Cloril Mechanism of Action

Pharmacology: Pharmacodynamics: Clozapine 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 drug products. In particular, although Clozapine does interfere with the binding of dopamine at D-1, D-2 , D-3, D-4 and D-5 receptors and have a high affinity for D-4 receptor, it does not induce catalepsy or inhibit apomorphine-induced stereotypy. 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. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.
Pharmacokinetics: Absorption, Distribution, Metabolism and Excretion: In man, following a dosage of 100 mg b.i.d., the average steady state peak plasma concentration was 319 ng/mL (range: 102-771 ng/mL), occurring at the average of 2.5 hours (range: 1-6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41-343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of Clozapine. Thus, Clozapine may be administered with or without food.
Clozapine is approximately 97% bound to serum proteins. The interaction between Clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. The mean elimination half-life of Clozapine after a single 75 mg dose was 8 hours (range: 4-12 hours), compared to a mean elimination half-life, after achieving steady state with 100 mg b.i.d. dosing, of 12 hours (range: 4-66 hours). A comparison of single-dose and multiple-dose administration of Clozapine showed that the elimination half-life 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 AUC (area under the curve), peak and minimum Clozapine plasma concentrations were observed after administration of 37.5 mg, 75 mg, and 150 mg b.i.d.
Human pharmacology: In contrast to more typical antipsychotic drugs, Clozapine therapy produces little or no prolactin elevation.
As is true of more typical antipsychotic drugs, clinical EEG studies have shown that Clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop. Patients on rare occasions may report an intensification of dream activity during Clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.