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DEA NFLIS-Drug Category -> Depressants and Tranquilizers

Pharmaceuticals -> Antipsychotics

Pharmaceuticals

Pharmaceuticals -> Nervous system -> Antipsychotics

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Antipsychotics

log Kow = 4.30

4

3.23

Crystals

WHITE TO FAINTLY YELLOWISH, AMORPHOUS OR MICRO-CRYSTALLINE POWDER

Crystals; mp 226-227.5 °C; sol in water at 300X10+1 mg/L /Hydrochloride/

In water, 1.4X10+1 mg/L @ 25 °C

16.7 mg/ml in alcohol at 25 °C

Freely sol in chloroform, methanol, acetone, benzene, dil acids

4.46e-03 g/L

Breast Feeding; Lactation; Milk, Human; Antipsychotic Agents; Butyrophenones

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Medicines for other common symptoms in palliative care

151.5 °C

151.5 °C

Positive

4.26592454

2.7

Thermo LTQ

Electrospray ionization

formic acid (5.3nM)

8.65

8.65

8.65

8.5

8.66

pKa= 8.66

200.2 Ų [M+Na]+ [CCS Type: DT; Buffer gas: N2; Ionization: ESI+; Dataset: TOXCAST; Source Identifier: DTXSID4034150]

193.7 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

185.12 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

191.7 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

193.9 Ų [M+H]+ [CCS Type: TW]

194.1 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]

This chemical does not meet GHS hazard criteria for 2.4% (2 of 85) of reports.

Danger

H301 (97.6%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P261, P264, P264+P265, P270, P271, P272, P280, P301+P316, P302+P352, P304+P340, P305+P351+P338, P318, P319, P321, P330, P332+P317, P333+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 85 reports by companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

Hazard Traits - Developmental Toxicity; Reproductive Toxicity

Haloperidol: Does not have an individual approval but may be used under an appropriate group standard

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl haloperidol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Jann MW, Richards AL; US Pharm 10 (Jan): PH1-5, H9, H12-H13 (1985). A review of the pharmacology, pharmacokinetics, dosage and side effects of haloperidol, loxapine, thiothixene and fluphenazine is presented along with the role of clinical pharmacists in the appropriate use and selection of antipsychotics in emergency medical situations and psychiatric crises.

Markowitz JC, Brown RP; Gen Hosp Psychiatry 9 (2): 135-41 (1987). The authors review the literature associating neuroleptic and antidepressant medications with seizures, discussing the relative "seizurogenicity" of different medications, risk factors for seizures, and drugs of choice for high-risk patients. Case histories are presented.

Acute Tox. 3 (97.6%)

Acute toxicity (Oral) - Category 4

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established by use of an oropharyngeal airway or endotracheal tube or, in prolonged cases of coma, by tracheostomy. Respiratory depression may be counteracted by artificial respiration and mechanical respirators. Hypotension and circulatory collapse may be counteracted by use of intravenous fluids, plasma, or concentrated albumin, and vasopressor agents such as metaraminol, phenylephrine and norepinephrine. Epinephrine should not be used. In case of severe extrapyramidal reactions, anti-Parkinson medication should be administered. ECG and vital signs should be monitored especially for signs of Q-T prolongation or dysrhythmias and monitoring should continue until the ECG is normal. Severe arrhythmias should be treated with appropriate anti-arrhythmic measures. (L1712)

Prior administration of haloperidol may decrease the pressor response to phenylephrine because of the alpha-adrenergic blocking action of haloperidol.

Prior administration of haloperidol may decrease the pressor effect and duration of action of methoxamine because of the alpha-adrenergic blocking action of haloperidol.

Concurrent use /of metaraminol/ with haloperidol usually decreases, but does not reverse or completely block, the pressor response to metaraminol, because of the alpha-adrenergic blocking action of haloperidol.

Concurrent use /with levodopa or pergolide/ may decrease the therapeutic effects of these agents because of blockade of dopamine receptors by haloperidol.

For more Interactions (Complete) data for HALOPERIDOL (26 total), please visit the HSDB record page.

Tachycardia, hypotension, and hypertension; Extrapyramidal Symptoms (EPS) such as akathisia, or dystonia; impaired liver function and/or jaundice have been reported. Maculopapular and acneiform skin reactions and isolated cases of photosensitivity and loss of hair.Laryngospasm, bronchospasm, cataracts, retinopathy and visual disturbances; lactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia (RxList, A308).

