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Linopirdine is a putative cognition-enhancing drug with a novel mechanism of action. Linopirdine blocks the KCNQ2\3 heteromer M current with an IC50 of 2.4nM,<ref name="pmid9694925">Schnee ME, Brown BS (1998) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9694925 Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons.] ''J Pharmacol Exp Ther'' 286 (2):709-17. PMID: [http://pubmed.gov/9694925 9694925]</ref> disinhibiting acetylcholine release, and increases hippocampal CA3-schaffer collateral glutamate release onto CA1 pyramidal neurons.<ref name="pmid22674722">Sun J, Kapur J (2012) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=22674722 M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission.] ''J Physiol'' 590 (Pt 16):3953-64. [http://dx.doi.org/10.1113/jphysiol.2012.235820 DOI:10.1113/jphysiol.2012.235820] PMID: [http://pubmed.gov/22674722 22674722]</ref> Linopirdine is able to nearly completely reverse the senescence-related decline in cortical c-FOS, this effect is blocked by atropine and MK-801, suggesting Linopirdine can compensate for the age related decline in acetylcholine release.<ref name="pmid11378256">Dent GW, Rule BL, Zhan Y, Grzanna R (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11378256 The acetylcholine release enhancer linopirdine induces Fos in neocortex of aged rats.] ''Neurobiol Aging'' 22 (3):485-94. PMID: [http://pubmed.gov/11378256 11378256]</ref> Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3.,<ref name="pmid9694925">Schnee ME, Brown BS (1998) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9694925 Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons.] ''J Pharmacol Exp Ther'' 286 (2):709-17. PMID: [http://pubmed.gov/9694925 9694925]</ref>
{{User sandbox}}
<!-- EDIT BELOW THIS LINE -->
{{Drugbox| verifiedrevid = 464369120
| IUPAC_name = 4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one
| image = Haloperidol.svg
| width = 250
| image2 = Haloperidol-from-xtal-3D-balls.png

<!--Clinical data-->
| tradename = Haldol
| Drugs.com = {{drugs.com|monograph|haloperidol}}
| MedlinePlus = a682180
| pregnancy_category = C
| legal_status = Rx-only
| routes_of_administration = Oral, [[Intramuscular injection|IM]], [[Intravenous therapy|IV]], [[Injection (medicine)#Depot injection|depot]] (as [[decanoate]] [[ester]])

<!--Pharmacokinetic data-->
| bioavailability = Approx. 50–60% (tablets and liquid)
| metabolism = hepatic
| elimination_half-life = 10–30 hours
| excretion = Biliary and [[kidney|renal]]

<!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 52-86-8
| ATC_prefix = N05
| ATC_suffix = AD01
| PubChem = 3559
| IUPHAR_ligand = 86
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00502
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3438
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = J6292F8L3D
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00136
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 5613
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 54

<!--Chemical data-->
| C=21 | H=23 | Cl=1 | F=1 | N=1 | O=2
| molecular_weight = 375.9 g/mol
| smiles = c1cc(ccc1C(=O)CCCN2CCC(CC2)(c3ccc(cc3)Cl)O)F
| InChI = 1/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
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = LNEPOXFFQSENCJ-UHFFFAOYSA-N
}}

'''Haloperidol''' is a [[dopamine antagonist]] of the [[typical antipsychotic]] class of medications. It is a [[butyrophenone]] derivative and has [[pharmacology|pharmacological effects]] similar to the [[phenothiazine]]s.

Haloperidol is an older antipsychotic used in the treatment of [[schizophrenia]] and acute [[psychosis|psychotic]] states and [[delirium]]. A long-acting [[decanoate]] [[ester]] is used as an injection given every four weeks to people with [[schizophrenia]] or related illnesses who have poor adherence to medication regimens 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''' (common tradename in the US and UK), '''Halosten''', '''Keselan''', '''Linton''', '''Peluces''', '''Serenace''', '''Serenase''', and '''Sigaperidol'''.

