Haloperidol
Clinical data | |
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Pronunciation | /ˌhæloʊˈpɛrɪdɒl/ |
Trade names | Haldol, Serenace, others |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682180 |
License data |
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Pregnancy category |
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decanoate ester) | |
Drug class | Typical antipsychotic |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 60–70% (by mouth)[4] |
Protein binding | ~90%[4] |
Metabolism | Liver-mediated[4] |
Elimination half-life | 14–26 hours (IV), 20.7 hours (IM), 14–37 hours (oral)[4] |
Excretion | Biliary (hence in feces) and in urine[4][5] |
Identifiers | |
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JSmol) | |
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Haloperidol, sold under the brand name Haldol among others, is a
Haloperidol may result in a movement disorder known as tardive dyskinesia which may be permanent.[6] Neuroleptic malignant syndrome and QT interval prolongation may occur, the latter particularly with IV administration.[6] In older people with psychosis due to dementia it results in an increased risk of death.[6] When taken during pregnancy it may result in problems in the infant.[6][9] It should not be used by people with Parkinson's disease.[6]
Haloperidol was discovered in 1958 by
Physicochemical properties
Haloperidol is a crystalline material with a melting temperature of 150 °C.[15] This drug has very low solubility in water (1.4 mg/100 mL), but it is soluble in chloroform, benzene, methanol, and acetone. It is also soluble in 0.1 M hydrochloric acid (3 mg/mL) with heating.[16]
Medical uses
Haloperidol is used in the control of the symptoms of:
- Acute psychosis, such as drug-induced psychosis caused by amphetamines, ketamine,[17] and phencyclidine,[18] and psychosis associated with high fever or metabolic disease. Some evidence has found haloperidol to worsen psychosis due to psilocybin.[19]
- Adjunctive treatment of alcohol and opioid withdrawal
- Agitation and confusion associated with cerebral sclerosis
- Alcohol-induced psychosis
- Hallucinations in alcohol withdrawal[7]
- Hyperactive delirium (to control the agitation component of delirium)
- Hyperactivity, aggression
- Otherwise uncontrollable, severe behavioral disorders in children and adolescents
- Schizophrenia[20]
- Therapeutic trial in personality disorders, such as borderline personality disorder
- Treatment of intractable
- Treatment of neurological disorders, including chorea
- Treatment of severe nausea and emesis in postoperative and Cannabinoid Hyperemesis Syndrome.
- As chemical restraint in acute care psychiatry, mainly for violent and self-harming patients (controversial use but very commonly found in movies).[23]
Haloperidol was considered indispensable for treating psychiatric emergency situations,[23][24] although the newer atypical drugs have gained a greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.[25][26][27]
In a 2013 comparison of 15 antipsychotics in schizophrenia, haloperidol demonstrated standard effectiveness. It was 13–16% more effective than ziprasidone, chlorpromazine, and asenapine, approximately as effective as quetiapine and aripiprazole, and 10% less effective than paliperidone.[28] A 2013 systematic review compared haloperidol to placebo in schizophrenia:[29]
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Haloperidol often causes troublesome adverse effects. If there is no other antipsychotic drug, using haloperidol to offset the consequences of untreated schizophrenia is justified. Where a choice of drug is available, however, an alternative antipsychotic with less likelihood of adverse effects such as parkinsonism, akathisia and acute dystonias may be more desirable.[29] | ||||||||||||||||||||||||||||||||||||||||||||
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Pregnancy and lactation
Data from
Haloperidol is excreted in breast milk. A few studies have examined the impact of haloperidol exposure on breastfed infants and in most cases, there were no adverse effects on infant growth and development.[30]
Other considerations
During long-term treatment of chronic psychiatric disorders, the daily dose should be reduced to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually.[citation needed] In addition, during long-term use, routine monitoring including measurement of BMI, blood pressure, fasting blood sugar, and lipids, is recommended due to the risk of side effects.[31]
