Chemistry:Pimozide

Short description: Chemical compound

Pimozide

Clinical data
Trade names	Orap
AHFS/Drugs.com	Monograph
MedlinePlus	a686018
License data	US FDA: Pimozide
Pregnancy category	AU: B1 US: C (Risk not ruled out)
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) 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
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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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, United States and Canada).

There have been numerous studies showing pimozide can be used successfully to treat delusional parasitosis and traditionally was the drug of choice. However, newer medications have become prevalent recently as the preferred medication. 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.

Pimozide has been used in the treatment of delusional disorder and paranoid personality disorder.

Efficacy

A 2013 systematic review compared pimozide with other antipsychotics for schizophrenia or related psychoses:

Pimozide versus any other antipsychotic

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.
Outcome Findings in words Findings in numbers Quality of evidence Global state Relapse Follow-up: average 38 weeks These is no clear difference between pimozide and other antipsychotic drugs. Data supporting this finding are based on moderate quality evidence. RR 0.82 (0.57 to 1.17) Moderate Mental state No improvement Follow-up: 16 weeks There is not a clear difference between pimozide and other antipsychotic drugs for this mental state outcome but data supporting this finding are very limited. RR 1.09 (0.08 to 15.41) Very low Presence of first-rank symptoms Follow-up: 3–12 months Pimozide may reduce the chance of experiencing these problematic symptoms but there is no clear difference between people given pimozide and those receiving any other antipsychotic. These findings are based on data of low quality. RR 0.53 (0.25 to 1.11) Low Adverse effects – Extrapyramidal adverse effects Parkinsonism (rigidity) Follow-up: mean 14 weeks In the short term these is no clear difference between pimozide and other antipsychotic drugs for this adverse effect. These findings are based on data of low quality. There are no data in the longer term. RR 1.25 (0.37 to 4.17) Low Parkinsonism (tremor) Follow-up: mean 29 weeks There is no clear difference between pimozide and other antipsychotic drugs for the adverse effect of causing tremor but these findings are based on data of low quality. RR 1.45 (0.68 to 3.09) Low Missing outcomes The outcome of quality of life was not measured/reported in the included studies.

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 selective serotonin reuptake inhibitors (SSRI) 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.

Binding profile

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
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 data

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.

See also

• Amisulpride
• Pipamperone
• Fluspirilene
• Penfluridol