Pimozide(sold under the brand nameOrap) is a neurolepticdrugof thediphenylbutylpiperidineclass. It was discovered atJanssen Pharmaceuticain 1963. It has a high potency compared tochlorpromazine(ratio 50-70:1). On a weight basis it is even more potent thanhaloperidol.It also has special indication forTourette syndromeand resistanttics.
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| Trade names | Orap |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a686018 |
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| Routes of administration | Oral |
| Drug class | Typical antipsychotic |
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| Pharmacokineticdata | |
| Bioavailability | 40-50% |
| Metabolism | CYP3A4,CYP1A2andCYP2D6 |
| Eliminationhalf-life | 55 hours (adults), 66 hours (children) |
| Excretion | Urine |
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| ECHA InfoCard | 100.016.520 |
| Chemical and physical data | |
| Formula | C28H29F2N3O |
| Molar mass | 461.557g·mol−1 |
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Medical uses
editPimozide is used for Tourette syndrome,[2]and resistanttics(Europe, United States, and Canada) and in Europe forschizophrenia,chronicpsychosis,delusional disorder,andparanoid personality disorder.[3]
Efficacy
editA 2013systematic reviewcompared pimozide with other antipsychotics for schizophrenia or related psychoses: Pimozide versus any other antipsychotic[4]
In one case a series of 33 patients with delusional parasitosis (median age, 60 years), pimozide was prescribed for 24 patients, 18 of whom took the drug. The dose ranged from 1 to 5 mg daily. No information regarding initial dosing was specified, although the dose was continued for 6 weeks prior to tapering. Of those patients receiving pimozide, 61% (11/18) experienced improvement in or full remission of symptoms. The use of pimozide for the treatment of delusional parasitosis is based primarily on data from case series/reports that demonstrate some efficacy in the majority of patients. Currently,atypical antipsychoticssuch asolanzapineorrisperidoneare used as first line treatment. However, patients who experience negative side-effects with the first line medications are typically given pimozide.[5][6]
Contraindications
editIt is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.[7]Its use is advised against in individuals with people with either a personal or a family history of arrhythmias ortorsades de pointes.[7]Likewise its use is also advised against in individuals with uncorrectedhypokalaemiaandhypomagnesaemiaor clinical significant cardiac disorders (e.g. a recentmyocardial infarctionorbradycardia.[7]It is also contraindicated in individuals being cotreated withselective serotonin reuptake inhibitors(SSRI) or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.[7]Likewise its use is contraindicated in individuals receiving treatment withCYP3A4,CYP1A2,orCYP2D6inhibitors.[7]
Side effects
editVery common (>10% frequency) side effects include:[8][7][9][10]
- Akinesia
- Constipation
- Dizziness
- Dry mouth
- Hyperhidrosis
- Nocturia
- Somnolence
- Speech disorder
Overdose
editPimozide overdose presents with severeextrapyramidal symptoms,hypotension,sedation,QT interval prolongation and ventricular arrhythmias includingtorsades de pointes.[7]Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.[7]Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.[7]
Pharmacology
editPimozide acts as anantagonistof theD2,D3,andD4receptorsand the5-HT7receptor.It is also ahERGblocker.
