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RANG AND DALE’S

Pharmacology
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Pharmacology
RANG AND DALE’S

EIGHTH EDITION

H P Rang MB BS MA DPhil Hon FBPharmacolS FMedSci FRS

Emeritus Professor of Pharmacology,
University College London, London, UK

J M Ritter DPhil FRCP FBPharmacolS FMedSci

Emeritus Professor of Clinical Pharmacology,
King’s College London, and Medical Research Director, Quintiles,
London, UK

R J Flower PhD DSc FBPharmacolS FMedSci FRS

Professor, Biochemical Pharmacology,
The William Harvey Research Institute,
Barts and the London School of Medicine and Dentistry,
Queen Mary University of London, London, UK

G Henderson BSc PhD FBPharmacolS FSB

Professor of Pharmacology, University of Bristol, Bristol, UK

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an imprint of Elsevier Limited

© 2016, Elsevier Ltd. All rights reserved.

First edition 1987

Second edition 1991
Third edition 1995
Fourth edition 1999
Fifth edition 2003
Sixth edition 2007
Seventh edition 2012

The right of H P Rang, J M Ritter, R J Flower and G Henderson to be identified as authors of this
work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.

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ISBN:
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ISBN-13 978-0-7020-5362-7

International edition
ISBN-13 978-0-7020-5363-4

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

Preface xv
Acknowledgements xv
4. How drugs act: cellular aspects – excitation,
contraction and secretion 50
Section 1: General principles Overview 50
Regulation of intracellular calcium 50
Calcium entry mechanisms 50
1. What is pharmacology? 1 Calcium extrusion mechanisms 53
Overview 1 Calcium release mechanisms 53
What is a drug? 1 Calmodulin 53
Origins and antecedents 1 Excitation 54
Pharmacology in the 20th and 21st centuries 2 The ‘resting’ cell 55
Alternative therapeutic principles 2 Electrical and ionic events underlying the action
The emergence of biotechnology 3 potential 55
Pharmacology today 3 Channel function 56
Muscle contraction 60
2. How drugs act: general principles 6 Skeletal muscle 60
Cardiac muscle 60
Overview 6
Smooth muscle 61
Introduction 6
Release of chemical mediators 63
Protein targets for drug binding 6
Exocytosis 63
Drug receptors 6
Non-vesicular release mechanisms 64
Drug specificity 7
Epithelial ion transport 64
Receptor classification 8
Drug–receptor interactions 8 5. Cell proliferation, apoptosis, repair and
Competitive antagonism 10
Partial agonists and the concept of efficacy 12 regeneration 67
Other forms of drug antagonism 15 Overview 67
Desensitisation and tolerance 17 Cell proliferation 67
Change in receptors 17 The cell cycle 67
Translocation of receptors 17 Interactions between cells, growth factors and
Exhaustion of mediators 17 the extracellular matrix 69
Altered drug metabolism 18 Angiogenesis 70
Physiological adaptation 18 Apoptosis and cell removal 71
Quantitative aspects of drug–receptor interactions 18 Morphological changes in apoptosis 71
The binding reaction 18 The major players in apoptosis 71
Binding when more than one drug is present 19 Pathways to apoptosis 72
The nature of drug effects 20 Pathophysiological implications 73
Repair and healing 74
3. How drugs act: molecular aspects 22 Hyperplasia 74
Overview 22 The growth, invasion and metastasis of
Targets for drug action 22 tumours 74
Receptors 22 Stem cells and regeneration 74
Ion channels 22 Therapeutic prospects 75
Enzymes 23 Apoptotic mechanisms 75
Transporters 23 Angiogenesis and metalloproteinases 75
Receptor proteins 24 Cell cycle regulation 75
Cloning of receptors 24
Types of receptor 24
6. Cellular mechanisms: host defence 78
Molecular structure of receptors 25 Overview 78
Type 1: Ligand-gated ion channels 26 Introduction 78
Type 2: G protein-coupled receptors 27 The innate immune response 78
Type 3: Kinase-linked and related receptors 39 Pattern recognition 78
Type 4: Nuclear receptors 42 The adaptive immune response 83
Ion channels as drug targets 45 The induction phase 84
Ion selectivity 45 The effector phase 85
Gating 45 Systemic responses in inflammation 88
Molecular architecture of ion channels 46 The role of the nervous system in inflammation 88
Pharmacology of ion channels 47 Unwanted inflammatory and immune
Control of receptor expression 47 responses 88
Receptors and disease 48 The outcome of the inflammatory response 89 v
 CONTENTS • SECTIONS 1 AND 2

7. Method and measurement in pharmacology 91 Drug elimination expressed as clearance 126

Single-compartment model 127
Overview 91 Effect of repeated dosing 127
Bioassay 91 Effect of variation in rate of absorption 128
Biological test systems 91 More complicated kinetic models 128
General principles of bioassay 92 Two-compartment model 129
Animal models of disease 94 Saturation kinetics 130
Genetic and transgenic animal models 95 Population pharmacokinetics 131
Pharmacological studies in humans 96 Limitations of pharmacokinetics 131
Clinical trials 96
Avoidance of bias 97 11. Individual variation, pharmacogenomics and
The size of the sample 98
Clinical outcome measures 98
personalised medicine 133
Placebos 99 Overview 133
Meta-analysis 99 Introduction 133
Balancing benefit and risk 99 Epidemiological factors and inter-individual variation
of drug response 134
8. Absorption and distribution of drugs 101 Ethnicity 134
Age 134
Overview 101
Pregnancy 135
Introduction 101 Disease 136
Physical processes underlying drug Drug interactions 136
disposition 101 Genetic variation in drug responsiveness 137
The movement of drug molecules across Relevant elementary genetics 137
cell barriers 101 Single-gene pharmacokinetic disorders 138
Binding of drugs to plasma proteins 106 Therapeutic drugs and clinically available
Partition into body fat and other tissues 107 pharmacogenomic tests 139
Drug absorption and routes of administration 108 HLA gene tests 140
Oral administration 109 Drug metabolism-related gene tests 140
Sublingual administration 110 Drug target-related gene tests 141
Rectal administration 110 Combined (metabolism and target) gene tests 141
Application to epithelial surfaces 110 Conclusions 141
Distribution of drugs in the body 112
Body fluid compartments 112
Volume of distribution 113
Special drug delivery systems 114
Section 2: Chemical mediators

