| Revision as of 16:28, 27 November 2017 editJytdog (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers, Rollbackers187,951 edits →Medical uses: screen hit is not use← Previous edit | Revision as of 16:29, 27 November 2017 edit undoJytdog (talk | contribs)Autopatrolled, Extended confirmed users, Pending changes reviewers, Rollbackers187,951 edits effiacy is part of medical uses; other sections are actual sections per MEDMOSNext edit → | ||
| Line 62: | Line 62: | ||
| Pimozide is used in its oral preparation in ] and chronic ] (on-label indications in Europe only), Tourette syndrome and resistant ] (Europe, USA and Canada). | Pimozide is used in its oral preparation in ] and chronic ] (on-label indications in Europe only), Tourette syndrome and resistant ] (Europe, USA and Canada). | ||
| ⚫ | Pimozide has been used in the treatment of ] and ].<ref>Munro, A. (1999)''Delusional disorder''. Cambridge: Cambridge University Press. {{ISBN|0-521-58180-X}}.</ref> It has also been used for ].<ref name="pmid12639456">{{cite journal |author = van Vloten WA |title = Pimozide: use in dermatology |journal = Dermatol. Online J. |volume = 9 |issue = 2 |pages = 3 |date = March 2003 |pmid = 12639456 |doi = |url = http://dermatology.cdlib.org/92/reviews/pimozide/vanvloten.html |deadurl = no |archiveurl = https://web.archive.org/web/20030819211712/http://dermatology.cdlib.org/92/reviews/pimozide/vanvloten.html |archivedate = 19 August 2003 |df = dmy-all }}</ref> | ||
| ⚫ | It has also been used once in the treatment of ], although whether the patient has since experienced remission is unknown. And it is recommended to be considered in cases of "doubtful gender dysphoria".<ref>{{cite journal |title = Pharmacotherapy with pimozide should be considered in cases of doubtful gender dysphoria |date = June 1996 |journal = Australian & New Zealand Journal of Psychiatry |first1 = B. K. |last1 = Puri |first2 = I. |last2 = Singh |pmid = 8839957 |doi = 10.3109/00048679609065010 |volume = 30 |issue = 3 |pages = 422–5 |url = http://journals.sagepub.com/doi/abs/10.3109/00048679609065010 }}</ref> | ||
| ⚫ | == Side effects == | ||
| ⚫ | Very common (>10% frequency) side effects include:<ref name = MSR /><ref name = EMC /><ref name = MD /><ref name = DM /> | ||
| ⚫ | * ] | ||
| ⚫ | * Constipation | ||
| ⚫ | * Dizziness | ||
| ⚫ | * Dry mouth | ||
| ⚫ | * ] | ||
| ⚫ | * ] | ||
| ⚫ | * ] | ||
| ⚫ | * Speech disorder | ||
| ⚫ | |||
| ⚫ | It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.<ref name = EMC /> Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or ].<ref name = EMC /> Likewise its use is also advised against in individuals with uncorrected ] and ] or clinical significant cardiac disorders (e.g. a recent ] or ].<ref name =EMC /> It is also contraindicated in individuals being cotreated with ] or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.<ref name = EMC /> Likewise its use is contraindicated in individuals receiving treatment with ], ], or ] inhibitors.<ref name = EMC /> | ||
| ⚫ | |||
| ⚫ | Pimozide overdose presents with severe ], ], ], QT interval prolongation and ventricular arrhythmias including ].<ref name = EMC /> Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.<ref name = EMC /> Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.<ref name = EMC /> | ||
| == Efficacy == | == Efficacy == | ||
| Line 133: | Line 108: | ||
| |} | |} | ||
| |} | |} | ||
| ⚫ | Pimozide has been used in the treatment of ] and ].<ref>Munro, A. (1999)''Delusional disorder''. Cambridge: Cambridge University Press. {{ISBN|0-521-58180-X}}.</ref> It has also been used for ].<ref name="pmid12639456">{{cite journal |author = van Vloten WA |title = Pimozide: use in dermatology |journal = Dermatol. Online J. |volume = 9 |issue = 2 |pages = 3 |date = March 2003 |pmid = 12639456 |doi = |url = http://dermatology.cdlib.org/92/reviews/pimozide/vanvloten.html |deadurl = no |archiveurl = https://web.archive.org/web/20030819211712/http://dermatology.cdlib.org/92/reviews/pimozide/vanvloten.html |archivedate = 19 August 2003 |df = dmy-all }}</ref> | ||
| ⚫ | It has also been used once in the treatment of ], although whether the patient has since experienced remission is unknown. And it is recommended to be considered in cases of "doubtful gender dysphoria".<ref>{{cite journal |title = Pharmacotherapy with pimozide should be considered in cases of doubtful gender dysphoria |date = June 1996 |journal = Australian & New Zealand Journal of Psychiatry |first1 = B. K. |last1 = Puri |first2 = I. |last2 = Singh |pmid = 8839957 |doi = 10.3109/00048679609065010 |volume = 30 |issue = 3 |pages = 422–5 |url = http://journals.sagepub.com/doi/abs/10.3109/00048679609065010 }}</ref> | ||
| ⚫ | == Contraindications == | ||
| ⚫ | It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.<ref name = EMC /> Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or ].<ref name = EMC /> Likewise its use is also advised against in individuals with uncorrected ] and ] or clinical significant cardiac disorders (e.g. a recent ] or ].<ref name =EMC /> It is also contraindicated in individuals being cotreated with ] or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.<ref name = EMC /> Likewise its use is contraindicated in individuals receiving treatment with ], ], or ] inhibitors.<ref name = EMC /> | ||
| ⚫ | == Side effects == | ||
| ⚫ | Very common (>10% frequency) side effects include:<ref name = MSR /><ref name = EMC /><ref name = MD /><ref name = DM /> | ||
| ⚫ | * ] | ||
| ⚫ | * Constipation | ||
| ⚫ | * Dizziness | ||
| ⚫ | * Dry mouth | ||
| ⚫ | * ] | ||
| ⚫ | * ] | ||
| ⚫ | * ] | ||
| ⚫ | * Speech disorder | ||
| ⚫ | == Overdose == | ||
| ⚫ | Pimozide overdose presents with severe ], ], ], QT interval prolongation and ventricular arrhythmias including ].<ref name = EMC /> Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.<ref name = EMC /> Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.<ref name = EMC /> | ||
| == Pharmacology == | == Pharmacology == | ||
Revision as of 16:29, 27 November 2017
Pharmaceutical compound
 | |
| Clinical data | |
|---|---|
| Trade names | Orap |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a686018 |
| License data | |
| Pregnancy category |
|
| Routes of administration | Oral |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 40-50% |
| Metabolism | CYP3A4, CYP1A2 and CYP2D6 |
| Elimination half-life | 55 hours (adults), 66 hours (children) |
| Excretion | Urine |
| Identifiers | |
IUPAC name
| |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.016.520  |
| Chemical and physical data | |
| Formula | C28H29F2N3O |
| Molar mass | 461.56 g/mol g·mol |
| 3D model (JSmol) | |
SMILES
| |
InChI
| |
| (verify) | |
Pimozide (sold under the brand name 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.
