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.

A single intraarterial injection of haloperidol (1 mg) reduces pancreatic secretion triggered by dopamine. The effects of 10 μg of dopamine in the dog pancreas are entirely inhibited by 3 mg of haloperidol [1]. Within 7 to 10 minutes, the injection of 50 mg/kg (2 µc) mescaline for 45 minutes was suppressed by haloperidol (10 mg/kg) and chlorpromazine (CPZ, 15 mg/kg). Deviation from mescaline causes behavioral alterations. The elimination of mescaline is unaffected by haloperidol [2].

In an open, double-blind study of phencyclidine intoxication, 21 white male subjects were later found to have instead ingested ketamine. These subjects were divided into two cohorts, one treated with 5 mg intramuscular haloperidol and the second with an active placebo. Assessment with the Brief Psychiatric Rating Scale revealed significant reduction in symptoms with haloperidol.[2]

Absorption
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 that the pharmacokinetic parameters of orally administered haloperidol vary considerably, 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 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.
Elimination Pathway
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 in the urine as haloperidol glucuronide. This indicates that haloperidol glucuronide is the main metabolite in human urine and plasma.
Volume of Distribution
The apparent volume of distribution is 9.5-21.7 L/kg. This high volume of distribution is consistent with its lipophilicity and also indicates that it can freely cross various tissues, including the blood-brain barrier.
Clearance
After intravenous administration, plasma or serum clearance (CL) is 0.39–0.708 L/h/kg (6.5–11.8 ml/min/kg). After oral administration, clearance is 141.65 L/h (range 41.34–335.80 L/h). After extravascular administration, haloperidol clearance ranges from 0.9–1.5 L/h/kg, but clearance is reduced in individuals with impaired CYP2D6 enzyme metabolism. Reduced CYP2D6 enzyme activity may lead to increased haloperidol concentrations. In a population pharmacokinetic analysis of patients with schizophrenia, the inter-individual variability (coefficient of variation, %) in haloperidol clearance was estimated at 44%. CYP2D6 gene polymorphism has been shown to be an important 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 is primarily (90-94%) bound to plasma proteins in the blood. In animals, after administration of haloperidol, 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%.

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Metabolism/Metabolite Haloperidol is extensively metabolized in the liver, with only about 1% of the administered dose excreted unchanged in the urine. In the human body, haloperidol can be bioconverted into a variety of metabolites, including p-fluorobenzoylpropionic acid, 4-(4-chlorophenyl)-4-hydroxypiperidine, reduced haloperidol, pyridine metabolites, and haloperidol glucuronide. In psychiatric patients receiving routine haloperidol treatment, the highest plasma concentration of haloperidol glucuronide was observed, followed by unmetabolized haloperidol, reduced haloperidol, and reduced haloperidol glucuronide.