==History==
Haloperidol was discovered by [[Paul Janssen]].<ref>{{cite book
|last=Healy
|first=David
|authorlink=David Healy (psychiatrist)
|title=The psychopharmacologists
|volume=1
|year=1996
|publisher=Chapman and Hall
|location=London
|isbn=978-1-86036-008-4
}}
</ref> It was developed in 1958 at the Belgian company [[Janssen Pharmaceutica]] and submitted to the first of clinical trials in [[Belgium]] later that year.<ref>{{cite journal
| author = Granger B, Albu S
| title = The haloperidol story
| journal = Annals of Clinical Psychiatry : Official Journal of the American Academy of Clinical Psychiatrists
| volume = 17
| issue = 3
| pages = 137–40
| year = 2005
| pmid = 16433054
| doi = 10.1080/10401230591002048
}}</ref>

Haloperidol was approved by the [[U.S. Food and Drug Administration]] (FDA) on April 12, 1967; it was 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 anti[[dopaminergic]] 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&nbsp;mg chlorpromazine is equivalent to 1&nbsp;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 [[dopamine]]rgic action in the [[nigrostriatal pathway]]s, which is the probable reason for the high frequency of [[Extrapyramidal system|extrapyramidal]]-motoric side effects ([[dystonia]]s, [[akathisia]], and [[Parkinson's disease|pseudoparkinsonism]]).

Haloperidol has minor [[histamine|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. Haloperidol antagonizes all dopamine receptor subtypes (D1, D2, D3, D4, and D5). The antipsychotic also inhibits histamine (H1) receptors and muscarinic (M1) receptors, to a lesser extent.

The peripheral antidopaminergic effects of haloperidol account for its strong [[antiemetic]] activity. There, it acts at the [[chemoreceptor trigger zone]]. 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 when injected intramuscularly. 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 six days after the injection, falling thereafter, with an approximate half-life of three weeks.<ref>{{cite web|url=http://www.drugs.com/pro/haldol-decanoate.html|title=drugs.com}}</ref>

===Intravenous injections===
The bioavailability is 100% in intravenous (IV) injection, and the very rapid onset of action is seen within seconds. The duration of action is four to six hours. If haloperidol is given as a slow IV infusion, the onset of action is slowed, and the duration of action is prolonged.

[[File:Haloperidol (Haldol).jpg|thumb|Haloperidol for injection]]

===Therapeutic concentrations===
Plasma levels of four 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 20-fold higher compared to blood levels. It is slowly eliminated from brain tissue,<ref name="Kornhuber1999">Kornhuber J, Schultz A, Wiltfang J, Meineke I, Gleiter CH, Zöchling R, Boissl KW, Leblhuber F, Riederer P. Persistence of haloperidol in human brain tissue. Am.J.Psychiatry 156:885-890, 1999. PMID 10360127</ref> which may explain the slow disappearance of side effects when the medication is stopped.<ref name="Kornhuber1999" /><ref>Kornhuber J, Wiltfang J, Riederer P, Bleich S. Neuroleptic drugs in the human brain: clinical impact of persistence and region-specific distribution. Eur.Arch.Psychiatry Clin.Neurosci. 256:274-280, 2006. PMID 16788768</ref>

==Uses==
A comprehensive review of haloperidol has found it to be an effective agent in treatment of symptoms associated with [[schizophrenia]].<ref name="pmid17054159">{{cite journal |author=Joy CB, Adams CE, Lawrie SM |title=Haloperidol versus placebo for schizophrenia |journal=Cochrane Database Syst Rev |volume= |issue=4 |pages=CD003082 |year=2006 |pmid=17054159 |doi=10.1002/14651858.CD003082.pub2|url=http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003082/frame.html |editor1-last=Irving |editor1-first=Claire B}}</ref> It is also used in the control of the symptoms of:

* Acute [[psychosis]], such as drug-induced psychosis (LSD, psilocybin, amphetamines, ketamine,<ref>{{cite journal
| author = Giannini AJ, Underwood NA, Condon M
| title = Acute ketamine intoxication treated by haloperidol: a preliminary study
| journal = American Journal of Therapeutics
| volume = 7
| issue = 6
| pages = 389–92
| year = 2000
| month = November
| pmid = 11304647
| doi = 10.1097/00045391-200007060-00008
}}</ref> and phencyclidine,<ref>{{cite journal
| author = Giannini AJ, Eighan MS, Loiselle RH, Giannini MC
| title = Comparison of haloperidol and chlorpromazine in the treatment of phencyclidine psychosis
| journal = Journal of Clinical Pharmacology
| volume = 24
| issue = 4
| pages = 202–4
| year = 1984
| month = April
| pmid = 6725621
| doi =
}}</ref> and psychosis associated with high fever or metabolic disease
* Acute [[mania|manic phases]] until the concomitantly given first-line drugs such as [[Lithium pharmacology|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 (medicine)|sclerosis]]
* Adjunctive treatment of alcohol and opioid withdrawal
* Treatment of severe nausea and emesis in postoperative and [[palliative care]], especially for palliating adverse effects of [[radiation therapy]] and [[chemotherapy]] in [[oncology]]
* Treatment of neurological disorders, such as [[tic disorder]]s, [[Tourette syndrome]], and [[Chorea (disease)|chorea]]
* Adjunctive treatment of severe chronic pain, always with [[analgesic]]s
* Therapeutic trial in personality disorders, such as [[borderline personality disorder]]
* Treatment of intractable [[hiccups]]
* Also used in aquaculture to block dopamine receptors 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 antipsychotic|atypical neuroleptics]] (e.g., [[clozapine]], [[risperidone]], [[olanzapine]], or [[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,<ref name="pmid3736271">{{cite journal |author=Cavanaugh SV |title=Psychiatric emergencies |journal=Med. Clin. North Am. |volume=70 |issue=5 |pages=1185–202 |year=1986 |pmid=3736271 |doi=}}</ref><ref name="pmid15985915">{{cite journal |author=Currier GW |title=The controversy over "chemical restraint" in acute care psychiatry |journal=J Psychiatr Pract |volume=9 |issue=1 |pages=59–70 |year=2003 |pmid=15985915|doi=10.1097/00131746-200301000-00006}}</ref> 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.<ref name="pmid17054159"/><ref name="pmid11500996">{{cite journal |author=Allen MH, Currier GW, Hughes DH, Reyes-Harde M, Docherty JP |title=The Expert Consensus Guideline Series. Treatment of behavioral emergencies |journal=Postgrad Med |volume= |issue=Spec No |pages=1–88; quiz 89–90 |year=2001 |pmid=11500996 |doi=}}</ref><ref name="pmid15985913">{{cite journal |author=Allen MH, Currier GW, Hughes DH, Docherty JP, Carpenter D, Ross R |title=Treatment of behavioral emergencies: a summary of the expert consensus guidelines |journal=J Psychiatr Pract |volume=9 |issue=1 |pages=16–38 |year=2003 |pmid=15985913|doi=10.1097/00131746-200301000-00004}}</ref><ref name="pmid16319571">{{cite journal |author=Allen MH, Currier GW, Carpenter D, Ross RW, Docherty JP |title=The expert consensus guideline series. Treatment of behavioral emergencies 2005 |journal=J Psychiatr Pract |volume=11 Suppl 1 |issue= |pages=5–108; quiz 110–2 |year=2005 |pmid=16319571 |doi=10.1097/00131746-200511001-00002}}</ref> 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 multiple-year UK study by the Alzheimer's Research Trust suggested this drug and other [[neuroleptic]] antipsychotic drugs commonly given to Alzheimer's patients with mild behavioural problems often make their condition worse.<ref>
{{cite journal
| author = Ballard C
| title = A randomised, blinded, placebo-controlled trial in dementia patients continuing or stopping neuroleptics (the DART-AD trial)
| journal = PLoS Medicine
| volume = 5
| issue = 4
| pages = e76
| year = 2008
| month = April
| pmid = 18384230
| pmc = 2276521
| doi = 10.1371/journal.pmed.0050076
| laysummary = http://news.bbc.co.uk/1/hi/health/7319393.stm
| laysource = BBC News
| laydate = 2008-04-01
| quote=Neuroleptics provided no benefit for patients with mild behavioural problems, but were associated with a marked deterioration in verbal skills
| author-separator = ,
| author2 = Lana MM
| author3 = Theodoulou M
| display-authors = 3
| editor1-last = Brayne
| editor1-first = Carol
| last4 = Douglas
| first4 = Simon
| last5 = McShane
| first5 = Rupert
| last6 = Jacoby
| first6 = Robin
| last7 = Kossakowski
| first7 = Katja
| last8 = Yu
| first8 = Ly-Mee
| last9 = Juszczak
| first9 = Edmund
}}</ref> The study concluded that

