66 ADVERSE DRUG REACTIONS
MONITORING FROM NATIONAL STATISTICSA great deal of information is available from death certificates,
hospital discharge diagnoses and similar records. From these
data, it may be possible to detect a change in disease trends
and relate this to drug therapy. Perhaps the best-known example
of this is the increased death rate in young asthmatics noted in
the mid-1960s, which was associated with overuse of bron-
chodilator inhalers containing non-specific β-adrenoceptor
agonists (e.g. adrenalineand/orisoprenaline). Although rel-
atively inexpensive, the shortcomings of this method are obvi-
ous, particularly in diseases with an appreciable mortality,
since large numbers of patients must suffer before the change is
detectable. Data interpretation is particularly difficult when
hospital discharges are used as a source of information, since
discharge diagnosis is often provisional or incomplete, and
may be revised during follow up.
However, they can combine with high molecular weight enti-
ties, usually proteins, to form an antigenic hapten conjugate.
The factors that determine the development of allergy to a
drug are not fully understood. Some drugs (e.g. penicillin)
are more likely to cause allergic reactions than others, and
type I (immediate anaphylactic) reactions are more common
in patients with a history of atopy. A correlation between aller-
gic reactions involving immunoglobulin E (IgE) and human
leukocyte antigen (HLA) serotypes has been reported, so genetic
factors may also be important. There is some evidence that
drug allergies are more common in older people, in women
and in those with a previous history of drug reaction. However,
this may merely represent increased frequencies of drug expo-
sure in these patient groups.TYPES OF ALLERGYDrugs cause a variety of allergic responses (Figure 12.1) and
sometimes a single drug can be responsible for more than one
type of allergic response.TYPE I REACTIONS
Type I reactions are due to the production of reaginic (IgE)
antibodies to an antigen (e.g. penicillins and cephalosporins).
The antigen binds to surface bound IgE on mast cells causing
degranulation and release of histamine, eicosanoids and
cytokines. It commonly occurs in response to a foreign serum
orpenicillin, but may also occur with streptomycinand some
local anaesthetics. With penicillin, it is believed that the peni-
cilloyl moiety of the penicillinmolecule is responsible for the
production of antibodies. Treatment of anaphylactic shock is
detailed in Chapter 50.TYPE II REACTIONS
These are due to antibodies of class IgG and IgM which, on
contact with antibodies on the surface of cells, bind comple-
ment, causing cell lysis (e.g. penicillin, cephalosporins,
methyldopaorquinine) causing, for example, Coombs’ posi-
tive haemolytic anaemia.TYPE III IMMUNE COMPLEX ARTHUS REACTIONS
Circulating immune complexes can produce several clinical
allergic states, including serum sickness and immune complex
glomerulonephritis, and a syndrome resembling systemic lupus
erythematosus. The onset of serum sickness is delayed for sev-
eral days until features develop such as fever, urticaria,
arthropathy, lymphadenopathy, proteinuria and eosinophilia.
Recovery takes a few days. Examples of causative agents
include serum, penicillin,sulfamethoxazole/trimethoprim,
streptomycinandpropylthiouracil.Amiodaronelung and
hydralazine-induced systemic lupus syndrome are also pos-
sibly mediated by immune complex-related mechanisms,
although these reactions are less well understood.TYPE IV DELAYED HYPERSENSITIVITY REACTIONS
Type IV reactions are delayed hypersensitivity reactions, the
classical example of which is contact dermatitis (e.g. to topicalKey points- Rare (and often severe) adverse drug events may not be
detected in early drug development but only defined in
the first few years post marketing (phase IV of drug
development). - Be aware of and participate in the MHRA yellow card
system for reporting suspected adverse drug reactions. - Use of any recently marketed drug, which is identified
with a black triangle on its data sheet or in the British
National Formulary, indicates the need to be particularly
suspicious about adverse drug reactions and to report
any suspected adverse drug reaction via the yellow card
system. - Constant vigilance by physicians for drug-induced
disease, particularly for new drugs, but also for more
established agents, is needed.
FEEDBACKThere is no point in collecting vast amounts of data on
adverse reactions unless they are analysed and conclusions
reported back to prescribing doctors. In addition to articles in
the medical journals and media, the Current Problems in
Pharmacovigilanceseries deals with important and recently
identified adverse drug reactions. If an acute and serious
problem is recognized, doctors will usually receive notifica-
tion from the MHRA/Commission on Human Medicines,
and often from the pharmaceutical company marketing the
product.
ALLERGIC ADVERSE DRUG REACTIONS
Immune mechanisms are involved in a number of adverse
effects caused by drugs (see below and Chapter 50). The
development of allergy implies previous exposure to the drug
or to some closely related substance. Most drugs are of low
molecular weight (300–500 Da) and thus are not antigenic.