This drug is believed to be primarily metabolized via the oxidative dealkylation of piperidinium, producing fluorophenyl carbonate and piperidine metabolites (which appear to be inactive), and the carbonyl reduction of butyryl phenylone to methanol, yielding hydroxyhaloperidol. Enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP) enzymes, including CYP3A4 and CYP2D6, carbonyl reductase, and uridine diphosphate glucuronide transferase. The intrinsic hepatic clearance of haloperidol is primarily via glucuronidation, followed by the reduction of haloperidol to reduced haloperidol and CYP-mediated oxidation. In vitro cytochrome-mediated metabolic studies indicate that CYP3A4 appears to be the main isoenzyme responsible for the metabolism of haloperidol in the human body. The intrinsic clearance rates of reduced haloperidol to the parent compound, oxidative dealkylation, and pyridinium formation are on the same order of magnitude. This suggests that these three metabolic reactions are handled by the same enzyme system. In vivo human studies have shown that glucuronidation accounts for 50% to 60% of the biotransformation of haloperidol, while the reduction pathway accounts for approximately 23%. The remaining 20% to 30% of the biotransformation is accomplished through N-dealkylation and the formation of pyridinium. Although the exact metabolic pathway is not fully understood, haloperidol appears to be primarily metabolized in the liver. The main metabolic pathway appears to be the oxidative N-dealkylation of piperidine nitrogen, yielding fluorophenyl carbonate and piperidine metabolites (which appear to be inactive), and the carbonyl reduction of butyryl benzophenone to methanol, yielding 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 reduced to reduced haloperidol, which is biologically inactive. Differences in the extent of enterohepatic circulation and racial differences in metabolism may also contribute to the observed variations in the in vivo distribution of haloperidol. PMID:2689040
Enzymes involved in the biotransformation of haloperidol include cytochrome P450 (CYP), carbonyl reductase, and uridine diphosphate glucuronide transferase. The primary intrinsic hepatic clearance pathway of haloperidol is glucuronidation, followed by reduction to reduced haloperidol and CYP-mediated oxidation. In vitro CYP-mediated metabolic studies indicate that CYP3A4 appears to be the main isoenzyme responsible for haloperidol metabolism in the human body. 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 may be catalyzed by the same enzyme system. Significant differences in catalytic activity were observed in CYP-mediated reactions, while the differences in catalytic activity were smaller in the glucuronidation and carbonyl reduction pathways. Haloperidol is a substrate of CYP3A4 and also an inhibitor and activator of CYP2D6. PMID:10628896
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 among different ethnic groups and pharmacogenetic factors may explain these observations. PMID:10628896
Known human metabolites of haloperidol include haloperidol pyridinium, (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, p-fluorobenzoylpropionic acid, and 4-(4-chlorophenyl)-4-hydroxypiperidine. Haloperidol is a known human metabolite of reduced haloperidol. Haloperidol is well absorbed from the gastrointestinal tract, but first-pass hepatic metabolism reduces oral bioavailability to 40% to 75%. Peak serum concentrations are reached 0.5 to 4 hours after oral administration. After 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 the oxidative dealkylation of piperidine nitrogen to produce fluorobenzoic acid and piperidine metabolites (which appear to be inactive); and the carbonyl reduction of butyrobenzophenone to methanol to produce 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

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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 is 12–38.3 hours. Bioavailability is approximately 60%; the volume of distribution is approximately 1300 liters. PMID: 822989
Haloperidol, elimination: Oral: 24 hours (range 12–37 hours). Intramuscular injection: 21 hours (range 17–25 hours). Intravenous injection: 14 hours (range 10–19 hours). Haloperidol decanoate, clearance time: Approximately 3 weeks (single or multiple doses).

Toxicity Overview
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 acts as a dopamine antagonist. Clinical Effects Overview: Consciousness may be suppressed and progress 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 observed following haloperidol use, particularly in children and adolescents. Therefore, it should be used with extreme caution in children. Haloperidol may also cause severe 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. The plasma concentrations and therapeutic effects of haloperidol vary considerably among individuals. Haloperidol decanoate is absorbed very slowly from the injection site, making it suitable for sustained-release administration. It is slowly released into the bloodstream and rapidly hydrolyzed to haloperidol in the blood. 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 is increased in children and decreased 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: In rodents, oral or parenteral administration of haloperidol increased embryo resorption, 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.

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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 formations.

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 its mechanism of action. Haloperidol may also inhibit the reuptake of multiple neurotransmitters in the midbrain and appears to have strong central antidopaminergic activity and weak central anticholinergic activity. The drug can induce rigidity in animals and inhibit spontaneous movement and conditioned avoidance behavior. The exact mechanism of haloperidol's antiemetic effect is not fully elucidated, but studies suggest that the drug can directly affect the chemoreceptor trigger zone (CTZ) by blocking dopamine receptors in the CTZ.

