Pharmacology: Pharmacodynamics: Risperidone with the precise mechanism of action as other antipsychotic drugs, is known but the antipsychotic activity is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism.
Risperidone is a selective monominergic antagonist with high affinity (Ki of 0.12 to 7.3 nM) for the serotonin type 2 (5HT2), dopamine type 2 (D2) a1 and a2 adrenergic, and H1 histaminic receptors. Risperidone has no affinity for cholinergic muscarinic or b1 and b2 adrenergic receptors.
The relative oral bioavailability of Risperidone after administration of a single 1 mg tablet was 94%. After oral administration of solution or tablet, mean peak plasma concentrations occurred at about 1 hour. The apparent half-life of Risperidone was three hours. Steady state concentrations of Risperidone are reached in 1 day in extensive metabolizers.
Total plasma protein binding of Risperidone was about 90% over the in vitro concentration range of 0.5 to 200 mg/mL and increased with increasing concentrations of a1 acid glycoprotein. After oral administration, the elimination half-life of the active antipsychotic fraction is 24 hours.
Total recovery of Risperidone at one week was nearly up to 85%, including 70% in the urine and 15% in the feces. Risperidone is extensively metabolized in the liver to a major active metabolite, 9-hydroxyrisperidone that is equi-effective with Risperidone with respect to receptor binding activity and some effects in animals. Plasma concentrations of Risperidone, 9-hydroxyrisperidone, and Risperidone plus 9-hydroxyrisperidone are dose proportional over the dosing range of 1 to 16 mg daily (0.5 to 8 mg b.i.d). Food does not affect either the rate of extent of absorption. Thus, Risperidone can be given with or without meals. The absolute oral bioavailability was 70%.
Pharmacokinetics: Risperidone is readily absorbed after oral doses, peak plasma concentrations being reached within 1 to 2 hours. It is extremely metabolized in the liver to hydroxylation to its main active metabolite, 9-hydroxylation; oxidative N-dealkylation is a minor metabolic pathway. Hydroxylation is mediated by the cytochrome P450 isozyme CYP2D6 and is the subject of genetic polymorphism. Excretion is mainly in the urine and to a lesser extent, in the feces. Risperidone and 9-hydroxyrisperidone are about 88% and 77% bound to plasma proteins, respectively.