membrane to the other in

an energy-dependent manner, usually against their

concentration gradient;

■ ion channels, which open to allow the selective, passive

transfer of ions down their concentration gradients.

Based on concentration gradients across the cell membrane:

■ both Na+

and Ca2+

ions will diffuse into the cell if their

channels are open, making the electrical potential of

the cytosol more positive and causing depolarisation of

excitable tissues;

■ K+

ions will diffuse out of the cell, making the electrical

potential of the cytosol more negative and inhibiting

depolarisation;

■ Cl−

ions will diffuse into the cell, making the cytosol more

negative and inhibiting depolarisation.

The two major families of ion channel are the ligand-gated

ion channels (LGICs) and the voltage-gated ion channels

(VGICs; also called ionotropic receptors). LGICs are opened

by the binding of a ligand, such as the neurotransmitter

acetylcholine, to an extracellular part of the channel. VGICs

in contrast are opened at particular membrane potentials by

voltage-sensing segments of the channel. Both channel types

can be targets for drug action. Both LGICs and VGICs can

control the movement of a specific ion, but a single type of

ion may flow through more than one type of channel, including

both LGIC and VGIC types. This evolutionary complexity can

be seen in the example of the multiple types of K+

channel

listed in Table 8.1.

LGICs include nicotinic acetylcholine receptors,

γ-aminobutyric acid (GABA) receptors, glycine receptors

and serotonin (5-hydroxytryptamine) 5-HT3 receptors. They

are typically pentamers, with each subunit comprising four

transmembrane helices clustering around a central channel or

pore. Each peptide subunit is orientated so that hydrophilic

chains face towards the channel and hydrophobic chains

towards the membrane lipid bilayer. Binding of an active

ligand to the receptor causes a conformational change in

the protein and results in extremely fast opening of the

ion channel. The nicotinic acetylcholine receptor is a good

example of this type of structure (Fig. 1.1). It requires the

binding of two molecules of acetylcholine for channel opening,

which lasts only milliseconds because the ligand rapidly

dissociates and is inactivated. Drugs may modulate LGIC

activity by binding directly to the channel, or indirectly by

acting on G-protein-coupled receptors (GPCRs; discussed

later), with the subsequent intracellular events then affecting

the status of the LGIC.

VGICs include Ca2+

, Na+

and K+

channels. The K+

channels

consist of four distinct peptide subunits, each of which

has between two and six transmembrane helices; in Ca2+

and Na+

channels there are four domains, each with six

transmembrane helices, within a single large protein. The

pore-forming regions of the transmembrane helices are largely

responsible for the selectivity of the channel for a particular

ion. Both Na+

and K+

channels are inactivated after opening;

this is produced by an intracellular loop of the channel,

which blocks the open channel from the intracellular end.

The activity of VGICs may thus be modulated by drugs acting

directly on the channel, such as local anaesthetics which

maintain Na+

channels in the inactivated site by binding at

an intracellular site (Chapter 18). Drugs may also modulate

tend to occur in different families (receptor types), reflecting

their evolution from common ancestors. Within any one family

of receptors, different receptor subtypes have evolved to

facilitate increasingly specific signalling and distinct biological

effects. As might be expected, different receptor families

have different characteristics, but subtypes within each family

retain common family traits.

In pharmacology, the perfect drug would be one that binds

only to one type or subtype of receptor and consistently

produces only the desired biological effect without the

unwanted effects that can occur when drugs bind to a

related receptor. Although this ideal is impossible to attain,

it has proved possible to develop drugs that bind avidly

to their target receptor to produce their desired effect and

have very much less (but not zero) ability to bind to other

receptors, even ones within the same family, which might

produce unwanted effects.

Where a drug binds to one type of receptor in preference

to another, it is said to show selectivity of binding or selectivity

of drug action. Selectivity is never absolute but is high with

some drugs and lower with others. A drug with a high degree

of selectivity is likely to show a greater difference between

the dose required for its biological action and the dose that

produces unwanted actions at other receptor types. Even

a highly selective drug may produce unwanted effects if

its target receptors are also found in tissues and organs

other than those in which the drug is intended to produce

its therapeutic effect.

MAJOR TYPES OF RECEPTORS

Despite the great structural diversity of drug molecules, most

act on the following major types of receptors to bring about

their pharmacological effects:

■ Transmembrane ion channels. These control the passage

of ions across membranes and are widely distributed.

■ Seven-transmembrane (7TM) (heptahelical) receptors.

This is a large family of receptors, most of which signal

via guanine nucleotide-binding proteins (G-proteins).

Following activation by a ligand, second messenger

substances are formed inside the cell, which can bring

about cellular molecular changes, including the opening

of transmembrane ion channels.

■ Enzyme-linked transmembrane receptors. This is a

family of transmembrane receptors with an integral or

associated enzymic component, such as a kinase or

phosphatase. Activation of these enzymes produces

changes in cells by phosphorylating or dephosphorylating

intracellular proteins, including the receptor itself, thereby

altering their activity.

■ Intracellular (nuclear) receptors. These receptors are

found in the nucleus or translocate to the nucleus from the

cytosol to modify gene transcription and the expression

of specific cellular proteins.

Transmembrane ion channels

Transmembrane ion channels that create pores across

phospholipid membranes are ubiquitous and allow the

transport of ions into and out of cells. The intracellular

concentrations of ions are controlled by a combination of

two types of ion channel:

1 6 Medical Pharmacology and Therapeutics

7TM receptors and they are the targets of over 30% of current

drugs. The function of over a hundred 7TM receptors is still

unknown. The structure of a hypothetical 7TM receptor is

shown in Fig. 1.2; the N-terminal region of the polypeptide

chain is on the extracellular side of the membrane, and

the polypeptide traverses the membrane seven times with

helical regions, so that the C terminus is on the inside of

the cell. The extracellular loops provide the receptor site

for an appropriate agonist (a natural ligand or a drug), the

binding of which alters the three-dimensional conformation

of the receptor protein. The intracellular loops are involved in

coupling this conformational change to the second messenger

system, usually via a heterotrimeric G-protein, giving rise to

the term GPCR.

The G-protein system

The heterotrimeric G-protein system (Fig. 1.3) consists of

α, β and γ subunits.

■ The α-subunit. More than 20 different types have been

identified, belonging to four families (αs, αi

, αq and α12/13).

The α-subunit is important because it binds guanosine

VGICs indirectly via intracellular signals from other receptors.

For example, L-type Ca2+

channels are inactivated directly

by calcium channel blockers, but also indirectly by drugs

which reduce intracellular signalling from the β1 subtype of

adrenoceptors (see Fig. 5.5).

The ability of highly variable transmembrane subunits to

assemble in a number of configurations leads to the existence

of many different subtypes of channels for a single ion.

For example, there are many different voltage-gated Ca2+

channels (L, N, P/Q, R and T types).

Seven-transmembrane receptors

Also known as 7TM receptors, heptahelical receptors and

serpentine receptors, this family is an extremely important

group, as the human genome has about 750 sequences for

ACh

C

N

ACh

α

α

γ

δ

β

M1 M2 M3 M4

Extracellular

Na+

Intracellular

A

B

Fig. 1.1 The acetylcholine nicotinic receptor, a typical

ligand-gated transmembrane ion channel. (A) The receptor

is constructed from subunits with four transmembrane

regions (M1–M4). (B) Five subunits are assembled into the ion

channel, which has two sites for acetylcholine binding, each

formed by the extracellular domains of two adjacent subunits.

On acetylcholine binding, the central pore undergoes

conformational change that allows selective Na+

ion flow

down its concentration gradient into the cell. N, amino

terminus; C, carboxyl terminus.

Extracellular

Intracellular

Lipid layer

Agonist

binding site

Cell membrane

Carboxyl end

Amino end

Fig. 1.2 Hypothetical seven-transmembrane (7TM)

receptor. The 7TM receptor is a single polypeptide chain

with its amino (N-) terminus outside the cell membrane

and its carboxyl (C-) terminus inside the cell. The chain

is folded such that it crosses the membrane seven times,

with each hydrophobic transmembrane region shown

here as a thickened segment. The hydrophilic extracellular

loops create a confined three-dimensional environment in

which only the appropriate ligand can bind. Other potential

ligands may be too large for the site or show much weaker

binding characteristics. Selective ligand binding causes

conformational change in the three-dimensional form of the

receptor, which activates signalling proteins and enzymes

associated with the intracellular loops, such as G-proteins

and nucleotide cyclases.

Principles of pharmacology and mechanisms of drug action 7

Cyclic nucleotide system

This system is based on cyclic nucleotides, such as:

■ Cyclic adenosine monophosphate (cAMP), which is

synthesised from adenosine triphosphate (ATP) by adenylyl

cyclase. cAMP induces numerous cellular responses by

activating protein kinase A (PKA), which phosphorylates

proteins, many of which are enzymes. Phosphorylation

can either activate or suppress cell activity.

■ Cyclic guanosine monophosphate (cGMP), which is

synthesised from GTP by guanylyl cyclase. cGMP exerts

most of its actions through protein kinase G, which, when

activated by cGMP, phosphorylates target proteins.

There are 10 isoforms of adenylyl cyclase; these

show different tissue distributions and could be important

sites of selective drug action in the future. The cyclic

nucleotide second messenger (cAMP or cGMP) is inactivated

by hydrolysis by phosphodiesterase (PDE) isoenzymes to

give AMP or GMP. There are 11 different families of PDE

isoenzymes (Table 1.1), some of which are the targets of

important drug groups, including selective PDE4 inhibitors

used in respiratory disease and PDE5 inhibitors used in

erectile dysfunction.

The phosphatidylinositol system

The other second messenger system is based on

inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG),

diphosphate (GDP) and guanosine triphosphate (GTP)

in its inactive and active states, respectively; it also has

GTPase activity, which is involved in terminating its own

activity. When an agonist binds to the receptor, GDP

(which is normally present on the α-subunit) is replaced

by GTP. The active α-subunit–GTP dissociates from the

βγ-subunits and can activate enzymes such as adenylyl

cyclase. The α-subunit–GTP complex is inactivated when

the GTP is hydrolysed back to GDP by the GTPase.

■ The βγ-complex. There are many different isoforms

of β- and γ-subunits that can combine into dimers,

the normal function of which is to inhibit the α-subunit

when the receptor is unoccupied. When the receptor is

occupied by a ligand, the βγ-complex dissociates from the

α-subunit and can itself activate cellular enzymes, such

as phospholipase C. The α-subunit–GDP and βγ-subunit

then recombine with the receptor protein to give the

inactive form of the receptor–G-protein complex.

Second messenger systems

Second messengers are the key distributors of an external

signal, as they are released into the cytosol as a consequence

of receptor activation and are responsible for affecting a wide

variety of intracellular enzymes, ion channels and transporters.

There are two complementary second messenger systems:

the cyclic nucleotide system and the phosphatidylinositol

system (Fig. 1.4).

β

Agonist

binding

Replacement

of GDP

E β γ E E α β E by GTP E α β E

γ γ

α γ γ

E E

α

Inactive receptor

GDP GDP GTP

Recombination of

GDP α- and βγ-subunits

with transmembrane

receptor

GTP

hydrolysis E

Dissociation

GDP

Intracellular

effects

Intracellular

effects

Intracellular

effects

β

E

α

GTP

Fig. 1.3 The functioning of G-protein subunits. Ligand (agonist) binding results in replacement of GDP on the α-subunit by

guanosine triphosphate (GTP) and the dissociation of the α- and βγ-subunits, each of which can affect a range of intracellular

systems (shown as E in the figure) such as second messengers (e.g. adenylyl cyclase and phospholipase C), or other enzymes

and ion channels (see Figs 1.4 and 1.5). Hydrolysis of GTP to GDP inactivates the α-subunit, which then recombines with the

βγ-dimer to reform the inactive receptor.

1 8 Medical Pharmacology and Therapeutics

consequences of GPCR dimerisation and its implications

for drug therapy are unclear.

Protease-activated receptors

Protease-activated receptors (PARs) are GPCRs stimulated

unusually by a ‘tethered ligand’ located within the N terminus

of the receptor itself, rather than by an independent ligand.

Proteolysis of the N-terminal sequence by serine proteases

such as thrombin, trypsin and tryptase enables the residual

tethered ligand to bind to the receptor within the second

extracellular loop (Fig. 1.6). To date, four protease-activated

receptors (PAR 1–4) have been identified, each with distinct

N-terminal cleavage sites and different tethered ligands. The

receptors appear to play roles in platelet activation and

clotting (Chapter 11), and in inflammation and tissue repair.

Most of the actions of PAR are mediated by Gi

, Gq and G12/13.

Enzyme-linked transmembrane

receptors

Enzyme-linked receptors, most notably the receptor

tyrosine kinases, are similar to the GPCRs in that they

have a ligand-binding domain on the surface of the cell

membrane; they traverse the membrane; and they have an

intracellular effector region (Fig. 1.7). They differ from GPCRs

in their extracellular ligand-binding domain, which is very

large to accommodate their polypeptide ligands (including

hormones, growth factors and cytokines), and in having

only one transmembrane helical region. Importantly, their

intracellular action requires a linked enzymic domain, most

commonly an integral kinase which activates the receptor

itself or other proteins by phosphorylation. Activation of

enzyme-linked receptors enables binding and activation of

many intracellular signalling proteins, leading to changes

which are synthesised from the membrane phospholipid

phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase

C (see Fig. 1.4). There are a number of isoenzymes of

phospholipase C, which may be activated by the α-subunit–

GTP or βγ-subunits of G-proteins. The main function of IP3

is to mobilise Ca2+

in cells. With the increase in Ca2+

brought

about by IP3, DAG is able to activate protein kinase C (PKC)

and phosphorylate target proteins. IP3 and DAG are then

inactivated and converted back to PIP2.

Which second messenger system is activated when a

GPCR binds a selective ligand depends primarily on the

nature of the Gα-subunit, as illustrated in Fig. 1.5:

■ Gs: Stimulation of adenylyl cyclase (increases cAMP),

activation of Ca2+

channels

■ Gi/o: Inhibition of adenylyl cyclase (reduces cAMP),

inhibition of Ca2+

channels, activation of K+

channels

■ Gq/11: Activation of phospholipase C, leading to DAG and

IP3 signalling

■ G12/13: Activation of cytoskeletal and other proteins via the

Rho family of GTPases, which influence smooth muscle

contraction and proliferation

The βγ-complex also has signalling activity: it can activate

phospholipases and modulate some types of K+

and Ca2+

channels.

Activation of these second messenger systems by

G-protein subunits thus affects many cellular processes

such as enzyme activity (either directly or by altering gene

transcription), contractile proteins, ion channels (affecting

depolarisation of the cell) and cytokine production. The many

different isoforms of Gα, Gβ and Gγ proteins may represent

important future targets for selective drugs.

It is increasingly recognised that GPCRs may assemble

into dimers of identical 7TM proteins (homodimers) or into

heterodimers of different receptor proteins; the functional

P

P P P

P

P

P P

P P

Phospholipase C

DAG

Inactivation by

phosphorylation

P

Hydrolysis

to inositol

IP3

adenosine ribose

ATP

Adenylyl

cyclase

adenosine ribose

cAMP

Inactivation by

phosphodiesterase

adenosine ribose

5¢- AMP

acyl glycerol inositol

acyl

PIP2

acyl

acyl glycerol

inositol

Fig. 1.4 Second messenger systems. Stimulation of G-protein-coupled receptors produces intracellular changes by

activating or inhibiting cascades of second messengers. Examples are cyclic adenosine monophosphate (cAMP), and

diacylglycerol (DAG) and inositol triphosphate (IP3) formed from phosphatidylinositol 4,5-bisphosphate (PIP2). See also Fig. 1.5.

Principles of pharmacology and mechanisms of drug action 9

receptors and signalling via the JAK/Stat pathways to

affect inflammatory gene expression.

■ Receptor serine-threonine kinase family. Activation of

these phosphorylates serine and threonine residues in

target cytosolic proteins; everolimus is a serine-threonine

kinase inhibitor used in renal and pancreatic cancer.

■ Receptor guanylyl cyclase family. Members of this family

catalyse the formation of cGMP from GTP via a cytosolic

domain.

Intracellular (nuclear) receptors

Many hormones act at intracellular receptors to produce

long-term changes in cellular activity by altering the genetic

expression of enzymes, cytokines or receptor proteins. Such

hormones are lipophilic to facilitate their movement across the

cell membrane. Examples include the thyroid hormones and

the large group of steroid hormones, including glucocorticoids,

mineralocorticoids and the sex steroid hormones. Their

actions on DNA transcription are mediated by interactions

with intracellular receptors (Table 1.2) located either in the

cytoplasm (type 1) or the nucleus (type 2).

in gene transcription and in many cellular functions. There

are five families of enzyme-linked transmembrane receptors:

■ Receptor tyrosine kinase (RTK) family. Ligand binding

causes receptor dimerisation and transphosphorylation of

tyrosine residues within the receptor itself and sometimes

in associated cytoplasmic proteins. Up to 20 classes of

RTK include receptors for growth factors, many of which

signal via proteins of the mitogen-activated protein (MAP)

kinase cascade, leading to effects on gene transcription,

apoptosis and cell division. Constitutive overactivity of

an RTK called Bcr-Abl causes leucocyte proliferation in

chronic myeloid leukaemia, which is treated with imatinib,

a drug that blocks the uncontrolled RTK activity. Several

other RTKs are also the targets of anticancer drugs.

■ Tyrosine phosphatase receptor family. These dephos-

phorylate tyrosines on other transmembrane receptors

or cytoplasmic proteins; they are particularly common in

immune cells.

■ Tyrosine kinase-associated receptor family (or

nonreceptor tyrosine kinases). These lack integral

kinase activity but activate separate kinases associated

with the receptor; examples include inflammatory cytokine

Table 1.1 Isoenzymes of phosphodiesterase

Enzyme Main substrate Main site(s) Examples of

inhibitors

Therapeutic potential

PDE1 cAMP + cGMP Heart, brain, lung, lymphocytes,

vascular smooth muscle

– Atherosclerosis?

PDE2 cAMP + cGMP Adrenal gland, brain, heart, lung,

liver, platelets, endothelial

cells

– Involved in memory?

PDE3 cAMP + cGMP Heart, lung, liver, platelets,

adipose tissue, inflammatory

cells, smooth muscle

Aminophylline

Enoximone

Milrinone

Cilostazol

Asthma (Chapter 12)

Congestive heart failure (Chapter 7)

Peripheral vascular disease

(Chapter 10)

PDE4 cAMP Sertoli cells, endothelial cells,

kidney, brain, heart, liver,

lung, inflammatory cells

Aminophylline

Roflumilast

Asthma, COPD (Chapter 12)

Inflammation

IBD?

PDE5 cGMP Smooth muscle, endothelium,

neurons, lung, platelets

Sildenafil

Tadalafil

Vardenafil

Dipyridamole

Erectile dysfunction (Chapter 16)

Pulmonary hypertension

(Chapter 6)

PDE6 cGMP Photoreceptors, pineal gland Dipyridamole

Sildenafil (weak)

Undefined

PDE7 cAMP Skeletal muscle, heart, kidney,

brain, pancreas, spinal cord,

T-lymphocytes

– Inflammation (combined with PDE4

inhibitor)?

Spinal cord injury?

PDE8 cAMP Testes, eye, liver, skeletal

muscle, heart, kidney, ovary,

brain, T-lymphocytes

– Undefined

PDE9 cGMP Kidney, liver, lung, brain – Undefined

PDE10 cAMP + cGMP Testes, brain, thyroid – Schizophrenia?

PDE11 cAMP + cGMP Skeletal muscle, prostate,

kidney, liver, pituitary and

salivary glands, testes

Tadalafil (weak) Undefined

cAMP, Cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; COPD, chronic obstructive pulmonary disease; IBD,

inflammatory bowel disease, PDE, phosphodiesterase.

1 10 Medical Pharmacology and Therapeutics

Adenylyl cyclase/

guanylyl cyclase

cAMP/

cGMP

Protein kinases

(e.g., A, G)

Receptor-

activated

G-protein

Gi

Gs

Gq

Phospholipase C

DAG

IP3

Protein kinase C

Release of Ca2+

from sarcoplasmic

reticulum

Intracellular enzymes

Ion channels (Ca2+ and K+)

Contractile proteins

+

+

–

Fig. 1.5 The intracellular consequences of receptor activation. The second messengers cyclic adenosine monophosphate

(cAMP), cyclic guanosine monophosphate (cGMP), diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) produce a number

of intracellular changes, either directly or indirectly via actions on protein kinases (which phosphorylate other proteins) or

by actions on ion channels. The pathways can be activated or inhibited depending upon the type of receptor and G-protein

and the particular ligand stimulating the receptor. The effect of the same second messenger can vary depending upon the

biochemical functioning of cells in different tissues.

G-protein G-protein G-protein

Protease

hydrolysis

Inactive receptor Protease activation Active receptor

Amino acid sequence with agonist activity

Second

messengers

Fig. 1.6 Protease-activated receptors. These G-protein-coupled receptors are activated by proteases such as thrombin

which hydrolyse the extracellular peptide chain to expose a segment that acts as a tethered ligand (shown in red) and activates

the receptor. The receptor is inactivated by phosphorylation of the intracellular (C-terminal) part of the receptor protein.

Principles of pharmacology and mechanisms of drug action 11

into the nucleus. Via their DNA-binding domain, the active

hormone–receptor complexes can interact with hormone

response elements (HRE) at numerous sites in the genome.

Binding to the HRE usually activates gene transcription, but

sometimes it silences gene expression and decreases mRNA

synthesis.

Translocation and binding to DNA involves a variety of

different chaperone, co-activator and co-repressor proteins,

and the system is considerably more complex than indicated

The intracellular receptor typically includes a highly con-

served DNA-binding domain with zinc-containing loops and

a variable ligand-binding domain (Table 1.3). The sequence

of hormone binding and action for type 1 intracellular recep-

tors is shown in Fig. 1.8. Type 1 receptors are typically found

in an inactive form in the cytoplasm linked to chaperone

proteins such as heat-shock proteins (HSPs). Binding of the

hormone induces conformational change in the receptor;

this causes dissociation of the HSP and reveals a nuclear

localisation sequence (or NLS) which enables the hormone–

receptor complex to pass through nuclear membrane pores

OH

OH

Ligand

OPO3

Ligand

2–

Ligand

OPO3

2–

OH

Ligand

Single

inactive

receptor

Activation

of

intracellular

enzymes

Ligand-binding site

Extracellular

Intracellular

Tyrosine

residue

Ligand binding

to two receptors

Mutual phosphorylation

and activation

Fig. 1.7 Enzyme-linked transmembrane receptors. This

receptor tyrosine kinase has a large extracellular domain,

a single transmembrane segment and an integral kinase

domain. Ligand binding causes phosphorylation of tyrosine

residues on the receptor and on other target proteins, leading

to intracellular changes in cell behaviour. Other enzyme-

linked receptors have tyrosine phosphatase, serine-threonine

kinase or guanylyl cyclase enzymic activity.

Table 1.2 Some families of intracellular receptors

Subtypes

Type 1 (cytoplasmic)

Oestrogen receptors ER (α, β)

Progesterone receptors PR (A, B)

Androgen receptors AR (A, B)

Glucocorticoid receptor GR

Mineralocorticoid receptor MR

Type 2 (nuclear)

Thyroid hormone receptors TR (α1, β1, β2)

Vitamin D receptor VDR

Retinoic acid receptors RAR (α, β, γ)

Retinoid X receptors RXR (α, β, γ)

Liver X (oxysterol) receptors LXR (α, β)

Peroxisome proliferator-activated

receptors

PPAR (α, β/δ, γ)

Table 1.3 The structure of steroid hormone

receptors

Section

of protein

Domain Role

A/B N-terminal

variable domain

Regulates transcriptional

activity

C DNA-binding

domain (DBD)

Highly conserved; binds

receptor to hormone

response element in

DNA by two zinc-

containing regions

D Hinge region Enables intracellular

translocation to the

nucleus

E Ligand-binding

domain (LBD)

Moderately conserved;

enables specific ligand

binding; contains

nuclear localisation

sequence (NLS); also

binds chaperone

proteins and facilitates

receptor dimerisation

F C-terminal

domain

Highly variable;

unknown function

1 12 Medical Pharmacology and Therapeutics

fibrate class of lipid-lowering drugs act on specific members

of the PPAR family of type 2 receptors.

OTHER SITES OF DRUG ACTION

Probably every protein in the human body has the

potential to have its structure or activity altered by foreign

compounds. Traditionally, all drug targets were described

pharmacologically as ‘receptors’, although many drug targets

would not be defined as receptors in biochemical terms; in

addition to the receptor types discussed previously, drugs

may act at numerous other sites.

■ Cell-membrane ion pumps. In contrast to passive

diffusion, primary active transport of ions against their

concentration gradients occurs via ATP-dependent ion

pumps, which may be drug targets. For example, Na+

/

K+

-ATPase in the brain is activated by the anticonvulsant

drug phenytoin, whereas in cardiac tissue it is inhibited by

digoxin; K+

/H+

-ATPase in gastric parietal cells is inhibited

by proton pump inhibitors such as omeprazole.

■ Transporter (carrier) proteins. Secondary active transport

involves carrier proteins, which transport a specific ion or

organic molecule across a membrane; the energy for the

transport derives not from a coupled ATPase but from the

co-transport of another molecule down its concentration

gradient, either in the same direction (symport) or in the

opposite direction (antiport). Examples include:

■ Na+

/Cl−

co-transport in the renal tubule, which is

blocked by thiazide diuretics (Chapter 14);

■ the reuptake of neurotransmitters into nerve terminals

by a number of transporters selectively blocked by

classes of antidepressant drugs (Chapter 22).

■ Enzymes. Many drugs act on the intracellular or

extracellular enzymes that synthesise or degrade the

endogenous ligands for extracellular or intracellular

receptors, or which are required for growth of bacterial,

viral or tumour cells. Table 1.4 provides examples of drug

groups that act on enzyme targets. The PDE isoenzymes

that regulate second messenger molecules are important

drug targets and are listed in Table 1.1. In addition to being

sites of drug action, enzymes are involved in inactivating

many drugs, while some drugs are administered as inactive

precursors (pro-drugs) that are enzymatically activated

(Chapter 2).

■ Adhesion molecules. These regulate the cell-surface

interactions of immune cells with endothelial and other

cells. Natalizumab is a monoclonal antibody directed

against the α4-integrin component of vascular cell

adhesion molecule (VCAM)-1 and is used to inhibit the

autoimmune activity of lymphocytes in acute relapsing

multiple sclerosis. Other monoclonal antibody-based

therapies are targeted at cellular and humoral proteins,

including cytokines and intracellular signalling proteins

to suppress inflammatory cell proliferation, activity and

recruitment in immune disease.

■ Organelles and structural proteins. Examples include

some antimicrobials that interfere with the functioning

of ribosomal proteins in bacteria, and some types of

anticancer drugs that interrupt mitotic cell division by

blocking microtubule formation.

The sites of action of some drugs remain unknown

or poorly understood. Conversely, many receptors have

in Fig. 1.8. Co-activators are transcriptional cofactors that

also bind to the receptor and increase the level of gene

induction; an example is histone acetylase, which facilitates

transcription by increasing the ease of unravelling of DNA from

histone proteins. Co-repressors also bind to the receptor and

repress gene activation; an example is histone deacetylase,

which prevents further transcription by tightening histone

interaction with the DNA.

Type 2 intracellular receptors, such as the thyroid hormone

receptors (TR) and the peroxisome proliferator-activated

receptor (PPAR) family (see Table 1.2), are found within the

nucleus bound to co-repressor proteins, which are liberated

by ligand binding without a receptor translocation step from

the cytoplasm. PPAR nuclear receptors function as sensors

for endogenous fatty acids, including eicosanoids (Chapter

29), and regulate the expression of genes that influence

metabolic events.

Intracellular receptors are the molecular targets of 10–15%

of marketed drugs, including steroid drugs acting at type 1

receptors and other drugs acting at type 2 receptors. Steroids

show selectivity for different type 1 intracellular receptors

(ER, PR, AR, GR, MR; see Table 1.2), which determine the

spectrum of gene expression that is affected (Chapters 14,

44, 45 and 46). Steroid effects are also determined by the

differential expression of these receptors in different tissues.

Intracellular hormone–receptor complexes typically dimerise

to bind to their HRE sites on DNA. Steroid receptors form

homodimers (e.g. ER–ER), while most type 2 receptors

form heterodimers, usually with RXR (e.g. RAR–RXR). The

thiazolidinedione drugs used in diabetes mellitus and the

Cell membrane

Nuclear

membrane

mRNA mRNA

Increased synthesis

of cytokines,

enzymes, receptors Decreased synthesis

of cytokines,

enzymes, receptors

HSP90

HR

HSP90

HR ST

HR ST

ST

HRE Gene

Fig. 1.8 The activation of intracellular hormone

receptors. Steroid hormones (ST) are lipid-soluble

compounds which readily cross cell membranes and bind

to their intracellular receptors (HR). This binding displaces a

chaperone protein called heat-shock protein (HSP90) and the

hormone–receptor complex enters the nucleus, where it can

increase or decrease gene expression by binding to hormone

response elements (HRE) on DNA. Intracellular receptors for

many other ligands are activated in the nucleus itself.

Principles of pharmacology and mechanisms of drug action 13

ligand and its receptor does not involve covalent chemical

bonds but weaker, reversible forces, such as:

■ ionic bonding between ionisable groups in the ligand

(e.g. NH3

+

) and the receptor (e.g. COO−

);

■ hydrogen bonding between amino-, hydroxyl-, keto- and

other groups in the ligand and the receptor;

■ hydrophobic interactions between lipid-soluble sites in

the ligand and receptor;

■ van der Waals forces, which are very weak interatomic

attractions.

The receptor protein is not a rigid structure: binding of

the ligand alters the conformation and biological properties

of the protein, enabling it to trigger intracellular signalling

pathways. There is growing recognition that different ligands

may stabilise different conformational states of the same

receptor that are distinct from those produced by the

endogenous ligand. Rather than simply switching a receptor

between inactive and active states, a ‘biased’ ligand may

produce preferential receptor signalling via specific G-protein

pathways or by non-G-protein effectors, such as the family

of arrestin proteins, leading to different cellular behaviours.

Drugs may therefore be developed with functional selectivity

been discovered for which the natural ligands are not yet

recognised; these orphan receptors may represent targets for

novel drugs when their pharmacology is better understood.

PROPERTIES OF RECEPTORS

Receptor binding

The binding of endogenous ligands and most drugs to their

receptors is normally reversible; consequently, the intensity

and duration of the intracellular changes are dependent on

repeated ligand–receptor interactions that continue for as

long as the ligand molecules remain in the local environment

of the receptors. The duration of activity of a reversible drug

therefore depends mainly on its distribution and elimination

from the body (pharmacokinetics), which typically requires

hours or days (Chapter 2), not on the duration of binding

of a drug molecule to its receptor, which may last only a

fraction of a second. For a reversible drug, the extent of drug

binding to the receptor (receptor occupancy) is proportional

to the drug concentration; the higher the concentration, the

greater the occupancy. The interaction between a reversible

Table 1.4 Examples of enzymes as drug targets

Enzyme Drug class or use Examples

Acetylcholinesterase (AChE) AChE inhibitors (Chapter 27) Neostigmine, edrophonium,

organophosphates

Angiotensin-converting enzyme (ACE) ACE inhibitors (Chapter 6) Captopril, perindopril, ramipril

Antithrombin (AT)III Heparin anticoagulants (enhancers of

antithrombin III) (Chapter 10)

Enoxaparin, dalteparin

Carbonic anhydrase Carbonic anhydrase inhibitors

(Chapters 14, 50)

Acetazolamide

Cyclo-oxygenase (COX)-1 Nonsteroidal anti-inflammatory drugs (NSAIDs)

(Chapter 29)

Ibuprofen, indometacin,

naproxen

Cyclo-oxygenase (COX)-2 Selective COX-2 inhibitors (Chapter 29) Celecoxib, etoricoxib

Dihydrofolate reductase Folate antagonists (Chapters 51, 52) Trimethoprim, methotrexate

DOPA decarboxylase Peripheral decarboxylase inhibitors (PDIs)

(Chapter 24)

Carbidopa, benserazide

Coagulation factor Xa Direct inhibitors of Factor Xa (Chapter 11) Rivaroxaban

HMG-CoA reductase Statins (HMG-CoA reductase inhibitors)

(Chapter 48)

Atorvastatin, simvastatin

Monoamine oxidases (MAOs) A and B MAO-A and MAO-B inhibitors

(Chapters 22, 24)

Moclobemide, selegiline

Phosphodiesterase (PDE) isoenzymes PDE inhibitors (Chapters 12, 16) Theophylline, sildenafil

(see Table 1.1)

Reverse transcriptase (RT) Nucleos(t)ide and nonnucleoside RT inhibitors

(Chapter 51)

Zidovudine, efavirenz

Ribonucleotide reductase Ribonucleotide reductase inhibitor (Chapter 52) Hydroxycarbamide (hydroxyurea)

Thrombin Direct thrombin inhibitors (Chapter 11) Dabigatran

Viral proteases HIV/hepatitis protease inhibitors (Chapter 51) Saquinavir, boceprevir

Vitamin K epoxide reductase Coumarin anticoagulants (Chapter 11) Warfarin

Xanthine oxidase Xanthine oxidase inhibitors (Chapter 31) Allopurinol

1 14 Medical Pharmacology and Therapeutics

to generate different cell responses from the same receptor,

in contrast to the classical concept of different responses

being generated by drugs acting at different receptors.

Receptor selectivity

There are numerous possible extracellular and intracellular

signals produced in the body, which can affect many different

processes. Therefore a fundamental property of a useful

ligand–receptor interaction is its selectivity; that is, the

extent to which the receptor can recognise and respond to

the correct signals, represented by one ligand or group of

related ligands. Some receptors show high selectivity and

bind a single endogenous ligand (e.g. acetylcholine is the

only endogenous ligand that binds to N1 nicotinic receptors;

see Chapter 4), whereas other receptors are less selective

and will bind a number of related endogenous ligands (e.g.

the β1-adrenoceptors on the heart will bind noradrenaline,

adrenaline and to some extent dopamine, all of which are

catecholamines).

The ability of receptors to recognise and bind the

appropriate ligand depends on the intrinsic characteristics

of the chemical structure of the ligand. The formulae of

a few ligand families that bind to different receptors are

shown in Fig. 1.9; differences in structure that determine

selectivity of action between receptors may be subtle,

such as the those illustrated between the structures of

testosterone and progesterone, which nevertheless have

markedly different hormonal effects on the body due to their

receptor selectivity. Receptors are protein chains folded into

tertiary and quaternary structures such that the necessary

arrangement of specific binding centres is brought together

in a small volume – the receptor site (Fig. 1.10). Receptor

selectivity occurs because the three-dimensional organisation

of the different sites for reversible binding (such as anion

and cation sites, lipid centres and hydrogen-bonding sites)

corresponds better to the three-dimensional structure of the

endogenous ligand than to that of other ligands.

There may be a number of subtypes of a receptor, all of

which can bind the same common ligand but which differ

in their ability to recognise particular variants or derivatives

of that ligand. The different characteristics of the receptor

subtypes therefore allow a drug (or natural ligand) with a

particular three-dimensional structure to show selective

actions by recognising one receptor preferentially, with

fewer unwanted effects from the stimulation or blockade

of related receptors. For example, α1-, α2-, β1-, β2- and

β3-adrenoceptors all bind adrenaline, but isoprenaline, a

synthetic derivative of adrenaline, binds selectively to the three

β-adrenoceptor subtypes rather than the two α-adrenoceptor

subtypes (Chapter 4). As the adrenoceptor subtypes occur to

a different extent in different tissues, and produce different

intracellular changes when stimulated or blocked, drugs

can be designed that have highly selective and localised

actions. The cardioselective β-adrenoceptor antagonists such

as bisoprolol are selective blockers of the β1-adrenoceptor

subtype that predominates on cardiac smooth muscle, with

much less binding to the β2-adrenoceptors that predominate

on bronchial smooth muscle. Although ligands may have a

much higher affinity for one receptor subtype over another,

this is never absolute, so the term selective is preferred

over specific.

CHCH2NH2

OH

OH

OH

CH2CH2NH2

OH

OH

HO CH2CH2NH2

N

H

Dopamine Noradrenaline

5-Hydroxytryptamine (5-HT; serotonin)

CH2CH2NH2 N

HN

A Histamine

NH2

CH2

COOH

NH2

CH2CH2CH

COOH

O

HO

CH2CH2CH2

NH2

HO

NH2 O

C

COOH

O

HO

CH2 CH

Glycine Glutamate

Aspartate - Aminobutyrate

(GABA)

γ

C

C

B

O

C O

CH3

Progesterone

O

Testosterone

OH

C

Fig. 1.9 Groups of related chemicals that show

selectivity for different receptor subtypes in spite of

similar structure. (A) Biogenic amines; (B) amino acids; (C)

steroids.

Principles of pharmacology and mechanisms of drug action 15

mode of treatment and selection of the optimal drug and

dosage (personalised medicine).

Drug stereochemistry and activity

The three-dimensional spatial organisation of receptors

means that the ligand must have the correct configuration

to fit the receptor, analogous to fitting a right hand into

a right-handed glove. Drugs and other organic molecules

show stereoisomerism if they contain four different chemical

groups attached to a single carbon atom, or one or more

double bonds, with the result that compounds with the same

molecular formula can exist in different three-dimensional

configurations. If a drug is an equal (racemic) mixture of two

stereoisomers, the stereoisomers may show different receptor

binding characteristics and biological properties. Most often,

one stereoisomer is pharmacologically active while the other

is inactive, but in some cases the inactive isomer may be

responsible for the unwanted effects of the racemic mixture.

Alternatively the two isomers may be active at different

receptor subtypes and have synergistic or even opposing

actions. The different isomers may also show different rates

of metabolism. As a consequence, there has been a trend

for the development of single stereoisomers of drugs for

therapeutic use; one of the earliest examples was the use of

levodopa, the levo-isomer of dihydroxyphenylalanine (DOPA)

in Parkinson’s disease (Chapter 24).

Receptor numbers

The number of receptors present in, or on the surface of, a cell

is not static. There is usually a high turnover of receptors being

formed and removed continuously. Cell-membrane receptor

proteins are synthesised in the endoplasmic reticulum

and transported to the plasma membrane. Regulation of

functional receptor numbers in the membrane occurs both by

transport to the membrane (often as homo- or heterodimers)

and by removal by internalisation. The number of receptors

within the cell membrane may be altered by the drug being

used for treatment, with either an increase in receptor

number (upregulation) or a decrease (downregulation) and

a consequent change in the ability of the drug to effect

the desired therapeutic response. This change may be an

unwanted loss of drug activity contributing to tolerance

to the effects of the drug (e.g. opioids; Chapter 19). As

a result, increased doses may be needed to maintain the

same activity. Alternatively, the change in receptor number

may be an important part of the therapeutic response itself.

One example is tricyclic antidepressants (Chapter 22);

these produce an immediate increase in the availability of

monoamine neurotransmitters, but the therapeutic response

is associated with a subsequent, adaptive downregulation in

monoamine receptor numbers occurring over several weeks.

PROPERTIES OF DRUG ACTION

Drug actions can show a number of important properties:

■ dose–response relationship,

■ selectivity,

■ potency,

■ efficacy.

Traditionally, receptor subtypes were discovered pharma-

cologically when a new agonist or antagonist compound was

found to alter some but not all of the activities of a currently

known receptor class. Developments in molecular biology,

including the Human Genome Project, have accelerated

the recognition and cloning of new receptors and receptor

subtypes, including orphan receptors for which the natural

ligands are unknown. These developments are important in

guiding development of new drugs with greater selectivity

and fewer unwanted effects. Based on such information it is

recognised that there are multiple types of most receptors,

and that there is genetic variation among individuals in the

structures, properties and abundance of these receptors,

which can lead to differences in drug responses (pharma-

cogenetic variation; discussed later). Greater understanding

of genetic differences underlying human variability in drug

responses offers the potential for individualisation of the

NH2

OH

HO

HO

R

+

+ O

N

O

OH OH HO

HO

HO

C OH

O O–

IV

II

I

VII VI

V

III

H-bonding Ionic centre

R centre

Aromatic

centre

H-bonding

–

Adrenoceptor

Muscarinic receptor

Fig. 1.10 Receptor ligand-binding sites. The coloured

areas are schematic representations of the regions of

the adrenoceptor (top) and muscarinic receptor (bottom)

responsible for binding their respective catecholamine

and acetylcholine ligands. In the muscarinic receptor,

cross-sections of the seven transmembrane segments are

labelled I–VII. Different segments provide different properties

(hydrogen bonding, anionic site, etc.) to make up the active

binding site.

1 16 Medical Pharmacology and Therapeutics

because the dose then produces the maximal response of

which the biological tissue is capable.

Potency

The potency of a drug in vitro is largely determined by the

strength of its binding to the receptor, which is a reflection of

the receptor affinity, and by the inherent ability of the drug/

receptor complex to elicit downstream signalling events.

The more potent a drug, the lower the concentration needed

to give a specified response. In Fig. 1.12, drug A1 is more

potent than drug A2 because it produces a specified level of

response at a lower concentration. It is important to recognise

that potencies of different drugs are compared using the

doses required to produce (or block) the same response

(often chosen arbitrarily as 50% of the maximal response).

The straight-line portions of log dose–response curves are

usually parallel for drugs that share a common mechanism

of action, so the potency ratio is broadly the same at most

response values – for example, 20%, 50% or 80%, but

not at 100% response. A drug concentration sufficient to

produce half of the greatest response achievable by that

DOSE–RESPONSE RELATIONSHIPS

Using a purified preparation of a single drug, it is possible to

define accurately and reproducibly the relationship between

the doses of drug administered (or concentrations applied) and

the biological effects (responses) at each dose. The results

for an individual drug can be displayed on a dose–response

curve. In many biological systems, the typical relationship

between an increasing drug dose (or concentration in plasma)

and the biological response is a hyperbola, with the response

curve rising with a gradually diminishing slope to a plateau,

which represents the maximal biological response. Plotting

instead the logarithm of the dose (or concentration) against

the response (plotted on a linear scale) generates a sigmoid

(S-shaped) curve. The sigmoid shape of the curve provides

a number of advantages for understanding the relationship

between drug dose and response: a very wide range of doses

can be accommodated easily on the graph, the maximal

response plateau is clearly defined, and the central portion

of the curve (between about 15% and 85% of maximum)

approximates to a straight line, allowing the collection of

fewer data points to delineate the relationship accurately.

