HuagongsheHuagongshe Chemie-Druckbericht · Nur für Forschungszwecke
gamma-(4-(p-Chlorphenyl)4-hydroxy-piperidino)-p-fluorbutyrophenon
ALDO · Haldol · Dihydrohaloperidol · Haloperidol for system suitability · 4-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-1-(4-fluorophenyl)butan-1-one · 4-[4-(4-Chlorophenyl)-4-hydroxypiperidine-1-yl]-1-(4-fluorophenyl)butane-1-ol · Dozic · Halol
Identifikatoren & physikalische Daten
| CAS No. | 52-86-8 |
|---|---|
| Summenformel | C21H23ClFNO2 |
| Durchschnittliche Molmasse | 375,9 g/mol |
| Monoisotopische Masse | 375,1401348 g/mol |
| SMILES | O=C(CCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1 |
| InChIKey | LNEPOXFFQSENCJ-UHFFFAOYSA-N |
| PubChem CID | 3559 |
| ChEMBL | CHEMBL54 |
| ChEBI | CHEBI:5613 |
| EC No. | 200-155-6 |
| DTXSID | DTXSID4034150 |
| Lokaler Name | gamma-(4-(p-Chlorphenyl)4-hydroxy-piperidino)-p-fluorbutyrophenon |
Chemische & physikalische Eigenschaften
| XLogP | 3,2 |
|---|---|
| Polarare Oberfläche (TPSA) | 40,5 |
| H-Brücken-Donoren | 1 |
| H-Brücken-Akzeptoren | 4 |
| Frei drehbare Bindungen | 6 |
| Schwere Atome | 26 |
| Formalladung | 0 |
| Komplexität | 451 |
| Arzneimittel | DEA NFLIS-Drug Category -> Depressants and TranquilizersPharmaceuticals -> AntipsychoticsPharmaceuticals -> Listed in ZINC15Pharmaceuticals -> Nervous system -> Antipsychotics |
| LogP (Verteilungskoeffizient) | log Kow = 4.303.23 |
| Color/Form | CrystalsWHITE TO FAINTLY YELLOWISH, AMORPHOUS OR MICRO-CRYSTALLINE POWDER |
| Löslichkeit | Crystalsmp 226-227.5 °Csol in water at 300X10+1 mg/L /Hydrochloride/In water, 1.4X10+1 mg/L @ 25 °C16.7 mg/ml in alcohol at 25 °CFreely sol in chloroform, methanol, acetone, benzene, dil acids4.46e-03 g/L45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 0.39 mg/mL2.058mg/L(22.5 ºC) |
| Human Drugs | Breast FeedingLactationMilk, HumanAntipsychotic AgentsButyrophenonesFDA approved drugs -> Active ingredientPharmaceuticalsMedicines for other common symptoms in palliative care |
| Schmelzpunkt | 151.5 °C152 °C |
| Dampfdruck | 4.8X10-11 mm Hg @ 25 °C /Estimated/ |
| Henry-Konstante | Henry's Law constant = 2.3X10-14 atm-cu m/mol @ 25 °C /Estimated/4.3×108 mol/(m3Pa) at 25℃, HSDB (2015) |
| Physical Description | Solid |
| Ionization Efficiency | Positive4.265924542.7Thermo LTQElectrospray ionizationformic acid (5.3nM) |
| Dissociation Constants | 8.658.58.66pKa= 8.66 |
| Collision Cross Section | 200.2 Ų [M+Na]+ [CCS Type: DTBuffer gas: N2Ionization: ESI+Dataset: TOXCASTSource Identifier: DTXSID4034150]193.7 Ų [M+H]+ [CCS Type: TWMethod: Major Mix IMS/Tof Calibration Kit (Waters)]185.12 Ų [M+Na]+ [CCS Type: TWMethod: calibrated with polyalanine and drug standards]191.7 Ų [M+H]+ [CCS Type: TW193.9 Ų [M+H]+ [CCS Type: TW]194.1 Ų [M+H]+ [CCS Type: DTMethod: single field calibrated] |
| Siedepunkt | 529.0±50.0 °C(Predicted) |
| Dichte | 1.1820 (estimate) |
| Flammpunkt | 9℃ |
| Lagerbedingungen | 2-8°C |
| Aggregatzustand | powder |
| pKa (Säurekonstante) | 8.3(at 25℃) |
| Farbe | white |
| Merck | 14,4598 |
| BCS Class | 4/3 |
| Hauptanwendungen | pharmaceutical (small molecule) |
| 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 |
| InChIKey | LNEPOXFFQSENCJ-UHFFFAOYSA-N |
| SMILES | OC1(CCN(CCCC(=O)c2ccc(F)cc2)CC1)c3ccc(Cl)cc3 |
| CAS Datenbank | 52-86-8(CAS DataBase Reference) |
| NIST chemische Informationen | Haloperidol(52-86-8) |
| EPA chemische Informationen | Haloperidol (52-86-8) |
Sicherheit & Vorschriften
| GHS-Einstufung | This chemical does not meet GHS hazard criteria for 2.4% (2 of 85) of reports.DangerH301 (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. |
|---|---|
| Regulatorische Informationen | Hazard Traits - Developmental ToxicityReproductive ToxicityHaloperidol: Does not have an individual approval but may be used under an appropriate group standard |
| Weitere Sicherheitsinformationen | IMAP assessments - 1-Butanone, 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-: Environment tier I assessment |
| FDA-Anforderungen | 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. |
| Special Reports | Jann MW, Richards ALUS 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 RPGen 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. |