Medical uses
Pimozide is used in its oral preparation in schizophrenia and chronic psychosis (on-label indications in Europe only), Tourette syndrome and resistant tics (Europe, USA and Canada).
Efficacy
A 2013 systematic review compared pimozide with other antipsychotics for schizophrenia or related psychoses:
| Summary | ||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Enough overall consistency over different outcomes and time scales is present to confirm that pimozide is a drug with effectiveness similar to that of other, more commonly used antipsychotic drugs such as chlorpromazine for people with schizophrenia. | ||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||
Pimozide has been used in the treatment of delusional disorder and paranoid personality disorder. It has also been used for delusional parasitosis.
It has also been used once in the treatment of gender dysphoria, although whether the patient has since experienced remission is unknown. And it is recommended to be considered in cases of "doubtful gender dysphoria".
Contraindications
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.
Side effects
Very common (>10% frequency) side effects include:
- Akinesia
- Constipation
- Dizziness
- Dry mouth
- Hyperhidrosis
- Nocturia
- Somnolence
- Speech disorder
Overdose
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.
Pharmacology
Pimozide acts as an antagonist of the D2, D3, and D4 receptors and the 5-HT7 receptor. It is also a hERG blocker.
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.
| Protein | Ki (nM) | Notes |
|---|---|---|
| 5-HT1A | 650 | |
| 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-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. |
| α1A | 197.7 | Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension. |
| α2A | 1,593 | |
| α2B | 821 | |
| α2C | 376.5 | |
| 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. |
| 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. |
| D3 | 0.25 | |
| D4 | 1.8 | |
| 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. |
| σ | 508 |
| Pharmacokinetic parameter | Value |
|---|---|
| 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 |
| Excretion pathways | Urine |
Orphan Drug 1985
In 1985 the orphan drug pimozide (brand name 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.
See also
Notes
- A lower Ki value indicates a stronger binding
References
- ^ Mothi, M; Sampson, S (2013). "Pimozide for schizophrenia or related psychoses". Cochrane Database of Systematic Reviews. 11: CD001949.pub3. doi:10.1002/14651858.CD001949.pub3. Archived from the original on 27 November 2017.
{{cite journal}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - Munro, A. (1999)Delusional disorder. Cambridge: Cambridge University Press. ISBN 0-521-58180-X.
- van Vloten WA (March 2003). "Pimozide: use in dermatology". Dermatol. Online J. 9 (2): 3. PMID 12639456. Archived from the original on 19 August 2003.
{{cite journal}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - Puri, B. K.; Singh, I. (June 1996). "Pharmacotherapy with pimozide should be considered in cases of doubtful gender dysphoria". Australian & New Zealand Journal of Psychiatry. 30 (3): 422–5. doi:10.3109/00048679609065010. PMID 8839957.
- ^ "Oral 4 mg tablets. - Summary of Product Characteristics". electronic Medicines Compendium. Janssen-Cilag Ltd. 2 April 2013. Archived from the original on 3 March 2016. Retrieved 4 December 2013.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - ^ "Oral (pimozide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 4 December 2013. Retrieved 4 December 2013.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - ^ Brayfield, A (12 February 2013). Pimozide. London, UK: Pharmaceutical Press. Retrieved 4 December 2013.
{{cite book}}:|work=ignored (help) - ^ "ORAP (pimozide) tablet [Teva Select Brands]". DailyMed. Teva Select Brands. July 2012. Archived from the original on 3 July 2013. Retrieved 4 December 2013.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - ^ Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
- Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 4 December 2013.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help) - "Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression" (PDF). Indian Journal of Pharmaceutical Education and Research. 45 (1): 46–53. January–March 2011.
- ^ Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
- Colvin, CL; Tankanow, RM (June 1985). "Pimozide: use in Tourette's syndrome". Drug Intell Clin Pharm. 19 (6): 421–4. PMID 3891283.
- "Orphan Drug Act of 1983" (PDF). US Food and Drug Administration. 4 January 1983. Archived from the original (PDF) on 24 September 2015. Retrieved 27 October 2015.
{{cite web}}: Unknown parameter|deadurl=ignored (|url-status=suggested) (help)