Tacrine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in Alzheimer's disease.

Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer's disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer's disease--a welcome advance in an area previously devoid of acceptable treatment options.