Other forms of therapy (psychotherapy, occupational therapy/ergotherapy, or social rehabilitation) should be instituted properly.[citation needed] PET imaging studies have suggested low doses are preferable. Clinical response was associated with at least 65% occupancy of D2 receptors, while greater than 72% was likely to cause hyperprolactinaemia and over 78% associated with extrapyramidal side effects. Doses of haloperidol greater than 5 mg increased the risk of side effects without improving efficacy.[32] Patients responded with doses under even 2 mg in first-episode psychosis.[33] For maintenance treatment of schizophrenia, an international consensus conference recommended a reduction dosage by about 20% every 6 months until a minimal maintenance dose is established.[31]
- Depot forms are also available; these are injected deeply intramuscularly at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.[citation needed]
The
Topical formulations of haloperidol should not be used as treatment for nausea because research does not indicate this therapy is more effective than alternatives.[35]
Adverse effects
Sources for the following lists of adverse effects:[36][37][38][39]
As haloperidol is a high-potency typical antipsychotic, it tends to produce significant
With more than 6 months of use 14 percent of users gain weight.[40] Haloperidol may be neurotoxic.[41]
Common (>1% incidence)
- Extrapyramidal side effects including:
- Akathisia (motor restlessness)
- Dystonia (continuous spasms and muscle contractions)
- Muscle rigidity
- Parkinsonism (characteristic symptoms such as rigidity)
- Hypotension
- Anticholinergic side effects such as: (These adverse effects are less common than with lower-potency typical antipsychotics, such as chlorpromazine and thioridazine.)
- Blurred vision
- Constipation
- Dry mouth
- Somnolence (which is not a particularly prominent side effect, as is supported by the results of the aforementioned meta-analysis.[28])
Unknown frequency
- Anemia
- Headache
- Increased respiratory rate
- Orthostatic hypotension
- Prolonged QT interval
- Visual disturbances
Rare (<1% incidence)
- Acute hepatic failure
- Agitation
- Agranulocytosis
- Anaphylactic reaction
- Anorexia
- Bronchospasm
- Cataracts
- Cholestasis
- Confusional state
- Depression
- Dermatitis exfoliative
- Dyspnea
- Edema
- Extrasystoles
- Face edema
- Gynecomastia
- Hepatitis
- Hyperglycemia
- Hypersensitivity
- Hyperthermia
- Hypoglycemia
- Hyponatremia
- Hypothermia
- Increased sweating
- Injection site abscess
- Insomnia
- Itchiness
- Jaundice
- Laryngeal edema
- Laryngospasm
- Leukocytoclastic vasculitis
- Leukopenia
- Liver function test abnormal
- Nausea
- Neuroleptic malignant syndrome
- Neutropenia
- Pancytopenia
- Photosensitivity reaction
- Priapism
- Psychotic disorder
- Pulmonary embolism
- Rash
- Retinopathy
- Seizure
- Sudden death
- Tardive dyskinesia
- Thrombocytopenia
- Torsades de pointes
- Urinary retention
- Urticaria
- Ventricular fibrillation
- Ventricular tachycardia
- Vomiting
Contraindications
- Pre-existing coma, acute stroke
- Severe intoxication with alcohol or other central depressant drugs
- Known allergy against haloperidol or other butyrophenones or other drug ingredients
- Known heart disease, when combined will tend towards cardiac arrest[citation needed]
Special cautions
- A multiple-year study suggested this drug and other neuroleptic antipsychotic drugs commonly given to people with Alzheimer's with mild behavioral problems often make their condition worse and its withdrawal was even beneficial for some cognitive and functional measures.[42] [43]
- Elderly patients with dementia-related psychosis: analysis of 17 trials showed the risk of death in this group of patients was 1.6 to 1.7 times that of placebo-treated patients. Most of the causes of death were either cardiovascular or infectious in nature. It is not clear to what extent this observation is attributed to antipsychotic drugs rather than the characteristics of the patients. The drug bears a boxed warning about this risk.[20]
- Impaired liver function, as haloperidol is metabolized and eliminated mainly by the liver
- In patients with hyperthyroidism, the action of haloperidol is intensified and side effects are more likely.