{{cquote|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 nonmedical uses ===
{{See also|Punitive psychiatry in the Soviet Union}}

[[Soviet dissident]]s, including medical staff, have reported several times on the use of haloperidol in the Soviet Union for punitive purposes or simply to break the prisoners' wills.<ref>{{cite book | last = Podrabinek | first = Aleksandr | title = Punitive Medicine | publisher = Karoma Publishers | location = Ann Arbor Mich. | year = 1980 | isbn = 0-89720-022-5 | pages= 15&ndash;20}}</ref><ref name="pmid7820004">{{cite journal
| author = Kosserev I, Crawshaw R
| title = Medicine and the Gulag
| journal = BMJ (Clinical Research Ed.)
| volume = 309
| issue = 6970
| pages = 1726–30
| year = 1994
| pmid = 7820004
| pmc = 2542687
}}</ref><ref>{{cite book | last = de Boer | first = S. P. | coauthors = E. J. Driessen, H. L. Verhaar | title = Biographical Dictionary of Dissidents in the Soviet Union, 1956-1975 | publisher = Martinus Nijhoff Publishers | location = The Hague | year = 1982 | isbn = 90-247-2538-0 }}</ref> Notable dissidents who were administered haloperidol as part of their court-ordered treatment were [[Sergei Kovalev]] and [[Leonid Plyushch]].<ref>{{cite journal
| author = Wade N
| title = Sergei Kovalev: Biologist Denied Due Process and Medical Care
| journal = Science
| volume = 194
| issue = 4265
| pages = 585–587
| year = 1976
| month = November
| pmid = 17818411
| doi = 10.1126/science.194.4265.585
}}</ref> The accounts Plyushch gave in the West, after he was allowed to leave the Soviet Union in 1976, were instrumental in triggering Western condemnation of Soviet practices at the [[World Psychiatric Association]]'s 1977 meeting.<ref>{{cite news
|title = Censuring the Soviets
|url = http://www.time.com/time/magazine/article/0,9171,915433,00.html
|work = TIME
|publisher = CNN
|date = 1977-09-12
|accessdate = 2009-06-21
}}
</ref> 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.<ref>[http://www.time.com/time/printout/0,8816,922041,00.html The Children of Pavlov], TIME, Jun. 23, 1980</ref>

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, it was given to only three detainees. Following lawsuits, U.S. officials changed the procedure so the drug is administered only by the recommendation of medical personnel and under court order.<ref>{{cite news
| title = Fewer US deportees being sedated for removal
| url = http://www.epilepsy.com/newsfeeds/view/5974
| agency = Associated Press
| publisher = Epilepsy.com
| date = 2008-12-30
| accessdate = 2009-06-21
}}
</ref><ref name=seat>{{cite news
| title = U.S. cuts back on sedating deportees with Haldol
| first = Dianne
| last = Solis
| url = http://seattletimes.nwsource.com/html/nationworld/2008590327_deport05.html
| publisher = Seattle Times
| date = 2009-01-05
| accessdate = 2009-06-21
}}
</ref>

==Contraindications==
===Absolute===
* 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

=== Special caution needed ===
* Pre-existing [[Parkinson's disease]]<ref>{{cite journal
| author = Leentjens AF, van der Mast RC
| title = Delirium in elderly people: an update
| journal = Current Opinion in Psychiatry
| volume = 18
| issue = 3
| pages = 325–30
| year = 2005
| month = May
| pmid = 16639157
| doi = 10.1097/01.yco.0000165603.36671.97
| url = http://www.medscape.com/viewarticle/503089_6
| accessdate = 2009-06-21
}}</ref> or [[dementia with Lewy bodies]]
* Patients at special risk for the development of [[Long QT syndrome|QT prolongation]] ([[hypokalemia]], concomitant use of other drugs causing QT prolongation)
* Compromised [[liver]] function (as haloperidol is metabolized and eliminated mainly by the liver)
* In 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 symptoms|extrapyramidal side effect]]s.<ref name="pmid17054159"/> The risk of the face-disfiguring [[tardive dyskinesia]] is around 4% per year in younger patients. Other predisposing factors may be female gender, pre-existing 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 or cramping, restlessness, [[tremor]]s, [[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. [[clinical depression|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]] 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.

