indication

For the management of major depressive disorder, posttraumatic stress disorder, obsessive-compulsive disorder, panic disorder with or without agoraphobia, premenstrual dysphoric disorder, social phobia, premature ejaculation, and vascular headaches.

pharmacology

Sertraline, an antidepressant drug similar to citalopram, fluoxetine, and paroxetine, is of the selective serotonin reuptake inhibitor (SSRI) type. Sertraline has one active metabolite and, like the other SSRIs, have less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs because it does not have clinically important anticholinergic, antihistamine, or adrenergic blocking activity.

mechanism of action

The exact mechanism of action sertraline is not fully known, but the drug appears to selectively inhibit the reuptake of serotonin at the presynaptic membrane. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. It is suggested that these modifications are responsible for the antidepressant action observed during long term administration of antidepressants. It has also been hypothesized that obsessive-compulsive disorder is caused by the dysregulation of serotonin, as it is treated by sertraline, and the drug corrects this imbalance.

toxicity

Symptoms of toxicity include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. The most frequently observed side effects include: GI effects such as nausea, diarrhea or loose stools, dyspepsia, and dry mouth; nervous system effects such as somnolence, dizziness, insomnia, and tremor; sexual dysfunction in males (principally ejaculatory delay); and sweating.

biotransformation

Extensively metabolized in the liver. Sertraline metabolism involves N-demethylation, N-hydroxylation, oxidative deamination, and glucuronidation of sertraline carbamic acid. Sertraline undergoes N-demethylation primarily catalyzed by cytochrome P450 (CYP) 2B6, with CYP2C19, CYP3A4 and CYP2D6 contributing to a lesser extent. Deamination occurs via CYP3A4 and CYP2C19. In vitro studies have shown that monoamine oxidase A and B may also catalyze sertraline deamination. Sertraline N-carbamoyl glucuronidation has also been observed in human liver microsomes.

absorption

The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.

half life

The elimination half-life of sertraline is approximately 25-26 hours. The elimination half-life of desmethylsertraline is approximately 62-104 hours.

route of elimination

Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination.

drug interactions

Almotriptan: Increased risk of CNS adverse effects

Carbamazepine: Sertraline increases the effect of carbamazepine

Carvedilol: The SSRI, sertraline, may increase the bradycardic effect of the beta-blocker, carvedilol.

Cilostazol: Sertraline increases the effect of cilostazol

Clarithromycin: Possible serotoninergic syndrome with this combination

Clozapine: The antidepressant increases the effect of clozapine

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Donepezil: Possible antagonism of action

Eletriptan: Increased risk of CNS adverse effects

Erythromycin: Possible serotoninergic syndrome with this combination

Fosphenytoin: Sertraline increases the effect of hydantoin

Frovatriptan: Increased risk of CNS adverse effects

Galantamine: Possible antagonism of action

Ginkgo biloba: Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.

Isocarboxazid: Possible severe adverse reaction with this combination

Ketoprofen: Concomitant therapy may result in additive antiplatelet effects and increase the risk of bleeding. Monitor for increased risk of bleeding during concomitant therapy.

Linezolid: Combination associated with possible serotoninergic syndrome

Metoprolol: The SSRI increases the effect of the beta-blocker

Moclobemide: Possible severe adverse reaction with this combination

Naratriptan: Increased risk of CNS adverse effects

Oxycodone: Increased risk of serotonin syndrome

Phenelzine: Possible severe adverse reaction with this combination

Phenytoin: Sertraline increases the effect of hydantoin

Pimozide: The SSRI, sertraline, increases the effect and toxicity of pimozide.

Propafenone: Fluoxetine increases the effect and toxicity of propafenone

Propranolol: The SSRI, sertraline, may increase the bradycardic effect of the beta-blocker, propranolol.

Rasagiline: Possible severe adverse reaction with this combination

Tamoxifen: Sertraline may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Sertraline, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Sertraline is initiated, discontinued, or dose changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Sertraline. Consider alternate therapy or monitor for therapeutic/adverse effects of Sertraline if Terbinafine is initiated, discontinued or dose changed.

Tiaprofenic acid: Additive antiplatelet effects increase the risk of bleeding. Consider alternate therapy or monitor for increased bleeding.

Tipranavir: Tipranavir increases the concentration of Sertraline. The Sertraline dose may require an adjustment.

Tolmetin: Increased antiplatelet effects may enhance the risk of bleeding. Alternate therapy may be considered or monitor for inreased bleeding during concomitant therapy.

Tolterodine: Sertraline may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

Tramadol: Tramadol increases the risk of serotonin syndrome and seizures. Sertraline may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Sertraline may decrease the effect of Tramadol by decreasing active metabolite production.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Treprostinil: The prostacyclin analogue, Treprostinil, increases the risk of bleeding when combined with the antiplatelet agent, Sertraline. Monitor for increased bleeding during concomitant thearpy.

Trimipramine: The SSRI, Sertraline, may decrease the metabolism and clearance of Trimipramine. Increased risk of serotonin syndrome. Monitor for changes in Trimipramine efficacy and toxicity if Sertraline is initiated, discontinued or dose changed.

Triprolidine: The CNS depressants, Triprolidine and Sertraline, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and sertraline, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.