Pimozide

Absorption

Greater than 50% absorption after oral administration. Serum peak appears 6-8 hours post ingestion.

Toxicity

LD50 = 1100 mg/kg (rat, oral), 228 mg/kg (mouse, oral)

Description

Pimozide is a dopamine receptor antagonist (Kis = 2.4, 0.3, and 1.8 nM for D2, D3, and D4 receptors, respectively). It also binds to eight additional receptors (Kds = 25-3,100 nM for the human receptors) and inhibits the voltage-gated sodium channel Nav1.2 and the voltage-gated potassium channel Kv11.1 (IC50s = 42 and 340 nM, respectively). Pimozide (0.5, 1, and 2 mg/kg) decreases the number of licks and reduces fluid intake of a sweetened solution in rats. It decreases the number of threats and attacks and increases immobility time in the neutral arena aggression test, indicating increased passiveness, in male mice when administered at a dose of 0.75 mg/kg for 10 days. Formulations containing pimozide have been used in the treatment of Tourette syndrome.

Chemical properties

White or almost white powder.

Originator

Orap ,Janssen, W. Germany ,1971

The Uses of Pimozide

Pimozide is a D2 dopamine receptor antagonist that binds to the cloned 5-HT7 receptor with high affinity (1,2,3,4). Pimozide is also a Ca2+ channel antagonist. Pimozide is used as an antipsychotic.

The Uses of Pimozide

Used for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.

Background

A diphenylbutylpiperidine that is effective as an antipsychotic agent and as an alternative to haloperidol for the suppression of vocal and motor tics in patients with Tourette syndrome. Although the precise mechanism of action is unknown, blockade of postsynaptic dopamine receptors has been postulated. (From AMA Drug Evaluations Annual, 1994, p403)

Indications

Used for the suppression of motor and phonic tics in patients with Tourette's Disorder who have failed to respond satisfactorily to standard treatment.

What are the applications of Application

Pimozide is a D2DR, SR-7, and calcium channel protein inhbitor

Definition

ChEBI: Pimozide is a member of the class of benzimidazoles that is 1,3-dihydro-2H-benzimidazol-2-one in which one of the nitrogens is substituted by a piperidin-4-yl group, which in turn is substituted on the nitrogen by a 4,4-bis(p-fluorophenyl)butyl group. It has a role as a H1-receptor antagonist, a serotonergic antagonist, a first generation antipsychotic, an antidyskinesia agent and a dopaminergic antagonist. It is a member of benzimidazoles, an organofluorine compound and a heteroarylpiperidine.

brand name

Orap (Teva).

General Description

Pimozide, 1-[1-[4,4-bis(p-fluorophenyl)butyl]-4-piperidyl]-2-benzimidazolinone (Orap), isa white to creamy white solid (pK_a＝9.42). Pimozide is 50%absorbed after oral administration. It is metabolized byCYP450 enzymes, in particular the CYP3A4 and CYP1A2isozymes, to inactive metabolites. Pimozide is excreted in theurine and to a lesser extent in the feces. Toxic effects may beproduced with pimozide in the presence of inducers or inhibitorsof CYP3A4 and CYP1A2. Pimozide is also a stronginhibitor of CYP2D6 without appearing to be an importantsubstrate of this isoform.99 The use of pimozide in the UnitedStates is small, but it is a critical drug for many patients withGilles de la Tourette disorder who cannot tolerate haloperidol.

Biological Activity

Dopamine D 2 -receptor antagonist and antipsychotic which binds with very high affinity to the cloned rat 5-HT 7 receptor (K i = 0.5 nM).

Biochem/physiol Actions

D2 dopamine receptor antagonist; binds with high affinity to the cloned 5-HT7 receptor; Ca2+ channel antagonist; antipsychotic

Pharmacokinetics

Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol).

Pharmacology

Pimozide is an orally active antipsychotic drug product which shares with other antipsychotics the ability to blockade dopaminergic receptors on neurons in the central nervous system. However, receptor blockade is often accompanied by a series of secondary alterations in central dopamine metabolism and function which may contribute to both pimozide's therapeutic and untoward effects. In addition, pimozide, in common with other antipsychotic drugs, has various effects on other central nervous system receptor systems which are not fully characterized. Pimozide also has less potential for inducing sedation and hypotension as it has more specific dopamine receptor blocking activity than other neuroleptic agents (and is therefore a suitable alternative to haloperidol).