| Hazard Classes and Categories | Acute Tox. 3 (97.6%)Acute toxicity (Oral) - Category 4 |
| Entsorgungsverfahren | 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 qualitypotential migration in soil or watereffects on animal, aquatic, and plant lifeand conformance with environmental and public health regulations. |
| Treatment | 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) |
| Wechselwirkungen | 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. |
| Gesundheitliche Auswirkungen | Tachycardia, hypotension, and hypertensionExtrapyramidal Symptoms (EPS) such as akathisia, or dystoniaimpaired 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 disturbanceslactation, breast engorgement, mastalgia, menstrual irregularities, gynecomastia, impotence, increased libido, hyperglycemia, hypoglycemia and hyponatremia (RxList, A308). |
| Hepatotoxicity | 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-limitedautoantibodies are rare. |
| Umweltverhalten | 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). |
| Unerwünschte Wirkungen | Typical antipsychotic medications, such as haloperidol, are associated with extrapyramidal symptoms due to their blockade of the dopamine pathway in the brain. |
| Expositionspfade | Inhalation, Oral (60%) |
| Milk Concentrations | Haloperidol is distributed into milk. |
| Toxizitätsübersicht | 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 comaparadoxically, 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 breathingtorticollis, 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 daysby 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 haloperidolthis 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 establishedhowever, 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 incidencethere 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 levelsthe 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. |
| Signs and Symptoms | LD<sub>50</sub>=165 mg/kg (rats, oral) |
| Soil Adsorption/Mobility | 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). |
| Human Toxicity Excerpts | /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. |
| Wassergefährdungsklasse (WGK) | 3 |
| UN-Transportnummer | UN 2811 6.1/PG 3 |
| Zollcode | 2933399090 |
| RTECS-Nr. | EU1575000 |
| R-Sätze (R) | 60-61-25-36/37/38-43-39/23/24/25-23/24/25-11 |
| Toxizität | LD50 orally in rats: 165 mg/kg (Goldenthal)i.p. in mice: 60 mg/kg (Collins, Horlington) |
| Gefahrensymbole | T,F |
| Sicherheitshinweise (S) | 53-26-36/37/39-45-36/37-16 |
| Gefahrenklasse | 6.1(b)Acute Tox. 3 OralEye Irrit. 2Repr. 2Skin Irrit. 2Skin Sens. 1STOT SE 3 |
| Verpackungsgruppe | III |
| Lagerklasse | 6.1C - Combustible acute toxic Cat.3toxic compounds or compounds which causing chronic effects |
| Gefahrstoffdaten | 52-86-8(Hazardous Substances Data) |
Anwendungen & Verwendung
Beschreibung
Haloperidol is a butyrophenone with a long duration of action. It has lile α- adrenoceptor blocking activity and minimal effect on the cardiovascular system. It is an effective antiemetic but has a high incidence of extrapyramidal adverse effects. Haloperidol may be used in the short-term management of the acutely agitated patient (when sinister causes of confusion such as hypoxaemia and sepsis have been excluded) and in the management of delirium in ICU. The duration of action of haloperidol is approximately 24–48h.
History
Haloperidol (brand name Haldol) was first approved by the FDA on April 12, 1967, for the treatment of schizophrenia. It is a typical antipsychotic drug. However, due to its severe neurotoxicity and significant harm to the human body, it has gradually been phased out of the market. Haldol is also approved by the FDA for Tourette syndrome and hyperactivity or severe behavioral problems in children who are unresponsive to treatment or other medications. However, this drug can only be obtained through a doctor's prescription.
Verwenden
Haloperidol is one of the most actively used modern neuroleptics. Its high antipsychotic activity is combined with a moderate sedative effect. It effectively stops various types of psychomotor excitement. It is used for schizophrenic psychoses, manic, paranoid, and delirious conditions, depression, psychomotor excitement of various origins, and for delirium and hallucinations of different origin.