Sertraline Sandoz Mechanism of Action

Pharmacotherapeutic group: Antidepressant, selective serotonin re-uptake inhibitor. ATC Code: N06A B06.
PHARMACOLOGY: Pharmacodynamics: Sertraline has proven in vitro to be a potent specific neuronal serotonin (5-HT) re-uptake inhibitor which led to increased effects of 5-HT in the animal trial. Sertraline has only poor effects on the neuronal re-uptake of noradrenaline and dopamine. In clinical doses, sertraline blocks the re-uptake of serotonin in human platelets. Sertraline has no stimulating, sedative or anticholinergic activity and is not cardiotoxic in the animal trial. In controlled studies with healthy volunteers, sertraline had no sedative effect and did not affect the psychomotor behaviour. In accordance with the selective inhibition of the 5-HT re-uptake, sertraline does not intensify the catecholaminergic activity. Sertraline has no affinity for muscarinergic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABAergic or benzodiazepinergic receptors. Chronic administration of sertraline in animals resulted in down-regulation of noradrenergic receptors of the brain. This was also seen after use of other clinically effective antidepressants.
No physical or mental dependence on sertraline was seen.
Pharmacokinetics: Absorption: After 14 days at a daily oral dose of 50-200 mg, peak plasma concentrations of sertraline will occur 4.5 - 8.4 hours after the daily administration in humans. On the basis of recovery rates in urine and faeces, it can be estimated that absorption after oral administration is at least 70%. Bioavailability is reduced by the first pass effect. Taking of food does not significantly change the bioavailability of sertraline tablets.
Distribution: Approx. 98% of the circulating active substance is bound to plasma proteins. Data from animal studies indicate a large distribution volume of sertraline. Steady-state concentrations are achieved after approx. 1 week with administration once daily.
Metabolism: Sertraline has marked first-pass hepatic metabolism. The main metabolite in plasma, N-desmethyl sertraline is significantly less active than sertraline (approximately 20 fold) in vitro and there are no signs of activity in vivo. The half-life of N-desmethyl sertraline ranges between 62-104 hours. Both sertraline and N-desmethyl sertraline are metabolised to a great extent, and the resulting metabolites are excreted in faeces and urine in equal amounts. Only a small amount of unchanged sertraline (less than 0.2%) is excreted in the urine. It has been demonstrated in in vitro investigations that the metabolism of sertraline is mainly mediated by the CYP 3A4 enzyme, with only limited involvement of CYP 2D6. At the standard dose of 50 mg, sertraline has only limited effects on the CYP 2D6- and CYP 3A4-mediated metabolism of other substances.
Elimination: The mean half-life of sertraline is approx. 26 hours (22-36 hours). In accordance with this, there is an about 2-fold accumulation up to the steady-state concentrations which are reached after a daily dose for one week. The pharmacokinetics of sertraline are proportional to the dose in the range from 50-200 mg.
Special patient groups: Elderly patients: The pharmacokinetic profile in elderly patients does not significantly differ from that of adults between 18 and 65 years of age.
Impaired organ function: Following multiple dosage, the pharmacokinetics of sertraline are unchanged in patients with moderately to severely impaired renal function (creatinine clearance 10-29 ml/min). In patients with impaired hepatic function, the half-life of sertraline is prolonged and the AUC increased by the 3-fold.
Toxicology: Preclinical safety data: Conventional studies of sertraline did not demonstrate mutagenicity nor carcinogenicity. No teratogenic effects have been observed in studies of reproductive toxicity in rats and rabbits. At 2.5 to 10-fold higher dosages in comparison with the maximum therapeutic dose in humans, however, ossification was delayed in foetal rats and rabbits. Administration of sertraline during the last trimenon of gestation until the end of lactation, at a dosage exceeding the 5-fold of the maximum therapeutic dose in humans, led to an increased number of stillbirths as well as to a decreased survival rate and reduced bodyweight of descendants. It has been demonstrated that intrauterine exposure results in a lower survival rate of descendants.