9. Drug metabolism and elimination 116 12. Chemical mediators and the autonomic
Overview 116 nervous system 143
Introduction 116 Overview 143
Drug metabolism 116 Historical aspects 143
Phase 1 reactions 116 The autonomic nervous system 144
Phase 2 reactions 118 Basic anatomy and physiology 144
Stereoselectivity 118 Transmitters in the autonomic nervous system 145
Inhibition of P450 118 Some general principles of chemical
Induction of microsomal enzymes 119 transmission 147
First-pass (presystemic [‘first-pass’] metabolism) 119 Dale’s principle 147
Pharmacologically active drug Denervation supersensitivity 147
metabolites 119 Presynaptic modulation 148
Drug interactions due to enzyme induction or Postsynaptic modulation 149
inhibition 120 Transmitters other than acetylcholine and
Drug and metabolite excretion 122 noradrenaline 149
Biliary excretion and enterohepatic Co-transmission 149
circulation 122 Termination of transmitter action 151
Renal excretion of drugs and metabolites 122 Basic steps in neurochemical transmission: sites of
Drug interactions due to altered drug drug action 153
excretion 123
13. Cholinergic transmission 155
10. Pharmacokinetics 125 Overview 155
Overview 125 Muscarinic and nicotinic actions of
Introduction: definition and uses of acetylcholine 155
pharmacokinetics 125 Acetylcholine receptors 155
Uses of pharmacokinetics 125 Nicotinic receptors 155
vi Scope of this chapter 126 Muscarinic receptors 157
 SECTION 2 • CONTENTS

Physiology of cholinergic transmission 158 Histamine receptors 213

Acetylcholine synthesis and release 158 Actions 213
Electrical events in transmission at fast cholinergic Eicosanoids 214
synapses 160 General remarks 214
Effects of drugs on cholinergic transmission 161 Structure and biosynthesis 214
Drugs affecting muscarinic receptors 161 Prostanoids 214
Drugs affecting autonomic ganglia 165 Leukotrienes 218
Drugs that act presynaptically 170 Leukotrienes receptors 219
Drugs that enhance cholinergic Leukotrienes actions 219
transmission 171 Lipoxins and resolvins 220
Other drugs that enhance cholinergic Platelet-activating factor 220
transmission 176 Biosynthesis 220
Actions and role in inflammation 220
14. Noradrenergic transmission 177 Concluding remarks 220
Overview 177
Catecholamines 177 18. Local hormones 2: peptides and proteins 222
Classification of adrenoceptors 177 Overview 222
Physiology of noradrenergic transmission 178 Introduction 222
The noradrenergic neuron 178 General principles of protein and peptide
Uptake and degradation of catecholamines 181 pharmacology 222
Drugs acting on noradrenergic Structure 222
transmission 182 Types of protein and peptide mediator 222
Drugs acting on adrenoceptors 182 Biosynthesis and regulation of peptides 223
Drugs that affect noradrenergic neurons 192 Peptide precursors 223
Diversity within peptide families 224
15. 5-Hydroxytryptamine and the pharmacology Peptide trafficking and secretion 224
of migraine 197 Bradykinin 224
Source and formation of bradykinin 224
Overview 197 Metabolism and inactivation of bradykinin 225
5-Hydroxytryptamine 197 Bradykinin receptors 225
Distribution, biosynthesis and degradation 197 Actions and role in inflammation 225
Pharmacological effects 197 Neuropeptides 226
Drugs acting at 5-HT receptors 201 Cytokines 226
Migraine and other clinical conditions in which Interleukins and related compounds 228
5-HT plays a role 203 Chemokines 228
Migraine and antimigraine drugs 203 Interferons 228
Carcinoid syndrome 205 The ‘cytokine storm’ 228
Pulmonary hypertension 206 Proteins and peptides that downregulate
inflammation 229
16. Purines 207 Concluding remarks 229
Overview 207
Introduction 207 19. Cannabinoids 231
Purinergic receptors 207 Overview 231
Adenosine as a mediator 207 Plant-derived cannabinoids and their
Adenosine and the cardiovascular system 209 pharmacological effects 231
Adenosine and asthma 209 Pharmacological effects 231
Adenosine in the CNS 210 Pharmacokinetic and analytical aspects 231
ADP as a mediator 210 Adverse effects 231
ADP and platelets 210 Tolerance and dependence 232
ATP as a mediator 210 Cannabinoid receptors 232
ATP as a neurotransmitter 210 Endocannabinoids 233
ATP in nociception 210 Biosynthesis of endocannabinoids 233
ATP in inflammation 210 Termination of the endocannabinoid signal 234
Future prospects 211 Physiological mechanisms 235
Pathological involvement 235
17. Local hormones 1: histamine and the biologically Synthetic cannabinoids 235
active lipids 212 Clinical applications 235
Overview 212
Introduction 212
20. Nitric oxide and related mediators 237
What is a ‘mediator’? 212 Overview 237
Histamine 212 Introduction 237
Synthesis and storage of histamine 212 Biosynthesis of nitric oxide and its control 237
Histamine release 213 Degradation and carriage of nitric oxide 239 vii
 CONTENTS • SECTIONS 2 AND 3

Effects of nitric oxide 240 Prevention of atheromatous disease 288

Biochemical and cellular aspects 240 Lipid-lowering drugs 289
Vascular effects 241 Statins: HMG-CoA reductase inhibitors 289
Neuronal effects 241 Fibrates 290
Host defence 241 Drugs that inhibit cholesterol absorption 290
Therapeutic aspects 242 Nicotinic acid 291
Nitric oxide 242 Fish oil derivatives 291
Nitric oxide donors/precursors 242
Inhibition of nitric oxide synthesis 242 24. Haemostasis and thrombosis 293
Nitric oxide replacement or potentiation 243 Overview 293
Clinical conditions in which nitric oxide may Introduction 293
play a part 243 Blood coagulation 293
Related mediators 244 Coagulation cascade 293
Vascular endothelium in haemostasis and
Section 3: Drugs affecting major thrombosis 295
Drugs that act on the coagulation cascade 296
organ systems Coagulation defects 296
Thrombosis 297
21. The heart 247 Platelet adhesion and activation 301
Overview 247 Antiplatelet drugs 302
Introduction 247 Fibrinolysis (thrombolysis) 304
Physiology of cardiac function 247 Fibrinolytic drugs 304
Antifibrinolytic and haemostatic drugs 307
Cardiac rate and rhythm 247
Cardiac contraction 250
Myocardial oxygen consumption and coronary
25. Haemopoietic system and treatment
blood flow 251 of anaemia 308
Autonomic control of the heart 252 Overview 308
Sympathetic system 252 Introduction 308
Parasympathetic system 253 The haemopoietic system 308
Cardiac natriuretic peptides 254 Types of anaemia 308
Ischaemic heart disease 254 Haematinic agents 309
Angina 254 Iron 309
Myocardial infarction 255 Folic acid and vitamin B12 311
Drugs that affect cardiac function 255 Haemopoietic growth factors 312
Antidysrhythmic drugs 255 Erythropoietin 313
Drugs that increase myocardial Haemolytic anaemia 315
contraction 259 Drugs used to treat haemolytic anaemias 315
Antianginal drugs 260