- IV injections: risk of hypotension or orthostatic collapse
- Patients at special risk for the development of QT prolongation (hypokalemia, concomitant use of other drugs causing QT prolongation)
- Patients with a history of leukopenia: a complete blood count should be monitored frequently during the first few months of therapy and discontinuation of the drug should be considered at the first sign of a clinically significant decline in white blood cells.[20]
- Pre-existing Parkinson's disease[44] or dementia with Lewy bodies
Interactions
- Amiodarone: Q-Tc interval prolongation (potentially dangerous change in heart rhythm).[45]
- ADHD
- Epinephrine: action antagonized, paradoxical decrease in blood pressure may result
- Guanethidine: antihypertensive action antagonized
- Levodopa: decreased action of levodopa
- Lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.[46]
- Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects
- Other central depressants (alcohol, tranquilizers, narcotics): actions and side effects of these drugs (sedation, respiratory depression) are increased. In particular, the doses of concomitantly used opioids for chronic pain can be reduced by 50%.
- Other drugs metabolized by the CYP3A4 enzyme system: inducers such as carbamazepine, phenobarbital, and rifampicin decrease plasma levels and inhibitors such as quinidine, buspirone, and fluoxetine increase plasma levels[20]
- Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold)
Potential neurotoxicity
Several lines of evidence suggest that haloperidol exhibits neurotoxicity.[47][48] Some studies report an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume.[49] Haloperidol may exert deleterious effects on the dorsolateral prefrontal cortex (DLPFC) by attenuating BDNF transcription and expression, associated with an increase in the long non-coding RNA BDNF-AS in the DLPFC.[50]
Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[51] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[52] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[52] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[52] Symptoms generally resolve after a short period of time.[52]
There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[53] It may also result in reoccurrence of the condition that is being treated.[54] Rarely tardive dyskinesia can occur when the medication is stopped.[52]
Overdose
Symptoms
Symptoms are usually due to side effects. Most often encountered are:
- Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, decreased perspiration)
- Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock
- Hypotension or hypertension
- Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time
- Sedation
- Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.
Treatment
Treatment is mostly symptomatic and involves intensive care with stabilization of vital functions. In early detected cases of oral overdose, induction of
Prognosis
An overdose of haloperidol can be fatal,[55] but in general the prognosis after overdose is good, provided the person has survived the initial phase.
Pharmacology
Haloperidol is a typical
Receptor | Action | Ki (nM) |
---|---|---|
D1 | silent antagonist
|
Unknown efficiency [citation needed] |
D5 | silent antagonist | Unknown efficiency[citation needed] |
D2 | inverse agonist | 0.7[58] |
D3 | inverse agonist | 0.2[59] |
D4 | inverse agonist | 5–9[60] |
σ1 | (irreversible inactivation by haloperidol metabolite HPP+) | 3[61] |
σ2 | agonist | 54[62] |
5-HT1A | agonist | 1,927[63] |
5-HT2A | silent antagonist | 53[63] |
5-HT2C | silent antagonist | 10,000[63] |
5-HT6 | silent antagonist | 3,666[63] |
5-HT7 | irreversible silent antagonist | 377.2[63] |
H1 | silent antagonist | 1,800[63] |
M1 | silent antagonist | 10,000[63] |
α1A | silent antagonist | 12[63] |
α2A | silent antagonist | 1,130[63] |
α2B | silent antagonist | 480[63] |
α2C | silent antagonist | 550[63] |
NR1/NR2B subunit containing NMDA receptor | antagonist; ifenprodil site | IC50 – 2,000[64] |
Pharmacokinetics
By mouth
The bioavailability of oral haloperidol ranges from 60 to 70%. However, there is a wide variance in reported mean Tmax and T1/2 in different studies, ranging from 1.7 to 6.1 hours and 14.5 to 36.7 hours respectively.[4]
Intramuscular injections
The drug is well and rapidly absorbed with a high bioavailability when injected intramuscularly. The Tmax is 20 minutes in healthy individuals and 33.8 minutes in patients with schizophrenia. The mean T1/2 is 20.7 hours.
