|Metabolism||CYP3A4, CYP1A2 and CYP2D6|
|Biological half-life||55 hours (adults), 66 hours (children)|
|Chemical and physical data|
|Molar mass||461.56 g/mol|
|3D model (Jmol)|
Pimozide (Orap) is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome and resistant tics. The side effects include akathisia, tardive dyskinesia, and, more rarely, neuroleptic malignant syndrome and prolongation of the QT interval.
It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation. Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or torsades de pointes. Likewise its use is also advised against in individuals with uncorrected hypokalaemia and hypomagnesaemia or clinical significant cardiac disorders (e.g. a recent myocardial infarction or bradycardia. It is also contraindicated in individuals being cotreated with SSRIs or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives. Likewise its use is contraindicated in individuals receiving treatment with CYP3A4, CYP1A2, or CYP2D6 inhibitors.
Pimozide overdose presents with severe extrapyramidal symptoms, hypotension, sedation, QT interval prolongation and ventricular arrhythmias including torsades de pointes. Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose. Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.
Similarly to other typical antipsychotics pimozide has a high affinity for the Dopamine D2 receptor and this likely results in its sexual (due to prolactin hypersecretion) and extrapyramidal side effects as well as its therapeutic efficacy against the positive symptoms of schizophrenia.
|5-HT2A||48.4||This receptor is believed to be responsible for the atypicality of other antipsychotics like clozapine, olanzapine and quetiapine. Pimozide's affinity towards this receptor is low compared to its affinity for the D2 receptor and hence this receptor unlikely contributes to its effects to any meaningful extent.|
|5-HT7||0.5||Relatively high affinity for this receptor may explain its supposed antidepressant-like effects in animal models of depression.|
|α1A||197.7||Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.|
|M3||1,955||This receptor is believed to be responsible for the interference with glucose homeostasis seen with some of the atypical antipsychotics such as clozapine and olanzapine. Pimozide's low affinity for this receptor likely contributes to the comparatively mild effects on glucose homeostasis.|
|D2||0.33||Likely the receptor responsible for the therapeutic effects against the positive symptoms of schizophrenia of antipsychotics like pimozide as well as the prolactin-elevating and extrapyramidal side effect-generating effects of typical antipsychotics like pimozide.|
|hERG||18||May be responsible for pimozide's high liability for prolonging the QT interval.|
|H1||692||Likely responsible for why pimozide tends to produce so little sedation.|
|Time to peak plasma concentration (Tmax)||6-8 hr|
|Peak plasma concentration (Cmax)||4-19 ng/mL|
|Elimination half-life (t1/2)||55 hours (adults), 66 hours (children)|
|Metabolising enzymes||CYP3A4, CYP1A2 and CYP2D6|
Orphan Drug 1985
In 1985 the orphan drug pimozide (Orap) was approved by the U.S. Food and Drug Administration (FDA or USFDA) for marketing in the U.S. for the treatment of Tourette's syndrome (TS) — one of a number of rare diseases — which also included Huntington's Disease, myoclonus, ALS, and muscular dystrophy — in the United States Orphan Drug Act of 1983, a law enacted to facilitate development of orphan drugs for conditions which affect small numbers of individuals residing in the United States.
- Lower the Ki value is the stronger the binding
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