22. The vascular system 265 26. Anti-inflammatory and immunosuppressant

Overview 265
drugs 317
Introduction 265 Overview 317
Vascular structure and function 265 Cyclo-oxygenase inhibitors 317
Control of vascular smooth muscle tone 266 Mechanism of action 318
The vascular endothelium 266 Pharmacological actions 320
The renin–angiotensin system 269 Therapeutic actions 320
Vasoactive drugs 271 Some important NSAIDs and coxibs 322
Vasoconstrictor drugs 271 Antirheumatoid drugs 325
Vasodilator drugs 272 Disease-modifying anti-rheumatic drugs 326
Clinical uses of vasoactive drugs 276 Immunosuppressant drugs 327
Systemic hypertension 276 Anticytokine drugs and other
Heart failure 279 biopharmaceuticals 329
Shock and hypotensive states 280 Drugs used in gout 330
Peripheral vascular disease 282 Antagonists of histamine 331
Raynaud’s disease 282 Possible future developments 333
Pulmonary hypertension 282
27. Skin 335
23. Atherosclerosis and lipoprotein metabolism 285 Overview 335
Overview 285 Introduction 335
Introduction 285 Structure of skin 335
Atherogenesis 285 Common diseases of the skin 337
Lipoprotein transport 286 Acne 337
viii Dyslipidaemia 286 Rosacea 338
 SECTION 3 • CONTENTS

Baldness and hirsutism 338 Gastric secretion 367

Eczema 338 The regulation of acid secretion by
Pruritus 338 parietal cells 367
Urticaria 338 The coordination of factors regulating acid
Psoriasis 338 secretion 368
Warts 339 Drugs used to inhibit or neutralise gastric acid
Other infections 339 secretion 339
Drugs acting on skin 339 Treatment of Helicobacter pylori infection 371
Formulation 339 Drugs that protect the mucosa 372
Principal drugs used in skin disorders 339 Vomiting 372
Antimicrobial agents 339 The reflex mechanism of vomiting 372
Glucocorticoids and other anti-inflammatory Antiemetic drugs 373
agents 340 The motility of the gastrointestinal tract 375
Drugs used to control hair growth 340 Purgatives 376
Retinoids 341 Drugs that increase gastrointestinal motility 376
Vitamin D analogues 341 Antidiarrhoeal agents 376
Agents acting by other mechanisms 342 Drugs for chronic bowel disease 378
Concluding remarks 342 Drugs affecting the biliary system 378
Future directions 378
28. Respiratory system 344
Overview 344 31. The control of blood glucose and drug treatment
The physiology of respiration 344 of diabetes mellitus 380
Control of breathing 344 Overview 380
Regulation of musculature, blood vessels and Introduction 380
glands of the airways 344 Control of blood glucose 380
Pulmonary disease and its treatment 345
Pancreatic islet hormones 380
Bronchial asthma 345
Insulin 380
Drugs used to treat and prevent
Glucagon 384
asthma 348
Somatostatin 384
Severe acute asthma (status asthmaticus) 351
Amylin (islet amyloid polypeptide) 385
Allergic emergencies 352
Incretins 385
Chronic obstructive pulmonary disease 352
Diabetes mellitus 385
Surfactants 353
Treatment of diabetes mellitus 386
Cough 353
Potential new antidiabetic drugs 391
29. The kidney and urinary system 355 32. Obesity 393
Overview 355 Overview 393
Introduction 355 Introduction 393
Outline of renal function 355 Definition of obesity 393
The structure and function of the Obesity as a health problem 393
nephron 355 Homeostatic mechanisms controlling
Tubular function 356 energy balance 394
Acid–base balance 360 The role of gut and other hormones in body
Potassium balance 360 weight regulation 394
Excretion of organic molecules 360 Neurological circuits that control body weight and
Natriuretic peptides 361 eating behaviour 394
Prostaglandins and renal function 361 The pathophysiology of human obesity 397
Drugs acting on the kidney 361 Food intake and obesity 397
Diuretics 361 Physical exercise and obesity 398
Drugs that alter the pH of the urine 365 Obesity as a disorder of the homeostatic control of
Drugs that alter the excretion of organic energy balance 398
molecules 365 Genetic factors and obesity 398
Drugs used in renal failure 365 Pharmacological approaches to the problem
Hyperphosphataemia 365 of obesity 399
Hyperkalaemia 366 Centrally acting appetite suppressants 399
Drugs used in urinary tract disorders 366 Orlistat 399
New approaches to obesity therapy 400
30. The gastrointestinal tract 367
Overview 367 33. The pituitary and the adrenal cortex 402
The innervation and hormones of the gastrointestinal Overview 402
tract 367 The pituitary gland 402
Neuronal control 367 The anterior pituitary gland 402
Hormonal control 367 Hypothalamic hormones 402 ix
 CONTENTS • SECTIONS 3 AND 4

