D₂ Receptor

Haloperidol is a compound composed of a central piperidine structure with hydroxy and p-chlorophenyl substituents at position 4 and an N-linked p-fluorobutyrophenone moiety. It has a role as a serotonergic antagonist, a first generation antipsychotic, a dopaminergic antagonist, an antidyskinesia agent and an antiemetic. It is a hydroxypiperidine, an organofluorine compound, an aromatic ketone, a tertiary alcohol and a member of monochlorobenzenes.

1. Effects of inhibitors of DOPA decarboxylase, dopamine beta-hydroxylase and monoamine oxidase, and haloperiodol on the secretion of pancreatic juice induced by L-DOPA and dopamine were studied in preparations of the isolated blood-perfused canine pancreas.2. The increased secretion induced by the infusion of L-DOPA (100 mug/min) was completely antagonized by Ro 4-4602 (300 mug), a DOPA decarboxylase inhibitor.3. The secretogogue effect of dopamine (1-10 mug) intra-arterially was not affected by Ro 4-4602, but was enhanced by the infusion of fusaric acid (100 mug/min), a dopamine beta-hydroxylase inhibitor.4. The increase in the secretion induced by dopamine (1-10 mug) was enhanced by treatment with nialamide (100 mg/kg), a monoamine oxidase inhibitor, given intravenously.5. Haloperidol (1 mg) intra-arterially attenuated the dopamine-induced pancreatic secretion.6. It is concluded that L-DOPA is converted to dopamine in the acinar cells which causes an increase in the secretion of pancreatic juice, thus the intracellular level of dopamine may be controlled by enzymatic equilibrium.[2]

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Haloperidol (1 mg) intra-arterially attenuates the dopamine-induced pancreatic secretion. The action of 10 μg of dopamine in the dog pancreas is completely inhibited by 3 mg of haloperidol[1]. Both haloperidol (10 mg/kg) and chlorpromazine (CPZ, 15 mg/kg), when administered to mice 45 minutes after 50 mg/kg (2 μc) of mescaline, block the altered behavior caused by the drug within 7 to 10 minutes. The disappearance of mescaline is unaffected by haloperidol[2].