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Hepatotoxicity
It has been reported that 20% of patients taking haloperidol long-term develop liver dysfunction, but elevations exceeding three times the upper limit of normal are uncommon. Aminotransferase abnormalities are usually mild, asymptomatic, and transient, and can be reversed with continued use. There have been reports of clinically significant acute liver injury following haloperidol use, but this is uncommon. Jaundice usually appears within 2 to 6 weeks after administration, and serum enzyme elevations are typically cholestatic or mixed. Hypersensitivity reactions (fever, rash, and eosinophilia) have been reported in some cases, but are usually mild and self-limiting; autoantibodies are rare. Probability Score: B (Possibly the cause of clinically significant liver injury). Health Effects: Tachycardia, hypotension, and hypertension have been reported; extrapyramidal symptoms (EPS), such as akathisia or dystonia; impaired liver function and/or jaundice. Maculopapular rash and acne-like skin reactions, and isolated cases of photosensitivity and alopecia. Laryngospasm, bronchospasm, cataracts, retinopathy, and visual impairment; lactation, breast tenderness, breast pain, menstrual irregularities, gynecomastia, impotence, hypersexuality, hyperglycemia, hypoglycemia, and hyponatremia (RxList, A308).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
Limited information suggests that low concentrations of haloperidol in breast milk, even when the mother takes up to 10 mg daily, generally do not affect breastfed infants. Very limited long-term follow-up data suggest that haloperidol alone does not produce adverse developmental effects. However, when used in combination with other antipsychotics, it may sometimes have negative effects on the infant. One expert guideline recommends against the use of haloperidol by breastfeeding women, but a safety rating system suggests that haloperidol can be used with caution by breastfeeding women. Infant drowsiness and developmental milestones should be monitored, especially when other antipsychotics are used concurrently.
◉ Effects on breastfed infants
In one case of a breastfed infant, the mother took 5 mg of haloperidol orally twice daily, and the infant did not experience sedation and fed well. When the mother took haloperidol during six weeks of breastfeeding, the infant reached all growth and developmental milestones at 6 and 12 months of age.
Another infant was breastfed for 5 weeks from 2 weeks of age while her mother was treated with haloperidol (dosage not specified) and imipramine (150 mg daily). The infant was tested at 1-4 months and 12-18 months of age, and development was normal.
In a small prospective study on the long-term effects of antipsychotic drugs on breastfed infants, researchers found that among four infants born to mothers taking chlorpromazine and haloperidol, two had decreased developmental scores at 12-18 months of age. The other two infants, as well as all infants taking one of the drugs alone, developed normally.
A woman with schizophrenia took haloperidol and trihexyphenidyl during all three pregnancies and postpartum. In the first two pregnancies, she took 7.5-10 mg of haloperidol daily, and in the third pregnancy, she took 15 mg of haloperidol daily. She breastfed all three children for 6-8 months (feeding duration not specified) using the same dosage. At the time of assessment, all children aged 16 months to 8 years were developmentally adequate. Two women, one with bipolar disorder and the other with chronic schizophrenia, were taking haloperidol 5 mg/day during pregnancy and lactation (medication details unspecified). One mother was also taking olanzapine 10 mg/day, and the other was taking amisulpride 400 mg/day. Breastfed infants were followed for 11 to 13 months without adverse events and showed normal development. A woman diagnosed with schizophrenia was taking risperidone 1.5 mg/day daily during late pregnancy and postpartum lactation (lactation details unspecified) while breastfeeding a full-term infant. Two weeks postpartum, due to symptom relapse, haloperidol 0.8 mg/day was added. At this dose, no adverse events were observed in the infant. However, due to recurring symptoms, the haloperidol dose was increased to 1.5 mg/day. Three days later, the infant developed excessive sedation, feeding difficulties, and bradykinesia. Pediatric evaluation revealed no medical cause for these symptoms. The infant's symptoms completely disappeared within 5 days after breastfeeding was discontinued. The infant's symptoms were most likely caused by the combination of medications.
◉ Effects on Lactation and Breast Milk
Halfoperidol has been reported to cause galactorrhea due to hyperprolactinemia. Hyperprolactinemia is caused by the drug's dopamine blocking effect on the tuberous-infundibular pathway. For mothers who have established lactation, their prolactin levels may not affect their ability to breastfeed.
Drugs and Lactation Database (LactMed)◈ What is Haloperidol?
Halfoperidol is a medication used to treat schizophrenia and other mental illnesses. It has also been used to treat severe nausea and vomiting during pregnancy (hyperemesis gravidarum). For more information on nausea and vomiting during pregnancy, please visit: https://mothertobaby.org/fact-sheets/nausea-vomiting-pregnancy-nvp/. Haloperidol is marketed as Haldol®. Sometimes, when people find out they are pregnant, they consider changing their medication regimen or even stopping it entirely. However, it is essential to consult your healthcare provider before changing your medication regimen. Your healthcare provider can discuss with you the benefits of treating your condition and the risks of not treating it during pregnancy.
◈ I am taking haloperidol. Will it affect my ability to get pregnant?
According to reviewed studies, haloperidol may cause higher than normal levels of prolactin (a hormone that helps the body produce milk) in the blood. This is called hyperprolactinemia. Hyperprolactinemia can make it more difficult to conceive.
◈ Does taking haloperidol increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There are currently no human studies confirming whether haloperidol increases the risk of miscarriage. Based on animal studies, haloperidol is not expected to increase the risk of miscarriage.
◈ Does taking haloperidol increase the risk of birth defects?
There is a 3-5% risk of birth defects at the start of each pregnancy. This is called background risk. Based on reviewed studies, haloperidol is not expected to increase the risk of birth defects. Most studies on haloperidol use during pregnancy have not found an increased risk of birth defects. There are currently two case reports of infants developing limb defects after exposure to haloperidol and other medications during pregnancy. A study of 188 pregnant women who took haloperidol during pregnancy found no increased risk of birth defects. One infant with a limb defect was reported in this study. It is currently unclear whether this limb defect was caused by haloperidol, other medications, or other factors.
◈ Does taking haloperidol during pregnancy increase the risk of other pregnancy-related problems?
Based on reviewed studies, haloperidol is not expected to increase the risk of other pregnancy-related problems, such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 2500 grams). One study reported that taking haloperidol during pregnancy increased the risk of preterm birth and low birth weight. However, the authors of that study stated that they lacked information on some key factors that may be associated with low birth weight and/or preterm birth. It is currently unclear whether haloperidol, other medications, or other factors increase the likelihood of these problems.
◈ I need to take haloperidol throughout my pregnancy. Will it cause my baby to experience withdrawal symptoms after birth?
There have been reports of newborns exposed to haloperidol during pregnancy experiencing withdrawal symptoms. Symptoms may include hypotonia (low muscle tone), irritability, abnormal sleep patterns, difficulty feeding, involuntary tremors, and dehydration. Not all infants exposed to haloperidol will experience these symptoms. It is important to inform your healthcare provider that you are taking haloperidol so that your baby can receive optimal care if symptoms occur.
◈ Will taking haloperidol during pregnancy affect my child's future behavior or learning abilities?
Based on reviewed studies, it is unclear whether haloperidol increases the risk of behavioral or learning problems.
◈ Breastfeeding while taking haloperidol:
Information is limited regarding the use of haloperidol while breastfeeding. Haloperidol can pass into breast milk. Most breastfed infants exposed to haloperidol did not report any symptoms. A breastfed infant reportedly experienced feeding difficulties, lethargy, and bradykinesia after being exposed to haloperidol and risperidone through breast milk. The infant's symptoms disappeared after breastfeeding was discontinued. The reported symptoms may be related to the combination of medications. If you suspect your baby has any symptoms (such as lethargy), contact your child's healthcare provider. Be sure to discuss all questions about breastfeeding with your healthcare provider.
◈ Does haloperidol use affect fertility (the ability to impregnate a partner) or increase the risk of birth defects?
Men taking haloperidol may experience hyperprolactinemia, which can lead to sexual desire or orgasmic disorders. There is currently no research indicating whether haloperidol use in men increases the risk of birth defects above the general risk. Generally, contact with the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the "Father Exposure" information sheet on the MotherToBaby website at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/. Massachusetts General Hospital has established a pregnancy registry system for psychiatric medications, including haloperidol. Please contact the registry: https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/.