[[Long QT syndrome|QT prolongation]] with sudden death is a rarely seen, but clinically significant, side effect. Likewise, the development of [[thrombosis|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 noncompliance. 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.<ref name="Silvestri S, Seeman MV, Negrete JC, et al. 2000 174–80">{{cite journal |author=Silvestri S |title=Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study |journal=Psychopharmacology |volume=152 |issue=2 |pages=174–80 |year=2000 |month=October |pmid=11057521 |doi=10.1007/s002130000532 |author-separator=, |author2=Seeman MV |author3=Negrete JC |display-authors=3 |last4=Houle |first4=Sylvain |last5=Shammi |first5=C.M. |last6=Remington |first6=Garry J. |last7=Kapur |first7=Shitij |last8=Zipursky |first8=Robert B. |last9=Wilson |first9=Alan A.}}</ref> In another study, a live survey of a patient showed the person has 90% more [[dopamine receptors]], of the D2 subtype, than before treatment with haloperidol.<ref name="Silvestri S, Seeman MV, Negrete JC, et al. 2000 174–80"/> The long-term effect of this is unknown, but the first study concludes 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.<ref name="pmid15756305">{{cite journal |author=Dorph-Petersen KA, Pierri JN, Perel JM, Sun Z, Sampson AR, Lewis DA |title=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 |journal=[[Neuropsychopharmacology (journal)|Neuropsychopharmacology]] |volume=30 |issue=9 |pages=1649–61 |year=2005 |month=September |pmid=15756305 |doi=10.1038/sj.npp.1300710}}</ref> 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.<ref name="pmid17945195">{{cite journal |author=Konopaske GT, Dorph-Petersen KA, Sweet RA, Pierri JN, Zhang W, Sampson AR, Lewis DA |title=Effect of chronic antipsychotic exposure on astrocyte and oligodendrocyte numbers in macaque monkeys |journal=[[Biol. Psychiatry]] |volume=63 |issue=8 |pages=759–65 |year=2008 |month=April |pmid=17945195 |pmc=2386415 |doi=10.1016/j.biopsych.2007.08.018}}</ref> A study in 2011 of rats given haloperidol in doses comparable to clinical use for eight weeks found a reduction in brain cortex volume of 10–12%.<ref name="doi:10.1016/j.biopsych.2010.11.010">{{cite journal |author=Vernon, A., Natesan, S., Modo, M. & Kapur, S. |title=Effect of Chronic Antipsychotic Treatment on Brain Structure: A Serial Magnetic Resonance Imaging Study with Ex Vivo and Postmortem Confirmation |journal=[[Biol. Psychiatry]] |volume=69 |issue=10 |pages=936–944 |month=May |doi=10.1016/j.biopsych.2010.11.010 |year=2011}}</ref>

In other studies, the use of potent antipsychotics has been associated with cognitive decline and permanent brain damage.<ref name="breggin2">{{cite book |title=Brain disabling treatments in psychiatry |last=Breggin |first=P |authorlink= |coauthors= |year=2007 |publisher=Springer Publishing Company |location= |isbn=0-8261-2934-X |page= |pages=320 |url=http://books.google.fi/books?id=hBd0V7Ex8PUC&lpg=PR11&dq=neuroleptics%20withdrawal%20death&pg=PA85#v=onepage&q=neuroleptics%20withdrawal%20death&f=false |accessdate=}}</ref>

==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.<ref>{{cite web|url=http://www.chemeurope.com/en/encyclopedia/Haloperidol.html|title=Haloperidol at Chemeurope}}</ref>

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

==Pregnancy and lactation==
Data from [[Animal testing|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.<ref>{{cite web|url=http://www.drugs.com/pro/haldol.html|title=Haldol at Drugs.com}}</ref>

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, or breastfeeding should be stopped.

