Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

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Pharmacotherapeutic group: antidepressants, selective serotonin reuptake inhibitors 
ATC-code: N 06 AB 04

Mechanism of action
Biochemical and behavioural studies have 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-HT 1A, 5-HT2, DA D1 and D2 receptors, 1-, 2-, 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, sedation, 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 anti- nociceptive effect of commonly used opioid analgesics. There was potentiation of d- amphetamine-induced hyperactivity following administration of citalopram.
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 (see section 4.8).


In a double-blind, placebo-controlled ECG study in healthy subjects, the change from baseline in QTc (Fridericia-correction) was 7.5 (90%CI 5.9-9.1) msec at the 20 mg/day dose and 16.7 (90%CI 15.0-18.4) msec at the 60 mg day/dose (see sections 4.3, 4.4, 4.5, 4.8 and 4.9).

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
Absorption is almost complete and independent of food intake (T maxaverage/mean 3.8 hours). Oral bioavailability is about 80%.
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Distribution
The apparent volume of distribution (Vd)β is about 12.3 L/kg. The plasma protein binding is below 80% for citalopram and its main metabolites.

Biotransformation
Citalopram is metabolized 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.

Elimination
The elimination half-life (T½β) is about 1.5 days and the systemic citalopram plasma clearance (Cls) is about 0.33 L/min, and oral plasma clearance (Cl oral) is about 0.41 L/min.
Citalopram is excreted mainly via the liver (85%) and the remainder (15%) via the kidneys. About 12 % of the daily dose is excreted in urine as unchanged citalopram.
Hepatic (residual) clearance is about 0.35 L/min and renal clearance about 0.068 L/min.
The kinetics are linear. Steady state plasma levels are achieved in 1-2 weeks. Average concentrations of 250 nmol/L (100-500 nmol/L) are achieved at a daily dose of 40 mg.
There is no clear relationship between citalopram plasma levels and therapeutic response or side effects.


Elderly patients     ( 65 years)
Longer half-lives and decreased clearance values due to a reduced rate of metabolism have been demonstrated in elderly patients.

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).