Haloperidol

Haloperidol
Systematic (IUPAC) name
4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one
Clinical data
Trade names Haldol
AHFS/Drugs.com monograph
MedlinePlus a682180
Pregnancy cat. C
Legal status Prescription only
Routes Oral, IM, IV, depot (as decanoate ester)
Pharmacokinetic data
Bioavailability Approx. 50–60% (tablets and liquid)
Metabolism hepatic
Half-life 10–30 hours
Excretion Biliary and renal
Identifiers
CAS number 52-86-8 YesY
ATC code N05AD01
PubChem CID 3559
IUPHAR ligand 86
DrugBank DB00502
ChemSpider 3438 YesY
UNII J6292F8L3D YesY
KEGG D00136 YesY
ChEBI CHEBI:5613 YesY
ChEMBL CHEMBL54 YesY
Chemical data
Formula C21H23ClFNO2 
Mol. mass 375.9 g/mol
SMILES eMolecules & PubChem
 YesY(what is this?)  (verify)

Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines.

Haloperidol is an older antipsychotic used in the treatment of schizophrenia and, more acutely, in the treatment of acute psychotic states and delirium. A long-acting decanoate ester is used as an injection given every 4 weeks to people with schizophrenia or related illnesses who have a poor compliance with medication and suffer frequent relapses of illness, or to overcome the drawbacks inherent to its orally administered counterpart that burst dosage increases risk or intensity of side effects. In some countries, injections of antipsychotics such as haloperidol can be ordered by a court at the request of a psychiatrist.

Haloperidol is sold under the tradenames Aloperidin, Bioperidolo, Brotopon, Dozic, Duraperidol (Germany), Einalon S, Eukystol, Haldol, Halosten, Keselan, Linton, Peluces, Serenace, Serenase, and Sigaperidol.

Contents

History

Haloperidol was discovered by Paul Janssen.[1] It was developed in 1958 by the Belgian company Janssen Pharmaceutica and submitted to the first of clinical trials in Belgium later that year.[2]

Haloperidol was approved by the U.S. Food and Drug Administration (FDA) on April 12, 1967, later marketed in the U.S. and other countries under the brand name Haldol by McNeil Laboratories.

Pharmacology

Haloperidol is an antipsychotic butyrophenone. Due to its strong central antidopaminergic action, it is classified as a highly potent neuroleptic. It is approximately 50 times more potent than chlorpromazine (sold under the brand name Thorazine, among others) on a weight basis (50 mg chlorpromazine is equivalent to 1 mg haloperidol). Haloperidol possesses a strong activity against delusions and hallucinations, most likely due to an effective dopaminergic receptor blockage in the mesocortex and the limbic system of the brain. It blocks the dopaminergic action in the nigrostriatal pathways, which is the probable reason for the high frequency of extrapyramidal-motoric side effects (dystonias, akathisia, pseudoparkinsonism).

Haloperidol has minor antihistaminic and anticholinergic properties, therefore cardiovascular and anticholinergic side effects such as hypotension, dry mouth, constipation, etc. are seen quite infrequently, compared with less-potent neuroleptics such as chlorpromazine. Haloperidol also has sedative properties and displays a strong action against psychomotor agitation due to a specific action in the limbic system. However, in some cases, haloperidol may worsen psychomotor agitation via its potent dopamine receptor antagonism. Dopamine receptor antagonism, mainly of the D2 receptor subtype, can cause akathisia, psychomotor agitation, anxiety, and restlessness, which may worsen the condition of some patients.

The peripheral antidopaminergic effects of haloperidol account for its strong antiemetic activity. There, it acts at the chemoreceptor trigger zone (CTZ). Haloperidol is useful to treat severe forms of nausea/emesis such as those resulting from chemotherapy. The peripheral effects lead also to a relaxation of the gastric sphincter muscle and an increased release of the hormone prolactin, with the possible emergence of breast enlargement and secretion of milk (galactorrhea) in both sexes.

Pharmacokinetics

Intramuscular injections

The drug is well and rapidly absorbed with a high bioavailability.

The decanoate injectable formulation is for intramuscular administration only and is not intended to be used intravenously.

The plasma concentrations of haloperidol decanoate reach a peak at about 6 days after the injection, falling thereafter, with an approx. half-life of 3 weeks.[3]

Intravenous injections

The bioavailability is 100% and the very rapid onset of action is seen within seconds.

The duration of action is 4–6 hours. If haloperidol is given as a slow IV infusion, the onset of action is slowed, and the duration of action is prolonged.