Fig. 1.11 shows the log dose–response relationship

between a drug and responses it produces at two types of

adrenoceptors. In each case, the upward slope of the curve

to the right reflects the chemical law that a greater number of

reversible molecular interactions of a drug (D) with its receptor

(R), due in this case to increasing drug dose, leads to more

intracellular signalling by active drug–receptor complexes (DR)

and hence a greater response of the cell or tissue (within

biological limits). This principle is diametrically opposed

to the principle of homeopathy, which argues that serially

diluting a drug solution until essentially no drug molecules

remain enhances its activity, a belief that is not supported

theoretically or experimentally.

Selectivity

As drugs may act preferentially on particular receptor types

or subtypes, such as β1- and β2-adrenoceptors, it is important

to be able to quantify the degree of selectivity of a drug.

For example, it is important in understanding the therapeutic

efficacy and unwanted effects of the bronchodilator drug

salbutamol to recognise that it is approximately 10 times

more effective in stimulating the β2-adrenoceptors in the

airway smooth muscle than the β1-adrenoceptors in the heart.

In pharmacological studies, selectivity is likely to

be investigated by measuring the effects of the drug in

vitro on different cells or tissues, each expressing only

one of the receptors of interest. Comparison of the two

log dose–response curves in Fig. 1.11 shows that for a

given response, smaller doses of the drug being tested

are required to stimulate the β1-adrenoceptor compared

with those required to stimulate the β2-adrenoceptor; the

drug is therefore said to have selectivity of action at the

β1-adrenoceptor. An example might be dobutamine, which is

used to selectively stimulate β1-adrenoceptors on the heart

in heart failure. The degree of receptor selectivity is given

by the ratio of the doses of the drug required to produce

a given level of response via each receptor type. It is clear

from Fig. 1.11 that the ratio is highly dose-dependent and

that the selectivity disappears at extremely high drug doses,

% Maximum response

Increasing dose of β-adrenoceptor agonist

(logarithmic scale)

100

50

0 D1 D2 D3

Drug action at

β1-adrenoceptor

Drug action at

β2-adrenoceptor

Fig. 1.11 Dose–response relationship and receptor

selectivity. Each curve shows the responses (expressed as

percentage of maximum on a linear vertical axis) produced

by a hypothetical β-adrenoceptor agonist drug at a range

of doses shown on a logarithmic horizontal axis. Plotting

the logarithmic dose allows a wide range of doses to be

shown on the same axes and transforms the dose–response

relationship from a hyperbolic curve to a sigmoid curve, in

which the central portion is close to a straight line. The two

curves illustrate the relative selectivity of the same drug for

the β1-adrenoceptor compared with the β2-adrenoceptor. At

most doses the drug produces β1-adrenoceptor stimulation

with less effect on β2-adrenoceptors. If dose D1 is 10 times

lower than dose D2, the selectivity of the drug for the β1-

adrenoceptor is 10-fold higher. This selectivity diminishes

at the higher end of the log dose–response curve and is

completely lost at a dose (D3) that produces a maximum

response on both β1- and β2-adrenoceptors.

Principles of pharmacology and mechanisms of drug action 17

obtained with a more efficacious drug, while a more potent

drug may merely allow a smaller dose to be given for the

same clinical benefit. In turn, efficacy and potency need

to be balanced against drug toxicity to produce the best

balance of benefit and risk for the patient. Drug toxicity and

safety are discussed in Chapters 3 and 53.

TYPES OF DRUG ACTION

Drugs can be classified by their receptor action as:

■ agonists,

■ antagonists,

■ partial agonists,

■ inverse agonists,

■ allosteric modulators,

■ enzyme inhibitors or activators,

■ nonspecific,

■ physiological antagonists.

AGONISTS

An agonist, whether a therapeutic drug or an endogenous

ligand, binds to the receptor or site of action and changes

the conformation of the receptor to its active state, leading

to signalling via second messenger pathways. An agonist

shows both affinity (the strength of binding for the receptor)

and intrinsic activity (the extent of conformational change

imparted to the receptor leading to receptor signalling). Drugs

differ in their affinity and intrinsic activity at the same receptor,

as well as between different receptors.

Agonists are traditionally divided into two main groups

(Fig. 1.12):

■ full agonists (curves A1 and A2), which give an increase

in response with an increase in concentration until the

maximum possible response is obtained for that system;

■ partial agonists (curve A3), which also give an increase

in response with increase in concentration, but cannot

produce the maximum possible response in the system.

The reasons for this difference, and also a third group of

agonists (inverse agonists), are described as follows.

Affinity and intrinsic activity

The affinity of a drug is related to the aggregate strength of

the atomic interactions between the drug molecule and its

receptor site of action, which determines the relative rates

of drug binding and dissociation. The higher the affinity, the

lower the drug concentration required to occupy a given

fraction of receptors. Affinity therefore determines the drug

concentration necessary to produce a certain response and

is directly related to the potency of the drug. In Fig. 1.12,

drug A1 is more potent than drug A2, but both are capable of

producing a maximal response (they have the same efficacy

as they are full agonists).

Intrinsic activity describes the ability of the bound drug

to induce the conformational changes in the receptor that

induce receptor signalling. Although affinity is a prerequisite

for binding to a receptor, a drug may bind with high affinity

but have low intrinsic activity. A drug with zero intrinsic

activity is an antagonist (as discussed later).

drug is described as its EC50 (the effective concentration

for 50% of the maximal response). The EC50 (or ED50 if drug

dose is considered) is a convenient way to compare the

potencies of similar drugs; the lower the EC50 (or ED50), the

more potent the drug.

In vivo the potency of a drug, defined as the dose of the

drug required to produce a desired clinical effect, depends not

only on its affinity for the receptor, the receptor number and

the efficiency of the stimulus–response mechanism, but also

on pharmacokinetic variables that determine the delivery of

the drug to its site of receptor action (Chapter 2). Therefore

the relative potencies of related drugs in vivo may not directly

reflect their in vitro receptor-binding properties.

Efficacy

The efficacy of a drug is its ability to produce the maximal

response possible for a particular biological system and

relates to the extent of functional change that can be imparted

to the receptor by the drug, based on its affinity for the

receptor and its ability to induce receptor signalling (discussed

later). Drug efficacy is arguably of greater clinical importance

than potency because a greater therapeutic benefit may be

A2 + RA

A2 + IA

Response (%)

Concentration of agonist (logarithmic scale)

100

50

0

A1 A2

A3

Fig. 1.12 Concentration–response curves for agonists

in the absence and presence of competitive and

noncompetitive antagonists. Responses are plotted at

different concentrations of two different full agonists (A1

being more potent than A2) and also a partial agonist (A3),

which is unable to produce a maximal response even at

high concentrations. Responses are also shown for the

full agonist A2 in the presence of a fixed concentration

of a competitive (reversible) antagonist (RA) or a fixed

concentration of a noncompetitive (irreversible) antagonist

(IA). The competitive antagonist reduces the potency of

agonist A2 (the curve is shifted parallel to the right), but high

concentrations of A2 are able to surmount the effects of the

competitive antagonist and produce a maximal response.

A noncompetitive antagonist reduces agonist activity either

by irreversibly blocking the agonist binding site, or by

changing its conformation by binding reversibly or irreversibly

at an allosteric site. Unlike competitive antagonists, a

noncompetitive antagonist reduces the maximal response

even at high agonist concentrations, as shown in the curve A2

+ IA compared with A2 alone.

1 18 Medical Pharmacology and Therapeutics

β1-adrenoceptor antagonists lower the heart rate markedly

only when it is already elevated by endogenous agonists such

as adrenaline and noradrenaline. The reversible binding of

competitive antagonists means that the receptor blockade can

be overcome (surmounted) by an increase in the concentration

of an agonist. Therefore competitive antagonist drugs move

the dose–response curve for an agonist in a parallel fashion

to the right but do not alter the maximum possible response

at high agonist concentrations (as shown in curve A2 + RA

when compared with A2 alone in Fig. 1.12).

Noncompetitive antagonists either bind to the receptor

irreversibly (covalently) at the ligand binding site, denying

access to the agonist, or they change the conformation

of the receptor by binding reversibly or irreversibly at

another (allosteric) site, producing conformational changes

that impede the ability of the agonist to access its binding

site or block the conformational changes in the receptor

needed for intracellular signalling. In either case, the

effects of noncompetitive antagonists cannot be negated

(surmounted) by competition from the agonist, so they

reduce the magnitude of the maximum response that can

be produced by any concentration of agonist (as shown by

curve A2 + IA in Fig. 1.12). A noncompetitive antagonist will

also cause a rightward shift of the agonist log dose–response

curve if there is no reserve of spare receptors.

Like agonists, antagonists exhibit varying degrees of

selectivity of action. For example, phenoxybenzamine

is an antagonist which blocks the ligand binding site of

α-adrenoceptors, but not that of β-adrenoceptors. Conversely,

propranolol is an antagonist of β-adrenoceptors, but not

α-adrenoceptors. Bisoprolol is further selective for the

β1-adrenoceptor subtype, and has less blocking action at

β2-adrenoceptors (or α-adrenoceptors).

PARTIAL AGONISTS

An agonist that is unable to produce a maximal response

is a partial agonist (e.g. drug A3 in Fig. 1.12). Even maximal

occupancy of all available receptors produces only a

submaximal response due to low intrinsic activity of the partial

agonist, for example because of incomplete amplification of

the receptor signal via the G-proteins. Despite their name,

partial agonists can be considered to have both agonist

and antagonist properties, depending on the presence and

type of other ligands. A partial agonist usually shows weak

agonist activity in the absence of another ligand, and such

partial agonism can be blocked by an antagonist. But in the

presence of a full agonist, a partial agonist will behave as a

weak antagonist because it prevents access to the receptor

of a molecule with higher intrinsic ability to initiate receptor

signalling; this results in a reduced response. Partial agonism

is responsible for the therapeutic efficacy of several drugs,

including buspirone, buprenorphine, pindolol and salbutamol.

These drugs can act as stabilisers of the variable activity of

the natural ligand, as they enhance receptor activity when

the endogenous ligand levels are low or zero, but block

receptor activity when endogenous ligand levels are high.

INVERSE AGONISTS

The previously provided definitions of agonists, partial

agonists and antagonists reflect the classical model of

It should be noted that the rate of binding and rate

of dissociation of a reversible drug at its receptor are of

negligible importance in determining its rate of onset or

duration of effect in vivo, because these depend mainly on

the rates of delivery of the drug to, and removal from, the

target organ; that is, on the overall absorption, distribution

and elimination rates of the drug from the body (Chapter 2).

Spare receptors

Some full agonists that have relatively low intrinsic activity

may have to occupy all of the available receptors to produce a

maximal response. However, many full agonists have sufficient

affinity and intrinsic activity that the maximal response can be

produced even though many receptors remain unoccupied;

that is, there may be spare receptors (or a receptor reserve).

The concept of spare receptors does not imply a distinct pool

of permanently redundant receptors, only that a proportion

of the receptor population is unoccupied at a particular

point in time. Spare receptors may function to enhance the

speed of cellular response, because an excess of available

receptors reduces the distance and therefore the time that

a ligand molecule needs to diffuse to find an unoccupied

receptor; an example is the excess of acetylcholine nicotinic

N2 receptors that contributes to fast synaptic transmission

in the neuromuscular junction (Chapter 27).

The concept of spare receptors is also helpful when

considering changes in receptor numbers during chronic

treatment, particularly receptor downregulation. As maximal

responses are often produced at drug concentrations that

do not attain 100% receptor occupancy, the same maximal

response may still be produced when receptor numbers

are downregulated, but only with higher percentage

occupancy of the reduced number of receptors. If receptors

are downregulated still further, the number remaining may

be insufficient to generate a maximal response. Receptor

downregulation may therefore contribute to a decline in

responsiveness to some drugs during chronic treatment

(drug tolerance).

ANTAGONISTS

Pharmacological antagonists (often called ‘blockers’) reduce

the activity of an agonist at the same receptor, and can

be contrasted with physiological antagonists (discussed

later) that act at another type of receptor or at other sites

of action to oppose the physiological response to the

agonist. Pharmacological antagonists can be competitive

(surmountable) or noncompetitive (nonsurmountable).

A competitive antagonist binds reversibly to the ligand

binding site of a receptor, either alone or in competition with

a drug agonist or natural ligand. It therefore must have affinity

for the ligand binding site (which may be as high as that

of any agonist), but it has zero intrinsic activity. It therefore

cannot cause the conformational change that converts the

receptor to its active state and induces intracellular signalling.

The antagonist will, however, competitively impair access

of agonist molecules to the ligand binding site and thereby

reduce receptor activation. The presence of a competitive

antagonist may only be detectable by its impairment of

agonist activity, and the extent of antagonism will depend on

the relative amounts of agonist and antagonist. For example,

Principles of pharmacology and mechanisms of drug action 19

an allosteric modulator may not bind to the allosteric site

(or only bind poorly) in the absence of the agonist, but its

allosteric binding increases when binding of the agonist to

the orthosteric site alters receptor conformation. An example

of allosteric modulators is the family of benzodiazepine

anxiolytic drugs, which allosterically alter the affinity of

chloride channels for the neurotransmitter ligand GABA

and enhance its inhibitory activity on neurons (Chapter 20).

ENZYME INHIBITORS AND ACTIVATORS

The site of action of many drugs is an enzyme, which may

be an intracellular or cell-surface enzyme or one found in

plasma or other body fluids. Such drugs act reversibly or

irreversibly either on the catalytic site or at an allosteric

site on the enzyme to modulate its catalytic activity; most

often the effect is inhibition, and important examples of

enzyme inhibitors are shown in Table 1.4. An example of

an enzyme activator is heparin, which enhances the activity

of antithrombin III, a protease that regulates the activity of

the coagulation pathway.

NONSPECIFIC ACTIONS

A few drugs produce their desired therapeutic outcome

without interaction with a specific site of action on a protein;

for example, the diuretic mannitol exerts an osmotic effect in

the lumen of the kidney tubule, which reduces reabsorption

of water into the blood (Chapter 14).

PHYSIOLOGICAL ANTAGONISTS

Physiological antagonism is said to occur when a drug

has a physiological effect opposing that of an agonist

but without binding to the same receptor. The increase

in heart rate produced by a β1-adrenoceptor agonist, an

effect which mimics the action of the sympathetic autonomic

nervous system, can be blocked pharmacologically with

an antagonist at β1-adrenoceptors or physiologically by a

muscarinic receptor agonist, which mimics the opposing

(parasympathetic) autonomic nervous system. The site of

action of the physiological antagonist may be on a different

cell, tissue or organ than that of the agonist.

TOLERANCE TO DRUG EFFECTS

Tolerance to drug effects is defined as a decrease in

response to repeated doses, often necessitating an increase

in dosage to maintain an adequate clinical response.

Tolerance may occur through pharmacokinetic changes in

the concentrations of a drug available at the receptor or

through pharmacodynamic changes at the drug receptor.

Pharmacokinetic effects are discussed in Chapter 2; some

drugs stimulate their own metabolism, so they are eliminated

more rapidly on repeated dosing, and lower concentrations

of the drug are available to produce a response.

Most clinically important examples of tolerance arise

from pharmacodynamic changes in receptor numbers and in

concentration–response relationships. Desensitisation is used

to describe both long-term and short-term changes arising

drug–receptor interactions, in which an unoccupied receptor

has no signalling activity. It is now recognised that many

GPCRs show constitutive signalling independently of an

agonist. Inverse agonists were first recognised when some

compounds were found to show negative intrinsic activity: they

acted alone on unoccupied receptors to produce a change

opposite to that caused by an agonist. Inverse agonists

shift the receptor equilibrium towards the inactive state,

thereby reducing the level of spontaneous receptor activity.

An inverse agonist can be distinguished from the typical

antagonists discussed previously, which, on their own, bind

to the receptor without affecting receptor signalling, as they

have zero intrinsic activity (‘neutral’ or ‘silent’ antagonists).

The action of a neutral antagonist depends on depriving

the access of agonists to the receptor; a neutral antagonist

can therefore block the effects of either a positive or inverse

agonist at a receptor with spontaneous signalling activity.

The role of inverse agonism in the therapeutic effects of

drugs remains to be fully elucidated, but a number of drugs

exhibit this type of activity (Table 1.5). The same drug may

even show a mixed pattern of full or partial agonism, inverse

agonism or antagonism at different receptors. Some drugs

(e.g. some β-adrenoceptor antagonists) can act as neutral

antagonists at a receptor in one tissue and as inverse agonists

when the same receptor is expressed in a different tissue,

probably due to association of the receptor with different

G-proteins.

ALLOSTERIC MODULATORS

Allosteric modulation has been described previously in the

context of one type of noncompetitive antagonist, which

does not compete directly with an agonist for access to the

ligand binding site (also called the orthosteric site), but binds

to a different (allosteric) site. Allosteric modulation changes

receptor activity by altering the conformation of the orthosteric

binding site or of sites involved in intracellular signalling.

Allosteric modulators can also enhance the binding of the

natural ligand or other drugs to the receptor or enhance their

propensity to induce receptor signalling. In some cases,

Table 1.5 Examples of drugs with inverse agonist

activity

Receptor Drugs

α1-Adrenoceptor Prazosin, terazosin

β1-Adrenoceptor Metoprolol, carvedilol,

propranolol

Angiotensin II receptor (AT1) Losartan, candesartan,

irbesartan

Cysteinyl-leukotriene (CysLT1) Montelukast

Dopamine (D2) Haloperidol, clozapine,

olanzapine

Histamine (H1) Cetirizine, loratadine

Histamine (H2) Cimetidine, ranitidine,

famotidine

Muscarinic (M1) Pirenzepine

Opioid (μ, MOR) Naloxone

1 20 Medical Pharmacology and Therapeutics

The phosphorylated receptor protein is endocytosed

and may undergo intracellular dephosphorylation prior

to re-entering the cytoplasmic membrane.

Downstream modulation of the signal may also occur

through feedback mechanisms or simply through depletion

of some essential cofactor. An example of the latter is the

depletion of the thiol (-SH or sulphydryl) groups necessary

for the generation of nitric oxide during chronic administration

of organic nitrates (Chapter 5).

GENETIC VARIATION IN

DRUG RESPONSES

Biological characteristics, including responses to drug

administration, vary among individuals, and genetic differences

can contribute to these inter-individual variations. For most

drugs, the nature of the response is broadly similar in different

individuals, but the magnitude of the response to the same

dose can differ markedly, at least partly due to genetic

factors. Such variability creates the need to individualise

drug dosages for different people.

Drug responses may follow a unimodal (Gaussian)

distribution, reflecting the sum of many small genetic variations

in receptors, enzymes or transporters that respond to or

handle the drug (Fig. 1.13A). Genetic variation may also give

rise to discrete subpopulations of individuals in which a drug

shows distinctly different responses (see Fig. 1.13B), such

that some individuals may have no response to a standard

dose, while others show toxicity. Understanding genetic

variation is of increasing importance in drug development

(see Chapter 3) because it allows the possibility of genetic

from a decrease in response of the receptor. Desensitisation

can occur by a number of mechanisms:

■ decreased receptor numbers (downregulation), due

to decreased transcriptional expression or receptor

internalisation;

■ decreased receptor binding affinity;

■ decreased G-protein coupling;

■ modulation of the downstream response to the initial

signal.

GPCRs can show rapid desensitisation (within minutes)

during continued activation, which occurs through three

mechanisms:

■ Homologous desensitisation. The enzymes activated

following selective binding of an agonist to its receptor–G-

protein complex include G protein-coupled receptor

kinases (GRKs), which interact with the βγ-subunit of the

G-protein and inactivate the occupied receptor protein by

phosphorylation; a related peptide, arrestin-2, enhances

the GRK-mediated desensitisation of the GPCR and may

itself activate distinct cell signalling pathways.

■ Heterologous desensitisation. Also known as cross-

desensitisation, this occurs when an agonist at one

receptor causes loss of sensitivity to other agonists.

The agonist increases intracellular cAMP which activates

protein kinase A or C; these phosphorylate the cross-

desensitised receptors (whether occupied or not), and

members of the arrestin family prevent them from coupling

with G-proteins. Other mechanisms of heterologous

desensitisation exist.

■ Receptor internalisation. Internalisation can occur

within minutes when constant activation of a GPCR

makes the receptor unavailable for further agonist

action by uncoupling the G-protein from the receptor.

Gaussian distribution of response Polymorphic distribution of response

Response Response

Number of subjects

Number of subjects

A B

Fig. 1.13 Inter-individual variation in response. The graphs show the numbers of individual subjects in a population

plotted against their varying levels of response to a single dose of a drug. (A) In the unimodal distribution most individuals

show a middling response and the overall shape is a normal (Gaussian) distribution. Part of this variability may result from

polymorphism in multiple genes encoding drug receptors and proteins involved in the drug’s absorption and elimination.

(B) The bimodal distribution shows discrete responder and nonresponder subgroups, possibly due to a single genetic

polymorphism in a drug receptor or drug-metabolising enzyme.

Principles of pharmacology and mechanisms of drug action 21

screening to optimise drug and dosage selection (personalised

or individualised medicine).

Pharmacogenetics has been defined as the study

of genetic variation that results in differing responses to

drugs. Such variation may arise from genetic factors that

alter the structure, expression or regulation of drug targets

(pharmacodynamic effects) or that change the metabolic fates

of drugs in the body, usually by altering proteins involved in

their absorption, distribution or elimination (pharmacokinetic

effects, discussed in Chapter 2). Pharmacogenetic research

has been undertaken for many decades, largely in relation

to variability in vivo, and has often used classic genetic

techniques such as studies of patterns of inheritance in twins.

