Contents

Preface........................................................................... vii Drug dosage and nomenclature....................................  ix

Section 5 The nervous system
17. General anaesthetics ........................................  247 18. Local anaesthetics . ...........................................  257 19. Opioid analgesics and the management of pain . ..............................................................  263 20. Anxiolytics, sedatives and hypnotics ...............  277 21. The major psychotic disorders: schizophrenia and mania .................................  287 22. Depression, attention deficit hyperactivity disorder and narcolepsy . ..................................  299 23. Epilepsy ............................................................  315 24. Extrapyramidal movement disorders and spasticity . ..........................................................  327 25. Other neurological disorders: multiple sclerosis, motor neuron disease and Guillain–Barré syndrome ..................................  341 26. Migraine ............................................................  345

Section 1 General principles
  1. Principles of pharmacology and mechanisms of drug action . .................................  3   2. Pharmacokinetics ...............................................  31   3. Drug discovery, safety and efficacy...................  63   4. The nervous system, neurotransmission and the peripheral autonomic nervous system ................................................................  71

Section 2 The cardiovascular system
  5. Ischaemic heart disease.....................................  91   6. Systemic and pulmonary hypertension . ...........  111   7. Heart failure ......................................................  133   8. Cardiac arrhythmias .........................................  145   9. Cerebrovascular disease and dementia . ..........  163 10. Peripheral vascular disease . .............................  171 11. Haemostasis .....................................................  177

Section 6 The musculoskeletal system
27. The neuromuscular junction and neuromuscular blockade ..................................  355 28. Myasthenia gravis . ............................................  361 29. Non-steroidal anti-inflammatory drugs ............  365 30. Rheumatoid arthritis, other inflammatory arthritides and osteoarthritis ............................  377 31. Hyperuricaemia and gout .................................  387

Section 3 The respiratory system
12. Asthma and chronic obstructive pulmonary disease . .............................................................  195 13. Respiratory disorders: cough, respiratory stimulants, cystic fibrosis and neonatal respiratory distress syndrome . .........................  211

Section 7 The gastrointestinal system
32. Nausea and vomiting .......................................  395 33. Dyspepsia and peptic ulcer disease ................  403 34. Inflammatory bowel disease . ............................  415 35. Constipation, diarrhoea and irritable bowel syndrome ...............................................  421 36. Liver disease . ....................................................  429 37. Obesity..............................................................  437

Section 4 The renal system
14. Diuretics............................................................  219 15. Disorders of micturition ....................................  231 16. Erectile dysfunction ..........................................  239

vi  Contents

Section 8 The immune system
38. The immune response and immunosuppressant drugs...............................  445 39. Antihistamines and allergic disease .................  455

Section 10 The skin and eyes
49. Skin disorders . ..................................................  565 50. The eye .............................................................  575

Section 9 The endocrine system and metabolism
40. Diabetes mellitus ..............................................  463 41. The thyroid and control of metabolic rate .......  477 42. Calcium metabolism and metabolic bone disease . .............................................................  483 43. Pituitary and hypothalamic hormones .............  493 44. Corticosteroids (glucocorticoids and mineralocorticoids) ...........................................  505 45. Female reproduction ........................................  515 46. Androgens and anabolic steroids ....................  535 47. Anaemia and haematopoietic colony-stimulating factors ................................  541 48. Lipid disorders..................................................  551

Section 11 Chemotherapy
51. Chemotherapy of infections .............................  587 52. Chemotherapy of malignancy ..........................  641

Section 12 General features: toxicity and prescribing
53. Drug toxicity and overdose ..............................  671 54. Substance abuse and dependence .................  687 55. Prescribing, adherence and information about medicines ...............................................  699 56. Drug therapy in special situations . ...................  703 Index ...........................................................................  715

Preface
peutics The third edition of Medical Pharmacology and Thera­ has been extensively revised and updated while preserving the widely popular approach of the second edition. The text is structured to reflect the ways that drugs are used in clinical practice. It provides information suitable for all healthcare professionals who require a sound knowledge of the basic science and clinical applications of drugs. As before, a disease-based approach has been taken wherever possible with the aim of explaining clinical pharmacology and therapeutics and the principles of drug use for the management of common diseases. Medical Pharmacology and Therapeutics provides sound basic pharmacology background material sufficient to underpin the clinical context. New sections on pulmonary hyper­ tension, attention deficit hyperactivity disorder, narcolepsy and macular degeneration have been added, reflecting the growing therapeutic options in these conditions. Many of the diagrams are new or modified to further clarify complex areas of pharmacology. Each chapter in this Third Edition includes:
n n

A structured approach to the principles of disease management, outlining core principles of drug choice and planning a therapeutic regimen for many common diseases. n An updated and reorganised drug compendium giving details of most drugs in the classes discussed in the chapter that have not been used as specific examples. For easy reference these tables set out key similarities and differences among drugs in each class and complement the information provided in the chapter. n Additional and new style self- assessment exercises and case studies to enable the reader to test their understanding of the principles covered in each chapter. Chapters covering generic concepts of pharmacology and therapeutics have been extensively updated and simplified and include: how drugs work at a cellular level, drug development, drug metabolism and pharmacokine­ tics, the autonomic nervous system, drug toxicity and drug prescribing. Information about genetic variations in both drug handling and drug responses, areas of increasing interest in drug development, has been expanded. It is our intention that the third edition of this book will encourage readers to develop a deeper understanding of the principles of drug usage that will help them to become safe and effective prescribers and to carry out basic and clinical research and to teach. As medical science advances these principles should underpin the life-long learning essential for the maintenance of these skills. DGW AGR KH

An updated and succinct explanation of the major pathogenic mechanisms of the disease and consequent clinical symptoms and signs, helping the reader to put into context the actions of drugs and the consequences of their therapeutic use. n An updated comprehensive review of major drugs classes relevant to the disease in question. Example drugs are used to illustrate pharmacological principles and to introduce the reader to drugs currently in widespread clinical use. n Basic pharmacology and mechanisms of drug action, key pharmacokinetic properties and important unwanted effects associated with individual drugs and drug classes.

uk/Howweregulate/Medicines/Namingofmedicines/ChangestomedicinesnamesBANstorINNs/ CON009669 A special case has been made for two medicinal substances: adrenaline (rINN – epinephrine) and noradrenaline (rINN – norepinephrine). the non-proprietary (generic) names of some drugs have varied from country to country. leading to potential confusion. procedures. especially with regard to drug usage. the rINN is now the accepted name and is used through this book. A source of minor irritation. however. . As new information becomes available. is that in most authoritative publications issuing from the UK the internationally accepted name is still being called its BAN or new BAN. the reader is referred to: http://www. equipment and the use of drugs become necessary. In keeping with European convention. The authors and the publishers have taken care to ensure that the information given in the text is accurate and up to date.Drug dosage and nomenclature Drug nomenclature In the past. Progressively. However. adrenaline and noradrenaline alone are used when referring to the physiological effects of the naturally occurring substances. and this is likely to continue. complies with the latest legislation and standards of practice. however. In this book where the use of these agents as administered drugs is being described dual names are given. Where the previously given British Approved Name (BAN) and the rINN have differed. manufacturers have been asked to continue to dual-label products adrenaline (epinephrine) and noradrenaline (norephinephrine).gov. For full information on this. Because of the clinical importance of these substances and the widespread European use and understanding of the terms adrenaline and noradrenaline. readers are strongly advised to confirm that the information. international agreement has been reached to rationalise these variations in names and a single recommended International Non-proprietary Name (rINN) given to all drugs. Drug dosages Medical knowledge is constantly changing.mhra. changes in treatment.

1 General principles .

org/bnf This contains entries for all drugs licensed for use in the UK.g.1 Conclusions n Principles of pharmacology and mechanisms of drug action 3 3 4 4 12 12 14 15 17 18 19 27 The frequently asked question ‘What do I need to know?’. if so. n RECEPTORS AND RECEPTORMEDIATED MECHANISMS OF TRANSMITTER AND DRUG ACTION The activities of most cellular processes are closely controlled in order to optimise homeostatic conditions in relation n . Your personal enthusiasm for pharmacology is also of importance! We suggest that the following list provides guiding principles. The appendix given at the end of this chapter provides a limited formulary list of core drugs taken from each drug class. you should be aware that the depth of knowledge required in different areas and topics may vary as you progress through your studies. has no single answer. treat or diagnose disease. Your year of study (both pre. which. Natural substances are con­ sidered to be drugs when they are administered for such purposes (e. you should know: n n n Studying pharmacology Receptors and receptor-mediated mechanisms of transmitter and drug action Actions of drugs at binding sites (receptors) Major types of receptors Other sites of drug action Properties of receptors Components of drug action Classification of drug action Tolerance to drug effects Pharmacogenomics. n n n n n n n the non-proprietary (generic) drug name (not trade name) the class to which the drug belongs whether the drug is available without prescription and. early in the course you might not be required to have detailed knowledge of drug monitoring. what problems may be associated with such uncontrolled usage – for example. physiology and pathology to provide a suitable framework to allow comparison of the relative benefits and risks of different drugs (drug selection) to be able to comprehend and to participate in research studies advancing knowledge of better treatment of patients. for example. propensity to cause drug interactions are there non-pharmacological treatments that are effective alternatives or will complement the drug treatment? n n The drug formulary that is the bible for prescribers in the UK is the British National Formulary (BNF).bnf. Some of the objectives of learning about pharmacology related to human medicine are: to realise that medicines should be prescribed safely and effectively. This will depend upon the individual requirements of the course you are studying and the examinations you will be taking. this also requires the development of numeracy skills for accurately calculating drug doses and dilutions to understand the ways that drugs work to affect biological systems to appreciate that pharmacology cannot be understood comprehensively without the parallel understanding of related biological and clinical sciences such as biochemistry. this could interact with a subsequently prescribed drug the main reasons for using the drug the way the drug works how the drug is given (route. available online at http://www. a patient may not report that he or she is taking a non-prescribed drug. For a drug you are studying in depth. drug monitoring) absorption. herbal medicines). The term ‘drug’ is used for all medicinal substances and not only illicit substances. Pharmacology is a study of the effect of chemicals on biological systems. but you should know if the drug has a narrow therapeutic index (when the plasma concentration of the drug that will cause unwanted effects is only slightly higher than the therapeutic plasma concentration). This book is confined to pharmacology as it relates to human medicine. should provide students in the early stages of training with reference points to know which key drugs they should be learning about. although exhaustive.and post-graduation) is also of relevance. pharmacogenetics and drug response Appendix – Limited Student Formulary STUDYING PHARMACOLOGY A drug is a chemical administered in an attempt to prevent. distribution and elimination of the drug unwanted effects and unusual characteristics of the drug.