Therapeutic concentrations

Plasma levels of 4 to 25 micrograms per liter are required for therapeutic action.

The determination of plasma levels can be used to calculate dose adjustments and to check compliance, particularly in long-term patients.

Plasma levels in excess of the therapeutic range may lead to a higher incidence of side-effects or even pose the risk of haloperidol intoxication.

The concentration of haloperidol in brain tissue is about 20fold higher compared to blood levels. Haloperidol is slowly eliminated from brain tissue,[4] which may explain the slow disappearence of side-effects when haloperdol medication is stopped.[4][5]

Uses

A comprehensive review of haloperidol has found it to be an effective agent in treatment of symptoms associated with schizophrenia.[6] Haloperidol is also used in the control of the symptoms of:

  • Acute psychosis, such as drug psychosis (LSD, psilocybin, amphetamines, ketamine,[7] and phencyclidine[8]), psychosis associated with high fever or metabolic disease
  • Acute manic phases until the concomitantly given first-line drugs such as lithium or valproate are effective
  • Hyperactivity, aggression.
  • Acute delirium
  • Otherwise uncontrollable severe behavioral disorders in children and adolescents
  • Agitation and confusion associated with cerebral sclerosis
  • Adjunctive treatment of alcohol and opioid withdrawal
  • Treatment of severe nausea and emesis in postoperative and palliative care, especially with regards to palliating adverse effects of radiation therapy and chemotherapy in oncology
  • Treatment of neurological disorders such as tic disorders, Tourette syndrome, and chorea
  • Adjunctive treatment of severe chronic pain, always together with analgesics
  • Therapeutic trial in personality disorders such as borderline personality disorder
  • Also used in the treatment of intractable hiccups

In Aquaculture

  • Also used to block dopamine receptor to enable GnrHA function for ovulation use in spawning fish.

Some weeks or even months of treatment may be needed before a remission of schizophrenia is evident.

In some clinics, the use of atypical neuroleptics (e.g., clozapine, risperidone, olanzapine, ziprasidone) is, in general, preferred over haloperidol, because these drugs have an appreciably lower incidence of extrapyramidal side effects. Each of these drugs, however, has its own spectrum of potentially serious side effects (e.g., agranulocytosis with clozapine, weight gain with increased risk of diabetes and of stroke). Atypical neuroleptics are also much more expensive and have recently been the subject of increasing controversy regarding their efficacy in comparison to older products and their side effects.

Haloperidol was considered indispensable for treating psychiatric emergency situations,[9][10] although the newer atypical drugs have gained greater role in a number of situations as outlined in a series of consensus reviews published between 2001 and 2005.[6][11][12][13] It is enrolled in the World Health Organization List of Essential Medicines.

As is common with typical neuroleptics, haloperidol is by far more active against "positive" psychotic symptoms (delusions, hallucinations, etc.) than against "negative" symptoms (social withdrawal, etc.).

A multi-year UK study by the Alzheimer's Research Trust suggested that this drug and other neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse.[14] The study concluded that

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status and by some measures improved functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this possibility must be weighed against the unwanted effects of therapy. The current study helps to inform a clinical management strategy for current practice, but the considerable risks of maintenance therapy highlight the urgency of further work to find, develop, and implement safer and more effective treatment approaches for neuropsychiatric symptoms in people with AD.

Controversial non-medical uses

There are multiple reports from Soviet dissidents, including medical staff, on the use of haloperidol in the Soviet Union for punitive purposes or simply to break the prisoners' will.[15][16][17] Notable dissidents that were administered haloperidol as part of their court ordered treatment were Sergei Kovalev and Leonid Plyushch.[18] The accounts of Plyushch in the West, after he was allowed to leave the Soviet Union in 1976, were instrumental in the triggering Western condemnation of Soviet practices at the World Psychiatric Association's 1977 meeting.[19] The use of haloperidol in the Soviet Union's psychiatric system was prevalent because it was one of the few psychotropic drugs produced in quantity in the USSR.[20]

Haloperidol has been used for its sedating effects during the deportations of immigrants by the United States Immigration and Customs Enforcement (ICE). During 2002-2008, federal immigration personnel used haloperidol to sedate 356 deportees. By 2008, following court challenges over the practice, haloperidol was given to only 3 detainees. Following lawsuits, U.S. officials changed the procedure so that the drug is administered only by the recommendation of medical personnel and under court order.[21][22]

Contraindications

Absolute

  • Preexisting 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

Special caution needed

  • Preexisting Parkinson's disease[23] or dementia with Lewy bodies
  • Patients at special risk for the development of QT prolongation (hypokalemia, concomitant use of other drugs causing QT prolongation)
  • Compromised liver-function (as haloperidol is metabolized and eliminated mainly by the liver)
  • Patients with hyperthyreosis; the action of haloperidol is intensified and side-effects are more likely.
  • IV injections: risk of hypotension or orthostatic collapse.

