Esidep Mechanism of Action

Pharmacology: Mechanism of action: Escitalopram is a selective serotonin reuptake inhibitor (SSRI).
The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). It is a highly selective SSRI with minimal effects on norepinephrine and dopamine neuronal reuptake.
Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has no or very low affinity for serotonergic (5-HT_1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D_1-5), histamine (H_1-3), muscarinic (M_1-5), and benzodiazepine receptors. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na⁺, K⁺, Cl-, and Ca⁺⁺ channels.
Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.
Pharmacokinetics: The single-and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day.
Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours.
With once-daily dosing, steady state plasma concentrations are achieved within approximately one week.
At steady state, the extent of accumulation of escitalopram in plasma is 2.2-2.5 times the plasma concentrations observed after a single dose.
Absorption and Distribution: Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours.
Absorption of escitalopram is not affected by food.
The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable.
The binding of escitalopram to human plasma proteins is approximately 56%.
Metabolism and Elimination: Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance.
Escitalopram is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects. It has been reported that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT_1-7) or other receptors including alpha-and beta-adrenergic, dopamine (D_1-5), histamine (H_1-3), muscarinic (M_1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na⁺, K⁺, Cl^-, and Ca⁺⁺ channels.
CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.
Population Subgroups: Age: Adolescents: Following single dose of 10 mg escitalopram, AUC of escitalopram decreased by 19%, and C_max increased by 26% in healthy adolescent (12 to 17 years of age) compared to adults. Following multiple dosing of 40 mg/day citalopram, escitalopram elimination half-life, steady-state C_max and AUC were similar in patients with MDD (12 to 17 years of age) compared to adult patients. No adjustment of dosage is needed in adolescent patients.
Elderly: Compared with younger subjects, AUC and half-life of escitalopram were increased by approximately 50% in elderly subjects (≥ 65 years of age), and C_max was unchanged. 10 mg is the recommended dose for elderly patients (see Dosage & Administration).
Gender: No dosage adjustment on the basis of gender is needed.
Reduced hepatic function: Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function. 10 mg is the recommended dose of escitalopram for most hepatically impaired patients (see Dosage & Administration).
Reduced renal function: In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min).
Drug-Drug Interactions: Reported literature on in vitro enzyme inhibition has revealed no inhibitory effect escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. While in vivo information to address this question are limited, results from clinical literature suggest that escitalopram, at a dose of 20 mg, has no 3A4 inhibitory effect and a modest 2D6 inhibitory effect (see Interactions).
Toxicology: Preclinical Safety Data: Carcinogenicity/Mutagenicity/Impairment of Fertility: Carcinogenesis: No evidence for carcinogenicity of racemic citalopram has been reported in mice receiving up to 240 mg/kg/day for 18 months. An increased incidence of small intestine carcinoma has been reported in rats receiving 8 or 24 mg/kg/day racemic citalopram for 24 months. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.
Mutagenesis: Racemic citalopram has been reported to be mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It has also been reported to be clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.
Impairment of Fertility: Decreased mating and decreased fertility have been reported in rats at oral doses of racemic citalopram 32, 48, and 72 mg/kg/day and at oral doses of racemic citalopram ≥ 32 mg/kg/day, respectively. Increased gestation duration has also been reported at 48 mg/kg/day of racemic citalopram.
Animal Toxicology and/or Pharmacology: Retinal Changes in Rats: Pathologic changes (degeneration/atrophy) have been reported in the retinas of albino rats in the 2-year carcinogenicity study with racemic citalopram. An increase in both incidence and severity of retinal pathology has been reported in both male and female rats receiving 80 mg/kg/day. Similar findings have not been reported in rats receiving 24 mg/kg/day of racemic citalopram for two years, in mice receiving up to 240 mg/kg/day of racemic citalopram for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic citalopram for one year.
Additional studies to investigate the mechanism for this pathology have not been reported, and the potential significance of this effect in humans has not been established.
Cardiovascular Changes in Dogs: Sudden deaths have been reported in beagle dogs between week 17 and week 31 following initiation of oral racemic citalopram (8 mg/kg/day). Sudden deaths have not been reported in rats at doses of racemic citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those reported in dogs at 8 mg/kg/day. QT prolongation (a known risk factor for the reported outcome in dogs) has been reported in beagle dogs with intravenous administration of racemic DDCT.