Where a drug binds to one type of receptor in preference to another it is said to show selectivity of binding or selectivity of drug action. Both LGICs and VGICs can control the transportation of a single ion (e. and ion channels (or gates). or in the cytoplasm.1). second messenger substances are formed which can bring about cellular molecular changes including the opening of transmembrane ion channels. Transmembrane ion channels Channels (pores) that cross lipophilic membranes (transmembrane channels) are ubiquitous and allow the transportation of ions into and out of cells. n ACTIONS OF DRUGS AT BINDING SITES (RECEPTORS) As shown in the receptor table at the end of this chapter. A drug with a high degree of selectivity is likely to show a greater difference between the dose required for its biological action and the dose required for an unwanted or toxic action. . Interaction of the signal and its site of action in responding cells results in functional changes within the cell that give rise to an appropriate biochemical or physiological response to the original homeostatic stimulus. They signal changes in cells by phosphorylating or dephosphorylating enzymes. Control can be divided into three main areas: 1. Communication is usually by signals in the form of chemical messengers. For most drugs the first step in producing a biological effect is by interaction of the drug with special recognition or binding site(s) [receptors] either on the cell membrane or inside the cell and it is this binding that triggers the cellular response. Cellular changes. Both channel types are the targets for drug action. which transport specific ions from one side of the membrane to the other. the cytoplasm or the nucleus. making the cytosol more positive and causing depolarisation of excitable tissues + n K will diffuse out of the cell. K+ channels – see Table 8. n Kinase-linked receptors. The signal is recognised by responding cells via interaction of the signal with a site of action. and VGICs are opened at particular membrane potentials by voltage-sensing segments of the channel. making the cytosol more negative and inhibiting depolarisation − n Cl will diffuse into the cell. tissues and organs in order to optimise bodily functions and responses to external changes. although individual members (receptor subtypes) of each family share some common traits inherent in the ‘family’. However. as an added complexity. n G-protein-coupled receptors. which may be in the cell membrane. The search for the ‘holy grail’ in pharmacology is for a ‘perfect drug’ that binds to only one type of receptor/ binding site and produces only one desired biological effect without unwanted effects. 3. LGICs are opened by the binding of a ligand to an extracellular part of the channel.1 4  Medical Pharmacology and Therapeutics to physiological and metabolic requirements. The intracellular concentrations of ions are controlled by a combination of ion pumps. Although perfection has not been attained. Transmembrane ion channels. it is also possible for some subtypes to produce distinct different biological effects. The chemical signal is termed a ligand. because it receives the ligand. The generation of a biological signal. Selectivity is never absolute but can be high with some drugs and low with others. for lipid-soluble ligands that can cross the cell membrane. because it ligates to (ties itself to) the specialised cellular macromolecule. This is a family of transmembrane receptors named because of their interaction with Guanine nucleotides. Within any one family of receptors there are different family members (receptor subtypes). 2. such as the opening of ion channels. Homeostasis is maintained by communications between cells. n Nuclear receptors. Ligand-gated ion channels (LGICs) are a superfamily of receptors including nicotinic acetylcholine receptors. types of LGICs for K+ exist that function in response to different ligands and different VGICs for K+ exist that respond to different membrane potentials. This is a large family of transmembrane receptors with a cytosolic enzymic component. Receptors may be either in the cell membrane. in order to react with extracellular ligands that cannot readily cross the cell membrane (such as peptides). Based on concentration gradients across the cell membrane: both Na+ and Ca2+ will diffuse into the cell if the channels are open. thereby altering their activity. MAJOR TYPES OF RECEPTORS Despite the great structural diversity of drug molecules. Following activation by a drug.g. receptors tend to occur in different families (different receptor types). Each of these three steps provides important targets for drug action and this chapter will outline the principles underlying drug action mainly in areas 2 and 3. This group of receptors responds to ligands by modification of gene transcription. to increase or decrease the expression of specific cellular proteins. it has proved possible to develop drugs that bind to one type of receptor to produce a desired effect but that have less (but not zero) ability to bind to other receptors which might produce unwanted effects. Examples of these are given in later sections. such as neurotransmitters or hormones. n The two major types of channel are superfamilies of ligandgated ion channels (LGICs) and voltage-gated ion channels (VGICs. making the cytosol more negative and inhibiting depolarisation. binding site or receptor. As might be expected. distinct families of receptors have different characteristics. most act on the following types of protein binding sites (loosely called superfamilies of receptors) to bring about biological change. also called ionotropic receptors). These control the passage of ions across membranes and are widely distributed. can be operated by direct interactions of drugs with the channel or by the G-protein-coupled mechanisms occurring as a first step and subsequent intracellular events may then activate transmembrane ion channels. The cellular macromolecule is termed a receptor. It should be noted that some mechanisms. Cellular recognition sites (receptors). which open to allow the selective transfer of ions down their concentration gradients.

see below) interacting with the channel. each of which is a transmembrane protein that crosses the membrane in a number of loops.Principles of pharmacology and mechanisms of drug action  5 Acetylcholine attaches to two binding domains causing the Na+ channel to open Na+ Outside Inside Na+ Fig. Voltage-gated ion channels (VGICs) consist of several sub­ units. so that the C-terminal is on the inside of the cell. gamma-aminobutyric acid (GABA) receptors. R and T) and voltage-gated K+ channels (see Table 8. They consist of a number of transmembrane subunits. The M2 transmembrane segment of each subunit (shown in blue) is part of the ion channel and undergoes conformational change on ligand binding that allows selective ion flow down its concentration gradient. Binding of an agonist to the receptor causes a conformational change in the protein and results in extremely fast opening of the ion channel. either indirectly via intracellular events. glycine receptors and 5HT3 receptors. 1. .1). which consists of five subunits (each of which comprises four transmembrane segments. Ion selectivity is determined by the amino acid composition of a short segment of the pore. The diagram is based on the acetylcholine nicotinic receptor. N. such as second messenger-mediated changes (see Fig. 5. 18) binding to and blocking activated Na+ channels. the transmembrane structure of only one of the five subunits is illustrated. via the G-protein subunits (α or βγ. For example. indirectly. 1.5) or directly. there are many different voltage-gated Ca2+ channels (L. which cluster around a central channel.2. which blocks the open channel from the intracellular end. this is produced by an intracellular loop of the channel. which is different for each type of ion channel. The activity of voltage-gated channels may be modulated by drugs. Most G-protein-coupled transmembrane receptors have the N-terminals on the extracellular side and cross the membrane seven times with helical segments (hepta­ helical). via the second messenger system affecting the status of the channel n directly. Each acetylcholine-binding site is formed by the extracellular domains of two adjacent α1 subunits. Each peptide subunit is orientated so that hydrophilic chains face towards the channel and hydrophobic chains towards the membrane lipid bilayer. The ligand-gated GABA-linked Cl− channel is shown in Figure 20. For clarity. M1–M4 – shown as dashed lines) surrounding the central ion channel and has two acetylcholine-binding sites (shown as red circles).1). Both Na+ and K+ G-protein-coupled receptors (GPCRs) and second messenger systems This is an extremely important type of receptor since the human genome has about 1000 sequences for Gprotein-coupled receptors.1  Typical ligand-gated transmembrane ion channel. P/Q.1. for example by local anaesthetics (see Ch. The ability of the transmembrane subunits to exist in a number of configurations leads to the existence of many different subtypes of channel for a single ion. It requires the binding of two molecules of acetylcholine for channel opening. The structure of a hypothetical G-protein-linked transmembrane receptor is shown in Figure 1. Ion channels may be influenced by ligand-operated G-proteincoupled receptors (see below) in two ways: n channels show fast inactivation after opening. Channel opening lasts only milliseconds because the ligand rapidly dissociates and is inactivated. The nicotinic acetylcholine receptor is a good example of this type of structure (Fig. The central unit contains the pore through which the ions pass and is largely responsible for the selectivity of the channel for a particular ion.

such as phospholipase C.5). There are many isoforms of adenylyl cyclase. The orientation of the receptor within the membrane is achieved by folding of the polypeptide chain resulting in seven transmembrane segments (shown as thick regions).4.e. . 1. although this has not been exploited successfully to date. which provide a potential site for selective drug action and a focus for successful drug development (Table 1.1 6  Medical Pharmacology and Therapeutics Amino end Agonist binding site Cyclic nucleotide system One system is based on cyclic nucleotides such as: n Extracellular Lipid layer Cell membrane cyclic adenosine monophosphate (cAMP). and to some extent on the substrate. cGMP exerts most of its actions through protein kinase G. usually via a G-protein (Figs 1. which is synthesised from guanosine triphosphate (GTP) via guanylyl cyclase. and is involved in numerous cellular functions by activating protein kinase A. There are 11 different families of phosphodiesterase enzymes. the intracellular enzymes and other systems to which it is linked. which are synthesised from the membrane phospholipid phosphatidylinositol 4. n The β-subunit. 1. phosphorylates target proteins. The γ-subunit remains associated with the β-subunit when the receptor is occupied. The second messengers produced by phospholipase C (IP3 and DAG) are inactivated and then converted back to PIP2. which alters the functioning of the cell. which. many of which are enzymes. The cyclic nucleotide second messenger is inactivated by hydrolysis by phosphodiesterase enzymes to give AMP or GMP. which is involved in terminating the activity. since they are released into the cytosol and are responsible for affecting a wide variety of enzymes. The α-subunit.2  Hypothetical seven-transmembrane receptor.3 and 1. which is synthesised from adenosine triphosphate (ATP) via the enzyme adenylyl cyclase. Other possible ligands may be too large for the site or may show much weaker binding characteristics.4) consists of three different subunits (i.5-triphosphate (IP3) and diacylglycerol (DAG). ion channels. which phosphorylates proteins. The consequences of the change in conformation depend on the nature of the receptor. GDP (which is normally present) is replaced by GTP and the α-subunit dissociates from the βγ-subunits. which orientate the peptide within the cell membrane. Five closely related forms have been identified. etc. n Second messenger systems Second messengers can be considered as the ‘foot soldiers’ of the extracellular signal. phosphorylation can either activate or suppress cell activity n cyclic guanosine monophosphate (cGMP). The α-subunit is important because it binds GDP/GTP. alters the three-dimensional conformation of the receptor protein. but it is inactivated when the GTP is hydrolysed to GDP.3 and 1. They are therefore universally called seven-transmembrane receptors (7TM receptors). the second messenger. on the extracellular side of the membrane. The intracellular enzyme systems produce an intracellular signal. αq and α12). these show different tissue distributions and could be important selective sites of drug action in the future.3 and 1. αi. When an agonist binds to the receptor. The receptor is stabilised across the membrane by the presence of polar groups where the chains leave the lipid bilayer.4). The outer loops produce the active site for ligand binding and the inner loops are involved in coupling to the second messenger system. when activated by cGMP. The receptor is a glycoprotein in which sites of glycosylation are present on intracellular loops.5). Ten different forms are known. Twenty-three different types have been identified that belong to four families (αs. The β-subunit remains associated with the γ-subunit when the receptor is occupied and the combined βγ-subunit may activate cellular enzymes. it also has GTPase activity. transporters. There are a number of isoenzymes of phospholipase C. Intracellular Carboxyl end Fig. n The γ -subunit.1). The α-subunit/GTP complex is active while GTP is bound to it. DAG is able to activate protein kinase C and phosphorylate target proteins. which may be activated by the α-subunits of G-proteins or the βγ-subunits of G-proteins (see below). The phosphatidylinositol system The other system is based on inositol 1. The G-protein system The G-protein system (Fig. There are two complementary second messenger systems (Figs 1. With the increase in Ca2+ brought about by IP3. The main function of IP3 is to mobilise Ca2+ in cells. The binding of an appropriate agonist (natural ligand or agonist drug) to the ligand-binding site.5-bisphosphate (PIP2) by the enzyme phospholipase C (Figs 1. The ligand-binding site represents a small volume in space in which regions of the polypeptide are orientated in such a way as to bind appropriate ligands only. it is a heterotrimer).

5 biphosphate (PIP2). adenylyl cyclase and phospholipase C).5). which affect a range of intracellular systems (shown as E on the figure) such as second messenger systems (e.2 and text) produces intracellular changes by activating or inhibiting cascades of second messengers.3  Second messenger systems. which then reforms the inactive transmembrane receptor.and β γ -subunits with transmembrane receptor Dissociation GTP E E Hydrolysis E E α GDP β γ α GTP β γ Intracellular effects Intracellular effects Intracellular effects Fig.g. Hydrolysis of GTP inactivates the α-subunit.α . diacylglycerol (DAG) or inositol triphosphate (IP3) formed from phosphatidyl inositol 4. Stimulation of transmembrane receptors (see Fig. Examples are cyclic adenosine monophosphate (cAMP). 1. As described in the text. 1. other enzymes and ion channels (see Fig.4  The functioning of G-protein subunits. . Ligand (agonist) binding results in replacement of GDP on the α-subunit by GTP and this is followed by dissociation of the α. 1.5). second messengers then go on to influence diverse cellular proteins and induce cellular responses. 1. 1. (See also Fig.Principles of pharmacology and mechanisms of drug action  7 acyl adenosine ATP Adenylyl cyclase acyl P cAMP Inactivation by phosphodiesterase adenosine ribose P acyl DAG Inactivation by phosphorylation glycerol ribose P P P acyl glycerol PIP2 Phospholipase C P inositol P P P inositol P IP3 P adenosine ribose Hydrolysis to inositol 5´-AMP Fig. Agonist E Replacement α β γ GDP E Binding E α β γ GDP E of GDP by GTP E α β γ GTP E Inactive Receptor Recombination of GDP.and βγ -subunits.

