Risperidone

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.

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).

Description

Risperidone is a novel antipsychotic introduced for the treatment of acute and chronic schizophrenia. It has a balanced serotonin 5-HT₂ and dopamine D₂ receptor antagonist activity. While the anti-D₂ activity may relate to the antipsychotic potency of neuroleptic agents, an antidepressive efficacy of substances with anti-5-HT₂ activity has been suggested. Risperidone, therefore, has therapeutic action on both positive and negative symptoms of schizophrenia and produces significantly fewer side effects especially extrapyramidal symptoms compared with commonly used pure D₂ antagonist antipsychotics. It also has potential for management of alcohol withdrawal and cocaine addiction.

Chemical properties

Crystalline Solid

Originator

Janssen (U.S.A.)

The Uses of Risperidone

Risperidone has been used:

• to study its effects on bone formation and differentiation
• to investigate the relationship between risperidone (RIS) dosages and RIS plasma levels in autism spectrum disorder (ASD) pediatric patients
• to reverse induced schizophrenia-like behavior in mice

The Uses of Risperidone

A combined serotonin (5-HT2) and dopamine (D2) receptor antagonist

The Uses of Risperidone

neuroprotectant, inhibitory neurotransmitter, GABA agonist

The Uses of Risperidone

For the treatment of schizophrenia in adults and in adolescents, ages 13 to 17, and for the short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents ages 10 to 17. May also be used to manage symptoms of inappropria

Indications

Risperidone is indicated for the treatment of schizophrenia and irritability associated with autistic disorder. It is also indicated as monotherapy, or adjunctly with lithium or valproic acid, for the treatment of acute mania or mixed episodes associated with bipolar I disorder.
Risperidone is additionally indicated in Canada for the short-term symptomatic management of aggression or psychotic symptoms in patients with severe dementia of the Alzheimer type unresponsive to nonpharmacological approaches.
Risperidone is also used off-label for a number of conditions including as an adjunct to antidepressants in treatment-resistant depression.

Background

Risperidone is a second-generation antipsychotic (SGA) medication used in the treatment of a number of mood and mental health conditions including schizophrenia and bipolar disorder. It is one of the most widely used SGAs. Paliperidone, another commonly used SGA, is the primary active metabolite of risperidone (i.e. 9-hydroxyrisperidone).
Schizophrenia and various mood disorders are 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. Risperidone is thought to reduce this overactivity through inhibition of dopaminergic D2 receptors and serotonergic 5-HT2A receptors in the brain.
Risperidone binds with a very high affinity to 5-HT2A receptors, approximately 10-20 fold greater than the drug's binding affinity to D2 receptors, and carries lesser activity at several off-targets which may responsible for some of its undesirable effects.

What are the applications of Application

Risperidone is an inhibitor of SR-2A and D2DR

Definition

ChEBI: A member of the class of pyridopyrimidines that is 2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one carrying an additional 2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl group at position 2.

brand name

Risperdal (Janssen).

General Description

Risperidone (Risperdal, a benzisoxazole)has the structural features of a hybrid molecule between abutyrophenone antipsychotic and a trazodone-like antidepressant.Its superior side effects profile (compared withhaloperidol) at dosage of 6 mg/d or less and the lower riskof tardive dyskinesia have contributed to its very widespreaduse. It benefited refractory psychotic patients, withparkinsonism controlled at one tenth the dose of antiparkinsoniandrugs used with haloperidol.Coexisting anxietyand depressive syndromes were also lessened. It is reportedto decrease the negative (e.g., withdrawal, apathy) as well asthe positive (e.g., delusions, hallucinations) symptoms ofschizophrenia. This is reportedly a consequence of the compound’scombination 5-HT₂–D₂ receptor antagonistic properties.Overall, the reasons for the decreased EPS and effectiveness against negative symptom are still under investigation.It is an important atypical antipsychotic.Risperidone is metabolized in the liver by CYP2D6 to anactive metabolite, 9-hydroxyrisperidone. Because thismetabolite and risperidone are nearly equipotent, the clinicalefficacy of the drug reflects both compounds.