Anterior pituitary hormones 403 Bone remodelling 439

Posterior pituitary gland 407 The action of cells and cytokines 439
The adrenal cortex 408 The turnover of bone minerals 441
Glucocorticoids 409 Hormones involved in bone metabolism
Mineralocorticoids 414 and remodelling 441
New directions in glucocorticoid therapy 415 Disorders of bone 444
Drugs used in bone disorders 444
34. The thyroid 418 Bisphosphonates 444
Overview 418 Oestrogens and related compounds 445
Synthesis, storage and secretion of Parathyroid hormone and teriparatide 446
thyroid hormones 418 Strontium 446
Uptake of plasma iodide by the follicle cells 418 Vitamin D preparations 446
Oxidation of iodide and iodination of Biologicals 447
tyrosine residues 418 Calcitonin 447
Secretion of thyroid hormone 418 Calcium salts 447
Regulation of thyroid function 418 Calcimimetic compounds 447
Actions of the thyroid hormones 420 Potential new therapies 447
Effects on metabolism 420
Effects on growth and development 420 Section 4: Nervous system
Mechanism of action 420
Transport and metabolism of thyroid
hormones 420 37. Chemical transmission and drug action in
Abnormalities of thyroid function 421 the central nervous system 449
Hyperthyroidism (thyrotoxicosis) 421
Overview 449
Simple, non-toxic goitre 421
Hypothyroidism 421 Introduction 449
Drugs used in diseases of the thyroid 421 Chemical signalling in the nervous system 449
Hyperthyroidism 421 Targets for drug action 450
Hypothyroidism 423 Drug action in the central nervous system 451
Blood–brain barrier 452
35. The reproductive system 425 The classification of psychotropic drugs 452
Overview 425
Introduction 425
38. Amino acid transmitters 454
Endocrine control of reproduction 425 Overview 454
Neurohormonal control of the female Excitatory amino acids 454
reproductive system 425 Excitatory amino acids as CNS transmitters 454
Neurohormonal control of the male reproductive Metabolism and release of excitatory amino
system 426 acids 454
Behavioural effects of sex hormones 427 Glutamate 455
Drugs affecting reproductive function 428 Glutamate receptor subtypes 455
Oestrogens 428 Synaptic plasticity and long-term potentiation 458
Antioestrogens 429 Drugs acting on glutamate receptors 459
Progestogens 429 γ-Aminobutyric acid (GABA) 462
Postmenopausal hormone replacement Synthesis, storage and function 462
therapy 430 GABA receptors: structure and pharmacology 462
Androgens 430 Drugs acting on GABA receptors 463
Anabolic steroids 431 Glycine 465
Antiandrogens 431 Concluding remarks 465
Gonadotrophin-releasing hormone: agonists
and antagonists 432 39. Other transmitters and modulators 467
Gonadotrophins and analogues 432 Overview 467
Drugs used for contraception 433 Introduction 467
Oral contraceptives 433 Noradrenaline 467
Other drug regimens used for contraception 434 Noradrenergic pathways in the CNS 467
The uterus 435 Functional aspects 467
The motility of the uterus 435 Dopamine 468
Drugs that stimulate the uterus 435 Dopaminergic pathways in the CNS 469
Drugs that inhibit uterine contraction 436 Dopamine receptors 470
Erectile dysfunction 436 Functional aspects 471
5-Hydroxytryptamine 472
36. Bone metabolism 439 5-HT pathways in the CNS 473
Overview 439 5-HT receptors in the CNS 473
Introduction 439 Functional aspects 473
x Bone structure and composition 439 Clinically used drugs 474
 SECTION 4 • CONTENTS

Acetylcholine 474 Analgesic drugs 515

Cholinergic pathways in the CNS 474 Opioid drugs 515
Acetylcholine receptors 475 Paracetamol 526
Functional aspects 476 Treatment of neuropathic pain 527
Purines 476 Other pain-relieving drugs 528
Histamine 477 New approaches 529
Other CNS mediators 477
Melatonin 477 43. Local anaesthetics and other drugs affecting
Nitric oxide 478 sodium channels 530
Lipid mediators 478
Overview 530
A final message 479
Local anaesthetics 530
40. Neurodegenerative diseases 482 Chemical aspects 530
Mechanism of action 530
Overview 482 Pharmacokinetic aspects 533
Protein misfolding and aggregation in chronic New approaches 533
neurodegenerative diseases 482 Other drugs that affect sodium channels 534
Mechanisms of neuronal death 482 Tetrodotoxin and saxitoxin 534
Excitotoxicity 484 Agents that affect sodium channel gating 535
Apoptosis 484
Oxidative stress 485 44. Anxiolytic and hypnotic drugs 536
Ischaemic brain damage 486 Overview 536
Pathophysiology 486 The nature of anxiety and its treatment 536
Therapeutic approaches 487 Measurement of anxiolytic activity 536
Alzheimer’s disease 487 Animal models of anxiety 536
Pathogenesis of Alzheimer’s disease 487 Tests on humans 537
Therapeutic approaches 489 Drugs used to treat anxiety 538
Parkinson’s disease 491 Benzodiazepines and related drugs 538
Features of Parkinson’s disease 491 Buspirone 543
Pathogenesis of Parkinson’s disease 492 Other potential anxiolytic drugs 543
Drug treatment of Parkinson’s disease 493 Drugs used to treat insomnia (hypnotic drugs) 544
Huntington’s disease 496
Neurodegenerative prion diseases 496 45. Antiepileptic drugs 546
41. General anaesthetic agents 498 Overview 546
Introduction 546
Overview 498 The nature of epilepsy 546
Introduction 498 Types of epilepsy 546
Mechanism of action of anaesthetic Neural mechanisms and animal models
drugs 498 of epilepsy 548
Lipid solubility 498 Antiepileptic drugs 549
Effects on ion channels 499 Carbamazepine 552
Effects on the nervous system 500 Phenytoin 553
Effects on the cardiovascular and respiratory Valproate 554
systems 500 Ethosuximide 554
Intravenous anaesthetic agents 501 Phenobarbital 554
Propofol 501 Benzodiazepines 555
Thiopental 501 Newer antiepileptic drugs 555
Etomidate 502 Development of new drugs 556
Other intravenous agents 502 Other uses of antiepileptic drugs 557
Inhalation anaesthetics 503 Antiepileptic drugs and pregnancy 557
Pharmacokinetic aspects 503 Muscle spasm and muscle relaxants 557
Individual inhalation anaesthetics 506
Isoflurane, desflurane, sevoflurane, enflurane and 46. Antipsychotic drugs 559
halothane 506 Overview 559
Nitrous oxide 507 Introduction 559
Balanced anaesthesia 507
The nature of schizophrenia 559
Aetiology and pathogenesis of schizophrenia 560
42. Analgesic drugs 509 Antipsychotic drugs 562
Overview 509 Classification of antipsychotic drugs 562
Neural mechanisms of pain 509 Clinical efficacy 562
Nociceptive afferent neurons 509 Pharmacological properties 565
Modulation in the nociceptive pathway 510 Unwanted effects 566
Neuropathic pain 511 Pharmacokinetic aspects 567
Chemical signalling in the nociceptive pathway 512 Future developments 568 xi
 CONTENTS • SECTIONS 4 AND 5
47. Antidepressant drugs 570
Overview 570
The nature of depression 570
Theories of depression 570
The monoamine theory 570
Neuroendocrine mechanisms 571
Trophic effects and neuroplasticity 571
Antidepressant drugs 572
Types of antidepressant drug 572
Testing of antidepressant drugs 573
Mechanism of action of antidepressant drugs 577
Monoamine uptake inhibitors 577
Monoamine receptor antagonists 582
Monoamine oxidase inhibitors 582
Melatonin agonist 584
Miscellaneous agents 584
Future antidepressant drugs 584
Brain stimulation therapies 585
Clinical effectiveness of antidepressant
treatments 585
Other clinical uses of antidepressant drugs 586
Drug treatment of bipolar disorder 586
Lithium 586
Antiepileptic drugs 587
Atypical antipsychotic drugs 587
48. CNS stimulants and psychotomimetic drugs 589
Overview 589
Psychomotor stimulants 589
Amphetamines 589
Methylphenidate 591
Modafinil 591
Cocaine 592
Methylxanthines 593
Cathinones 594
Other stimulants 594
Cognition-enhancing drugs 594
Psychotomimetic drugs 595
LSD, psilocybin and mescaline 595
MDMA (ecstasy) 596
Ketamine and phencyclidine 596
Other psychotomimetic drugs 597
49. Drug addiction, dependence and abuse 598
Overview 598
Drug use and abuse 598
Drug administration 598
Drug harm 600
Drug dependence 600
Tolerance 601
Pharmacological approaches to treating
drug addiction 603
Nicotine and tobacco 603
Pharmacological effects of smoking 603
Pharmacokinetic aspects 605
Tolerance and dependence 605
Harmful effects of smoking 606
Pharmacological approaches to treating
nicotine dependence 607
Ethanol 608
Pharmacological effects of ethanol 608
xii Pharmacokinetic aspects 611
Tolerance and dependence 612
Pharmacological approaches to treating alcohol
dependence 613
Section 5: Drugs used for the treatment of
infections and cancer
50. Basic principles of antimicrobial
chemotherapy 615
Overview 615
Background 615
The molecular basis of chemotherapy 615
Biochemical reactions as potential targets 616
The formed structures of the cell as potential
targets 620
Resistance to antibacterial drugs 621
Genetic determinants of antibiotic resistance 622
Biochemical mechanisms of resistance to antibiotics 623
Current status of antibiotic resistance in bacteria 624
51. Antibacterial drugs 626
Overview 626
Introduction 626
Antimicrobial agents that interfere with folate synthesis
or action 626
Sulfonamides 626
Trimethoprim 629
β-Lactam antibiotics 630
Penicillins 630
Cephalosporins and cephamycins 631
Other β-lactam antibiotics 632
Glycopeptides 632
Antimicrobial agents affecting bacterial
protein synthesis 632
Tetracyclines 632
Chloramphenicol 634
Aminoglycosides 634
Macrolides 635
Antimicrobial agents affecting topoisomerase 635
Quinolones 635
Miscellaneous and less common
antibacterial agents 637
Antimycobacterial agents 638
Drugs used to treat tuberculosis 638
Drugs used to treat leprosy 639
Possible new antibacterial drugs 640
52. Antiviral drugs 642
Overview 642
Background information about viruses 642
An outline of virus structure 642
Examples of pathogenic viruses 642
Virus function and life history 642
The host–virus interaction 643
Host defences against viruses 643
Viral ploys to circumvent host defences 644
HIV and AIDS 644
Antiviral drugs 645
Reverse transcriptase inhibitors 645
Non-nucleoside reverse transcriptase inhibitors 647
Protease inhibitors 647
 SECTIONS 5 AND 6 • CONTENTS

