Benzisoxazoles - Atypical Neuroleptics

Benzisoxazoles

·              The most important (and virtually the sole) member of this group is risperidone.

Uses

■■   Risperidone is a useful antipsychotic drug for the treat-ment of schizophrenia with specific benefit on “negative” symptoms—affective blunting, paucity of speech, and emotional apathy.

■■   It is also said to be useful in the treatment of psychotic depression.

■■   Risperidone is considered to be the treatment of choice for Pervasive Developmental Disorders (PDD) of childhood.

Toxicokinetics

·              Risperidone is rapidly absorbed on oral administration and peak plasma levels are seen in 2 hours. After oral dosing, mean peak plasma concentrations of the active 9-hydroxyrisperidone metabolite generally occur after 3 hours in extensive metabolisers and after 17 hours in poor metabolisers. Because of moderate first pass metabolism, bioavailability of the parent compound is 66% in extensive metabolisers compared with 82% in poor metabolisers.

·              Risperidone is metabolised in the liver by hydroxylation and oxidative n-dealkylation to the active moiety 9-hydroxy- risperidone. It has an apparent volume of distribution of 1 to 2 L/kg and is 88% bound to plama proteins.

·              Upto 30% of the drug is excreted unchanged in the urine, while 15 to 30% of an administered dose is excreted in the faeces.

·              Elimination half-life of risperidone is 2.8 hours in extensive metabolisers and 16 hours in poor metabolisers, while the half life of 9-hydroxy-risperidone is 20 to 22 hours in both groups.

Mode of Action

■■  Risperidone exhibits weak dopamine D₂ antagonism, but is a potent centrally acting serotonin 5-HT₂ and catecholamine antagonist. In vitro studies have shown that risperidone acts primarily as a serotonin (5-HT₂) and dopamine (D₂) antago-nist. It binds with highest affinity to serotonergic receptors.

■■  Risperidone also binds to alpha-1 and alpha-2 adrenergic and histamine H₁ receptors, although with much less affinity. Dissociation from 5-HT₂ and H₁ receptors is slow; however, the drug rapidly dissociates from dopaminergic and alpha adrenergic receptors.

Adverse Effects

■■   Blurred vision, vertigo, confusion, anorexia, asthenia, orthostatic hypotension, increase in plasma prolactin levels, and sedation.

■■Males may experience erectile and ejaculatory disturbances. Priapism, although rare, has been reported in association with risperidone use.

■■Constipation, diarrhoea, nausea, and dyspepsia have been reported following therapeutic administration of risperi- done.

■■Hyperglycaemia has also been reported, and may be asso- ciated with ketoacidosis or hyperosmolar coma and death. Patients with diabetes mellitus, or who have predisposing risk factors for the development of diabetes mellitus, may experience a worsening of glucose control during risperi- done therapy.

Drug Interactions

·              Concurrent administration of clozapine with risperidone decreases the clearance of risperidone.

·              Coadministered ritonavir increases serum concentrations of risperidone, potentially resulting in toxicity.

·              Increased risperidone levels may occur when it is combined with fluoxetine. Severe extrapyramidal side-effects have been reported with fluoxetine-risperidone combination. speech, hypotension, tremor, agitation, extrapyramidal

Clinical (Toxic) Features

·              Tachycardia, drowsiness, CNS depression, miosis, slurred effects, auditory hallucinations, hyponatraemia, hypoka- laemia and ECG changes (QRS and QTc prolongation).

·              Chorea and tardive dyskinesia occurred in some reported cases.

·              A few cases of mania developing after starting risperidone therapy have been reported. Sexual disinhibition was one of the most predominant symptoms.

Treatment

·              Early gastric lavage, followed by activated charcoal and a cathartic may minimise the severity of poisoning.

·              Monitor serum electrolytes including sodium, potassium and magnesium after significant overdose. Cardiac and electrolyte monitoring is advisable for at least 12 to 24 hours in an intensive care unit.

·              Sodium bicarbonate is generally first line therapy for QRS widening and ventricular arrhythmias. In patients unrespon- sive to bicarbonate, consider lignocaine or amiodarone.

·              Treat hypotension and circulatory collapse with appropriate measures such as intravenous fluids and/or sympathomi- metic agents. Adrenaline and dopamine are best avoided, since beta stimulation may worsen hypotension in the setting of risperidone-induced alpha blockade. Because dopamine is more easily administered and can often be instituted more readily, it is recommended as the agent of choice. If hypotension does not respond to dopamine, an agent with more selective alpha adrenergic activity is a logical second choice (noradrenaline, metaraminol). If extrapyramidal symptoms develop, anticholinergic agents can be administered.

·              In the case of seizures, attempt initial control with a benzo- diazepine (diazepam or lorazepam). If seizures persist or recur administer phenobarbitone.

·      Neuroleptic malignant syndrome can be successfully managed with diphenhydramine, oral bromocriptine, benzodiazepines, or intravenous or oral dantrolene sodium in conjunction with cooling and other supportive care.

·      Haemodialysis and haemoperfusion are unlikely to be useful in risperidone overdose because of high degree of protein binding.