Brian A. Baldo - Drug Allergy: Clinical Aspects, Diagnosis, Mechanisms, Structure-Activity Relationships

Formerly-Molecular Immunology Unit Kolling Institute of Medical Research, Royal North Shore Hospital of Sydney, Sydney, Australia

A major and seemingly ever-present risk of pharmacotherapy is adverse drug reactions (ADRs). Drug reactions occur frequently and may need expert management. Reactions can be severe and even life-threatening, necessitating the substitution or discontinuation of preferred medications. An additional unwanted clinical response in a sick patient already under treatment constitutes extra burdens for the patient and the managing physician. With approximately 5 % of patients developing adverse reactions during drug therapy and up to 10 % said to react in hospitals, this adds up to a significant public health problem. The often quoted WHO definition of an ADR, published 40 years ago, is a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function. Questioning this definition and in particular the inclusiveness of the wording for minor reactions, Laurence and Carpenter in A dictionary of pharmacology and allied topics: Elsevier, 1998 , suggested: A harmful or significantly unpleasant effect caused by a drug at doses intended for therapeutic effect (or prophylaxis or diagnosis) which warrants reduction of dose or withdrawal of the drug and/or foretells hazard from future administration. I.R. Edwards of the Uppsala Monitoring Centre, a WHO collaborating centre for international drug monitoring, and J.K. Aronson of the Radcliffe Infirmary, Oxford, regard the WHO definition as vague, especially with regard to the term noxious, ask just how minor can an adverse reaction be, query the narrowness of the term drug and disagree with what they regarded as ambiguities in other published definitions. To cover these perceived deficiencies, Edwards and Aronson proposed their own succinct definition: An appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.

The United States Food and Drug Administration (FDA) states that any serious adverse event should be reported to the FDA and defines such an event as any undesirable experience associated with the use of a medical product in a patient. The event is said to be serious when the patient outcome is death, life-threatening, hospitalization (initial or prolonged), disability or permanent damage, congenital anomaly/birth defect, required intervention to prevent permanent impairment or damage (devices), and other serious important medical events (e.g., allergic bronchospasm, serious blood dyscrasias, or seizures or convulsions that do not result in hospitalization).

The study of ADRs falls within the discipline of pharmacovigilance. In an early pharmacological classification, ADRs were distinguished primarily on the basis of dose-related and non-dose-related reactions. These two types of reactions were sometimes called types A and B, respectively. Approximately 80 % or more of ADRs are predictable, can be anticipated from the drugs pharmacological actions, are dose-dependent, and resolve when the dose is reduced or withdrawn. Unpredictable reactions, sometimes called idiosyncratic drug reactions, are generally unrelated to the drugs pharmacological actions, are independent of dose, and, even though they usually resolve when treatment is stopped, reactions sometimes progress. From about the early 1980s, three further reaction categories were recognized, one related to dose and time and one classified as delayed but divided into time-related and withdrawal reactions. More recently, a sixth category, unexpected failure of therapy has been added. In some classifications of ADRs, a seventh category G, genetic reactions, is included. This essentially pharmacologically based overall classification of ADRs, together with some distinguishing features and examples of drug reactions, are shown in Table .