Jovia Mechanism of Action

Pharmacology: Pharmacodynamics: Escitalopram, a selective serotonin-reuptake inhibitor (SSRI), is bicyclic pthalane-derivative antidepressant. Escitalopram is the S-enantiomer of citalopram, an SSRU that occurs as a 50:50 racemic mixture of the R- and S-enantiomers. Escitalopram is at least 100-fold more potent as an inhibitor of the reuptake of serotonin (5-hydroxy tryptamine or 5-HT) at the presynaptic membranes and the 5-HT neuronal firing rate than the R-enantiomer and is twice as potent as the racemic mixture.
Like other SSRIs, escitalopram's antidepressant effect is believed to involve potentiation of serotonin activity in the central nervous system (CNS) resulting from its inability effect on the reuptake of 5-HT from the synaptic cleft. Escitalopram appears to have little or no effect on reuptake of other neurotransmitters such as norepinephrine and dopamine. In vitro studies also have shown that escitalopram possesses little or no affinity for α- or β-adrenergic, dopamine D_1-5, histamine H_1-3, GABA-benzodiazepine, muscarinic M_1-5, or 5-HT_1-7 receptors or various ion channels (e.g., calcium, chloride, potassium, sodium channels).
Escitalopram has high affinity for the primary binding site and an allosteric modulating effect on the serotonin transporter. Allosteric modulating of the serotonin transporter enhances binding of escitalopram to the primary binding site, resulting in more complete serotonin reuptake inhibition.
Pharmacokinetics: Absorption is almost complete and independent of food intake. The mean time to maximum concentration (T_max) is about four hours after multiple dosing. As with racemic citalopram, the absolute bioavailability of escitalopram is expected to be about 80%. There is a linear pharmacokinetics. Steady-state plasma levels are achieved in about one week. Average steady-state concentrations of 50 nmol/L (range: 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.
The apparent volume of distribution (V_d/f) of escitalopram is about 12 to 26 L/kg. The binding of escitalopram to plasma proteins is independent of drug plasma levels and averages 55%.
Escitalopram is metabolized in the liver to the demethylated and didemethylated metabolites. Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidized to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronide. After multiple dosing, the mean concentrations of the dimethyl and didemethyl metabolites are usually 28 to 31% and <5%, respectively, of the escitalopram concentration. Biotransformation of escitalopram to the demethylated metabolite is primarily mediated by CYP2C19. Some contribution by the enzymes CYP3A4 and CYP2D6 is possible.
The elimination half-life (t_1/2) after multiple dosing is about 30 hours and the oral plasma clearance is about 0.6 L/min. The major metabolites have a significantly longer t_1/2. Escitalopram and major metabolites are assumed to be eliminated by both the hepatic and the renal routes, with the major part of the dose excreted as metabolites in the urine. Approximately 8% of escitalopram is eliminated unchanged in urine and 9.6% as the S-demethylcitalopram metabolite.
Special Population: Hepatic Impairment: In patients with mild to moderate hepatic impairment (Child-Pugh Criteria A and B), the t_¹/2 of escitalopram was about twice as long and the exposure was about 60% higher than in subjects with normal liver function.
Renal Impairment: While there are no specific data, the use of escitalopram in reduced renal function may be extrapolated from that of racemic citalopram. Escitalopram is expected to be eliminated more slowly in patients with mild to moderate reduction of renal function with no major impact on the escitalopram concentration in serum. At present no information is available for the treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min).
Geriatric (65 years and older): Escitalopram appears to be eliminated more slowly in elderly patients compared to younger patients. Systemic exposure (AUC) is about 50% higher in elderly compared to young health volunteers.
Polymorphism: It has been observed that poor metabolizers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolizers. No significant change in exposure was observed in poor metabolizers with respect to CYP2D6.