DNA polymerase inhibitors 648

Neuraminidase inhibitors and inhibitors of viral coat Section 6: Special topics
disassembly 649
Drugs acting through other mechanisms 649
Biopharmaceutical antiviral drugs 650
57. Harmful effects of drugs 692
Other agents 650 Overview 692
Combination therapy for HIV 650 Introduction 692
Prospects for new antiviral drugs 651 Classification of adverse drug reactions 692
Adverse effects related to the known pharmacological
53. Antifungal drugs 653 action of the drug 692
Overview 653 Adverse effects unrelated to the known
Fungi and fungal infections 653 pharmacological action of the drug 693
Drugs used to treat fungal infections 654 Drug toxicity 693
Antifungal antibiotics 654 Toxicity testing 693
Synthetic antifungal drugs 655 General mechanisms of toxin-induced cell damage
Future developments 657 and cell death 693
Mutagenesis and assessment of genotoxic
54. Antiprotozoal drugs 658 potential 696
Immunological reactions to drugs 700
Overview 658
Immunological mechanisms 700
Host–parasite interactions 658 Clinical types of allergic response to drugs 700
Malaria and antimalarial drugs 658
The life cycle of the malaria parasite 659 58. Lifestyle drugs and drugs in sport 703
Antimalarial drugs 661
Potential new antimalarial drugs 666 Overview 703
Amoebiasis and amoebicidal drugs 666 What are lifestyle drugs? 703
Trypanosomiasis and trypanocidal drugs 667 Classification of lifestyle drugs 703
Other protozoal infections and drugs used Drugs in sport 703
to treat them 668 Anabolic steroids 705
Leishmaniasis 668 Human growth hormone 706
Trichomoniasis 668 Stimulant drugs 706
Giardiasis 669 Conclusion 706
Toxoplasmosis 669
Pneumocystis 669 59. Biopharmaceuticals and gene therapy 708
Future developments 669 Overview 708
Introduction 708
55. Anthelmintic drugs 671 Biopharmaceuticals 708
Overview 671 Proteins and polypeptides 709
Helminth infections 671 Monoclonal antibodies 710
Anthelmintic drugs 672 Gene therapy 711
Resistance to anthelmintic drugs 674 Gene delivery 711
Vaccines and other novel approaches 675 Controlling gene expression 713
Safety and societal issues 714
56. Anticancer drugs 676 Therapeutic applications 714
Gene therapy for cancer 714
Overview 676
Single-gene defects 715
Introduction 676
Gene therapy and infectious disease 716
The pathogenesis of cancer 676
Gene therapy and cardiovascular disease 716
The genesis of a cancer cell 676 Oligonucleotideapproaches 716
The special characteristics of cancer cells 677
General principles of cytotoxic anticancer drugs 679 60. Drug discovery and development 718
Anticancer drugs 679
Alkylating agents and related compounds 680 Overview 718
Antimetabolites 683 The stages of a project 718
Cytotoxic antibiotics 685 The drug discovery phase 718
Plant derivatives 685 Preclinical development 720
Hormones 686 Clinical development 720
Hormone antagonists 686 Biopharmaceuticals 721
Monoclonal antibodies 687 Commercial aspects 721
Protein kinase inhibitors 687 Future prospects 721
Miscellaneous agents 688 A final word 722
Resistance to anticancer drugs 689
Combination therapies 689
Control of emesis and myelosuppression 689 Appendix 723
Future developments 690 Index 724 xiii
This page intentionally left blank
 Rang and Dale’s Pharmacology
Eighth Edition Preface
In this edition, as in its predecessors, we set out not just
to describe what drugs do but also to emphasise the mech-
anisms by which they act. This entails analysis not only
at the cellular and molecular level, where knowledge and
techniques are advancing rapidly, but also at the level of
physiological mechanisms and pathological disturbances.
Pharmacology has its roots in therapeutics, where the aim
is to ameliorate the effects of disease, so we have attempted
to make the link between effects at the molecular and cel-
lular level and the range of beneficial and adverse effects
that humans experience when drugs are used for thera-
peutic or other reasons. Therapeutic agents have a high
rate of obsolescence, and more than 100 new ones have
been approved since the last edition of this book. An
appreciation of the mechanisms of action of the class of
drugs to which a new agent belongs provides a good start-
ing point for understanding and using a new compound
intelligently.
Pharmacology is a lively scientific discipline in its own
right, with an importance beyond that of providing a basis
for the use of drugs in therapy, and we aim to provide a
good background, not only for future doctors but also for
scientists in other disciplines who need to understand
how drugs act. We have, therefore, where appropriate,
described how drugs are used as probes for elucidating
cellular and physiological functions, even when the com-
pounds have no clinical use.
Names of drugs and related chemicals are established
through usage and sometimes there is more than one
name in common use. For prescribing purposes, it is
important to use standard names, and we follow, as far as
possible, the World Health Organization’s list of recom-
mended international non-proprietary names (rINN).
Sometimes these conflict with the familiar names of drugs
(e.g. amphetamine becomes amfetamine in the rINN list),
and the endogenous mediator prostaglandin I2 – the
standard name in the scientific literature – becomes ‘epo-
prostenol’ – a name unfamiliar to most scientists – in
the rINN list. In general, we use rINN names as far as
possible in the context of therapeutic use, but often use
the common name in describing mediators and familiar
drugs. Sometimes English and American usage varies
(as with adrenaline/epinephrine and noradrenaline/
norepinephrine). Adrenaline and noradrenaline are the
official names in EU member states and relate clearly to
terms such as ‘noradrenergic’, ‘adrenoceptor’ and ‘adrenal
gland’ and we prefer them for these reasons.
Drug action can be understood only in the context of
what else is happening in the body. So at the beginning
of most chapters, we briefly discuss the physiological and
biochemical processes relevant to the action of the drugs
described in that chapter. We have included the chemical
structures of drugs only where this information helps in
understanding their pharmacological and pharmacoki-
netic characteristics, secure in the knowledge that chemi-
cal structures are readily available online.
The overall organisation of the book has been retained,
with sections covering: (1) the general principles of drug
action; (2) the chemical mediators and cellular mecha-
nisms with which drugs interact in producing their
therapeutic effects; (3) the action of drugs on specific
organ systems; (4) the action of drugs on the nervous
system; (5) the action of drugs used to treat infectious
diseases and cancer; (6) a range of special topics such as
adverse effects, non-medical uses of drugs, etc. This
organisation reflects our belief that drug action needs to
be understood, not as a mere description of the effects of
individual drugs and their uses, but as a chemical inter-
vention that perturbs the network of chemical and cellular
signalling that underlies the function of any living organ-
ism. In addition to updating all of the chapters, we have
covered the receptor-related topics of biased agonism,
allosteric modulation and desensitisation in more detail
in Chapters 2 and 3, as well as revamping the section on
nuclear receptors. A new Chapter 27 on the pharmacology
of the skin has been added, and Chapters 17 and 18
on local hormones have been revised. Additional material
on cognition-enhancing drugs has been included in
Chapter 48.
Despite the fact that pharmacology, like other branches
of biomedical science, advances steadily, with the acquisi-
tion of new information, the development of new con-
cepts and the introduction of new drugs for clinical use,
we have avoided making the 8th edition any longer than
its predecessor by cutting out-dated and obsolete mate-
rial, and have made extensive use of small print text to
cover more specialised and speculative information that
is not essential to understanding the key message, but
will, we hope, be helpful to students seeking to go into
greater depth. In selecting new material for inclusion, we
have taken into account not only new agents but also
recent extensions of basic knowledge that presage further
drug development. And where possible, we have given a
brief outline of new treatments in the pipeline. Reference
lists are largely restricted to guidance on further reading,
together with review articles that list key original papers.
ACKNOWLEDGEMENTS
We would like to thank the following for their help
and advice in the preparation of this edition: Dr Alistair
Corbett, Dr Hannah Gill, Professor Eamonn Kelly,
Professor Alastair Poole, Dr Emma Robinson, Dr Maria
Usowicz and Professor Federica Marelli-Berg. We would
like to put on record our appreciation of the team at
Elsevier who worked on this edition: Meghan Ziegler
(commissioning editor), Alexandra Mortimer (develop-
ment editor), Joanna Souch (project manager), Brett
MacNaughton (illustration manager), Peter Lamb, Antbits
and Jason McAlexander (freelance illustrators), Elaine
Leek (freelance copyeditor), Marcela Holmes (freelance
proofreader) and Innodata Inc. (freelance indexing
services).
London 2014 H. P. Rang
J. M. Ritter
R. J. Flower
G. Henderson xv
This page intentionally left blank

