Rang and Dale's pharmacology

Rang & Dale\'s Pharmacology
Copyright Page
Rang and Dale’s Pharmacology Ninth Edition Preface
Acknowledgements
1 • General Principles
	1 What is pharmacology?
		Overview
		What Is a Drug?
		Origins and Antecedents
		Pharmacology in the 20Th and 21St Centuries
			Alternative Therapeutic Principles
			The Emergence of Biotechnology
			Pharmacology Today
				Pharmacogenomics.
				Pharmacoepidemiology.
				Pharmacoeconomics.
		References and Further Reading
1 General Principles
	2 How drugs act
		Overview
		Introduction
		Protein Targets for Drug Binding
			Drug Receptors
				What Do We Mean by Receptors?
				Receptors in Physiological Systems
			Drug Specificity
			Receptor Classification
			Drug–Receptor Interactions
				The Binding of Drugs to Receptors
				The Relation Between Drug Concentration and Effect
				Spare Receptors
			Competitive Antagonism
				Irreversible Competitive Antagonism
			Partial Agonists and the Concept of Efficacy
			Partial Agonists as Antagonists
				Constitutive Receptor Activation and Inverse Agonists
					The two-state receptor model
				Biased Agonism
				Allosteric Modulation
			Other Forms of Drug Antagonism
				Chemical Antagonism
				Pharmacokinetic Antagonism
				Block of Receptor–Response Linkage
				Physiological Antagonism
		Desensitisation and Tolerance
			Change in Receptors
			Translocation of Receptors
			Exhaustion of Mediators
			Altered Drug Metabolism
			Physiological Adaptation
		Quantitative Aspects of Drug–Receptor Interactions
			The Binding Reaction
			Binding When More Than One Drug Is Present
		The Nature of Drug Effects
		References and Further Reading
			General
			Receptor mechanisms: agonists and efficacy
1 • General Principles
	3 How drugs act
		Overview
		Protein Targets for Drug Action
			Receptors
			Ion Channels
			Enzymes
			Transporters
		Receptor Proteins
			Cloning of Receptors
			Types of Receptor
			Molecular Structure of Receptors
				Receptor Heterogeneity and Subtypes
			Type 1: Ligand-Gated Ion Channels
				Molecular Structure
				The Gating Mechanism
			Type 2: G Protein–Coupled Receptors
				Molecular Structure
				Proteinase-Activated Receptors
				G Proteins and Their Role
				Targets for G Proteins
					The adenylyl cyclase/cAMP system
					The phospholipase C/inositol phosphate system
						Inositol phosphates and intracellular calcium
						Diacylglycerol and protein kinase C
					Ion channels as targets for G proteins
					The Rho/Rho kinase system
					The MAP kinase system
				Further Developments in GPCR Biology
					GPCR desensitisation
					GPCR oligomerisation
					Constitutively active receptors
					Agonist specificity
					Receptor activity-modifying proteins
					G protein–independent signalling
			Type 3: Kinase-Linked and Related Receptors
				Receptor tyrosine kinases (RTKs).
				Receptor serine/threonine kinases.
				Cytokine receptors.
				Protein Phosphorylation and Kinase Cascade Mechanisms
			Type 4: Nuclear Receptors
				Structure of Nuclear Receptors
				Control of Gene Transcription
				Classification of Nuclear Receptors
		Ion Channels as Drug Targets
			Ion Selectivity
			Gating
				Voltage-Gated Channels
				Ligand-Gated Channels
				Calcium Release Channels
				Store-Operated Calcium Channels
			Molecular Architecture of Ion Channels
			Pharmacology of Ion Channels
		Control of Receptor Expression
		Receptors and Disease
		References and Further Reading
			General
			Ion channels
			G protein–coupled receptors
			Signal transduction
			Kinase-linked receptors
			Nuclear receptors
1 • General Principles
	4 How drugs act
		Overview
		Regulation of Intracellular Calcium
			Calcium Entry Mechanisms
				Voltage-Gated Calcium Channels
				Ligand-Gated Channels
				Store-Operated Calcium Channels (SOCs)
			Calcium Extrusion Mechanisms
			Calcium Release Mechanisms
				Other Second Messengers
				The Role of Mitochondria
			Calmodulin
		Excitation
			The ‘Resting’ Cell
			Electrical and Ionic Events Underlying the Action Potential
			Channel Function
				Use Dependence and Voltage Dependence
				Sodium Channels
				Potassium Channels
		Muscle Contraction
			Skeletal Muscle
			Cardiac Muscle
			Smooth Muscle
		Release of Chemical Mediators
			Exocytosis
			Non-Vesicular Release Mechanisms
		Epithelial Ion Transport
		References and Further Reading
			General references
			Excitation and ion channels
			Muscle contraction
			Secretion and exocytosis
1 • General Principles
	5 How drugs act
		Overview
		Introduction
		Protein and Oligonucleotide Biopharmaceuticals
			Proteins and Polypeptides
				Production methods
				Engineered proteins
			Monoclonal Antibodies
		Oligonucleotides
			Pharmacology of Protein and Oligonucleotide Pharmaceuticals
		Gene Therapy
			Gene Delivery
				Viral Vectors
					Retroviruses
					Adenovirus
					Other viral vectors
				Non-Viral Vectors
					Liposomes
					Microspheres
					Plasmid DNA
			Controlling Gene Expression
		Safety and Societal Issues
		Therapeutic Applications
		Concluding Remarks
		References and Further Reading
			General reviews on biopharmaceuticals, gene therapy and utilities
			Problems
			Therapeutic uses
1 • General Principles
	6 Cell proliferation, apoptosis, repair and regeneration
		Overview
		Cell Proliferation
			The Cell Cycle
				Positive Regulators of the Cell Cycle
				Negative Regulators of the Cell Cycle
					Inhibition of the cycle at check point 1
					Inhibition of the cycle at check point 2
			Interactions Between Cells, Growth Factors and the Extracellular Matrix
				The Role of Integrins
				The Role of Matrix Metalloproteinases
		Angiogenesis
		Apoptosis and Cell Removal
			Morphological Changes in Apoptosis
			The Major Players in Apoptosis
			Pathways to Apoptosis
				The Extrinsic Pathway
					The mitochondrial pathway
					MicroRNAs, the cell cycle and apoptosis
		Pathophysiological Implications
			Repair and Healing
			Hyperplasia
			The Growth, Invasion and Metastasis of Tumours
			Stem Cells and Regeneration
		Therapeutic Prospects
			Apoptotic Mechanisms
			Angiogenesis and Metalloproteinases
			Cell Cycle Regulation
		References and Further Reading
			Cell cycle and apoptosis (general)
			Integrins, extracellular matrix, metalloproteinases and angiogenesis
			Stem cells, regeneration and repair
1 • General Principles
	7 Cellular mechanisms
		Overview
		Introduction
		The Innate Immune Response
			Pattern Recognition
				Responses to Pattern Recognition
					Vascular events
					Cellular events
						Polymorphonuclear leukocytes
						Mast cells
						Monocytes/macrophages
						Dendritic cells
						Eosinophils
						Basophils
						Vascular endothelial cells
						Platelets
						Natural killer cells
		The Adaptive Immune Response
			The Induction Phase
			The Effector Phase
				The Antibody-Mediated (Humoral) Response
					Antibodies and complement
					Antibodies and the phagocytosis of bacteria
					Antibodies and cellular toxicity
					Antibodies and mast cells or basophils
				The Cell-Mediated Immune Response
					Cytotoxic T cells
					Macrophage activating CD4+ Th1 cells
		Systemic Responses in Inflammation
			The Role of the Nervous System in Inflammation
			Unwanted Inflammatory and Immune Responses
				Type I hypersensitivity
				Type II hypersensitivity
				Type III hypersensitivity
				Type IV hypersensitivity
			The Outcome of the Inflammatory Response
		References and Further Reading
			The innate and adaptive responses
			Books
1 • General Principles
	8 Method and measurement in pharmacology
		Overview
		Bioassay
			Biological Test Systems
			General Principles of Bioassay
				The Use of Standards
				The Design of Bioassays
		Animal Models of Disease
			Genetic and Transgenic Animal Models
		Pharmacological Studies in Humans
		Clinical Trials
			Avoidance of Bias
			The Size of the Sample
			Clinical Outcome Measures
			Placebos
			Meta-Analysis
			Balancing Benefit and Risk
				Therapeutic Index
				Other Measures of Benefit and Risk
		References and Further Reading
			General references
			Molecular methods
			Animal models
			Clinical trials
1 • General Principles
	9 Absorption and distribution of drugs
		Overview
		Introduction
		Physical Processes Underlying Drug Disposition
			The Movement of Drug Molecules Across Cell Barriers
				Diffusion Through Lipid
				Ion Trapping
					pH and ionisation
					pH partition and ion trapping
				Carrier-Mediated Transport
					Organic cation transporters and organic anion transporters
					P-glycoprotein transporters
					Plasma protein and tissue partition of drugs
			Binding of Drugs to Plasma Proteins
			Partition Into Body Fat and Other Tissues
		Drug Absorption and Routes of Administration
			Oral Administration
				Drug Absorption From the Intestine
				Factors Affecting Gastrointestinal Absorption
					Bioavailability and bioequivalence