Adverse effects

Haloperidol is noted for its strong early and late extrapyramidal side effects.[6]

The risk of the facial disfiguring tardive dyskinesia is around 4% per year in younger patients. Other predispositive factors may be female gender, preexisting affective disorder, and cerebral dysfunction.

Akathisia often manifests itself with anxiety, dysphoria, and an inability to remain motionless.

Other side effects include dry mouth, lethargy, restlessness of akathisia, muscle-stiffness, muscle-cramping, restlessness, tremors, Rabbit syndrome, and weight-gain; side effects like these are more likely to occur when the drug is given in high doses and/or during long-term treatment. Depression, severe enough to result in suicide, is quite often seen during long-term treatment. Care should be taken to detect and treat depression early in course. Sometimes the change from haloperidol to a mildly potent neuroleptic (e.g., chlorprothixene or chlorpromazine), together with appropriate antidepressant therapy, does help. Sedative and anticholinergic side effects occur more frequently in the elderly. The likelihood of one's experiencing one or more of these side-effects is quite high regardless of age and gender, especially with prolonged use.

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

The potentially fatal neuroleptic malignant syndrome (NMS) is a significant possible side effect. Haloperidol and fluphenazine are the two drugs that cause NMS most often. NMS involves fever and other symptoms. Allergic and toxic side effects occur. Skin rash and photosensitivity both occur in fewer than 1% of patients. Children and adolescents are particularly sensitive to the early and late extrapyramidal side effects of haloperidol. It is not recommended to treat pediatric patients.

QT prolongation with sudden death is a rarely seen but clinically significant side-effect. Likewise, the development of thromboembolic complications are also seen.

Haloperidol may have a negative impact on vigilance or decrease the ability of the patient to drive or operate a machine, particularly initially.

Haloperidol is not devoid of potential psychological dependence. However, due to the debilitating side effects, patients prescribed this drug have a high rate of non-compliance. The current recommendation is to pay close attention to the patient's experience, and taper or discontinue use if the patient has a high rate of dissatisfaction with treatment, as it may lead to dangerously rapid discontinuation.

Haloperidol has been shown to dramatically increase dopamine activity, up to 98%, in test subjects after two weeks on a "moderate to high" dose compared to chronic schizophrenics.[24] In another study, a live survey of a patient showed that the person has 90% more dopamine receptors, of the D2 subtype, than before treatment with haloperidol.[24] The long term effect of this is unknown, but the first study concludes that this upregulation is positively associated with severe dyskinesias (more upregulation, more dyskinesia).

Some research studies have suggested effects of haloperidol on brain tissue. In a 2005 placebo-compared study of six macaques receiving haloperidol for up to 27 months, a significant brain volume change of about 10% and weight decreases were detected.[25] In later studies (2008) of the stored samples, the previously reported changes were attributed primarily to astrocyte and oligodendrocyte loss, with the neuron loss at about 5%, which was not statistically significant.[26] A study in 2011 of rats given haloperidol in doses comparable to clinical use for 8 weeks found a reduction in brain cortex volume of 10–12%.[27]

In other studies, the use of potent antipsychotics has been associated with cognitive decline and permanent brain damage.[28]

Other remarks

During long-term treatment of chronic psychiatric disorders, it should be tried—in regular intervals—to reduce the daily dose to the lowest level needed for maintenance of remission. Sometimes, it may be indicated to terminate haloperidol treatment gradually.

Other forms of therapy (psychotherapy, occupational therapy/ergotherapie, social rehabilitation) should be instituted properly.

Pregnancy and lactation

Data from animal experiments indicate haloperidol is not teratogenic, but is embryotoxic in high doses. In humans, no controlled studies exist. Unconfirmed studies in pregnant women revealed possible damage to the fetus, although most of the women were exposed to multiple drugs during pregnancy. Following accepted general principles, haloperidol should be given during pregnancy only if the benefit to the mother clearly outweighs the potential fetal risk.

Haloperidol, when given to lactating women, is found in significant amounts in their milk. Breastfed children sometimes show extrapyramidal symptoms. If the use of haloperidol during lactation seems indicated, the benefit for the mother should clearly outweigh the risk for the child. Consider termination of breastfeeding.

