indication

For the management of psychotic disorders (eg. schizophrenia) and delirium, as well as to control tics and vocal utterances of Tourette's syndrome (Gilles de la Tourette's syndrome). Also used for the treatment of severe behavioural problems in children with disrubtive behaviour disorder or ADHD (attention-deficit hyperactivity disorder). Haloperidol has been used in the prevention and control of severe nausea and vomiting.

pharmacology

Haloperidol is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Haloperidol principal pharmacological effects are similar to those of piperazine-derivative phenothiazines. The drug has action at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Haloperidol has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity.

mechanism of action

The precise mechanism whereby the therapeutic effects of haloperidol are produced is not known, but the drug appears to depress the CNS at the subcortical level of the brain, midbrain, and brain stem reticular formation. Haloperidol seems to inhibit the ascending reticular activating system of the brain stem (possibly through the caudate nucleus), thereby interrupting the impulse between the diencephalon and the cortex. The drug may antagonize the actions of glutamic acid within the extrapyramidal system, and inhibitions of catecholamine receptors may also contribute to haloperidol's mechanism of action. Haloperidol may also inhibit the reuptake of various neurotransmitters in the midbrain, and appears to have a strong central antidopaminergic and weak central anticholinergic activity. The drug produces catalepsy and inhibits spontaneous motor activity and conditioned avoidance behaviours in animals. The exact mechanism of antiemetic action of haloperidol has also not been fully determined, but the drug has been shown to directly affect the chemoreceptor trigger zone (CTZ) through the blocking of dopamine receptors in the CTZ.

toxicity

LD₅₀=165 mg/kg (rats, oral)

biotransformation

Hepatic

absorption

Oral-60%

half life

3 weeks

drug interactions

Anisotropine Methylbromide: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atomoxetine: The CYP2D6 inhibitor could increase the effect and toxicity of atomoxetine

Atropine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Benzatropine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Biperiden: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Carbamazepine: Carbamazepine may decrease the serum concentration of haloperidol by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of haloperidol if carbamazepine is initiated, discontinued or dose changed.

Clidinium: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Clozapine: Clozapine, a moderate CYP2D6 inhibitor, may increase the serum concentration of haloperidol by decreasing its metabolism. Additive CNS despresant and anticholinergic effects may also occur. Monitor for changes in the therapeutic and adverse effects of haloperidol if clozapine is initiated, discontinued or dose changed. Also monitor for increased CNS depressant and anticholinergic effects during concomitant therapy.

Dicyclomine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Ethopropazine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Fluconazole: Fluconazole may increase the effect and toxicity of haloperidol.

Glycopyrrolate: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Guanethidine: Haloperidol may decrease the effect of guanethidine.

Homatropine Methylbromide: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Hyoscyamine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Isopropamide: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Itraconazole: Itraconazole may increase the effect and toxicity of haloperidol.

Ketoconazole: Ketoconazole may increase the effect and toxicity of haloperidol.

Lithium: Possible extrapyramidal effects and neurotoxicity with this combination

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mepenzolate: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Methantheline: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Methyldopa: Methyldopa increases haloperidol effect or risk of psychosis

Orphenadrine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Oxyphencyclimine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Procyclidine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Propantheline: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Propranolol: Increased effect of both drugs

Rifabutin: The rifamycin decreases the effect of haloperidol

Rifampin: The rifamycin decreases the effect of haloperidol

Scopolamine: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Haloperidol, 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.

Tamoxifen: Haloperidol may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Haloperidol, a CYP3A4/2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP3A4/2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Haloperidol is initiated, discontinued, or dose changed.

Telithromycin: Telithromycin may reduce clearance of Haloperidol. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Haloperidol if Telithromycin is initiated, discontinued or dose changed.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Haloperidol. Consider alternate therapy or monitor for therapeutic/adverse effects of Haloperidol if Terbinafine is initiated, discontinued or dose changed.

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.

Tolterodine: Haloperidol may decrease the metabolism and clearance of Tolterodine. Adjust Tolterodine dose and monitor for efficacy and toxicity.

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.

Tramadol: Haloperidol may increase Tramadol toxicity by decreasing Tramadol metabolism and clearance. Haloperidol may decrease the effect of Tramadol by decreasing active metabolite production.

Trazodone: The CYP3A4 inhibitor, Haloperidol, may increase Trazodone efficacy/toxicity by decreasing Trazodone metabolism and clearance. The CYP2D6 inhibitor, Trazodone, may increase the efficacy of Haloperidol by decreasing Haloperidol metabolism and clearance. Monitor for changes in Trazodone and Haloperidol efficacy/toxicity if either agent is initiated, discontinued or dose changed.

Tridihexethyl: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Trihexyphenidyl: The anticholinergic increases the risk of psychosis and tardive dyskinesia

Trimethobenzamide: Trimethobenzamide and Haloperidol, 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 Haloperidol, 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.

Trospium: Trospium and Haloperidol, 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 haloperidol by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of haloperidol if voriconazole is initiated, discontinued or dose changed.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).