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Antipsychotic.
Pharmacology: Clozapine is classified as an atypical antipsychotic agent, which differs from conventional antipsychotics. It has a weak dopamine receptor blocking activity at D2 receptors, but has a D1 anti-adrenergic, anticholinergic, antihistaminergic and arousal reaction inhibiting effects. It has also been shown to possess antiserotonergic property. Clozapine produces rapid and marked sedation and exerts strong antipsychotic effects. It is effective in patients exhibiting both positive and negative schizophrenic symptoms.
Pharmacokinetics: Although clozapine is well absorbed from the gastrointestinal tract, its bioavailability is limited to about 50% by first-pass metabolism. Peak plasma concentrations are achieved an average of about 2.5 hours after oral administration. Clozapine is about 95% bound to plasma proteins and has mean terminal elimination half-life of about 12 hours at a steady state. It is almost completely metabolized and routes of metabolism include N-demethylation, hydroxylation, and N-oxidation, the desmethyl metabolite (norclozapine) has limited activity. The metabolism of clozapine is mediated mainly by the cytochrome P450 isoenzyme CYP1A2. Metabolites and trace amounts of unchanged drug are excreted mainly in the urine and also in the feces. There is wide interindividual variation in plasma concentrations of clozapine and no simple correlation has been found between plasma concentrations and therapeutic effect.
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