			Oromucosal (Sublingual or Buccal) Administration
			Rectal Administration
			Application to Epithelial Surfaces
				Cutaneous Administration
				Nasal Sprays
				Eye Drops
				Administration by Inhalation
				Administration by Injection
				Methods for Delaying Absorption
				Intrathecal Injection
				Intravitreal Injection
		Distribution of Drugs in the Body
			Body Fluid Compartments
				The Blood–Brain Barrier
			Volume of Distribution
				Drugs Largely Confined to the Plasma Compartment
				Drugs Distributed in the Extracellular Compartment
				Distribution Throughout the Body Water
				Drug Interactions Caused by Altered Absorption (See Ch. 12 for a General Approach to Drug Interactions)
				Drug Interactions Caused by Altered Distribution (See Ch. 12 for a General Approach to Drug Interactions)
		Special Drug Delivery Systems
			Prodrugs
			Antibody–Drug Conjugates
			Packaging in Liposomes
			Coated Implantable Devices
		References and Further Reading
			Drug absorption and bioequivalence
			Drug distribution (including blood–brain barrier)
			Drug delivery and routes of administration
1 • General Principles
	10 Drug metabolism and elimination
		Overview
		Introduction
			Drug Metabolism
			Phase 1 Reactions
				The P450 Monooxygenase System
					Nature, classification and mechanism of P450 enzymes
					P450 and biological variation
				Hydrolytic Reactions
			Phase 2 Reactions
			Stereoselectivity
			Inhibition of P450
			Induction of Microsomal Enzymes
			Presystemic (‘First-Pass’) Metabolism
			Pharmacologically Active Drug Metabolites
			Drug Interactions Due to Enzyme Induction or Inhibition
				Interactions Caused by Enzyme Induction
				Interactions Caused by Enzyme Inhibition
		Drug and Metabolite Excretion
			Biliary Excretion and Enterohepatic Circulation
			Renal Excretion of Drugs and Metabolites
				Renal Clearance
				Glomerular Filtration
				Tubular Secretion
				Diffusion Across the Renal Tubule
			Drug Interactions Due to Altered Drug Excretion
				Inhibition of Tubular Secretion
				Alteration of Urine Flow and Ph
		References and Further Reading
			General further reading
			Drug metabolism
			P450 enzyme induction and inhibition
			Drug elimination
1 • General Principles
	11 Pharmacokinetics
		Overview
		Introduction: Definition and Uses of Pharmacokinetics
			Uses of Pharmacokinetics
			Scope of This Chapter
		Drug Elimination Expressed as Clearance
		Single-Compartment Model
			Effect of Repeated Dosing
			Effect of Variation in Rate of Absorption
		More Complicated Kinetic Models
			Two-Compartment Model
			Saturation Kinetics
		Population Pharmacokinetics
		Limitations of Pharmacokinetics
		References and Further Reading
			Population pharmacokinetics
1 • General Principles
	12 Individual variation, pharmacogenomics and personalised medicine
		Overview
		Introduction
		Epidemiological Factors and Inter-Individual Variation of Drug Response
			Ethnicity
			Age
				Effect of Age on Renal Excretion of Drugs
				Effect of Age on Drug Metabolism
				Age-Related Variation in Sensitivity to Drugs
			Pregnancy
			Disease
			Drug Interactions
				Pharmacodynamic Interaction
					Pharmacokinetic interaction
		Genetic Variation in Drug Responsiveness
			Single-Gene Pharmacokinetic Disorders
				Plasma Cholinesterase Deficiency
				Acute Intermittent Porphyria
				Drug Acetylation Deficiency
				Aminoglycoside Ototoxicity
		Therapeutic Drugs and Clinically Available Pharmacogenomic Tests
			Hla Gene Tests
				Abacavir and HLAB*5701
				Anticonvulsants and HLAB*1502
			Drug Metabolism-Related Gene Tests
				Thiopurines and TPMT
				5-Fluorouracil (5-FU) and DPYD
				Tamoxifen, Opioid Analgesics and CYP2D6
			Drug Target-Related Gene Tests (‘Companion Diagnostics’)
				Trastuzumab and HER2
				Dasatinib, Imatinib and BCR-ABL1
			Combined (Metabolism and Target) Gene Tests
				Warfarin and CYP2C9 + VKORC1 Genotyping
		Conclusions
		References and Further Reading
			Further reading
			References
2 Chemical Mediators
	13 Chemical mediators and the autonomic nervous system
		Overview
		Historical Aspects
		The Autonomic Nervous System
			Basic Anatomy and Physiology
			Transmitters in the Autonomic Nervous System
		Some General Principles of Chemical Transmission
			Presynaptic Modulation
			Postsynaptic Modulation
			Transmitters Other Than Acetylcholine and Noradrenaline
			Co-Transmission
			Termination of Transmitter Action
			Denervation Supersensitivity
		Basic Steps in Neurochemical Transmission: Sites of Drug Action
		References and Further Reading
			General references
			Presynaptic modulation
			Co-transmission
			Transporters
2 Chemical Mediators
	14 Cholinergic transmission
		Overview
		Muscarinic and Nicotinic Actions of Acetylcholine
		Acetylcholine Receptors
		Nicotinic Receptors
			Muscarinic Receptors
		Physiology of Cholinergic Transmission
			Acetylcholine Synthesis and Release
				Presynaptic Modulation
			Electrical Events in Transmission at Fast Cholinergic Synapses
				Depolarisation Block
		Effects of Drugs on Cholinergic Transmission
			Drugs Affecting Muscarinic Receptors
				Muscarinic Agonists
					Structure–activity relationships
					Effects of muscarinic agonists
						Cardiovascular effects.
						Smooth muscle.
						Sweating, lacrimation, salivation and bronchial secretion.
						Effects on the eye.
					Clinical use
				Muscarinic Antagonists
					Effects of muscarinic antagonists
						Inhibition of secretions.
						Effects on heart rate.
						Effects on the eye.
						Effects on the gastrointestinal tract.
						Effects on other smooth muscle.
						Effects on the CNS.
					Clinical use
			Drugs Affecting Autonomic Ganglia
				Ganglion Stimulants
				Ganglion-Blocking Drugs
					Effects of ganglion-blocking drugs
				Neuromuscular-Blocking Drugs
				Non-Depolarising Blocking Agents
					Mechanism of action
					Effects of non-depolarising blocking drugs
						Unwanted effects
					Pharmacokinetic aspects
				Depolarising Blocking Agents
					Unwanted effects and dangers of suxamethonium
						Bradycardia.
						Potassium release.
						Increased intraocular pressure.
						Prolonged paralysis.
						Malignant hyperpyrexia.
			Drugs That Act Presynaptically
				Drugs That Inhibit Acetylcholine Synthesis
				Drugs That Inhibit Acetylcholine Release
			Drugs That Enhance Cholinergic Transmission
				Distribution and Function of Cholinesterase
				Drugs That Inhibit Cholinesterase
					Short-acting anticholinesterases
					Medium-duration anticholinesterases
					Irreversible anticholinesterases
					Effects of anticholinesterase drugs
						Effects on autonomic cholinergic synapses.
						Effects on the neuromuscular junction.
						Effects on the CNS.
						Toxicity of organophosphates.
				Cholinesterase Reactivation
					Myasthenia gravis
			Other Drugs That Enhance Cholinergic Transmission
		References and Further Reading
			Further reading
			Acetylcholine receptors
			Cholinergic transmission
			Drugs affecting the neuromuscular junction
			Cholinesterase
2 Chemical Mediators
	15 Noradrenergic transmission
		Overview
		Catecholamines
		Classification of Adrenoceptors
		Physiology of Noradrenergic Transmission
			The Noradrenergic Neuron
				Noradrenaline Synthesis
				Noradrenaline Storage
				Noradrenaline Release
					Regulation of noradrenaline release
			Uptake and Degradation of Catecholamines
				Uptake of Catecholamines
				Metabolic Degradation of Catecholamines
		Drugs Acting on Noradrenergic Transmission
			Drugs Acting on Adrenoceptors
				Adrenoceptor Agonists
					Actions
					Smooth muscle
					Nerve terminals
					Heart
					Metabolism
					Other effects
					Clinical use
				Adrenoceptor Antagonists
					α-Adrenoceptor antagonists
						Non-selective α-adrenoceptor antagonists
						Selective α1 antagonists
						Selective α2 antagonists
						Clinical uses and unwanted effects of α-adrenoceptor antagonists
					β-Adrenoceptor antagonists
						Actions
						Clinical use
						Unwanted effects
							Bronchoconstriction.
							Cardiac depression.
							Bradycardia.
							Hypoglycaemia.
							Fatigue.
							Cold extremities.
			Drugs That Affect Noradrenergic Neurons
				Drugs That Affect Noradrenaline Synthesis
				Drugs That Affect Noradrenaline Storage
				Drugs That Affect Noradrenaline Release
				Noradrenergic Neuron-Blocking Drugs
					Actions
				Indirectly Acting Sympathomimetic Amines
					Mechanism of action and structure–activity relationships
					Actions
				Inhibitors of Noradrenaline Uptake
		References and Further Reading
			General
			Adrenoceptors
			Miscellaneous topics
2 Chemical Mediators
	16 5-Hydroxytryptamine and the pharmacology of migraine
		Overview
		5-Hydroxytryptamine
			Distribution, Biosynthesis and Degradation
				Classification of 5-HT Receptors
					5-HT1 receptors.
					5-HT2 receptors.