What is pharmacology?
OVERVIEW
In this introductory chapter we explain how phar-
macology came into being and evolved as a scien-
tific discipline, and describe the present day structure
of the subject and its links to other biomedical
sciences. The structure that has emerged forms the
basis of the organisation of the rest of the book.
Readers in a hurry to get to the here-and-now of
pharmacology can safely skip this chapter.
WHAT IS A DRUG?
For the purposes of this book, a drug can be defined as a
chemical substance of known structure, other than a nutrient
or an essential dietary ingredient,1 which, when administered
to a living organism, produces a biological effect.
A few points are worth noting. Drugs may be synthetic
chemicals, chemicals obtained from plants or animals, or
products of genetic engineering. A medicine is a chemical
preparation, which usually, but not necessarily, contains
one or more drugs, administered with the intention of
producing a therapeutic effect. Medicines usually contain
other substances (excipients, stabilisers, solvents, etc.)
besides the active drug, to make them more convenient to
use. To count as a drug, the substance must be adminis-
tered as such, rather than released by physiological mech-
anisms. Many substances, such as insulin or thyroxine, are
endogenous hormones but are also drugs when they are
administered intentionally. Many drugs are not used in
medicines but are nevertheless useful research tools. In
everyday parlance, the word drug is often associated with
addictive, narcotic or mind-altering substances – an unfor-
tunate negative connotation that tends to bias uninformed
opinion against any form of chemical therapy. In this book
we focus mainly on drugs used for therapeutic purposes
but also describe important examples of drugs used as
experimental tools. Although poisons fall strictly within
the definition of drugs, they are not covered in this book.
ORIGINS AND ANTECEDENTS
Pharmacology can be defined as the study of the effects
of drugs on the function of living systems. As a science,
it was born in the mid-19th century, one of a host of new
biomedical sciences based on principles of experimenta-
tion rather than dogma that came into being in that
remarkable period. Long before that – indeed from the
dawn of civilisation – herbal remedies were widely used,
1
Like most definitions, this one has its limits. For example, there are a
number of essential dietary constituents, such as iron and various
vitamins, that are used as medicines. Furthermore, some biological
products (e.g. epoietin) show batch-to-batch variation in their chemical
constitution that significantly affects their properties.
GENERAL PRINCIPLES SECTION 1
1
pharmacopoeias were written, and the apothecaries’ trade
flourished. However, nothing resembling scientific prin-
ciples was applied to therapeutics, which was known at
that time as materia medica.2 Even Robert Boyle, who laid
the scientific foundations of chemistry in the middle of the
17th century, was content, when dealing with therapeu-
tics (A Collection of Choice Remedies, 1692), to recommend
concoctions of worms, dung, urine and the moss from a
dead man’s skull. The impetus for pharmacology came
from the need to improve the outcome of therapeutic
intervention by doctors, who were at that time skilled at
clinical observation and diagnosis but broadly ineffectual
when it came to treatment.3 Until the late 19th century,
knowledge of the normal and abnormal functioning of the
body was too rudimentary to provide even a rough basis
for understanding drug effects; at the same time, disease
and death were regarded as semisacred subjects, appro-
priately dealt with by authoritarian, rather than scientific,
doctrines. Clinical practice often displayed an obedience
to authority and ignored what appear to be easily ascer-
tainable facts. For example, cinchona bark was recognised
as a specific and effective treatment for malaria, and a
sound protocol for its use was laid down by Lind in 1765.
In 1804, however, Johnson declared it to be unsafe until
the fever had subsided, and he recommended instead the
use of large doses of calomel (mercurous chloride) in
the early stages – a murderous piece of advice that was
slavishly followed for the next 40 years.
The motivation for understanding what drugs can and
cannot do came from clinical practice, but the science
could be built only on the basis of secure foundations in
physiology, pathology and chemistry. It was not until
1858 that Virchow proposed the cell theory. The first use
of a structural formula to describe a chemical compound
was in 1868. Bacteria as a cause of disease were discovered
by Pasteur in 1878. Previously, pharmacology hardly had
the legs to stand on, and we may wonder at the bold
vision of Rudolf Buchheim, who created the first pharma-
cology institute (in his own house) in Estonia in 1847.
In its beginnings, before the advent of synthetic organic
chemistry, pharmacology concerned itself exclusively
with understanding the effects of natural substances,
mainly plant extracts – and a few (mainly toxic) chemicals
such as mercury and arsenic. An early development in
chemistry was the purification of active compounds from
plants. Friedrich Sertürner, a young German apothecary,
purified morphine from opium in 1805. Other substances
quickly followed, and, even though their structures were
unknown, these compounds showed that chemicals, not
magic or vital forces, were responsible for the effects that
2
The name persists today in some ancient universities, being attached to
chairs of what we would call clinical pharmacology.
3
Oliver Wendell Holmes, an eminent physician, wrote in 1860: ‘[I]
firmly believe that if the whole materia medica, as now used, could be
sunk to the bottom of the sea, it would be all the better for mankind
and the worse for the fishes’ (see Porter, 1997). 1
1 SECTION 1 GENERAL PRINCIPLES
plant extracts produced on living organisms. Early phar-
macologists focused most of their attention on such plant-
derived drugs as quinine, digitalis, atropine, ephedrine,
strychnine and others (many of which are still used today
and will have become old friends by the time you have
finished reading this book).4
PHARMACOLOGY IN THE 20TH AND
21ST CENTURIES
Beginning in the 20th century, the fresh wind of synthetic
chemistry began to revolutionise the pharmaceutical
industry, and with it the science of pharmacology. New