Synthesis

Pimozide, 1-[1-[4,4-bis-(p-fluorophenyl)butyl]-4-piperidyl]-2-benzymidazolinone (6.6.5), is structurally very similar to droperidol with the exception of the presence of a double bond in the piperidine ring and the substitution of a p-fluorobutyrophenone group on the nitrogen atom of the piperidine ring with a 4,4-bis-(p-fluorophenyl)-butyl radical. 4,4-bis-(p-fluorophenyl)-butylchloride (bromide) (6.6.3), which is needed for the synthesis of pimozide as well as fluspirylene and penfluridol, is synthesized by reacting of two moles of 4-p-fluorophenylmagnesiumbromide with cyclopropancarboxylic acid ester, which results in the formation of bis-(4-p-fluorophenyl)cyclopropylcarbinol (6.6.1). Treatment of this with thionyl chloride (phosphorous tribromide) leads to opening of the cyclopropyl ring, forming 1,1-bis-(4-fluorophenyl)-4-chloro(bromo)-1- butene (6.6.2). Reduction of the double bond using hydrogen over a palladium catalyst leads to the formation of 1,1-bis-(4-fluoro- phenyl)butyl chloride (bromide) (6.6.3) [60–63].

in vitro

pimozide displayed high affinity for dopamine receptors. the ki values for d2, d3, and d4 were 2.4, 0.2, and 1.8 nm, respectively [3].

in vivo

in hungry rats, pimozide attenuated lever-pressing and running for food reward. pimozide pretreatment attenuated acquisition of a lever-pressing habit motivated by food reward in a dose-dependent manner[4]. in 31 male wistar rats self-administering cocaine, pimozide caused a dose-dependent (0.0625–0.5 mg/kg) acceleration of responding [5].

Drug interactions

Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect.
Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; increased risk of ventricular arrhythmias with methadone.
Anti-arrhythmics: increased risk of ventricular arrhythmias with anti-arrhythmics that prolong the QT interval - avoid with amiodarone and disopyramide (risk of ventricular arrhythmias).
Antibacterials: avoid with macrolides and moxifloxacin (increased risk of ventricular arrhythmias).
Antidepressants: concentration increased by SSRIs - avoid; increased risk of ventricular arrhythmias with SSRIs and tricyclics - avoid; increased risk of ventricular arrhythmias with delamanid.
Antiepileptics: antagonises anticonvulsant effect.
Antifungals: avoid with imidazoles and triazoles - risk of ventricular arrhythmias.
Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol; increased risk of ventricular arrhythmias with mefloquine and quinine - avoid.
Antipsychotics: increased risk of ventricular arrhythmias with droperidol, phenothiazines, risperidone or sulpiride - avoid; concentration possibly increased by lurasidone.
Antivirals: concentration increased by atazanavir, boceprevir, efavirenz, fosamprenavir, indinavir, ritonavir, saquinavir and telaprevir, increased risk of ventricular arrhythmias - avoid.
Anxiolytics and hypnotics: increased sedative effects.
Aprepitant: avoid concomitant use.
Atomoxetine: increased risk of ventricular arrhythmias.
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Cobicistat: concentration possibly increased by cobicistat - avoid.
Cytotoxics: use crizotinib with caution; avoid with lapatinib and idelalisib; increased risk of ventricular arrhythmias with panobinostat and vandetanib - avoid; increased risk of ventricular arrhythmias with arsenic trioxide.
Diuretics: increased risk of ventricular arrhythmias due to hypokalaemia.
Fosaprepitant: avoid concomitant use.
Grapefruit juice: avoid concomitant use.
Ivabradine: increased risk of ventricular arrhythmias.

Metabolism

Notable first-pass metabolism in the liver, primarily by N-dealkylation via the cytochrome P450 isoenzymes CYP3A and CYP1A2 (and possibly CYP2D6). The activity of the two major metabolites has not been determined.

Metabolism

Pimozide is metabolised in the liver via the cytochrome P450 isoenzyme CYP3A4 and to a lesser extent by CYP2D6 mainly by N-dealkylation and excreted in the urine and faeces in the form of metabolites and unchanged drug.

storage

Store at RT

References

[1] janssen p a, niemegeers c j, schellekens k h, et al. pimozide, a chemically novel, highly potent and orally long-acting neuroleptic drug. i. the comparative pharmacology of pimozide, haloperidol, and chlorpromazine[j]. arzneimittel-forschung, 1968, 18(3): 261-279.
[2] beaulieu j m, gainetdinov r r. the physiology, signaling, and pharmacology of dopamine receptors[j]. pharmacological reviews, 2011, 63(1): 182-217.
[3] burstein e s, ma j, wong s, et al. intrinsic efficacy of antipsychotics at human d2, d3, and d4 dopamine receptors: identification of the clozapine metabolite n-desmethylclozapine as a d2/d3 partial agonist[j]. journal of pharmacology and experimental therapeutics, 2005, 315(3): 1278-1287.
[4] wise r a, schwartz h v. pimozide attenuates acquisition of lever-pressing for food in rats[j]. pharmacology biochemistry and behavior, 1981, 15(4): 655-656.
[5] de wit h, wise r a. blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine[j]. canadian journal of psychology/revue canadienne de psychologie, 1977, 31(4): 195.
[6] opler l a, feinberg s s. the role of pimozide in clinical psychiatry: a review[j]. journal of clinical psychiatry, 1991.