					5-HT3 receptors.
					5-HT4 receptors.
					5-HT5, 5-HT6 and 5-HT7 receptors.
			Pharmacological Effects
				Gastrointestinal tract.
				Smooth muscle.
				Blood vessels.
				Platelets.
				Nerve endings.
				Central nervous system.
			Drugs Acting at 5-HT Receptors
				Ergot Alkaloids
					Actions
						Vascular effects.
						Clinical use.
						Unwanted effects.
		Migraine and Other Clinical Conditions in Which 5-HT Plays a Role
			Migraine and Antimigraine Drugs
				Pathophysiology
			Antimigraine Drugs
			Carcinoid Syndrome
			Pulmonary Hypertension
		References and Further Reading
			5-Hydroxytryptamine
			Migraine and other pathologies
			Books
2 • Chemical Mediators
	17 Purines
		Overview
		Introduction
		Purinergic Receptors
		Adenosine as a Mediator
			Adenosine and the Cardiovascular System
			Adenosine in Asthma
			Adenosine in Inflammation
			Adenosine in the CNS
		ADP as a Mediator
			ADP and Platelets
		ATP as a Mediator
			ATP as a Neurotransmitter
			ATP in Nociception
			ATP in Inflammation
		Future Prospects
		References and Further Reading
2 • Chemical Mediators
	18 Local hormones 1
		Overview
		Introduction
		What Is a ‘Mediator’?
		Histamine
			Synthesis and Storage of Histamine
			Histamine Release
			Histamine Receptors
			Actions
				Smooth muscle effects.
				Cardiovascular effects.
				Gastric secretion.
				Effects on skin.
		Eicosanoids
			General Remarks
			Structure and Biosynthesis
			Prostanoids
				Catabolism of the Prostanoids
				Prostanoid Receptors
				Actions of the Prostanoids
				The Role of Prostanoids in Inflammation
		Leukotrienes
			Leukotriene Receptors
			Leukotriene Actions
				The respiratory system.
				The cardiovascular system.
				The role of leukotrienes in inflammation.
		Other Important Fatty Acid Derivatives
		Platelet-Activating Factor
			Biosynthesis
			Actions and Role in Inflammation
		Concluding Remarks
		References and Further Reading
2 • Chemical Mediators
	19 Local hormones 2
		Overview
		Introduction
		General Principles of Protein and Peptide Pharmacology
			Structure
			Types of Protein and Peptide Mediator
		Biosynthesis and Regulation of Peptides
			Peptide Precursors
			Diversity Within Peptide Families
				Gene Splicing as a Source of Diversity
				Post-Translational Modifications as a Source of Peptide Diversity
			Peptide Trafficking and Secretion
		Bradykinin
			Source and Formation of Bradykinin
			Metabolism and Inactivation of Bradykinin
			Bradykinin Receptors
			Actions and Role in Inflammation
		Neuropeptides
		Cytokines
			Interleukins and Related Compounds
			Chemokines
			Interferons
				Clinical Use of Interferons
			The ‘Cytokine Storm’
		Proteins and Peptides That Down-Regulate Inflammation
		Concluding Remarks
		References and Further Reading
			Books
2 • Chemical Mediators
	20 Cannabinoids
		Overview
		Plant-Derived Cannabinoids and Their Pharmacological Effects
			Pharmacological Effects
			Pharmacokinetic Aspects
			Adverse Effects
			Tolerance and Dependence
		Cannabinoid Receptors
		Endocannabinoids
			Biosynthesis of Endocannabinoids
			Termination of the Endocannabinoid Signal
			Physiological Mechanisms
			Pathological Involvement
		Synthetic Cannabinoids
		Clinical Applications
		References and Further Reading
			General reading
			Specific aspects
2 • Chemical Mediators
	21 Nitric oxide and related mediators
		Overview
		Introduction
		Biosynthesis of Nitric Oxide and Its Control
		Degradation and Carriage of Nitric Oxide
		Effects of Nitric Oxide
			Biochemical and Cellular Aspects
			Vascular Effects (see also Ch. 23)
			Neuronal Effects (see also Ch. 13)
			Host Defence (see Ch. 7)
		Therapeutic Aspects
			Nitric Oxide
			Nitric Oxide Donors/Precursors
			Inhibition of Nitric Oxide Synthesis
			Nitric Oxide Replacement or Potentiation
		Clinical Conditions in Which Nitric Oxide May Play A Part
		Related Mediators
			Carbon Monoxide (CO)
			Hydrogen Sulfide (H2S)
				Pharmacological effects and therapeutic potential.
		References and Further Reading
			Biochemical aspects
			Physiological aspects
			Pathological aspects
			Clinical and therapeutic aspects
			Carbon monoxide as possible mediator
			Hydrogen sulfide as possible mediator
3 • Drugs Affecting Major Organ Systems
	22 The heart
		Overview
		Introduction
		Physiology of Cardiac Function
			Cardiac Rate and Rhythm
				Disturbances of Cardiac Rhythm
			Cardiac Contraction
				Myocardial Contractility and Viability
				Ventricular Function Curves and Heart Failure
			Myocardial Oxygen Consumption and Coronary Blood Flow
				Physiological Factors
					Physical factors
					Vascular control by metabolites/mediators
					Neural and humoral control
		Autonomic Control of the Heart
			Sympathetic System
			Parasympathetic System
		Cardiac Natriuretic Peptides
		Ischaemic Heart Disease
			Angina
				Stable angina.
				Unstable angina.
				Variant angina.
			Myocardial Infarction
		Drugs That Affect Cardiac Function
			Antidysrhythmic Drugs
				Mechanisms of Action
					Class I drugs
					Class II drugs
					Class III drugs
					Class IV drugs
				Details of Individual Drugs
					Quinidine, procainamide and disopyramide (class Ia)
					Lidocaine (class Ib)
					Flecainide and encainide (class Ic)
					β-Adrenoceptor antagonists (class II)
					Class III
					Verapamil and diltiazem (class IV)
					Adenosine (unclassified in the Vaughan Williams classification)
			Drugs That Increase Myocardial Contraction
				Cardiac Glycosides
					Actions and adverse effects
					Mechanism
					Rate and rhythm
					Force of contraction
					The effect of extracellular potassium
					Pharmacokinetic aspects
				Other Drugs That Increase Myocardial Contraction
			Anti-Anginal Drugs
				Organic Nitrates
					Actions
					Mechanism of action
					Tolerance and unwanted effects
					Pharmacokinetic and pharmaceutical aspects
				Potassium-Channel Activators
				β-Adrenoceptor Antagonists
				Calcium Antagonists
					Mechanism of action: types of calcium channel
					Pharmacological effects
					Cardiac actions
					Vascular smooth muscle
					Protection of ischaemic tissues
					Pharmacokinetics
					Unwanted effects
		References and Further Reading
			Further reading
			Specific aspects
			Therapeutic aspects
3 • Drugs Affecting Major Organ Systems
	23 The vascular system
		Overview
		Introduction
		Vascular Structure and Function
		Control of Vascular Smooth Muscle Tone
			The Vascular Endothelium
				The Endothelium in Angiogenesis
				Endothelin
					Discovery, biosynthesis and secretion
					Endothelin receptors and responses
					Functions of endothelin
			The Renin–Angiotensin System
		Vasoactive Drugs
			Vasoconstrictor Drugs
				Angiotensin II
				Antidiuretic Hormone
				Endothelin
			Vasodilator Drugs
				Direct Acting Vasodilators
					Calcium antagonists
					Drugs that activate potassium channels
					Drugs that act via cyclic nucleotides
						Cyclase activation
						Phosphodiesterase inhibition
				Vasodilators With Uncertain Mechanism of Action
					Hydralazine
					Ethanol
				Indirectly Acting Vasodilator Drugs
					Renin inhibitors
					Angiotensin-converting enzyme inhibitors
						Pharmacological effects
						Unwanted effects
					Angiotensin II receptor antagonists
					Neutral endopeptidase (NEP, neprilysin) inhibition
		Clinical Uses of Vasoactive Drugs
			Systemic Hypertension
			Heart Failure
				Increase natriuresis.
				Inhibit the renin–angiotensin–aldosterone system/potentiate NEP.
				Block β adrenoceptors.
				Increase the force of cardiac contraction.
			Vasodilatory Shock and Hypotensive States
			Peripheral Vascular Disease
			Raynaud’s Disease
			Pulmonary Hypertension
		References and Further Reading
			Vascular endothelium (see Ch. 21 for further reading on nitric oxide)
			Endothelium-derived hyperpolarising factor
			Endothelin
			Renin–angiotensin system
			Circulation research
			Vasodilator drugs (see Ch. 22 for further reading on calcium antagonists)
			Hypertension
			Heart failure
			Shock
			Pulmonary arterial hypertension (PAH)
3 • Drugs Affecting Major Organ Systems
	24 Atherosclerosis and lipoprotein metabolism
		Overview
		Introduction
		Atherogenesis
		Lipoprotein Transport
			Dyslipidaemia
		Prevention of Atheromatous Disease
		Lipid-Lowering Drugs
			Statins: HMG-Coa Reductase Inhibitors
				Other actions of statins
				Pharmacokinetics
				Adverse effects
			Proprotein Convertase Subtilisin/Kexin Type-9 (PCSK9) Inhibitors
			Fibrates
				Adverse effects
			Drugs That Inhibit Cholesterol Absorption
				Ezetimibe
			Nicotinic Acid
			Fish Oil Derivatives
			Mipomersen
			Lomitapide
		References and Further Reading
			Atherosclerosis and dyslipidaemia
			Statins
			Other therapies
			Fibrates
			Fish oil
			Ezetimibe
			Lomitapide
			Mipomersen
			Potential therapies
3 • Drugs Affecting Major Organ Systems
	25 Haemostasis and thrombosis
		Overview
		Introduction
		Blood Coagulation
			Coagulation Cascade
				The Role of Thrombin
			Vascular Endothelium in Haemostasis and Thrombosis
		Drugs That Act on the Coagulation Cascade
			Coagulation Defects
				Vitamin K
					Administration and pharmacokinetic aspects
			Thrombosis
				Heparin (Including Low Molecular- Weight Heparins)
					Mechanism of action
					Administration and pharmacokinetic aspects
					Unwanted effects
						Haemorrhage.
						Thrombosis.
				Direct Thrombin Inhibitors and Related Drugs
					Orally active direct inhibitors.
				Warfarin
					Mechanism of action
					Administration and pharmacokinetic aspects
				Factors That Potentiate Warfarin
					Disease
					Drugs (see also Ch. 10)
						Agents that inhibit hepatic drug metabolism.
						Drugs that inhibit platelet function.
						Drugs that displace warfarin from binding sites on plasma albumin.
						Drugs that inhibit reduction of vitamin K.
						Drugs that decrease the availability of vitamin K.
				Factors That Lessen the Effect of Warfarin
					Physiological state/disease
					Drugs (see also Ch. 10)
						Vitamin K.
						Drugs that induce hepatic P450 enzymes.
						Drugs that reduce absorption.
				Unwanted Effects of Warfarin
		Platelet Adhesion and Activation
			Antiplatelet Drugs
				Aspirin
				Dipyridamole
				Adenosine (P2Y12) Receptor Antagonists
					Pharmacokinetics and unwanted effects
					Clinical use
				Glycoprotein Iib/Iiia Receptor Antagonists
				Other Antiplatelet Drugs
		Fibrinolysis (Thrombolysis)
			Fibrinolytic Drugs
				Unwanted Effects and Contraindications
				Clinical Use
				Antifibrinolytic and Haemostatic Drugs
		References and Further Reading
			Blood coagulation and anticoagulants
			Endothelium, platelets and antiplatelet agents
			Clinical and general aspects
3 • Drugs Affecting Major Organ Systems
	26 Haematopoietic system and treatment of anaemia
		Overview
		Introduction
		The Haematopoietic System
		Types of Anaemia
		Haematinic Agents
			Iron
				Iron Turnover and Balance
				Administration of Iron
					Unwanted effects
					Iron overload
			Folic Acid and Vitamin B12
				Folic Acid
					Mechanism of action
					Pharmacokinetic aspects
					Unwanted effects
				Vitamin B12
					Mechanism of action
					Administration of vitamin B12
		Haematopoietic Growth Factors
			Erythropoietin
				Unwanted effects
				Clinical use
			Colony-Stimulating Factors
				Administration and unwanted effects
		Haemolytic Anaemia
			Drugs Used to Treat Haemolytic Anaemias
				Mechanism of action
				Administration and unwanted effects
		References and Further Reading
			General
			Iron and iron deficiency
			EPO and pure red cell aplasia
			Colony-stimulating factors
			Haemolytic anaemias
			Thrombopoietin and prolonged thrombocytopenia
3 • Drugs Affecting Major Organ Systems
	27 Anti-inflammatory and immunosuppressant drugs
		Overview
		Introduction
		Cyclo-Oxygenase Inhibitors
			Mechanism of Action
			Pharmacological Actions
			Therapeutic Actions
				Anti-Inflammatory Effects
				Antipyretic Effects
				Analgesic Effects
				Unwanted Effects
					Gastrointestinal disturbances
					Skin reactions
					Adverse renal effects
					Cardiovascular side effects
					Other unwanted effects
			Some Important Nsaids and Coxibs
				Aspirin
					Pharmacokinetic aspects
					Unwanted effects
					Drug interactions
				Paracetamol
					Pharmacokinetic aspects
					Unwanted effects
				Coxibs
					Celecoxib and etoricoxib
					Parecoxib
		Antirheumatoid Drugs
			Disease-Modifying Antirheumatic Drugs
				Methotrexate
				Sulfasalazine
				Penicillamine
				Gold
				Antimalarial drugs
			Immunosuppressant Drugs
				Ciclosporin
				Tacrolimus
				Azathioprine
				Cyclophosphamide
				Mycophenolate mofetil
				Leflunomide
				Glucocorticoids
		Anticytokine Drugs and Other Biopharmaceuticals
		Drugs Used in Gout
			Allopurinol
			Uricosuric agents
			Colchicine
		Antagonists of Histamine
			Pharmacological actions
			Pharmacokinetic aspects
		Possible Future Developments IN ANTIINFLAMMATORY THERAPY
		References and Further Reading
			NSAIDs and coxibs
			Antirheumatoid drugs
			Anticytokine drugs and other biopharmaceuticals
			Antihistamines
			New directions
3 • Drugs Affecting Major Organ Systems
	28 Skin
		Overview
		Introduction
		Structure of Skin
		Common Diseases of the Skin
			Acne
			Rosacea
			Baldness and Hirsutism
			Eczema
			Pruritus
			Urticaria
			Psoriasis
			Warts
			Other Infections
		Drugs Acting on Skin
			Formulation
		Principal Drugs Used in Skin Disorders
			Antimicrobial Agents
			Glucocorticoids and Other Anti-Inflammatory Agents
				Unwanted effects.
			Drugs Used to Control Hair Growth
			Retinoids
				Unwanted effects.
			Vitamin D Analogues
				Unwanted effects.
		Agents Acting by Other Mechanisms
		Concluding Remarks
		References and Further Reading
3 • Drugs Affecting Major Organ Systems
	29 Respiratory system
		Overview
		The Physiology of Respiration
			Control of Breathing
			Regulation of Musculature, Blood Vessels and Glands of the Airways
				Efferent Pathways
					Autonomic innervation
						Parasympathetic innervation.
						Sympathetic innervation.
				Sensory Receptors and Afferent Pathways
		Pulmonary Disease and Its Treatment
			Bronchial Asthma
				Characteristics of Asthma
				Pathogenesis of Asthma
					The immediate phase of an asthma attack
					The late phase
					‘Aspirin-sensitive’ asthma
			Drugs Used to Treat and Prevent Asthma
				Bronchodilators
					β-Adrenoceptor agonists
						Unwanted effects
					Methylxanthines (see Chs 17 and 49)
						Mechanism of action
						Unwanted effects
						Pharmacokinetic aspects
					Muscarinic receptor antagonists
					Cysteinyl leukotriene receptor antagonists
					Histamine H1-receptor antagonists
				Anti-Inflammatory Agents
					Glucocorticoids
						Actions and mechanism
						Unwanted effects
					Cromoglicate and nedocromil
					Anti-IgE treatment
					Inhibition of interleukin-5
					Drugs in development
			Severe Acute Asthma (Status Asthmaticus)
			Allergic Emergencies
			Chronic Obstructive Pulmonary Disease
				Clinical features.
				Pathogenesis.
				Principles of treatment.
				Specific aspects of treatment.
				Acute exacerbations.
			Idiopathic Pulmonary Fibrosis
			Surfactants
			Cough
				Drugs Used for Cough
		References and Further Reading
			General
			Asthma
			Chronic obstructive pulmonary disease
			Cough
			Drugs and therapeutic aspects
3 • Drugs Affecting Major Organ Systems
	30 The kidney and urinary system
		Overview
		Introduction
		Outline of Renal Function
		The Structure and Function of the Nephron
			The Blood Supply to the Nephron
			The Juxtaglomerular Apparatus
			Glomerular Filtration
			Tubular Function
				The Proximal Convoluted Tubule
				The Loop of Henle, Medullary Counter-Current Multiplier and Exchanger
				The Distal Tubule
				The Collecting Tubule and Collecting Duct
					ADH and nephrogenic diabetes insipidus.