synthetic drugs, such as barbiturates and local anaesthet-
ics, began to appear, and the era of antimicrobial chemo-
therapy began with the discovery by Paul Ehrlich in 1909
of arsenical compounds for treating syphilis. Further
breakthroughs came when the sulfonamides, the first anti-
bacterial drugs, were discovered by Gerhard Domagk in
1935, and with the development of penicillin by Chain
and Florey during the Second World War, based on the
earlier work of Fleming.
These few well-known examples show how the growth
of synthetic chemistry, and the resurgence of natural
product chemistry, caused a dramatic revitalisation of
therapeutics in the first half of the 20th century. Each new
drug class that emerged gave pharmacologists a new chal-
lenge, and it was then that pharmacology really estab-
lished its identity and its status among the biomedical
sciences.
In parallel with the exuberant proliferation of therapeu-
tic molecules – driven mainly by chemistry – which gave
pharmacologists so much to think about, physiology was
also making rapid progress, particularly in relation to
chemical mediators, which are discussed in depth else-
where in this book. Many hormones, neurotransmitters
and inflammatory mediators were discovered in this
period, and the realisation that chemical communication
plays a central role in almost every regulatory mechanism
that our bodies possess immediately established a large
area of common ground between physiology and phar-
macology, for interactions between chemical substances
and living systems were exactly what pharmacologists
had been preoccupied with from the outset. The concept
of ‘receptors’ for chemical mediators, first proposed by
Langley in 1905, was quickly taken up by pharmacologists
such as Clark, Gaddum, Schild and others and is a con-
stant theme in present-day pharmacology (as you will
soon discover as you plough through the next two chap-
ters). The receptor concept, and the technologies devel-
oped from it, have had a massive impact on drug discovery
4
A handful of synthetic substances achieved pharmacological
prominence long before the era of synthetic chemistry began. Diethyl
ether, first prepared as ‘sweet oil of vitriol’ in the 16th century, and
nitrous oxide, prepared by Humphrey Davy in 1799, were used to liven
up parties before being introduced as anaesthetic agents in the
mid-19th century (see Ch. 41). Amyl nitrite (see Ch. 21) was made in
1859 and can claim to be the first ‘rational’ therapeutic drug; its
therapeutic effect in angina was predicted on the basis of its
physiological effects – a true ‘pharmacologist’s drug’ and the smelly
forerunner of the nitrovasodilators that are widely used today. Aspirin
(Ch. 26), the most widely used therapeutic drug in history, was first
synthesised in 1853, with no therapeutic application in mind. It was
rediscovered in 1897 in the laboratories of the German company Bayer,
2 who were seeking a less toxic derivative of salicylic acid. Bayer
commercialised aspirin in 1899 and made a fortune.
and therapeutics. Biochemistry also emerged as a distinct
science early in the 20th century, and the discovery of
enzymes and the delineation of biochemical pathways
provided yet another framework for understanding drug
effects. The picture of pharmacology that emerges from
this brief glance at history (Fig. 1.1) is of a subject evolved
from ancient prescientific therapeutics, involved in com-
merce from the 17th century onwards, and which gained
respectability by donning the trappings of science as soon
as this became possible in the mid-19th century. Signs of
its carpetbagger past still cling to pharmacology, for the
pharmaceutical industry has become very big business
and much pharmacological research nowadays takes
place in a commercial environment, a rougher and more
pragmatic place than the glades of academia.5 No other
biomedical ‘ology’ is so close to Mammon.
ALTERNATIVE THERAPEUTIC PRINCIPLES
Modern medicine relies heavily on drugs as the main
tool of therapeutics. Other therapeutic procedures, such
as surgery, diet, exercise, psychological treatments etc.,
are also important, of course, as is deliberate non-
intervention, but none is so widely applied as drug-based
therapeutics.
Before the advent of science-based approaches, repeated
attempts were made to construct systems of therapeutics,
many of which produced even worse results than pure
empiricism. One of these was allopathy, espoused by James
Gregory (1735–1821). The favoured remedies included
blood letting, emetics and purgatives, which were used
until the dominant symptoms of the disease were sup-
pressed. Many patients died from such treatment, and it
was in reaction against it that Hahnemann introduced the
practice of homeopathy in the early 19th century. The
implausible guiding principles of homeopathy are:
• like cures like
• activity can be enhanced by dilution.
The system rapidly drifted into absurdity: for example,
Hahnemann recommended the use of drugs at dilutions
of 1 : 1060, equivalent to one molecule in a sphere the size
of the orbit of Neptune.
Many other systems of therapeutics have come and
gone, and the variety of dogmatic principles that they
embodied have tended to hinder rather than advance sci-
entific progress. Currently, therapeutic systems that have
a basis that lies outside the domain of science are actually
gaining ground under the general banner of ‘alternative’
or ‘complementary’ medicine. Mostly, they reject the
‘medical model’, which attributes disease to an underlying
derangement of normal function that can be defined in
biochemical or structural terms, detected by objective
means, and influenced beneficially by appropriate chemi-
cal or physical interventions. They focus instead mainly
on subjective malaise, which may be disease-associated or
5
Some of our most distinguished pharmacological pioneers made
their careers in industry: for example, Henry Dale, who laid the
foundations of our knowledge of chemical transmission and the
autonomic nervous system (Ch. 12); George Hitchings and Gertrude
Elion, who described the antimetabolite principle and produced
the first effective anticancer drugs (Ch. 56); and James Black, who
introduced the first β-adrenoceptor and histamine H2-receptor
antagonists (Chs 13 and 17). It is no accident that in this book, where
we focus on the scientific principles of pharmacology, most of our
examples are products of industry, not of nature.