Absorption, Distribution and Excretion
Haloperidol is a highly lipophilic compound with extensive metabolism in the human body, which may lead to significant individual variability in its pharmacokinetics. Studies have found considerable differences in the pharmacokinetic parameters of orally administered haloperidol, with a time to peak concentration (tmax) of 1.7–6.1 hours, a half-life (t1/2) of 14.5–36.7 hours, and an AUC of 43.73 μg/L•h [range 14.89–120.96 μg/L•h]. After oral administration, haloperidol is well absorbed in the gastrointestinal tract, but first-pass hepatic metabolism reduces its oral bioavailability to 40–75%. After intramuscular injection, the time to peak plasma concentration (tmax) is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia, with a mean half-life of 20.7 hours. Bioavailability after intramuscular injection is higher than that after oral administration. Dissolving haloperidol decanoate (a sustained-release formulation of haloperidol used for long-term treatment) in sesame oil allows for slow drug release, thus achieving long-term efficacy. The plasma concentration of haloperidol gradually increases, reaching peak concentration approximately 6 days after injection, with an apparent half-life of approximately 21 days. Steady-state plasma concentrations are reached after three or four doses. Radiolabeling studies show that after a single oral administration of 14C-labeled haloperidol, approximately 30% of the radioactive material is excreted in the urine, while 18% is excreted as haloperidol glucuronide, indicating that haloperidol glucuronide is the main metabolite in human urine and plasma. The apparent volume of distribution is 9.5-21.7 L/kg. Such a high volume of distribution is consistent with its lipophilicity, indicating its ability to freely cross various tissues, including the blood-brain barrier. Following intravenous administration, plasma or serum clearance (CL) ranges from 0.39 to 0.708 L/h/kg (6.5 to 11.8 ml/min/kg). Following oral administration, clearance is 141.65 L/h (range 41.34 to 335.80 L/h). Following extravascular administration, haloperidol clearance ranges from 0.9 to 1.5 L/h/kg, but clearance is reduced in patients with impaired CYP2D6 enzyme metabolism. Reduced CYP2D6 enzyme activity may lead to increased haloperidol concentrations. In a population pharmacokinetic analysis of schizophrenia patients, the inter-individual variability (coefficient of variation, %) in haloperidol clearance was estimated at 44%. CYP2D6 gene polymorphism has been shown to be a significant source of inter-individual variability in haloperidol pharmacokinetics and may affect treatment response and the incidence of adverse reactions. Haloperidol is well absorbed from the gastrointestinal tract, but first-pass hepatic metabolism reduces its oral bioavailability to 40% to 75%. Peak serum concentrations are reached 0.5 to 4 hours after oral administration. The apparent volume of distribution is approximately 20 L/kg, consistent with the drug's high lipophilicity. Haloperidol circulates in the blood primarily (90-94%) bound to plasma proteins. In animals, after administration, the drug is mainly distributed in the liver, with smaller amounts distributed in the brain, lungs, kidneys, spleen, and heart. ...The binding rate of haloperidol to plasma proteins is approximately 92%. Metabolisms/Metabolites Haloperidol is extensively metabolized in the liver, with only about 1% of the administered dose excreted unchanged in the urine. In humans, haloperidol is bioconverted into various metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridine metabolites, and haloperidol glucuronide. In psychiatric patients receiving routine haloperidol treatment, plasma concentrations of haloperidol glucuronide were highest, followed by unchanged haloperidol, reduced haloperidol, and reduced haloperidol glucuronide. The drug is believed to be primarily metabolized via the oxidative N-dealkylation of piperidine nitrogen to produce fluorobenzoic acid and piperidine metabolites (which appear to be inactive), and the carbonyl reduction of butyryl benzophenone to methanol to produce hydroxyhaloperidol. Enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) enzymes, including CYP3A4 and CYP2D6, carbonyl reductase, and uridine diphosphate glucuronide transferase. Hepatic clearance of haloperidol is primarily via glucuronidation, followed by reduction to reduced haloperidol and CYP-mediated oxidation. In in vitro cytochrome-mediated drug disposal studies, CYP3A4 appears to be the main isoenzyme responsible for in vivo haloperidol metabolism. The intrinsic clearance rates of the three metabolic reactions of reduced haloperidol—anti-oxidation to the parent compound, oxidative dealkylation, and pyridinium formation—are on the same