Pharmacogenomics has been defined as the investigation

of variation in DNA and RNA characteristics related to

drug response, and the term refers mainly to genome-wide

approaches that define the presence of single-nucleotide

polymorphisms (SNPs) which affect the activity of the gene

product. Molecular biological techniques have predicted more

than 3 million SNPs in the human genome. SNPs can be:

■ in the upstream regulatory sequence of a coding gene,

which can result in increased or decreased expression

of the gene product (this product remains identical to

the normal or ‘wild-type’ gene product);

■ in the coding region of the gene resulting in a gene product

with an altered amino acid sequence (this may have higher

activity, although this is unlikely; similar activity; lower

activity or no activity at all, compared with the wild-type

protein);

■ inactive, because they are in noncoding or nonregulatory

regions of the genome, or, if in a coding region, because

the base change does not alter the amino acid encoded,

due to the redundancy of the genetic code.

There is still a major challenge in defining the functional

consequences of the large numbers of identified SNPs (func-

tional genomics), particularly in the context of combinations of

genetic variants (haplotypes). Such studies often require very

large numbers of subjects to allow comparison of function

in multiple, small haplotype subgroups.

Rapid advances in molecular biology have allowed analysis

of interindividual differences in the sequences of many genes

encoding drug receptors and proteins involved in drug

metabolism and transport. Polymorphism in the latter is likely

to have the greatest impact on dosage selection (Chapter 2),

while polymorphism in drug targets may be more important

in determining the optimal drug for a particular condition.

For example, genetic variation in angiotensin AT1 receptors,

β1-adrenoceptors and Ca2+

ion channels may determine the

relative effectiveness of angiotensin II receptor antagonists,

β-adrenoceptor antagonists (β-blockers) and calcium channel

blockers in the treatment of essential hypertension.

In practice, although genetic polymorphism has been

reported in many receptor types and these have been a

major focus of research in relation to the aetiology of disease,

relatively few studies to date have demonstrated a clear

influence on drug responses. Common polymorphisms have

been identified in the human β2-adrenoceptor gene ADRB2,

and certain variants have been associated with differences

in receptor downregulation and loss of therapeutic response

in people with asthma while using β2-adrenoceptor agonist

inhalers (Chapter 12). The clinical response in people with

asthma to treatment with leukotriene modulator drugs is

influenced by genetic polymorphism in enzymes of the

leukotriene (5-lipoxygenase) pathway. Variants in the

epidermal growth factor receptor (EGFR), an RTK, have been

reported to predict tumour response to the EGFR inhibitor

gefitinib in individuals with nonsmall-cell lung cancer. Such

examples may support genotyping to target drug treatments

to those individuals most likely to respond.

Conversely, pharmacogenetic information may be used

to avoid a particular treatment in people likely to experience

serious adverse reactions to a specific drug. Variation in

human leucocyte antigen (HLA) genes has been associated

with adverse skin and liver reactions to several drugs,

including abacavir, an antiretroviral drug used in HIV infection.

Compared with pharmacodynamic targets, genetic

variation has been more extensively characterised in drug-

metabolising enzymes, particularly in cytochrome P450

isoenzymes and others involved in glucuronidation, acetylation

and methylation. Gene variations in drug-metabolising

enzymes are discussed at the end of Chapter 2. Detailed

information on human genotypic variation can be found in

the Online Mendelian Inheritance in Man (OMIM) database

(www.ncbi.nlm.nih.gov/omim). Therapeutic exploitation of

genotypic differences will require specific information about

individuals based on detailed genetic testing. Until such

genetic information is routinely incorporated in clinical trials,

careful monitoring of clinical response will remain the best

guide to successful treatment.

SUMMARY

The therapeutic benefits of drugs arise from their ability to

interact selectively with target receptors, most of which are

regulatory molecules involved in the control of cellular and

systemic functions by endogenous ligands. Drugs may also

cause unwanted effects; judging the balance of benefit and

risk is at the heart of safe and effective prescribing. Increasing

knowledge of the complexity of receptor pharmacology and

improvements in drug selectivity offer the promise of safer

drugs in the future, especially when information on genetic

variation is more routinely available.

SELF-ASSESSMENT

True/false questions

1. Clinical pharmacology is the study of drugs that doctors

use to treat disease.

2. Drugs act at receptors only on the external surface of

cells.

3. Diluting drugs enhances their pharmacological effects.

4. Drugs produce permanent biochemical changes in their

receptors.

5. Plotting drug dose (or plasma concentration) against

response usually produces a sigmoid curve.

6. The EC50 is the concentration of drug that produces a

half-maximal response.

7. On a log dose–response plot, the drug with a curve to

the right is more potent than a drug with a curve on

the left.

1 22 Medical Pharmacology and Therapeutics

reversible; irreversible drugs may act by covalent

chemical bonding.

5. False. Plotting drug dose or plasma concentration

against response typically produces a hyperbola; a

sigmoid (S-shaped) curve is produced by plotting the

logarithm of dose or concentration against the response.

6. True. The EC50 (or ED50) is the concentration (or dose)

effective in producing 50% of the maximal response

and is a convenient way of comparing drug potencies.

7. False. A drug with its log dose–response curve to the

left is the more potent, as it produces a given level of

response at a lower dose.

8. False. A full (‘neutral’ or ‘silent’) antagonist must have

affinity to bind to its receptor, but it has zero intrinsic

ability to activate the receptor. Partial agonists can

also have an antagonist effect in the presence of a

full agonist. Receptors with inherent signalling activity,

even when unoccupied, can be antagonised by inverse

agonists.

9. True. A fixed dose of a competitive antagonist shifts the

log dose–response curve of the agonist to the right in a

parallel fashion; it can be surmounted by increasing the

dose of agonist, so that the same maximal response

can be achieved.

10. True. A partial agonist has low intrinsic ability to induce

conformational change in the receptor so it does not

elicit a maximal response even with full receptor

occupancy.

11. False. Many full agonists are able to elicit a maximal

response when less than 100% of receptors are

occupied; the unoccupied receptors are termed ‘spare

receptors’.

12. True. Tolerance may be caused by desensitisation,

internalisation or downregulation of receptors, requiring

higher drug doses to maintain the same response.

Tolerance also often results from enhanced drug

elimination that alters the concentrations of drugs

available to interact with the receptor.

8. A receptor antagonist is defined as a drug with zero

affinity for the receptor.

9. A competitive antagonist shifts the log dose–response

curve of an agonist to the right, without affecting the

maximal response.

10. A partial agonist is one that, even at its highest dose,

cannot achieve the same maximal response as a full

agonist at the same receptor.

11. A full agonist achieves a maximal response when all

its receptors are occupied.

12. Changes in receptor numbers can cause tolerance to

drug effects.

ANSWERS

True/false answers

1. True. Clinical pharmacology also deals with drugs

used in disease prevention and diagnosis, and in the

alleviation of pain and suffering.

2. False. While many types of receptors are found in cell

membranes, including ion channels, GPCRs and tyrosine

kinase receptors, other drug targets, including steroid

receptors and many enzymes (e.g. cyclo-oxygenase,

PDE), are intracellular and others are humoral, such as

thrombin in plasma.

3. False. The relationship between the dose or concentra-

tion of a drug and the response may be complex but

is typically dependent on the number of interactions

between the drug molecules and their molecular target,

a consequence of the Law of Mass Action, and so are

usually greater at higher drug concentrations, within

biological limits.

4. False. Molecular interactions between most drugs

and their receptors are typically transient, and the

conformational changes induced in the receptor are

FURTHER READING

Alexander, S.P.H., Davenport, A.P., Kelly, E., et al., 2015. IUPHAR/

BPS concise guide to pharmacology 2015–16. Br. J. Pharmacol.

172, 5729–6202.

Baker, E.H., Pryce Roberts, A., Wilde, K., et al., 2011. Development

of a core drug list towards improving prescribing education and

reducing errors in the UK. Br. J. Clin. Pharmacol. 71, 190–198.

Katritch, V., Cherezov, V., Stevens, R.C., 2012. Diversity and

modularity of G protein-coupled receptor structures. Trends

Pharmacol. Sci. 33, 17–27.

Kenakin, T., 2004. Principles: receptor theory in pharmacology.

Trends Pharmacol. Sci. 25, 186–192.

Keravis, T., Lugnier, C., 2012. Cyclic nucleotide phosphodiesterase

(PDE) isozymes as targets of the intracellular signalling network:

benefits of PDE inhibitors in various diseases and perspectives

for future therapeutic developments. Br. J. Pharmacol. 165,

1288–1305.

Khilnani, G., Khilnani, A.J., 2011. Inverse agonism and its

therapeutic significance. Indian J. Pharmacol. 43, 492–501.

Luttrell, L.M., 2014. More than just a hammer: ligand ‘bias’ and

pharmaceutical discovery. Mol. Endocrinol. 28, 281–294.

Maxwell, S., Walley, T., 2003. Teaching safe and effective

prescribing in UK medical schools: a core curriculum for

tomorrow’s doctors. Br. J. Clin. Pharmacol. 55, 496–503.

Rosenbaum, D.M., Rasmussen, S.G.F., Kobilka, B.K., 2009. The

structure and function of G-protein-coupled receptors. Nature

459, 356–363.

Schöneberg, T., Kleinau, G., Brüser, A., 2016. What are they

waiting for? – Tethered agonism in G protein-coupled receptors.

Pharmacol. Res. http://dx.doi.org/10.1016/j.phrs.2016.03.027.

Wang, L., McLeod, H.L., Weinshilboum, R.M., 2011. Genomics and

drug response. N. Engl. J. Med. 364, 1144–1153.

Principles of pharmacology and mechanisms of drug action 23

Examples of cell surface receptor families and their properties

This is a reference list of members of important families of GPCRs, LGICs and VGICs, many of which are therapeutic drug

targets. Examples of agonists and antagonists are also shown; these include endogenous ligands and some drugs not

currently in clinical use. For further information see the relevant sections of Alexander, S.P.H., et al., 2015. IUPHAR/BPS

concise guide to pharmacology 2015–16. Br. J. Pharmacol. 172, 5729–6202 (available at http://guidetopharmacology.org).

For examples of important intracellular receptors and enzymes targeted by therapeutic drugs, see Tables 1.2 and 1.4.

Type Typical

location(s)

Principal

transduction

mechanism

Major biological

actions

Agonists Antagonists

G-protein-coupled receptors (GPCRs)

Cholinergic

Muscarinic

M1 CNS, salivary,

gastric; minor role in

autonomic ganglia

Gq Neurotransmission

in CNS, gastric

secretion

Nonselective for

all M receptors:

carbachol

Pirenzepine

Nonselective for

all M receptors:

atropine,

ipratropium,

oxybutynin,

tolterodine

M2 Heart, CNS Gi Bradycardia,

smooth muscle

contraction (GI tract,

airways, bladder)

M3 Smooth muscles,

secretory glands,

CNS

Gq Contraction,

secretion

I Darifenacin,

tiotropium

M4 CNS Gi Unclear

M5 CNS Gq Unclear

Adrenergic

α-Adrenoceptors

α1 (α1A, α1B,

α1D)

CNS, postsynaptic

in sympathetic

nervous system,

human prostate (α1A)

Gq Contraction of

arterial smooth

muscle, decrease

in contractions of

gut, contraction of

prostate tissue

Phenylephrine,

methoxamine, NA

≥ Adr

Prazosin,

indoramin

(tamsulosin α1A)

α2 (α2A, α2B,

α2C)

Presynaptic (in both

α- and β-adrenergic

neurons)

Gi Decreased NA

release

Clonidine, Adr > NA

(oxymetazoline α2A)

Yohimbine

β-Adrenoceptors

β1 CNS, heart (nodes

and myocardium),

kidney

Gs Increased force

and rate of cardiac

contraction, renin

release

Dobutamine, NA

> Adr

Atenolol,

metoprololol

β2 Bronchial smooth

muscle, also

widespread

Gs Bronchodilation,

decrease in

contraction of gut,

glycogenolysis

Salbutamol,

salmeterol,

terbutaline, Adr >

NA

Butoxamine

β3 Adipocytes, bladder Gs Lipolysis, bladder

emptying

Adr = NA –

Cannabinoids

CB1 Cortex,

hippocampus,

amygdala, basal

ganglia, cerebellum

Gi/o Behaviour,

pain, nausea,

stimulation of

appetite, addiction,

depression,

hypotension

Tetrahydrocannabinol,

anandamide,

2-arachidonylglycerol

Rimonabant

1 24 Medical Pharmacology and Therapeutics

CB2 Leucocytes,

osteocytes

Gi/o Immunity, bone

growth

Tetrahydrocannabinol

Dopamine

D1 CNS (N, O, P,

S – see footnote for

key to CNS areas),

kidney, heart

Gs Vasodilation in

kidney

Fenoldepam Chlorpromazine

D2 CNS (C, N, O, SN),

pituitary gland,

chemoreceptor

trigger zone,

gastrointestinal tract

Gi Cognition

(schizophrenia),

prolactin secretion,

nigrostrial control of

movement, memory

Cabergoline,

pramipexole,

ropinirole, rotigotine

Butyrophenones,

chlorpromazine

domperidone,

metoclopramide,

sulpiride

D3 CNS (F, Me, Mi)

(limbic system)

Gi Cognition, emotion Cabergoline,

pramipexole,

ropinirole, rotigotine

Chlorpromazine,

sulpiride

D4 CNS, heart Gi Cognition

(schizophrenia)

Cabergoline,

ropinirole, rotigotine

Chlorpromazine,

clozapine

D5 CNS (Hi, Hy) Gs Similar to D1

5-Hydroxytryptamine (5-HT, serotonin)

5-HT1A CNS, blood vessels Gi Anxiety, appetite,

mood, sleep

Buspirone

5-HT1B CNS, blood vessels Gi Vasoconstriction

presynaptic

inhibition

Sumatriptan,

eletriptan

5-HT1D CNS, blood vessels Gi Anxiety,

vasoconstriction

Sumatriptan,

eletriptan

Metergoline

5-HT1E CNS, blood vessels Gi

5-HT1F CNS Gi Sumatriptan,

eletriptan

5-HT2A CNS, GI tract,

platelets, smooth

muscle

Gq Schizophrenia,

platelet aggregation,

vasodilation/

vasoconstriction

LSD, psilocybin Ketanserin,

atypical

antipsychotics,

e.g. olanzapine

5-HT2B CNS, GI tract,

platelets

Gq Contraction,

morphogenesis

5-HT2C CNS, GI tract,

platelets

Gq Satiety

5-HT4 CNS, myenteric

plexus, smooth

muscle

Gs Anxiety, memory,

gut motility

Metoclopramide,

renzapride

5-HT5a CNS Gi Anxiety, memory,

mood

5-HT6 CNS Gs Anxiety, memory,

mood

5-HT7 CNS, GI, blood

vessels

Gs Anxiety, memory,

mood

LSD

Histamine

H1 CNS, endothelium,

smooth muscle

Gq Sedation,

sleep, vascular

permeability,

inflammation

Cetirizine,

desloratadine

Examples of cell surface receptor families and their properties (cont’d)

Type Typical

location(s)

Principal

transduction

mechanism

Major biological

actions

Agonists Antagonists

Principles of pharmacology and mechanisms of drug action 25

H2 CNS, cardiac

muscle, stomach

Gs Gastric acid

secretion

Dimaprit Cimetidine,

ranitidine

H3 CNS (presynaptic),

myenteric plexus

Gi Appetite, cognition Thioperamide

H4 Eosinophils,

basophils, mast

cells

Gi 4-Methylhistamine

Gamma-aminobutyric acid receptor type B (GABAB)

GABAB Brain neurons,

glial cells, spinal

motor neurons and

interneurons

Gi Inhibition of

neurotransmission

in brain and spinal

cord

Baclofen

Peptides

Angiotensin II

AT1 Blood vessels,

adrenal cortex, brain

Gq/Go Vasoconstriction,

salt retention,

aldosterone

synthesis, increased

noradrenergic

activity, cardiac

hypertrophy

Candesartan,

losartan,

valsartan

AT2 Blood vessels,

endothelium,

adrenal cortex, brain

Gi/o, tyrosine

and ser/thr

phosphatases

Weak vasodilation

(endothelial nitric

oxide release),

foetal development,

vascular growth

Bradykinin

B1

(induced)

Widespread

(induced by injury,

cytokines)

Gq Acute inflammation;

stimulates nitric

oxide synthesis

ACE inhibitors

(indirect, by

blocking bradykinin

breakdown)

B2

(constitutive)

Gq Chronic

inflammation.

Most kinin actions

(vasodilation, pain)

Icatibant

Endothelin

ETA Endothelium Gq Vasoconstriction,

angiogenesis

Bosentan

ETB Endothelium Gq, Gi Indirect vasodilation

(nitric oxide

release), direct

vasoconstriction,

natriuresis

Bosentan

Opioids

DOP (δ),

KOP (κ),

MOP (μ),

nociception

Brain, spinal cord,

peripheral sensory

neurons

Gi Analgesia, sedation,

respiratory

depression

Endogenous

opioids, opioid

drugs (morphine)

Naloxone,

naltrexone

Protease-activated receptors

PAR1,

PAR2,

PAR3, PAR4

Platelets, endothelial

cells, epithelial cells,

myocytes, neurons

Gq, Gi Activated by

proteolytic cleavage

Trypsin, thrombin,

tryptase

Examples of cell surface receptor families and their properties (cont’d)

Type Typical

location(s)

Principal

transduction

mechanism

Major biological

actions

Agonists Antagonists

1 26 Medical Pharmacology and Therapeutics

Vasopressin and oxytocin

Vasopressin

V1a

Brain, uterus, blood

vessels, platelets

Gq Vasoconstriction,

platelet aggregation

Desmopressin Conivaptan,

demeclocycline

Vasopressin

V1b

Pituitary, brain Gq Modulates ACTH

secretion

Desmopressin Conivaptan,

demeclocycline

Vasopressin

V2

Kidney Gs Antidiuretic effect

on collecting duct

and ascending limb

of loop of Henle

Desmopressin Conivaptan

demeclocycline,

tolvaptan

Oxytocin

OXT

Brain, uterus Gq, Gi Lactation, uterine

contraction, CNS

actions (mood)

Oxytocin > arginine-

vasopressin

Atosiban

Purinergic receptors (purinoceptors)

Adenosine

A1

Heart, lung Gi Cardiac depression,

vasoconstriction,

bronchoconstriction

Methylxanthines

Adenosine

A2A

Widespread Gs Vasodilation,

inhibition of platelet

aggregation,

bronchodilation

Regadenoson Methylxanthines

Adenosine

A2B

Leucocytes Gs Bronchoconstriction Methylxanthines

Adenosine

A3

Leucocytes Gi Inflammatory

mediator release

Methylxanthines

Purinergic

P2Y family

(P2Y1,

P2Y2, P2Y4,

P2Y6,

P2Y11–

P2Y14)

Widespread Gq, Gs or Gi Depends upon

G-protein coupling

ATP, ADP, UTP,

UDP, UDP-glucose

P2Y12:

clopidogrel,

ticlopidine

Ligand-gated ion channels (LGICs)

Nicotinic N1 Autonomic ganglia LGIC Ganglionic

neurotransmission

Carbachol, nicotine Trimetaphan,

mecamylamine

Nicotinic N2 Neuromuscular

junction

LGIC Skeletal muscle

contraction

Nicotine,

suxamethonium

(depolarising)

Gallamine,

vecuronium,

atracurium

Serotonin

5-HT3

CNS (A), enteric

nerves, sensory

nerves

Ligand-gated

Na+

/K+

channel

Emesis Granisetron,

ondansetron,

metoclopramide

GABAA Brain neurons,

spinal motor

neurons and

interneurons

Ligand-gated

Cl−

channel

(open)

Inhibition of

neurotransmission

in brain and spinal

cord

Muscimol,

barbiturates,

benzodiazepines,

zolpidem

Picrotoxin,

flumazenil

(benzodiazepine

antagonist)

Glycine

GlyR

Brain neurons,

spinal motor

neurons and

interneurons

Ligand-gated

Cl−

channel

(open)

Inhibition of

neurotransmission

in brain and spinal

cord

Intravenous

anaesthetics,

alanine, taurine

Strychnine,

caffeine,

tropisetron,

endocannabinoids

Ionotropic

glutamate

(NMDA)

receptor

CNS (B, C, sensory

pathways)

Ligand-gated

Ca2+

channel

(slow)

Synaptic plasticity,

excitatory

transmitter release;

excessive amounts

may cause neuronal

damage

NMDA Ketamine,

phencyclidine,

memantine

Examples of cell surface receptor families and their properties (cont’d)

Type Typical

location(s)

Principal

transduction

mechanism

Major biological

actions

Agonists Antagonists

Principles of pharmacology and mechanisms of drug action 27

Ionotropic

glutamate

(kainate)

receptor

CNS (Hi) Ligand-gated

Ca2+

channel

(fast)

Synaptic plasticity,

transmitter release

Kainate Topiramate

Ionotropic

glutamate

(AMPA)

receptor

CNS (similar to

NMDA receptors)

Ligand-gated

Ca2+

channel

(fast)

Synaptic plasticity,

transmitter release

AMPA Topiramate

Purinergic

P2X family

(P2X1–P2X7)

CNS, autonomic

nervous system

(P2X2), smooth

muscle (P2X1),

leucocytes

LGICs (Na+

,

Ca2+

, K+

)

Neuronal

depolarisation, influx

of Na+

and Ca2+

,

efflux of K+

ATP Suramin

Voltage-gated ion channels (VGICs)

Epithelial

sodium

channel

(ENaC)

Renal tubule,

airways, colon

Na+

channel,

tonically open

Sodium

reabsorption in

aldosterone-

sensitive distal

tubule and

collecting duct

Expression

upregulated by

aldosterone

Amiloride,

triamterene

L-type

calcium

channels

(Cav1.1–1.4)

Widespread Voltage-gated

Ca2+

channels

(dihydropyridine-

sensitive)

Vascular and

cardiac smooth

muscle contraction,

prolong cardiac

action potential

Nifedipine,

amlodipine,

diltiazem,

verapamil

Ryanodine

(RyR1,

RyR2,

RyR3)

Skeletal muscle

(RyR1), heart

(RyR2), widespread

(RyR3)

Ca2+

channels Calcium-induced

Ca2+

release (CICR)

Cytosolic Ca2+

, ATP,

ryanodine, caffeine

Dantrolene

Abbreviations: ACE, Angiotensin-converting enzyme; ACTH, adrenocorticotropic hormone (corticotropin); Adr, adrenaline; AMPA, α-amino-

3-hydroxy-5-methyl-4-isoxazole propionic acid; CNS, central nervous system; GI, gastrointestinal; LSD, lysergic acid diethylamide; NA,

noradrenaline; NMDA, N-methyl D-aspartate.