Carcinogenicity

In an unconfirmed study at the Buffalo Psychiatric Center, relative risks of breast cancer in inmates undergoing long-term treatment with haloperidol were 3.5 times higher than that of patients at the general hospital, and 9.5 times higher than the reported incidents in the general population.[29] These results need confirmation by larger studies and so far, no statistically acceptable evidence has been found to associate long-term use of haloperidol with the potential for increased breast cancer risk in female patients.

Interactions

  • 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%.
  • Methyldopa: increased risk of extrapyramidal side effects and other unwanted central effects
  • Levodopa: decreased action of levodopa
  • Tricyclic antidepressants: metabolism and elimination of tricyclics significantly decreased, increased toxicity noted (anticholinergic and cardiovascular side effects, lowering of seizure threshold)
  • Quinidine, buspirone, and fluoxetine: increased plasma levels of haloperidol, decrease haloperidol dose, if necessary
  • Carbamazepine, phenobarbital, and rifampicin: plasma levels of haloperidol significantly decreased, increase haloperidol dose, if necessary
  • lithium: rare cases of the following symptoms have been noted: encephalopathy, early and late extrapyramidal side effects, other neurologic symptoms, and coma.
  • Guanethidine: antihypertensive action antagonized
  • Epinephrine: action antagonized, paradoxical decrease in blood pressure may result

Doses

As directed by the physician, depends on the condition to be treated, age, and weight of patient:

  • Acute problems: single doses of 1 mg to 5 mg (up to 10 mg) oral or i.m., usually repeated every 4–6 hours, not exceeding an oral dose of 100 mg daily. Doses used for IV injection are usually 5 to 10 mg as a single dose; not exceeding 50 mg daily.
  • Chronic conditions: 0.5 to 20 mg daily oral, rarely more. The lowest dose that maintains remission is employed.
  • Experimental doses: In resistant cases of psychosis small studies with oral doses of up to 300 mg – 500 mg daily have been conducted (in most cases together with an anticholinergic antiparkinsonian drug (Biperiden, Benzatropine, etc.) to avoid severe early extrapyramidal side effects. These studies showed no superior results and led to severe side effects. Also, the frequency of otherwise unusual side effects (hypotension, QT-time prolongation, and serious cardiac arrhythmias) was dramatically increased. The clinical use of haloperidol in these doses is discouraged now and it is recommended to switch the patient gradually to a different neuroleptic (e.g., clozapine, olanzapine, aripiprazole).

Depot forms are also available; these are injected deeply i.m. at regular intervals. The depot forms are not suitable for initial treatment, but are suitable for patients who have demonstrated inconsistency with oral dosages.

Overdose

Experimental evidence from animal studies indicates that doses needed for acute poisoning are quite high in relation to therapeutic doses.

Overdoses with depot injections are uncommon, because only certified personnel are legally permitted to administer them to patients.

Symptoms

Symptoms are usually due to exaggerated side effects. Most often encountered are:

  • Severe extrapyramidal side effects with muscle rigidity and tremors, akathisia, etc.
  • Hypotension or hypertension
  • Sedation
  • Anticholinergic side effects (dry mouth, constipation, paralytic ileus, difficulties in urinating, massive sweating)
  • Coma in severe cases, accompanied by respiratory depression and massive hypotension, shock
  • Rarely, serious ventricular arrhythmia (torsades de pointes), with or without prolonged QT-time
  • Epileptic seizures.

Treatment

Treatment is merely symptomatic and involves intensive care with stabilization of vital functions. In early detected cases of oral overdose induction of emesis, gastric lavage, and the use of activated charcoal can all be tried. Avoid epinephrine for treatment of hypotension and shock, because its action might be reversed.

Prognosis

In general, the prognosis of overdose is good and lasting damage is not known, provided that the patient has survived the initial phase.

Other formulations

Skeletal formula of haloperidol decanoate. The decanoate group is highlighted in blue.

The decanoate ester of haloperidol (Haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, and therefore is often used in people known to be noncompliant with oral medication. A dose of 25 to 250 mg is given by intramuscular injection once every two to four weeks.[30]

The IUPAC name of haloperidol decanoate is 4-(4-chlorophenyl)-1-1[4-(4-fluorophenyl)-4-oxobutyl]-4 piperidinyl decanoate.

Veterinary use

Haloperidol is also used on many different kinds of animals. It appears to be particularly successful when given to birds, e.g., a parrot that will otherwise continuously pluck its feathers out.