order of magnitude. This suggests that these three metabolic reactions may be handled by the same enzyme system. In vivo human studies indicate that glucuronidation accounts for 50% to 60% of haloperidol's biotransformation, while the reduction pathway accounts for approximately 23%. The remaining 20% to 30% of biotransformation occurs via dealkylation and pyridinium formation. Although the exact metabolic pathway is not fully understood, haloperidol appears to be primarily metabolized in the liver. The drug appears to be primarily metabolized via oxidative N-dealkylation of piperidine nitrogen to produce fluorobenzoic acid and piperidine metabolites (which appear to be inactive), and via carbonyl reduction of butyryl benzophenone to methanol to produce hydroxyhaloperidol. Limited data suggest that the reduced metabolite hydroxyhaloperidol possesses some pharmacological activity, although its activity appears to be lower than that of haloperidol. Rat urinary metabolites include p-fluorophenylacetic acid, β-p-fluorobenzoylpropionic acid, and several unidentified acids.
...It is metabolized to reduced haloperidol, which is biologically inactive. Differences in enterohepatic circulation and metabolic differences among ethnic groups may also contribute to the observed variations in the in vivo distribution of haloperidol.
Enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase, and uridine diphosphate glucuronide transferase. The primary pathway for the intrinsic clearance of haloperidol in the liver is glucuronidation, followed by the reduction of haloperidol to reduced haloperidol and CYP-mediated oxidation. In vitro CYP-mediated in vivo distribution studies indicate that CYP3A4 appears to be the main isoenzyme responsible for haloperidol metabolism in humans. The intrinsic clearance rates of reduced haloperidol to the parent compound, oxidative dealkylation, and pyridinium formation are on the same order of magnitude, suggesting that these three reactions are handled by the same enzyme system. Significant differences in catalytic activity were observed in the CYP-mediated reactions, while the differences in the glucuronidation and carbonyl reduction pathways appear to be small. Haloperidol is a substrate of CYP3A4 and also an inhibitor and activator of CYP2D6. In vivo pharmacogenetic studies suggest that the metabolism and distribution of haloperidol may be regulated by genetically determined polymorphisms in CYP2D6 activity. However, these findings appear to contradict results from in vitro human liver microsomal studies and in vivo drug interaction studies. Differences in haloperidol metabolism due to racial and pharmacogenetic factors may explain these observations. Known human metabolites of haloperidol include p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, (2S,3S,4S,5R)-6-[4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl]oxy-3,4,5-trihydroxyoxacyclohexane-2-carboxylic acid, and haloperidol pyridinium. Haloperidol is a known human metabolite of reduced haloperidol. Haloperidol is well absorbed from the gastrointestinal tract, but its first-pass metabolism in the liver reduces its oral bioavailability to 40% to 75%. Peak serum concentrations are reached 0.5 to 4 hours after oral administration. Following administration, haloperidol is primarily distributed in the liver, with smaller amounts distributed in the brain, lungs, kidneys, spleen, and heart. Although its exact metabolic pathway is not fully understood, haloperidol appears to be primarily metabolized in the liver. The main metabolic pathway appears to be: oxidative dealkylation of piperidine nitrogen to fluorobenzoic acid and piperidine metabolites (these metabolites appear to be inactive); and carbonyl reduction of butyrophenone to methanol to generate hydroxyhaloperidol. Limited data suggest that the reduced metabolite hydroxyhaloperidol has some pharmacological activity, but its activity appears to be lower than that of haloperidol. Urinary metabolites include p-fluorophenylacetic acid, β-p-fluorobenzoylpropionic acid, and several unidentified acids (A637, A566, A637). Half-life: 3 weeks. Biological half-life: After oral administration, the half-life is 14.5–36.7 hours. After intramuscular injection, the mean half-life is 20.7 hours. In healthy volunteers, intravenous and oral administration of 10 mg haloperidol: The serum half-life after intravenous administration is 10–19 hours, and after oral administration, it is 12–38.3 hours. Bioavailability is approximately 60%; volume of distribution is approximately 1300 liters. Haloperidol, elimination: Oral: 24 hours (range 12–37 hours). Intramuscular: 21 hours (range 17–25 hours). Intravenous: 14 hours (range 10–19 hours). Haloperidol decanoate, elimination: Approximately 3 weeks (single or multiple doses).

