Rosemide Mechanism of Action

Pharmacotherapeutic group: Other antipsychotics. ATC code: N05AX08.
Pharmacology: Pharmacodynamics: Mechanism of action: Risperidone is a selective monoaminergic antagonist with unique properties. It has a high affinity for serotoninergic 5-HT₂ and dopaminergic D₂ receptors. Risperidone binds also to alpha₁-adrenergic receptors, and, with lower affinity, to H₁-histaminergic and alpha -adrenergic receptors. Risperidone has no affinity for cholinergic receptors. Although risperidone is a potent D₂ antagonist, which is considered to improve the positive symptoms of schizophrenia, it causes less depression of motor activity and induction of catalepsy than classical antipsychotics. 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 metabolised to 9-hydroxy-risperidone, which has a similar pharmacological activity to risperidone (see Biotransformation and Elimination as follows).
Absorption: Risperidone is completely absorbed after oral administration, reaching peak plasma concentrations within 1 to 2 hours. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) compared with a solution. The absorption is not affected by food and thus risperidone can be given with or without meals. Steady-state of risperidone is reached within 1 day in most patients. Steady-state of 9-hydroxy-risperidone is reached within 4-5 days of dosing.
Distribution: Risperidone is rapidly distributed. The volume of distribution is 1-2 l/kg. In plasma, risperidone is bound to albumin and alpha -acid glycoprotein. The plasma protein binding of 1 risperidone is 90% that of 9-hydroxy-risperidone is 77%.
Biotransformation and elimination: Risperidone is metabolised by CYP2D6 to 9-hydroxy-risperidone, which has a similar pharmacological activity as risperidone. Risperidone plus 9-hydroxy-risperidone form the active antipsychotic fraction. CYP2D6 is subject to genetic polymorphism. Extensive CYP2D6 metabolisers convert risperidone rapidly into 9-hydroxy-risperidone, whereas poor CYP2D6 metabolisers convert it much more slowly. Although extensive metabolisers have lower risperidone and higher 9-hydroxy-risperidone concentrations than poor metabolisers, the pharmacokinetics of risperidone and 9-hydroxy-risperidone combined (i.e., the active antipsychotic fraction), after single and multiple doses, are similar in extensive and poor metabolisers of CYP2D6.
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 metabolised by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. One week after administration, 70% of the dose is excreted in the urine and 14% in the faeces. In urine, risperidone plus 9-hydroxy-risperidone represent 35-45% of the dose. The remainder is inactive metabolites. After oral administration to psychotic patients, risperidone is eliminated with a half-life of about 3 hours. The elimination half-life of 9-hydroxy-risperidone and of the active antipsychotic fraction is 24 hours.
Linearity/non-linearity: Risperidone plasma concentrations are dose-proportional within the therapeutic dose-range.
Elderly, hepatic and renal impairment: A single-dose PK-study with oral risperidone showed on average a 43% higher active antipsychotic fraction plasma concentrations, a 38% longer half-life and a reduced clearance of the active antipsychotic fraction by 30% in the elderly.
In adults with moderate renal disease the clearance of the active moiety was ~48% of the clearance in young healthy adults. In adults with severe renal disease the clearance of the active moiety was ~31% of the clearance in young healthy adults. The half-life of the active moiety was 16.7 h in young adults, 24.9 h in adults with moderate renal disease (or ~1.5 times as long as in young adults), and 28.8 h in those with severe renal disease (or ~1.7 times as long as in young adults). Risperidone plasma concentrations were normal in patients with liver insufficiency, but the mean free fraction of risperidone in plasma was increased by 37.1%.
The oral clearance and the elimination half-life of risperidone and of the active moiety in adults with moderate and severe liver impairment were not significantly different from those parameters in young healthy adults.
Pediatric population: The pharmacokinetics of risperidone, 9-hydroxy-risperidone and the active antipsychotic fraction in children are similar to those in adults.
Gender, race and smoking habits: A population pharmacokinetic analysis revealed no apparent effect of gender, race or smoking habits on the pharmacokinetics of risperidone or the active antipsychotic fraction.