Key to CNS areas: A, Area postrema; B, basal ganglia; C, caudate putamen; F, frontal cortex; Hi, hippocampus; Hy, hypothalamus; Me,

medulla; Mi, midbrain: N, nucleus accumbens; O, olfactory tubercle; P, putamen; S, striatum; SN, substantia nigra.

Examples of cell surface receptor families and their properties (cont’d)

Type Typical

location(s)

Principal

transduction

mechanism

Major biological

actions

Agonists Antagonists

1 28 Medical Pharmacology and Therapeutics

Appendix: student formulary

This student formulary used for educational purposes at Southampton University Faculty of Medicine is adapted from

the formulary originally described by Maxwell and Walley (Br. J. Clin. Pharmacol. 2003; 55:496–503). See also the lists of

commonly prescribed drugs in Baker et al. (Br. J. Clin. Pharmacol. 2011; 71:190–198) and the World Health Organisation

(WHO) Model List of Essential Medicines (www.who.int/medicines/publications/essentialmedicines/en/).

Therapeutic problem Core drugs

Gastrointestinal system

Emergency treatment of poisoning Adsorbant: activated charcoal

Paracetamol antidotes, e.g. acetylcysteine, methionine

Opioid antagonist, e.g. naloxone

Organophosphate antidote, e.g. pralidoxime

Dyspepsia, GORD and gastric

ulcer healing

Antacids, e.g. magnesium salts

Compound alginates, e.g. Gaviscon

Proton pump inhibitors, e.g. omeprazole, lansoprazole

H2 receptor antagonists, e.g. ranitidine, cimetidine

Helicobacter pylori antibiotics: clarithromycin, amoxicillin, metronidazole

Motility stimulants, e.g. metoclopramide

Others: misoprostol, sulcralfate

Inflammatory bowel disease

(ulcerative colitis, Crohn’s

disease)

Corticosteroids, e.g. prednisolone

Aminosalicylates, e.g. sulfasalazine, mesalazine

Cytokine inhibitors, e.g. infliximab

Antibiotic-associated colitis Antibiotics for Clostridium difficile, e.g. metronidazole, vancomycin

Diarrhoea Oral rehydration therapy

Opiate antimotility drugs, e.g. loperamide

Constipation Bulk-forming laxatives, e.g. ispaghula, methylcellulose

Stimulant laxatives, e.g. senna, docusate

Osmotic laxatives, e.g. magnesium hydroxide, lactulose

Antispasmodics Antimuscarinics, e.g. atropine, hyoscine

Others: mebeverine

Cardiovascular system

Hypertension β-Adrenoceptor antagonists, e.g. atenolol

α-Adrenoceptor antagonists, e.g. doxazosin

Centrally acting drugs, e.g. clonidine

Angiotensin-converting enzyme (ACE) inhibitors, e.g. captopril, ramipril, perindopril

Angiotensin receptor antagonists, e.g. candesartan, losartan

Thiazide diuretics, e.g. bendroflumethazide, indapamide

Loop diuretics, e.g. furosemide

Potassium-sparing diuretics, e.g. amiloride, spironolactone

Compound potassium-sparing diuretic: co-amilofruse

Calcium channel antagonists, e.g. nifedipine verapamil

Potassium channel openers, e.g. minoxidil, nicorandil

Heart failure Many of the above plus the following positive inotropic drugs:

Cardiac glycosides, e.g. digoxin

PDE inhibitors, e.g. milrinone

β-Adrenoceptor antagonist: bisoprolol

Acute coronary syndrome (angina,

myocardial infarction)

Many drugs listed under hypertension plus the following:

Inhibitors of platelet aggregation, e.g. low-dose aspirin, dipyridamole, clopidogrel,

abciximab

Thrombolytics, e.g. streptokinase, tenecteplase

Heparin (unfractionated)

Heparins (low molecular weight), e.g. enoxaparin

Oral anticoagulants, e.g. warfarin

Hyperlipidaemia Statins, e.g. simvastatin, atorvastatin, pravastatin, rosuvastatin

Fibrates, e.g. gemfibrozil, fenofibrate

Arrhythmias Antiarrhythmic drugs, e.g. digoxin, adenosine, amiodarone, lidocaine, β-adrenoceptor

antagonists, calcium channel blockers

Principles of pharmacology and mechanisms of drug action 29

Respiratory system

Asthma, COPD, respiratory failure Oxygen

β2-Adrenoceptor agonists, e.g. salbutamol, salmeterol

Antimuscarinics, e.g. ipratropium, tiotropium

Methylxanthines, e.g. theophylline, aminophylline

PDE type 4 inhibitor, e.g. roflumilast

Leukotriene antagonists, e.g. montelukast

Antiallergic drugs, e.g. cromoglicate, nedocromil

Magnesium sulphate

Inhaled corticosteroids, e.g. beclometasone, fluticasone

Oral corticosteroid, e.g. prednisolone

β2-Agonist/corticosteroid coformulations, e.g. Seretide

Allergy, anaphylaxis Antihistamines, e.g. cetirizine, loratadine

Adrenaline, e.g. Epipen

Cough suppression Dextromethorphan, codeine

Central nervous system

Insomnia, anxiety Benzodiazepines, e.g. temazepam, diazepam

Z-drugs, e.g. zopiclone, zolpidem

Others, e.g. buspirone, propranolol

Schizophrenia, mania Classical antipsychotics, e.g. chlorpromazine, haloperidol, flupentixol

Atypical antipsychotics, e.g. olanzapine, risperidone, quetiapine

Depot preparations, e.g. fluphenazine decanoate

Mood stabilisers, e.g. lithium

Depression Tricyclic antidepressants (TCAs), e.g. amitriptyline

Selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine, citalopram, sertraline

Serotonin-noradrenaline reuptake inhibitors, e.g. venlafaxine

Monoamine oxidase-B inhibitors, e.g. moclobemide

Others, e.g. mirtazepine

Analgesia Nonsteroidal anti-inflammatory drugs (NSAIDs): see section on musculoskeletal

disease

Compound analgesics, e.g. co-codamol, co-dydramol

Moderately potent opioid analgesics, e.g. tramadol

Potent opioid analgesics, e.g. codeine, morphine, fentanyl

Nausea and vertigo Dopamine antagonists, e.g. metoclopramide

Serotonin receptor antagonists, e.g. ondansetron

Muscarinic receptor antagonists, e.g. hyoscine

Others: betahistine

Migraine Acute: 5-HT1 receptor agonists, e.g. sumatriptan

Prophylaxis: β-adrenoceptor antagonists, e.g. propranolol

Epilepsy Anticonvulsant drugs, e.g. diazepam, carbamazepine, clonazepam, ethosuximide,

gabapentin, lamotrigine, phenytoin, tiagabine, valproate

Parkinson’s disease Levodopa/DOPA decarboxylase coformulations, e.g. co-careldopa, co-beneldopa

Dopamine receptor agonists, e.g. ropinirole

COMT inhibitors, e.g. entacapone

MAO-B inhibitors: selegiline, rasagiline

Antimuscarinic drugs, e.g. procyclidine

Dementia (Alzheimer’s) Anticholinesterases, e.g. donepezil

NMDA receptor antagonists, e.g. memantine

Appendix: student formulary (cont’d)

Therapeutic problem Core drugs

1 30 Medical Pharmacology and Therapeutics

Infectious diseases

Community- and hospital-acquired

infections

Penicillins, e.g. benzylpenicillin

Penicillinase-resistant penicillins, e.g. flucloxacillin

Broad-spectrum penicillins, e.g. amoxicillin, co-amoxiclav

Cephalosporins, e.g. cefalexin, cefuroxime

Tetracyclines, e.g. oxytetracycline

Folate inhibitors, e.g. trimethoprim

Aminoglycosides, e.g. gentamicin

Vancomycin (for C. difficile)

Macrolides, e.g. erythromycin

Chloramphenicol

Quinolones, e.g. ciprofloxacin

Metronidazole (for anaerobes and protozoans)

Antituberculosis drugs, e.g. isoniazid, rifampicin, ethambutol

Antifungal drugs, e.g. amphotericin, fluconazole, miconazole, terbinafine

Viral DNA polymerase inhibitors, e.g. aciclovir (herpes), ganciclovir (CMV)

Neuraminidase inhibitors, e.g. zanamivir (influenza)

Nucleoside reverse transcriptase inhibitors, e.g. zidovudine, abacavir

Nonnucleotide reverse transcriptase inhibitors, e.g. efavirenz

HIV protease inhibitors, e.g. saquinavir

Antimalarial drugs, e.g. mefloquine, proguanil, malarone

Endocrine system

Diabetes mellitus, thyroid disease

and hypothalamo pituitary

hormones

Insulins (long- and short-acting)

Secretagogues

Sulfonylureas, e.g. gliclazide

Meglitinides, e.g. repaglinide

DPP4 inhibitors, e.g. saxagliptin

GLP agonists, e.g. exenatide

Sensitisers:

Biguanides, e.g. metformin

Thiazolidinediones, e.g. pioglitazone

Thyroid disease, e.g. levothyroxine, carbimazole

ADH mimetics, e.g. desmopressin

LHRH, e.g. gonadorelin

Human growth hormone, e.g. somatropin

Osteoporosis Calcium, vitamin D, calcitonin, parathyroid hormone, teriparatide

Bisphosphonates, e.g. alendronic acid, risedronate

Selective estrogen receptor modulators (SERMs), e.g. clomifene

Genitourinary system

Urinary retention, benign prostatic

hypertrophy and prostate cancer

α1-Adrenoceptor antagonists, e.g. doxazosin

5α-Reductase inhibitors, e.g. finasteride

Antiandrogens, e.g. flutamide

Urinary frequency/incontinence Antimuscarinic drugs, e.g. darifenacin, fesoterodine

Erectile dysfunction PDE5 inhibitors, e.g. sildenafil, tadalafil

Obstetrics and gynaecology

Steroidal contraception Combined hormonal contraceptives (oral, transdermal patch)

Progestogen-only contraceptives (oral, subdermal implant)

Progestogen-containing intrauterine device

Emergency contraception, e.g. levonorgestrel, ulipristal

Injectable contraception, e.g. medroxyprogesterone acetate

Dysmenorrhoea` Combined oral hormonal contraceptives

NSAIDs, e.g. mefenamic acid

Menorrhagia Antifibrinolytic agent, e.g. tranexamic acid

Progestogen-containing intrauterine device

Endometriosis Progestins

Gonadorelin analogues, e.g. goserelin

Danazol

Appendix: student formulary (cont’d)

Therapeutic problem Core drugs

Principles of pharmacology and mechanisms of drug action 31

Induction of labour Oxytocics, e.g. oxytocin

Prostaglandin analogues, e.g. gemeprost

Prevention of pre-term labour

(tocolysis)

Calcium channel blockers, e.g. nifedipine

β-Adrenoceptor agonists, e.g. terbutaline

Induction of abortion Oxytocics, mifepristone

Antiprogestogen, e.g. mifepristone

Prostaglandin analogues, e.g. gemeprost

Postpartum haemorrhage Oxytocics, ergometrine

Menopause Oestrogens (with progestins)

Others: tibolone, raloxifene

Malignant disease and immunosuppression

Cancer and immunosuppression Alkylating agents, e.g. cyclophosphamide

Cytotoxic antibiotics, e.g. doxorubicin

Antimetabolites, e.g. methotrexate, fluorouracil

Vinca alkaloids, e.g. vinblastine

Taxanes, e.g. paclitaxel

Tyrosine kinase inhibitors, e.g. gefitinib, imatinib

Topoisomerase I and II inhibitors, e.g. irinotecan, etoposide

Other cytotoxic drugs, e.g. crisantaspase, cisplatin

Antioestrogens, e.g. tamoxifen, anastrazole

Immunosuppressant drugs, e.g. azathioprine, corticosteroids, ciclosporin

Immunobiologicals, e.g. rituximab (anti-B-lymphocyte CD20), interferon alfa,

bevacizumab (anti-VEGF), trastuzumab (anti-HER2)

Musculoskeletal disease

Rheumatoid arthritis NSAIDs, e.g. indometacin, diclofenac

Corticosteroids, e.g. prednisolone

Immunosuppressants, e.g. methotrexate, azathioprine, leflunomide

Cytokine (TNFα) modulators, e.g. adalimumab, etanercept, golimumab, infliximab

Others: gold, penicillamine, sulfasalazine, hydroxychloroquine

Myasthenia gravis Anticholinesterases, e.g. pyridostigmine

Spasticity Skeletal muscle relaxants, e.g. baclofen, dantrolene

Gout Acute: colcichine; chronic: allopurinol

Ophthalmology

Glaucoma β-Adrenoceptor antagonists, e.g. timolol

Prostaglandin analogues, e.g. latanoprost

Sympathomimetics (α2-agonists), e.g. brimonidine

Carbonic anhydrase inhibitors, e.g. acetazolamide

Miotics, e.g. pilocarpine

Conjunctivitis Topical antibiotics, e.g. chloramphenicol

Tear deficiency Ocular lubricants, e.g. hypromellose

Others Mydriatics, e.g. phenylephrine

Mydriatics/cycloplegics, e.g. atropine, tropicamide

Topical formulations (eye drops) of many drugs, including anti-inflammatory

corticosteroids (e.g. betamethasone), antivirals and local anaesthetics (e.g. tetracaine)

Surgery, anaesthetics and intensive care

Surgery, anaesthetics and

intensive care

Many drugs used are listed in other sections, including opioid analgesics,

sympathomimetics and antiemetics, plus the following:

Intravenous (induction) anaesthetics, e.g. thiopental, propofol

Inhalation (maintenance) anaesthetics, e.g. isoflurane

Muscle relaxants, e.g. suxamethonium, atracurium

Antimuscarinics, e.g. atropine, glycopyrronium

Anticholinesterases, e.g. neostigmine

Local anaesthetics, e.g. lidocaine, bupivacaine

Abbreviations: ADH, Antidiuretic hormone; CMV, cytomegalovirus; COMT, catechol-O-methyltransferase; COPD, chronic obstructive pulmonary

disease; DPP4, dipeptidyl peptidase 4; GLP, glucagon-like peptide; GORD, gastro-oesophageal reflux disease; HER2, human epidermal

growth factor receptor 2; LHRH, luteinising hormone-releasing hormone; MAO-B, monoamine oxidase B; NMDA, N-methyl D-aspartate; NSAID,

nonsteroidal anti-inflammatory drug; PDE, phosphodiesterase; TNFα, tumour necrosis factor alpha; VEGF, vascular endothelial growth factor.

Appendix: student formulary (cont’d)

Therapeutic problem Core drugs

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2 Pharmacokinetics

The biological basis of pharmacokinetics 33

General considerations 34

Absorption 38

Absorption from the gut 38

Absorption from other routes 39

Distribution 39

Reversible protein binding 40

Irreversible protein binding 41

Distribution to specific organs 41

Elimination 42

Metabolism 42

Excretion 45

The mathematical basis

of pharmacokinetics 48

General considerations 48

Absorption 49

Rate of absorption 49

Extent of absorption 50

Distribution 51

Rate of distribution 51

Extent of distribution 52

Elimination 53

Rate of elimination 53

Extent of elimination 54

Chronic administration 54

Time to reach steady state 55

Plasma concentration at steady state 55

Oral administration 55

Loading dose 56

Pharmacokinetics of biological drugs 56

Genetic variation and pharmacokinetics 56

Self-assessment 57

Answers 60

Further reading 62

Pharmacokinetics refers to the movement of drugs into,

through and out of the body. The type of response of an

individual to a particular drug depends on the inherent

pharmacological properties of the drug at its site of action.

However, the speed of onset, the intensity and the duration

of the response usually depend on parameters such as:

■ the rate and extent of uptake of the drug from its site of

administration;

■ the rate and extent of distribution of the drug to different

tissues, including the site of action;

■ the rate of elimination of the drug from the body.

Overall, the response of an individual to a drug depends

upon a combination of the effects of the drug at its site

of action in the body called pharmacodynamics (or ‘what the

drug does to the body’) and the way the body influences drug

delivery to its site of action (pharmacokinetics, or ‘what the

body does to the drug’; Fig. 2.1). Both pharmacodynamic

and pharmacokinetic aspects are subject to a number of

variables, which affect the dose–response relationship.

Pharmacodynamic aspects are determined by processes

such as drug–receptor interaction and are specific to the class

of the drug (see Chapter 1). These aspects are determined

by general processes, such as transfer across membranes,

metabolism and renal elimination, which apply irrespective

of the pharmacodynamic properties.

Pharmacokinetics may be divided into four basic processes,

sometimes referred to collectively as ‘ADME’:

■ Absorption. The transfer of the drug from its site of

administration to the general circulation

■ Distribution. The transfer of the drug from the general

circulation into the different organs of the body

■ Metabolism. The extent to which the drug molecule is

chemically modified in the body

■ Excretion. The removal of the parent drug and any

metabolites from the body; metabolism and excretion

together account for drug elimination.

This chapter will first describe each of these processes

qualitatively in biological terms, and then in mathematical

terms, which determine many of the quantitative aspects

of drug prescribing.

THE BIOLOGICAL BASIS OF

PHARMACOKINETICS

Most drug structures bear little resemblance to normal dietary

constituents such as carbohydrates, fats and proteins, and

they are handled in the body by different processes. Drugs

that bind to the same receptor as an endogenous ligand rarely

resemble the natural ligand sufficiently closely in chemical

structure to share the same carrier processes or metabolising

1 34 Medical Pharmacology and Therapeutics

enzymes. Consequently, the movement of drugs in the tissues

is mostly by simple passive diffusion rather than by specific

transporters, whereas metabolism is usually by enzymes of

low substrate specificity that can handle a wide variety of

drug substrates and other xenobiotics (foreign substances).

GENERAL CONSIDERATIONS

Passage across membranes

With the exception of intravenous or intra-arterial injections,

a drug must cross at least one membrane in its movement

from the site of administration into the general circulation.

Drugs acting at intracellular sites must also cross the cell

membrane to exert an effect. The main mechanisms by

which drugs can cross membranes (Fig. 2.2) are:

■ passive diffusion through the lipid layer,

■ diffusion through pores or ion channels,

■ carrier-mediated processes,

■ pinocytosis.

Passive diffusion

All drugs can move passively down a concentration gradient.

To cross the phospholipid bilayer directly (see Fig. 2.2),

a drug must have a degree of lipid solubility, such as

ethanol or steroids. Eventually a state of equilibrium will

be reached in which equal concentrations of the diffusible

form of the drug are present in solution on each side of the

membrane. The rate of diffusion is directly proportional to

the concentration gradient across the membrane, and to

the area and permeability of the membrane, but inversely

proportional to its thickness (Fick’s law). In the laboratory,

transient water-filled pores can be created in the phospholipid

Pharmacology

Pharmacodynamics

Dose–response relationship

Pharmacokinetics

Specific to drug or

drug class

Interaction with cellular

component, e.g. receptor

or target site

Effects at the site of action

Concentration–effect

relationship

Reduction in symptoms

Modification of disease

progression

Unwanted effects

Drug interactions

Inter- and intraindividual

differences

Absorption from the site

of administration

Delivery to the site of

action

Elimination from the body

Time to onset of effect

Duration of effect

Accumulation on repeat

dosage

Drug interactions

Inter- and intraindividual

differences

Nonspecific, general

processes

Fig. 2.1 Factors determining the response of an

individual to a drug.

Extracellular fluid D

D

D

D

D

D

D

D

Closed

ion channel

Passive diffusion

through lipid

bilayer (lipid-

soluble drugs)

Diffusion

through open

ion channel

(small molecules,

water-soluble drugs)

Facilitated

diffusion

(SLC transporters)

(nutrients, e.g.,

glucose, and some

amine

neurotransmitters)

Active

transport

(ABC transporters)

(numerous drugs,

see Table 2.1)

ATP

ADP

NBD

TMD TMD TMD

NBD

Fig. 2.2 The passage of drugs across membranes. Molecules can cross the membrane by simple passive diffusion

through the lipid bilayer or via a channel, or by facilitated diffusion, or by ATP-dependent active transport. ABC, ATP-binding

cassette superfamily of transport proteins; D, drug; NBD, nucleotide-binding domain; SLC, solute carrier superfamily of

transporters; TMD, transmembrane domain (see Table 2.1).

