Postgraduate Medical Journal (1985) 61, 925-933 Postgrad Med J: first published as 10.1136/pgmj.61.720.925 on 1 October 1985. Downloaded from Drug eruptions S.K. Goolamali Central Middlesex Hospital, London andNorthwick Park Hospital and Clinical Research Centre, Harrow, Middlesex, UK. Introduction Mechanisms of adverse drug reactions The last four decades have seen an enormous increase An adverse drug reaction is commonly defined as any in the use of potent and toxic drugs as therapy. The response to a drug that is unintended and occurs at considerable advances that these drugs have provided doses used in the prophylaxis or therapy of disease. in the control and prevention of disease are matched Adverse reactions may occur as a result of inap- by their potential to produce unwanted side effects propriate metabolism, idiosyncrasy or hypersen- many of which are reflected in the skin. sitivity to a drug. Impaired metabolism may result These side effects cannot in the main be predicted. from altered oxidation or acetylation ofa drug as may Tests in animals may not reliably be extrapolated to be seen in slow-acetylators in isoniazid-induced acne. the human and only occasionally can the occurrence of An idiosyncratic reaction is an inbuilt abnormal side effects be gauged from the structural formula of a response to a drug such as may occur when bar- new drug. With some fifty new drugs developed each biturates or sulphonamides are given to a patient with year the practitioner is challenged simply to keep pace porphyria. Hypersensitivity or allergy to a drug is with their therapeutic indications. The results of one mediated by an antigen-antibody reaction. Previous that 30% of from and sensitization to the is a survey suggested prescriptions exposure drug copyright. general practitioners was based on data supplied by prerequisite though it is possible for a drug to induce drug companies. In 1985 it is also increasingly com- antibody formation without clinical symptoms of mon to find that patients, when faced with a chronic hypersensitivity. disease have sought several medical opinions or have Hypersensitivity reactions are normally classified taken refuge in remedies which rely more on advertis- into four types (Gell & Coombs, 1963) - Type 1 ing than their therapeutic effectiveness. The available (immediate or anaphylactic), Type 2 (cytotoxic or information suggests then that drug reactions are autoallergic), Type 3 (immune complex disease) and likely to be common. Type 4 (cell-mediated or delayed). The vast majority of In a recent study (Black & Somers, 1984), drug- drug reactions are due to hypersensitivity and this related illness accounted for some 6% of hospital review will be restricted to a brief discussion of these http://pmj.bmj.com/ admissions in a year. It has been estimated that the allergic responses and a description of some of the average inpatient in a British hospital receives five common skin reactions provoked by drugs. drugs whilst one in an American hospital receives nine. Since a large majority of allergic reactions affect the Type 1 reaction skin the incidence of drug-induced cutaneous erup- tions probably reflects the risk of allergic drug reac- This is mediated by IgE or reagin. IgE antibodies are tions in Reactions to in over in to a or general. drugs twenty produced response drug drug-hapten on October 2, 2021 by guest. Protected thousand medical inpatients were studied in a large complex and attach themselves preferentially to the collaborative study (Arndt & Jick, 1976). Skin reac- mast cell. On exposure to antigen there is mediator tions occurred in a little over 2%. Despite the lack of release from the mast cell which then results in the data on non-hospitalized patients it is clear that even if well-described reactions of urticaria, angio-oedema, only 2% ofpatients receiving drugs experience a 'rash' asthma and, in severe cases, anaphylaxis. it is a number that we can all ill afford. Type 2 reaction This may present with thrombocytopenia, leucopenia or haemolytic anaemia. In this reaction the antigen Correspondence: S.K. Goolamali, M.D., F.R.C.P., North- (drug) combines with a platelet or red cell, for wick Park Hospital, Watford Road, Harrow, Middlesex example, and stimulates the formation ofantibodies to HA1 3UJ, UK. the drug-cell combination. Sedormid purpura, quinine © The Fellowship of Postgraduate Medicine, 1985 926 S.K. GOOLAMALI Postgrad Med J: first published as 10.1136/pgmj.61.720.925 on 1 October 1985. Downloaded from purpura, many of the haemolytic anaemias, including (PABA) and therefore may cross-react with other that due to high dose penicillin therapy (Petz & PABA compounds such as procaine and dubucaine. Fudenberg, 1966) and methyldopa, are examples of Topical antihistamine, freely available as an over-the- this type of reaction. Some 10 to 20% of patients counter preparation, is a commmon sensitizer as is receiving methyldopa develop a positive Coombs' test neomycin especially when applied to chronic stasis but only 0.5 to 1.0% develop a haemolytic anaemia. dermatitis or otitis externa (Leyden & Kligman, 1979). Approximately 70% of reported drug-induced immune haemolytic anaemias are a result of methyl- dopa. Leucopenia of immunological origin often with Types of cutaneous reactions the presence of anti-leucocyte agglutinins is not in- frequently a reaction of drugs. Skin reactions to drugs are diverse. In a series of 464 cases during 1966-1970, Kuokkanen (1972) found Type 3 reaction that exanthematous eruptions were the most common and accounted for 46% of reactions. Urticaria The initial exposure to the drug sensitizes and results occurred in 23% ofcases, fixed drug eruption in 10%, in antibody, usually IgM or IgG, production. After an erythema multiforme in some 5% and other reactions interval antigen-antibody complexes form and are in less than 5% each. In another more recent study deposited in the peripheral circulation. Complement is (Kauppinen & Stubb, 1984) exanthemas again formed activated and causes accumulation of neutrophilic the largest group, 42% of 446 inpatients, fixed erup- leucocytes which release lysosomal enzyme that des- tions occurred in 21%, urticaria-angioedema in 12.5% troys tissues. The commonly recognized systemic and erythema multiforme with Stevens-Johnson syn- reaction in this category is the serum sickness syn- drome accounted for approximately 6%. The remain- drome. Fever, arthralgia and lymphadenopathy are der comprised eczema, toxic epidermal necrolysis, typical features and classically arise from hypersen- photosensitivity reactions, purpura and the systemic sitivity to foreign serum. A similar clinical picture may lupus erythematosus (SLE) syndrome. result 1 to 3 weeks after treatment with penicillin, acid or para-aminosalicylic sulphonamides. Vas- Exanthematous eruption copyright. culitis, when a feature of the Type 3 reaction, is often attributed to sulphonamides but may also be caused This type of reaction can be caused by almost any by phenytoin, thiouracils, chlorpromazine, aspirin, drug. Itch may or may not be associated and differen- gold and penicillin. tiation from a viral exanthem may at times be difficult. The greatest incidence occurs with the penicillins and Type 4 reaction the eruption commonly consists of maculo-papular erythematous lesions. The risk ofdeveloping penicillin This T-cell mediated or delayed hypersensitivity type hypersensitivity is increased in patients with a previous of reaction is the basis of an allergic dermatitis often history ofother drug allergy and in those ofwhom the due to a topical medication. In a large European study drug is given parenterally. In one study (Shapiro et al., http://pmj.bmj.com/ (Bandmann et al., 1972), a third ofthe patients with an 1969) a rash was reported in 4.5% of 622 patients allergic contact dermatitis showed a hypersensitivity treated with penicillins other than ampicillin, in 9.5% to a topical medicament. Sensitization is more likely to of422 patients treated with ampicillin and in 1.8% of occur if the medication is applied to damaged skin. 2941 patients not receiving either of these drugs. The importance of this 'contact' allergy is that it Although ampicillin may provoke urticaria, it com- prohibits the systemic use of the same or related drug. monly causes a morbilliform eruption If the is (Figure 1) offending drug mistakenly taken it produces a which lasts a few days. An increased incidence of on October 2, 2021 by guest. Protected widespread dermatitis. Amongst the contact sen- ampicillin rash occurs in infectious mononucleosis, sitizers ethylenediamine hydrochloride used as a cytomegalovirusmononucleosis, lymphatic leukaemia stabilizer in some creams is of particular importance. and in viral respiratory infections (Almeyda & Levan- It cross-reacts with drugs used systemically such as tine, 1972). In these conditions the rash may also be aminophylline which consists of two-thirds theo- somewhat prolonged. phylline and one-third ethylenediamine. Some antihis- Other drugs commonly associated with an exanth- tamines which are derived from ethylenediamine may ematous eruption include barbiturates, sulphon- also cause a generalized eruption if given to a sen- amides and allied anti-diabetic and diuretic drugs, sitized patient (Fisher, 1976). Another recognized phenytoin, erythromycin, allopurinol and gold salts. sensitizer is benzocaine found in anti-pruritic prepara- Gold salts were first used in France in the 1920s and tions, in local applications for the treatment of 1930s though their efficacy as an anti-rheumatic drug haemorrhoids and in some sunburn remedies. Ben- was confirmed very much later (Fraser, 1945). Two zocaine is a derivative of para-aminobenzoic acid forms of these drugs are in common use, the aqueous Postgrad Med J: first published as 10.1136/pgmj.61.720.925 on 1 October 1985. Downloaded from DRUG ERUPTIONS 927 Figure 1 Ampicillin reaction. Figure 2 Penicillin induced urticaria. based sodium aurothiomalate and the oil based restarted without incident (Klinefelter, 1975). copyright. aurothioglucose. Both drugs are administered in- Allopurinol, an analogue of hypoxanthine, is an tramuscularly.