Toxicity Summary
Identification: Haloperidol is an antipsychotic drug. Haloperidol is a synthetic drug. Haloperidol is the first member of the butyrophenone class of major sedatives. Haloperidol is indicated for the treatment of symptoms of psychotic disorders such as schizophrenia and mania. It is indicated for the control of tics and vocalizations in Tourette syndrome in children and adults. It is effective in treating serious behavioral problems in children, such as aggression and explosive hyperexcitability. It is also used to treat Tourette syndrome, intractable hiccups, and can be used as an antiemetic. Human Exposure: Major Risks and Target Organs: The main characteristics of serious overdose are extrapyramidal reactions, hypotension, dyspnea, and altered consciousness. Haloperidol primarily functions as a dopamine antagonist. Clinical Manifestations Overview: Consciousness may decline, even progressing to coma; paradoxically, some patients may experience confusion, agitation, and restlessness. Tremors or muscle twitches, muscle spasms, rigidity, and seizures may be observed. Extrapyramidal signs include dystonia, sometimes severe enough to affect swallowing or breathing; torticollis, oculomotor crisis, and opisthotonus. Mydriasis or dilation may occur. Hypotension and tachycardia are common. Arrhythmias, including ventricular fibrillation, conduction block, and cardiac arrest, may sometimes occur. Contraindications: Severe dystonia has been reported following haloperidol use, particularly in children and adolescents. Therefore, caution should be exercised when using haloperidol in children. Haloperidol may also cause serious neurotoxicity in patients with hyperthyroidism and those taking lithium. Haloperidol is contraindicated in cases of severe central nervous system toxicity, depression or coma from any cause, and in patients with hypersensitivity to the drug or Parkinson's disease. It is also contraindicated in late pregnancy because neonates may experience dystonia. Infants should not be breastfed during treatment. Route of administration: Oral: This is the primary route of administration. Parenteral administration: By intravenous and intramuscular injection. Absorption: Haloperidol is readily absorbed from the gastrointestinal tract. Due to the first-pass effect of the liver, plasma concentrations after oral administration are lower than those after intramuscular injection. There is significant individual variability in plasma concentrations and therapeutic effects of haloperidol. Haloperidol decanoate is absorbed very slowly from the injection site, making it suitable for sustained-release injection. It is slowly released into the bloodstream and rapidly hydrolyzed in the blood to haloperidol. Distribution by exposure route: Haloperidol has a very high binding rate to plasma proteins (90%). It is widely distributed throughout the body and can cross the blood-brain barrier. Biological half-life by exposure route: The plasma half-life at therapeutic doses has been reported to be approximately 13 to nearly 40 hours (Reynolds, 1989), with an average of 20 hours. Metabolism: Haloperidol is metabolized in the liver via oxidative N-dealkylation. Clearance by exposure route: Total systemic clearance increases in children and decreases in elderly patients. After metabolism, haloperidol is excreted in urine, bile, and feces, with evidence suggesting a 40% enterohepatic circulation. In the first 5 days, approximately 26% of the drug was excreted in the urine of healthy subjects and approximately 20% in patients; by day 3, approximately 15% was excreted in the feces. Complete clearance of a single oral dose takes 28 days. Mechanism of action: Pharmacodynamics: Dopamine receptors are currently classified into D1 (stimulating adenylate cyclase) and D2 (inhibiting adenylate cyclase). Antipsychotic drugs can block both D1 and D2 receptors, but the significance of their ratio is unclear. The therapeutic dose of antipsychotic drugs appears to be related to their affinity for dopamine D2 receptors in the brain. Antipsychotic drugs can also block a variety of other receptors, including H1 and H2 histamine receptors, α1 and α2 adrenergic receptors, muscarinic receptors, and serotonergic receptors. Toxicity: Human data: Three cases of sudden death occurred after daily administration of 20 to 140 mg for 1 to 4 days. Children: A 29-month-old girl and an 11-month-old boy experienced drowsiness, hypothermia, hyperreflexia, neuromuscular rigidity, gait instability, and intention tremor after co-administration of 265 mg of haloperidol. While adverse reactions such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels in most patients remains unclear. There are currently no well-controlled studies on the use of haloperidol in pregnant women. However, there are reports of fetal limb malformations observed after pregnant women took haloperidol and other suspected teratogenic drugs in early pregnancy. However, causality has not been established in these cases. Because such experience does not rule out the possibility of fetal harm from haloperidol, this drug should only be used in pregnant women or women who may become pregnant when the benefits clearly outweigh the potential risks to the fetus. Interactions: Due to the potential for additive effects and hypotension, this drug should not be used concomitantly with alcohol. A small number of patients receiving lithium salts in combination with haloperidol have developed encephalopathy syndrome (characterized by weakness, somnolence, fever, tremor, confusion, extrapyramidal symptoms, leukocytosis, elevated serum enzymes, blood urea nitrogen, and fasting blood glucose), followed by irreversible brain injury. A causal relationship between these events and the concomitant use of lithium salts and haloperidol has not been established; however, patients receiving such combination therapy should be closely monitored for early signs of neurotoxicity, and treatment should be discontinued immediately upon the appearance of such symptoms (Physician's Desk Reference, 1987). Other reported interactions involve the following drugs and their adverse reactions: Beta-blockers: severe hypotension or pulmonary arrest. Methyldopa: dementia, psychomotor retardation, memory loss, and inattention. Indomethacin: severe somnolence and confusion. Major adverse reactions: Generally, overdose symptoms manifest as an exacerbation of known pharmacological effects and adverse reactions. Anticholinergic side effects and sedation occur less frequently than with aliphatic phenothiazines, but extrapyramidal reactions are more common. Concomitant use with antidopaminergic and anticholinergic drugs may exacerbate or prematurely induce extrapyramidal reactions. Concomitant use with indomethacin may cause specific reactions, leading to severe drowsiness. Animal/Plant Studies: Carcinogenicity: Carcinogenicity studies of oral haloperidol were conducted in Wistar rats and Swiss albino mice. In rat studies, survival rates were below ideal in all dose groups, thus reducing the number of rats at tumor risk. However, although the number of surviving male and female rats in the high-dose groups was relatively high at the end of the study, the tumor incidence in these animals was not higher than in the control group. Therefore, although this study is not perfect, it does indicate that haloperidol does not lead to an increased incidence of tumors in rats. In female mice, there was a statistically significant increase in both mammary tumor and total tumor incidence; there was also a statistically significant increase in pituitary tumor incidence. In male mice, no statistically significant differences were observed in total tumor incidence or the incidence of specific tumor types. Antipsychotic drugs increase prolactin levels; this increase persists during long-term use. Teratogenicity: Oral or parenteral administration of haloperidol to rodents increased embryo reuptake, decreased fertility, delayed parturition, and increased pup mortality. No teratogenic effects were reported in rats, rabbits, or dogs at this dose range, but cleft palate was observed in mice. Mutagenicity: Haloperidol was not found to be mutagenic in the Ames Salmonella microsomal activation assay. The exact mechanism of action of haloperidol is unclear, but the drug appears to inhibit the central nervous system in the subcortical, midbrain, and brainstem reticular formation. Haloperidol appears to inhibit the ascending reticular activating system in the brainstem (possibly via the caudate nucleus), thereby blocking impulse transmission between the diencephalon and cortex. The drug may antagonize the effects of glutamate in the extrapyramidal system, and inhibition of catecholamine receptors may also be part of the mechanism of action of haloperidol. Haloperidol may also inhibit the reuptake of multiple neurotransmitters in the midbrain and appears to have strong central anti-dopaminergic activity and weak central anticholinergic activity. This drug can cause rigidity in animals and inhibit their spontaneous movement and conditioned avoidance behavior. The exact mechanism of haloperidol's antiemetic effect is not fully understood, but studies have shown that the drug directly affects the chemoreceptor trigger zone (CTZ) by blocking dopamine receptors in the CTZ.