chronic obstructive pulmonary disease. lung. testes Drug(s) Under development. cGMP. brain. brain. A. or by actions on ion channels (Fig. heart. eye. neurons. diacylglycerol (DAG) and inositol triphosphate (IP3) produce a number of intracellular changes either directly. brain Skeletal muscle. IBD. liver. prostate.g. platelets Heart. 10) Asthma (Ch. cAMP. skeletal muscle. COPD.1 8  Medical Pharmacology and Therapeutics – Gi Gs + Adenylyl cyclase/ guanylyl cyclase cAMP/ cGMP Protein kinases (e. inflammatory cells Smooth muscle. kidney. The pathways can be activated or inhibited depending upon the type of receptor and G-protein and the particular ligand stimulating the receptor. pancreas.5  The intracellular consequences of receptor activation and G-protein dissociation. IBD Erectile dysfunction (Ch. brain.G) Receptoractivated G-protein Gq G12 + DAG Phospholipase C IP3 Release of Ca2+ from sarcoplasmic reticulum Protein kinase C Intracellular enzymes Ion channels (Ca2+ and K+) Contractile proteins Fig. liver. lung. inflammatory cells.1  Isoenzymes of phosphodiesterase (PDE) Enzyme PDE1 PDE2 PDE3 Main substrate cAMP + cGMP cGMP cAMP Main site(s) Heart.3). ovary. heart. 12) Congestive heart failure (see Ch. Table 1. kidney. 1. 12) Inflammation COPD. lung. pituitary and salivary glands. lung. lung. brain Testes. The effect of the same second messenger can vary enormously depending upon the biochemical functioning of the cell type in different tissues.5). peripheral vascular disease (Ch. T-lymphocytes Testes. liver. The G-proteins affect the second messenger systems (Fig. cGMP. platelets Photoreceptors Skeletal muscle. cyclic guanosine monophosphate. adipose tissue. liver. or indirectly via actions on protein kinases (which change the activities of other proteins by phosphorylation). 1. liver. liver. 16) Undefined Inflammation (combined with PDE4 inhibitor) Undefined PDE4 cAMP PDE5 PDE6 PDE7 cGMP cGMP cAMP Sildenafil Dipyridamole Dipyridamole Under development PDE8 cAMP Under development PDE9 PDE10 PDE11 cGMP cGMP cGMP Under development Under development Under development Undefined Schizophrenia? Undefined cAMP. cyclic adenosine monophosphate. T-lymphocytes Kidney. kidney. endothelium. smooth muscle Adrenal gland. platelets. inflammatory bowel disease. 7). brain. lung. kidney. (vinpocetine) Under development Aminophylline Enoximone Milrinone Cilostazol Aminophylline Therapeutic potential Undefined Undefined Asthma (Ch. smooth muscle Sertoli cells. . 5. heart.

7). The subunits dissociate from the receptor protein and exert their intracellular effects via enzymes. which release Ca2+ from intracellular stores via the action of IP3 on its receptors on the endoplasmic reticulum. 11). activate receptor kinases or activate the transmembrane Ca2+ pump. The effects on ion channels may be: direct. the GTP-α-subunit may close K+ channels. The sequence of hormone binding and actions for most nuclear receptors are shown in Figure l. The phosphorylated intracellular kinases can either act directly on metabolising enzymes or alter the gene transcription of enzymes. or + n indirect. and these phosphorylate each other. Protease-activated receptors (PARs) Protease-activated receptors (also called proteinaseactivated receptors) are recently identified transmembrane G-protein-coupled receptors which are stimulated by cleavage of the N-terminal of the receptor by a serine protease. which can then bring about the relevant intracellular changes appropriate to the biological activities of the extracellular ligand. while the βγ-subunit may open K+ channels. activate phospholipase C or activate adenylyl cyclase. Clinically useful and selective drugs for these receptors are currently under development. Activation of the receptor/G-protein complex can produce a number of intracellular events (Fig. Proteolysis by proteases such as thrombin and trypsin produces a new N-terminal sequence of the receptor protein that can act as a ligand. which bind extracellular peptide signalling substances such as insulin. rather than by the usual receptor occupancy (as described above). activate or inhibit adenylyl cyclase. which inhibit N and P/Q type Ca2+ channels. close Ca2+ channels. and the α.and βγ-subunits of the G-protein are activated. which are peptides such as insulin and cytokines n there is a single transmembrane helical region n the intracellular region possesses tyrosine kinase activity. contractile proteins.Principles of pharmacology and mechanisms of drug action  9 The sequence from receptor binding to activation of second messenger systems is illustrated in Figure 1.4. 1. such as occurs during inflammation and tissue repair.2). they differ in a number of important respects: n Gs: stimulates membrane-bound adenylyl or guanylyl cyclase to increase cAMP or cGMP n Gi (and Go): inhibits adenylyl or guanylyl cyclase to decrease cAMP or cGMP n Gq (and G12): activates phospholipase C. which stimulate L and P/Q channels. ion channels (affecting depolarisation of the cell) and cytokine production. Gs proteins. four protease-activated receptors (PAR 1–4) have been identified.and βγ-subunits recombine with the receptor protein to give the inactive form of the receptor/ G-protein complex. this is related to the size of the endogenous ligands. for example the βγ-subunit of the acetylcholine muscarinic receptor acts directly to open K+ channels in the sinoatrial node to hyperpolarise the cell. The α-subunit has GTPase activity. Such actions on DNA expression are mediated by interactions with intracellular receptors. The cytosolic hormone receptor is usually in an inactive form linked to a protein called heat shock protein (HSP). which becomes ‘teth- Intracellular (nuclear) hormone receptors Many hormones produce long-term changes in cellular activity by altering the genetic expression of enzymes. which converts the active α-subunit/ GTP complex to an inactive α-subunit/GDP complex.8. They may also be involved in brain development. The receptors appear to play roles in platelet activation and clotting (Ch. The intracellular effects are mediated by the GTP-α-subunit or the βγ-subunit. and act to transfer information on extracellular changes to intracellular functions. However. activate phospholipase A or C.5) which affect many cellular processes such as enzyme activity (via the enzyme protein per se or via gene transcription). The phosphorylated intra­ cellular proteins are active enzymes. To date. 1. such as enzymes and transporters. 1. There are three main types of G-proteins. which may provide additional future sites for selective drug actions. Phosphorylation and dephosphorylation are important regulatory steps in the activation/deactivation of numerous intracellular proteins. different receptors have different intracellular effector regions. The intracellular concentration of Ca2+ is important for many processes and this is affected by Gi and Go proteins. The GDPα. are similar to the G-protein-linked receptors in that they have a ligand-binding domain on the surface of the cell membrane. Binding of the hormone causes dissociation of the HSP and the . for example the opening of a K channel via phosphorylation of channels through cAMP-mediated activation of protein kinase A. GDP binds more strongly than GTP to the non-activated receptor. traverse the membrane and have an intracellular ‘effector’ region (Fig. each with distinct N-terminal cleavage sites and different tethered ligands (Table 1. but the reverse is true once the ligand binds to the receptor. Binding of an agonist to the receptor results in the replacement of GDP by GTP.6). such as kinases or phospholipases. ion channels and transporters that respond to the presence of the second messengers. Kinase-linked transmembrane receptors Kinase-linked transmembrane receptors. cytokines or receptor proteins. n the extracellular region associated with the ligand-binding domain is very large. This activated ‘pair of receptors’ then phosphorylates specific intracellular protein(s). detecting noxious stimuli at sensory nerve endings. but are probably similar to those outlined above for other G-protein-coupled receptors. the GTPase activity is regulated by a family of proteins. the properties of which are largely determined by the nature of the α-subunit: n ered’ back onto the receptor within extracellular loop-2 (Fig. The processes of receptor inactivation and intracellular events have not been fully defined. Depending on the type of G-protein. and Gq and G12 proteins. Ligand binding is accompanied by dimerisation of two kinase-linked receptors. and regulation of intestinal secretions and permeability.

cathepsin-G Possible future therapeutic uses of specific inhibitors Atherosclerosis. kidney.8. cancer.1 10  Medical Pharmacology and Therapeutics Protease hydrolysis G-protein G-protein G-protein Second messengers Inactive receptor Protease activation Active receptor Amino acid sequence with agonist activity Fig. Binding of the hormone/receptor complex to the hormone response element usually activates genes (transactivation). but binding sometimes silences gene expression and results in a decrease in mRNA synthesis (transrepression). respiratory epithelium Inflammatory cells.2  Protease-activated G-protein-coupled receptors Receptor Main sites Functions Activating proteasea Thrombin. Table 1. gastrointestinal tract. hormone binds to its receptor. fibrotic diseases PAR-1 Inflammatory cells. The hormone/receptor complex passes through pores in the nuclear membrane and interacts with hormone response elements on the genome to modify the expression of downstream genes. platelets and endothelium. trypsin. respiratory epithelium Inflammatory cells Inflammatory cells Regulation of inflammation. plasmin. gastrointestinal tract. cathepsin-G Allergic airway inflammation. ion transport Regulation of inflammation Regulation of inflammation PAR-2 Trypsin. Co-activators are transcrip- . Translocation and binding to DNA involves a variety of different chaperone. arthritis Accessory receptor to PAR-1 or PAR-4 Inflammation PAR-3 PAR-4 a Main enzymes. and the system is considerably more complex than indicated in Figure 1. angiogenesis. tryptase. The G-protein-coupled receptor is activated by a protease (see Table 1.6  Protease-activated receptor. thrombin signalling Regulation of inflammation. 1. The activated receptor is inactivated by phosphorylation of the intracellular (C-terminal) part of the receptor protein.2) which hydrolyses the extracellular peptide chain to expose a segment that acts as a ligand (shown in red) and activates the G-protein-coupled receptor. cathepsin-G None known Thrombin. co-activator and co-repressor proteins.

enzymes. receptors OH OH Mutual phosphorylation and activation L ig a nd L ig a nd Fig. Frequently. tional cofactors that also bind to the receptor and increase the level of gene induction. 48 for more details of PPARs). a single transmembrane segment and an intracellular tyrosine kinase domain which is responsible for intracellular effects (see text for details). ER–ER) while the others. Some steroid hormone/receptor complexes (e. show selectivity for different receptors.7  Kinase-linked transmembrane receptor. receptors Decreased synthesis of cytokines. Steroid hormones (ST) are lipid-soluble compounds which readily cross membranes and bind to intracellular receptors (HR).8  The activation of intracellular hormone receptors. e.1 Some families of intracellular receptors Activation of intracellular enzymes OPO3 = OPO3 = Fig. In some cases. Steroid hormones (and some other hormones) are recognised by specific members of the steroid/thyroid receptor superfamily (Box 1. 1. AR.g.g. an example is histone acetylase. The receptor has a large extracellular domain. enzymes.1). which prevents further transcription. form heterodimers (molecules of two different hormone/receptor complexes. Co-repressors also bind to the receptor and repress gene activation. Oestrogen receptor Progesterone receptor Androgen receptor Glucocorticoid receptor Mineralocorticoid receptor Thyroid hormone receptor Vitamin D receptor Retinoic acid receptor 9-cis-Retinoic acid receptor Peroxisome proliferator-activated receptor ER PR AR GR MR TR VDR RAR RXR PPAR Steroids. The intracellular receptor protein that binds steroids is made up of five regions with different functions (Table 1. PPAR-α and PPAR-δ) function as lipid sensors and regulate the expression of genes that influence metabolic events (see Chs 29. 40. Box 1. . the hormone response element needs two hormone/ receptor complexes to form a dimer in order to alter gene expression. involving ER.Principles of pharmacology and mechanisms of drug action  11 Ligand-binding site Single inactive receptor ST Cell membrane Extracellular Intracellular OH Tyrosine residue Ligand binding to 2 receptors L ig HR HSP90 HSP90 HR ST HR ST HRE Gene Nuclear membrane a nd L ig a nd mRNA mRNA Increased synthesis of cytokines. GR and MR – see Box 1. which then determines the spectrum of gene expression that is affected. an example is histone deacetylase. where it can either increase or decrease gene expression by binding to hormone response elements (HRE) on DNA.g. RAR and RXR). VDR. This binding displaces a protein called heat shock protein (HSP90) and the hormone/receptor complex enters the nucleus. the receptor is present within the nucleus and binding of the ligand (usually a lipid molecule) occurs without the translocation step.3). which facilitates transcription by increasing the ease of unravelling of DNA. especially receptors present within the nucleus (TR.1) form homodimers (two molecules of the same hormone/receptor complex. RAR–RXR). for example peroxisome proliferatoractivated receptor (PPAR). 1. and synthetic steroid analogues. The PPARs (PPAR-γ. e. PR.

