NEFAZODONE - STRUCTURE, MODE OF ACTION AND PHARMACOKINETICS

Nefazodone is a synthetically derived analogue of phenylpiperazine wit h a unique dual mode of action. Nefazodone, and its primary metabolite hydroxynefazodone, block 5-HT2 receptors post-synaptically and inhibi t serotonin re-uptake pre-synaptically, resulting in increased duratio n and concentration of serotonin in the synapse. As with all antidepre ssants, chronic administration of nefazodone results in a down-regulat ion of 5-HT2 receptors which may be responsible for its antidepressant effect. The blockade of 5-HT2 receptors is also thought to explain ne fazodone's particular benefit on sleep disturbance and anxiety associa ted with depression. Nefazodone has minimal anticholinergic, antidopam inergic, and antihistamine activity and only weak cr,adrenergic antago nist action. Nefazodone is absorbed rapidly and completely, achieving peak plasma concentrations within 1-3 h of dosing. It undergoes extens ive first-pass metabolism and has a systemic bioavailability of 15-23% . Its pharmacokinetics are non-linear; treatment should be initiated a t a lower dose in elderly and hepatically impaired patients. The recom mended starting dose for healthy patients is 100 mg bd for 7 days risi ng to 200 mg bd as the normal maintenance dose.