Liver test abnormalities have been reported to occur in 20% of patients on long term therapy with haloperidol, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. Instances of clinically apparent acute liver injury have been reported due to haloperidol, but they are uncommon. The onset of jaundice is within 2 to 6 weeks, and the pattern of serum enzyme elevations is typically cholestatic or mixed. Signs of hypersensitivity (fever, rash and eosinophilia) have been reported in some cases, but they are usually mild and self-limited; autoantibodies are rare.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5,200(SRC), determined from a log Kow of 4.30(2) and a regression-derived equation(3), indicates that haloperidol is expected to be immobile in soil(SRC). Volatilization of haloperidol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.3X10-14 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Haloperidol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.8X10-11 mm Hg(SRC), determined from a fragment constant method(5).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5,200(SRC), determined from a log Kow of 4.3(2) and a regression-derived equation(3), indicates that haloperidol is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.3X10-14 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The pKa of haloperidol is 8.66(5), indicating that this compound will exist primarily in the protonated form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(6). According to a classification scheme(7), an estimated BCF of 59(SRC), from its log Kow(2) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), haloperidol, which has estimated vapor pressure of 4.8X10-11 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase haloperidol may be removed from the air by wet and dry deposition(SRC).

IDENTIFICATION: Haloperidol is an antipsychotic agent. Haloperidol is a synthetic product. Haloperidol is the first of the butyrophenone series of major tranquillizers. Haloperidol is indicated for use in the management of manifestations of psychotic disorders such as schizophrenia and mania. It is indicated for the control of tics and vocal utterances of Tourette's Disorder in children and adults. It is effective for the treatment of severe behaviour problems in children of combative, explosive hyperexcitability. It is also used in the management of Gilles de La Tourette's syndrome, intractable hiccup and as an anti-emetic. HUMAN EXPOSURE: Main risks and target organs: The main features of severe overdosage are extrapyramidal reactions, hypotension, respiratory difficulty and impairment of consciousness. Haloperidol acts mainly as a dopamine antagonist. Summary of clinical effects: Consciousness may be depressed, progressing to coma; paradoxically, some patients manifest confusion, excitement and restlessness. Tremor or muscle twitching, muscle spasm, rigidity and convulsions are seen. Extrapyramidal signs can include dystonia, sometimes severe enough to impair swallowing or breathing; torticollis, oculogyric crises and opisthotonos. The pupils may be constricted or dilated. Hypotension and tachycardia are common. Sometimes there can be cardiac arrhythmias, including ventricular fibrillation, conduction defects and cardiac arrest. Contraindications: Severe dystonic reactions have followed the use of haloperidol, particularly in children and adolescents. It should therefore be used with extreme care in children. Haloperidol may also cause severe neurotoxic reactions in patients with hyperthyroidism and in patients receiving lithium. Haloperidol is contraindicated in severe toxic central nervous system depression or comatose states from any cause and individuals who are hypersensitive to this drug or have Parkinson's disease. Also contraindicated in late pregnancy because of dystonic reaction in the neonate. Infants should not be nursed during drug treatment. Routes of entry: Oral: It is the main route of administration. Parenteral: Through intravenous and intramuscular injection. Absorption by route of exposure: Haloperidol is readily absorbed from the gastrointestinal tract. Owing to the first-pass effect of metabolism in the liver, plasma concentrations following oral administration are lower than those following intramuscular administration. There is wide intersubject variation in plasma concentration of haloperidol and its therapeutic effects. The decanoate ester of haloperidol is very slowly absorbed from the site of injection and is therefore suitable for depot injection. It is gradually released into the bloodstream where it is rapidly hydrolysed to haloperidol. Distribution by route of exposure: Haloperidol is very extensively bound to plasma proteins (90%). It is widely distributed in body and crosses the bloodbrain barrier. Biological half-life by route of exposure: The plasma half-life in therapeutic doses is reported to range from about 13 to nearly 40 hours (Reynolds, 1989), with a mean of 20 hours. Metabolism: Haloperidol is metabolized in the