Nirva Mechanism of Action

Pharmacology: Clozapine is a dibenzodiazepine-derivative atypical antipsychotic agent. While clozapine shares some of the pharmacologic actions of other antipsychotic agents, it is classified as an "atypical" antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by more typical antipsychotic drugs. In pharmacological experiments, clozapine does not induce catalepsy or inhibit apomorphine- or amphetamine-induced stereotyped behavior. Clozapine has only weak dopamine-receptor-blocking activity at D₁, D₂, D₃, and D₅ receptors, but shows high potency for the D₄ receptor. This evidence, consistent with the view that clozapine is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of clozapine from extrapyramidal side effects. In addition, clozapine has potent anti-α-adrenergic, anticholinergic, antihistaminic, and arousal-reaction-inhibiting effects. It has also been shown to possess antiserotoninergic properties. Clinically, clozapine produced rapid and marked sedation with strong antipsychotic effects in patients resistant to other drug treatment. In these patients, clozapine has been shown to be effective in the relief of both positive and negative symptoms of schizophrenia. In contrast to typical antipsychotics, clozapine produces little or no prolactin elevation, thus avoiding adverse effects such as gynecomastia, amenorrhea, galactorrhea, and impotence.
Pharmacokinetics: Clozapine is well absorbed from the gastrointestinal tract (90 to 95%); neither the rate nor extent of absorption is affected by food intake. However, clozapine is subject to moderate first-pass metabolism resulting in an absolute bioavailability of 50 to 60%. After administration of 100 mg tablet twice a day, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL). Clozapine is rapidly and extensively distributed throughout the body and crosses the blood brain barrier freely. Its volume of distribution is 1.6 L/kg. Clozapine is approximately 97% bound to plasma proteins. Clozapine is metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. It may undergo N-demethylation, N-oxidation, 3'-carbon oxidation, epoxidation of the chlorine-containing aromatic ring, substitution of chlorine by hydroxyl or thiomethyl groups, and sulfur oxidation. A glucuronide metabolite, tentatively identified as a quaternary ammonium N-glucuronide of clozapine, has also been identified. Metabolism of clozapine may occur by one or more of these routes. The desmethyl metabolite of clozapine (norclozapine) has limited activity while the hydroxylated and N-oxide derivatives are inactive. Approximately 50% of the administered dose is excreted as metabolites in the urine and 30% in the feces. The mean elimination half-life (t_1/2) of clozapine after a single 75-mg dose was eight hours (range: 4 to 12 hours) compared to 12 hours (range: 4 to 66 hours) at steady state with 100 mg twice a day dosing. The elimination t_1/2 of clozapine increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, linearly dose-proportional changes with respect to area-under-the curve (AUC), peak and minimum clozapine plasma concentration were observed after administration of clozapine 37.5 mg, 75 mg and 150 mg twice a day.