Pharmacokinetics 35

5-HT), noradrenaline, histamine and agmatine; although some

drugs are substrates for the transporters (see Table 2.1),

many basic drugs act as inhibitors of the transporters.

Members of the ABC and SLC transporter families are

therefore important in many of the processes by which

drugs are absorbed in the gut, distributed into tissues and

eliminated in the liver or kidney. Interactions between drugs

at the same transporter, or between drugs and the natural

substrates of the transporter, may contribute to variation in

kinetic parameters for individual drugs between patients and

over time. Genetic variation in the expression and functioning

of transporters may also contribute to drug toxicity.

Pinocytosis

This can be regarded as a form of carrier-mediated entry

into the cell cytoplasm. Pinocytosis is normally concerned

with the uptake of endogenous macromolecules and may be

involved in the uptake of recombinant therapeutic proteins;

drugs can also be incorporated into a lipid vesicle or liposome

for pinocytotic uptake (e.g. amphotericin and doxorubicin;

see Chapter 51).

Drug ionisation and membrane

diffusion

Ionisation is a fundamental property of most drugs that are

either weak acids, such as aspirin, or weak bases, such as

propranolol. The presence of an ionisable group(s) is essential

for the mechanism of action of most drugs, because ionic

forces represent a key part of ligand–receptor interactions

(see Chapter 1). The extent of ionisation may also influence

the extent of absorption of a drug, its distribution into organs

such as the brain or adipose tissue, and the mechanism and

route of its elimination from the body.

Drugs with ionisable groups exist in equilibrium between

charged (ionised) and uncharged (un-ionised) forms (Fig. 2.3).

The extent of ionisation of a drug depends on the strength

of the ionisable group and the pH of the solution. The extent

of ionisation is given by the acid dissociation constant, Ka.

Ka

conjugate base H

conjugate acid =

+ [ ][ ]

[ ] (2.1)

The term conjugate acid refers to a form of the drug able

to release a proton, such as:

■ an un-ionised acidic drug (Drug–COOH), or

■ an ionised basic drug (Drug–NH3

+

).

The conjugate base is the corresponding equilibrium form

of the drug that has lost a proton, such as:

■ an ionised acidic drug (Drug–COO−

), or

■ an un-ionised basic drug (Drug–NH2).

The value of Ka is normally much less than 1, so it is

easier to compare compounds using the negative logarithm

of Ka, which is called pKa. For example, a Ka of 10−5

becomes

pKa 5, and a Ka of 10−10 becomes pKa 10. Based on the

equation given previously, a strong acid (such as an −SO3H

functional group) that readily donates its H+

ion will have a

relatively high Ka value (e.g. 10−1

or 10−2

) and hence a low

pKa (i.e. 1 or 2), whereas weakly acidic groups, which donate

their H+

ion less readily, have a pKa of 4–5. Conversely, for

basic functional groups, the stronger the base, the greater

bilayer by applying a strong external electric field, and this

process (electroporation) is used to introduce large or charged

molecules, such as DNA, drugs and probes into live cells

in suspension.

Passage through membrane pores or

ion channels

Movement through channels occurs down a concentration

gradient and is restricted to extremely small water-soluble

molecules (<100 Da), such as ions. This is applicable to

therapeutic ions such as lithium and also to radioactive iodine.

Water itself crosses membranes rapidly via a ubiquitous

family of aquaporins.

Carrier-mediated processes

Two carrier-mediated processes are of widespread importance

in the transport of drugs, particularly those with low lipid

solubility, across membranes.

Active transport utilises energy (adenosine triphosphate

[ATP]) and transports drugs into or out of cells against their

concentration gradient. It is performed particularly by a family

of nonspecific carriers termed the ATP-binding cassette (ABC)

superfamily of membrane transporters (see Fig. 2.2 and Table

2.1). In humans, the ABC active-transporter superfamily

contains 49 members organised into seven subfamilies

(A–G) based on their relative sequence homology. Interest

in this area has expanded rapidly since the discovery of

P-glycoprotein (P-gp), also known as multidrug resistance

1 (MDR1) or ABCB1 transporter. P-gp transports a wide

range of drug substrates, including anticancer drugs, steroids

and immunosuppressive agents, from the cytoplasm to the

extracellular side of the cell membrane, and therefore acts as

an efflux transporter. Verapamil increases the concentrations

of anticancer drugs at their intracellular sites of action by

inhibiting P-gp (see Chapter 52). ABCB transporter proteins

contain two hydrophobic transmembrane domains, which

consist of different numbers of membrane-spanning α-helices

(12 in P-gp), and two hydrophilic nucleotide (ATP)-binding

domains, which bind and hydrolyse intracellular ATP. The

transporter is on the apical surface and acts as an efflux pump

that transports substrates from the cell into the interstitial

fluid, plasma, bile, urine or gut lumen. Examples of other

ABC transporters are given in Table 2.1.

Facilitated transport of a molecule by a carrier either aids

its passive movement down its own concentration gradient,

or uses the electrochemical gradient of a co-transported

solute to transport the molecule against its own concentration

gradient; in neither case is the use of ATP required. The

major examples are members of the solute carrier (SLC)

superfamily of transporters (see Fig. 2.2 and Table 2.1).

The SLC superfamily comprises over 300 types of organic

anion transporters (OATs), organic anion-transporting

polypeptides (OATPs), organic cation transporters (OCTs),

organic cation/carnitine transporters (OCTNs), and members

of other transporter families (see Table 2.1). OAT1 to OAT4

are present in various tissues; OAT1 is the classic organic

anion transporter in the kidney, which secretes urate and

penicillins and is blocked by probenecid (see Chapter

31). Organic cation transporters (OCT1, OCT2 and OCT3)

effect facilitated diffusion and can transport cations in both

directions across the membrane. Substrates common to all

three OCT transporters are serotonin (5-hydroxytryptamine,

1 36 Medical Pharmacology and Therapeutics

and most ionised in acid solutions (low pH). In either case,

the ionised form of the molecule can generally be regarded

as the water-soluble form and the un-ionised form as the

lipid-soluble form. The ease with which an ionisable drug

can diffuse across a lipid bilayer is determined by the lipid

solubility of its un-ionised form (Fig. 2.4).

The pH of body fluids is controlled by the buffering

capacity of the ionic groups present in endogenous molecules

its ability to retain the H+

, resulting in low Ka and high pKa

values. Thus strongly basic groups have a pKa of 10–11,

while weakly basic groups have a pKa of 7–8.

Drugs are 50% ionised when the pH of the solution equals

the pKa of the drug. Acidic drugs (low pKa values) are least

ionised in acidic solutions (low pH) and most ionised in

alkaline solutions (high pH). Conversely, basic drugs (high

pKa values) are least ionised in alkaline solutions (high pH),

Table 2.1 Examples of carrier molecules involved in drug transport

Transporter Typical substrates Sites in the body

ABC superfamily ATP-binding cassette superfamily of transport proteins. All use ATP hydrolysis and function

as active efflux or uptake transporters. Although there are a number of transporters in each

family, the four ABC transporters listed here can explain multidrug resistance in most cells

analysed to date.

MDR1 or

P-glycoprotein

(ABCB1)

Hydrophobic and cationic (basic)

molecules; numerous drugs,

including anticancer drugs

Apical surface of membranes of epithelial cells of

intestine, liver, kidney, blood–brain barrier, testis,

placenta and lungs

MRP1 (ABCC1) Numerous, including anticancer

drugs, glucuronide and glutathione

conjugates

Basolateral surface of membranes of most cell types

with high levels in lung, testis and kidney and in

blood–tissue barriers

MRP2 (ABCC2) Numerous, including anticancer

drugs, glucuronide and glutathione

conjugates

Apical surface of membranes; mainly in liver, intestine

and kidney tubules

BCRP (ABCG2)

Breast cancer

resistance protein

Anticancer, antiviral drugs,

fluoroquinolones, flavonoids

Apical surface of breast ducts and lobules, small

intestine, colon epithelium, liver, placenta, brain barrier

and lung

SLC superfamily Solute carrier superfamily of transporters. Comprises organic anion transporters (OATs),

organic anion-transporting polypeptides (OATPs), organic cation transporters (OCTs), organic

cation/carnitine transporters (OCTNs) and many other families. Solute carriers do not use ATP

hydrolysis and most function as uptake transporters

OAT1 (SLC22A6) Anionic drugs, acyclovir, adefovir,

NSAIDs, penicillins, diuretics and

phase 2 drug metabolites

Kidney (basolateral), brain, placenta, smooth muscle

OAT2 (SLC22A7) Anionic drugs, acyclovir, salicylate,

acetylsalicylate, PGE2, dicarboxylates

Kidney (basolateral), liver

OAT3 (SLC22A8) Similar to OAT1 Kidney (basolateral), liver, brain, smooth muscle, testis

OAT4 (SLC22A11) Methotrexate, pravastatin, sulfated

sex steroids

Kidney (apical), placenta

OATP1B1 (SLCO1B1) Pravastatin, rosuvastatin Liver

OATP1B3 (SLCO1B3) Methotrexate, rosuvastatin Liver

OCT1 (SLC22A1) Cationic drugs, serotonin,

noradrenaline, histamine, agmatine,

aciclovir, ganciclovir, metformin

Mainly in the liver, but also in kidney, small intestine,

heart, skeletal muscle and placenta

OCT2 (SLC22A2) Cationic drugs, serotonin,

noradrenaline, histamine, agmatine,

amantadine, metformin, cimetidine

Mainly in the kidney, but also in placenta, adrenal gland,

neurons and choroid plexus

OCT3 (SLC22A3) Cationic drugs, serotonin,

noradrenaline, histamine, agmatine,

metformin

Liver, kidney, intestine, skeletal and smooth muscle,

heart, lung, spleen, neurons, placenta and the choroid

plexus

OCTN1 (SLC22A4) Carnitine, acetylcholine Kidney, intestine

OCTN2 (SLC22A5) Carnitine, choline Kidney, skeletal muscle

ABC, ATP-binding cassette; NSAIDs, nonsteroidal anti-inflammatory drugs; PGE2, prostaglandin E2; SLC, solute carrier.

For details of other ABC and SLC transporters, see Nigam, S.K., 2015. What do drug transporters really do? Nat. Rev. Drug. Discov. 14, 29–44.

Pharmacokinetics 37

it in the plasma. The opposite situation prevails with basic

drugs, which are enabled to diffuse from the plasma into

urine, where they become trapped.

After drug overdose, when the aim is to enhance drug

elimination, alkalinisation of the urine (using intravenous

sodium bicarbonate) can be used to reduce reabsorption of

acidic drugs, such as aspirin, leading to their faster elimination

in the urine. Acidification of the urine (with oral ammonium

chloride) can enhance ionisation and renal elimination of

basic drugs, such as dexamfetamine.

The pH difference between gastric contents (pH 1–2)

and plasma (pH 7.4) affects the absorption of many oral

drugs. The acidity of stomach contents means that an acidic

drug is present largely in its un-ionised (protonated) form,

allowing it to pass into plasma where its ionised form becomes

such as phosphate ions and proteins. When the fluids on

each side of a membrane have the same pH value, there will

be equal concentrations of both the diffusible (un-ionised)

form and the nondiffusible (ionised) form of the drug on each

side of the membrane at equilibrium (see Fig. 2.4).

When the fluids on each side of a membrane are at

different pH values, the concentrations of the un-ionised form

on each side of the membrane at equilibrium will remain equal,

as it can diffuse reversibly across the membrane, but the

concentrations of the ionised form will be determined by the

pH of the solution. This results in pH-dependent differences

in total drug concentration on each side of a membrane (pH

trapping or partitioning), with the total drug concentration

being higher on the side of the membrane on which it is most

ionised. This is exemplified by the pH difference between

urine (pH 5–7) and plasma (pH 7.4), which can influence

renal elimination of drugs (Fig. 2.5). The relatively low pH

of the urine forces an acidic drug to become predominantly

un-ionised, allowing its reabsorption into the plasma, while

the higher pH in plasma (7.4) converts the drug to the ionised

form, preventing it diffusing back and trapping (partitioning)

Extracellular fluid Intracellular fluid

Administration

Ionisation

Redistribution

to other tissues

Protein

binding

Metabolism Excretion

Protein

binding

Dissolution

in fat

D D D Ionisation

Fig. 2.3 The effect of pH on drug ionisation. Acidic conditions (low pH, high H+

concentrations) push the equilibrium of

acidic drugs towards their un-ionised (protonated) form, and basic drugs towards their ionised form. Basic conditions (high pH)

have the opposite effect.

Acid–

Base-H+ Base

Acid-H

Low pH

High pH

(e.g. – COO–) (e.g. – COOH)

(e.g. – NH3

+) (e.g. – NH2)

Low pH

High pH

Ionised

water-

soluble form

Un-ionised

lipid-

soluble form

Fig. 2.4 Passive diffusion and the factors that affect

drug concentrations in equilibrium between un-ionised

and ionised forms. In this case, the pH is assumed to be

the same on each side of the membrane; see Fig. 2.5 for

drug partitioning when there is a pH gradient across the

membrane.

For an acidic

drug (DH)

Urine (pH 6) Membrane Plasma (pH 7.4)

Overall

Overall

For a basic drug (D)

–

+ DH D D D + DH

– D DH DH DH D

Fig. 2.5 Partitioning of acidic and basic drugs across

a pH gradient. Only the un-ionised forms (DH and D) are

able to diffuse across the membrane. In urine (pH 6), the

un-ionised acidic drug (DH) can be readily reabsorbed

into the plasma, where its ionised form (D−

) becomes

concentrated, while the ionised basic drug (D+

) is trapped

within the urine. Alkalinising the urine would reduce

reabsorption of the acid drug and enhance that of the basic

drug.

1 38 Medical Pharmacology and Therapeutics

of drug from the formulation determines the rate of absorption.

In modified-release (i.e. slow-release) formulations the drug

is either incorporated into a complex matrix from which

it diffuses slowly or in a crystallised form that dissolves

slowly. Dissolution of a tablet in the stomach can also be

prevented by coating it in an acid-insoluble layer, producing

enteric-coated formulations. This is useful for drugs such

as omeprazole (see Chapter 31), which is unstable in an

acid environment, and allows delivery of the intact drug to

the duodenum.

Gastric emptying

The rate of gastric emptying determines how soon a drug

taken orally is delivered to the small intestine, the major site

of absorption. Delay between oral drug ingestion and the

drug being detected in the circulation is usually caused by

delayed gastric emptying. Drugs that slow gastric emptying

(e.g. antimuscarinics) can delay the absorption of other drugs

taken at the same time.

Food has complex effects on drug absorption; it slows

gastric emptying and delays drug absorption, and it can also

bind drugs and reduce the total amount of drug absorbed.

First-pass metabolism

Metabolism of drugs can occur before and during their

absorption, and this can limit the amount of parent compound

that reaches the general circulation. Drugs taken orally have

to pass four major metabolic barriers before they reach the

general circulation. If there is extensive metabolism of a

drug at one or more of the sites listed in the sections that

follow, only a fraction of the original oral dose reaches the

general circulation as the parent compound. This process

is known as first-pass metabolism because it occurs at the

first passage through the organ.

Intestinal lumen

The intestinal lumen contains digestive enzymes secreted

by the mucosal cells and pancreas that are able to split

peptide, ester and glycosidic bonds. Intestinal proteases

prevent the oral administration of peptide drugs, such as

insulin and other products of molecular biological approaches

to drug development. In addition, the lower bowel contains

large numbers of aerobic and anaerobic bacteria that are

capable of performing a range of metabolic reactions on

drugs, especially hydrolysis and reduction.

Intestinal wall

The walls of the upper intestine are rich in cellular enzymes

such as monoamine oxidase (MAO), aromatic L-amino acid

decarboxylase, cytochrome P450 isoenzymes (e.g. CYP3A4)

and the enzymes responsible for phase 2 conjugation

reactions described later. In addition, the luminal membrane

of the intestinal cells (enterocytes) contains efflux transporters

such as P-gp (noted previously), which may limit the

absorption of a drug by transporting it back into the intestinal

lumen. Drug molecules that enter the enterocyte may thus

undergo three possible fates – that is, diffusion into the

hepatic portal circulation, metabolism within the cell or

transport back into the gut lumen (by P-gp). The substrate

partitioned. In contrast, basic drugs are highly ionised in

the stomach, and absorption is negligible until the stomach

empties and the drug can be absorbed from the more alkaline

lumen of the duodenum (pH ~8).

Drugs that are fixed in their ionised form at all pH values,

such as the quaternary amine compound suxamethonium

(see Chapter 27), cross cell membranes extremely slowly

or not at all; they are given by injection (because of lack of

absorption from the gastrointestinal tract) and have limited

effects on the brain (because of lack of entry).

ABSORPTION

Absorption is the process of transfer of the drug from the

site of administration into the general or systemic circulation.

ABSORPTION FROM THE GUT

The easiest and most convenient route of administration of

medicines is orally by tablets, capsules or syrups. The large

surface area of the small intestine combined with its high

blood flow can give rapid and complete absorption of oral

drugs. However, this route presents a number of obstacles

for a drug before it reaches the systemic circulation.

Drug structure

Drug structure is a major determinant of absorption. Drugs

need to be lipid-soluble to be absorbed from the gut. Highly

polar acids and bases tend to be absorbed only slowly

and incompletely, with much of the unabsorbed dose being

voided in the faeces. High polarity may, however, be useful

for delivery of the drug to a site of action in the lower bowel

(see Chapter 34). The structures of some drugs can make

them unstable either at the low pH of the stomach (e.g.

benzylpenicillin) or in the presence of digestive enzymes

(e.g. insulin). Such compounds have to be given by injection,

but administration by other routes may be possible (e.g.

inhalation for insulin).

Drugs that are weak acids or bases undergo pH

partitioning between the gut lumen and mucosal cells.

Acidic drugs will be least ionised in the stomach lumen,

and most absorption would be expected at this site, but

absorption in the stomach is limited by its relatively low

surface area (compared with the small intestine) and the

presence of a zone of neutral pH on the immediate surface of

the gastric mucosal cells (the mucosal bicarbonate layer; see

Chapter 33). As a consequence, the bulk of the absorption of

drugs, even weak acids such as aspirin, occurs in the small

intestine.

Drug formulation

A drug cannot be absorbed when it is taken in a tablet

or capsule until the vehicle disintegrates and the drug is

dissolved in the gastrointestinal contents to form a molecular

solution. Most tablets disintegrate and dissolve quickly and

completely, and the whole dose rapidly becomes available

for absorption. However, some formulations are designed to

disintegrate slowly so that the rate of release and dissolution

Pharmacokinetics 39

Absorption of drugs from the injection site can be prolonged

intentionally by incorporation of the drug into a lipophilic

vehicle, such as flupentixol decanoate (see Chapter 21),

creating a depot formulation from which the drug is released

over days or weeks.

Intranasal administration

The nasal mucosa provides a good surface area for absorption,

combined with low levels of proteases and drug-metabolising

enzymes compared with the gastrointestinal tract. As a

consequence, intranasal administration is used for the

administration of some drugs, such as triptan drugs for

migraines (see Chapter 26) and desmopressin (see Chapter

43), as well as drugs designed to produce local effects,

such as nasal decongestants and topical corticosteroids

(see Chapter 39).

Inhalation

Although the lungs possess the characteristics of a good site

for drug absorption (a large surface area and extensive blood

flow), inhalation is rarely used to produce systemic effects.

The principal reasons for this are the difficulty of delivering

nonvolatile drugs to the alveoli and the potential for local

toxicity to alveolar membranes. Therefore drug administration

by inhalation is largely restricted to:

■ volatile compounds, such as general anaesthetics (see

Chapter 17);

■ locally acting drugs, such as bronchodilators and

corticosteroids used in the treatment of airway disease

such as asthma and chronic obstructive pulmonary disease

(see Chapter 12).

Drugs in the latter group are not volatile and have to be

given either as aerosols containing droplets of dissolved

drug or as fine particles of the solid drug (dry powder; see

Chapter 12). Particles greater than 10 μm in diameter settle

out in the pharynx and upper airways, which are poor sites

for absorption, and the drug then passes back up the airways

via ciliary motion and is eventually swallowed. Particles less

than 1 μm in diameter are not deposited in the airways and

are immediately exhaled. It was shown some years ago

that only 4–6% of an inhaled dose is deposited in the small

airways, although the percentage of deposited drug may

be higher with modern inhaler devices delivering particle

sizes closer to the optimum for airways deposition (2–5 μm).

Minor routes

Drugs may be applied to any body surface or orifice to produce

a local effect. Absorption from the site of administration may

be important in limiting the duration of local action and the

production of unwanted systemic actions.

DISTRIBUTION

Distribution is the process by which the drug is transferred

reversibly from the general circulation into the tissues as the

concentrations in blood increase, and then returns from the

specificities of CYP3A4 and P-gp overlap, and for common

substrates their combined actions can prevent most of

the oral dose of some drugs reaching the hepatic portal

circulation.

Liver

Blood from the intestine is delivered by the splanchnic

circulation directly to the liver, which is the major site of

drug metabolism in the body. Hepatic first-pass metabolism

can be avoided by administering the drug to a region of the

gut from which the blood does not drain into the hepatic

portal vein (e.g. the buccal cavity or rectum); a good example

of this is the buccal administration of glyceryl trinitrate (see

Chapter 5).

Lung

Cells of the lungs have high affinities for many basic drugs

and are the main site of metabolism for many local hormones

via monoamine oxidase or peptidase activity.

ABSORPTION FROM OTHER ROUTES

Percutaneous (transcutaneous)

administration

The human epidermis (especially the stratum corneum) is

an effective permeability barrier to water loss and to the

transfer of water-soluble compounds. Although lipid-soluble

drugs are able to cross this barrier, the rate and extent

of entry are very limited. As a consequence, this route is

only effective for use with potent, nonirritant drugs, such as

glyceryl trinitrate (see Chapter 5) or fentanyl (see Chapter

19), or to produce a local effect. The slow and continued

absorption from dermal administration (e.g. via adhesive

patches) can be used to produce low but relatively constant

blood concentrations of some drugs (e.g. nicotine replacement

therapy; see Chapter 54).

Intradermal and

subcutaneous injection

Intradermal or subcutaneous injection avoids the barrier

presented by the stratum corneum, and entry into the general

circulation is limited mainly by the rate of blood flow to the

site of injection. However, these sites generally only allow

the administration of small volumes of drugs and tend to be

used mostly for local effects, such as local anaesthesia, or to

deliberately limit the rate of drug absorption (e.g. insulin; see

Chapter 40). Subdermal implants are increasingly used for

long-term hormonal contraception; the implants are flexible

polymer rods or tubes inserted under the skin of the upper

arm that slowly release the hormone for up to 3 years, with

contraception being reversible by removal of the implant

(see Chapter 45).

Intramuscular injection

The rate of absorption from an intramuscular injection

depends on two variables: the local blood flow and the

water solubility of the drug. An increase in either of these

factors enhances the rate of removal from the injection site.

1 40 Medical Pharmacology and Therapeutics

REVERSIBLE PROTEIN BINDING

Many drugs show an affinity for sites on nonreceptor proteins,

resulting in reversible binding:

Drug + − protein D  rug protein complex

Such binding occurs with plasma proteins, most commonly

with albumin, which binds many acidic or steroidal drugs, and

α1-acid glycoprotein, which binds many basic or neutral drugs

(Table 2.3). Drugs may also bind reversibly with intracellular

Table 2.2 Relative organ perfusion rates in a typical

adult at rest

Organ Proportion

of cardiac

output (%)

Blood flow

(mL/min

per 100 g

of tissue)

Well-perfused organs

Lung 100 1000

Adrenals 0.5 200

Kidneys 15 350

Thyroid 1.5 500

Liver 27 110

Heart 4 100

Gastrointestinal tract 15 300

Brain 12 56

Placenta (full term) — 10–15

Poorly perfused organs

Skin 5 12

Skeletal muscle 12 4

Bone, connective

tissue

3 3

Adipose (fat) 4 3

Plasma

Concentration

Concentration Concentration

Time

Time

Poorly perfused tissues

Well-perfused tissues

A

B

A

B

A

B

Time

Fig. 2.6 A simplified scheme for the redistribution of

drugs between tissues. The initial decrease in plasma

concentrations results from uptake into well-perfused tissues,

which essentially reaches equilibrium at point A. Between

points A and B, the drug continues to enter poorly perfused

tissues, resulting in a decrease in the concentrations in both

plasma and well-perfused tissues. At point B all tissues are

in equilibrium. The additional presence of an elimination

process would produce a decrease from point B (shown as a

dashed line), which would be parallel in all tissues.

Table 2.3 Examples of drugs that undergo

extensive binding to plasma protein

Bound to albumin Bound to α1-acid glycoprotein

Dexamethasone Chlorpromazine

Digitoxin Erythromycin

Furosemide Lidocaine

Ibuprofen Methadone

Indometacin Propranolol

Phenytoin Quinine

Salicylates Tricyclic antidepressants

Sulphonamides

Thiazides

Tolbutamide

Warfarin

tissues into blood when the blood concentrations decrease.

For most lipid-soluble drugs this occurs by passive diffusion

across cell membranes (see Fig. 2.2). Once equilibrium is

reached, any process that removes the drug from one side

of the membrane results in movement of drug across the

membrane to re-establish the equilibrium (see Fig. 2.4). Drugs

that are less lipid-soluble can penetrate tissues by diffusing

through intercellular junctions.

After an intravenous injection of the drug, there is a high

initial plasma concentration and the drug may rapidly enter

well-perfused tissues such as the brain, liver and lungs (Table

2.2). This may be so rapid that these tissues can be assumed

to equilibrate instantaneously with plasma and represent part

of the ‘central’ compartment (described later). However, the

drug will continue to enter poorly perfused tissues, and this

will lower the plasma concentration. The high concentrations

in the rapidly perfused tissues then decrease in parallel with

the decreasing plasma concentration, resulting in a transfer

of drug back into the plasma (Fig. 2.6). This redistribution is

important for terminating the action of some drugs given as a

rapid intravenous injection or bolus. For example, intravenous

thiopental produces rapid anaesthesia, but effects in the brain

are short-lived because continued uptake into muscle lowers

the concentrations in the blood and therefore indirectly in

the brain (see Figs 2.6 and 17.2).

The processes of elimination (such as metabolism and

excretion) are of major importance and are discussed in

detail in the upcoming sections. Elimination results in a net

transfer of the drug from other tissues via the circulation

to the organ(s) of elimination (see the dashed lines in

Fig. 2.6).

Pharmacokinetics 41

re-enter the circulation. In contrast, some covalent binding

may be slowly reversible, such as the formation of disulphide

bridges by captopril with its target (angiotensin-converting

enzyme [ACE]) and with plasma proteins (see Chapter 6); the

covalently bound drug will not dissociate rapidly in response

to a decrease in the concentration of unbound drug, and such

binding represents a slowly equilibrating reservoir of drug.

DISTRIBUTION TO SPECIFIC ORGANS

Two systems require more detailed consideration of drug

distribution: the brain, because of the difficulty of drug entry,

and the fetus, because of the potential for drug toxicity.

Brain

Lipid-soluble drugs readily pass from the blood into the

brain, and for such drugs the brain represents a typical

well-perfused tissue (see Table 2.2). In contrast, the entry of

water-soluble drugs into the brain is much slower than into

other well-perfused tissues, giving rise to the concept of a

blood–brain barrier as a highly selective permeability barrier

that separates the blood from the extracellular fluid of the

brain. The functional basis of the barrier to water-soluble drugs

(Fig. 2.7) is reduced permeability of brain capillaries owing to:

■ tight junctions between adjacent endothelial cells

(capillaries are composed of an endothelial layer a single

cell thick, with no smooth muscle),

■ smaller size and lower number of pores in the endothelial

cell membranes,

■ the presence of a contiguous surrounding layer of

astrocytes.

proteins. The drug–protein binding interaction resembles

the drug–receptor interaction since it is rapid, reversible

and saturable, and different ligands can compete for the

same site. It does not result in a pharmacological effect but

lowers the free concentration of the drug available to act at

receptors; the amounts of drug remaining available may be

only a minute fraction of the total body load. Proteins such

as albumin can therefore act as depots, rapidly releasing

the bound drug when the free drug is distributed to other

compartments or eliminated.

Competition for binding to proteins in plasma or inside

cells can occur between different drugs (drug interaction; see

Chapter 56) and between drugs and endogenous ligands.

A highly protein-bound drug such as aspirin can displace

other drugs such as warfarin from their binding sites on

plasma proteins; the increase in unbound drug concentration

can increase the biological activity of the displaced drug.

Relatively few such interactions have important clinical

consequences, although an example of drug interaction

with an endogenous ligand is the displacement of bilirubin

from albumin by sulphanilamide drugs, causing a potentially

dangerous increase in the bilirubin concentration in plasma,

leading to kernicterus.

IRREVERSIBLE PROTEIN BINDING

Certain drugs, because of chemical reactivity of the parent

compound or a metabolite, undergo covalent binding to

plasma or tissue components such as proteins or nucleic

acids. When the binding is irreversible (e.g. the interaction

of some cytotoxic drugs with DNA), this can be considered

as equivalent to elimination, because the parent drug cannot

Tight junctions between

endothelial cells

Endothelial cell

Mitochondrion

Nontight

junction

Astrocyte foot

projection

Mitochondrion

Carrier

system

Basal

lamina

Endothelial cell Nucleus

Tight

junction

Active transport

Astrocyte

Foot process of astrocyte

Fig. 2.7 The blood–brain barrier. The barrier arises from the low number of membrane pores, the tight junctions between

adjacent cells and the presence of efflux transporters that remove any drug that enters the endothelial cell. The presence of

astrocytes is the stimulus for these changes in endothelial structure and function. Astrocytes are one of the several types of

cells found in the central nervous system that make up the glia; they have numerous sheet-like processes and may provide

nutrients to neurons.

1 42 Medical Pharmacology and Therapeutics

■ Increase in activity. Sometimes metabolites may be more

potent than the parent drug; for example a prodrug is

an inactive compound that is converted by metabolism

into an active molecular species.

■ Change in the nature of the activity. The metabolite shows

qualitatively different pharmacological or toxicological

properties.

Drug metabolism can be divided into two phases (Fig.

2.8). Although many compounds undergo both phases of

metabolism, it is possible for a drug to undergo only a phase

1 or a phase 2 reaction, or for a proportion of the drug

to be excreted unchanged. Phase 1 metabolism (often an

oxidation, reduction or hydrolysis reaction) is sometimes

described as preconjugation, because it produces a molecule

that is a suitable substrate for a phase 2 or conjugation

reaction. The enzymes involved in these reactions have low

substrate specificities and can metabolise a wide range of

drug substrates and other xenobiotics.

Phase 1

Cytochrome P450 is a superfamily of membrane-bound

haemoprotein isoenzymes (Table 2.4). They are present in the

smooth endoplasmic reticulum of cells (Fig. 2.9), particularly in

the liver, which is the major site of drug oxidation; the amounts

in other tissues are low in comparison. The cytochrome P450

families CYP1 to CYP4 are involved in drug metabolism; the

specific isoenzymes CYP2C9, CYP2D6 and CYP3A4 are

involved in the phase 1 metabolism of approximately 10%,

24% and 55% of drugs, respectively.

Oxidation reactions (Table 2.5) are the most important of

the phase 1 reactions and can occur at carbon, nitrogen or

sulphur atoms within the drug structure. In most cases, an

oxygen atom is retained in the metabolite, although some

reactions, such as dealkylation, result in loss of the oxygen

atom in a small fragment of the original molecule. Oxidation

reactions are catalysed by a diverse group of enzymes, of

which the cytochrome P450 system is the most important.

The cytochrome P450 isoenzyme binds both the drug and

molecular oxygen (Fig. 2.10), and catalyses the transfer of

one oxygen atom to the substrate, while the other oxygen

atom is reduced to water:

RH + + O NADPH + → H ROH + + H O NADP + + 2 2

In addition, efflux transporters in the endothelial cells

are an important part of the blood–brain barrier and return

drug molecules back into the circulation, thereby preventing

their entry into the brain and reducing effects in the central

nervous system.

Water-soluble endogenous compounds needed for normal

brain functioning, such as carbohydrates and amino acids,

enter the brain via specific uptake transporters of the SLC

superfamily (see Table 2.1). Some drugs (e.g. levodopa) may

enter the brain using these transport processes, and in such

cases the rate of transport of the drug will be influenced by

the concentrations of competitive endogenous substrates.

There is limited drug-metabolising ability in the brain,

and drugs leave by diffusion back into plasma, by active

transport processes in the choroid plexus or by elimination

in the cerebrospinal fluid. Organic acid transporters of the

SLC superfamily (see Table 2.1) are important in removing

polar neurotransmitter metabolites from the brain.

Fetus

Lipid-soluble drugs can readily cross the placenta and enter

the fetus. The placental blood flow is low compared with that

in the liver, lung and spleen (see Table 2.2); consequently,

the fetal drug concentration equilibrates slowly with that

in the maternal circulation. Highly polar and very large

molecules (such as heparin; see Chapter 11) do not readily

cross the placenta. The fetal liver has only low levels of

drug-metabolising enzymes, so it is mainly the maternal

elimination that clears the fetal circulation of drugs.

After delivery, the neonate may show effects from drugs

given to the mother close to delivery (such as pethidine for

pain control; see Chapter 19). Such effects may be prolonged

because the neonate now has to rely on his/her own immature

elimination processes (see Chapter 56).

ELIMINATION

Elimination is the removal of a drug’s activity from the body

and may involve metabolism, by which the drug molecule

is transformed into a different molecule, and/or excretion,

in which the drug molecule is expelled in the body’s liquid,

solid or gaseous ‘waste’.

METABOLISM

A degree of lipid solubility is a useful property of most

drugs, since it allows the compound to cross lipid barriers

and hence to be given via the oral route. Metabolism is

necessary for the elimination of lipid-soluble drugs from the

body because it converts a lipid-soluble molecule into a

water-soluble species capable of rapid elimination in the

urine. A lipid-soluble molecule filtered into the kidney tubule

would otherwise be reabsorbed from the tubule into the

circulation (discussed later).

Metabolism of the drug produces one or more new

chemical entities, which may show different pharmacological

properties from the parent compound:

■ Decrease in biological activity. The most common result

of drug metabolism, arising from reduced receptor binding

due to the changed molecular structure.

Phase

1

Benzene

0%

Phenol

0.3%

Phenyl sulfate

99.9%+

Phase

2

Percentage

ionised

at pH 7.4

OH O – SO3

–

Fig. 2.8 The two phases of drug metabolism. Benzene

is shown as a simple example of a lipid-soluble substance

undergoing phase 1 and phase 2 metabolism. In Phase 1

benzene is oxidised to phenol and in Phase 2 the phenol

metabolite is conjugated with sulfate to produce a highly

hydrophilic metabolite-conjugate (phenyl sulfate).

Pharmacokinetics 43

Table 2.4 Cytochrome P450 superfamily

Isoenzyme Comments

CYP1A Important for

methylxanthines and

paracetamol; induced by

smoking

CYP2A Limited number of

substrates; significant

interindividual variability

CYP2B Limited number of

substrates

CYP2C CYP2C9 is an important

isoform; CYP2C19 shows

genetic polymorphism

CYP2D Metabolises numerous

drugs; CYP2D6 shows

genetic polymorphism

CYP2E Metabolises alcohol

CYP3A Main isoform in liver and

intestine; metabolises

50–60% of current drugs

CYP4 Metabolises fatty acids

Human liver contains at least 20 isoenzymes of cytochrome P450.

Families CYP1–4 are involved in drug metabolism.

D

Cytochrome

P450

Active

site

D

D in

cytosol

M

M

MS

D in

cytosol

M

MS

M

MGA

P450

Active

site

UDPGT

Phospholipid

bilayer

Fig. 2.9 Drug metabolism in the smooth endoplasmic reticulum. The lipid-soluble drug (D) partitions into the lipid bilayer

of the endoplasmic reticulum. The cytochrome P450 oxidises the drug to a metabolite (M) that is more water-soluble and

diffuses out of the lipid layer. The metabolite may undergo a phase 2 (conjugation) reaction catalysed by UDP-glucuronyl

transferase (UDPGT) in the endoplasmic reticulum to give a glucuronide conjugate (MGA) or with sulfate in the cytosol to give a

sulfate conjugate (MS).

Table 2.5 Examples of oxidation, reduction and

hydrolytic reactions

Oxidation

Alkyl groups RCH3 → RCH2OH → RCHO → RCOOH

Deamination RCH2NH2 → RCHO + NH3

Amines R′-NH-R → R′-N(OH)-R

Reduction

Aldehydes RCHO → RCH2OH

Disulfides R–S–S–R′ → RSH + HSR′

Hydrolysis

Esters RCO⋅OR′ → RCOOH + HOR′

Amides RCO⋅NHR′ → RCOH + H2NR′

R, R′, Aliphatic groups.

1 44 Medical Pharmacology and Therapeutics

Hydrolysis and hydration reactions (see Table 2.5) involve

the addition of water to the drug molecule. In hydrolysis, the

molecule is then split by the addition of water. A number of

ubiquitous enzymes are able to hydrolyse ester and amide

bonds in drugs. Intestinal bacteria are also important for the

hydrolysis of esters and amides, and of drug conjugates

eliminated in the bile (discussed later). In hydration reactions,

the water molecule is retained in the drug metabolite.

Hydration of an epoxide ring by epoxide hydrolase is an

important reaction in the metabolism and toxicity of a number

of aromatic drugs (e.g. carbamazepine; see Chapter 23).

Phase 2

Phase 2 (conjugation) reactions involve the formation of a

covalent bond between the drug, or its phase 1 metabolite,

and an endogenous substrate. Table 2.6 shows the types

The reaction involves initial binding of the drug substrate

to the ferric (Fe3+

) form of cytochrome P450, followed by

reduction (via a specific cytochrome P450 reductase) and then

binding of molecular oxygen. Further reduction is followed

by molecular rearrangement, with release of the reaction

products (drug metabolite and water) and regeneration of

ferric cytochrome P450.

Oxidations at nitrogen and sulphur atoms are frequently

performed by a second enzyme of the endoplasmic reticulum,

the flavin-containing mono-oxygenase, which also requires

molecular oxygen and NADPH. A number of other enzymes,

such as alcohol dehydrogenase, aldehyde oxidase and MAO,

may be involved in the oxidation of specific functional groups.

Reduction reactions (see Table 2.5) are less common

than oxidation reactions, but occur at unsaturated carbon

atoms and at nitrogen and sulfur centres by the actions of

cytochrome P450 and cytochrome P450 reductase (and also

by the intestinal microflora).

ROH

H2O Fe3+

Fe3+–RH

Fe2+–RH

Fe2+–RH

Fe3+–RH

Fe3+–RH

O2

_

O2

O2

e–

RH

e–

O2

2–

2H+

From reduced

cytochrome b5

or cytochrome

P450 reductase

From NADPH-

cytochrome P450

reductase

Fig. 2.10 The oxidation of substrate (RH) by cytochrome P450. Fe3+

, the active site of cytochrome P450 in its ferric state;

RH, drug substrate; ROH, oxidised metabolite. Cytochrome b5 is present in the endoplasmic reticulum and can transfer an

electron to cytochrome P450 as part of its redox reactions. NADPH, nicotinamide adenine dinucleotide phosphate.

Table 2.6 Major conjugation reactions

Reaction Functional group Activated species Products

Glucuronidation –OH

–COOH

–NH2

Uridine-diphosphate

glucuronic acid (UDPGA)

Glucuronide conjugates

Sulfation –OH

–NH3

3′-Phosphoadenosine-5′-

phosphosulfate (PAPS)

–O–SO3H

–NH–SO3H

Acetylation –NH2 Acetyl-CoA –NH–COCH3

Methylation –OH

–NH2

–SH

S-Adenosyl methionine –OCH3

–NHCH3

–SCH3

Amino acid conjugation –COOH Drug-CoA CO-NH⋅CHR⋅COOH

Glutathione conjugation Various – Glutathione conjugates

Pharmacokinetics 45

few days, during which the inducer interacts with nuclear

receptors to increase mRNA transcription of genes coding

for cytochrome P450. The increased amounts of the enzyme

last for a few days after the removal of the inducing agent,

and are removed by normal protein turnover. Environmental

contaminants such as organochlorine compounds (e.g.

dioxins) and polycyclic aromatic hydrocarbons (e.g. benzo[a]

pyrene in cigarette smoke) induce CYP1A. Therapeutic drugs

can induce members of the CYP2 and CYP3 families. Chronic

consumption of alcohol induces CYP2E.

In contrast, inhibition of cytochrome P450 by drugs

occurs by direct reversible competition for the enzyme site,

not a change in enzyme expression, so the time course

closely follows the absorption and elimination of the inhibitor

substance. Examples of inhibitors are the histamine H2 receptor

antagonist cimetidine (see Chapter 33) and components of

grapefruit juice (see Table 2.7).

The activity of drug-metabolising enzymes is also

dependent on the delivery of their drug substrates by the

circulation. The metabolism of many drugs is affected

significantly by lower hepatic blood flow in the very young

and in the elderly (see Chapter 56). Genetic variation in

drug-metabolising enzymes is discussed at the end of this

chapter.

EXCRETION

Drugs and their metabolites may be eliminated via circulation

by various routes:

■ In fluids (urine, bile, sweat, tears, breast milk, etc.).

Important for low-molecular-weight polar compounds;

of phase 2 reactions, the functional group necessary in the

drug molecule and the activated species needed for the

reaction. The products of conjugation reactions are usually

highly water-soluble and lack biological activity.

The activated endogenous substrate for glucuronide

synthesis is uridine-diphosphate glucuronic acid (UDPGA).

UDP-glucuronyl transferases in the endoplasmic reticulum

close to the cytochrome P450 system (see Fig. 2.9) transfer

glucuronate to the drug. Glucuronide conjugation in the gut

wall and liver is important in the first-pass metabolism of

substrates such as simple phenols.

Sulfate conjugation is performed by a cytosolic enzyme,

which utilises high-energy sulphate (3′-phosphoadenosine-5′-

phosphosulfate or PAPS) as the rate-limiting endogenous

substrate. Saturation of sulfate conjugation contributes to

the hepatotoxic consequences of overdose with paracetamol

(acetaminophen; see Chapter 53).

Acetylation and methylation reactions often decrease

polarity because they block an ionisable functional group

(see Table 2.6), but they mask active groups such as amino

and catechol moieties. These reactions are primarily involved

in inactivation of neurotransmitters such as noradrenaline

and local hormones such as histamine.

