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Pharmacotherapeutic group: Antidepressants - selective serotonin reuptake inhibitors. ATC Code: N06A B05.
Pharmacology: Pharmacodynamics: Mechanism of Action: Paroxetine is a potent and selective inhibitor of serotonin (5-hydroxytryptamine, 5-HT) re-uptake and its antidepressant action and efficacy in the treatment of OCD and panic disorder is thought to be related to its specific inhibition of serotonin re-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.
Pharmacokinetics: Absorption: Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. Paroxetine CR tablets control the dissolution rate of paroxetine over a period of four to five hours. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until SEROXAT CR tablets have left the stomach. Compared to immediate release formulations of paroxetine, controlled release tablets have a reduced absorption rate.
Due to first-pass metabolism, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract.
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).
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 the therapeutic effects of paroxetine.
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.
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 one day.
Special Patient Populations: Elderly and Renal/Hepatic Impairment: Increased plasma concentrations of paroxetine occur in elderly subjects, in subjects with severe renal and in those with hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.
Toxicology: Non-Clinical Information: Toxicology studies have been conducted in rhesus monkeys and albino rats; in both, the metabolic pathway is similar to that described for humans. As expected with lipophilic amines, including tricyclic antidepressants, phospholipidosis was detected in rats. Phospholipidosis was not observed in primate studies of up to one year duration at doses that were 6 times higher than the recommended range of clinical doses.
Carcinogenesis: In two year studies conducted in mice and rats, paroxetine had no tumorigenic effect.
Genotoxicity: Genotoxicity was not observed in a battery of in vitro and in vivo tests.