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not. Abandoning objectivity in defining and measuring
disease goes along with a similar departure from scientific
principles in assessing therapeutic efficacy and risk, with
the result that principles and practices can gain acceptance
without satisfying any of the criteria of validity that would
convince a critical scientist, and that are required by law
to be satisfied before a new drug can be introduced into
therapy. Demand for ‘alternative’ therapies by the general
public, alas, has little to do with demonstrable efficacy.6
THE EMERGENCE OF BIOTECHNOLOGY
Since the 1980s, biotechnology has emerged as a major
source of new therapeutic agents in the form of antibod-
ies, enzymes and various regulatory proteins, including
hormones, growth factors and cytokines (see Buckel, 1996;
Walsh, 2003). Although such products (known as biophar-
maceuticals) are generally produced by genetic engineer-
ing rather than by synthetic chemistry, the pharmacological
principles are essentially the same as for conventional
drugs. Looking further ahead, gene- and cell-based thera-
pies (Ch. 59), although still in their infancy, will take
therapeutics into a new domain. The principles governing
the design, delivery and control of functioning artificial
genes introduced into cells, or of engineered cells intro-
6
The UK Medicines and Healthcare Regulatory Agency (MHRA)
requires detailed evidence of therapeutic efficacy based on controlled
clinical trials before a new drug is registered, but no clinical trials data
for homeopathic products or for the many herbal medicines that were
on sale before the Medicines Act of 1968.
What is pharmacology? 1
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duced into the body, are very different from those of
drug-based therapeutics and will require a different con-
ceptual framework, which texts such as this will increas-
ingly need to embrace if they are to stay abreast of modern
medical treatment.
PHARMACOLOGY TODAY
As with other biomedical disciplines, the boundaries of
pharmacology are not sharply defined, nor are they
constant. Its exponents are, as befits pragmatists, ever
ready to poach on the territory and techniques of other
disciplines. If it ever had a conceptual and technical
core that it could really call its own, this has now dwindled
almost to the point of extinction, and the subject is defined
by its purpose – to understand what drugs do to living
organisms, and more particularly how their effects can
be applied to therapeutics – rather than by its scientific
coherence.
Figure 1.2 shows the structure of pharmacology as it
appears today. Within the main subject fall a number of
compartments (neuropharmacology, immunopharmacol-
ogy, pharmacokinetics, etc.), which are convenient, if not
watertight, subdivisions. These topics form the main
subject matter of this book. Around the edges are several
interface disciplines, not covered in this book, which form
important two-way bridges between pharmacology and
other fields of biomedicine. Pharmacology tends to have
more of these than other disciplines. Recent arrivals on
the fringe are subjects such as pharmacogenomics, phar- 3
macoepidemiology and pharmacoeconomics.
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