liver and the paths of metabolism include oxidative N-dealkylation. Elimination by route of exposure: This rate of total systemic clearance increases in children and decreases in aged patients. After metabolism, haloperidol is excreted in the urine, via the bile and in the feces, there is evidence of enterohepatic recycling by 40%. About 26% was excreted in the urine by the healthy subjects and 20% by the patients in the first 5 days; by the third day about 15% had been excreted in the feces. It takes 28 days to fully eliminate a single oral dose. Mode of action: Pharmacodynamics: Dopamine receptors currently are classified as D-1(stimulate adenylate cyclase) and D-2(inhibit adenylate cyclase). Neuroleptic drugs block both D-1 and D-2 receptors but the significance of the ratio remains unclear. The therapeutic dose of neuroleptic drug appears to correlate with its affinity for brain dopamine D-2 receptors. Neuroleptic drugs also block a number of other receptors including H1 and H2 histamine, alfa 1 and alfa 2 adrenergic, muscarinic and serotoninergic receptors. Toxicity: Human data: Three cases of sudden death after taking 20 to 140 mg daily for one to four days. Children: A 29-month-old girl and an 11 month old boy who divided 265 mg of haloperidol between them developed lethargy, hypothermia, hyperreflexia, neuromuscular rigidity, unsteady gait and intention tremors. Although disturbances such as galactorrhea, amenorrhea, gynaecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. There are no well controlled studies with haloperidol in pregnant women. There are reports, however, of cases of limb malformations observed following maternal use of haloperidol along with other drugs which have suspected teratogenic potential during the first trimester of pregnancy. Causal relationships were not established in these cases. Since such experience does not exclude the possibility of fetal damage due to haloperidol; this drug should be used during pregnancy or in women likely to become pregnant only if the benefit clearly justifies a potential risk to the fetus. Interactions: The use of alcohol with this drug should be avoided due to possible additive effects and hypotension. An encephalopathic syndrome (characterised by weakness, lethargy, fever, tremulousness and confusion, extrapyramidal symptoms, leucocytosis, elevated serum enzymes, BUN, and FBS) followed by irreversible brain damage has occurred in a few patients treated with lithium plus haloperidol. A casual relationship between these events and the concomitant administration of lithium and haloperidol has not been established; however, patients receiving such combination therapy should be monitored closely for early evidence of neurological toxicity and treatment discontinued promptly if such signs appear (Physician's Desk Reference, 1987). Other reported interactions involve the following drugs and adverse effects: Beta-blockers: Severe hypotension or pulmonary arrest. Methyldopa: Dementia, psychomotor retardation, memory impairment and inability to concentrate. Indomethacin: Severe drowsiness and confusion. Main adverse effects: In general, the symptoms of overdose would be an exaggeration of known pharmacological effects and adverse reactions. Anticholinergic side effects and sedation occur less often than with aliphatic phenothiazines, but extrapyramidal reactions are more common. Administration of antidopaminergic and anticholinergics may worsen or bring forward the onset of extrapyramidal effects. Idiosyncratic reaction producing severe drowsiness when used with indomethacin. ANIMAL/PLANT STUDIES: Carcinogenicity: Carcinogenicity studies using oral haloperidol were conducted in Wistar rats and in Albino Swiss mice. In the rat study, survival was less than optimal in all dose groups, reducing the number of rats at risk for developing tumors. However, although a relatively greater number of rats survived to the end of the study in high dose male and female groups, these animals did not have a greater incidence of tumors than control animals. Therefore, although not optimal, this study does suggest the absence of haloperidol related increase in the incidence of neoplasia in rats. In female mice there was a statistically significant increase in mammary gland neoplasia and total tumor incidence; there was a statistically significant increase in pituitary gland neoplasia. In male mice, no statistically significant differences in incidence of total tumors or specific tumor types were noted. Neuroleptic drugs elevate prolactin levels; the elevation persists during chronic administration. Teratogenicity: Rodents haloperidol by oral or parenteral routes showed an increase in incidence of resorption, reduced fertility, delayed delivery and pup mortality. No teratogenic effect has been reported in rats, rabbits or dogs at dosages within this range, but cleft palate has been observed in mice. Mutagenicity: No mutagenic potential of haloperidol was found in the Ames Salmonella microsomal activation assay.

