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Idiosyncratic hepatotoxicity is a rare adverse effect associated with antiepileptic drug (AED) therapy. Carbamazepine, phenytoin, phenobarbital (pheno-barbitone) and structurally related compounds may produce hepatic injury as part of a more widespread hypersensitivity reaction. Reactive compounds, the arene oxides, are generated by the cytochrome P450 enzyme system during the metabolism of these drugs. Arene oxides bind to cellular molecules and appear to trigger an immune response. Laboratory monitoring of asymptomatic effects may allow for the early detection of hepatotoxicity, but is complicated by the incidence of dose-related increases in serum transaminase levels associated with the administration of some AEDs. Signs such as fever, rash and eosinophilia typically accompany the hepatic injury associated with these agents. Treatment is supportive, and prompt withdrawal of medication may improve the prognosis. Valproic acid (sodium valproate) is associated with rare idiosyncratic hepato-toxicity without concomitant signs of hypersensitivity. The effects of valproic acid on fatty acid metabolism appear to be a factor in the aetiology of hepatotoxicity. A febrile illness often precedes the onset of this condition, and anorexia, vomiting, seizure exacerbation and lethargy are also common presenting signs. Children less than 2 years of age receiving valproic acid as polytherapy constitute the highest risk group for the development of hepatotoxicity. Asymptomatic monitoring has been recommended in patients receiving valproic acid, but this is also limited by dose-related changes in laboratory values. Specific treatment regimens have been recommended, but not prospectively studied. Of the drugs recently introduced into the US, felbamate has been linked to cases of hepatotoxicity, while gabapentin and lamotrigine have not. |
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