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Route of exposure: Inhalation, oral (60%)

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Symptoms: LD50 = 165 mg/kg (rat, oral) Toxicity data: LD50: 128 mg/kg (rat, oral); LD50: 71 mg/kg (mouse, oral); LD50: 90 mg/kg (dog, oral); LD50: 165 mg/kg (rat, oral)

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Treatment
Since there is no specific antidote, treatment is primarily supportive. A patent airway must be established using an oropharyngeal airway or endotracheal intubation; in cases of prolonged coma, a tracheotomy is necessary. Respiratory depression can be counteracted with artificial respiration and mechanical ventilation. Hypotension and circulatory failure can be corrected with intravenous fluids, plasma or albumin concentrate, and vasopressors (such as metaraminol, phenylephrine, and norepinephrine). Epinephrine is contraindicated. In case of severe extrapyramidal reactions, anti-Parkinson's drugs should be administered. ECG and vital signs should be closely monitored, especially for signs of QT interval prolongation or arrhythmia, and monitoring should continue until the ECG returns to normal. Severe arrhythmias should be treated with appropriate antiarrhythmic drugs. (L1712)

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

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Protein binding rate
Studies have found that the proportion of free haloperidol in human plasma is 7.5-11.6%. This proportion is comparable in healthy adults, young adults, elderly patients with schizophrenia, and even patients with cirrhosis.