Dose forms

  • Liquid: 2 mg/mL, also 10 mg/mL
  • Tablets: 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 20 mg
  • Injection: 5 mg (1 mL)
  • Depot injection forms
  • The original brand Haldol and many generics are available

See also

References

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  3. ^ "drugs.com". http://www.drugs.com/pro/haldol-decanoate.html. 
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  7. ^ Giannini AJ, Underwood NA, Condon M (November 2000). "Acute ketamine intoxication treated by haloperidol: a preliminary study". American Journal of Therapeutics 7 (6): 389–92. doi:10.1097/00045391-200007060-00008. PMID 11304647. 
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  17. ^ de Boer, S. P.; E. J. Driessen, H. L. Verhaar (1982). Biographical Dictionary of Dissidents in the Soviet Union, 1956-1975. The Hague: Martinus Nijhoff Publishers. ISBN 9024725380. 
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  20. ^ The Children of Pavlov, TIME, Jun. 23, 1980
  21. ^ "Fewer US deportees being sedated for removal". Associated Press. Epilepsy.com. 2008-12-30. http://www.epilepsy.com/newsfeeds/view/5974. Retrieved 2009-06-21. 
  22. ^ Solis, Dianne (2009-01-05). "U.S. cuts back on sedating deportees with Haldol". Seattle Times. http://seattletimes.nwsource.com/html/nationworld/2008590327_deport05.html. Retrieved 2009-06-21. 
  23. ^ Leentjens AF, van der Mast RC (May 2005). "Delirium in elderly people: an update". Current Opinion in Psychiatry 18 (3): 325–30. doi:10.1097/01.yco.0000165603.36671.97. PMID 16639157. http://www.medscape.com/viewarticle/503089_6. Retrieved 2009-06-21. 
  24. ^ a b Silvestri S, Seeman MV, Negrete JC et al. (October 2000). "Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study". Psychopharmacology 152 (2): 174–80. doi:10.1007/s002130000532. PMID 11057521. 
  25. ^ Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA (September 2005). "The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys". Neuropsychopharmacology 30 (9): 1649–61. doi:10.1038/sj.npp.1300710. PMID 15756305. 
  26. ^ Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, Lewis DA (April 2008). "Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys". Biol. Psychiatry 63 (8): 759–65. doi:10.1016/j.biopsych.2007.08.018. PMC 2386415. PMID 17945195. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2386415. 
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External links


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  • Halopéridol — Structure de l’halopéridol Général DCI haldoperidol …   Wikipédia en Français

  • Haloperidol — Nombre (IUPAC) sistemático 4 [4 (4 chlorophenyl) 4 hydroxy 1 piperidyl] 1 (4 fluorophenyl) butan 1 one …   Wikipedia Español

  • haloperidol — fármaco antipsicótico utilizado en el tratamiento de la esquizofrenia, fobias, demencia senil, autismo y otros síndromes psicóticos (fórmula química [véase http://www.iqb.es/diccio/h/ha.htm#haloperidol]) Diccionario ilustrado de Términos Médicos …   Diccionario médico

  • halopéridol — ● halopéridol nom masculin Neuroleptique appartenant au groupe des butyrophénones, utilisé pour ses propriétés antihallucinatoires et sédatives dans le traitement des psychoses. halopéridol [alopeʀidɔl] n. m. ÉTYM. Mil. XXe (synthétisé par… …   Encyclopédie Universelle

  • haloperidol — [hal΄ō per′ə dôl, hal΄ō per′ədäl΄] n. [ HALO + (PI)PERID(INE) + OL1] a powerful tranquilizer, C21H23ClFNO2, used in treating schizophrenia, Tourette s syndrome, nausea, etc …   English World dictionary

  • Haloperidol — Strukturformel Allgemeines Freiname Haloperidol Andere Namen …   Deutsch Wikipedia

  • haloperidol — {{#}}{{LM H19769}}{{〓}} {{[}}haloperidol{{]}} ‹ha·lo·pe·ri·dol› {{《}}▍ s.m.{{》}} Fármaco muy utilizado en psiquiatría: • El haloperidol provoca una sedación psicomotora.{{○}} …   Diccionario de uso del español actual con sinónimos y antónimos

  • haloperidol — noun Etymology: hal + piperidine + 1 ol Date: 1960 a depressant C21H23ClFNO2 of the central nervous system used especially as an antipsychotic drug …   New Collegiate Dictionary

  • haloperidol — /hal oh per i dawl , dol /, n. Pharm. a major antipsychotic agent, C21H23ClFNO2, used in the management of schizophrenia, severe anxiety, and other behavioral disorders. [1955 60; HALO + (PI)PERID(INE) + OL1] * * * …   Universalium


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