A Textbook of Clinical Pharmacology and Therapeutics

● 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,
and often 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.