TACRINE-INDUCED HEPATOTOXICITY - TOLERABILITY AND MANAGEMENT

Tacrine, a centrally acting, reversible acetylcholinesterase inhibitor , is effective in the treatment of Alzheimer's disease. However, a maj or adverse effect of the drug is hepatotoxicity, which affects about o ne-half of patients treated. The pathogenic mechanisms of this hepatot oxicity are poorly understood, but probably involve reactive metabolit es. The liver injury is predominantly that of hepatocellular necrosis, and manifests as an increase in serum alanine aminotransferase (ALT) levels; 25 and 2% of patients will experience ALT levels greater than 3 times and 20 times the upper limit of the normal range, respectively . Although hepatotoxicity is generally asymptomatic and has not led to death, severe reactions have been reported, and careful monitoring of ALT levels is mandatory in all patients, especially during initiation of therapy and following dose escalation. An ALT level exceeding 3 ti mes the upper limit of the normal range should prompt withdrawal of th e drug. Following cessation of tacrine, ALT levels generally decrease rapidly and usually normalise within 6 weeks. Rechallenge can be safel y attempted once ALT levels are near normal, except in patients whose ALT levels were markedly increased or in whom a moderate increase of A LT levels was associated with features of hypersensitivity (e.g. rash, fever, eosinophilia). Approximately 90% of those patients rechallenge d with tacrine will tolerate the drug and continue with therapy on a l ong term basis. Minimisation of morbidity and maximisation of the numb er of patients treated in the long term can be achieved by following s ensible guidelines and by the early recognition of danger signs.