Ketipinor Mechanism of Action

Pharmacotherapeutic group: Diazepines, oxazepines and thiazepines. ATC code: N05A H04.
Pharmacology: Pharmacodynamics: Mechanism of action: Quetiapine is an atypical antipsychotic agent which interacts with a broad range of neurotransmitter receptors. Quetiapine exhibits 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 antipsychotic properties and low extrapyramidal side effects (EPS) liability of quetiapine. Quetiapine also has high affinity at histaminergic and adrenergic α1- receptors, with a lower affinity at adrenergic α2- receptors, but no appreciable affinity at cholinergic muscarinic or benzodiazepine receptors.
Quetiapine is active in tests for antipsychotic activity, such as conditioned avoidance. It also blocks the action of dopamine agonists, measured either behaviourally or electrophysiologically, and elevates dopamine metabolite concentrations, a neurochemical index of D2- receptor blockage.
Pharmacodynamic effects: Unlike standard antipsychotics, quetiapine has an atypical profile. Quetiapine does not produce dopamine D2- receptor supersensitivity after chronic administration. Quetiapine produces only weak catalepsy at effective dopamine D2- receptor blocking doses. Quetiapine demonstrates selectivity for the limbic system by producing depolarisation blockade of the mesolimbic but not the nigrostriatal dopamine-containing neurones following chronic administration. Quetiapine exhibits minimal dystonic liability in haloperidol-sensitised or drug-naïve Cebus monkeys after acute and chronic administration. Quetiapine shows minimal EPS liability, and it has been hypothesised that agents with a lower EPS liability may also have a lower liability to produce tardive dyskinesia (see Adverse Reactions).
Clinical Efficacy: Lack of induction of EPS is considered a feature of atypical antipsychotics. Unlike many other antipsychotics, quetiapine does not produce sustained elevations in prolactin, which is considered a feature of atypical antipsychotics. In the treatment of moderate to severe manic episodes, quetiapine demonstrated efficacy in reduction of manic symptoms at 3 and 12 weeks. Use of quetiapine in combination with divalproex or lithium in moderate have been found to be well-tolerated in moderate to severe manic episodes.
Quetiapine is effective when given twice a day, although it has a pharmacokinetic half-life of approximately 7 hours. This is further supported by the data from a positron emission tomography (PET) study which identified that for quetiapine, 5HT2- and D2- receptor occupancy are maintained for up to 12 hours. The safety and efficacy of doses greater than 800 mg/day have not been established.
The long-term efficacy of quetiapine in prevention of relapses has not been verified. In patients with schizophrenia, quetiapine was effective in maintaining the clinical improvement during continuation therapy in those who showed an initial treatment response, suggesting some long-term efficacy.
Pharmacokinetics: Quetiapine is well absorbed and extensively metabolised following oral administration. The principal human plasma metabolites do not have significant pharmacological activity.
The bioavailability of quetiapine is not significantly affected by administration with food. The elimination half-life of quetiapine is approximately 7 hours. Quetiapine is approximately 83% bound to plasma proteins. The pharmacokinetics of quetiapine are linear, and do not differ between men and women.
The mean clearance of quetiapine in the elderly is approximately 30 to 50% lower than that seen in adults aged 18 to 65 years.
The mean plasma clearance of quetiapine was reduced by approximately 25% in subjects with severe renal impairment (creatinine clearance less than 30 ml/min/1.73m2), but the individual clearance values are within the range for normal subjects.
Quetiapine is extensively metabolized in the liver, with parent compound accounting for less than 5% of unchanged drug-related material in the urine or faeces, following the administration of radiolabelled quetiapine. Approximately 73% of the radioactivity is excreted in the urine and 21% in the faeces. The mean quetiapine plasma clearance decreases with approx. 25% in persons with known hepatic impairment (stable alcoholic cirrhosis). As quetiapine is extensively metabolized in the liver, elevated plasma levels are expected in the population with hepatic impairment. Dose adjustments may be necessary in these patients (see Dosage & Administration).
CYP3A4 is the primary enzyme responsible for cytochrome P450 mediated metabolism of quetiapine.
Quetiapine and several of its metabolites were found to be weak inhibitors of human cytochrome P450 1A2, 2C9, 2C19, 2D6 and 3A4 activities, but only at concentrations at least 10- to 50-fold higher than those observed in the usual effective dose range of 300 to 450 mg/day in humans. Based on this, 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.