NH3+) and in the receptor (e. which can affect different processes. K+/ H+-ATPase in gastric parietal cells is inhibited by proton pump inhibitors (e. reversible forces such as: ionic bonding between ionisable groups in the ligand (e. n . 33). There are numerous possible extracellular and intracellular chemical signals produced in the body. hydroxyl-. Binding of the natural ligand alters the three-dimensional conformation of the protein. drugs may also bind to and either activate or inhibit other sites. ketofunctions.g. leading to the intracellular changes that are described above. lipid centres and hydrogen bonding sites. some antibiotics interfere with the functioning of the bacterial ribosome. β1-.10). For example. which are very weak interatomic attractions. adrenaline and to some extent dopamine. which are all catecholamines). omeprazole. which triggers the receptor activity. a number of anticancer drugs inhibit enzymes involved in purine. In addition to the sites and mechanisms of actions discussed above.g.e. The formulae of a few representative endogenous ligands that bind to different receptors are shown in Figure 1.e. For example.and β3-adrenoceptors all bind adrenaline. in the drug and the receptor n hydrophobic interactions between lipid-soluble sites in the ligand and receptor n van der Waals forces. as an agonist) but often the drug has a longer half-life (Ch.3  The structure of steroid hormone receptor proteins PROPERTIES OF RECEPTORS Section of protein N-terminus A/B Action Role Receptor binding The binding of the ligand to the receptor is normally reversible.g. Na+/K+-ATPase in the brain is activated by the anticonvulsant phenytoin whereas that in cardiac tissue is inhibited by digoxin. n Enzymes. For example. so that the list of ‘other sites’ is almost limitless. i. The ability of receptors to recognise and bind the appropriate ligand depends on an interaction between the receptor molecule and certain characteristics of the chemical structure of the ligand. n Organelles. whereas other receptors are less selective and will bind a number of related endogenous ligands (e.g. 4). the higher the concentration. COO−) n hydrogen bonding between amino-. the extent to which it can recognise and respond to only one ligand or a group of related ligands (such as adrenaline and noradrenaline). a fundamental property of a receptor is its selectivity. diuretics affect Na transport in the renal tubules. the β1-adrenoceptors on the heart will bind noradrenaline. Some drugs act on the enzymes that synthesise or degrade the endogenous ligands for extracellular or intracellular receptors. Therefore. the greater the occupancy. The extent of drug binding to the receptor (receptor occupancy) is proportional to the drug concentration.1). β2. Ch. Hormone drugs act primarily by mimicking the endogenous hormone (i. n Transactivation Activates target genes and gives the specificity of the receptor response Binds receptor to DNA by two zinc finger regions Hinge region to allow correct conformation Ligand specificity of receptor. α1-. or second messenger molecules (Table 1. 2 and Ch. Some drugs act as antagonists by blocking the binding of the normal ligand. consequently. For example. each of which specifically recognises or binds the same ligand. Cell membrane ion pumps. the intensity and duration of the intracellular changes are dependent on the continuing presence of the ligand. 14). The receptor protein is not a rigid structure: binding of the ligand alters its conformation and the biological properties of the protein.g. see Ch. differences in structure that determine selectivity of action between receptors may be subtle. The interaction between the ligand and its receptor does not usually involve permanent covalent chemical bonds but weaker. pyrimidine or DNA synthesis. 1. Some receptors show high selectivity and bind a single endogenous ligand (e. a large complex region. this region also binds heat shock protein Deletion of this region does not alter functioning C DNA binding and dimerisation Nuclear localization Ligand binding D E F C-terminus Unknown Receptor selectivity Different regions of the receptor are involved in hormone binding. but they occur to a different extent in different tissues. + n Transport proteins. α2-. and probenecid inhi­ bits renal tubular secretion of anions (see Ch. acetylcholine is the only endo­ genous ligand that binds to N1 nicotinic receptors. Receptor selectivity occurs because the three-dimensional organisation of the different sites for reversible binding interactions (such as anion and cation sites. For example. see above) corresponds to the three-dimensional structure of the endogenous ligand. There may be a number of subtypes of a receptor. Receptors are proteins that are folded into a tertiary structure such that the necessary specific arrangement of bonding centres is brought together within a small volume – the receptor site (Fig. and produce different intracellular changes when OTHER SITES OF DRUG ACTION Probably every protein in the human body has the potential to have its structure or activity altered by foreign compounds.9. 2) than the endogenous ligand and produces a long-term change. etc.1 12  Medical Pharmacology and Therapeutics Table 1. DNA binding and DNA modulation.

(a) Biogenic amines. Recent developments in molecular biology have enhanced our abilities to detect receptor subtypes. a racemate) could be a mixture of 50% active compound plus 50% inactive. there has been a trend in recent years for the development of single isomers for therapeutic uses. It should be noted that although ligands may have a high affinity for one receptor subtype. .and β-adrenoceptor antagonist drug labetalol bind to different types of receptor. in some cases.aminobutyrate (GABA) (c) CH3 C O OH O Progesterone O Testosterone Receptor numbers The number of receptors present in a cell is not static. the ligand has to be presented to the receptor in the correct configuration (rather like fitting a right hand into a right-handed glove). the different stereo­ isomers of the α. or. 3). and also that there is genetic variation between individuals in the properties or abundance of these receptors (pharmacogenetics – see the end of this chapter). Cell membrane receptor Fig. receptor subtypes were ‘discovered’ when a pharmaceutical company developed a new agonist or antagonist that was found to alter some. this is never absolute. Based on genetic information it is now recognised that there are multiple types of most receptors. 1.forms. In consequence. CH COOH Drug stereochemistry and activity Receptors have a three-dimensional organisation in space and. In addition. and there is a high turnover of receptors which are being formed and removed continuously. (b) amino acids. the neurotransmitter acetylcholine stimulates acetylcholine receptors on ganglia (nicotinic N1 receptor subtype). one of the earliest examples was the use of levodopa (the levo-isomer of dopa) in Parkinson’s disease (Ch. Because some drugs are a mixture of stereoisomers (the same chemical structures but with different three-dimensional configurations).and dextro-isomers (or S. synthetic drugs have been produced which show selectivity of action between these different receptors (due to different affinities/efficacies – see later) and are used for different clinical purposes. This aspect is discussed in detail in Chapter 4. the different isomers may show different rates of metabolism (see Ch. these receptors all respond to acetylcholine at low concentrations but have been shown to be structurally different by using a variety of pharmacological techniques. 24). but not all. of the activities of a currently known receptor class. The different characteristics of the receptor subtypes allow a drug (or natural hormone) with a particular three-dimensional structure to show selective actions by recognising and then acting preferentially on one particular receptor. with fewer unwanted effects from stimulation of related receptors.Principles of pharmacology and mechanisms of drug action  13 (a) CH2CH2NH2 OH CHCH2NH2 OH OH Dopamine HO OH OH Noradrenaline CH2CH2NH2 N H 5-Hydroxytryptamine (5HT) HN N Histamine CH2CH2NH2 (b) NH2 CH2 COOH Glycine O C HO Glutamate NH2 O C HO NH2 CH2CH2CH COOH O C HO Aspartate CH2 NH2 CH2CH2CH2 stimulated or blocked (see Ch. However. the different isomers may show very different binding characteristics and biological properties. 2). For example.and R. The recognition and cloning of subtypes of receptors is important in that it should facilitate the development of drugs showing greater selectivity and hopefully fewer unwanted effects. 4). . a mixture of 50% therapeutic drug and 50% inactive but toxic compound. A drug that is an equal mixture of levo. For example. the neuromuscular junction of skeletal muscle (nicotinic N2 receptor subtype) and at smooth muscle (muscarinic receptor subtype). (c) steroids. Greater understanding of genetic differences underlying human variability in drug responses offers the potential for individualisation of the mode of treatment and selection of the correct drug and dosage (see Ch. therefore.9  Groups of chemicals that show preference for different receptors in spite of similar structure. Until recently.

) to make up the active binding site. A well-recognised example is the therapeutic benefit of tricyclic antidepressants (Ch. 22). for only one receptor subtype. etc. although they produce an almost immediate increase in the availability of monoamine neurotransmitters. as a result. anionic site.e. For example. regulation of functioning receptor numbers in the membrane occurs via both transport to the membrane (often as homo. there is the need for increased doses to produce the same analgesic activity (Ch.1 14  Medical Pharmacology and Therapeutics ADRENOCEPTOR H-Bonding OH HO H-Bonding Ionic centre – + NH2 R HO R centre Aromatic centre MUSCARINIC RECEPTOR VII OH I N OH HO HO + VI O O HO V II O C O– III OH IV Fig. proteins are synthesised in the endoplasmic reticulum and transported to the membrane. such as β1. 1. it is the subsequent relatively slow adaptive downregulation in monoamine receptor numbers that takes many days or weeks which is associated with the time taken to produce a therapeutic response. Changes in receptor numbers following treatment with some drugs can be an important part of the therapeutic response. Tolerance to the effects of some drugs (e. it is therapeutically important in understanding therapeutic efficacy and unwanted effects that the bronchodilator salbutamol is approximately ten times more effective in stimulating the β2-adrenoceptors in the airways smooth muscle than the β1-adrenoceptors in the heart. to different extents (see above) but no drug is specific.or heterodimers) and removal by internalisation.10  Receptor ligand-binding sites. It is important to be able to measure the degree of selectivity of a drug and to be able to express numerically the extent to which a drug affects one receptor in relation to another. Different segments provide different properties (hydrogen bonding. . COMPONENTS OF DRUG ACTION Drug actions can show a number of important properties: n n selectivity potency n efficacy. i. 19). The coloured areas are schematic cross-sections of the seven transmembrane segments of the receptor protein (labelled I to VII). opioids) may arise from downregulation of opioid receptor numbers. The numbers of receptors within the cell membrane may be altered as a consequence of exposure of the receptor to the drug being used for treatment.g. with either an increase (upregulation) or a decrease (downregulation) in receptor numbers. Selectivity Many drugs may act preferentially on particular receptor types or subtypes.and β2-adrenoceptors. 100% selective.

It is clear from Figure 1. efficiency of the stimulus response mechanism. The more potent a drug. If dose D1 was 10 times less than dose D2. A3. In Figure 1. A1. which give an increase in response with increase in concentration until the maximum possible response is obtained (curves A1 and A2) n partial agonists. the lower will be the concentration needed to bind to the receptor and to give a response for an agonist (or to block a response for an antagonist).11). reversible antagonist.Principles of pharmacology and mechanisms of drug action  15 100 100 A1 A2 A2 + RA A3 50 % maximum response 50 Drug action at β1-adrenoceptor Drug action at β2-adrenoceptor Response (%) A2 + IA 0 0 Concentration of agonist D1 D2 D3 Increasing dose of β-adrenoceptor agonist agonist.11  Selectivity of action of a β-adrenoceptor Fig. 2) that determine the delivery of the drug to its site of action). because at low doses it produces dose-related β1-adrenoceptor stimulation with less effect on β2-adrenoceptors. 1. partial agonist. They can be classified as: n n n n n n n agonists antagonists partial agonists inverse agonists allosteric modulators enzyme inhibitors/activators non-specific. The drug shows β1-adrenoceptor selectivity. Under many circumstances it is possible to determine for an individual drug the relationship between the dose applied and the biological effect (response) on different receptor subtypes by constructing dose–response curves (Fig 1. This selectivity diminishes at the higher end of the dose–response curve and is completely lost at doses that produce a maximum response of the drug on both β1. This illustrates the relative selectivity of action for the β1-adrenoceptor of a hypothetical drug and that selectivity is maintained only over a particular dose range. CLASSIFICATION OF DRUG ACTION Different types of drug action will be introduced throughout this book. 1. For example. Because dose–response curves are usually parallel in part (for drugs that share a common mechanism of action). Efficacy The efficacy of a drug is its ability to produce the maximal response possible and relates to the extent of functional change imparted to the receptor. the ratio is the same at different response values. 10%. Fig. In modern pharmacological studies it is likely that this type of experiment would be performed by studying the effects of the drugs on isolated cell lines expressing the particular receptor being studied. 20% or 50% response.and β2-adrenoceptors (D3). which also give an increase in response with increase in concentration but cannot produce the maximum possible response (curve A3). The degree of receptor selectivity is given by the ratio of the levels of response by each receptor type when measured at equimolar doses or concentrations. which is a reflection of the receptor affinity.11 that the ratio is highly concentration-dependent and is not apparent at high concentrations. agonists can be divided into two groups (Fig. 1. RA. Potencies of different drugs have to be compared using the ratio of the doses required to produce (or block) the same percentage response. Potency The potency of a drug in vitro is largely determined by the strength of its binding to the receptor. the in vivo potencies of a series of related drugs may not reflect their in vitro receptor-binding properties. and the ability of the receptor/drug complex to elicit downstream events. affinity and efficacy (as well as pharmacokinetic variables (Ch.g. the selectivity ratio for the β1adrenoceptor is 10.12  Dose–response curves for agonists in the absence or presence of reversible (competitive) or irreversible (non-competitive) antagonists. A2. . Therefore. irreversible antagonist. two different agonists (A1 more potent than A2). e.11. smaller concentrations of the drug being tested are required to stimulate the β1-adrenoceptor compared with those required to stimulate the β2-adrenoceptor and the drug is therefore said to have selectivity of action at the β1-adrenoceptor. The potency of a drug in vivo is the amount or dose of drug necessary to produce a specified level of effect.12): n full agonists. and is dependent on receptor density. when a maximal stimulation at both receptor subtypes occurs. but not at 100% response. IA.