Toxicities are the exaggerated symptoms of known pharmacological effects and adverse drug reactions. The most prominent toxicities of haloperidol are severe extrapyramidal symptoms, hypotension, and sedation. The patient may appear comatose with severe respiratory depression or shock from hypotension. The extrapyramidal symptoms include akathisia, rigidity, bradykinesia, tremor, and acute dystonia. Haloperidol overdose can cause torsades de pointes, a type of ECG change that leads to arrhythmia or cardiac arrest.

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.

The Koc of haloperidol is estimated as 5,200(SRC), using a log Kow of 4.3(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that haloperidol is expected to be immobile in soil. The pKa of haloperidol is 8.66(1), indicating that this compound will exist primarily in the protonated form in the environment and cations generally adsorb more strongly to organic carbon and clay than their neutral counterparts(4).

/SIGNS AND SYMPTOMS/ Laryngospasm, bronchospasm, and increased depth of respiration have occurred in patients receiving haloperidol. ... It has been suggested that lethargy and decreased thirst, resulting from central inhibition, may cause dehydration, hemoconcentration, and reduced pulmonary ventilation.

/SIGNS AND SYMPTOMS/ Tachycardia, hypotension, hypertension, and ECG changes, including those compatible with QT-interval prolongation and the polymorphous configuration of torsades de pointes, may occur in patients receiving haloperidol. ...

/SIGNS AND SYMPTOMS/ Neuroleptic malignant syndrome (NMS) may occur in patients receiving haloperidol or other antipsychotic therapy. NMS is potentially fatal and requires immediate discontinuance of the drug and initiation of intensive symptomatic and supportive care.

/SIGNS AND SYMPTOMS/ Overdose is associated with severe extrapyramidal symptoms, hypotension, and sedation. The risk of torsade de pointes should be considered.

For more Human Toxicity Excerpts (Complete) data for HALOPERIDOL (6 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl haloperidol, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N05AD01

N - Nervous system

QN - Nervous system

N05AD01

Use of the first-generation antipsychotics (including haloperidol) is considered highly effective for the management of the "positive" symptoms of schizophrenia including hallucinations, hearing voices, aggression/hostility, disorganized speech, and psychomotor agitation. However, this class is limited by the development of movement disorders such as drug-induced parkinsonism, akathisia, dystonia, and tardive dyskinesia, and other side effects including sedation, weight gain, and prolactin changes. Compared to the lower-potency first-generation antipsychotics such as [DB00477], [DB01624], [DB00623], and [DB01403], haloperidol typically demonstrates the least amount of side effects within class, but demonstrates a stronger disposition for causing extrapyramidal symptoms (EPS). Low‐potency medications have a lower affinity for dopamine receptors so that a higher dose is required to effectively treat symptoms of schizophrenia. In addition, they block many receptors other than the primary target (dopamine receptors), such as cholinergic or histaminergic receptors, resulting in a higher incidence of side effects such as sedation, weight gain, and hypotension. The balance between the wanted drug effects on psychotic symptoms and unwanted side effects are largely at play within dopaminergic brain pathways affected by haloperidol. Cortical dopamine-D2-pathways play an important role in regulating these effects and include the nigrostriatal pathway, which is responsible for causing extrapyramidal symptoms (EPS), the mesolimbic and mesocortical pathways, which are responsible for the improvement in positive schizophrenic symptoms, and the tuberoinfundibular dopamine pathway, which is responsible for hyperprolactinemia. A syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Cases of sudden death, QT-prolongation, and Torsades de Pointes have been reported in patients receiving haloperidol. Higher than recommended doses of any formulation and intravenous administration of haloperidol appear to be associated with a higher risk of QT-prolongation and Torsades de Pointes. Although cases have been reported even in the absence of predisposing factors, particular caution is advised in treating patients with other QT-prolonging conditions (including electrolyte imbalance [particularly hypokalemia and hypomagnesemia], drugs known to prolong QT, underlying cardiac abnormalities, hypothyroidism, and familial long QT-syndrome). A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

