TARGETED PHARMACOTHERAPY IN DEPRESSION MANAGEMENT - COMPARATIVE PHARMACOKINETICS OF FLUOXETINE, PAROXETINE AND SERTRALINE

In contrast to tricyclic antidepressants (TCAs), the selective seroton in reuptake inhibitors (SSRIs) have a high affinity for the serotonin uptake site with little or no affinity for alpha-adrenergic, cholinerg ic or histaminic receptors. SSRIs, again in contrast to TCAs, do not s low intracardiac conduction. These differences between TCAs and SSRIs are important in terms of both discomforting and more serious adverse effects. Despite their more focused effects, the SSRIs are as effectiv e as TCAs in treating major depression. The SSRIs have similar propert ies in terms of their pharmacodynamics, but important differences in t erms of pharmacokinetics and their effects on hepatic function. Sertra line, and the starting dose of paroxetine have an elimination half-lif e (t(1/2)) of approximately 24 h. However, the half-life of paroxetine , but not of sertraline, becomes longer at higher doses due to paroxet ine's inhibition of its own clearance. A t(1/2) of 24 h makes once-dai ly dosing feasible and allows for new steady-state concentrations and wash-out within a reasonable time after dose adjustment. Fluoxetine ha s a t(1/2) of 2-4 days and has an active metabolite with a t(1/2) of 7 -15 days. Such a half-life makes dose titration more difficult, and ca n result in prolonged effects even after dose reduction or drug discon tinuation. Sertraline has dose-proportional changes in plasma concentr ations, in contrast to fluoxetine and paroxetine. Thus, dose increases with fluoxetine and paroxetine produce greater than expected changes in plasma drug concentration, and hence, in concentration-dependent ef fects. Both fluoxetine and paroxetine at their usually effective minim um dose can inhibit the hepatic isoenzyme CYP2D6, which is important i n the oxidative metabolism of a variety of drugs. Fluoxetine also inhi bits another hepatic isoenzyme, CYP3A4, which is also important in oxi dative drug metabolism. Additional research is required to understand the differential effects of the various SSRIs on this and other hepati c isoenzymes. Currently, sertraline is notable for having few clinical ly meaningful drug interactions at its usually effective, minimum dose .