Concomitant host disease may also influence susceptibility to adverse reactions. The best recent example is HIV disease, which increases the frequency of idiosyncratic toxicity with anti-infective drugs such as co-trimoxazole. (30) Around 50% of patients receiving high doses of co-trimoxazole for Pneumocystis carinii pneumonia and 30% receiving prophylactic doses develop skin rashes. (31) This contrasts with a frequency of 3% in people who are negative for HIV infection. (31) Glutathione deficiency has been suggested by some (32,33) but not all (34,35) investigators to be responsible for the increased frequency of reactions. (30,31) The reasons are likely to be more complex and to include not only changes in drug metabolising capacity (bioactivation and bioinactivation) but also immune dysregul! ation.
Spontaneous reporting schemes
The exposure of 1500 patients to a drug by the time of licensing (1,2) will allow the more common adverse
reactions to be detected but not necessarily characterised. At least 30 000 people need to
be treated with a drug to discover-with a power of 0.95-at least one patient with an
adverse reaction which has an incidence of 1 in 10 000. (36)
Thus, postmarketing surveillance is important to permit detection of less common
adverse effects.
Spontaneous adverse drug reaction reporting schemes, as exemplified by the yellow card system in the United Kingdom, form the cornerstone of postmarketing drug safety surveillance. Indeed, spontaneous reporting schemes remain the only way of monitoring the safety of a drug throughout its marketed life. The yellow card scheme is important in identifying previously undetected adverse reactions (37) and over the years has provided many early warnings of drug safety hazards-for example, remoxipride and aplastic anaemia-to allow appropriate drug regulatory action to be taken. A problem with spontaneous reporting is that less than 10% of all serious and 2-4% of non-serious adverse reactions are reported. (2,38) All doctors need to be aware that adverse drug reaction reporting is part of overall patient care and is not simply an afterhought. Since 1964 reporting in the United Kingdom has been restricted to doctors, dentists! , and coroners, although more recently a reporting scheme for pharmacists has been introduced. In some European countries all healthcare professionals are allowed to report adverse drug reactions, while in the United States patients can also report through the MEDWatch scheme. (39)
Strategy to improve drug safety
- Avoidance of chemical functional groups that are well recognised to cause toxicity
during drug design-for example, aromatic amines, phenols, epoxides, and quinones
- Development of metabolically inert drugs to avoid metabolic interactions and prevent formation of toxic metabolites-for example, vigabatrin and gabapentin
- Development of suitable in vitro and in vivo systems to elucidate the role of shortlived, potentially toxic metabolitcs in the pathogenesis of idiosyncratic toxicity
- Increased use of in vitro systems, such as cell lines expressing drug metabolising enzymes, to predict the potential for adverse drug interactions and polymorphic routes of metabolism
- Study of high risk patients during the premarketing drug development phase to identify pharmacokinetic and pharmacodynamic factors that influence susceptibility to drug toxicity
- Development of computer based schemes to monitor for adverse reactions and adverse events in primary and secondary care
- Encouragement to report adverse drug reactions to regulatory agencies
- Identification of risk factors for different types of drug toxicity by using pharmacoepidemiological approaches
- Identification of multigenetic predisposing factors to allow the prediction of individual susceptibility
Conclusion
The importance of adverse drug reactions is often underestimated. They are common and
can be life threatening and unnecessarily expensive. The measures outlined in the box
above are important to improve the benefit to risk ratio of drug treatment by reducing the
burden of drug toxicity. Because of the wide range of drugs available, the manifestations
of toxicity may vary and affect any organ system. In fact, adverse reactions have taken
over from syphilis and tuberculosis as the great mimics of other diseases. The pattern of
toxicity is likely to change with the introduction of new biotechnology products. It is
therefore important for prescribing clinicians to be aware of the toxic profile of drugs
they prescribe and to be ever vigilant for the occurrence of unexpected adverse
reactions.
