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Jeffrey K Aronson
Department of Clinical Pharmacology
Adverse drug reactions (ADRs) have been estimated to account for 2–6% of all hospital admissions, to occur in 10–20% of hospital inpatients, and to cause death in 0.1% of medical and 0.01% of surgical inpatients.(1) Here, the definition, classification, description and management of ADRs are discussed.
An ADR can be defined(2,3) as an appreciably harmful or unpleasant reaction resulting from an intervention related to the use of a medicinal product; adverse reactions usually predict hazard from future administration and warrant prevention, specific treatment, alteration of the dosage regimen or withdrawal of the product. The colloquial term “side-effect” is better avoided, as it implies particular mechanisms, is ambiguous and can be used to describe beneficial as well as adverse effects.
The well-established A/B classification of ADRs has defects; a more comprehensive, alternative classification has been proposed, based on features of the three important aspects of an adverse reaction: the drug (dose and pharmacology), the patient (susceptibility) and the reaction itself (its time- course). This has been called the DoTS (Dose, Time and Susceptibility) system.(4) The implications of this tripartite classification are listed in Table 1.
There are three types of reactions based on dose:
Toxic reactions occur through exaggeration of the pharmacological effect of a drug. For example, bleeding due to warfarin is a toxic effect: it occurs by the same mechanism as the therapeutic effect (anticoagulation).
Collateral reactions generally occur in a tissue other than that in which the therapeutic action is sought, although not necessarily in another organ. They can occur: (i) through the same pharmacological effect as that whereby the therapeutic action is produced (eg, colour vision disturbance from sildenafil); or (ii) through a distinct pharmacological effect (eg, a dry mouth due to the anticholinergic effect of a tricyclic antidepressant).
Hypersusceptibility reactions can be immune-mediated (eg, penicillin allergy) or not (eg, angio-oedema due to an angiotensin-converting enzyme [ACE] inhibitor).
Adverse reactions can occur independently of the time over which a course of treatment has been taken (time- independent reactions) or can follow a definite time pattern (time-dependent reactions).
Time-independent reactions are usually toxic reactions due to excess of drug. Their mechanisms can be:
There are six types of time-dependent reactions:
There are several reasons for hypersusceptibility, including genetic factors, age, sex, physiological factors (eg, pregnancy), endogenous factors (eg, other drugs, foods) and diseases.
Other important features
Other important features of ADRs that should be specified whenever possible(3) include seriousness (a measure of the extent to which the reaction can or does cause harm), intensity (or severity; a measure of the extent to which the adverse effect develops in an individual) and its causal probability (sometimes called causality). Intensity can be classified as trivial, mild, moderate or severe. Causal probability relates to the likelihood that the drug can cause the adverse effect (the general problem), or to the likelihood that it was the cause in an individual case (the specific problem). If precise probabilities cannot be stated (as is often the case), terms such as probable, possible and unclassified, although problematic, are used.
Describing specific adverse reactions
Specific adverse effects (eg, anaphylaxis, apnoea or tachyarrhythmia) require specific description and definition. Several dictionaries have been developed to deal with this problem, and others have been incorporated into them:(2,3)
Rapid action may be necessary to treat a serious ADR (such as anaphylactic shock).(11) In some cases, withdrawal of all medicines may be essential, followed by cautious reintroduction of essential medicines. Otherwise, which medicine or medicines should be withdrawn should be decided as a trial. If the culprit is relatively easy to identify, a benefit–harm balance decision about the need for the drug should be taken (eg, are there equally effective substitutes that are unlikely to produce the same ADR?), and the seriousness and intensity of the reaction and its potential for treatment evaluated.
When several medicines may be causative, the least essential medicines should be first withdrawn, preferably (if the reaction is not too severe) one at a time; alternatively, dosage reduction can be considered. If an adverse drug interaction is possible, the medicines involved should be withheld or their dosages adjusted.
The patient should be observed during withdrawal. The waiting period will vary, depending on the rate of elimination of the drug from the body and the type of pathology. For example, urticaria usually disappears quickly, whereas fixed psoriatic skin reactions can take weeks. If there is no response, the same procedure should be repeated with other suspected drugs. If the patient recovers and it was necessary to withhold more than one drug, essential medicines can be reintroduced one at a time, starting with the one least likely to be the culprit.
If a medicine that has caused an adverse reaction is essential and cannot be withdrawn, symptomatic relief should be provided. For example, severe nausea and vomiting are routinely treated symptomatically in patients receiving anticancer drugs.