Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antidepressants – selective serotonin reuptake inhibitors, ATC code: N06A B05

Mechanism of Action
Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) uptake and its antidepressant action and effectiveness in the treatment of OCD, Social Anxiety disorder/Social Phobia, General Anxiety Disorder, Post-Traumatic Stress Disorder 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 noradrenaline, paroxetine has a much reduced propensity to inhibit the antihypertensive effects of guanethidine.

In the treatment of depressive disorders, paroxetine exhibits comparable efficacy to standard antidepressants.

There is also some evidence that paroxetine may be of therapeutic value in patients who have failed to respond to standard therapy.

Morning dosing with paroxetine does not have any detrimental effect on either the quality or duration of sleep. Moreover, patients are likely to experience improved sleep as they respond to paroxetine therapy.

Adult suicidality analysis
A paroxetine-specific analysis of placebo controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behaviour in young adults (aged 18-24 years) treated with paroxetine compared with placebo (2.19% vs 0.92%). In the older age groups, no such increase was observed. In adults with major depressive disorder (all ages), there was an increase in the frequency of suicidal 12/15
behaviour in patients treated with paroxetine compared with placebo (0.32% vs 0.05%); all of the events were suicide attempts. However, the majority of these attempts for paroxetine (8 of 11) were in younger adults (see section 4.4).

Dose response
In the fixed dose studies there is a flat dose response curve, providing no suggestion of advantage in terms of efficacy for using higher than the recommended doses. However, there are some clinical data suggesting that up-titrating the dose might be beneficial for some patients.

Long-term efficacy
The long-term efficacy of paroxetine in depression has been demonstrated in a 52-week maintenance study with relapse prevention design: 12% of patients receiving paroxetine (20-40mg daily) relapsed, versus 28% of patients on placebo.

The long-term efficacy of paroxetine in treating obsessive compulsive disorder has been examined in three 24-week maintenance studies with relapse prevention design. One of the three studies achieved a significant difference in the proportion of relapsers between paroxetine (38%) compared to placebo (59%).

The long-term efficacy of paroxetine in treating panic disorder has been demonstrated in a 24-week maintenance study with relapse prevention design: 5% of patients receiving paroxetine (10-40mg daily) relapsed, versus 30% of patients on placebo. This was supported by a 36-week maintenance study.

The long-term efficacy of paroxetine in treating social anxiety disorder and generalised anxiety disorder and Post-Traumatic Stress Disorder has not been sufficiently demonstrated.

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 is protein bound at therapeutic concentrations.

No correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy).

Biotransformation
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.

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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 Population and Renal/Hepatic Impairment
Increased plasma concentrations of paroxetine occur in elderly subjects and in those subjects with severe renal impairment or in those with hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects.