Pimozide

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Pimozide
Pimozide.svg
Pimozide-based-on-xtal-3D-bs-17.png
Clinical data
Trade names Orap
AHFS/Drugs.com Monograph
MedlinePlus a686018
License data
Pregnancy
category
  • AU:B1
Routes of
administration
Oral
Drug class Typical antipsychotic
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
  • 1-[1-[4,4-Bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.016.520 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C28H29F2N3O
Molar mass 461.557 g·mol−1
3D model (JSmol)
  • Fc1ccc(cc1)C(c2ccc(F)cc2)CCCN5CCC(N4c3ccccc3NC4=O)CC5
  • 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) Yes check.svgY
  • Key:YVUQSNJEYSNKRX-UHFFFAOYSA-N Yes check.svgY
   (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.

Contents

Medical uses

Pimozide is used in its oral preparation in schizophrenia and chronic psychosis (on-label indications in Europe only), Tourette syndrome, [2] 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. [3] [4]

Pimozide has been used in the treatment of delusional disorder and paranoid personality disorder. [5]

Efficacy

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

Pimozide versus any other antipsychotic [6]
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. [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]

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]
ProteinKi (nM) [12] Notes
5-HT1A 650
5-HT2A 48.4This 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 0.5Relatively high affinity for this receptor may explain its supposed antidepressant-like effects in animal models of depression. [13]
α1A 197.7Low 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 1,955This 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 0.33Likely 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 18May be responsible for pimozide's high liability for prolonging the QT interval. [14]
H1 692Likely responsible for why pimozide tends to produce so little sedation. [14]
σ 508
Pharmacokinetic data [8] [7] [9] [10]
Pharmacokinetic parameterValue
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 pathwaysUrine

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

Notes

  1. A lower Ki value indicates a stronger binding

Related Research Articles

<span class="mw-page-title-main">Antipsychotic</span> Class of medications

Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis, principally in schizophrenia but also in a range of other psychotic disorders. They are also the mainstay together with mood stabilizers in the treatment of bipolar disorder.

<span class="mw-page-title-main">Haloperidol</span> Typical antipsychotic medication

Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosis, and hallucinations from alcohol withdrawal. It may be used by mouth or injection into a muscle or a vein. Haloperidol typically works within 30 to 60 minutes. A long-acting formulation may be used as an injection every four weeks by people with schizophrenia or related illnesses, who either forget or refuse to take the medication by mouth.

<span class="mw-page-title-main">Atypical antipsychotic</span> Class of pharmaceutical drugs

The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs largely introduced after the 1970s and used to treat psychiatric conditions. Some atypical antipsychotics have received regulatory approval for schizophrenia, bipolar disorder, irritability in autism, and as an adjunct in major depressive disorder.

<span class="mw-page-title-main">Quetiapine</span> Atypical antipsychotic medication

Quetiapine, sold under the brand name Seroquel among others, is an atypical antipsychotic medication used for the treatment of schizophrenia, bipolar disorder, borderline personality disorder, and major depressive disorder. Despite being widely used as a sleep aid due to its sedating effect, the benefits of such use do not appear to generally outweigh the side effects. It is taken orally.

<span class="mw-page-title-main">Ziprasidone</span> Antipsychotic medication

Ziprasidone, sold under the brand name Geodon among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It may be used by mouth and by injection into a muscle (IM). The IM form may be used for acute agitation in people with schizophrenia.

<span class="mw-page-title-main">Olanzapine</span> Atypical antipsychotic medication

Olanzapine is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is taken by mouth or by injection into a muscle.

<span class="mw-page-title-main">Perphenazine</span> Antipsychotic medication

Perphenazine is a typical antipsychotic drug. Chemically, it is classified as a piperazinyl phenothiazine. Originally marketed in the United States as Trilafon, it has been in clinical use for decades.

<span class="mw-page-title-main">Sertindole</span> Antipsychotic medication

Sertindole, sold under the brand name Serdolect among others, is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

<span class="mw-page-title-main">Amisulpride</span> Atypical antipsychotic and antiemetic medication

Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys and Solian, Socian, Deniban and others. At very low doses it is also used to treat dysthymia.

<span class="mw-page-title-main">Sulpiride</span> Atypical antipsychotic

Sulpiride, sold under the brand name Dogmatil among others, is an atypical antipsychotic medication of the benzamide class which is used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and sometimes used in low dosage to treat anxiety and mild depression. Sulpiride is commonly used in Asia, Central America, Europe, South Africa and South America. Levosulpiride is its purified levo-isomer and is sold in India for similar purpose. It is not approved in the United States, Canada, or Australia. The drug is chemically and clinically similar to amisulpride.

<span class="mw-page-title-main">Droperidol</span> Antidopaminergic drug

Droperidol is an antidopaminergic drug used as an antiemetic and as an antipsychotic. Droperidol is also often used as a rapid sedative in intensive-care treatment, and where "agitation aggression or violent behavior" are present.

<span class="mw-page-title-main">Flupentixol</span> Typical antipsychotic drug of the thioxanthene class

Flupentixol (INN), also known as flupenthixol, marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. It was introduced in 1965 by Lundbeck. In addition to single drug preparations, it is also available as flupentixol/melitracen—a combination product containing both melitracen and flupentixol . Flupentixol is not approved for use in the United States. It is, however, approved for use in the UK, Australia, Canada, Russian Federation, South Africa, New Zealand, Philippines, Iran, Germany, and various other countries.

<span class="mw-page-title-main">Zotepine</span> Chemical compound

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<span class="mw-page-title-main">Asenapine</span> Medication to treat schizophrenia

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<span class="mw-page-title-main">Melperone</span> Antipsychotic drug

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Rabbit syndrome is a rare form of extrapyramidal side effect of antipsychotic drugs in which perioral tremors occur at a rate of approximately 5 Hz. Rabbit syndrome is characterized by involuntary, fine, rhythmic motions of the mouth along a vertical plane, without involvement of the tongue, and resembling the chewing movements of a rabbit. It is usually seen after years of pharmacotherapy, and is more prominent with high potency drugs like haloperidol, fluphenazine, and pimozide. There is also a low incidence with thioridazine, clozapine, olanzapine, aripiprazole, and low doses of risperidone.

<span class="mw-page-title-main">Perospirone</span> Chemical compound that acts as an atypical antipsychotic

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References

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  4. Meehan WJ, Badreshia S, Mackley CL (March 2006). "Successful treatment of delusions of parasitosis with olanzapine". Archives of Dermatology. 142 (3): 352–355. doi:10.1001/archderm.142.3.352. PMID   16549712.
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