and acquired factors, notably disease of the organs responsible for drug metabolism and excretion. Pharmacokinetic modelling is crucial in drug development to plan a rational therapeutic regime, and understanding pharmacokinetics is also important for prescribers individualizing therapy for a particular patient. Pharmacokinetic principles are described in Chapter 3 from the point of view of the prescriber. Genetic influences on pharmacodynamics and pharmacokinetics (pharmacogenetics) are discussed in Chapter 14 and effects of disease are addressed in Chapter 7, and the use of drugs in pregnancy and at extremes of age is discussed in Chapters 9–11. There are no good animal models of many important human diseases. The only way to ensure that a drug with promising pharmacological actions is effective in treating or preventing disease is to perform a specific kind of human experiment, called a clinical trial. Prescribing doctors must understand the strengths and limitations of such trials, the principles of which are described in Chapter 15, if they are to evaluate the literature on drugs introduced during their professional lifetimes. Ignorance leaves the physician at the mercy of sources of information that are biased by commercial interests. Sources of unbiased drug information include Dollery’s encyclopaedic Therapeutic drugs, 2nd edn (published by Churchill Livingstone in 1999), which is an invaluable source of reference. Publications such as the Adverse Reaction Bulletin, Prescribers Journal and the succinctly argued Drug andTherapeutics Bulletin provide up-to-date discussions of therapeutic issues of current importance. Key points • Drugs are prescribed by physicians of all specialties. • This carries risks as well as benefits. • Therapy is optimized by combining general knowledge of drugs with knowledge of an individual patient. • Evidence of efficacy is based on clinical trials. • Adverse drug effects may be seen in clinical trials, but the drug side effect profile becomes clearer only when widely prescribed. • Rational prescribing is encouraged by local formularies. SCIENTIFIC BASIS OF USE OF DRUGS IN HUMANS 5 Case history A general practitioner reviews the medication of an 86-year-old woman with hypertension and multi-infarct dementia, who is living in a nursing home. Her family used to visit daily, but she no longer recognizes them, and needs help with dressing, washing and feeding. Drugs include bendroflumethiazide, atenolol, atorvastatin, aspirin, haloperidol, imipramine, lactulose and senna. On examination, she smells of urine and has several bruises on her head, but otherwise seems well cared for. She is calm, but looks pale and bewildered, and has a pulse of 48 beats/min regular, and blood pressure 162/96 mmHg lying and 122/76 mmHg standing, during which she becomes sweaty and distressed. Her rectum is loaded with hard stool. Imipramine was started three years previously. Urine culture showed only a light mixed growth. All of the medications were stopped and manual evacuation of faeces performed. Stool was negative for occult blood and the full blood count was normal. Two weeks later, the patient was brighter and more mobile. She remained incontinent of urine at night, but no longer during the day, her heart rate was 76 beats/min and her blood pressure was 208/108 mmHg lying and standing. Comment It is seldom helpful to give drugs in order to prevent something that has already happened (in this case multi-infarct dementia), and any benefit in preventing further ischaemic events has to be balanced against the harm done by the polypharmacy. In this case, drug-related problems probably include postural hypotension (due to imipramine, bendroflumethiazide and haloperidol), reduced mobility (due to haloperidol), constipation (due to imipramine and haloperidol), urinary incontinence (worsened by bendroflumethiazide and drugs causing constipation) and bradycardia (due to atenolol). Drug-induced torsades de pointes (a form of ventricular tachycardia, see Chapter 32) is another issue. Despite her pallor, the patient was not bleeding into the gastro-intestinal tract, but aspirin could have caused this. FURTHER READING Dukes MNG, Swartz B. Responsibility for drug-induced injury. Amsterdam: Elsevier, 1988. Weatherall DJ. Scientific medicine and the art of healing. In: Warrell DA, Cox TM, Firth JD, Benz EJ (eds), Oxford textbook of medicine, 4th edn. Oxford: Oxford University Press, 2005.
● Introduction 6 ● Receptors and signal transduction 6 ● Agonists 7 ● Antagonism 8 CHAPTER 2 MECHANISMS OF DRUG ACTION (PHARMACODYNAMICS) INTRODUCTION Pharmacodynamics is the study of effects of drugs on biological processes. An example is shown in Figure 2.1, demonstrating and comparing the effects of a proton pump inhibitor andof a histamine H 2 receptor antagonist (both drugs used for the treatment of peptic ulceration and other disorders related to gastric hyperacidity) on gastric pH. Many mediators exert their effects as a result of high-affinity binding to specific receptors in plasma membranes or cell cytoplasm/nuclei, and many therapeutically important drugs exert their effects by combining with these receptors and either mimicking the effect of the natural mediator (in which case they are called ‘agonists’) or blocking it Median gastric pH 10 9 8 7 6 5 4 3 2 1 0 Pre Rx pH ≥ 5.0 4.1-5.0 2.0-4.0 n 90 37 38 41 37 25 < 2.0 21 15 Predose Postdose Predose Postdose Predose Postdose 1 1 2 2 3 3 Figure 2.1: Effect of omeprazole and cimetidine on gastric pH in a group of critically ill patients. This was a study comparing the effect of immediate-release omeprazole with a loading dose of 40 mg, a second dose six to eight hours later, followed by 40 mg daily, with a continuous i.v. infusion of cimetidine. pH monitoring of the gastric aspirate was undertaken every two hours and immediately before and one hour after each dose. Red, omeprazole; blue, cimetidine. (Redrawn with permission from Horn JR, Hermes-DeSantis ER, Small, RE ‘New Perspectives in the Management of Acid-Related Disorders: The Latest Advances in PPI Therapy’. Medscape Today http://www.medscape.com/viewarticle/503473_9 17 May 2005.) ● Partial agonists 9 ● Slow processes 9 ● Non-receptor mechanisms 10 (in which case they are termed ‘antagonists’). Examples include oestrogens (used in contraception, Chapter 41) and antioestrogens (used in treating breast cancer, Chapter 48), alphaand beta-adrenoceptor agonists and antagonists (Chapters 29 and 33) and opioids (Chapter 25). Not all drugs work via receptors for endogenous mediators: many therapeutic drugs exert their effects by combining with an enzyme or transport protein and interfering with its function. Examples include inhibitors of angiotensin converting enzyme and serotonin reuptake. These sites of drug action are not ‘receptors’ in the sense of being sites of action of endogenous mediators. Whether the site of action of a drug is a receptor or another macromolecule, binding is usually highly specific, with precise steric recognition between the small molecular ligandand the binding site on its macromolecular target. Binding is usually reversible. Occasionally, however, covalent bonds are formed with irreversible loss of function, e.g. aspirin binding to cyclooxygenase (Chapter 30). Most drugs produce graded concentration-/dose-related effects which can be plotted as a dose–response curve. Such curves are often approximately hyperbolic (Figure 2.2a). If plotted semi-logarithmically this gives an S-shaped (‘sigmoidal’) shape (Figure 2.2b). This method of plotting dose–response curves facilitates quantitative analysis (see below) of full agonists (which produce graded responses up to a maximum value), antagonists (which produce no response on their own, but reduce the response to an agonist) and partial agonists (which produce some response, but to a lower maximum value than that of a full agonist, and antagonize full agonists) (Figure 2.3). RECEPTORS AND SIGNAL TRANSDUCTION Drugs are often potent (i.e. they produce effects at low concentration) and specific (i.e. small changes in structure lead to profound changes in potency). High potency is a consequence of high binding affinity for specific macromolecular receptors.
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