Clinical Implications of the Pharmacology of Sertraline

Abstract

Sertraline is slowly absorbed after oral administration, with peak plasma concentrations at 6-8 h. Plasma concentrations are linearly related to dose. The elimination half-life is about 32 h; metabolism is by demethylation to an inactive metabolite. Once-daily dosing is recommended, with steady state being reached after about 7 days. The kinetics of sertraline in the elderly and in patients with renal impairment are similar to those in young healthy female volunteers. In young male volunteers, peak plasma concentrations were lower, and elimination half-life shorter, than in elderly men or both groups of women. Nevertheless, no reduction in dosage is recommended for these groups. Sertraline is highly active in animal models of depression, and administration of the drug to healthy human beings causes a selective, dose-related inhibition of 5-hydroxytryptamine (5-HT) uptake into blood platelets. Single doses of sertraline in volunteers caused changes in the quantitative pharmaco-electroencephalogram suggesting antidepressant and anxiolytic actions, with sedative potential evident only at doses of 200 mg or more. Sertraline does not impair psychomotor performance, including simulated car driving, and overall seems neither stimulating nor sedating: an increase in critical flicker fusion threshold suggests a slight alerting effect, whereas subjective tests indicate an increase in perceived sedation at doses of 100 mg or more. No potentiation of the effects of ethanol has been noted in either young or elderly subjects. No adverse effects on the electrocardiogram, blood pressure, or systolic time intervals have been detected, and sertraline lacks anticholinergic action. These studies imply a low probability of adverse central nervous and cardiovascular effects. Sertraline is probably a weak inducer of hepatic microsomal enzyme activity. Sertraline does not affect the clearance of lithium but there may be a pharmacodynamic interaction which leads to increased tremor when the drugs are given together. No clinically relevant effects were noted in the interaction studies with digoxin, atenolol and diazepam. The pharmacokinetics and pharmacodynamics of sertraline are generally favourable. However, caution is needed when sertraline is given to patients receiving lithium or drugs with a low therapeutic ratio, such as corticosteroids, oral hypoglycaemic agents, and warfarin.