Pimozide

Pimozide (sold under the brand name Orap) is a neuroleptic 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 indication for Tourette syndrome and resistant tics.

Pimozide

Clinical data
Trade names	Orap
AHFS/Drugs.com	Monograph
MedlinePlus	a686018
License data	US FDA: Pimozide
Pregnancy category	AU: B1
Routes of administration	Oral
Drug class	Typical antipsychotic
ATC code	N05AG02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances)[1] US: ℞-only
Pharmacokinetic data
Bioavailability	40-50%
Metabolism	CYP3A4, CYP1A2 and CYP2D6
Elimination half-life	55 hours (adults), 66 hours (children)
Excretion	Urine
Identifiers
IUPAC name 1-[1-[4,4-Bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one
CAS Number	2062-78-4 Y
PubChem CID	16362
IUPHAR/BPS	90
DrugBank	DB01100 Y
ChemSpider	15520 Y
UNII	1HIZ4DL86F
KEGG	D00560 Y
ChEBI	CHEBI:8212 Y
ChEMBL	ChEMBL1423 Y
CompTox Dashboard (EPA)	DTXSID8023474
ECHA InfoCard	100.016.520
Chemical and physical data
Formula	C28H29F2N3O
Molar mass	461.557 g·mol−1
3D model (JSmol)	Interactive image
SMILES Fc1ccc(cc1)C(c2ccc(F)cc2)CCCN5CCC(N4c3ccccc3NC4=O)CC5
InChI InChI=1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34) Y Key:YVUQSNJEYSNKRX-UHFFFAOYSA-N Y
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Medical uses

Pimozide is used for Tourette syndrome,^[2] and resistant tics (Europe, United States, and Canada) and in Europe for schizophrenia, chronic psychosis, delusional disorder, and paranoid personality disorder.^[3]

Efficacy

A 2013 systematic review compared 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 antipsychotics such as olanzapine or risperidone are used as first line treatment. However, patients who experience negative side-effects with the first line medications are typically given pimozide.^[5][6]

Contraindications

It 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 or torsades de pointes.^[7] 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.^[7] It is also contraindicated in individuals being cotreated with selective 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 with CYP3A4, CYP1A2, or CYP2D6 inhibitors.^[7]

Side effects

Very common (>10% frequency) side effects include:^{[8][7][9][10]}

• 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.^[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

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.^[11]

Binding profile^{[Note 1]}

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 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.[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 glucose homeostasis seen with some of the atypical antipsychotics such as clozapine and olanzapine.[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 data^{[8][7][9][10]}

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

History

In 1985 pimozide was approved by the FDA for marketing as an orphan drug for the treatment of Tourette's syndrome.^[2]

See also

• Medicine portal

• Amisulpride
• Pipamperone
• Fluspirilene
• Penfluridol

Notes

1. A lower K_i value indicates a stronger binding