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Pimozide

Pimozide
Systematic (IUPAC) name
1-[1-[4,4-bis(4-fluorophenyl)butyl]-
4-piperidinyl]-1,3-dihydro-
2H-benzimidazole-2-one
Clinical data
Trade names Orap
AHFS/Drugs.com
MedlinePlus
Licence data US FDA:
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
oral
Pharmacokinetic data
Bioavailability 40-50%
Metabolism CYP3A4, CYP1A2 and CYP2D6
Biological half-life 55 hours (adults), 66 hours (children)
Excretion Urine
Identifiers
CAS Registry Number  Y
ATC code N05
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
Chemical data
Formula C28H29F2N3O
Molecular mass 461.56
 Y   

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.

Contents

  • Medical uses 1
  • Side effects 2
    • Contraindications 2.1
    • Overdose 2.2
  • Pharmacology 3
  • Orphan Drug 1985 4
  • See also 5
  • Notes 6
  • References 7
  • External links 8

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).

Pimozide has been used in the treatment of delusional disorder, gender dysphoria and paranoid personality disorder.[1][2] It has also been used for delusions of parasitosis.[3]

Use as a Listeria monocytogenes inhibitor has been described.[4]

Side effects

Very common (>10% frequency) side effects include:[5][6][7][8]

Contraindications

It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.[6] Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or torsades de pointes.[6] 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.[6] It is also contraindicated in individuals being cotreated with SSRIs or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.[6] Likewise its use is contraindicated in individuals receiving treatment with CYP3A4, CYP1A2, or CYP2D6 inhibitors.[6]

Overdose

Pimozide overdose presents with severe extrapyramidal symptoms, hypotension, sedation, QT interval prolongation and ventricular arrhythmias including torsades de pointes.[6] Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.[6] Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.[6]

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.[9]

Binding profile[Note 1]
Protein Ki (nM)[10] 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.[11]
α1A 197.7 Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.[9]
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.[12] 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.[12]
D3 0.25
D4 1.8
hERG 18 May be responsible for pimozide's high liability for prolonging the QT interval.[12]
H1 692 Likely responsible for why pimozide tends to produce so little sedation.[13]
σ 508
Pharmacokinetic data[5][6][7][8]
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 (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)[14] — 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 to facilitate development of orphan drugs for conditions which affect small numbers of individuals residing in the United State.[15]

See also

Notes

  1. ^ Lower the Ki value is the stronger the binding

References

  1. ^ Munro, A. (1999)Delusional disorder. Cambridge: Cambridge University Press. ISBN 0-521-58180-X.
  2. ^ http://www.ncbi.nlm.nih.gov/pubmed/8839957
  3. ^ van Vloten WA (March 2003). "Pimozide: use in dermatology". Dermatol. Online J. 9 (2): 3.  
  4. ^ Lieberman LA, Higgins DE (February 2009). "A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection". Antimicrob. Agents Chemother. 53 (2): 756–64.  
  5. ^ a b "Oral (pimozide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 4 December 2013. 
  6. ^ a b c d e f g h i j "Oral 4 mg tablets. - Summary of Product Characteristics". electronic Medicines Compendium. Janssen-Cilag Ltd. 2 April 2013. Retrieved 4 December 2013. 
  7. ^ a b Brayfield, A (12 February 2013). Pimozide. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). Retrieved 4 December 2013. 
  8. ^ a b "ORAP (pimozide) tablet [Teva Select Brands]". DailyMed. Teva Select Brands. July 2012. Retrieved 4 December 2013. 
  9. ^ a b Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell.  
  10. ^ Roth, BL; Driscol, J (12 January 2011). Database"i"PDSP K. Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 4 December 2013. 
  11. ^ "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. 
  12. ^ a b c Brunton, L; Chabner, B; Knollman, B (2010).  
  13. ^
  14. ^ Colvin CL; Tankanow RM (June 1985). "Pimozide: use in Tourette's syndrome". Drug Intell Clin Pharm 19 (6): 421–4.  
  15. ^ "Orphan Drug Act of 1983" (PDF). US Food and Drug Administration. 4 January 1983. Retrieved 27 October 2015. 

External links

  • Pimozide (A medical white paper on its use)
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