such as phenoxybenzamine. particularly when the rate is increased by stimulation of the sympathetic nervous system).e. Agonists An agonist whether a therapeutic drug (ligand) or the endogenous agonist (also a ligand). with downregulation. because it will prevent access of the naturally occurring agonist to the receptor and thereby result in a submaximal response. agonist-independent activity. the β-adrenoceptor antagonist propranolol is a non-selective antagonist acting equally on β1. for example because of incomplete amplification of the receptor signal via the G-proteins. Receptors with a low energy barrier show a higher tendency for spontaneous activity. The Gprotein can exist in two different low energy states. by enhancing deficient systems while simultaneously blocking excessive activity. A partial agonist will show agonist activity at low concentrations of the natural ligand. therefore. has zero efficacy). At high concentrations of the naturally occurring agonist. there may be spare receptors. in consequence. they acted on unoccupied receptors to produce a change opposite to that caused by an agonist. The presence of an inverse agonist shifts the receptor equilibrium towards the inactive state. The binding of most clinically useful antagonists is reversible and competitive. 1. inactive and active.e. reversible antagonist drugs move the dose– response curve for an agonist to the right but do not alter the maximum possible response (as shown in curve A2+RA when compared with A2 alone in Fig. Therefore. however. the receptor blockade can be overcome by an increase in the concentration of the naturally occurring receptor agonist or by the administration of an agonist drug. which are separated by an energy barrier. For example. but for most drugs/receptors the maximal response is produced while some receptors remain unoccupied. The compound will. Because the receptors exist as an equilibrium between active and inactive forms. Partial agonism is responsible for the therapeutic efficacy of several drugs. An agonist shows both affinity (the strength of binding for the receptor) and efficacy (the extent of functional change imparted to the receptor). that is. the response obtained depends upon the extent of downregulation and also on the extent of occupancy that is necessary to produce a maximal response. In the examples in Figure 1. 1. a partial agonist will behave as an antagonist. has affinity) but does not cause the conformational change that converts the receptor to its active state (i.1 16  Medical Pharmacology and Therapeutics These represent the classic descriptions of drug actions. on the overall absorption or elimination rate of the drug from the body (see Ch. It is now recognised that many G-protein-linked receptors can show basal. In practice. is directly related to the potency of the drug. but a number . n n Antagonists An antagonist binds to the receptor (i. the basal activity can be either increased or decreased by different types of ligands as follows: agonists fully activate the receptor antagonists have no effect on basal activity. and changes the conformation of the receptor to its active state. whereas atenolol shows selective antagonism of β1-adrenoceptors and has less effect on β2-adrenoceptors. drug A1 is more potent than drug A2. the same maximal response may be produced but only with higher percentage occupancy of the reduced number of receptors and hence with higher concentrations/doses. 2). in the absence of a ligand. but the dose–response will not reach the maximal activity even when all receptors are occupied (see Fig.g. For some compounds a maximal response may require all of the receptors to be occupied. including buspirone. The rate of binding/dissociation This is usually of negligible importance in determining the rates of onset or termination of effect in vivo. Antagonists also exhibit selectivity of action. Drugs may differ in their affinity and efficacy. Changes in the number of receptors The effect of changes in the numbers of receptors on dose– response relationships is complex. but competitively block the access of other ligands n partial agonists induce submaximal activation of the G-protein even at saturating concentrations n inverse agonists inhibit basal activity. block access to the receptorbinding site of the naturally occurring agonist. The affinity or strength of binding of the drug to the receptor This determines the concentration necessary to produce a response and. maximal drug effects are normally produced at concentrations that do not give 100% receptor occupancy.12). buprenorphine. The role of inverse agonist activity in the therapeutic effects of drugs remains to be fully elucidated. Inverse agonists The concept of an inverse agonist arose because some compounds were found to show ‘negative efficacy’ – in other words. that is. in consequence. With downregulation of receptors. significant effects will occur only if there is a high level of basal (spontaneous) activity. The drug effect may only be detectable when the natural agonist is present (e. drug A3). thereby reducing the level of basal activity.12. Even maximal occupancy of a partial agonist at all available receptors produces a submaximal response. binds to the receptor or site of action. The presence of spare receptors becomes important when considering changes in receptor numbers owing to adaptive responses during chronic treatment (tolerance) or caused by irreversible binding of an antagonist (see below). these drugs can be thought of as stabilisers of cell communication.12). Irreversible antagonists. As a consequence. and a full response cannot be achieved even by a very large increase in agonist concentration (as shown in curve A2+IA compared with A2 alone in Fig. β-adrenoceptor antagonists lower heart rate. Partial agonists A drug showing both agonist and antagonist properties is known as a partial agonist: the activity expressed at any time is dependent on the concentration of the natural ligand or agonist. because these depend mainly on the rates of delivery to and removal from the target organ.12. 1. but both are capable of producing a maximal response (they have the same efficacy). bind covalently to their site of action.and β2-adrenoceptors. pindolol and salbutamol.

candesartan. which alter the affinity of Cl− channels for the neurotransmitter GABA (Ch. Homologous desensitisation. may be an inverse agonist when the receptor is expressed on a different tissue (possibly due to association of the receptor protein with different G-proteins). they are eliminated more rapidly on repeated dosage and lower concentrations of drug are available to produce a response. β-arrestin. An example of the latter is the depletion of the SH groups necessary for the generation of nitric oxide during chronic administration of organic nitrates (see angina. which act as an antagonist at some tissue receptors. n Heterologous desensitisation. for example β-adrenoceptor antagonists. A final complication is that some drugs. Tolerance may occur through: n Receptor α1-Adrenoceptor β1-Adrenoceptor Muscarinic M1 Histamine H1 Histamine H2 Dopamine D2 Angiotensin II receptor subtype AT1 Cysteinyl leukotriene CysLT1 Drugs Prazosin. Ch. The relationship between drug dosage and the concentrations delivered to the receptor is discussed in Chapter 2: some drugs stimulate their own metabolism. famotidine Haloperidol. ranitidine. irbesartan Montelukast. the drug acts either on the catalytic site or at an allosteric site. However.Principles of pharmacology and mechanisms of drug action  17 Table 1. An example is the anticholinesterase group of drugs (see Ch. most clinically important examples of tolerance arise from changes in receptor numbers and concentration–response relationships. Antagonists (see above) bind to the receptor and block the activity of both agonists and inverse agonists. loratadine Cimetidine. zafirlukast a decrease in the concentrations of drug at the receptor n a decrease in response produced by the receptor to the same concentration of drug n a decrease in the number of receptors (so that an increased % occupancy is necessary to produce the same response). Binding to the allosteric site can change receptor activity by altering the conformation of the protein so as to affect the normal (orthosteric) binding site and thereby enhance or decrease the binding of the natural ligand to its receptor. The receptor (whether occupied or not) is inactivated through phosphorylation by a cAMP-dependent kinase (protein kinase A or protein kinase C). high doses of indirectly acting .4). Enzyme inhibitors/activators Some drugs have a site of action that is an enzyme. as a result. Desensitisation is used to describe both long-term and short-term changes in dose–response relationships arising from a decrease in response of the receptor. which causes uncoupling of the G-protein and can be switched on by a variety of signals that increase cAMP. Non-specific actions Some compounds produce their desired therapeutic outcome without interaction with a specific site of action on a protein – for example. n Allosteric modulators An allosteric modulator does not act directly on the ligand/ receptor site (also called the orthosteric site) but binds to a different (allosteric) site on the receptor. The phosphorylated receptor protein may then be internalised and undergo intracellular dephosphorylation prior to reentering the cytoplasmic membrane. but they may destabilise the receptor/G-protein coupling. which interact with the βγ-subunit of the G-protein and inactivate the occupied receptor protein by phosphorylation. allosteric modulators may change the conformation of the receptor protein so that it alters the receptor signalling (second messenger) domain without affecting the orthosteric site. 5). enhances the GRKmediated desensitisation. n Receptor internalisation.4  Drugs that show inverse agonist activity TOLERANCE TO DRUG EFFECTS Tolerance to drug effects is characterised by a decrease in response with repeated doses. Alternatively. or they may preferentially bind to the inactivated form of the receptor. The enzymes activated following ligand binding to a receptor/G-protein complex include G-protein-coupled receptor kinases (GRKs). terazosin Metoprolol Pirenzepine (not available for clinical use in the UK) Cetirizine. a related peptide. and. thereby shifting the equilibrium away from the active form. 4). Endocytosis of the agonistcoupled receptor can occur within minutes of constant activation of G-protein-coupled receptors and makes the receptor unavailable for further agonist actions by uncoupling the G-protein from the receptor. Downstream modulation of the signal may also occur through feedback mechanisms or simply through depletion of some essential cofactor. decreased receptor numbers (downregulation): a slow process taking hours or days n decreased receptor binding affinity n decreased G-protein coupling n modulation of the downstream response to the initial signal. which occurs through three mechanisms. An example is the benzodiazepine drugs. Desensitisation can occur by a number of mechanisms: n of drugs exhibit this type of activity (Table 1. 20). olanzapine Losartan. The mechanism of action of inverse agonists is not well characterised. the action of osmotic diuretics on the kidney. clozapine. Extracellular receptors coupled to G-proteins show rapid desensitisation (within minutes) during continued activation.

3) and also because it allows the future possibility for genetic screening to be used to optimise drug and dosage selection. Pharmacogenetics has been defined as ‘the influence of variations in DNA sequence on drug response’. but rather in defining the functional consequences of the genetic difference and the magnitude of phenotypic differences. this variation is reflected in a single Gaussian distribution (Fig. 1. and relates to genome-wide approaches that define the presence of single-nucleotide polymorphisms (SNPs) in the genes which affect the activity of the gene product.13a). which will result in a gene product with an altered amino acid sequence that may have higher activity (although this is unlikely). including the responses to drug administration. The rapid advances in molecular biology have allowed analysis of person-toperson differences in the sequences of the genes involved (a) Gaussian distribution of response (b) Polymorphic distribution of response Number of subjects Response Number of subjects Response Fig. the gene product will be the same as the normal or ‘wild’ type of gene product n in the coding region of the gene.1 18  Medical Pharmacology and Therapeutics sympathomimetic amines may cause depletion of neuronal noradrenaline. Both the coefficient of variation and the magnitude of the difference between phenotypes affect the variation in a polymorphic distribution (Fig. The nature of the response is usually similar in all individuals. SNPs can be: n in the upstream regulatory sequence of a coding gene. or because the base change does not alter the amino acid encoded. In consequence.13a). and relates to how genetic differences between individuals affect the response to a drug or the fate of a drug in the body (Ch. The genetic origins of many polymorphisms is of increasing importance in relation to drug development (see Ch.13  Inter-individual variation in response to a single dose.13b). lower activity or no activity at all. there can be inactive SNPs because they are in non-coding or silent regions of the genome. and such variability is an inherent part of the need to individualise dosage for the person. 1. which can result in increased or decreased expression of the gene in response to the regulatory transcription factors that control the gene product. The graphs show the numbers of individuals in a population showing a particular level of response to a single dose of a drug against the magnitude of the response. PHARMACOGENETICS AND DRUG RESPONSES There are person-to-person variations for any biological property. but the magnitude of the response to the same dose of a drug can differ markedly within a group of individuals. In addition. 1.4 million SNPs in the human genome. For many responses. In Figure 1. Molecular biological techniques have allowed recognition of more than 1. Future research will also focus on the importance of different combinations of genetic variants (haplotypes) rather than on single gene differences. 4).13a. similar activity. largely in relation to in vivo variability. the magnitude of inter-individual variability is indicated by the coefficient of variation (the dotted line in Fig.13a is for a response showing wider inter-individual variation). The presence of a genetic polymorphism in a receptor. 1. such that some individuals may have no response to a standard dose while others show toxicity. enzyme or transporter (Fig. Pharmacogenomics has been defined as ‘the investigation of variations of DNA and RNA characteristics as related to drug response’.13b) can give rise to much wider person-to-person variation in response. a major challenge for the future is not in identifying SNPs and the presence of genotypic differences. most individuals show the average response and the overall shape is a normal distribution. 1. which is necessary for their activity (see Ch. and has often used classic genetic techniques such as studies in twins and patterns of inheritance. . because they share the same underlying biology. Pharmacogenetic research has been undertaken for more than four decades. site of action. 2). PHARMACOGENOMICS. In a normal monomorphic distribution (Fig. 1.