[1]. Joy CB, et al. Haloperidol versus placebo for schizophrenia. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD003082.
[2]. Giannini AJ, et al. Acute ketamine intoxication treated by haloperidol: a preliminary study. Am J Ther. 2000 Nov;7(6):389-91

According to state or federal labeling requirements, haloperidol can cause developmental toxicity and female reproductive toxicity. Haloperidol is a compound with a central piperidine structure, a hydroxyl group at the 4-position, a p-chlorophenyl substituent, and an N-fluorobutyrophenone moiety. It is a serotonergic antagonist, a first-generation antipsychotic, a dopaminergic antagonist, an anti-movement disorder agent, and an antiemetic. It is a hydroxypiperidine, organofluorine compound, aromatic ketone, tertiary alcohol, and monochlorobenzene compound. Haloperidol is a highly potent first-generation (typical) antipsychotic and one of the most commonly used antipsychotics worldwide. Although haloperidol has been shown to have pharmacological activity against multiple receptors in the brain, its antipsychotic effects are primarily achieved through potent antagonism of dopamine receptors (mainly D2 receptors), particularly in the mesolimbic system and mesocortical system of the brain. Haloperidol is indicated for the treatment of symptoms of a variety of mental disorders, including schizophrenia, acute psychosis, Tourette syndrome, and other severe behavioral disorders. In addition, due to its potent antiemetic effect, haloperidol has also been used off-label to treat Huntington's disease-related chorea and intractable hiccups. Dopamine antagonists like haloperidol are believed to improve psychotic symptoms and states caused by excessive dopamine production, such as schizophrenia, which is theoretically based on a state of dopaminergic hyperactivity within the limbic system of the brain. First-generation antipsychotics (including haloperidol) were considered highly effective in treating the "positive" symptoms of schizophrenia, including hallucinations, auditory hallucinations, aggression/hostility, speech disturbances, and psychomotor agitation. However, these drugs also have limitations, such as dopamine blockade-induced motor disorders like drug-induced Parkinson's syndrome, akathisia, dystonia, tardive dyskinesia, and other side effects, including sedation, weight gain, and changes in prolactin levels. Although high-quality studies are currently limited, haloperidol is generally the least affected of low-potency first-generation antipsychotics (such as [DB00477], [DB01624], [DB00623], and [DB01403]) in terms of efficacy, but it is more likely to cause extrapyramidal symptoms (EPS). Other low-potency antipsychotics are limited by their lower affinity for dopamine receptors, thus requiring higher doses to effectively treat schizophrenia symptoms. Furthermore, they block many other receptors besides the primary target (dopamine receptor), such as cholinergic or histaminergic receptors, leading to a higher incidence of side effects such as sedation, weight gain, and hypotension. Interestingly, in vivo pharmacogenetic studies suggest that haloperidol metabolism may be regulated by genetically determined polymorphisms in CYP2D6 activity. However, these findings contradict results from in vitro human liver microsomal studies and in vivo drug interaction studies. Racial and pharmacogenetic differences in haloperidol metabolism may explain these observations. First-generation antipsychotics have been largely replaced by second- and third-generation (atypical) antipsychotics, such as [DB00734], [DB00334], [DB00363], [DB01224], [DB01238], and [DB00246]. However, haloperidol remains widely used and is considered a benchmark drug in clinical trials of next-generation antipsychotics. The efficacy of haloperidol was first demonstrated in controlled trials in the 1960s. Haloperidol is a typical antipsychotic. Haloperidol is a traditional antipsychotic used to treat acute and chronic psychosis. Haloperidol treatment typically results in a mild elevation of serum transaminases, and in rare cases, is associated with clinically significant acute liver injury. Haloperidol is a phenylbutyridine derivative with antipsychotic, antipsychotic, and antiemetic effects. Haloperidol exerts its anti-delusional and anti-hallucinatory effects by competitively blocking postsynaptic dopamine (D2) receptors in the limbic system of the brain, thereby eliminating dopamine neurotransmission. Its antiemetic effect stems from its antagonistic effect on D2 dopamine receptors in the chemoreceptor trigger zone (CTZ). Haloperidol is a phenylpiperidinylbutyrophenone compound primarily used to treat schizophrenia and other psychoses. It is also used to treat schizoaffective disorder, delusional disorder, chorea, and Tourette syndrome (as a first-line drug), and sometimes as adjunctive therapy for intellectual disability and Huntington's disease. It is a potent antiemetic and is also used to treat intractable hiccups. A phenylpiperidinylbutyrophenone compound primarily used to treat schizophrenia and other psychoses. It is also used to treat schizoaffective disorder, paranoia, throwing disorder, and Tourette syndrome (as the first-line drug), and sometimes as adjunctive therapy for intellectual disability and Huntington's disease. It is a potent antiemetic used to treat intractable hiccups.