			Acid–Base Balance
			Potassium Balance
			Excretion of Organic Molecules
			Natriuretic Peptides
			Prostaglandins and Renal Function
		Drugs Acting on the Kidney
			Diuretics
				Diuretics Acting Directly on Cells of the Nephron
					Loop diuretics
						Pharmacokinetic aspects
						Unwanted effects
					Diuretics acting on the distal tubule
						Pharmacokinetic aspects
						Unwanted effects
					Aldosterone antagonists
						Pharmacokinetic aspects
						Unwanted effects
					Triamterene and amiloride
						Pharmacokinetic aspects
						Unwanted effects
					Carbonic anhydrase inhibitors
				Diuretics That Act Indirectly by Modifying the Content of the Filtrate
					Osmotic diuretics
		Drugs That Alter the pH of the Urine
		Drugs That Alter the Excretion of Organic Molecules
		Drugs Used in Renal Failure
			Hyperphosphataemia
			Hyperkalaemia
		Drugs Used in Urinary Tract Disorders
		References and Further Reading
			Physiological aspects
			Drugs and therapeutic aspects
			Ca2+/PO4− (see also Diuretics section, above)
			Antihypertensives and renal protection
			Sodium and potassium ion disorders
			Drug utilisation in kidney disease
3 • Drugs Affecting Major Organ Systems
	31 The gastrointestinal tract
		Overview
		The Innervation and Hormones of the Gastrointestinal Tract
			Neuronal Control
			Hormonal Control
		Gastric Secretion
			The Regulation of Acid Seceretion by Parietal Cells
				Histamine
				Gastrin
				Acetylcholine
				Prostaglandins
				Somatostatin
			The Coordination of Factors Regulating Acid Secretion
			Drugs Used to Inhibit or Neutralise Gastric Acid Secretion
				Histamine H2 Receptor Antagonists
					Pharmacokinetic aspects and unwanted effects
				Proton Pump Inhibitors
					Pharmacokinetic aspects and unwanted effects
				Antacids
			Treatment of Helicobacter Pylori Infection
			Drugs That Protect the Mucosa
				Bismuth chelate
				Sucralfate
				Misoprostol
		Vomiting
			The Reflex Mechanism of Vomiting
			Antiemetic Drugs
				Receptor Antagonists
					H1 receptor antagonists
					Muscarinic receptor antagonists
					5-HT3 receptor antagonists
					Dopamine antagonists
					Metoclopramide and domperidone
					NK1 receptor antagonists
				Other Antiemetic Drugs
		The Motility of the GI Tract
			Purgatives
				Bulk and Osmotic Laxatives
				Faecal Softeners
				Stimulant Laxatives
			Drugs That Increase Gastrointestinal Motility
			Antidiarrhoeal Agents
				Travellers’ Diarrhoea
				Antimotility and Spasmolytic Agents
				Adsorbents
		Drugs for Chronic Bowel Disease
			Glucocorticoids
			Aminosalicylates
			Other Drugs
		Drugs Affecting the Biliary System
		Future Directions
		References and Further Reading
			Innervation and hormones of the gastrointestinal tract
			Gastric secretion
			Drugs in GI disorders
			Nausea and vomiting
			Motility of the gastrointestinal tract
			The biliary system
			Useful Web resources
3 • Drugs Affecting Major Organ Systems
	32 The control of blood glucose and drug treatment of diabetes mellitus
		Overview
		Introduction
		Control of Blood Glucose
		Pancreatic Islet Hormones
			Insulin
				Synthesis and Secretion
				Actions
					Long-term effects of insulin
					Mechanism of action
			Glucagon
				Synthesis and Secretion
				Actions
			Somatostatin
			Amylin (Islet Amyloid Polypeptide)
			Incretins
		Diabetes Mellitus
			Drugs Used in the Treatment of Diabetes
				Insulin Treatment
					Pharmacokinetic aspects and insulin preparations
					Unwanted effects
					Biguanides
						Actions and mechanism
						Unwanted effects
						Clinical use
					Sulfonylureas
						Mechanism of action
						Pharmacokinetic aspects
						Unwanted effects
						Drug interactions
						Clinical use
				Other Drugs That Stimulate Insulin Secretion
					Thiazolidinediones (glitazones): pioglitazone
						Effects
						Mechanism of action
						Unwanted effects
						Clinical use
					α-Glucosidase inhibitors
					Incretin mimetics and related drugs
					Gliptins
					Glucose transport inhibitors
						Mechanism of action
						Effects
						Pharmacokinetic aspects
						Unwanted effects
						Clinical use
			Treatment of Diabetes Mellitus
		References and Further Reading
			References
			Further reading
				Insulins
				Oral hypoglycaemic drugs
				Other drugs for diabetes, and therapeutic aspects
3 • Drugs Affecting Major Organ Systems
	33 Obesity
		Overview
		Introduction
			Definition of Obesity
		Obesity as a Health Problem
		Homeostatic Mechanisms Controlling Energy Balance
			The Role of Gut and Other Hormones in Body Weight Regulation
			Neurological Circuits That Control Body Weight and Eating Behaviour
				Control of Food Intake
				Control of Energy Expenditure
		The Pathophysiology of Human Obesity
			Food Intake and Obesity
			Physical Exercise and Obesity
			Obesity as a Disorder of the Homeostatic Control of Energy Balance
			Genetic Factors and Obesity
		Pharmacological Approaches to the Problem of Obesity
			Centrally Acting Appetite Suppressants
			Orlistat
				Pharmacokinetic Aspects and Unwanted Effects
		New Approaches to Obesity Therapy
		References and Further Reading
			Body weight regulation and obesity
			Drugs in obesity
			Useful web resource
3 • Drugs Affecting Major Organ Systems
	34 The pituitary and the adrenal cortex
		Overview
		The Pituitary Gland
			The Anterior Pituitary Gland
			Hypothalamic Hormones
				Somatostatin
				Gonadotrophin-Releasing Hormone
				Growth Hormone-Releasing Factor (Somatorelin)
				Thyrotrophin-Releasing Hormone
				Corticotrophin-Releasing Factor
			Anterior Pituitary Hormones
				Growth Hormone (Somatotrophin)
					Regulation of secretion
					Actions
					Disorders of production and clinical use
				Prolactin
				Regulation of Secretion
					Actions
					Modification of prolactin secretion
				Adrenocorticotrophic Hormone
					Actions
				Melanocyte-Stimulating Hormone (MSH)
			Posterior Pituitary Gland
				Vasopressin
					Regulation of secretion and physiological role
					Vasopressin receptors
					Actions
						Renal actions
						Other non-renal actions
					Pharmacokinetic aspects
					Unwanted effects
		The Adrenal Cortex
			Glucocorticoids
				Synthesis and release
				Mechanism of glucocorticoid action
				Actions
					General metabolic and systemic effects
					Negative feedback effects on the anterior pituitary and hypothalamus
					Anti-inflammatory and immunosuppressive effects
				Unwanted effects
				Pharmacokinetic aspects
			Mineralocorticoids
				Regulation of aldosterone synthesis and release
				Mechanism of action
				Clinical use of mineralocorticoids and antagonists
		New Directions in Glucocorticoid Therapy
		References and Further Reading
			The hypothalamus and pituitary
			Glucocorticoids
			Mineralocorticoids
3 • Drugs Affecting Major Organ Systems
	35 The thyroid
		Overview
		Synthesis, Storage and Secretion of Thyroid Hormones
			Uptake of Plasma Iodide by the Follicle Cells
			Oxidation of Iodide and Iodination of Tyrosine Residues
			Secretion of Thyroid Hormone
		Regulation of Thyroid Function
		Actions of the Thyroid Hormones
			Effects on Metabolism
			Effects on Growth and Development
			Mechanism of Action
		Transport and Metabolism of Thyroid Hormones
		Abnormalities of Thyroid Function
			Hyperthyroidism (Thyrotoxicosis)
			Simple, Non-Toxic Goitre
			Hypothyroidism
		Drugs Used in Diseases of the Thyroid
			Hyperthyroidism
				Radioiodine
				Thioureylenes
					Mechanism of action
					Pharmacokinetic aspects
					Unwanted effects
				Iodine/Iodide
				Other Drugs Used
			Hypothyroidism
		References and Further Reading
3 • Drugs Affecting Major Organ Systems
	36 The reproductive system
		Overview
		Introduction
		Endocrine Control of Reproduction
			Neurohormonal Control of the Female Reproductive System
			Neurohormonal Control of the Male Reproductive System
			Behavioural Effects of Sex Hormones
		Drugs Affecting Reproductive Function
			Oestrogens
				Actions
				Mechanism of action
				Preparations
				Pharmacokinetic aspects
				Unwanted effects
				Oestrogen Receptor Modulators
			Antioestrogens
			Progestogens
				Preparations
				Actions
					Pharmacokinetic aspects
				Unwanted effects
				Antiprogestogens
			Postmenopausal Hormone Replacement Therapy (HRT)
			Androgens
				Actions
				Mechanism of action
				Preparations
				Pharmacokinetic aspects
				Unwanted effects
			Anabolic Steroids
			Anti-Androgens
			Gonadotrophin-Releasing Hormone: Agonists and Antagonists
				Pharmacokinetics and clinical use
				Unwanted effects of GnRH analogues
				Danazol
					Actions and pharmacokinetics
			Gonadotrophins and Analogues
				Preparations
				Pharmacokinetics and clinical use
		Drugs Used for Contraception
			Oral Contraceptives
				The Combined Pill
					Common adverse effects
					Questions that need to be considered
						Is there an increased risk of cardiovascular disease (venous thromboembolism, myocardial infarction, stroke)?
						Is cancer risk affected?
						Is blood pressure increased?