While haloperidol has demonstrated pharmacologic activity at a number of receptors in the brain, it exerts its antipsychotic effect through its strong antagonism of the dopamine receptor (mainly D2), particularly within the mesolimbic and mesocortical systems of the brain. Schizophrenia is theorized to be caused by a hyperdopaminergic state within the limbic system of the brain. Dopamine-antagonizing medications such as haloperidol, therefore, are thought to improve psychotic symptoms by halting this over-production of dopamine. The optimal clinical efficacy of antipsychotics is associated with the blockade of approximately 60 % - 80 % of D2 receptors in the brain. While the exact mechanism is not entirely understood, haloperidol is known to inhibit the effects of dopamine and increase its turnover. Traditional antipsychotics, such as haloperidol, bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. It is believed that haloperidol competitively blocks post-synaptic dopamine (D2) receptors in the brain, eliminating dopamine neurotransmission and leading to the relief of delusions and hallucinations that are commonly associated with psychosis. It acts primarily on the D2-receptors and has some effect on 5-HT2 and α1-receptors, with negligible effects on dopamine D1-receptors. The drug also exerts some blockade of α-adrenergic receptors of the autonomic system. Antagonistic activity regulated through dopamine D2 receptors in the chemoreceptive trigger zone (CTZ) of the brain renders its antiemetic activity. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs in direct relation to their clinical antipsychotic abilities. Clinical brain-imaging findings show that haloperidol remains tightly bound to D2 dopamine receptors in humans undergoing 2 positron emission tomography (PET) scans with a 24h pause in between scans. A common adverse effect of this drug is the development of extrapyramidal symptoms (EPS), due to this tight binding of haloperidol to the dopamine D2 receptor. Due to the risk of unpleasant and sometimes lifelong extrapyramidal symptoms, newer antipsychotic medications than haloperidol have been discovered and formulated. Rapid dissociation of drugs from dopamine D2 receptors is a plausible explanation for the improved EPS profile of atypical antipsychotics such as [DB00734]. This is also consistent with the theory of a lower affinity for D2 receptors for these drugs. As mentioned above, haloperidol binds tightly to the dopamine receptor, potentiating the risk of extrapyramidal symptoms, and therefore should only been used when necessary.

Haloperidol has less prominent autonomic effects than do other antipsychotic drugs. It has little anticholinergic activity ... it blocks activation of alpha receptors by sympathomimetic amines but is much less potent than chlorpromazine in this action.

Although the complex mechanism of the therapeutic effect is not clearly established, haloperidol is known to produce a selective effect on the central nervous system (CNS) by competitive blockade of postsynaptic dopamine (D2) receptors in the mesolimbic dopaminergic system and an increased turnover of brain dopamine to produce its tranquilizing effects. With subchronic therapy, depolarization blockade, or diminished firing rate of the dopamine neuron (decreased release) along with D2 postsynaptic blockade results in the antipsychotic action.

Following oral administration, the half-life was found to be 14.5-36.7 hours. Following intramuscular injection, mean half-life was found to be 20.7 hours.

10 MG Haloperidol IV and oral administration to healthy volunteers: serum T1/2 10-19 hr after IV and 12-38.3 hr after oral administration. Bioavailability in the order of 60%; distribution volume around 1300 L.

Haloperidol, Elimination: Oral: 24 hours (range 12 to 37 hours). Intramuscular: 21 hours (range, 17 to 25 hours). Intravenous: 14 hours (range, 10 to 19 hours). Haloperidol decanoate, Elimination: Approximately 3 weeks (single or multiple doses).

Haloperidol is extensively metabolised in the liver with only about 1% of the administered dose excreted unchanged in urine. In humans, haloperidol is biotransformed to various metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridinium metabolites, and haloperidol glucuronide. In psychiatric patients treated regularly with haloperidol, the concentration of haloperidol glucuronide in plasma is the highest among the metabolites, followed, in rank order, by unchanged haloperidol, reduced haloperidol and reduced haloperidol glucuronide. The drug is thought to be metabolized primarily by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming _hydroxyhaloperidol_. The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) including CYP3A4 and CYP2D6, carbonyl reductase and uridine di-phosphoglucose glucuronosyltransferase enzymes. The greatest proportion of the intrinsic hepatic clearance of haloperidol is performed by glucuronidation and followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of cytochrome-mediated disposition in vitro, CYP3A4 appears to be the major isoform of the enzyme responsible for the metabolism of haloperidol in humans. The intrinsic clearance of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude. This suggests that the same enzyme system is responsible for the above three metabolic reactions. In vivo human studies on haloperidol metabolism have shown that the glucuronidation of haloperidol accounts for 50 to 60% of haloperidol biotransformation and that approximately 23% of the biotransformation was accounted for by the reduction pathway. The remaining 20 to 30% ofthe biotransformation of haloperidol would be via N-dealkylation and pyridinium formation.