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Toxicity Data
LD50: 128 mg/kg (oral, rat)
LD50: 71 mg/kg (oral, mouse)
LD50: 90 mg/kg (oral, dog)
LD50: 165 mg/kg (oral, rat)

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Drug Interactions
Because haloperidol has α-adrenergic blocking effects, pre-administration of haloperidol may reduce the pressor response to phenylephrine.
Because haloperidol has α-adrenergic blocking effects, pre-administration of haloperidol may reduce the pressor effect and duration of action of methoxyamine. Haloperidol.
Concomitant use of metaraminol usually reduces the pressor response induced by metaraminol, but does not reverse or completely block this response because haloperidol has alpha-adrenergic blocking effects.
Concomitant use of levodopa or pergolide may reduce the efficacy of these drugs because haloperidol blocks dopamine receptors.
For more complete data on drug interactions of haloperidol (26 in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 165 mg/kg
Intraperitoneal LD50 in mice: 60 mg/kg

[1]. Effects of enzyme inhibitors of catecholamine metabolism and of haloperidol on the pancreatic secretion induced by L-DOPA and by dopamine in dogs. Br J Pharmacol. 1973 Jan;47(1):77-84.

[2]. Effects of chlorpromazine and haloperidol on the disposition of mescaline-14C in mice. J Pharmacol Exp Ther. 1973 Aug;186(2):297-304.

Therapeutic Uses
Haloperidol is indicated for the treatment of acute and chronic psychotic disorders, including schizophrenia, manic states, and drug-induced psychosis, such as steroid psychosis. It can also be used to treat aggressive and agitated patients, including those with organic mental syndromes or intellectual disabilities. Haloperidol decanoate is a long-acting injectable formulation suitable for maintenance therapy in patients requiring long-term injection therapy, such as those with chronic schizophrenia. /US product label includes/ Haloperidol is effective in treating children with severe behavioral problems who exhibit marked, unprovoked aggression and explosive hyperactivity. Haloperidol can also be used for short-term treatment of hyperactivity in children with behavioral disorders such as aggression, impulsivity, irritability, inattention, and/or mood swings. For both groups of children, haloperidol should only be considered if psychotherapy or other non-antipsychotic medications have failed. /US Product Label Includes/
Haloperidol is used to control tic and vocal symptoms of Tourette syndrome in children and adults. /US Product Label Includes/
For more complete data on the therapeutic uses of haloperidol (of 8 types), please visit the HSDB record page.

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Drug Warnings
Pregnancy Risk Grade: C/Risk cannot be ruled out. There are a lack of adequate, well-controlled human studies, and animal studies have not shown any risk to the fetus.Taking this drug during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. /
Extrapyramidal reactions are more common after taking haloperidol, especially in the first few days of treatment. Most patients experience Parkinson's disease symptoms (e.g., marked somnolence and drowsiness, excessive salivation or drooling, staring), which are usually mild to moderate and generally reversible upon discontinuation of the drug. Other adverse neuromuscular reactions are less frequently reported, but are often more severe, including motor restlessness (i.e., akathisia), tardive dystonia, and dystonia reactions (e.g., hyperreflexia, opisthotonus, oculomotor crisis, torticollis, trismus). Drowsiness or dizziness may occur; caution should be exercised when driving, operating machinery, or engaging in activities requiring alertness. Dizziness or lightheadedness may occur; extra caution should be exercised when suddenly rising from a lying or sitting position. Haloperidol should be used with caution in patients with severe cardiovascular disease due to the potential for transient hypotension and/or induction of angina. If hypotension occurs, metaraminol, norepinephrine, or phenylephrine can be used; epinephrine should not be used because haloperidol reverses the vasopressor effect of epinephrine and further lowers blood pressure. For more complete data on haloperidol (24 in total), please visit the HSDB record page.

