Sertraline

🧬 Receptor activity

Target	Action	Affinity	Source
SERT	Inhibition (Inhibitor)	9.1 pKi	GTOPDB
Sodium-dependent serotonin transporter	—	Ki 0.075 nM	CHEMBL
Sodium-dependent dopamine transporter	—	Ki 25.8 nM	CHEMBL
Sigma non-opioid intracellular receptor 1	—	Ki 29.3 nM	CHEMBL
Alpha-2B adrenergic receptor	—	Ki 82.8 nM	CHEMBL
Alpha-2A adrenergic receptor	—	Ki 108.3 nM	CHEMBL
Norepinephrine transporter	—	Ki 159 nM	CHEMBL
Muscarinic acetylcholine receptor M1	—	Ki 310.2 nM	CHEMBL
Alpha-1B adrenergic receptor	—	Ki 334.9 nM	CHEMBL
Muscarinic acetylcholine receptor M5	—	Ki 364.5 nM	CHEMBL
Muscarinic acetylcholine receptor M4	—	Ki 366.9 nM	CHEMBL
5-hydroxytryptamine receptor 2C	—	Ki 567.3 nM	CHEMBL
Alpha-2C adrenergic receptor	—	Ki 650.5 nM	CHEMBL
5-hydroxytryptamine receptor 2A	—	Ki 783.1 nM	CHEMBL
Sodium-dependent noradrenaline transporter	—	Ki 976.6 nM	CHEMBL
Muscarinic acetylcholine receptor M2	—	Ki 984 nM	CHEMBL
Unchecked	—	Ki 1304 nM	CHEMBL
5-hydroxytryptamine receptor 2B	—	Ki 2159.5 nM	CHEMBL
Melanocortin receptor 5	—	Ki 4313.2 nM	CHEMBL
Sigma intracellular receptor 2	—	Ki 5297 nM	CHEMBL
Voltage-gated inwardly rectifying potassium channel KCNH2	—	Ki 6814.1 nM	CHEMBL

Mechanism of action

Sertraline selectively inhibits the reuptake of serotonin (5-HT) at the presynaptic neuronal membrane, thereby increasing serotonergic activity. This results in an increased synaptic concentration of serotonin in the CNS, which leads to numerous functional changes associated with enhanced serotonergic neurotransmission. These changes are believed to be responsible for the antidepressant action and beneficial effects in obsessive-compulsive (and other anxiety related disorders). It has been hypothesized that obsessive-compulsive disorder, like depression, is also caused by the disregulation of serotonin. In animal studies, chronic administration of sertraline results in down-regulation of brain norepinephrine receptors. Sertraline displays affinity for sigma-1 and 2 receptor binding sites, but binds with stronger affinity to sigma-1 binding sites. In vitro, sertraline shows little to no affinity for GABA, dopaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors. It exerts weak inhibitory actions on the neuronal uptake of norepinephrine and dopamine and exhibits no inhibitory effects on the monoamine oxidase enzyme.
Sertraline is a selective 5-HT reuptake inhibitor. It does not have cardiovascular, anticholinergic, antidopaminergic, convulsant, or monoamine oxidase-inhibiting effects. Most antidepressants are associated with either norepinephrine reuptake inhibition, 5-HT reuptake inhibition, & monoamine oxidase inhibition. Sertraline does not cause significant reuptake blockade of dopamine or norepinephrine. Sertraline through inhibition of 5-HT release, may cause beta-adrenoceptor downregulation.

Pharmacodynamics

Sertraline improves or relieves the symptoms of depression, OCD, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, and premenstrual dysphoric disorder via the inhibition of serotonin reuptake. Clinical studies have shown that it improves cognition in depressed patients. It has less sedative, anticholinergic, and cardiovascular effects than the tricyclic antidepressant drugs because it does not exert significant anticholinergic, antihistamine, or adrenergic (alpha1, alpha2, beta) blocking activity. The onset of action and beneficial effects are usually noticed after 4-6 weeks, for reasons that are not fully understood and currently under investigation.

Pharmacokinetics

Half-life

The elimination half-life of sertraline is approximately 26 hours. One reference mentions an elimination half-life ranging from 22-36 hours.
Elimination half-life, parent (metabolite): 24 (65) hours. /from table/
Elimination half-life: 24 to 26 hours

Absorption

Following once-daily administration of 50 to 200 mg for two weeks, the mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours after administration, and measured at 20 to 55 μg/L. Steady-state concentrations are reached after 1 week following once-daily administration, and vary greatly depending on the patient. Bioavailability has been estimated to be above 44%. The area under the curve in healthy volunteers after a 100mg dose of sertraline was 456 μg × h/mL in one study. **Effects of food on absorption** The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects given a single dose with and without food. For the tablet, AUC was slightly increased when sertraline was administered with food, the Cmax was 25% greater, and the time to peak plasma concentration was shortened by about 2.5 hours. For the oral concentrate preparation of sertraline, peak concentration was prolonged by approximately 1 hour with the ingestion of food.
Since sertraline is extensively metabolized, excretion of unchanged drug in the urine is a minor route of elimination, with 12-14% of unchanged sertraline excreted in the feces.
Sertraline is widely distributed, and its volume of distribution is estimated to be more than 20L/kg. Post-mortem studies in humans have measured liver tissue concentrations of 3.9–20 mg/kg for sertraline and between 1.4 to 11 mg/kg for its active metabolite, N-desmethyl-sertraline (DMS). Studies have also determined sertraline distributes into the brain, plasma, and serum.
In pharmacokinetic studies, the clearance of a 200mg dose of sertraline in studies of both young and elderly patients ranged between 1.09 ± 0.38 L/h/kg - 1.35 ± 0.67 L/h/kg.
GI absorption: >or= 44%; time to reach peak plasma concn: 6-8 hr; oral clearance (single dose): 96 L/hr; protein binding: 99%; urinary excretion (radioactivity): 44% of oral dose; fecal excretion (radioactivity): 44% of oral dose. /from table/
Sertraline is absorbed readily through the GI tract. Its absolute bioavailability has not been determined in humans. It displays first-order kinetics. Max plasma concns following doses of 50 & 200 mg are 22-29 ug/L (ng/ml). These concns are reached in 4.5-8.4 hr. Serum levels at steady state are 10-120 ng/mL of sertraline & its desmethyl metabolites. Plasma protein binding is extensive (approx 98%) to both albumin & alpha1-acid glycoprotein. At concns up to 300 & 200 ug/mL, respectively, sertraline & N-desmethyl-sertraline do not appear to alter the plasma protein binding of two other highly protein-bound drugs, warfarin & propranolol. Distribution following oral admin of sertraline is biphasic with a prolonged absorption phase. The elimination phase begins 12-16 hr following the dose. The volume of distribution has not been determined in humans but is more than 20 L/kg in rats & dogs. Both sertraline & its metabolites exhibit extensive distribution into tissues outside the blood. ... The elimination half-life (beta) of sertraline in humans is 24-25 hr. The clinically active desmethyl metabolite is eliminated more slowly than the parent drug with a half-life of approx 66 hr. Unchanged sertraline is not detected in the urine.

Metabolism

Sertraline is heavily metabolized in the liver and has one major active metabolite. It undergoes N-demethylation to form N-desmethylsertraline, which is much less potent in its pharmacological activity than sertraline. In addition to N-demethylation, sertraline metabolism involves N-hydroxylation, oxidative deamination, and finally, glucuronidation. The metabolism of sertraline is mainly catalyzed by CYP3A4 and CYP2B6, with some activity accounted for by CYP2C19 and CYP2D6.
Sertraline undergoes extensive metabolism. The parent drug is N-demethylated, followed by glucuronidation, deamination, or both. Most metabolites in the urine are alpha-hydroxy-ketone glucuronides.
Depression is one of the most common psychiatric disorders. A variety of different chemical structures have been found to have antidepressant activity. The number is constantly growing; however, as yet, no one group has been found to have a clear therapeutic advantage over the others. The major indication for antidepressant drugs is depression, but a number of side effects have been established by clinical experience and controlled trials. It is clear that, to some extent, any drug or chemical substance administered to the mother is able to cross the placenta unless it is destroyed or altered during metabolism. Placental transport of maternal substrates to the fetus and of substances from the fetus to the mother is established at about the fifth week of fetal life. Traditionally, teratogenic effects of antidepressants or other drugs have been noted as anatomic malformation. It is clear that these are dose- and time-related and that the fetus is at great risk during the first 3 months of gestation. However, it is possible for antidepressants to exert their effects on the fetus at other times during pregnancy as well as to infants during lactation. Administration of antidepressants to pregnant women presents a unique problem for the physician. Not only must maternal pharmacologic mechanisms be taken into consideration when prescribing an antidepressant drug, but the fetus must also be regarded as a potential recipient of the drug. Certain results are evident with regard to drugs administered during lactation. It is essential that physicians need to be aware of the results of animal studies in this area and of the potential risk of maternal drug ingestion to the suckling infant.
Sertraline has known human metabolites that include N-desmethylsertraline.
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.
Route of Elimination: Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination.
Half Life: The elimination half-life of sertraline is approximately 25-26 hours. The elimination half-life of desmethylsertraline is approximately 62-104 hours.

Protein binding

Sertraline is highly bound to serum proteins, at about 98%-99%.