RiteMED Risperidone Mechanism of Action

Antipsychotic.
Pharmacology: Pharmacodynamics: Risperidone is a selective monoaminergic antagonist with a high affinity for serotonergic 5-HT₂ and dopaminergic D₂ receptors. Risperidone binds also to α₁-adrenergic receptors, and with lower affinity, to H₁-histaminergic and α₂-adrenergic receptors. Risperidone does not bind to dopamine D₁ receptors and has no affinity for muscarinic cholinergic receptors. Due to the lack of muscarinic receptor binding, risperidone is not expected to produce anticholinergic adverse effects.
The antipsychotic activity of risperidone is considered to be attributable to both risperidone and its active metabolite 9-hydroxy risperidone. Central dopamine D₂-receptor antagonism is considered to be the mechanism of action by which conventional antipsychotics improve the positive symptoms of schizophrenia, but also induce extrapyramidal symptoms and release of prolactin.
Although risperidone antagonizes dopamine D₂ receptors and causes release of prolactin, it is less potent than classical antipsychotics for depression of motor activity and for induction of catalepsy in animals. Balanced central serotonin and dopamine antagonism may reduce extrapyramidal side effect liability and extend the therapeutic activity to the negative and affective symptoms of schizophrenia.
Pharmacokinetics: Risperidone is well absorbed after oral administration. The absolute oral bioavailability of risperidone is 70%. The relative oral bioavailability of risperidone from a tablet is 94% when compared to a solution. Mean peak plasma concentrations of risperidone and 9-hydroxyrisperidone were reached at about 1 and 3 hours, respectively, after administration. Food did not affect the extent of absorption; thus, risperidone can be given with or without meals.
Risperidone is rapidly distributed. The volume of distribution is 1 to 2 L/kg. Steady-state concentrations of risperidone and 9-hydroxyrisperidone were reached within 1 to 2 days and 5 to 6 days, respectively. In plasma, risperidone is bound to albumin and α₁-acid glycoprotein (AGP). The plasma protein binding of risperidone is approximately 88%, that of the metabolite 77%. Neither risperidone nor 9-hydroxyrisperidone displaces each other from plasma binding sites.
Risperidone is extensively metabolized in the liver by CYP2D6 to a major active metabolite, 9-hydroxyrisperidone, which appears approximately equi-effective with risperidone with respect to receptor-binding activity. Consequently, the clinical effect of the drug likely results from the combined concentrations of risperidone plus 9-hydroxyrisperidone. CYP2D6, also called debrisoquin hydroxylase, is the enzyme responsible for the metabolism of many antipsychotics, antidepressants, antiarrhythmics, and other drugs. CYP2D6 is subject to genetic polymorphism (about 6 to 8% of Caucasians, and a very low percentage of Asians, have little or no activity and are "poor metabolizers") and to inhibition by a variety of substrates and some non-substrates, notably quinidine. Extensive CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas poor CYP2D6 metabolizers convert it much more slowly.
Another metabolic pathway of risperidone is N-dealkylation. In vitro studies in human liver microsomes showed that risperidone at clinically relevant concentration does not substantially inhibit the metabolism of medicines metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5.
Risperidone and its metabolites are eliminated via the urine and, to a much lesser extent, via the feces. One week after administration, 70% of the dose is excreted in the urine and 14% in the feces. In urine, risperidone plus 9-hydroxyrisperidone represents 35 to 45% of the dose. The remainder is inactive metabolites. The apparent half-life of risperidone was three hours in extensive metabolizers and 20 hours in poor metabolizers. The apparent half-life of 9-hydroxyrisperidone was about 21 hours in extensive metabolizers and 30 hours in poor metabolizers. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of risperidone and 9-hydroxyriperidone combined, after single and multiple doses, are similar in extensive and poor metabolizers, with an overall mean elimination half-life of about 20 hours.
Special Population: Children: The pharmacokinetics of risperidone and 9-hydroxydsperidone in children were similar to those in adults after correcting for the difference in body weight.
Elderly: In healthy elderly subjects, renal clearance of both risperidone and 9-hydroxyrisperidone was decreased, and elimination half-lives were prolonged compared to young healthy subjects. Dosing should be modified accordingly in the elderly patients.
Hepatic Impairment: Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by about 35%.
Renal Impairment: In patients with moderate to severe renal disease, clearance of the sum of risperidone and its active metabolite decreased by 60% compared to young healthy subjects. Risperidone doses should be reduced in these patients.
Race and Gender: There is no specific pharmacokinetic study conducted to investigate race and gender effects, but a population pharmacokinetic analysis did not identify important differences in the disposition of risperidone due to gender (whether corrected for body weight or not) or race.