A Textbook of Clinical Pharmacology and Therapeutics

●Introduction 62

●Identification of the drug at fault 63

●Adverse drug reaction monitoring/surveillance

(pharmacovigilance) 63

●Allergic adverse drug reactions 66

●Prevention of allergic drug reactions 67

●Examples of allergic and other adverse

drug reactions 68

CHAPTER 12

ADVERSE DRUG REACTIONS

INTRODUCTION

Adverse drug reactions are unwanted effects caused by nor-
mal 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. intracra-
nial 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 under-
stood, and often has a genetic or immunological basis. Type B
reactions occur infrequently (1:1000–1:10 000 treated subjects
being typical).

Adverse drug reactions due to specific drug–drug inter-

actions are considered in Chapter 13. Three further minor cat-

egories 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 Eend-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 sug-

gest that approximately 80% of adults take some kind of medi-

cation 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 hospi-

tal 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 reac-

tions often occur early in therapy (during the first one to ten

days). Drugs most commonly implicated include low-dose

aspirin(antiplatelet agents), diuretics, warfarinand NSAIDs.

A systematic review by Howard et al. (2006) of preventable

adverse drug reactions which caused hospitalization, impli-

cated the same major drug classes.

Table 12.1:Some examples of type A and type B reactions.

Drug Type A Type B

Chlorpromazine Sedation Cholestatic jaundice

Naproxen Gastro-intestinal Agranulocytosis

haemorrhage

Phenytoin Ataxia Hepatitis,

lymphadenopathy

Thiazides Hypokalaemia Thrombocytopenia

Quinine Tinnitus Thrombocytopenia

Warfarin Bleeding Breast necrosis