few studies have been performed on the influence of genetic differences in receptor structure on drug responses. Page CP (2006) Phosphodiesterase inhibitors. Nine polymorphisms have been identified in the β2-adrenoceptor. Genomic studies have identified SNPs in nearly every receptor type found in the autonomic system. clear relationships of variants of the different dopamine receptors to diseases have not been established. a genetic variant of major clinical importance has yet to be identified. prior to the subject being administered any drug. Until such information is available routinely. XL. and certain genetic variants have been associated with different asthma phenotypes and also with differences in drug responses. 381–388 Catterall WA (1995) Structure and function of voltage-gated ion channels. Pharmacol Rev 55. Clapham DE (1997) Ion-channels – basic science and clinical disease. Germain P. the clinical and therapeutic implications of few of these have been characterised. Sallese M. polymorphisms in receptors may be more important for drug selection. Akiyama TE. careful monitoring of the subject’s response will remain the best guide to successful treatment. available at http://www. Compendium of voltage-gated ion channels: sodium channels. Pharmacogenetic variability will be increasingly important to optimise drug responses and to minimise adverse effects in individuals. Striessnig J. α2B and α2C).nlm. Polymorphisms of various G-protein receptors have been found in different domains of the protein with a range of different effects (given in parentheses): the N-terminal domain (altered ligand binding or downregulation). whereas a β-adrenoceptor antagonist would still be effective. Br J Pharmacol 147. While polymorphisms in pharmacokinetics (see Ch. Knowledge of the precise nature of the differences (SNPs) that result in genetic polymorphisms is beyond the scope of an undergraduate text.Principles of pharmacology and mechanisms of drug action  19 in receptors (pharmacodynamics – this chapter) and in drug metabolism and drug transport (pharmacokinetics – Ch. Snutch TP et al (2003) International Union of Pharmacology. N Engl J Med 336. Genetic polymorphisms have been reported in many receptor types. Sixteen different human α1A-adrenoceptor isoforms have been identified. Mathie A. it should be remembered that: n not all effects seen following drug administration are caused by the drug (a ‘placebo effect’ can be produced just by a clinical consultation) n nearly all drugs show multiple effects no matter how receptor-selective they are n not all effects produced by a drug will be therapeutically beneficial. Trends Pharmacol Sci 17. Gronemeyer H (2000) Nuclear receptor ligand-binding domains: three-dimensional structures. Goldin AL.gov/omim CONCLUSIONS The selectivity of drugs arises from their ability to interact with and affect certain target sites within a cell. Trends Pharmacol Sci 26. 575–578 Catterall WA. despite the vast amount of research undertaken. Polymorphisms in dopamine D2 receptors have been observed and studied in various conditions. some of which have been linked to abnormal cardiovascular or respiratory drug responses. the intracellular loop (altered ligand binding or coupling to G-protein) and the C-terminal domain (altered coupling to G-protein). 579–581 Chuang TT. Spina D. However. a functional deficit in the β1-adrenoceptor could make an ACE inhibitor a better choice than a β-adrenoceptor antagonist for treating cardiovascular conditions.nih. in general. Genetic polymorphisms in receptors and second messenger systems are likely to be of increasing importance in the future. However. FURTHER READING Ackerman MJ. 3rd edition (2008 revision). In contrast. and these have been a major focus of research in relation to the aetiology of diseases. Pharmacol Rev 55. Polymorphisms have been reported for each of the three main α2-adrenoceptor types (α2A. 2) are likely to have an important impact on dosage selection. 2) and receptors can be taken into account using individual genetic information. In principle. however. the transmembrane domain (altered ligand binding or coupling to G-protein). XL. such as alcohol and drug dependency. de Blasi A (1996) G protein-coupled receptors: heterologous regulation of homologous desensitization and its implications. 6) nor an AT2 receptor antagonist would be a good choice to lower blood pressure in such subjects. S1–S209 Berger JP. 2). and is not necessary to understand or appreciate either the current position or possible future developments in the area of pharmacogenomics. S252–S257 Bourguet W. but. Annu Rev Biochem 64. molecular interactions and pharmacological implications. Exploitation of genetic differences will require specific individual genetic information. Trends Pharmacol Sci 21. discovery of a major polymorphism that caused a functional deficit in the angio­ tensin (AT2) receptor would mean that neither an angio­ tensin-converting enzyme (ACE) inhibitor (Ch. but the consequences for drug activities in clinical practice have not been defined. 1575–1586 Alexander SPH. Iacovelli L. Peters JA (2008) Guide to receptors and channels (GRAC).ncbi. 493–531 Catterell WA. Br J Pharmacol 153(suppl 2). especially when genetic differences in pharmacokinetics (Ch. To date. Johns Hopkins University) database. Waxman SG (2003) International Union of Pharmacology. including five full-length and 11 truncated versions (which are incapable of ligand binding and signal transduction). 416–421 . Compendium of voltage-gated ion channels: calcium channels. Meinke PT (2005) PPARs: therapeutic targets for metabolic disease. Information on genetic polymorphisms in different receptors can be found on the OMIM® (Online Mendelian Inheritance in Man®. Our increasing knowledge of the complexity of receptor pharmacology offers the promise of safer drugs in the future. 244–251 Boswell-Smith V. despite the large number of variants identified. high selectivity should result in safer drugs with fewer adverse effects. For example.

Michelotti GA. Annu Rev Pharmacol Toxicol 41. Annu Rev Pharmacol Toxicol 36. Chandy KG. Pharmacol Rev 53. Caron MG. Guenin S-P. Biel M. Annu Rev Pharmacol Toxicol 36. Annu Rev Pharmacol Toxicol 41. 10–13 Polson JB (1996) Cyclic nucleotide phosphodiesterases and vascular smooth muscle. XL. Trends Pharmacol Sci 25.1 20  Medical Pharmacology and Therapeutics Costa T. 429–459 Gutman GA. 219–233 Sunahara RK. 1–24 Fredholm BB. Coge F. Annu Rev Pharmacol Toxicol 43. 101–121 Milligan G. 461–480 Tsai M-J. Insel PA (2004) Autonomic nervous system pharmacogenomics: a progress report. Pharmacol Rev 52. Strathmann MP. IJzerman AP. 653–688 Dolphin A (2003) International Union of Pharmacology. 101–132 Strange PG (2003) Mechanisms of inverse agonism at G-proteincoupled receptors. Pharmacol Rev 54. Compendium of voltage-gated ion channels: cyclic nucleotide modulated channels. Defer N (2001) Regulation and role of adenylyl cyclase isoforms. Kanaide H (2005) Physiology and pathophysiology of proteinase-activated receptors (PARs): regulation of the expression of PARs. Pharmacol Rev 55. Shiina T. 403–427 Privalsky ML (2004) The role of corepressors in transcriptional regulation by nuclear hormone receptors. Gautam N (1991) Diversity of G proteins in signal transduction. Dessauer CW. 308–313 Wong AHC. Lefkowitz RJ (1991) Model systems for the study of seven-transmembrane-segment receptors. Cotecchia S (2005) Historical review: Negative efficacy and the constitutive activity of G-protein coupled receptors. 802–808 Strader CD. Trends Pharmacol Sci 25. Pitari GM. Yufu T. 315–360 Rana BK. 527–552 Gudermann T. Trends Pharmacol Sci 25. Annu Rev Pharmacol Toxicol 36. 607–627 Essayan DM (2001) Cyclic nucleotide phosphodiesterases. Trends Pharmacol Sci 28. Tota MR. Dixon RAF (1994) Structure and function of G-protein-coupled receptors. Thomer J. Trends Pharmacol Sci 26. Schwinn DA (2004) Update on human α1-adrenoceptor subtype signaling and genomic organization. 583–586 Hanoune J. Science 252. Trends Pharmacol Sci 23. Jacobson KA. Insel PA (2001) Genetic variations and polymorphisms of G protein-coupled receptors: functional and therapeutic implications. 276–287 Lefkowitz RJ (2004) Historical review: A brief history and personal retrospective of seven-transmembrane receptors. 47–72 Wess J (1993) Molecular basis of muscarinic acetylcholine receptor function. XXV. 183–203 . 449–455 Hirano K. Hepler JR (2002) Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. J Pharm Pract 20. Pharmacol Rev 55. 527–559 Kenakin T (2004) Principles: Receptor theory in pharmacology. 89–95 Streetman DS (2007) Clinical pharmacogenetics of the major adenosine triphosphate-binding cassette and solute carrier drug transporters. Hirano M. Annu Rev Biochem 60. Compendium of voltage-gated ion channels: G protein modulation of voltage-gated calcium channels. 413–422 Lucas KA. Edwardson JM (1997) Endocytosis and recycling of G protein-coupled receptors. Linden J (2001) International Union of Pharmacology. Kalkbrenner F. Kaupp UB (2003) International Union of Pharmacology. Van Tol HHM (2000) Polymorphisms in dopamine receptors: what do they tell us? Eur J Pharmacol 410. 671–680 Ferguson FFG (2001) Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Buckle CE. Fong TM. 587–589 Hollinger S. Annu Rev Physiol 66. Pharmacol Rev 53. Kazerounian S et al (2000) Guanylyl cyclases and signaling by cyclic GMP. Deupi X (2007) Conformational complexity of G-proteincoupled receptors. Schultz G (1996) Diversity and selectivity of receptor–G-protein interaction. Compendium of voltage-gated ion channels: potassium channels. XL. Trends Pharmacol Sci 14. Evans WE (2001) Pharmacogenomics: unlocking the human genome for better drug therapy. XL. J Pharmacol Sci 97. Gilman AG (1996) Complexity and diversity of mammalian adenylyl cyclases. Adelman JP et al (2003) International Union of Pharmacology. J Allergy Clin Immunol 108. Annu Rev Biochem 63. 375–413 McLeod HL. 31–52 Kobilka BK. O’Malley BW (1994) Molecular mechanisms of action of steroid/thyroid receptor superfamily members. 31–37 Hofmann F. Pharmacol Rev 55. 618–624 Dohlman HG. Nishimura J. 593–624 Simon MI. Annu Rev Pharmacol Toxicol 41. Bond RA. Lee M (1995) Inverse agonism: pharmacological curiosity or potential therapeutic strategy? Trends Pharmacol Sci 16. Underwood D. Nomenclature and classification of adenosine receptors. 186–192 Kirstein SL. Pharmacol Rev 56. 145–174 Hawrylyshyn KA. 451–486 Wei LN (2003) Retinoid receptors and their coregulators. Annu Rev Biochem 63. 397–406 Koenig JA. Trends Pharmacol Sci 18. Klotz KN.

and β-adrenergic neurons) Gq Contraction of arterial smooth muscle. propantheline M2 Heart. contraction of prostate tissue Decreased noradrenaline release Phenylephrine. pain. CCK-33. secretory glands Gq CNS and postsynaptic in sympathetic nervous system human prostate (α1A ) Presynaptic (in both α. amygdala. nociception. terbutaline. methoxamine (tamsulosin α1A) Prazosin. smooth muscle contraction (GI. inhibits gut motility. secretion I Darifenacin M3 Adrenergic α-Adrenoceptorsb α1 (α1Aα1Bα1D) Smooth muscles. AD > NA β3 Cannabinoids CB1. carbachol Pirenzepine nonselective for all M receptors – atropine. depression N-arachidonoylethanolamine (anandamide). CCK-8. anxiety. indoramin α2 (α2Aα2Bα2C) Gi Clonidine (oxymetazoline α2A) Yohimbine β-Adrenoceptorsc β1 CNS and heart (nodes and myocardium) Widespread Gs Increased force and rate of cardiac contraction Bronchial dilation. inflammation CGRP .hippocampus. airways. bladder) Contraction. CB2 Adipocytes Gs AD = NA – Cortex. primarily GI CCK2 primarily in CNS Gq/Gs CCK1. decrease in contraction of gut. hyoscine. decrease in contractions of gut. gall bladder emptying. CCK2 CNS nociception. gastric secretion non-selective for all M receptors-bethanecol. CCK2 CCK1.Principles of pharmacology and mechanisms of drug action  21 Examples of some types of receptors and their properties (some of this information was derived from Alexander. gastric Gq Neurotransmission in CNS. nausea. appetite CCK-4. stimulation of appetite. metabolic effects Mobilisation of fat stores Dobutamine NA > AD Atenolol. cerebellum Gi/G0 Behaviour. CNS Gi Bradycardia. 2-arachidonylglyceryl Cholecystokinin CCK1. metoprololol Butoxamine β2 Gs Salmeterol. pilocarpine. Mathie and Peters 2008) Type Typical location(s) Principal transduction mechanism Biological actions Agonists1 Antagonists1 7-transmembrane receptors Acetylcholine Muscarinica M1 CNS and autonomic ganglia (minor role). basal ganglia. gastrin Calcitonin–gene related peptide CGRP Sensory nerve endings Gq/Gs Vasodilation.