Intravenous injections
The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The T1/2 is 14.1 to 26.2 hours. The apparent volume of distribution is between 9.5 and 21.7 L/kg.[4] The duration of action is four to six hours.
Therapeutic concentrations
Plasma levels of five to 15 micrograms per liter are typically seen for therapeutic response (Ulrich S, et al. Clin Pharmacokinet. 1998). The determination of plasma levels is rarely used to calculate dose adjustments but can be useful to check compliance.
The concentration of haloperidol in brain tissue is about 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue,[67] which may explain the slow disappearance of side effects when the medication is stopped.[67][68]
Distribution and metabolism
Haloperidol is heavily protein bound in human plasma, with a free fraction of only 7.5 to 11.6%. It is also extensively metabolized in the liver with only about 1% of the administered dose excreted unchanged in the urine. The greatest proportion of the hepatic clearance is by glucuronidation, followed by reduction and CYP-mediated oxidation, primarily by CYP3A4.[4]
History
Haloperidol was discovered by
Haloperidol was approved by the
Society and culture
Cost
Haloperidol is relatively inexpensive, being up to 100 fold less expensive than newer antipsychotics.[72][73]
Brand names
Haloperidol is the
approved name.It is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol (common tradename in the US and UK), Halol, Halosten, Keselan, Linton, Peluces, Serenace Norodol (Turkey) and Sigaperidol.[citation needed]
Veterinary use
Haloperidol is also used on many different kinds of animals for nonselective tranquilization and diminishing behavioral arousal, in veterinary and other settings including captivity management.[74]
References
- ^ a b "Haloperidol Use During Pregnancy". Drugs.com. 10 February 2020. Retrieved 13 September 2020.
- FDA. Retrieved 22 October 2023.
- ^ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
- ^ S2CID 71360020.
- ^ "Product Information Serenace" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. 29 September 2011. Archived from the original on 14 March 2017. Retrieved 29 May 2014.
- ^ a b c d e f g h i j "Haloperidol". The American Society of Health-System Pharmacists. Archived from the original on 2 January 2015. Retrieved 2 January 2015.
- ^ S2CID 205116954.
- PMID 22559293.
- ^ "Prescribing medicines in pregnancy database". Australian Government. 3 March 2014. Archived from the original on 8 April 2014. Retrieved 2 January 2015.
- ISBN 978-0-471-89979-2. Archivedfrom the original on 8 December 2015.
- ISBN 978-3-527-32669-3. Archivedfrom the original on 8 December 2015.
- hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
- ISBN 978-1-85775-892-4. Archivedfrom the original on 8 December 2015.
- ^ "Haloperidol - Drug Usage Statistics". ClinCalc. Retrieved 7 October 2022.
- S2CID 221826541.
- ^ "Sigma data sheet on haloperidol" (PDF).
- PMID 11304647.
- S2CID 42278510.
- PMID 18593734.
- ^ a b c d e f "Haldol Official FDA information, side effects and uses". Drugs.com. Archived from the original on 5 October 2013. Retrieved 3 October 2013.
- ISBN 978-0-85711-084-8.
- ^ a b Brayfield, A, ed. (13 December 2013). "Haloperidol". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. Retrieved 29 May 2014.
- ^ S2CID 22342074.
- PMID 3736271.
- PMID 11500996.
- S2CID 29363701.
- S2CID 72366588.
- ^ S2CID 32085212.
- ^ from the original on 20 August 2017.
- ^ "LACTMED: Haloperidol". 31 October 2018. Retrieved 18 January 2019.
