Cimetidine and dapsone‐mediated methaemoglobinaemia

Abstract

I read with interest the case report from Choi et al. [1] relating to dapsone-mediated methaemoglobinaemia. The role of cimetidine in partially attenuating the haematological side-effects of dapsone does not appear to have been discussed in the anaesthesia literature. I wish to suggest the possible therapeutic benefit of peri-operative administration of cimetidine in patients receiving dapsone. The oxidative metabolism of dapsone leads to its toxicity. The majority of dapsone undergoes reversible acetylation in liver followed by elimination as N-hydroxylamine and to a lesser degree monoacetylated hydroxylamine. Dapsone N- hydroxylation is responsible for the haematological side-effects such as methaemoglobinaemia and haemolysis. Dapsone hydroxylamine depletes glutathione within glucose-6-phosphate dehydrogenase (G6PD)-deficient cells. The nitroso derivative then causes peroxidation reactions, leading to rapid haemolysis. Doses of 100 mg or less in normal healthy persons and 50 mg or less in G6PD-deficient individuals do not cause haemolysis [2]. A maximum dose of 150–300 mg a day, in divided doses, is recommended to minimise the risk of methaemoglobinaemia [3]. Cimetidine, an H2-recector antagonist, competes with dapsone for cytochrome P 450 enzymes. Thus cimetidine may be used as a selective inhibitor of N-hydroxylation and decrease the quantity of methaemoglobinaemia produced by dapsone [3, 4]. Cimetidine 400 mg three times daily has been shown to lead to a significant (> 25%) and sustained fall in methaemoglobin in patients on chronic dapsone therapy [5]. This dose appears to be well tolerated and not associated with adverse effects. The peri-operative use of cimetidine is likely to benefit patients by increasing the clinical safety margin, minimising the incidence and severity of methaemoglobinaemia and, possibly, avoiding the complications associated with treatment modalities such as methylene blue or ascorbic acid [6]. The mean elimination half-life of dapsone is about 20–30 h. Sulphones are retained in the circulation for long periods because of intestinal re-absorption from bile, requiring periodic interruption of treatment in dermatological diseases [2]. It is imperative to discontinue dapsone at least 4–7 days pre-operatively in patients listed for elective surgery. Furthermore, the G6PD level should be checked in all patients receiving dapsone therapy to identify patients at risk of peri-operative methaemoglobinaemia.