Similarly to other typical antipsychotics pimozide has a high affinity for thedopamine D2receptorand this likely results in its sexual (due toprolactin hypersecretion) and extrapyramidal side effects as well as its therapeutic efficacy against the positive symptoms ofschizophrenia.[11]
| Protein | Ki(nM)[12] | Notes |
|---|---|---|
| 5-HT1A | 650 | |
| 5-HT2A | 48.4 | This receptor is believed to be responsible for the atypicality of other antipsychotics likeclozapine,olanzapineandquetiapine.Pimozide's affinity towards this receptor is low compared to its affinity for the D2receptor and hence this receptor unlikely contributes to its effects to any meaningful extent. |
| 5-HT2C | 2,112 | |
| 5-HT6 | 71 | |
| 5-HT7 | 0.5 | Relatively high affinity for this receptor may explain its supposed antidepressant-like effects in animal models of depression.[13] |
| α1A | 197.7 | Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.[11] |
| α2A | 1,593 | |
| α2B | 821 | |
| α2C | 376.5 | |
| M3 | 1,955 | This receptor is believed to be responsible for the interference with glucosehomeostasisseen with some of theatypical antipsychoticssuch asclozapineandolanzapine.[14]Pimozide's low affinity for this receptor likely contributes to the comparatively mild effects on glucose homeostasis. |
| D1 | >10,000 | |
| 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.[14] |
| D3 | 0.25 | |
| D4 | 1.8 | |
| hERG | 18 | May be responsible for pimozide's high liability for prolonging the QT interval.[14] |
| H1 | 692 | Likely responsible for why pimozide tends to produce so little sedation.[14] |
| σ | 508 |
| Pharmacokinetic parameter | Value |
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| 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,CYP1A2andCYP2D6 |
| Excretion pathways | Urine |
History
editIn 1985 pimozide was approved by the FDA for marketing as anorphan drugfor the treatment of Tourette's syndrome.[2]
See also
edit
Notes
edit- ^A lower Kivalue indicates a stronger binding
References
edit- ^Anvisa(31 March 2023)."RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial"[Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese).Diário Oficial da União(published 4 April 2023).Archivedfrom the original on 3 August 2023.Retrieved16 August2023.
- ^abColvin CL, Tankanow RM (June 1985). "Pimozide: use in Tourette's syndrome".Drug Intelligence & Clinical Pharmacy.19(6): 421–424.doi:10.1177/106002808501900602.PMID3891283.S2CID19179304.
- ^Munro A (1999).Delusional disorder.Cambridge: Cambridge University Press.ISBN0-521-58180-X.
- ^Mothi M, Sampson S (November 2013)."Pimozide for schizophrenia or related psychoses".The Cochrane Database of Systematic Reviews.11(11): CD001949.doi:10.1002/14651858.CD001949.pub3.PMID24194433.Archivedfrom the original on 27 November 2017.
- ^Generali JA, Cada DJ (February 2014)."Pimozide: parasitosis (delusional)".Hospital Pharmacy.49(2): 134–135.doi:10.1310/hpj4902-134.PMC3940679.PMID24623867.
- ^Meehan WJ, Badreshia S, Mackley CL (March 2006). "Successful treatment of delusions of parasitosis with olanzapine".Archives of Dermatology.142(3): 352–355.doi:10.1001/archderm.142.3.352.PMID16549712.
- ^abcdefghij"Oral 4 mg tablets. - Summary of Product Characteristics".electronic Medicines Compendium.Janssen-Cilag Ltd. 2 April 2013. Archived fromthe originalon 3 March 2016.Retrieved4 December2013.
- ^ab"Oral (pimozide) dosing, indications, interactions, adverse effects, and more".Medscape Reference.WebMD.Archivedfrom the original on 4 December 2013.Retrieved4 December2013.
- ^abBrayfield A (12 February 2013).Pimozide.London, UK: Pharmaceutical Press.Retrieved4 December2013.
{{cite book}}:|work=ignored (help) - ^ab"ORAP (pimozide) tablet [Teva Select Brands]".DailyMed.Teva Select Brands. July 2012.Archivedfrom the original on 3 July 2013.Retrieved4 December2013.
- ^abTaylor D, Paton C, Shitij K (2012).The Maudsley prescribing guidelines in psychiatry.West Sussex: Wiley-Blackwell.ISBN978-0-470-97948-8.
- ^Roth BL,Driscol J (12 January 2011)."PDSP KiDatabase ".Psychoactive Drug Screening Program (PDSP).University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived fromthe originalon 8 November 2013.Retrieved4 December2013.
- ^Mahesh R, Pandey DK, Bhatt S, Gautam BK (January–March 2011). "Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression".Indian Journal of Pharmaceutical Education and Research.45(1): 46–53.
- ^abcdBrunton L, Chabner B, Knollman B (2010).Goodman and Gilman's The Pharmacological Basis of Therapeutics(12th ed.). New York: McGraw-Hill Professional.ISBN978-0-07-162442-8.