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, which occur at supratherapeutic concentrations.
- Collateral reactions, which occur at standard therapeutic concentrations.
- Hypersusceptibility reactions, which occur at subtherapeutic concentrations in susceptible patients.
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:
- Pharmaceutical (eg, by altered availability from a pharmaceutical formulation, such as phenytoin availability altered by a change in its formulation).
- Pharmacokinetic (eg, digoxin toxicity when renal function worsens).
- Pharmacodynamic (eg, digoxin toxicity in association with potassium depletion).
There are six types of time-dependent reactions:
- Rapid reactions, which occur when a drug is administered too rapidly (eg, the “red man” syndrome with vancomycin). They are typically toxic reactions.
- First-dose reactions, which occur after the first dose of a course of treatment and not necessarily thereafter. They are typically hypersusceptibility reactions. Examples include hypotension after the first dose of an ACE inhibitor and type I hypersensitivity reactions.
- Early reactions, which occur early in treatment, then abate with continuing treatment. They are typically collateral reactions. These are reactions to which patients develop tolerance (eg, nitrate-induced headache).
- Intermediate reactions, which occur after some delay (although risk decreases during longer-term therapy). They can be collateral or hypersusceptibility reactions. Examples are allergic reactions of types II, III and IV, an increased risk of neutropenia with carbimazole and of venous thromboembolism with antipsychotic drugs. Intermediate reactions occur in populations of individuals with different susceptibilities; those at high risk have the reaction and stop taking the drug; those at low risk do not have the reaction and can be regarded as “healthy survivors”. Thus, after a certain period of time, the population risk appears to fall.
- Late reactions (including withdrawal reactions), which occur rarely or not at all at first; however, the risk increases with continued or repeated exposure. They are typically collateral effects. Examples include many of the adverse effects of corticosteroids and tardive dyskinesia with dopamine receptor antagonists. Withdrawal reactions are late reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced.
- Delayed reactions, which are observed some time after exposure, even if the drug is withdrawn before the reaction appears. They are typically collateral reactions. Examples are carcinogenesis (eg, vaginal adenocarcinoma in women who were exposed to diethylstilbestrol in utero) and teratogenesis (eg, phocomelia due to thalidomide).
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)
- ADROIT: the Adverse Drug Reactions On-line Information Tracking Medical Dictionary.(5)
- COSTART: Codings Symbols for a Thesaurus of Adverse Reaction Terms.
- WHO-ART: the World Health Organization Adverse Reaction Terminology.(6)
- ICD: the International Classification of Disease, now in its 10th edition (ICD-10).
- SNOMED: the Systematized Nomenclature of Human and Veterinary Medicine.(7)
- The series of papers by the Council for International Organizations of Medical Sciences (CIOMS), starting in 1992(8) and published fully in 1999.(9)
- MedDRA: Medical Dictionary for Regulatory Affairs.(10)
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.
- Pirmohamed M, Breckenridge AM, Kitteringham NR, et al. Adverse drug reactions. BMJ 1998;316:1295-8.
- Edwards IR, Aronson JK. Adverse drug reactions – definitions, classification, diagnosis, management, surveillance. Lancet 2000;356:1255-60.
- Aronson JK, Ferner RE. Clarification of terminology in drug safety. Drug Saf 2004; in press.
- Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ 2003;327:1222-5.
- Wood SM, Coulson R. Adverse drug reactions on-line information tracking (ADROIT). Pharm Med 1993;7:203-13.
- Brown EG. Effects of coding dictionary on signal generation: a consideration of use of MedDRA compared with WHO-ART. Drug Saf 2002;25:445-52.
- Wang AY, Sable JH, Spackman KA. The SNOMED clinical terms development process: refinement and analysis of content. Proc AMIA Symp 2002;845-9.
- Council for International Organizations of Medical Sciences. Basic requirements for the use of terms for reporting adverse drug reactions. Pharmacoepidemiol Drug Saf 1992;1:39-45.
- Bankowski Z, Bruppacher R, Crusius I, et al, editors. Reporting adverse drug reactions. Definitions of terms and criteria for their use. Geneva: CIOMS, 1999.
- Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf 1999;20:109-17.
- McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ 2003;327:1332-5.