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Pharmacotherapeutic group: antidepressants, selective serotonin reuptake inhibitor. ATC code: N 06 AB 04.
Pharmacology: Pharmacodynamics: Mechanism of action: Biochemical and behavioural studies have been shown that citalopram is a potent inhibitor of the serotonin (5-HT)-uptake. Tolerance to the inhibition of 5-HT-uptake is not induced by long-term treatment with citalopram.
Citalopram is a very Selective Serotonin Reuptake Inhibitor (SSRI) with no, or minimal, effect on noradrenaline (NA), dopamine (DA) and gamma aminobutyric acid (GABA) uptake.
In contrast to many tricyclic antidepressants and some of the newer SSRIs, citalopram has no or very low affinity for a series of receptors including 5-HT1A, 5-HT2, DA D1 and D2 receptors, α1-, α2-, β-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors. A series of functional in vitro tests in isolated organs as well as functional in vivo tests have confirmed the lack of receptor affinity. This absence of effects on receptors could explain why citalopram produces fewer of the traditional side effects such as dry mouth, bladder and gut disturbance, blurred vision, somnolence, cardiotoxicity and orthostatic hypotension.
The main metabolites of citalopram are all SSRIs although their potency and selectivity ratios are lower than those of citalopram. However, the selectivity ratios of the metabolites are higher than those of many of the newer SSRIs. The metabolites do not contribute to the overall antidepressant effect.
Pharmacodynamic effects: Suppression of rapid eye movement (REM) sleep is considered a predictor of antidepressant activity. Like tricyclic antidepressants, other SSRIs and MAO inhibitors, citalopram suppresses REM-sleep and increases deep slow-wave sleep.
Although citalopram does not bind to opioid receptors, it potentiates the antinociceptive effect of commonly used opioid analgesics.
In humans, citalopram does not impair cognitive (intellectual function) and psychomotor performance and has no or minimal sedative properties, either alone or in combination with alcohol.
Citalopram did not reduce saliva flow in a single dose study in human volunteers and in none of the studies in healthy volunteers did citalopram have significant influence on cardiovascular parameters. Citalopram has no effect on the serum levels of growth hormone. Citalopram like other SSRIs may increase plasma prolactin, an effect secondary to the prolactin-stimulating role of serotonin and of no clinical importance.
In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline to QTc (Fridericia-correction) was 7.5 (90% CI 5.9 - 9.1) ms at the 20 mg/day dose and 16.7 (90% CI 15.0 - 18.4) ms at the 60 mg/day dose (see Contraindications, Precautions, Interactions, Adverse Reactions, and Overdosage).
Pharmacokinetics: Absorption: Absorption is almost complete and independent of food intake (Tmax mean 3 hours). Oral bioavailability is about 80%.
Distribution: The apparent volume of distribution (Vd) is about 12-17 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites.
Biotransformation: Citalopram is metabolised to the active demethylcitalopram, didemethylcitalopram, citalopram-N-oxide and an inactive deaminated propionic acid derivative. All the active metabolites are also SSRIs, although weaker than the parent compound. Unchanged citalopram is the predominant compound in plasma. The concentrations of demethylcitalopram and didemethylcitalopram are usually 30-50% and 5-10% of the citalopram concentration, respectively. The biotransformation of citalopram to demethylcitalopram is mediated by CYP2C19 (approx. 38%), CYP3A4 (approx. 31%) and CYP2D6 (approx. 31%).
Elimination: The elimination half-life (T½β) is about 1½ days, and the systemic citalopram plasma clearance (Cls) is about 0.3-0.4 L/min, and oral plasma clearance (Cloral) is about 0.4 L/min.
Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys; 12-23% of the daily dose is excreted in urine as unchanged citalopram. Hepatic (residual) clearance is about 0.3 L/min and renal clearance about 0.05-0.08 L/min.
Linearity: The kinetics is linear. Steady sate plasma levels are achieved in 1-2 weeks. Average concentrations of 300 nmol/L (165-405 nmol/L) are achieved at a daily dose of 40 mg.
Elderly patients (>65 years): Longer half-lives (1.5-3.75 days) and decreased clearance values (0.08-0.3 L/min) due to a reduced rate of metabolism have been demonstrated in elderly patients. Steady state values were about twice as high in the elderly as in younger patients treated with the same dose.
Reduced hepatic function: Citalopram is eliminated more slowly in patients with reduced hepatic function. The half-life of citalopram is about twice as long and steady state citalopram concentrations at a given dose will be about twice as high as in patients with normal liver function.
Reduced renal function: Citalopram is eliminated more slowly in patients with mild to moderate reduction of renal function, without any major impact on the pharmacokinetics of citalopram. At present, no information is available for treatment of patients with severely reduced renal function (creatinine clearance <20 mL/min).
Polymorphism: In vivo investigations have shown that the metabolism of citalopram exhibits no clinically important polymorphism of the sparteine/debrisoquine oxidation (CYP2D6). For CYP2C19, as a precaution, an initial dose of 10 mg should be considered for known poor metabolisers (see Dosage & Administration and Precautions).
Pharmacokinetic / pharmacodynamic relationship: There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.
The metabolites do not contribute to the overall antidepressant effect.
Toxicology: Preclinical safety data: Acute toxicity: Citalopram has low acute toxicity.
Chronic toxicity: In chronic toxicity studies, there were no findings of concern for the therapeutic use of citalopram.
Reproduction studies: Based on data from reproduction toxicity studies (segment I, II and III), there is no reason to have special concern for the use of citalopram in women of childbearing potential.
Citalopram appears in milk in low concentrations.
Embryotoxicity studies in rats with doses of 56 mg/kg/day, which cause maternal toxicity, showed bone anomalies in the region of the vertebral column and ribs. The maternal plasma level was then 2-3 times the therapeutic concentration in man. In rats, citalopram did not have any effect on fertility, pregnancy and postnatal development, but diminished the birth weight of the pups. Citalopram and its metabolites reach foetal concentrations, which are 10-15 times the maternal plasma level. Clinical experience of use in pregnant women and during lactation is limited.
Animal data have shown that citalopram induces a reduction of fertility index and pregnancy index, reduction in number in implantation and abnormal sperm at exposure well in excess of human exposure.
Mutagenic and carcinogenic potential: Citalopram has no mutagenic or carcinogenic potential.