General Description

Risperidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2]pyrimidin-4-one (Risperdal), is awhite to slightly beige powder that is essentially insoluble inwater. Risperidone is also available as a 1-mg/mL oral solutionand as orally disintegrating tablets (Risperdal M-Tab).Risperidone is well absorbed, and peak levels occur about 1hour after administration. The absorption of risperidone is notaffected by food. Risperidone is about 90% bound to albuminand 1-acid glycoprotein, whereas its metabolite 9-hydroxyrisperidoneis bound about 77%. Risperidone is primarilymetabolized in humans to the active metabolite 9-hydroxyrisperidone..The major side effects associated with risperidonetherapy are orthostatic hypotension, dose-related hyperprolactinemia,mild weight gain, EPS, and insomnia.Athigher doses (6 mg/day), risperidone is the atypical antipsychoticthat most closely resembles conventional agents. APET study in a group of individuals with schizophreniashowed that D₂ receptor occupancy was dose dependent. Ifthe dose was increased such that D₂ receptor occupancy was79% to 85%, the majority of patients developed EPS.Risperidone is associated with increased mortality in elderlypatients with dementia-related psychosis and is not recommendedfor these individuals.23 Risperidone binds with highaffinity at 5-HT_2A, 5-HT₇, D₂, 1, 2, and H1 receptors. Theantipsychotic action of risperidone has been proposed tobe the result of D₂ and 5-HT_2A antagonism.

Biological Activity

Atypical antipsychotic agent that displays 5-HT 2A receptor antagonism. Also displays high affinity at D 2 receptors (K i values are 0.4 and 3.13 nM for 5-HT 2A and D 2 receptors respectively).

Biochem/physiol Actions

Risperidone is an antipsychotic; serotonin-dopamine antagonist.

Pharmacokinetics

The primary action of risperidone is to decrease dopaminergic and serotonergic pathway activity in the brain, therefore decreasing symptoms of schizophrenia and mood disorders.
Risperidone has a high binding affinity for serotonergic 5-HT2A receptors when compared to dopaminergic D2 receptors in the brain. Risperidone binds to D2 receptors with a lower affinity than first-generation antipsychotic drugs, which bind with very high affinity. A reduction in extrapyramidal symptoms with risperidone, when compared to its predecessors, is likely a result of its moderate affinity for dopaminergic D2 receptors.

Clinical Use

Schizophrenia
Psychoses
Mania
Persistent aggression in Alzheimer’s dementia

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; increased risk of ventricular arrhythmias with methadone - avoid.
Antidepressants: concentration increased by fluoxetine and possibly paroxetine; concentration of tricyclics possibly increased.
Antiepileptics: antagonism, convulsive threshold may be lowered; metabolism accelerated by carbamazepine.
Antimalarials: avoid with artemether with lumefantrine; possible increased risk of ventricular arrhythmias with mefloquine and quinine.
Antipsychotics: possible increased risk of ventricular arrhythmias with other antipsychotics that prolong the QT interval; avoid concomitant use of depot formulations with clozapine (cannot be withdrawn quickly if neutropenia occurs).
Antivirals: ritonavir may increase concentration of risperidone.
Anxiolytics and hypnotics: enhanced sedative effects.
Atomoxetine: increased risk of ventricular arrhythmias.
Beta blockers: possible increased risk of ventricular arrhythmias with sotalol.
Cytotoxics: increased risk of ventricular arrhythmias with arsenic trioxide.
Lithium: increased risk of extra-pyramidal side effects and possible neurotoxicity.

Metabolism

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

Metabolism

Risperidone is metabolised in the liver by CYP 2D6 to its main active metabolite, 9-hydroxy-risperidone (paliperidone), which has a similar pharmacological activity as risperidone. This hydroxylation is subject to genetic polymorphism. Oxidative N-dealkylation is a minor metabolic pathway.
Excretion is mainly in the urine and, to a lesser extent, in the faeces.

storage

+4°C