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Pharmacodynamics
First-generation antipsychotics (including haloperidol) are considered highly effective in treating the "positive" symptoms of schizophrenia, including hallucinations, auditory hallucinations, aggression/hostility, speech disturbances, and psychomotor agitation. However, these drugs are limited by their ability to cause motor disorders such as drug-induced Parkinson's syndrome, akathisia, dystonia, and tardive dyskinesia, as well as other side effects including sedation, weight gain, and changes in prolactin levels. Haloperidol is generally the least likely to cause side effects compared to lower-potency first-generation antipsychotics (such as [DB00477], [DB01624], [DB00623], and [DB01403]), but it is more likely to cause extrapyramidal symptoms (EPS). Lower-potency drugs have a lower affinity for dopamine receptors, thus requiring higher doses to effectively treat the symptoms of schizophrenia.
Furthermore, they can block many other receptors besides the primary target (dopamine receptor), such as cholinergic or histamine receptors, leading to a higher incidence of side effects such as sedation, weight gain, and hypotension. The balance between the expected efficacy of the drug for psychotic symptoms and adverse side effects depends primarily on the dopaminergic brain pathways affected by haloperidol. The cortical dopamine D2 pathway plays a crucial role in modulating these efficacies, including the nigrostriatal pathway (responsible for inducing extrapyramidal symptoms), the mesolimbic and mesocortical pathways (responsible for improving positive symptoms of schizophrenia), and the tuberous-infundibular dopamine pathway (responsible for hyperprolactinemia). Patients may develop a syndrome consisting of potentially irreversible, involuntary motor disorders. Although the syndrome appears to have the highest incidence in older populations, particularly older women, prevalence estimates cannot be used to predict which patients will develop the syndrome at the start of antipsychotic medication treatment. There have been case reports of sudden death, QT interval prolongation, and torsades de pointes in patients taking haloperidol. Doses of any formulation exceeding the recommended dose and intravenous administration of haloperidol appear to be associated with an increased risk of QT interval prolongation and torsades de pointes. Although case reports exist even in the absence of precipitating factors, extreme caution should be exercised when treating patients with other QT prolongation disorders, including electrolyte disturbances [particularly hypokalemia and hypomagnesemia], medications known to prolong the QT interval, underlying cardiac abnormalities, hypothyroidism, and familial long QT syndrome. Antipsychotic medications can sometimes cause a potentially fatal symptom cluster, sometimes referred to as neuroleptic malignancy (NMS). Clinical manifestations of NMS include high fever, muscle rigidity, altered mental status (including symptoms of catatonic psychosis), and evidence of autonomic dysfunction (irregular pulse or blood pressure, tachycardia, excessive sweating, and arrhythmias). Other symptoms may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

C21H23CLFNO2

375.86

375.14

C, 67.11; H, 6.17; Cl, 9.43; F, 5.05; N, 3.73; O, 8.51

52-86-8

Haloperidol-d4; 1189986-59-1; Haloperidol-d4-1; 136765-35-0; Haloperidol hydrochloride; 1511-16-6; Haloperidol lactate; 53515-91-6; Haloperidol-d4 N-Oxide; 1246815-56-4; Haloperidol-13C6

3559

White to light yellow crystalline powder.

1.2±0.1 g/cm3

529.0±50.0 °C at 760 mmHg

152 °C

273.8±30.1 °C

0.0±1.5 mmHg at 25°C

1.581

3.01

1

4

6

26

451

0

ClC1C([H])=C([H])C(=C([H])C=1[H])C1(C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])C(C2C([H])=C([H])C(=C([H])C=2[H])F)=O)C([H])([H])C1([H])[H])O[H]

LNEPOXFFQSENCJ-UHFFFAOYSA-N

InChI=1S/C21H23ClFNO2/c22-18-7-5-17(6-8-18)21(26)11-14-24(15-12-21)13-1-2-20(25)16-3-9-19(23)10-4-16/h3-10,26H,1-2,11-15H2

4-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)butan-1-one

R1625; HSDB3093; R 1625; HSDB 3093; R-1625; HSDB-3093; Eukystol ;Serenace; Haloperidol; Aloperidin; Eukystol; Brotopon; Haldol; Aloperidin; Aloperidol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~100 mg/mL (~266.1 mM)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.44 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 1.67 mg/mL (4.44 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 1.67 mg/mL (4.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)