The conjugation of drug carboxylic acid groups with amino

acids is unusual because the drug is converted to a high-energy

form (a Coenzyme A derivative) prior to the formation of the

conjugate bond by transferase enzymes. Conjugation with the

tripeptide glutathione (GSH or L-α-glutamyl-L-cysteinylglycine)

is catalysed by a family of transferases which covalently bind

the drug to the thiol group in the cysteine (Fig. 2.11). The

substrates are often reactive drugs or activated metabolites,

which are inherently unstable (see Chapter 53), and the reaction

can also occur nonenzymatically. The glutathione conjugate

then undergoes further metabolic reactions.

Glutathione conjugation is a detoxification process in which

glutathione acts as a scavenging agent to protect the cell

from toxic damage. Glutathione conjugates and endogenous

cysteine conjugates, such as the cysteinyl-leukotriene (LT)

C4, are transported out of cells by the MRP1 transporter

(see Table 2.1).

The complex array of biotransformation reactions typically

involved in drug metabolism is illustrated by the anxiolytic

drug diazepam (see Chapter 20), which is metabolised

to biologically active intermediates before undergoing

conjugation with glucuronide (Fig. 2.12).

Factors affecting drug metabolism:

inducers and inhibitors

The liver is the main site of drug metabolism; the large surface

area of the sinusoids, combined with high levels of enzyme

activity in hepatocytes, can result in very rapid drug uptake and

metabolism as the blood flows through the liver (see Chapter

56 for normal sinusoid architecture and the effects of liver

disease on hepatic drug uptake). Environmental influences

including chemical contaminants and therapeutic drugs may

induce or inhibit the activity of hepatic drug-metabolising

enzymes, particularly cytochrome P450 (Table 2.7). This can

affect both the bioavailability and the elimination of other drugs

undergoing hepatic elimination (discussed later).

Inducing agents increase the cellular expression of

cytochrome P450 enzymes. This occurs over a period of a

RX

R S CYS

GLU

GLY

Hydrolysis

R S Cysteine

Lyase

R SH

Further metabolism

Excretory

product

N-acetylation

GLU

CYS

GLY

HS

Glutathione transferase

or spontaneous reaction

Glutathione Unstable drug or

reactive metabolite

Fig. 2.11 The formation and further metabolism

of glutathione conjugates. There are multiple types

of glutathione transferase that detoxify substances by

glutathione conjugation.

1 46 Medical Pharmacology and Therapeutics

compounds free in the plasma enter the filtrate on each pass.

Plasma proteins and protein-bound drugs are not filtered, so

the efficiency of glomerular filtration for a drug is influenced

by the extent of plasma protein binding.

Reabsorption

The glomerular filtrate contains numerous constituents

that the body cannot afford to lose. Most of the water is

reabsorbed, and there are specific tubular uptake processes

for carbohydrates, amino acids, vitamins and so on (see

Chapter 14). A few drugs also pass from the tubule back

into the plasma, as they are substrates for these specific

uptake processes. The urine is concentrated on its passage

down the renal tubule; as the tubule-to-plasma concentration

gradient increases, only the most polar molecules remain in

the urine. Because of extensive reabsorption, lipid-soluble

drugs are not eliminated via the urine, but are returned to

the circulation until they are metabolised to water-soluble

products, which are then efficiently removed from the body

by renal excretion. The pH of urine is usually less than that

of plasma; consequently, pH partitioning between urine (pH

5–6) and plasma (pH 7.4) may increase or decrease the

tendency of the compound to be reabsorbed (see Fig. 2.5).

Tubular secretion

The renal tubule also has secretory transporters (see Table

2.1) on both the basolateral and apical membranes

urine is the major route; milk is important because of

the potential for exposure of the breastfed infant.

■ In solids (faeces, hair, etc.). Faecal elimination is

most important for high-molecular-weight compounds

excreted in bile; the sequestration of drugs into hair is

not quantitatively important, but the distribution of a drug

along the hair shaft can indicate the history of drug intake

during the preceding weeks.

■ In gases (expired air). Important only for volatile

compounds

Excretion via the urine

There are three processes involved in the handling of drugs

and their metabolites in the kidney: glomerular filtration,

reabsorption and tubular secretion. The total urinary excretion

of a drug depends on the balance of these three processes:

Total excretion glomerular filtration

tubular secretion re

=

+ − absorption

Glomerular filtration

All molecules less than about 20 kDa undergo filtration under

positive hydrostatic pressure through pores of 7–8 nm diameter

in the glomerular membrane. The glomerular filtrate comprises

about 20% of the flow of plasma to the glomeruli, and

hence about 20% of all water-soluble, low-molecular-weight

Cytochrome P450

Cytochrome P450

Ring oxidation

N-demethylation

N

N

CH3

O

Cl

Diazepam

UDPGT

Cytochrome P450

Water-soluble

glucuronide

conjugate

Water-soluble

glucuronide

conjugate

N-demethylation

N

N

CH3

O

Cl

Temazepam

N

N

H

O

Cl

Oxazepam

Cytochrome P450

N

N

H

O

Cl

Desmethyldiazepam

(nordiazepam)

OH

UDPGT

OH

Ring oxidation

Fig. 2.12 Complex pathways of metabolism in humans. This figure illustrates that a single drug, in this case diazepam,

may generate a number of active metabolites before phase 2 conjugation terminates the activity of the parent drug and

metabolites.

Pharmacokinetics 47

Excretion via the faeces

Uptake into hepatocytes and subsequent elimination in

bile is the principal route of elimination of larger molecules

(molecular weight >500 Da). Conjugation with glucuronic

acid increases the molecular weight of the substrate by

almost 200 Da, so bile is an important route for eliminating

glucuronide conjugates. Once the drug or its conjugate has

entered the intestinal lumen via the bile (Fig. 2.13), it passes

down the gut and may eventually be eliminated in the faeces.

However, some drugs may be reabsorbed from the lumen of

for compounds that are acidic (OATs) or basic (organic

cation transporters [OCTs]). Drugs and their metabolites,

especially the glucuronic acid and sulphate conjugates, may

undergo an active carrier-mediated elimination, primarily by

OATs but also by multidrug-resistance-associated proteins

(MRPs). Because tubular secretion rapidly lowers the plasma

concentration of unbound drug, there will be a rapid

dissociation of any drugs bound to proteins in the plasma.

As a result, even highly protein-bound drugs may be cleared

almost completely from the blood in a single passage through

the kidney.

Table 2.7 Examples of common substrates, inhibitors and inducers of cytochrome P450 isoenzymes

Isoenzyme Substrates Inhibitors Inducers

CYP1A2 Caffeine, clozapine,

haloperidol, naproxen,

olanzapine, paracetamol,

theophylline, verapamil

Amiodarone, cimetidine,

efavirenz, grapefruit juice

Carbamazepine, chargrilled

meat, cigarette smoke,

rifampicin

CYP2A6 Coumarin, halothane,

nicotine

Grapefruit juice,

ketoconazole,

tranylcypromine

Dexamethasone,

phenobarbital, rifampicin

CYP2B6 Bupropion,

cyclophosphamide,

efavirenz, ifosfamide,

ketamine, methadone,

propofol, selegiline

Orphenadrine, ticlopidine,

voriconazole

Artemisinin, carbamazepine,

phenobarbital, phenytoin,

rifampicin

CYP2C8 Montelukast, repaglinide Gemfibrozil, montelukast Phenobarbital, rifampicin

CYP2C9 Celecoxib, diclofenac,

glibenclamide, glipizide,

ibuprofen, losartan,

tolbutamide, S-warfarin

Amiodarone, efavirenz,

fluconazole, isoniazid,

metronidazole, paroxetine,

voriconazole

Carbamazepine,

phenobarbital, rifampicin, St

John’s wort

CYP2C19 Citalopram, clopidogrel,

diazepam, omeprazole,

pantoprazole, phenytoin,

proguanil

Cimetidine, fluoxetine,

fluvoxamine, ketoconazole,

lansoprazole,

moclobemide, omeprazole,

oral contraceptives,

pantoprazole, voriconazole

Efavirenz, rifampicin,

ritonavir, St John’s wort

CYP2D6 Amitriptyline, bisoprolol,

codeine, desipramine,

encainide, many SSRIs,

metamfetamine, metoprolol,

ondansetron, propranolol,

risperidone

Amiodarone, bupropion,

cimetidine, duloxetine,

fluoxetine, paroxetine,

quinidine

Carbamazepine,

phenobarbital, phenytoin,

rifampicin

CYP2E Chlorzoxazone, ethanol,

halothane (and other

inhalation anaesthetics),

paracetamol

Disulfiram Ethanol

CYP3A4 Numerous drugs of many

different classes, e.g.

amlodipine, alfentanil,

atorvastatin, carbamazepine,

ciclosporin, diazepam,

diltiazem, erythromycin,

fluconazole, lidocaine,

midazolam, nifedipine,

saquinavir, sildenafil,

tamoxifen, terfenadine

Antivirals (indinavir,

nelfinavir, ritonavir),

clarithromycin, erythromycin,

grapefruit juice, itraconazole,

ketoconazole

Carbamazepine, efavirenz,

phenobarbital, phenytoin,

pioglitazone, rifampicin, St

John’s wort

SSRIs, Selective serotonin re-uptake inhibitors.

Information taken mainly from Flockhart, D.A., 2007. Drug interactions: cytochrome P450 drug interaction table. Indiana University School of

Medicine. <http://medicine.iupui.edu/clinpharm/ddis/clinical-table> (accessed 16.04.2016).

1 48 Medical Pharmacology and Therapeutics

■ the dosage adjustment that may be necessary in hepatic

and renal disease,

■ the calculation of dosages for vulnerable patient groups.

Calculation of drug doses may be required in the UK

Prescribing Safety Assessment (PSA) (see Chapter 55).

GENERAL CONSIDERATIONS

The processes of drug absorption, distribution, metabolism

and excretion (ADME) are described in this section in

mathematical terms, as it is important to quantify the rate

and extent to which the drug undergoes each process.

For nearly all physiological and metabolic processes,

the rate of reaction is not uniform but proportional to the

amount of substrate (drug) available: this is described

as a first-order reaction. Diffusion down a concentration

gradient, glomerular filtration and enzymatic hydrolysis are

examples of first-order reactions. At higher concentrations,

more drug diffuses or is filtered or hydrolysed than at

lower concentrations. Protein-mediated reactions, such as

metabolism and active transport, are also first order, because

if the concentration of the substrate is doubled, then the rate

of formation of product is also doubled. However, as the

substrate concentration increases, the enzyme or transporter

can become saturated with substrate, and the rate of reaction

cannot respond to a further increase in concentration. The

process then occurs at a fixed maximum rate independent

of substrate concentration, and the reaction is described as

a zero-order reaction; rare examples are the metabolism of

ethanol (see Chapter 54) and phenytoin (see Chapter 23).

When the substrate concentration has decreased sufficiently

for protein sites to become available again, then the reaction

will revert to first order.

Zero-order reactions

If a drug is being processed (absorbed, distributed or

eliminated) according to zero-order kinetics, then the change

in concentration with time (dC/dt) is a fixed amount (mass)

of the drug per time, independent of concentration:

d

d

C

t = −k (2.2)

The units of k (the reaction rate constant) are therefore a

mass per unit time (e.g. mg/min). A graph of concentration

against time will produce a straight line with a slope of −k

(Fig. 2.14A).

First-order reactions

In first-order reactions, the change in concentration at any

time (dC/dt) is proportional to the concentration present

at that time:

d

d

C

t = −kC (2.3)

The rate of change will be high at high drug concentrations

but low at low concentrations (see Fig. 2.14B), and a graph

of concentration against time will produce an exponential

the gut and re-enter the hepatic portal vein. As a result, the

drug is recycled between the gut lumen, hepatic portal vein,

liver, bile and back to the gut lumen; this is described as

enterohepatic circulation. Some of the reabsorbed drug may

escape hepatic extraction and proceed into the hepatic vein,

maintaining the drug concentrations in the general circulation.

Highly polar glucuronide conjugates of drugs or their

oxidised metabolites that are excreted into the bile undergo

little reabsorption in the upper intestine. However, the bacterial

flora of the lower intestine may hydrolyse the conjugate, so

the original, lipid-soluble drug or its metabolite is liberated and

can be reabsorbed and undergo enterohepatic circulation.

THE MATHEMATICAL BASIS

OF PHARMACOKINETICS

The use of mathematics to describe the fate of a drug in

the body can be complex and daunting for undergraduates.

Nevertheless, a basic knowledge is essential for understanding

many aspects of drug handling and the rational prescribing

of drugs:

■ why oral and intravenous treatments may require different

doses,

■ the calculation of dosages and dose intervals during

chronic therapy,

■ why a loading dose may be needed,

General circulation

Bile

Drug

Drug

Drug

Conjugate

Liver

Conjugate

Conjugate

Conjugate

Drug

Drug

Small

intestine

Colon/rectum

Bacterial hydrolysis

Fig. 2.13 Enterohepatic circulation of drugs. Drug

molecules may circulate repeatedly between the bile, gut,

portal circulation, liver and general circulation, particularly if

the drug conjugate is hydrolysed by the gut flora.

Pharmacokinetics 49

ABSORPTION

The mathematics of absorption apply to all nonintravenous

routes (e.g. oral, inhalation, percutaneous) and are illustrated

by absorption from the gut lumen.

RATE OF ABSORPTION

The rate of absorption after oral administration is determined

by the rate at which the drug is able to pass from the gut

lumen into the systemic circulation. Following oral doses

of some drugs, particularly lipid-soluble drugs with very

rapid absorption, it may be possible to see three distinct

phases in the plasma concentration–time curve, which reflect

distinct phases of absorption, distribution and elimination

(Fig. 2.16A). However, for most drugs slow absorption masks

the distribution phase (see Fig. 2.16B). A number of factors

can influence this pattern.

■ Gastric emptying. Basic drugs undergo negligible

absorption from the stomach, so there can be a delay

of up to an hour between drug administration and the

detection of drug in the general circulation.

■ Food. Food in the stomach slows drug absorption and

also slows gastric emptying.

■ Decomposition or first-pass metabolism before or

during absorption. This will reduce the amount of drug

that reaches the general circulation but will not affect the

rate of absorption, which is usually determined by lipid

solubility.

■ Modified-release formulation. If a drug is eliminated

rapidly, the plasma concentrations will show rapid

fluctuations during regular oral dosing, and it may be

necessary to take the drug at very frequent intervals

to maintain a therapeutic plasma concentration. The

frequency with which a drug is taken can be reduced

by giving a modified-release formulation that releases

drug at a slower rate. The plasma concentration then

becomes more dependent on the rate of absorption than

the rate of elimination.

decrease. Such a curve can be described by an exponential

equation:

C C kt = − 0e (2.4)

where C is the concentration at time t and C0 is the initial

concentration (when time = 0). This equation may be written

more simply by taking natural logarithms:

lnC C= − 0 kt (2.5)

and a graph of lnC against time will produce a straight line

with a slope of −k and an intercept of lnC0 (see Fig. 2.14C).

The units of the rate constant k (1/time, e.g. per hour)

may be regarded as the proportional change per unit of time

but are difficult to use practically, so the rate of a first-order

reaction is usually described in terms of its half-life (t1/2),

which is the time taken for a concentration to decrease by

one-half. In the next half-life, the drug concentration falls

again by one-half, to a quarter of the original concentration,

and then to one-eighth in the next half-life, and so on. The

half-life is therefore independent of concentration and is

a characteristic for a particular first-order process and a

particular drug. The intravenous drug shown in Fig. 2.15

has a t1/2 of 1 hours.

The relationship between the half-life and the rate constant

is derived by substituting C0 = 2 and C = 1 into the previous

equation, when the time interval t will be one half-life (t1/2),

giving:

ln ln

.

. .

1 2

0 0 693

0 693 0 693

1 2

1 2

1 2 1 2

= −

= −

= =

kt

kt

t k or k t

(2.6)

(Note: 0.693 = ln2.)

A half-life can be calculated for any first-order process

(e.g. for absorption, distribution or elimination). In practice,

the ‘half-life’ normally reported for a drug is the half-life for

the elimination rate from plasma (the slowest, terminal phase

of the plasma concentration–time curve; discussed later).

C

Slope = –k

(units = mass/time)

Time Time Time

Slope = –k

(units = 1/time)

InC0

Zero order First order

C

In

C

A B C

Fig. 2.14 Zero- and first-order kinetics. (A) The zero-order reaction is a uniform change in concentration C over time,

representing the same amount (mass) of drug being removed per unit of time. (B) The first-order reaction is an exponential

curve in which concentrations fall fastest when they are highest; the curve reflects the same proportion of drug being removed

per unit of time. (C) Plotting the natural logarithm of the concentration (lnC) in a first-order reaction against time generates a

straight line with slope −k (where k is the rate constant) and the intercept gives the concentration at time zero, C0.

1 50 Medical Pharmacology and Therapeutics

The bioavailability of a drug has important therapeutic

implications, because it is the major factor determining

the drug dosage for different routes of administration.

For example, if a drug has an oral bioavailability of 0.1,

the oral dose needed for therapeutic effectiveness will

need to be 10 times higher than the corresponding

intravenous dose.

The bioavailability is a characteristic of the drug and

independent of dose, providing that absorption and

elimination are not saturated. Bioavailability is normally

determined by comparison of plasma concentration data

obtained after oral administration (when the fraction F of

the parent drug enters the general circulation) with data

following intravenous administration (when, by definition,

EXTENT OF ABSORPTION

Bioavailability (F) is defined as the fraction of the administered

dose that reaches the systemic circulation as the parent drug

(unaltered, not as metabolites). For intravenous administration

the bioavailability (F) is therefore 1, as 100% of the parent

drug enters the general circulation. For oral administration,

incomplete bioavailability (F < 1) may result from:

■ incomplete absorption and loss in the faeces, because

either the molecule is too polar to be absorbed or the

tablet did not release all of its contents;

■ first-pass metabolism in the gut lumen, during passage

across the gut wall or by the liver before the drug reaches

the systemic circulation.

100

80

60

40

20

0

0 1 2 3 4

5

4

3

2

1

0

0 1 2 3 4

Time (h) Time (h)

C

In (concentration)

Slope = –k

Fig. 2.15 The elimination half-life of a drug in plasma. Here the drug concentration C decreases by 50% every hour (i.e.

the half-life is 1 hour).

Rate of absorption > rate of distribution

Time after dosage

Plasma drug

concentration

Absorption phase

Distribution phase

Elimination phase

Rate of absorption < rate of distribution

Time after dosage

Plasma drug

concentration

Absorption phase

Distribution phase

Elimination phase

A B

Fig. 2.16 Plasma concentration–time profiles after oral administration of drugs with different rates of absorption.

The processes of distribution and elimination start as soon as some of the drug has entered the general circulation. (A) A clear

distribution phase is seen if the rate of absorption is so rapid as to be essentially complete before distribution is finished. (B)

For most drugs, the rate of absorption is slower and masks the distribution phase.

Pharmacokinetics 51

DISTRIBUTION

Distribution concerns the rate and extent of movement

of the parent drug from the blood into the tissues after

administration and its return from the tissues into the blood

during elimination.

RATE OF DISTRIBUTION

Because a distinct distribution phase is not usually seen

when a drug is taken orally (see Fig. 2.16B), the rate of

distribution is normally measured following an intravenous

bolus dose. Some intravenous drugs reach equilibrium

between blood and tissues very rapidly, and a distinct

distribution phase is not apparent. In Fig. 2.17A the slope

of plasma concentration against time therefore mainly reflects

elimination of the drug; this is described as a one-compartment

model.

Most intravenous drugs, however, take a finite time to

distribute into the tissues; the initial distribution out of the

plasma, combined with underlying elimination, produces a

steep initial slope (slope A–B in Fig. 2.17B), followed by

a slower terminal phase (slope B–C) in which distribution

has been largely completed and elimination predominates.

Back-extrapolation of this terminal elimination phase to

F = 1). The amount in the circulation cannot be compared

at a single time point, because intravenous and oral dosing

show different concentration–time profiles, so instead

the total area under the plasma concentration–time curve

(AUC) from t = 0 to t = infinity is used, as this reflects

the total amount of drug that has entered the general

circulation. If the oral and intravenous (iv) doses administered

are equal:

F = AUC

AUC

oral

iv

(2.7)

or if different doses are used:

F = ×

×

AUC Dose

AUC Dose

oral iv

iv oral

(2.8)

This calculation assumes that the elimination is first order.

An alternative method to calculate F is to measure

the total urinary excretion of the parent drug (Aex)

following oral and intravenous administration of identical

doses:

F = Aex

Aex

oral

iv

(2.9)

A

B

In

C

In

C

Time

Slope = –k

Model Model

Dose V Elimination

One-compartment Two-compartment

Instantaneous distribution

A

B

Time

Dose V1

Slower distribution

C

V2

Elimination

D

A B

Fig. 2.17 Plasma concentration–time curves for the distribution of intravenous drugs into one- and two-compartment

models. (A) When distribution of an intravenous drug bolus into tissues is so rapid as to be essentially instantaneous, the slope

of the plasma concentration–time curve mainly reflects the rate of elimination (one-compartment model). (B) When distribution

is slower, the initial fall in concentration (slope A–B) is due to simultaneous distribution and elimination followed by the terminal

elimination phase (two-compartment model; slope B–C). Back-extrapolating to D at time zero allows the contribution of

distribution during A–B to be distinguished from the underlying contribution of elimination.