indication

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

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).

mechanism of action

The ability of pimozide to suppress motor and phonic tics in Tourette's Disorder is thought to be primarily a function of its dopaminergic blocking activity. Pimozide binds and inhibits the dopamine D2 receptor in the CNS.

toxicity

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

biotransformation

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.

absorption

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

half life

29 ± 10 hours (single-dose study of healthy volunteers).

drug interactions

Amprenavir: Amprenavir may increase the effect and toxicity of pimozide.

Aprepitant: Increased risk of cardiotoxicity and arrhythmias

Artemether: Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.

Atazanavir: The protease inhibitor, atazanavir, may increase the effect and toxicity of pimozide.

Citalopram: The SSRI, citalopram, may increase the effect and toxicity of pimozide.

Clarithromycin: Increased risk of cardiotoxicity and arrhythmias

Donepezil: Possible antagonism of action

Erythromycin: Increased risk of cardiotoxicity and arrhythmias

Escitalopram: The SSRI, escitalopram, increases the effect and toxicity of pimozide.

Fluconazole: Increased risk of cardiotoxicity and arrhythmias

Fosamprenavir: Amprenavir increases the effect and toxicity of pimozide

Galantamine: Possible antagonism of action

Imatinib: Imatinib may increase the effect and toxicity of pimozide.

Indinavir: The protease inhibitor, indinavir, may increase the effect and toxicity of pimozide.

Itraconazole: Increased risk of cardiotoxicity and arrhythmias

Josamycin: Increased risk of cardiotoxicity and arrhythmias

Ketoconazole: Increased risk of cardiotoxicity and arrhythmias

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy is contraindicated.

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Nefazodone: Nefazodone may increase the effect and toxicity of pimozide.

Nelfinavir: Nelfinavir increases the effect and toxicity of pimozide

Paroxetine: Increased risk of cardiotoxicity and arrhythmias.

Posaconazole: Contraindicated co-administration

Ritonavir: The protease inhibitor, ritonavir, may increase the effect and toxicity of pimozide.

Rivastigmine: Possible antagonism of action

Saquinavir: The protease inhibitor, saquinavir, may increase the effect and toxicity of pimozide.

Sertraline: The SSRI, sertraline, increases the effect and toxicity of pimozide.

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Pimozide, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Telithromycin: Telithromycin may reduce clearance of Pimozide. Concomitant therapy is contraindicated.

Tetrabenazine: May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Tipranavir: Tipranavir, co-administered with Ritonavir, may increase the plasma concentration of Pimozide. Concomitant therapy is contraindicated.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Trimethobenzamide: Trimethobenzamide and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Troleandomycin: Increased risk of cardiotoxicity and arrhythmias

Trospium: Trospium and Pimozide, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of pimozide by decreasing its metabolism. Increased risk of QTc prolongation and development arrhythmias. Concomitant use is contraindicated.

Vorinostat: Additive QTc prolongation may occur. Concomitant therapy is contraindicated.

Zileuton: Increased risk of cardiotoxicity and arrhythmias

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.

Zuclopenthixol: Additive QTc-prolonging effects increases risk of cardiac arrhythmias. Concomitant therapy is contraindicated.