Paroxetine - How It Works

CLINICAL PHARMACOLOGY Pharmacodynamics The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT).

Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets.

In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake.

In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha 1 -, alpha 2 -, beta-adrenergic-, dopamine (D 2 )-, 5-HT 1 -, 5-HT 2 -, and histamine (H 1 )-receptors; antagonism of muscarinic, histaminergic, and alpha 1 -adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs.

Because the relative potencies of paroxetine’s major metabolites are at most 1/50 of the parent compound, they are essentially inactive.

Pharmacokinetics Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt.

The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine daily for 30 days.

Paroxetine is extensively metabolized and the metabolites are considered to be inactive.

Nonlinearity in pharmacokinetics is observed with increasing doses.

Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces.

Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).

In a meta-analysis of paroxetine from 4 studies done in healthy volunteers following multiple dosing of 20 mg/day to 40 mg/day, males did not exhibit a significantly lower C max or AUC than females.

Absorption and Distribution Paroxetine is equally bioavailable from the oral suspension and tablet.

Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt.

In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient.

At steady state, mean values of C max , T max , C min , and T½ were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively.

The steady-state C max and C min values were about 6 and 14 times what would be predicted from single-dose studies.

Steady-state drug exposure based on AUC 0-24 was about 8 times greater than would have been predicted from single-dose data in these subjects.

The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable.

The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food.