					Beneficial effects
				The Progestogen-Only Pill
					Potential beneficial and unwanted effects
				Pharmacokinetics of Oral Contraceptives: Drug Interactions
			Other Drug Regimens Used for Contraception
				Postcoital (Emergency) Contraception
				Long-Acting Progestogen-Only Contraception
		The Uterus
			The Motility of the Uterus
			Drugs That Stimulate the Uterus
				Oxytocin
				Ergometrine
				Prostaglandins
					Prostaglandin preparations
					Unwanted effects
			Drugs That Inhibit Uterine Contraction
		Erectile Dysfunction
			Phosphodiesterase Type V Inhibitors
				Mechanism of action
				Pharmacokinetic aspects and drug interactions
				Unwanted effects
		References and Further Reading
			Sex hormones and their control
			Contraceptives
			Postmenopausal aspects
			The uterus
			Erectile dysfunction
			Useful Web resource
3 • Drugs Affecting Major Organ Systems
	37 Bone metabolism
		Overview
		Introduction
		Bone Structure and Composition
		Bone Remodelling
			The Action of Cells and Cytokines
			The Turnover of Bone Minerals
				Calcium Metabolism
				Phosphate Metabolism
			Hormones Involved in Bone Metabolism and Remodelling
				Parathyroid Hormone
				Vitamin D
				Oestrogens
				Calcitonin
				Other Hormones
		Disorders of Bone
		Drugs Used in Bone Disorders
			Bisphosphonates
				Mechanism of action
				Pharmacokinetic aspects
				Clinical use
			Oestrogens and Related Compounds
				Raloxifene
			Parathyroid Hormone and Teriparatide
			Vitamin D Preparations
			Biopharmaceuticals
			Calcitonin
			Calcium Salts
			Calcimimetic Compounds
		Potential New Therapies
		References and Further Reading
			Bone disorders and bone remodelling
			Drugs used to treat bone disorders
4 • Nervous System
	38 Chemical transmission and drug action in the central nervous system
		Overview
		Introduction
		Chemical Signalling in the Nervous System
		Targets for Drug Action
		Drug Action in the Central Nervous System
			Blood–Brain Barrier
		The Classification of Psychotropic Drugs
		References and Further Reading
4 • Nervous System
	39 Amino acid transmitters
		Overview
		Excitatory Amino Acids
			Excitatory Amino Acids as CNS Transmitters
			Metabolism and Release of Excitatory Amino Acids
		Glutamate
			Glutamate Receptor Subtypes
				Ionotropic Glutamate Receptors
					Special features of NMDA receptors
				Metabotropic Glutamate Receptors
			Synaptic Plasticity and Long-Term Potentiation
			Drugs Acting on Glutamate Receptors
				Antagonists and Negative Modulators
					Inotropic glutamate receptor antagonists
					Metabotropic glutamate receptor antagonists
				Agonists and Positive Modulators
					Ionotropic glutamate receptors
					Metabotropic glutamate receptors
		γ-Aminobutyric Acid (GABA)
			Synthesis, Storage and Function
			GABA Receptors: Structure and Pharmacology
				GABAA Receptors
				GABAB Receptors
			Drugs Acting on GABA Receptors
				GABAA Receptors
				GABAB Receptors
				γ-Hydroxybutyrate
		Glycine
		Concluding Remarks
		References and further reading
			Excitatory amino acids
			Inhibitory amino acids
			Physiological aspects
4 • Nervous System
	40 Other transmitters and modulators
		Overview
		Introduction
		Noradrenaline
			Noradrenergic Pathways in the CNS
			Functional Aspects
				Arousal and mood
				Blood pressure regulation
		Dopamine
			Dopaminergic Pathways in the CNS
			Dopamine Receptors
			Functional Aspects
				Dopamine and motor systems
				Behavioural effects
				Neuroendocrine function
				Vomiting
		5-Hydroxytryptamine
			5-HT Pathways in the CNS
			5-HT Receptors in the CNS
			Functional Aspects
				Hallucinatory effects
				Sleep, wakefulness and mood
				Feeding and appetite
				Sensory transmission
				Other roles
			Clinically Used Drugs
		Acetylcholine
			Cholinergic Pathways in the CNS
			Acetylcholine Receptors
			Functional Aspects
		Purines
		Histamine
		Other CNS Mediators
			Melatonin
			Nitric Oxide
			Lipid Mediators
		A Final Message
		References and Further Reading
			General references
			Noradrenaline
			Dopamine
			5-Hydroxytryptamine
			Acetylcholine
			Other messengers
4 • Nervous System
	41 Neurodegenerative diseases
		Overview
		Protein Misfolding and Aggregation in Chronic Neurodegenerative Diseases
		Mechanisms of Neuronal Death
			Excitotoxicity
			Apoptosis
			Oxidative Stress
		Ischaemic Brain Damage
			Pathophysiology
			Therapeutic Approaches
		Alzheimer’s Disease
			Pathogenesis of Alzheimer’s Disease
				Loss of cholinergic neurons
			Therapeutic Approaches
				Cholinesterase Inhibitors
				Memantine
					Future drug development
		Parkinson’s Disease
			Features of Parkinson’s Disease
				Neurochemical changes
			Pathogenesis of Parkinson’s Disease
				Neurotoxins
				Molecular aspects
			Drug Treatment of Parkinson’s Disease
				Levodopa
					Therapeutic effectiveness
					Unwanted effects
				Dopamine Agonists
				MAO-B Inhibitors
				Other Drugs Used in Parkinson’s Disease
					Amantadine
					Acetylcholine antagonists
				New Pharmacological Approaches
				Neural Transplantation, Gene Therapy and Brain Stimulation
		Huntington’s Disease
		Amyotrophic Lateral Sclerosis
		Spinal Muscular Atrophy
		Multiple Sclerosis
		References and Further Reading
			General mechanisms of neurodegeneration
			Alzheimer’s disease
			Parkinson’s disease
			Stroke
			Huntington’s disease
			Amyotrophic lateral sclerosis
			Motor neuron disease
			Multiple sclerosis
4 • Nervous System
	42 General anaesthetic agents
		Overview
		Introduction
		Mechanism of Action of Anaesthetic Drugs
			Lipid Solubility
			Effects on Ion Channels
				Cys-loop ligand-gated ion channels.
				Two-pore domain K+ channels.
				NMDA receptors.
				Other ion channels.
			Effects on the Nervous System
			Effects on the Cardiovascular and Respiratory Systems
		Intravenous Anaesthetic Agents
			Propofol
			Thiopental
			Etomidate
			Other Intravenous Agents
				Ketamine
				Midazolam
		Inhalation Anaesthetics
			Pharmacokinetic Aspects
				Solubility of Inhalation Anaesthetics
				Induction and Recovery
				Metabolism and Toxicity
		Individual Inhalation Anaesthetics
			Isoflurane, Desflurane, Sevoflurane, Enflurane and Halothane
			Nitrous Oxide
		Balanced Anaesthesia
		References and Further Reading
4 • Nervous System
	43 Analgesic drugs
		Overview
		Neural Mechanisms of Pain
			Nociceptive Afferent Neurons
			Modulation in the Nociceptive Pathway
				Hyperalgesia and Allodynia
				Transmission of Pain to Higher Centres
				Descending Inhibitory Controls
				Placebo Analgesia
			Neuropathic Pain
			Chemical Signalling in the Nociceptive Pathway
				Chemosensitivity of Nociceptive Nerve Endings
					TRP channels – thermal sensation and pain
					Kinins
					Prostaglandins
					Other peripheral mediators
		Analgesic Drugs
			Opioid Drugs
				Chemical Aspects
				Opioid Receptors
				Mechanism of Action of Opioids
					Cellular actions
						Sites of action of opioids to produce analgesia
				Pharmacological Actions
					Effects on the CNS
						Analgesia
						Hyperalgesia
						Euphoria
						Respiratory depression
						Depression of cough reflex
						Nausea and vomiting
						Pupillary constriction
					Effects on the gastrointestinal tract
					Other actions of opioids
				Tolerance and Dependence
					Tolerance
					Physical dependence
				Pharmacokinetic Aspects
				Unwanted Effects
					Individual variability
				Other Opioid Analgesics
				Opioid Antagonists
			Paracetamol
				Use of Opioids and Nsaids in Combination
			Treatment of Chronic Pain
				Treatment of Fibromyalgia
			Other Pain-Relieving Drugs
			New Approaches
		References and further reading
			General
			TRP channels
			BDNF and TrkA
			Opioids
			Neuropathic pain and new drug targets
4 • Nervous System
	44 Local anaesthetics and other drugs affecting sodium channels
		Overview
		Local Anaesthetics
			History
			Chemical Aspects
			Mechanism of Action
				Unwanted Effects
			Pharmacokinetic Aspects
			New Approaches
		Other Drugs That Affect Sodium Channels
			Tetrodotoxin and Saxitoxin
			Agents That Affect Sodium-Channel Gating
		References and Further Reading
4 • Nervous System
	45 Anxiolytic and hypnotic drugs
		Overview
		The Nature of Anxiety and Its Treatment
		Measurement of Anxiolytic Activity
			Animal Models of Anxiety
			Tests on Humans
		Drugs Used to Treat Anxiety
		Delayed Anxiolytic Effect of SSRIs and Buspirone
			Benzodiazepines and Related Drugs
				Mechanism of Action
				Antagonism and Negative Allosteric Modulation
				Is There an Endogenous Benzodiazepine-Like Mediator?
				Pharmacological Effects and Uses
					Reduction of anxiety and aggression
					Reduction of muscle tone
					Anticonvulsant effects
					Anterograde amnesia
				Pharmacokinetic Aspects
				Unwanted Effects
					Acute toxicity
					Side effects during therapeutic use
					Tolerance and dependence
					Abuse potential
			Other Potential Anxiolytic Drugs
		Drugs Used to Treat Insomnia (Hypnotic Drugs)
			Induction of Sleep by Benzodiazepines
		References and Further Reading
4 • Nervous System
	46 Antiepileptic drugs
		Overview
		Introduction
		The Nature of Epilepsy
			Types of Epilepsy
				Partial Seizures
				Generalised Seizures
			Neural Mechanisms and Animal Models of Epilepsy
		Antiepileptic Drugs
			Mechanism of Action
				Enhancement of GABA action
				Inhibition of sodium channel function
				Inhibition of calcium channels
				Other mechanisms
			Carbamazepine
				Pharmacokinetic aspects
				Unwanted effects
			Phenytoin
				Pharmacokinetic aspects
				Unwanted effects
			Valproate
				Unwanted effects
			Ethosuximide
			Phenobarbital
				Pharmacokinetic aspects
				Unwanted effects
			Benzodiazepines
			Newer Antiepileptic Drugs
				Vigabatrin
				Lamotrigine
				Felbamate
				Gabapentin and Pregabalin
				Tiagabine
				Topiramate
				Levetiracetam
				Zonisamide
				Rufinamide
				Perampanel
				Lacosamide
				Stiripentol
			New Drugs
			Other Uses of Antiepileptic Drugs
			Antiepileptic Drugs and Pregnancy
		Muscle Spasm and Muscle Relaxants
		References and Further Reading
			General
			Pathogenesis and types of epilepsy
			Antiepileptic drugs
4 • Nervous System
	47 Antipsychotic drugs
		Overview
		Introduction
		The Nature of Schizophrenia
			Positive symptoms
			Negative symptoms
			Cognition
			Aetiology and Pathogenesis of Schizophrenia
				Genetic and Environmental Factors
				The Neuroanatomical and Neurochemical Basis of Schizophrenia
					Dopamine
					Glutamate
					Animal models
		Antipsychotic Drugs
			Classification of Antipsychotic Drugs
			Clinical Efficacy in Treatment of Schizophrenia
			Other Uses of Antipsychotic Drugs
			Pharmacological Properties
				Dopamine Receptors
				5-Hydroxytryptamine Receptors
				Muscarinic Acetylcholine Receptors
			Unwanted Effects
				Extrapyramidal Motor Disturbances
				Endocrine Effects
				Other Unwanted Effects
			Pharmacokinetic Aspects
		Future Developments
		References and Further Reading
			General reading
			Pathogenesis of schizophrenia
			Dopamine, glutamate and 5-hydroxytryptamine
			Animal models
			Antipsychotic drugs
			Extrapyramidal side effects
4 • Nervous System
	48 Antidepressant drugs
		Overview
		The Nature of Depression
		Theories of Depression
			The Monoamine Theory
			Negative Affective Bias
			Neuroendocrine Mechanisms
			Trophic Effects and Neuroplasticity
		Antidepressant Drugs
			Types of Antidepressant Drug
				Inhibitors of monoamine uptake
				Monoamine receptor antagonists
				Monoamine oxidase inhibitors (MAOIs)
				Melatonin receptor agonist
				Miscellaneous agents
			Testing of Antidepressant Drugs
				Animal Models
				Tests on Humans
			Mechanism of Action of Antidepressant Drugs
				Chronic Adaptive Changes
				Noradrenergic Control of 5-HT Release
				Gene Expression and Neurogenesis
			Monoamine Uptake Inhibitors
				Selective 5-Hydroxytryptamine Uptake Inhibitors
					Pharmacokinetic aspects
					Unwanted effects
				Tricyclic Antidepressant Drugs
					Mechanism of action
					Unwanted effects
					Interactions with other drugs
					Acute toxicity
					Pharmacokinetic aspects
				Serotonin and Noradrenaline Uptake Inhibitors (Snris)
				Other Noradrenaline Uptake Inhibitors
			Monoamine Receptor Antagonists
			Monoamine Oxidase Inhibitors
				Chemical aspects
				Pharmacological effects
				Unwanted effects and toxicity
				Interaction with other drugs and foods
			Melatonin Agonist
			Ketamine
			Other Antidepressant Approaches
		Clinical Effectiveness of Antidepressant Treatments
			Pharmacogenetic factors
			Suicide and antidepressants
		Future Antidepressant Drugs
		Brain Stimulation Therapies
		Drug Treatment of Bipolar Disorder
			Lithium
				Pharmacological effects and mechanism of action
				Pharmacokinetic aspects and toxicity
			Antiepileptic Drugs
			Second-Generation Antipsychotic Drugs
		References and Further Reading
			Pathogenesis of depressive illness
			Antidepressant treatments
			Lithium
4 • Nervous System
	49 Psychoactive drugs
		Overview
		Introduction
		Psychomotor Stimulants
			Amphetamines
				Pharmacological effects
				Chronic use, tolerance and dependence
				Pharmacokinetic aspects
			Methylphenidate
			Modafinil
				Clinical Use of Stimulants
					Attention deficit/hyperactivity disorder (ADHD)
					Narcolepsy
			Cocaine
				Pharmacological effects
				Chronic use, dependence and tolerance
				Pharmacokinetic aspects
				Adverse effects
			MDMA
				Pharmacological effects
			Cathinones
			Methylxanthines
				Pharmacological effects
				Clinical use and unwanted effects
			Nicotine
			Pharmacological Effects of Nicotine
				Effects on the CNS
					Peripheral effects
			Pharmacokinetic Aspects
			Tolerance and Dependence
			Harmful Effects of Tobacco Smoking
				Other Effects of Tobacco Smoking
		Cognition-Enhancing Drugs
			Effectiveness
			Non-Stimulant Drugs
		Psychedelic Drugs
			LSD, Psilocybin and Mescaline
				Pharmacological effects
				Dependence and adverse effects
			Other Psychedelic Drugs
		Ketamine and Related Drugs
			Pharmacological effects
			Adverse effects
		Depressants
			Ethanol
			Pharmacological Effects of Ethanol
				Effects on CNS neurons
				Behavioural effects
				Neurotoxicity
				Effects on other systems
				Effects of ethanol on the liver
				The effect of ethanol on fetal development
			Pharmacokinetic Aspects
				Metabolism of ethanol
				Genetic factors
				Metabolism and toxicity of methanol and ethylene glycol
		Tolerance and Dependence
		Synthetic Cannabinoids
		References and Further Reading
			General reference
			Stimulants
			Nicotine
			Cognition enhancers
			Psychedelics
			Ethanol
			Dissociative drugs
			Synthetic cannabinoids
4 • Nervous System
	50 Drug abuse and dependence
		Overview
		Drug Use and Abuse
			Drug Administration
			Drug Harm
			Drug Dependence
				Drug-Induced Reward
				Reward Pathways
				Physical Dependence
				Psychological Dependence
			Tolerance
			Pharmacological Approaches to Treating Drug Dependence
		References and Further Reading
			General
			Reward
			Dependence and tolerance
5 • Drugs Used for the Treatment of Infections and Cancer
	51 Basic principles of antimicrobial chemotherapy
		Overview
		Background
		The Molecular Basis of Chemotherapy
			Bacteria
			Biochemical Reactions as Potential Targets
				Class I Reactions
				Class II Reactions
					Folate biosynthesis and utilisation
				Class III Reactions
					The synthesis of peptidoglycan
					Protein synthesis
					Nucleic acid synthesis
						Inhibition of the synthesis of nucleotides
						Alteration of the base-pairing properties of the template
						Inhibition of either DNA or RNA polymerase
						Inhibition of DNA gyrase
			The Formed Structures of the Cell as Potential Targets
				The Membrane
				Intracellular Organelles
					Microtubules and/or microfilaments
					Food vacuoles
					Muscle fibres
		Resistance to Antibacterial Drugs
			The Spread of Antibiotic Resistance
				Movement of Genetic Information
					Plasmids and mobile elements
					Transposons
					Gene cassettes and integrons
				The Transfer of Resistance Genes Between Bacteria
					Conjugation
					Transduction
					Transformation
				Chromosomal Mutations
				Gene Amplification
			Biochemical Mechanisms of Resistance to Antibiotics
				The Production of Enzymes That Inactivate Drugs
					Inactivation of β-lactam antibiotics
					Inactivation of chloramphenicol
					Inactivation of aminoglycosides
				Alteration of Drug-Binding Site
				Decreased Accumulation of Drugs by Bacteria
				Alteration of Enzyme Selectivity
		Current Status of Antibiotic Resistance in Bacteria
		References and Further Reading
			Useful web resources
5 • Drugs used for the treatment of infections and cancer
	52 Antibacterial drugs
		Overview
		Introduction
			Gram staining and bacterial cell wall structure
		Antibacterial Agents That Interfere With Folate Synthesis or Action
			Sulfonamides
				Mechanism of action
			Trimethoprim
				Mechanism of action
		β-Lactam Antibiotics and Other Agents That Interfere With Bacterial Wall or Membrane Synthesis
			Penicillins
				Mechanisms of action
				Types of penicillin and their antimicrobial activity
			Cephalosporins and Cephamycins
			Other β-Lactam Antibiotics
				Carbapenems
				Monobactams
			Other Antibiotics That Inhibit Bacterial Cell Wall Peptidoglycan Synthesis
				Glycopeptides
				Polymixins
		Antimicrobial Agents Affecting Bacterial Protein Synthesis
