Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Mechanism of Action
Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) uptake and itsantidepressant action and effectiveness in the treatment of OCD and Panic Disorder is thought to be related to its specific inhibition of 5-HT uptake in brain neurones.
Paroxetine is chemically unrelated to the tricyclic, tetracyclic and other available antidepressants.
Paroxetine has low affinity for muscarinic cholinergic receptors and animal studies have indicated only weak anticholinergic properties.
In accordance with this selective action, in vitro studies have indicated that, in contrast to tricyclic antidepressants, paroxetine has little affinity for alpha1, alpha2 and beta-adrenoceptors, dopamine (D2), 5-HT1 like, 5-HT2 and histamine (H1) receptors. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate lack of CNS depressant and hypotensive properties.
Pharmacodynamic Effects
Paroxetine does not impair psychomotor function and does not potentiate the depressant effects of ethanol. As with other selective 5-HT uptake inhibitors, paroxetine causes symptoms of excessive 5-HT receptor stimulation when administered to animals previously given monoamine oxidase (MAO) inhibitors or tryptophan.
Behavioural and EEG studies indicate that paroxetine is weakly activating at doses generally above those required to inhibit 5-HT uptake. The activating properties are not "amphetamine-like" in nature.
Animal studies indicate that paroxetine is well tolerated by the cardiovascular system.
Paroxetine produces no clinically significant changes in blood pressure, heart rate and ECG after administration to healthy subjects. Studies indicate that, in contrast to antidepressants which inhibit the uptake of nor- adrenaline, paroxetine has a much reduced propensity to inhibit the antihypertensive effects of guanethidine.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption
Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism.
Due to first-pass metabolism, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract. Partial saturation of the first-pass effect and reduced plasma clearance occur as the body burden increases with higher single doses or on multiple dosing. This results in disproportionate increases in plasma concentrations of paroxetine and hence pharmacokinetic parameters are not constant, resulting in non-linear kinetics. However, the non-linearity is generally small and is confined to those subjects who achieve low plasma levels at low doses.
Steady state systemic levels are attained by 7 to 14 days after starting treatment with immediate or controlled release formulations and pharmacokinetics do not appear to change during long-term therapy.
Distribution
Paroxetine is extensively distributed into tissues and pharmacokinetic calculations indicate that only 1% of the paroxetine in the body resides in the plasma.
Approximately 95% of the paroxetine present in the plasma is protein bound at therapeutic concentrations.
No correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy).
Transfer to human breast milk, and to the foetuses of laboratory animals, occurs in small amounts.
Metabolism
The principal metabolites of paroxetine are polar and conjugated products of oxidation and methylation which are readily cleared. In view of their relative lack of pharmacological activity, it is most unlikely that they contribute to paroxetine's therapeutic effects.
Metabolism does not compromise paroxetine's selective action on neuronal 5-HT uptake.
Elimination
Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of metabolites is about 64% of dose. About 36% of the dose is excreted in faeces, probably via the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism.
NOTE: The alternative wording given below may be used to replace the above statement: About 64% of the dose is excreted in the urine; urinary excretion of unchanged paroxetine is generally less than 2% of the dose. About 36% of the dose is excreted in the faeces, probably via the bile; faecal excretion of unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism.
Metabolite excretion is biphasic, being initially a result of first-pass metabolism and subsequently controlled by systemic elimination of paroxetine.
The elimination half-life is variable but is generally about 1 day.
Special Patient Populations
• Elderly and Renal/Hepatic Impairment
Increased plasma concentrations of paroxetine occur in elderly subjects and in those subjects with severe renal and hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.
The results of studies performed to date have revealed no evidence of any effect of paroxetine on the immune system.