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Drug Indications
Haloperidol is indicated for a variety of conditions, including the treatment of schizophrenia, manifestations of psychotic disorders, control of tics and vocalizations in children and adults with Tourette syndrome, and the treatment of serious behavioral problems in children such as aggression and explosive hyperexcitability (which cannot be explained by immediate provocation). Haloperidol is also indicated for short-term treatment of ADHD in children who exhibit hyperactivity and some or all of the following symptoms: impulsivity, difficulty concentrating, aggression, mood instability, and poor frustration tolerance. Haloperidol should only be used in these two groups of children after psychotherapy or other medications other than antipsychotics have failed.

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Therapeutic Uses
Anti-movement disorder medication; antiemetic; antipsychotic, butyrophenone derivative; dopamine antagonist
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 patients requiring long-term injection therapy, such as those with chronic schizophrenia, for maintenance therapy.
Haloperidol is effective in treating severe behavioral problems in children, such as unprovoked aggression and explosive hyperexcitability. It is also effective for short-term treatment of ADHD in children with behavioral disorders such as aggression, impulsivity, frustration, inattention, and/or mood swings. For both groups of children, haloperidol should only be considered when psychotherapy or other non-antipsychotic medications are ineffective.
Haloperidol is used to control tic and vocal symptoms of Tourette syndrome in children and adults.

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Drug Warnings
Pregnancy Risk Level: C / Risk cannot be ruled out. There is a lack of adequate and well-controlled human studies, and animal studies have not shown any risk to the fetus, or relevant data are missing. Use during pregnancy may cause harm to the fetus; however, the potential benefits may outweigh the potential risks. /
Extrapyramidal reactions are common after taking haloperidol, especially in the first few days of treatment. Most patients experience Parkinson's-like symptoms (e.g., marked somnolence and drowsiness, excessive salivation or drooling, blank stare), which are usually mild to moderate and usually 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 dystonic 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; caution should be exercised when suddenly rising from a lying or sitting position.
Because transient hypotension and/or angina may occur, haloperidol should be used with caution in patients with severe cardiovascular disease. If hypotension occurs, metaraminol, norepinephrine, or phenylephrine can be used; because haloperidol reverses the vasopressor effect of epinephrine and further lowers blood pressure, epinephrine should not be used.