Although the exact metabolic fate has not been clearly established, it appears that haloperidol is principally metabolized in the liver. The drug appears to be metabolized principally by oxidative N-dealkylation of the piperidine nitrogen to form fluorophenylcarbonic acids and piperidine metabolites (which appear to be inactive), and by reduction of the butyrophenone carbonyl to the carbinol, forming hydroxyhaloperidol. Limited data suggest that the reduced metabolite, hydroxyhaloperidol, has some pharmacologic activity, although its activity appears to be less than that of haloperidol. Urinary metabolites in rats include p-fluorophenaceturic acid, beta-p-fluorobenzoylpropionic acid, and several unidentified acids.

... it is metabolized via reduction to reduced haloperidol, which is biologically inactive. Different extents of enterohepatic recycling, and ethnic differences in metabolism, could also account for the observed variability in haloperidol disposition.

The enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase and uridine diphosphoglucose glucuronosyltransferase. The greatest proportion of the intrinsic hepatic clearance of haloperidol is by glucuronidation, followed by the reduction of haloperidol to reduced haloperidol and by CYP-mediated oxidation. In studies of CYP-mediated disposition in vitro, CYP3A4 appears to be the major isoform responsible for the metabolism of haloperidol in humans. The intrinsic clearances of the back-oxidation of reduced haloperidol to the parent compound, oxidative N-dealkylation and pyridinium formation are of the same order of magnitude, suggesting that the same enzyme system is responsible for the 3 reactions. Large variation in the catalytic activity was observed in the CYP-mediated reactions, whereas there appeared to be only small variations in the glucuronidation and carbonyl reduction pathways. Haloperidol is a substrate of CYP3A4 and an inhibitor, as well as a stimulator, of CYP2D6.

... In vivo pharmacogenetic studies have indicated that the metabolism and disposition of haloperidol may be regulated by genetically determined polymorphic CYP2D6 activity. However, these findings appear to contradict those from studies in vitro with human liver microsomes and from studies of drug interactions in vivo. Interethnic and pharmacogenetic differences in haloperidol metabolism may explain these observations.

Haloperidol has known human metabolites that include (2S,3S,4S,5R)-6-[4-(4-Chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid, p-Fluorobenzoylpropionic acid and 4-(4-chlorophenyl)-4-hydroxypiperidine, and Haloperidol pyridinium.

J6292F8L3D

HALOPERIDOL

Established Pharmacologic Class [EPC] - Typical Antipsychotic

Haloperidol is a Typical Antipsychotic.

HALOPERIDOL

Typical Antipsychotic [EPC]

Drugs used to prevent NAUSEA or VOMITING.

Agents that control agitated psychotic behavior, alleviate acute psychotic states, reduce psychotic symptoms, and exert a quieting effect. They are used in SCHIZOPHRENIA; senile dementia; transient psychosis following surgery; or MYOCARDIAL INFARCTION; etc. These drugs are often referred to as neuroleptics alluding to the tendency to produce neurological side effects, but not all antipsychotics are likely to produce such effects. Many of these drugs may also be effective against nausea, emesis, and pruritus.

Drugs that bind to but do not activate DOPAMINE RECEPTORS, thereby blocking the actions of dopamine or exogenous agonists. Many drugs used in the treatment of psychotic disorders (ANTIPSYCHOTIC AGENTS) are dopamine antagonists, although their therapeutic effects may be due to long-term adjustments of the brain rather than to the acute effects of blocking dopamine receptors. Dopamine antagonists have been used for several other clinical purposes including as ANTIEMETICS, in the treatment of Tourette syndrome, and for hiccup. Dopamine receptor blockade is associated with NEUROLEPTIC MALIGNANT SYNDROME.

Drugs used in the treatment of movement disorders. Most of these act centrally on dopaminergic or cholinergic systems. Among the most important clinically are those used for the treatment of Parkinson disease (ANTIPARKINSON AGENTS) and those for the tardive dyskinesias.

