RISPERDAL CONSTA FOR INJECTION 25mg/VIAL

Indication

Risperidone belongs to the class of medications known as ​second generation atypical antipsychotics [A1114, A1115, L1213]. It is widely used in the treatment of schizophrenia and mood disorders, including bipolar disorder and depression with pyschosis [A1115, A1116, L1212, L1213].

Mechanism of Action

Though its mechanism of action is not fully understood at this time, current focus is on the ability of risperidone to inhibit the D2 dopaminergic receptors and 5-HT2A serotonergic receptors in the brain. Schizophrenia is thought to be caused by an excess of dopaminergic D2 and serotonergic 5-HT2A activity, resulting in overactivity of central mesolimbic pathways and mesocortical pathways, respectively [A1115, A1116, A1117]. D2 dopaminergic receptors are transiently inhibited by risperidone, reducing dopaminergic neurotransmission, therefore decreasing positive symptoms of schizophrenia, such as delusions and hallucinations. Risperidone binds transiently and with loose affinity to the dopaminergic D2 receptor, with an ideal receptor occupancy of 60-70% for optimal effect [A1119, A31773]. Rapid dissociation of risperidone from the D2 receptors contributes to decreased risk of extrapyramidal symptoms (EPS), which occur with permanent and high occupancy blockade of D2 dopaminergic receptors [A1118, A1119]. Low affinity binding and rapid dissociation from the D2 receptor distinguish risperidone from the traditional antipsychotic drugs. A higher occupancy rate of D2 receptors is said to increase the risk of extrapyramidal symptoms and is therefore to be avoided [A1118, A1119, A31771]. Increased serotonergic mesocortical activity in schizophrenia results in negative symptoms, such as depression and decreased motivation [L1212, L1213]. The high affinity binding of risperidone to 5-HT2A receptors leads to a decrease in serotonergic activity. In addition, 5-HT2A receptor blockade results in decreased risk of extrapyramidal symptoms, likely by increasing dopamine release from the frontal cortex, and not the nigrostriatal tract. Dopamine level is therefore not completely inhibited [A1117, A1119]. Through the above mechanisms, both serotonergic and D2 blockade by risperidone are thought to synergistically work to decrease the risk of extrapyramidal symptoms. Risperidone has also been said to be an antagonist of alpha-1 (α1) alpha-2 (α2) receptors, and histamine (H1) receptors [L1212]. Blockade of these receptors is thought to improve symptoms of schizophrenia, however the exact mechanism of action on these receptors is not fully understood at this time [L1212, L1213].

Pharmacokinetics

Absorption

Well absorbed. The absolute oral bioavailability of risperidone is 70% (CV=25%). The relative oral bioavailability of risperidone from a tablet is 94% (CV=10%) when compared to a solution.

Distribution

1 to 2 L/kg

Metabolism

Extensively metabolized by hepatic cytochrome P450 2D6 isozyme to 9-hydroxyrisperidone, which has approximately the same receptor binding affinity as risperidone [A1118, A31772]. Hydroxylation is dependent on debrisoquine 4-hydroxylase and metabolism is sensitive to genetic polymorphisms in debrisoquine 4-hydroxylase [A11119, A31772]. Risperidone also undergoes N-dealkylation to a lesser extent [A1119, A31772].

Elimination

Clearance

Risperidone is cleared by the kidneys. Clearance is decreased in the elderly and those with renal creatinine clearance of 15 mL/min to 59 mL/min, which decreases clearance by 60% [L1214].

Toxicity

Symptoms of overdose include lethargy, dystonia/spasm, tachycardia, bradycardia, and seizures. LD₅₀=57.7 mg/kg (rat, oral) and 34 mg/kg (rat, intravenous) [A1117, A1118, A1119].

Active Ingredient/Synonyms

risperdone | Risperidona | Risperidonum | Risperin | Rispolept | Rispolin | Sequinan | Risperidone |