Hypersensitivity to pyrazolones.

To the allergologist, hypersensitivity to drugs means immunological drug reactions as classified in the Gell and Coombs system. To others, it may also include non-dose related adverse drug reactions including the non-immune mediated idiosyncratic drug reactions (type B). In the following discussion the broad definition of idiosyncrasy including all type B reactions and a clinical approach rather than a mechanistic one will be used. Pyrazolones are veteran drugs. Antipyrine was synthesised for clinical use in 1883. The methylated nitrogen derivative aminopyrine was introduced in 1897 and taken oV the market in the 1970s because of its propensity to form nitrosamines. Dipyrone has been in clinical use since 1922. In some countries it was banned because of the risk of agranulocytosis. In others it is the leading analgesic/antipyretic drug. Annual sales figures of pyrazolones amount to kilotons, mainly dipyrone and propyphenazone. Unlike the acidic non-steroidal antiinflammatory drugs (NSAIDs) which are known to act on inflamed tissue by the inhibition of prostaglandin synthesis, pyrazolones produce analgesic/antipyretic eVects associated with a much less potent anti-inflammatory eVect on peripheral tissues. As shown in several animal species and also in humans, dipyrone acts on the central nervous system by the inhibition of prostanoids. 2 Dipyrone has more than 20 known metabolites. A central hypothesis of immune mediated (hypersensitivity) drug reactions has been that drugs are metabolised to a reactive metabolite which can act as an hapten. There are limited reports concerning the immunogenic potential of pyrazolone and pyrazolidine metabolites. 6 Genetic heterogeneity could also predispose patients to adverse drug reactions by the formation or inability to detoxify a reactive metabolite. In 1977 Szczeklik et al put forward the hypothesis that, in sensitive patients, induction of asthmatic attacks by aspirin-like drugs is due to inhibition of tissue prostaglandin biosynthesis. In about 10% of adult asthmatics NSAIDS precipitate such attacks. Inhibition of cyclooxygenase leading to changes in the metabolism of arachidonic acid can also be the cause of urticaria/angio-oedema. As for pyrazolones, hypersensitivity can be of two distinct forms. There are patients, usually with chronic asthma, whose idiosyncratic reactions resemble aspirin induced asthma and probably involve prostaglandin inhibition and overproduction of cysteinyl leukotrienes. The second group comprises patients who develop anaphylaxis, urticaria, and other forms of rash where the hypersensitivity seems to have an immunological background. 10 Virtually all adverse reactions to pyrazolones are non-dose related. The following syndromes of pyrazolone hypersensitivity have been reported.