- ^ a b Work Group on Schizophrenia. "Practice Guideline for the Treatment of Patients With Schizophrenia" (Second ed.). Archived from the original on 27 March 2012. Retrieved 21 April 2014.
- S2CID 40788955.
- S2CID 30091494.
- ^ Goodman and Gilman's Pharmacological Basis of Therapeutics, 10th edition (McGraw-Hill, 2001).[page needed]
- ^ American Academy of Hospice and Palliative Medicine. "Five Things Physicians and Patients Should Question". Choosing Wisely: An Initiative of the ABIM Foundation. American Academy of Hospice and Palliative Medicine. Archived from the original on 1 September 2013. Retrieved 1 August 2013., which cites
- Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G (May 2012). "ABH gel is not absorbed from the skin of normal volunteers". Journal of Pain and Symptom Management. 43 (5): 961–966. PMID 22560361.
- Weschules DJ (December 2005). "Tolerability of the compound ABHR in hospice patients". Journal of Palliative Medicine. 8 (6): 1135–1143. PMID 16351526.
- Smith TJ, Ritter JK, Poklis JL, Fletcher D, Coyne PJ, Dodson P, Parker G (May 2012). "ABH gel is not absorbed from the skin of normal volunteers". Journal of Pain and Symptom Management. 43 (5): 961–966.
- ^ Product Information [Internet]. 2011 [cited 2013 Sep 29]. Available from: "TGA eBS - Product and Consumer Medicine Information Licence". Archived from the original on 14 March 2017. Retrieved 29 May 2014.
- ^ HALDOL® Injection For Intramuscular Injection Only Product Information [Internet]. Janssen; 2011 [cited 2013 Sep 29]. Available from: "TGA eBS - Product and Consumer Medicine Information Licence". Archived from the original on 14 March 2017. Retrieved 29 September 2013.
- ^ Truven Health Analytics, Inc. DrugPoint® System (Internet) [cited 2013 Sep 29]. Greenwood Village, CO: Thomsen Healthcare; 2013.
- ^ Joint Formulary Committee. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
- ^ FDA Psychopharmacological Drugs Advisory Committee (9 July 2000). "Briefing Document for ZELDOX CAPSULES (Ziprasidone HCl)" (PDF). Food and Drug Administration. Archived from the original (PDF) on 19 January 2017. Retrieved 30 September 2016.
- PMID 28738100.
- PMID 18384230.
Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills
- ^ "Medication 'worsens Alzheimer's'". BBC NEWS. 1 April 2008. Retrieved 3 August 2016.
- S2CID 24709695.
- PMID 19020191.
- PMID 6415823.
- PMID 28738100.
- ^ Pierre JM. "Time to retire haloperidol?". Current Psychiatry. 19 (5): 19.
- ^ Id.
- PMID 36816400.
- ISBN 978-0-85369-845-6.
Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
- ^ ISBN 9780198527480.
- S2CID 6267180.
- ISBN 9788847026797.
- ^ "Haloperidol at Drugs.com". Archived from the original on 22 November 2011.
- PMID 9577836.
- S2CID 34455982.
- PMID 1372084.
- PMID 9536001.
- PMID 7520908.
- S2CID 24130758.
- S2CID 24971006.
- ^ PMID 12629531.
- PMID 8967976.
- ^ "Haldol Decanoate - Summary of Product Characteristics (SmPC) - (emc)". www.medicines.org.uk. Retrieved 26 December 2021.
- ^ "drugs.com". Archived from the original on 10 August 2011.
- ^ PMID 10360127.
- S2CID 9565741.
- ISBN 978-1-86036-008-4.[page needed]
- ^ PMID 16433054.
- S2CID 7720401.
- ISBN 978-981-4578-37-0.
- ISBN 978-1-4557-3394-1.
- PMID 6122740.
External links
- "Haloperidol". Drug Information Portal. U.S. National Library of Medicine.