O. renoxipride. stomach Gs Cimetidine.1 22  Medical Pharmacology and Therapeutics Examples of some types of receptors and their properties (some of this information was derived from Alexander. N. pituitary gland. memory Cognition emotion Linked to schizophrenia Fenoldopam Bromocriptine. heart CNS (Hi. memory. ↓ Ca2+ channels Vasodilation in kidney (see notes) Linked to schizophrenia. appetite. smooth muscle Gi Gi Gi Gq Sumatriptan. Hy) e Gs Gi↑ K+ channels. Mathie and Peters 2008) Type Typical location(s) Principal transduction mechanism Biological actions Agonists1 Antagonists1 Dopamined D1 D2 CNS (N. nerve inhibition Vasoconstriction presynaptic inhibition Vasoconstriction behaviour Buspirone 5HT1B CNS blood vessels Gi Sumatriptan. smooth muscle Gq Sedation. serotonin) 5HT1A CNS Gi Anxiety sleep. platelet aggregation. sleep. movement control. morphogenesis Satiety Anxiety.d heartd CNS (C. SN). smooth muscle CNS CNS CNS CNS GI blood vessels Gq Gq Gs Metoclopramide. sulpiride. eletriptan 5HT1D 5HT1E 5HT1F 5HT2A CNS. chemoreceptor trigger zone gastrointestinal tract CNS (F. Mi) (limbic system) CNS. domperidone Sulpiride Clozapine D3 D4 D5 Gi Gi Gs 5-Hydroxytryptamine (5HT). prolactin secretion. renzapride 5HT5A 5HT5B 5HT6 5HT7 Histamine H1 Gi ? Gs Gs LSD Clozapine CNS. O. kidney. P. inflammation Gastric acid secretion Dimaprit Mepyramine H2 CNS. eletriptan Metergoline Schizophrenia. vascular permeability. S). myenteric plexus. Me. endothelium. pergolide Butyrophenones. cardiac muscle. ranitidine . vasodilation/ vasoconstriction Contraction. blood vessels CNS CNS CNS platelets. gut motility LSD Ketanserin 5HT2B 5HT2C 5HT4 Stomach CNS CNS.

myenteric plexus Eosinophils. adrenal cortex brain Tyrosine phosphatases Bradykinin B1 (induced) Widespread (induced by injury. vasodilation. Mathie and Peters 2008) Type Typical location(s) Principal transduction mechanism Gi Gi Biological actions Agonists1 Antagonists1 H3 H4 CNS (presynaptic). Stimulates NO synthesis in endothelium Losartan. pain perception. cognition Thioperamide Gamma-aminobutyric acid receptor type B (GABAB) GABAB Brain neurons. mglu6. memory. increased noradrenergic activity. learning.g. proliferation blood vessels Sitaxentan. brain Gq/G0 Vasconstriction. valsartan Gq Gi Gi Multiple possible roles. spinal motor neurons and interneurons Gi effects on Ca2+ channel (closes) and K+ channel (opens) Widespread reduction of impulse transmission in CNS. DA and NA) ?schizophrenia AT2 Blood vessels. mast cells Appetite. vascular growth. modulation of transmission (e. mglu7 and mglu8) Peptides Angiotensin II AT1 Blood vessels. pain response ACE inhibitors (indirect via BK stimulation) B2 (constitutive) Gq Endothelins ETA Endothelium Gq Vasoconstriction. aldosterone synthesis. adrenal cortex. cytokines) Gq Acute inflammation. suppression of polysynaptic reflexes in spine. basophils. salt retention. anxiety. endothelium.Principles of pharmacology and mechanisms of drug action  23 Examples of some types of receptors and their properties (some of this information was derived from Alexander. fetal development. Most actions of kinins. glial cells. bosentan . Stimulates NO synthesis Chronic inflammation. generation of spike and wave discharges in absence epilepsy Baclofen Glutamate (metabotropic)f Group I (mglu1 and mglu5) Group II (mglu2 and mglu3) Group III (mglu4. cardiac hypertrophy Weak vasodilation.

N/OFQ (nociceptin/ orphanin) Orexin (OX1 OX2) (also known as hypocretins) (Ch. ghrelin receptors are widespread Gq Melanocortin receptor family [MC1-MC5] (Ch. 37) Gs Melanocyte stimulating hormone (MSH) agouti-related protein (AGRP) (Ch. Gi . NPY secreted into blood from stomach Gi Increase Na+ excretion Increase Na+ excretion Increases appetite. feeding behaviour. myocytes.1 24  Medical Pharmacology and Therapeutics Examples of some types of receptors and their properties (some of this information was derived from Alexander. memory learning ANPB Neuropeptide Y (NPY) receptor family Y1–Y6) (Ch. PAR4) Hypothalamus and other areas of brain Substance P Gi Gq Increases food intake. direct vasoconstriction. induces appetite MSH skin pigmentation. κ. neurons Gq. guanylyl cyclase G-protein. D-Phe5. stress. ACTH (specifically at MC2) skin pigmentation HPA function [D-Arg1. 6) Release of nitric oxide (indirect vasodilation). wakefulness.9. D-Trp7. guanylyl cyclase Y receptors wide distribution in CNS hypothalamus. PAR2. Leu11]-substance P Bosentan Ghrelin Stomach. Mathie and Peters 2008) Type Typical location(s) Principal transduction mechanism Gq Biological actions Agonists1 Antagonists1 ETB Endothelium (Ch. PAR3. 37) Natriuretic peptides ANPA G-protein. 37) Tachykinins (neurokinins) NK1 Gq: slow build-up of response Gq: slow build-up of response Gq Nociception (substance P) Nociception (neurokinin A) (Neurokinin B) Substance P NK2 Substance P NK3 Opioids δ. natriuresis Ligand for GH secretagogue receptor. endocrine cells. 37) Proteinase activated receptors (PAR1. Activated by orexin-A and B Activated by proteolytic cleavage Trypsin. endothelial cells. µ. thrombin Platelets. body temperature.

cardiac depression. nicotine Nicotine Trimetaphan. inhibition of platelet aggregation. Gs Vasoconstriction. platelet aggregation Modulates ACTH secretion Antidiuretic effect on collecting duct and ascending limb of loop of Henle Lactation. – – Methylxanthines A2A Gs Methylxanthines A2B A2B A3 Gq Gs Ca2+ influx Gi Enprofylline P2Y-receptors (P2Y1. uterine contraction. Mathie and Peters 2008) Type Typical location(s) Principal transduction mechanism Biological actions Agonists1 Antagonists1 Vasopressin and Oxytocin V1a V1b V2 Pituitary. P2Y2. CNS actions Arginine vasopressin > oxytocin Arginine vasopressin > oxytocin Arginine vasopressin > oxytocin OT Breast. Gs Ligand-gated receptors or channels (also called transmitter-gated receptors or channels) Nicotinic N1 Nicotinic N2 5HT3 Autonomic ganglia Neuromuscular junction CNS (A). release of mediators from mast cells Biological effect depends upon G protein coupling Activated by ATP. brain Kidney Gq Gq plus Gi. UTP. decreased CNS activity. sensory nerves Brain neurons. decreased CNS activity. brain Pituitary. spinal motor neurons and interneurons Ligand-gated ion channel Ligand-gated ion channel Ligand-gated Na+/K+ channels Ligand-gated Cl. vasoconstriction.Principles of pharmacology and mechanisms of drug action  25 Examples of some types of receptors and their properties (some of this information was derived from Alexander. ADP. bronchoconstriction Vasodilation. inhibition of sensory signals at spinal level .channel (open)g Postganglionic activation Muscle contraction Emesis Carbachol. bronchodilation Action on intestine and bladder Release of mediators from mast cells? Wide tissue distribution. vecuronium Granisetron. P2Y6) A family of peptides present in almost all tissues Gq. enteric nerves. UDP and UDPglucose. mecamylamine Gallamine. P2Y4. brain uterus Gq Oxytocin > arginine vasopressin Purinergic receptors (purinoreceptors) Adenosine A1 Gi↑ K+ conduction in heart Decreased glomerular filtration rate. ondansetron Muscimol (benzodiazepines) (zolpidem) (Picrotoxin) (flumazenil) GABAAh Widespread reduction of impulse transmission in CNS.

diacylglycerol. S. Hy. Many of these are investigational tools and have no clinical use. α1B. Mathie and Peters 2008) Type Typical location(s) Principal transduction mechanism Ligand-gated Cl− channel (open)g Biological actions Agonists1 Antagonists1 Glycine Brain neurons.D4). Hi. Gi = ↓ adenylyl cyclase. with the exception of 5HT3 and emesis. F. ATP Neuronal depolarisation. frontal cortex. e There are many experimental drugs that are selective agonists and antagonists for receptors subtypes and some are undergoing clinical trials for various conditions. tropisetron. globus pallidus. midbrain: N. area postrema. NA = AD. P2X2-3 ganglia Ligand-gated ion channels (Na+. NMDA. RyR2. caudate putamen. D3. 0. excitatory transmitter release. decreased protein kinase A. increased IP3. T. c The β-adrenoceptors differ in their affinities for noradrenaline (NA) and adrenaline (AD): β1. R. Ca2+ and K+ and exceptionally Cl-) Cytosolic Ca2+. G. Co. f Glutamate produces increased neuronal activity in many regions of the CNS. cortex. Gq = ↑ phospholipase C. g Part of response to vascular damage. striatum. hippocampus. transmitter release Synaptic plasticity. sensory pathways) Ligand-gated Ca2+ channel (slow) Synaptic plasticity. NA – noradrenaline. caffeine >100 mM Ca2+. olfactory tubercle. picrotoxin and steroids. d Commonly divided into D1-like (D1 and D5) and D2-like (D2. NA > AD.channel has a binding site for GABA and also adjacent binding sites for benzodiazepines (which affect the response to GABA). raphe nucleus. C. b a . B. Effects associated with the different receptors are not well established. ?myasthenia gravis Ryanodine.1 26  Medical Pharmacology and Therapeutics Examples of some types of receptors and their properties (some of this information was derived from Alexander. basal ganglia. α1B. choroid. Mg2+ dantrolene Only selected agonists and antagonists are included. The transduction processes are Gs = ↑ adenylyl cyclase. Three α1-adrenoceptors have been identified (α1A. RyR3 (widespread. AD – adrenaline. a number of variants have been demonstrated for each. increased protein kinase A. CNS areas: A. Mi. Only clinically useful examples are given. kainate)f N-Methyl d-aspartate(NMDA)i CNS (B. all of which act via Gq proteins: α1A-adrenoceptors have a higher affinity for noradrenaline than for adrenaline.The GABAA receptor Cl. influx of Na+ and Ca2+ > efflux of K+ Endogenous ligand ATP Ryanodine receptors (RyR1. SN. thalamus. substantia nigra. nucleus accumbens. Additional muscarinic receptors (M4 (Gi) and M5 (Gq)) have been identified recently but their clinical importance is unclear. Ch. endocannabinoids Ionotropic glutamate-like receptors (AMPA. spinal motor neurons and interneurons Widespread reduction of impulse transmission in CNS. β2. putamen. h GABA produces inhibition of neurotransmission widely throughout the brain. brain) Intracellular Ca2+ concentrations. the different receptors are formed from subunits that can exist in different isoforms. RyR3) 1 RyR (skeletal muscle). 5HT is involved in numerous pathways within the CNS and the roles of the different receptor types has not been fully characterised. transmitter release Aspartate Ketamine. AD > NA: β3. excessive amounts may cause neuronal damage Synaptic plasticity. barbiturates. The type of receptor in heart and kidney remains questionable as the mRNA for D1 receptors has not been found (it could be D5). inhibition of sensory signals at spinal level Intravenous anaesthetics Strychnine. phenyclidine (inhibit Ca2+ flux) Kainate CNS (Hi) Ligand-gated Ca2+ channel (fast) Ligand-gated Ca2+ channel (fast) Kainate a-amino-3hydroxy-5-methyl4-isoxazole propionic acid (AMPA) Purinergic P2X family (P2X1-P2X7) CNS (similar to NMDA receptors) P2X1 smooth muscle. C. hypothalamus. The identification and classification of 5HT receptors is a complex and rapidly changing field. RyR2 (heart). LSD – lysergic acid diethylamide. P. Me.and α1D-adrenoceptors do not show selectivity. α1D). medulla.