			Tetracyclines
				Mechanism of action
				Antibacterial spectrum
			Chloramphenicol
				Antibacterial spectrum
			Aminoglycosides
				Mechanism of action
				Resistance
				Antibacterial spectrum
			Macrolides
				Mechanism of action
				Antimicrobial spectrum
			Oxazolidinones
			Fusidic Acid
			Streptogramins
			Clindamycin
		Antimicrobial Agents Affecting Topoisomerase
			Quinolones
				Antibacterial spectrum and clinical use
		Miscellaneous Antibacterial Agents
			Metronidazole
			Nitrofurantoin
		Antimycobacterial Agents
			Drugs Used to Treat Tuberculosis
				Isoniazid
				Rifampicin
				Ethambutol
				Pyrazinamide
				Capreomycin
				Cycloserine
			Drugs Used to Treat Leprosy
				Dapsone
				Clofazimine
		Possible New Antibacterial Drugs
		References and Further Reading
			Antibacterial drugs
			Resistance (see also reading list in Ch. 51)
			New approaches to antibacterial drug discovery
			Useful website
5 • Drugs used for the treatment of infections and cancer
	53 Antiviral drugs
		Overview
		Background Information About Viruses
			An Outline of Virus Structure
			Examples of Pathogenic Viruses
			Virus Function and Life History
				Replication of DNA viruses
				Replication of RNA viruses
				Replication in retroviruses
		The Host–Virus Interaction
			Host Defences Against Viruses
			Viral Ploys to Circumvent Host Defences
				Subversion of the immune response
				Evasion of immune detection and attack by killer cells
		HIV and AIDS
			Induction of the Disease
			Progress of Infection
		Antiviral Drugs
			Reverse Transcriptase Inhibitors
				Zidovudine
			Non-Nucleoside Reverse Transcriptase Inhibitors
			Protease Inhibitors
			DNA Polymerase Inhibitors
				Aciclovir
			Neuraminidase Inhibitors and Inhibitors of Viral Coat Disassembly
			Drugs Acting Through Other Mechanisms
			Biopharmaceutical Antiviral Drugs
				Immunoglobulins
				Palivizumab
				Interferons
			Other Agents
		Combination Therapy for HIV
		Prospects for New Antiviral Drugs
		References and further reading
			Viral infections in general
			HIV infections
			Mechanisms of antiviral drug action
			Combination treatment for HIV
			New leads in antiviral drug therapy
			Books
			Useful Web resources
5 • Drugs used for the treatment of infections and cancer
	54 Antifungal drugs
		Overview
		Fungi and Fungal Infections
		Drugs Used to Treat Fungal Infections
			Antifungal Antibiotics
				Amphotericin
					Pharmacokinetic aspects
					Unwanted effects
				Nystatin
				Griseofulvin
					Pharmacokinetic aspects
					Unwanted effects
				Echinocandins
			Synthetic Antifungal Drugs
				Azoles
					Ketoconazole
						Unwanted effects
					Fluconazole
						Unwanted effects
					Itraconazole
						Unwanted effects
					Miconazole
					Other azoles
				Other Antifungal Drugs
		Future Developments
		References and Further Reading
			Useful Web resources
5 • Drugs Used for the Treatment of Infections and Cancer
	55 Antiprotozoal drugs
		Overview
		Background
		Host–Parasite Interactions
		Malaria and Antimalarial Drugs
			The Life Cycle of the Malaria Parasite
			Antimalarial Drugs
				Drugs used to treat the acute attack
				Drugs that effect a radical cure
				Drugs used for chemoprophylaxis
				Drugs used to prevent transmission
				Drug resistance
				Chloroquine
					Resistance
					Administration and pharmacokinetic aspects
					Unwanted effects
				Quinine
					Resistance
					Pharmacokinetic aspects
					Unwanted effects
				Mefloquine
					Resistance
					Pharmacokinetic aspects and unwanted effects
				Lumefantrine
				Drugs Affecting Folate Metabolism
					Resistance
					Pharmacokinetic aspects
					Unwanted effects
				Primaquine
					Resistance
					Pharmacokinetic aspects
					Unwanted effects
				Artemisinin and Related Compounds
					Pharmacokinetic aspects
					Resistance
				Atovaquone
					Resistance
			Potential New Antimalarial Drugs
		Amoebiasis and Amoebicidal Drugs
			Metronidazole
			Diloxanide
		Trypanosomiasis and Trypanocidal Drugs
			Suramin
			Pentamidine
			MELARSOPROL
			Eflornithine
		Other Protozoal Infections and Drugs Used to Treat Them
			Leishmaniasis
			Trichomoniasis
			Giardiasis
			Toxoplasmosis
			Pneumocystis
		Future Developments
		References and Further Reading
			Host–parasite interactions
			Malaria
			Amoebiasis
			Trypanosomiasis
			Leishmaniasis
			Pneumocystis pneumonia
			Useful Web resources
5 • Drugs Used for the Treatment of Infections and Cancer
	56 Antihelminthic drugs
		Overview
		Helminth Infections
		Antihelminthic Drugs
			Benzimidazoles
			Praziquantel
			Piperazine
			Diethylcarbamazine
			Niclosamide
			Levamisole
			Ivermectin
		Resistance to Antihelminthic Drugs
		Vaccines and Other Novel Approaches
		References and Further Reading
			General papers on helminths and their diseases
			Antihelminthic drugs
			Antihelminthic vaccines
			Immune evasion by helminths and therapeutic exploitation
5 • Drugs Used for the Treatment of Infections and Cancer
	57 Anticancer drugs
		Overview
		Introduction
		The Pathogenesis of Cancer
			The Genesis of a Cancer Cell
			The Special Characteristics of Cancer Cells
				Uncontrolled Proliferation
					Resistance to apoptosis
					Telomerase expression
					The control of tumour-related blood vessels
				De-Differentiation and Loss of Function
				Invasiveness
				Metastasis
		General Principles of Cytotoxic Anticancer Drugs
		Anticancer Drugs
			Alkylating Agents and Related Compounds
				Nitrogen mustards
				Nitrosoureas
				Other alkylating agents
				Platinum compounds
			Antimetabolites
				Folate antagonists
				Pyrimidine analogues
				Purine analogues
			Cytotoxic Antibiotics
				Doxorubicin and the anthracyclines
				Dactinomycin
				Bleomycins
				Mitomycin
			Plant Derivatives
				Vinca alkaloids
				Paclitaxel and related compounds
				Camptothecins
				Etoposide
			Hormones
				Glucocorticoids
				Oestrogens
				Progestogens
				Gonadotrophin-releasing hormone analogues
				Somatostatin analogues
			Hormone Antagonists
				Antioestrogens
				Antiandrogens
			Monoclonal Antibodies
				Rituximab
				Trastuzumab
				Bevacizumab
				Catumaxomab
				Nivolumab
				Ipilimumab
			Protein Kinase Inhibitors
				Imatinib
			Miscellaneous Agents
				Crisantaspase
				Hydroxycarbamide
				Bortezomib
				Thalidomide
				Biological response modifiers and others
			Resistance to Anticancer Drugs
			Combination Therapies
			Control of Emesis and Myelosuppression
				Emesis
				Myelosuppression
		Future Developments
		References and Further Reading
			General textbook
			Mechanisms of carcinogenesis
			Anticancer therapy
			New directions and miscellaneous
			Useful Web resources
6 • Special Topics
	58 Harmful effects of drugs
		Overview
		Introduction
		Classification of Adverse Drug Reactions
			Adverse Effects Related to the Known Pharmacological Action of the Drug
			Adverse Effects Unrelated to the Known Pharmacological Action of the Drug
		Drug Toxicity
			Toxicity Testing
			General Mechanisms of Toxin-Induced Cell Damage and Cell Death
				Non-Covalent Interactions
					Lipid peroxidation
					Reactive oxygen species
					Depletion of glutathione
					Modification of sulfhydryl groups
				Covalent Interactions
				Hepatotoxicity
				Nephrotoxicity
			Mutagenesis and Assessment of Genotoxic Potential
				Biochemical Mechanisms of Mutagenesis
				Carcinogenesis
				Measurement of Mutagenicity and Carcinogenicity
				Teratogenesis and Drug-Induced Congenital Anomalies
				Mechanism of Teratogenesis
				Testing for Teratogenicity
				Some Definite and Probable Human Teratogens
					Thalidomide
					Cytotoxic drugs
					Retinoids
					Heavy metals
					Antiepileptic drugs (see Ch. 46)
					Warfarin
		Immunological Reactions to Drugs
			Immunological Mechanisms
			Clinical Types of Allergic Response to Drugs
				Anaphylactic Shock
				Haematological Reactions
				Allergic Liver Damage
				Other Hypersensitivity Reactions
		References and further reading
			Adverse drug reactions
			Drug toxicity: general and mechanistic aspects
			Drug toxicity: carcinogenesis, teratogenesis
			Drug toxicity: organ involvement
6 • Special Topics
	59 Lifestyle and drugs in sport
		Overview
		What Are Lifestyle Drugs?
		Classification of Lifestyle Drugs
		Drugs and Sex
		Drugs in Sport
			Anabolic Steroids
			Human Growth Hormone
			Stimulant Drugs
		Conclusion
		References and Further Reading
			Drugs in sport
6 • Special Topics
	60 Drug discovery and development
		Overview
		The Stages of a Project
			The Drug Discovery Phase
				Target Selection
				Lead Finding
					Natural products as lead compounds
				Lead Optimisation
			Preclinical Development
			Clinical Development
				Disclosure and publication of trials data
		Biopharmaceuticals
		Commercial Aspects
		Future Prospects
		A Final Word
		References and Further Reading