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Pharmacodynamics
First-generation antipsychotics (including haloperidol) are considered very effective in treating the “positive” symptoms of schizophrenia, including hallucinations, auditory hallucinations, aggression/hostility, speech disorders, and psychomotor agitation. However, these drugs have limitations in causing movement 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. Compared to low-potency first-generation antipsychotics (such as [DB00477], [DB01624], [DB00623], and [DB01403]), haloperidol generally has the fewest side effects in its class, but is more likely to cause extrapyramidal symptoms (EPS). Low-potency drugs have a lower affinity for dopamine receptors, thus requiring higher doses to effectively treat schizophrenia symptoms. Furthermore, they block many other receptors besides their primary target (dopamine receptors), such as cholinergic or histaminergic receptors, leading to a higher incidence of side effects such as sedation, weight gain, and hypotension. Haloperidol acts on dopaminergic brain pathways, and this balance is primarily reflected in the drug's expected efficacy against psychotic symptoms and its adverse side effects. The cortical dopamine D2 pathway plays a crucial role in regulating these effects, including the nigrostriatal pathway (responsible for inducing extrapyramidal symptoms (EPS)), the mesolimbic and mesocortical pathways (responsible for improving positive symptoms of schizophrenia), and the tuberoinfundibular dopamine pathway (responsible for hyperprolactinemia). Patients may develop a syndrome consisting of potentially irreversible, involuntary motor disturbances. Although the prevalence of this syndrome appears to be highest in the elderly, particularly older women, prevalence estimates cannot be relied upon to predict which patients will develop the syndrome at the start of antipsychotic medication treatment. Case reports of sudden death, QT interval prolongation, and torsades de pointes have been reported in patients taking haloperidol. Doses exceeding the recommended dose for any formulation 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 drugs 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 signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Mechanism of Action: While haloperidol has been shown to have pharmacological activity against multiple receptors in the brain, its antipsychotic effects are primarily achieved through potent antagonism of dopamine receptors (mainly D2 receptors), particularly in the mesolimbic system and mesocortical system of the brain. Schizophrenia is believed to be caused by a dopaminergic hyperactivity within the limbic system of the brain. Therefore, dopamine antagonists like haloperidol are thought to improve psychotic symptoms by inhibiting excessive dopamine production. The optimal clinical efficacy of antipsychotic drugs is associated with blocking approximately 60-80% of D2 receptors in the brain. While the exact mechanism is not fully understood, haloperidol is known to inhibit the effects of dopamine and accelerate its metabolism. Traditional antipsychotics, such as haloperidol, bind more strongly to dopamine D2 receptors than dopamine itself, and have a lower dissociation constant. Haloperidol is thought to competitively block postsynaptic dopamine (D2) receptors in the brain, thereby blocking dopamine neurotransmission and alleviating delusions and hallucinations commonly associated with psychosis. It primarily acts on D2 receptors, with some effect on 5-HT2 and α1 receptors, while its effect on dopamine D1 receptors is negligible. Furthermore, the drug can also block α-adrenergic receptors in the autonomic nervous system. The drug exerts its antiemetic effect by antagonizing dopamine D2 receptors in the chemoreceptor trigger zone (CTZ) of the brain. Of the three D2-like receptors, only the D2 receptor is blocked by antipsychotic drugs, which is directly related to their clinical antipsychotic efficacy. Clinical brain imaging studies have shown that haloperidol remains tightly bound to the D2 dopamine receptor even after two positron emission tomography (PET) scans performed 24 hours apart. A common adverse reaction to this drug is the occurrence of extrapyramidal symptoms (EPS), which is due to the tight binding of haloperidol to the dopamine D2 receptor. Given that extrapyramidal symptoms can be distressing and even lifelong, newer antipsychotic drugs than haloperidol have been developed. The rapid dissociation of the drug from the dopamine D2 receptor is a plausible explanation for the improvement of extrapyramidal symptoms with atypical antipsychotics such as [DB00734]. This is also consistent with the theory that these drugs have a low affinity for the D2 receptor. As mentioned above, haloperidol binds tightly to dopamine receptors, increasing the risk of extrapyramidal symptoms; therefore, it should only be used when necessary. Haloperidol has a weaker autonomic effect compared to other antipsychotics. Its anticholinergic activity is also low… It blocks the activation of α-receptors by sympathomimetic drugs, but its effect is far weaker than chlorpromazine. Although the complex mechanism of its therapeutic action is not fully elucidated, haloperidol is known to exert a selective effect on the central nervous system (CNS) by competitively blocking postsynaptic dopamine (D2) receptors in the mesolimbic dopaminergic system and increasing the turnover rate of dopamine in the brain, thereby exerting a sedative effect. In subchronic treatment, depolarization blockade or a decrease in the firing frequency (reduced release) of dopamine neurons, along with D2 postsynaptic receptor blockade, contribute to the antipsychotic effect.

C21H23NO2FCL.HCL

412.32516

411.117

1511-16-6

Haloperidol;52-86-8;Haloperidol-d4;1189986-59-1;Haloperidol-d4-1;136765-35-0;Haloperidol lactate;53515-91-6

11495267

Typically exists as solid at room temperature

5.165

2

4

6

27

451

0

ClC(C=C1)=CC=C1C2(O)CCN(CCCC(C3=CC=C(F)C=C3)=O)CC2.Cl

JMRYYMBDXNZQMH-UHFFFAOYSA-N

InChI=1S/C21H23ClFNO2.ClH/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;1H

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

haloperidol hydrochloride; 1511-16-6; Haloperidol chloride; Haloperidol (hydrochloride); Haloperidol chlorohydrate; Haloperidol hydrochloride [MI]; UNII-UM06W2ADRY; UM06W2ADRY;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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