Pimozide

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Pimozide
Pimozide2DACS.svg
Pimozide3Dan.gif
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 monograph
MedlinePlus a686018
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes oral
Pharmacokinetic data
Bioavailability 40-50%
Metabolism CYP3A4, CYP1A2 and CYP2D6
Half-life 55 hours (adults), 66 hours (children)
Excretion Urine
Identifiers
CAS number 2062-78-4 YesY
ATC code N05AG02
PubChem CID 16362
IUPHAR ligand 90
DrugBank DB01100
ChemSpider 15520 YesY
UNII 1HIZ4DL86F YesY
KEGG D00560 YesY
ChEBI CHEBI:8212 YesY
ChEMBL CHEMBL1423 YesY
Chemical data
Formula C28H29F2N3O 
Mol. mass 461.56
 YesY (what is this?)  (verify)

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.

Medical uses[edit]

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 and paranoid personality disorder.[1] It has also been used for delusions of parasitosis.[2]

Use as a Listeria monocytogenes inhibitor has been described.[3]

Side effects[edit]

Very common (>10% frequency) side effects include:[4][5][6][7]

Contraindications[edit]

It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.[5] Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or torsades de pointes.[5] 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.[5] It is also contraindicated in individuals being cotreated with SSRIs or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.[5] Likewise its use is contraindicated in individuals receiving treatment with CYP3A4, CYP1A2 and CYP2D6.[5]

Overdose[edit]

Pimozide overdose presents with severe extrapyramidal symptoms, hypotension, sedation, QT interval prolongation and ventricular arrhythmias including torsades de pointes.[5] Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.[5] Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.[5]

Pharmacology[edit]

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.[8]

Binding profile[Note 1]
Protein Ki (nM)[9] 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.[10]
α1A 197.7 Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.[8]
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.[11] 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.[11]
D3 0.25
D4 1.8
hERG 18 May be responsible for pimozide's high liability for prolonging the QT interval.[11]
H1 692 Likely responsible for why pimozide tends to produce so little sedation.[11]
σ 508
Pharmacokinetic data[4][5][6][7]
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



(See also: droperidol)

Notes[edit]

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

References[edit]

  1. ^ Munro, A. (1999)Delusional disorder. Cambridge: Cambridge University Press. ISBN 0-521-58180-X.
  2. ^ van Vloten WA (March 2003). "Pimozide: use in dermatology". Dermatol. Online J. 9 (2): 3. PMID 12639456. 
  3. ^ 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. doi:10.1128/AAC.00607-08. PMC 2630664. PMID 19015342. 
  4. ^ a b "Oral (pimozide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 4 December 2013. 
  5. ^ 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. 
  6. ^ a b Brayfield, A (12 February 2013). Pimozide. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). Retrieved 4 December 2013. 
  7. ^ a b "ORAP (pimozide) tablet [Teva Select Brands]". DailyMed. Teva Select Brands. July 2012. Retrieved 4 December 2013. 
  8. ^ a b Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.  edit
  9. ^ 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. Retrieved 4 December 2013. 
  10. ^ "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. 
  11. ^ a b c d 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.  edit

External links[edit]