g.g. bendroflumethazide.g.g. docusate Sodium picosulfate Antimuscarinics.g. candesartan. e.g.g. amiloride. e.g.Principles of pharmacology and mechanisms of drug action  27 Appendix LIMITED STUDENT FORMULARY This formulary has been derived from the formulary put together by Maxwell and Walley (2003). clarithromycin.g. proton pump inhibitors and H2 receptor antagonists (see peptic ulcer disease drugs). e. e. codeine Bulk forming laxatives. eg aluminium hydroxide and magnesium carbonate Acid secretion inhibition e. ispaghula Stimulant laxatives. minoxidil. e. milrinone β-adrenoceptor antagonists. e. magnesium and aluminium-containing antacids. gastrointestinal system Therapeutic problem Dyspepsia and gastro-oesophageal reflux disease Core drugs Antacids e.g. metronidazole Vancomycin Oral rehydration therapy. e. e. loperamide. e. omeprazole H2 receptor antagonists. captopril Angiotensin-II receptor antagonists. e. clonidine. e. e.g. amoxicillin. hyoscine Other antispasmodics.g. ranitidine.g. Anti-reflux drugs. mebeverin cardiovascular system   Motility stimulants Peptic ulcer disease   Helicobacter pylori eradication Inflammatory bowel disease (ulcerative colitis. Centrally-acting antihypertensives.g. senna Osmotic laxatives. infliximab Antibiotics for C. mesalazine Cytokine inhibitors.g.g. e. nicorandil Many drugs used for hypertension are of benefit. sulfasalazine. in addition positive inotropic drugs: cardiac glycosides.g.g. amlodipine Potassium channel openers.g. prednisolone Other drugs e. the Southampton University Hospitals Trust formulary and the Southampton Medical School Pharmacology Course documents. e. e.g.g. e. digoxin. sucralfate. e. moxonidine Angiotensin-converting enzyme inhibitors. furosemide Potassium-sparing diuretics. e. losartan Thiazide and related diuretics. metolazone. e. cimetidine.g. e.g. lactulose Faecal softeners. atenolol α-adrenoceptor antagonists. e. e.g. It is not exhaustive.g. doxazosin. other drugs e. magnesium hydroxide. metoclopramide Proton-pump inhibitors. spironolactone Calcium channel blockers. Antimotility drugs. bisoprolol Heart failure . Phosphodiesterase inhibitors. difficile. misoprostil Antibiotics.g. e. Its purpose is to introduce students in the early years of their undergraduate course in medicine to representative examples of core drugs and their uses in major areas of medicine.g.g. gaviscon These may be used in gastrointestinal reflux disease e.g. e.g. e. Loop diuretics. metronidazole Corticosteroids. Crohn’s disease)   Clostridium difficile colitis Diarrhoea Constipation   Bowel cleansing Antispasmodics Therapeutic problem Hypertension Core drugs β-adrenoceptor antagonists.

Nonsteroidal analgesics – see section on Musculoskeletal and Joint Diseases Compound analgesics e. e. salbutamol. e. hyperlipidaemia respiratory system Therapeutic problem Asthma (acute and chronic). e.g. montelukast Other drugs. fluoxetine Monoamine oxidase inhibitors. abciximab Thrombolytics. digoxin.g. e. morphine. gabapentin e. e. dipyridamole. ondansetron Muscarinic receptor antagonists.g.g.g. stroke treatment and prevention. chlorpromazine.g. simvastatin Antiarrhythmic drugs. buspirone.g.g. phenelzine Simple analgesics without anti-inflammatory properties. respiratory failure Core drugs Oxygen. warfarin Lipid-regulating drugs. e.g. e. donepizil NMDA receptor antagonists. beclometasone central nervous system Therapeutic problem Insomnia.g. bromocriptine. diazepam Other drugs. e.g. e.g. streptokinase. co-codamol Opioid analgesics. diazepam Drugs enhancing dopaminergic activity. diamorphine Dopamine antagonists. e. e.g. diazepam. sumatriptan Serotonin type 2 receptor antagonists. amiodarone. e. isosorbide mononitrate inhibitors of platelet aggregation. co-careldopa Other drugs influencing dopamine or dopamine receptors. codeine.g. clozapine Mood stablisers.1 28  Medical Pharmacology and Therapeutics cardiovascular system Therapeutic problem Acute coronary syndrome (angina. chronic obstructive pulmonary disease.g. e.g. betahistine Serotonin type 1 receptor agonists. propranolol Antipsychotic drugs. e.g. paracetalmol.g. salmeterol Antimuscarinc bronchodilators. lidocaine.g.g. e. lithium Tricyclic and related antidepressants. e.g. e. ropinirole Antimuscarinic drugs. mania Depression Core drugs Benzodiazepines and other drugs.g. Bronchodilators: β2-adrenoceptor agonists. e. e. low molecular weigh heparins Oral anticoagulants. in addition: Glyceryl trinitrate. procyclidine Anticholinesterases.g.g. amitriptyline Selective serotonin re-uptake inhibitors. calcium channel blockers Appropriate drugs chosen from the classes already described for the Cardiovascular System Arrhythmias Cardiac arrest.g. memantine Analgesia Nausea and vertigo Acute and chronic migraine   Acute migraine   Prophylaxis of chronic migraine Epilepsy Status epilepicus Parkinson’s disease Dementia (Alzheimer’s disease) . phenytoin. e. metoclopramide Serotonin type 3 (5HT3) receptor antagonists.g. anxiety Schizophrenia. cromoglicate. adenosine. e. sodium valproate. β-adrenoceptor antagonists. Pulmonary oedema. hyoscine Other agents. e. pizotifen Anticonvulsant therapy.g. e. clopidogrel. entacapone.g.g. deep vein thrombosis. e. e. L-dopa and dopa decarboxylase inhibitor combinations. e. pulmonary embolus.g.g. aspirin. myocardial infarction) Core drugs Many drugs listed under hypertension. e. carbamazepine.g.g. e. e. e. unfractionated heparins. aminophylline. tenecteplase Heparins. ipratropium Leukotriene receptor antagonists. magnesium sulphate Corticosteroids. e.

e. e. proguanil endocrine system Therapeutic problem Diabetes mellitus. e. e. amoxicillin. e.g. propranolol. amphotericin. e.g.g. cefalexin Tetracyclines e. levothyroxine. benzyl penicillin.g.g. fluconazole Antiviral drugs. e. mefloquine. e.g.g. e. e. somatotropin Hypothalamic hormones. oxybutynin Phosphodiesterase inhibitors. doxazosin 5α-reductase inhibitors.g.g. e. isoniazid. progestins Oxytocics.g. e.g. carbimazole Bisphosphonates.g.g.g.g.g. e.g. long and short-acting insulins Sulphonylureas.g. e. e. sildenafil obstetrics and gynaecology Therapeutic problem Steroid oral contraception Injectable contraception Intrauterine contraception Menstrual disorders   Dysmenorrhoea   Menorrhagia   Endometriosis Hormone replacement therapy (menopause) Induction of labour Prevention of pre-term labour and myometrial relaxation Induction of abortion Post-partum haemorrhage Core drugs Combined oral contraceptives.g. desmopressin. danazol Oestrogens (natural and synthetic). acyclovir Nucleoside reverse transcriptase inhibitor. finasteride Antimuscarinic drugs. vasopressin Genito-urinary disorders   Urinary retention   Benign prostatic hypertrophy   Urinary frequency and incontinence   Erectile dysfunction α-blockers. erythromycin Chloramphenicol Quinolones. e.g.g.g. gentamicin Vancomycin Macrolides. ethambutol Antifungal drugs. fungi. e. tranexamic acid Combined contraceptive. alendronic acid.g. nifedipine β-adrenoceptor agonists.g. e.g. gonadorelin (LHRH) Posterior pituitary hormones and antagonists. terbutaline Oxytocics. prostaglandins. ciprofloxacin Metronidazole Antituberculosis drugs. e. abacavir Protease inhibitors. mifepristone Oxytocics. progestin Injectable steroidal contraceptives. gliclazide Biguanides.g. pituitary hormones and anti-oestrogens: Anti-oestrogens. e.g. e.g.g. calcium. rifampicin. oxytetracycline Trimethoprim Aminoglycosides. ergometrine . e. progestogen-only contraceptives Emergency contraception. e. osteoporosis.g. co-amoxiclav. e.Principles of pharmacology and mechanisms of drug action  29 infectious diseases Therapeutic problem Community and hospital acquired infections (bacteria. saquinavir Antimalarial drugs. thyroid disease. e. medroxyprogesterone acetate Intra-uterine progestogen containing device Mefenamic acid Progestogens Antifibrinolytic agent. e. flucloxacillin Cephalosporins. e. e. rosiglitazone Thyroid disease. vitamin D Hypothalamic. viruses) Core drugs Penicillins.g. e. metformin The glitazones. clomifene Anterior pituitary hormones. e. oxytocin Calcium channel blockers. hormone deficiencies and excess Core drugs Diabetes.

g. e.g. herceptin Immunosuppressant agents acting in a variety of ways. fentanyl Mydriatics and cycloplegics Surgery. e. e. bupivacaine Analgesics. atracurium Antimuscarinics.g. e. e. cisplatin Anti-oestrogens. cyclosporine Anti CD20 monoclonal antibody.g. sympathomimetics. anti-emetics Intravenous anaesthetics for induction.g.g. e.g.1 30  Medical Pharmacology and Therapeutics malignant disease and immunosuppression Therapeutic problem Anti-cancer and immunosuppression Core drugs Anti-cancer drugs: alkylating agents. e. e.g. methotrexate Vinca alkaloids.g.g. methotrexate. e. doxorubicin Antimetabolites. indometacin. anastrazole. penicillamine. diclofenac Corticosteroids e. lidocaine. e. e.g. infliximab Anticholinesterases.g. glycopyrronium Anticholinesterases. e. vinblastin Other drugs. cyclophosphamide Cytotoxic antibiotics. prednisolone Disease modifying drugs. .g.g. tropicamide Many drugs listed from other sections would be used including opioids.g. neostigmine Local anaesthesia.g. phenylephrine Mydriatics and cycloplegics. e. e.g. e. e. Nonsteroidal anti-inflammatory drugs.g.55:496-503. brimonidine Carbonic anhydrase inhibitors. acetazolamide Miotics.g. antimalarials (hydroxychloroquine). Walley T. e. e.g. Teaching safe and effective prescribing in UK medical schools: a core curriculum for tomorrow’s doctors. tamoxifen. e. pyridostigmine Skeletal muscle relaxants. latenoprost Sympathomimetics. morphine. azathioprine. e. e.g. anaesthetics and intensive care Maxwell S. e. gold. atropine. thiopental.g. propofol Inhalation anaesthetics. cytokine inhibitors. asparaginase. corticosteroids. rituximab Interferon alfa Musculoskeletal and joint disease Rheumatoid arthritis Simple analgesic e.g.g. timolol Prostaglandin analogues. azathioprine.g. Br J Clin Pharmacol 2003. suxamethonium. myasthenia gravis Spasticity Ophthalmology Glaucoma β-Blockers. e. e. e. sulfasalazine. atropine. pilocarpine Mydriatics. paracetamol. e.g. isoflurane Muscle relaxants.g. e. baclofen Impaired neuromuscular transmission.g.g.g. e.