Haldol Drops Mechanism of Action

ATC Code: N05AD01.
Pharmacology: Pharmacodynamics: Haloperidol is a neuroleptic, belonging to the group of the butyrophenones. Haloperidol is a potent central dopamine receptor antagonist and, therefore, is classified among the very incisive neuroleptics. Haloperidol has no antihistaminergic or anticholinergic activity.
As a direct consequence of the central dopamine blocking effect, haloperidol has an incisive activity on delusions and hallucinations (probably due to an interaction in the mesocortical and limbic tissues) and an activity on the basal ganglia (nigrostriatal bundles). Haloperidol causes efficient psychomotor sedation, which explains the favourable effect on mania and other agitation syndromes (see Indications/Uses).
On the basis of its limbic activity, haloperidol exerts a neuroleptic sedative activity and has been shown to be useful as an adjuvant in the treatment of chronic pain.
The activity on the basal ganglia probably underlies the extrapyramidal motor side effects (dystonia, akathisia and parkinsonism).
The more peripheral antidopaminergic effects explain the activity against nausea and vomiting (via the chemoreceptor-trigger zone), the relaxation of the gastro-intestinal sphincters and the increased prolactin release (through an inhibition of the activity of the prolactin inhibiting factor, PIF, at the level of the adenohypophysis).
Pharmacokinetics: Absorption: Following oral administration, the bioavailability of the drug is 60 to 70%. Peak plasma levels of haloperidol occur within two to six hours of oral dosing and about twenty minutes after intramuscular administration.
Distribution: Plasma protein binding is 92%. The volume of distribution at steady state (VDss) is large (7.9 ± 2.5 L/kg). Haloperidol crosses the blood-brain barrier easily.
Metabolism: Haloperidol is metabolized by several routes including the cytochrome P450 enzyme system (particularly CYP3A4 or CYP2D6) and glucuronidation.
Elimination: The mean plasma half-life (terminal elimination) is 24 hours (range 12 to 38 hours) after oral administration and 21 hours (range 13 to 36 hours) after intramuscular administration. Excretion occurs with the faeces (60%) and the urine (40%). About 1% of the ingested haloperidol is excreted unchanged with the urine.
Therapeutic Concentrations: It has been suggested that a plasma haloperidol concentration range from 4 μg/L to an upper limit of 20 to 25 μg/L is required for a therapeutic response.
Toxicology: Preclinical Safety Data: Nonclinical data reveal no special hazards for humans based on conventional studies of repeat dose toxicity, genotoxicity and carcinogenicity. In rodents, haloperidol administration showed a decrease in fertility, limited teratogenicity as well as embryo-toxic effects.
Haloperidol has been shown to block the cardiac hERG channel in several published studies in vitro. In a number of in vivo studies intravenous administration of haloperidol in some animal models has caused significant QTc prolongation, at doses around 0.3 mg/kg i.v., giving C_max plasma levels 3 to 7 times higher than the effective human plasma concentrations of 4 to 20 ng/ml. These intravenous doses which prolonged QTc did not cause arrhythmias. In some studies higher intravenous doses of 1 to 5 mg/kg haloperidol i.v. caused QTc prolongation and/or ventricular arrhythmias at C_max plasma levels 19 to 68 times higher than the effective human plasma concentrations.