FURTHER READING Dhesi JK, Allain TJ, Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 4. Vitamin D and bisphosphonates for fractures and osteoporosis. British Journal ofClinicalPharmacology 2006; 61: 520–8. Hanratty CG, McGlinchey P, Johnston GD, Passmore AP. Differential pharmacokinetics of digoxin in elderly patients. Drugs and Aging 2000; 17: 353–62. Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 1. Statins for primary and secondary cardiovascular prevention. British Journal ofClinicalPharmacology 2006; 61: 494–501. RESEARCH 61 Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 2. ACE inhibitors and angiotensin receptor blockers in heart failure and high cardiovascular risk patients. British Journal ofClinicalPharmacology 2006; 61: 502–12. Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 3. β-adrenoceptor blockers in heart failure and thrombolytics in acute myocardial infarction. British Journal ofClinicalPharmacology 2006; 61: 513–20. Sproule BA, Hardy BG, Shulman KI. Differential pharmacokinetics in elderly patients. Drugs and Aging 2000; 16: 165–77.
● Introduction 62 ● Identification of the drug at fault 63 ● Adverse drug reaction monitoring/surveillance (pharmacovigilance) 63 INTRODUCTION CHAPTER 12 ADVERSE DRUG REACTIONS Adverse drug reactions are unwanted effects caused by normal therapeutic doses. Drugs are great mimics of disease, and adverse drug reactions present with diverse clinical signs and symptoms. The classification proposed by Rawlins and Thompson (1977) divides reactions into type A and type B (Table 12.1). Type A reactions, which constitute approximately 80% of adverse drug reactions, are usually a consequence of the drug’s primary pharmacological effect (e.g. bleeding from warfarin) or a low therapeutic index (e.g. nausea from digoxin), and they are therefore predictable. They are dose-related and usually mild, although they may be serious or even fatal (e.g. intracranial bleeding from warfarin). Such reactions are usually due to inappropriate dosage, especially when drug elimination is impaired. The term ‘side effects’ is often applied to minor type A reactions. Type B (‘idiosyncratic’) reactions are not predictable from the drug’s main pharmacological action, are not dose-related and are severe, with a considerable mortality. The underlying pathophysiology of type B reactions is poorly if at all understood, andoften has a genetic or immunological basis. Type B reactions occur infrequently (1:1000–1:10 000 treated subjects being typical). Table 12.1: Some examples of type A and type B reactions. Drug Type A Type B Chlorpromazine Sedation Cholestatic jaundice Naproxen Gastro-intestinal haemorrhage Agranulocytosis Phenytoin Ataxia Hepatitis, lymphadenopathy Thiazides Hypokalaemia Thrombocytopenia Quinine Tinnitus Thrombocytopenia Warfarin Bleeding Breast necrosis ● Allergic adverse drug reactions 66 ● Prevention of allergic drug reactions 67 ● Examples of allergic and other adverse drug reactions 68 Adverse drug reactions due to specific drug–drug interactions are considered in Chapter 13. Three further minor categories of adverse drug reaction have been proposed: 1. type C – continuous reactions due to long-term drug use (e.g. neuroleptic-related tardive dyskinesia or analgesic nephropathy); 2. type D – delayed reactions (e.g. alkylating agents leading to carcinogenesis, or retinoid-associated teratogenesis); 3. type E end-of-use reactions, such as adrenocortical insufficiency following withdrawal of glucocorticosteroids, or withdrawal syndromes following discontinuation of treatment with benzodiazepines or β-adrenoceptor antagonists. In the UK there are between 30 000 and 40 000 medicinal products available directly or on prescription. Surveys suggest that approximately 80% of adults take some kind of medication during any two-week period. Exposure to drugs in the population is thus substantial, and the incidence of adverse reactions must be viewed in this context. Type A reactions are reported to be responsible for 2–3% of consultations in general practice. In a recent prospective analysis of 18 820 hospital admissions by Pirmohamed et al. (2004), 1225 were related to an adverse drug reaction (prevalence 6.8%), with the adverse drug reaction leading directly to admission in 80% of cases. Median bed stay was eight days, accounting for 4% of hospital bed capacity. The projected annual cost to the NHS is £466 million. Overall fatality was 0.15%. Most reactions were either definitely or probably avoidable. Adverse drug reactions are most frequent and severe in the elderly, in neonates, women, patients with hepatic or renal impairment, and individuals with a history of previous adverse drug reactions. Such reactions often occur early in therapy (during the first one to ten days). Drugs most commonly implicated include low-dose aspirin (antiplatelet agents), diuretics, warfarin and NSAIDs. A systematic review by Howard et al. (2006) of preventable adverse drug reactions which caused hospitalization, implicated the same major drug classes.