Haloperidol is a highly lipophilic compound and is extensively metabolized in humans, which may cause a large interindividual variability in its pharmacokinetics. Studies have found a wide variance in pharmacokinetic values for orally administered haloperidol with 1.7-6.1 hours reported for time to peak plasma concentration (tmax), 14.5-36.7 hours reported for half-life (t1⁄2), and 43.73 μg/L•h [range 14.89-120.96 μg/L•h] reported for AUC. Haloperidol is well-absorbed from the gastrointestinal tract when ingested orally, however, the first-pass hepatic metabolism decreases its oral bioavailability to 40 - 75%. After intramuscular administration, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals or 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours. Bioavailability following intramuscular administration is higher than that for oral administration. Administration of haloperidol decanoate (the depot form of haloperidol for long-term treatment) in sesame oil results in slow release of the drug for long-term effects. The plasma concentrations of haloperidol gradually rise, reaching its peak concentration at about 6 days after the injection, with an apparent half-life of about 21 days. Steady-state plasma concentrations are achieved after the third or fourth dose.

In radiolabeling studies, approximately 30% of the radioactivity is excreted in the urine following a single oral administration of 14C-labelled haloperidol, while 18% is excreted in the urine as haloperidol glucuronide, demonstrating that haloperidol glucuronide is a major metabolite in the urine as well as in plasma in humans.

The apparent volume of distribution was found to range from 9.5-21.7 L/kg. This high volume of distribution is in accordance with its lipophilicity, which also suggests free movement through various tissues including the blood-brain barrier.

Following intravenous administration, the plasma or serum clearance (CL) was found to be 0.39-0.708 L/h/kg (6.5 to 11.8 ml/min/kg). Following oral administration, clearance was found to be 141.65 L/h (range 41.34 to 335.80 L/h). Haloperidol clearance after extravascular administration ranges from 0.9-1.5 l/h/kg, however this rate is reduced in poor metabolizers of C_YP2D6_ enzyme. Reduced CYP2D6 enzyme activity may result in increased concentrations of haloperidol. The inter-subject variability (coefficient of variation, %) in haloperidol clearance was estimated to be 44% in a population pharmacokinetic analysis in patients with schizophrenia. Genetic polymorphism of CYP2D6 has been demonstrated to be an important source of inter-patient variability in the pharmacokinetics of haloperidol and may affect therapeutic response and incidence of adverse effects.

Haloperidol is well absorbed from the gastrointestinal tract but first-pass hepatic metabolism decreases oral bioavailability to 40 to 75%. Serum concentration peaks 0.5 to 4 hours after an oral dose.

The apparent volume of distribution is about 20 L/kg, consistent with the high lipophilicity of the drug. Haloperidol circulates in blood bound predominantly (90-94%) to plasma proteins.

MEDICATION (VET)

MEDICATION: Antidyskinetic (in Gilles de la Tourette's disease); antipsychotic

Use (kg; approx.) in Germany (2009): >100

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.

/CONDENSATION OF/ 4-(P-CHLOROPHENYL)-4-PIPERIDINOL ... WITH 4-CHLORO-4'-FLUOROBUTYROPHENONE BY HEATING TOLUENE SOLN OF REACTANTS IN PRESENCE OF SUITABLE CONDENSING AGENT. ... ISOLATION FROM REACTION MIXTURE & RECRYSTALLIZATION FROM SUITABLE SOLVENT ... (DIISOPROPYL ETHER).

Oral tablet - 0.5, 1, 2, 5, 10, 20 mg, Haldol (scored), (Ortho-McNeil)

Haloperidol Decanoate: Parenteral: Injection for IM use only: 50, 100 mg (haloperidol) per mL, Haldol Decanoate (with benzyl alcohol 1.2% in sesame oil), (Ortho-McNeil), also promoted by Scios Nova), Haloperidol Decanoate Injection (with benzyl alcohol 1.2% in sesame oil), (American Pharmaceutical Partners, Apotex, Bedford, GensiaSicor). /Haloperidol decanoate/

Haloperidol Lactate: Oral solution: 2 mg (haloperidol) per mL, Haldol Concentrate (with methylparaben), (Ortho-McNeil), Haloperidol Intensol (with parabens and propylene glycol), (Roxane). Parenteral injection: 5 mg (haloperidol) per mL, Haldol (with parabens), (Ortho-McNeil). /Haloperidol lactate/