Qtipine 25/Qtipine 300 Mechanism of Action

Antipsychotic.
Pharmacology: Mechanism of Action: Quetiapine is an atypical antipsychotic agent. Quetiapine and the active human plasma metabolite, norquetiapine interact with a broad range of neurotransmitter receptors. Quetiapine and norquetiapine exhibit affinity for brain serotonin (5HT2) and dopamine D1- and D2-receptors. It is this combination of receptor antagonism with a higher selectivity for 5HT2 relative to D2-receptors, which is believed to contribute to the clinical antipsychotic properties and low extrapyramidal side effect (EPS) liability of Quetiapine compared to typical antipsychotics. Quetiapine and norquetiapine have no appreciable affinity at benzodiazepine receptors but high affinity at histaminergic and adrenergic alpha1 receptors moderate affinity at adrenergic alpha2 receptors and moderate to high affinity at several muscarinic receptors. Inhibition of NET and partial agonist action at 5HT1A sites by norquetiapine may contribute to Quetiapine Extended-Release therapeutic efficacy as an antidepressant.
Pharmacodynamic effects: Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviorally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2-receptor blockade.
In pre-clinical tests predictive of EPS, quetiapine is unlike typical antipsychotics and has an atypical profile. Quetiapine does not produce dopamine D2-receptor super sensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2-receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarization blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitized or drug-naive Cebus monkeys after acute and chronic administration.
Pharmacokinetics: Absorption: Quetiapine is well absorbed following oral administration. The bioavailability of quetiapine is not significantly affected by administration with food. Steady-state peak molar concentrations of the active metabolite norquetiapine are 35% of that observed for quetiapine. The pharmacokinetics of quetiapine and norquetiapine are linear across the approved dosing range.
Distribution: Quetiapine is approximately 83% bound to plasma proteins.
Biotransformation: Quetiapine is extensively metabolized by the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or feces, following the administration of radiolabeled quetiapine.
In vitro investigations established that CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine.
Norquetiapine is primarily formed and eliminated via CYP3A4.
Quetiapine and several of its metabolites (including norquetiapine) were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities in vitro. In vitro CYP inhibition is observed only at concentrations approximately 5 to 50 folds higher than those observed at a dose range of 300 to 800 mg/day in humans. Based on these in vitro results, it is unlikely that co-administration of quetiapine with other drugs will result in clinically significant drug inhibition of cytochrome P450 mediated metabolism of the other drug. From animal studies it appears that quetiapine can induce cytochrome P450 enzymes. In a specific interaction study in psychotic patients, however, no increase in the cytochrome P450 activity was found after administration of quetiapine.
Elimination: The elimination half-lives of quetiapine and norquetiapine are approximately 7 and 12 hours, respectively. Approximately 73% of a radiolabeled drug was excreted in the urine and 21% in the feces with less than 5% of the total radioactivity representing unchanged drug-related material. The average molar dose fraction of free quetiapine and the active human plasma metabolite norquetiapine is <5% excreted in the urine.
Special populations: Gender: The pharmacokinetics of quetiapine does not differ between men and women.
Elderly: The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
Renal impairment: The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73 m²) but the individual clearance values are within the range for normal subjects.
Hepatic impairment: The mean quetiapine plasma clearance decreases with approximately 25% in persons with known hepatic impairment (stable alcohol cirrhosis). As quetiapine is extensively metabolized by the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients.
Children and adolescents (10-17 years of age): At steady state, the pharmacokinetics of the parent compound in children and adolescents, (10-17 years of age) were similar in adults, while AUC and Cmax of the active metabolite, norquetiapine, were higher in children and adolescents than in adults, 45% and 31% respectively. However, when adjusted for weight AUC and Cmax of the parent compound in children and adolescents were lower in adults, 41% and 39% respectively, while the pharmacokinetics of the metabolite, norquetiapine, was similar.