Pharmacotherapeutic Group: antidepressants, selective serotonin reuptake inhibitors. ATC Code: N06AB10.
Pharmacology: Pharmacodynamics: Mechanism of action: Escitalopram is a selective inhibitor of serotonin (5-HT) re-uptake with high affinity for the primary binding site. It also binds to an allosteric site on the serotonin transporter, with a 1000 fold lower affinity.
Allosteric modulation of the serotonin transporter enhances binding of escitalopram to the primary binding site, resulting in more complete serotonin reuptake inhibition.
Escitalopram has no or low affinity for a number of receptors including 5-HT1A, 5-HT2, DA D1 and D2 receptors, α1-, α2-, β-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors.
The inhibition of 5-HT re-uptake is the only likely mechanism of action explaining the pharmacological and clinical effects of escitalopram.
Escitalopram is the S-enantiomer of the racemate (citalopram) and the enantiomer to which the therapeutic activity is attributed. Pharmacological studies have shown that the R-enantiomer is not inert but counteracts the serotonin-enhancing and consequent pharmacological properties of the S-enantiomer.
Pharmacokinetics: Absorption: Absorption is almost complete and independent of food intake. Mean time to maximum concentration (mean Tmax) is 4 hours after multiple dosing.
As with racemic citalopram, the absolute bioavailability of escitalopram is expected to be about 80%.
Distribution: The apparent volume of distribution (Vd,β/F) after oral administration is about 12 to 26 L/kg. The plasma protein binding is below 80% for escitalopram and its main metabolites.
Biotransformation: Escitalopram is metabolised in the liver to the demethylated and didemethylated metabolites. Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidised to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucuronides.
Biotransformation of escitalopram to the demethylated metabolite is mediated primarily by CYP2C19. Some contribution by the enzymes CYP3A4 and CYP2D6 is possible.
Elimination: The elimination half-life (t½β) after multiple dosing is about 30 hours and the oral plasma clearance (Cloral) is about 0.6 L/min. The major metabolites have a significantly longer half-life. Escitalopram and major metabolites are assumed to be eliminated by both the hepatic (metabolic) and the renal routes, with the major part of the dose excreted as metabolites in the urine.
Linearity: There is linear pharmacokinetics. Steady-state plasma levels are achieved in about 1 week. Average steady-state concentrations of 50 nmol/L (range 20 to 125 nmol/L) are achieved at a daily dose of 10 mg.
Elderly patients (> 65 years): 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 healthy volunteers (see Dosage & Administration).
Reduced hepatic function: In patients with mild or moderate hepatic impairment (Child-Pugh Criteria A and B), the half-life of escitalopram was about twice as long and the exposure was about 60% higher than in subjects with normal liver function (see Dosage & Administration).
Reduced renal function: With racemic citalopram, a longer half-life and a minor increase in exposure have been observed in patients with reduced kidney function (CLcr 10-53 ml/min). Plasma concentrations of the metabolites have not been studied, but they may be elevated (see Dosage & Administration).
Polymorphism: It has been observed that poor metabolisers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolisers. No significant change in exposure was observed in poor metabolisers with respect to CYP2D6 (see Dosage & Administration).