== 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 those of patients at the general hospital, and 9.5 times higher than the reported incidents in the general population.<ref name="pmid8599407">{{cite journal |author=Halbreich U, Shen J, Panaro V |title=Are chronic psychiatric patients at increased risk for developing breast cancer? |journal=Am J Psychiatry |volume=153 |issue=4 |pages=559–60 |year=1996 |pmid=8599407 |doi= |url=http://ajp.psychiatryonline.org/cgi/pmidlookup?view=long&pmid=8599407}}</ref> 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.

==Neurotoxic metabolites==
Haloperidol has been shown to metabolize in murine<ref>{{cite journal|title=Studies on the metabolism of haloperidol (HP): the role of CYP3A in the production of the neurotoxic pyridinium metabolite HPP+ found in rat brain following ip administration of HP.|journal=Life Sci. 1995 Nov 17;57(26):2439-46.|pmid=8847965|url=http://www.ncbi.nlm.nih.gov/pubmed/8847965}}</ref>, and human<ref>{{cite journal|title=Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes.|journal=Chem Res Toxicol. 1996 Jun;9(4):800-|pmid=8831826|url=http://www.ncbi.nlm.nih.gov/pubmed/8831826}}</ref> hepatocytes via CYP-3A4 to the neurotoxic pyridinium metabolites 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxobutylpyridinium(HPP+)and 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-hydroxybutylpyridinium (RHPP+). <ref>{{cite journal|title=Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites.|journal=Chem Res Toxicol. 2006 Jul;19(7):914-20.|pmid=16841959|url=http://www.ncbi.nlm.nih.gov/pubmed/16841959}}</ref> HPP+ and RHPP+ are lipophilic and have elimination half lives of 67.3 hrs and 63.3 hrs, respectively.<ref>{{cite journal|title=Metabolism of haloperidol to pyridinium species in patients receiving high doses intravenously: is HPTP an intermediate?|journal=Life Sci. 1997;61(24):2383-90.|pmid=9399630|url=http://www.ncbi.nlm.nih.gov/pubmed/9399630}}</ref> HPP+ is a structural analog of the more widely known Parkinson’s producing neurotoxin [[MPP+]] and its precursor [[MTPT]]. Unlike MPP+, HPP+ is not dependent MAO-B for metabolism to toxic species and does not require functional dopamine transporter protein for intracellular uptake.<ref>{{cite journal|title=Binding of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]pyridinium ion (HPP+), a metabolite of haloperidol, to synthetic melanin: implications for the dopaminergic neurotoxicity of HPP+.|journal=Neurotox Res. 2004;6(7-8):535-42.|pmid=15639785|url=http://www.ncbi.nlm.nih.gov/pubmed/15639785}}</ref>

Microdialysis studies were performed in the striatum, substantia nigra and cortex of conscious rats to compare the neurotoxic potential of 1-methyl-4-phenylpyridinium (MPP+) and HPP+ to dopaminergic and serotonergic neurons. HPP+ was a less potent neurotoxin than MPP+ to dopaminergic neurons and displayed equipotent serotonergic neurotoxicity.<ref>{{cite journal|title=MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies.|journal=J Pharmacol Exp Ther. 1994 Jan;268(1):380-7|pmid=8301579|url=http://www.ncbi.nlm.nih.gov/pubmed/8301579}}</ref> Impairment of cortico-striatal mitochondrial complex I is pathognomic of MPP+ neurotoxicity and parkinson’s cellular dysfunction.<ref>{{cite journal|title=Mitochondrial complex I inhibition in Parkinson's disease: how can curcumin protect mitochondria?|journal=Antioxid Redox Signal. 2007 Mar;9(3):399-408.|pmid=17184173|url=http://www.ncbi.nlm.nih.gov/pubmed/17184173}}</ref><ref>{{cite journal|title=Mitochondria, oxidative damage, and inflammation in Parkinson's disease.|journal=Ann N Y Acad Sci. 2003 Jun;991:120-31.|pmid=12846981|url=http://www.ncbi.nlm.nih.gov/pubmed/12846981}}</ref> HPP+ is more potent than MPP+ at inhibiting murine mitochondrial complex I with an IC50 of 12mMol for HPP+ and 160mMol for MPP+.<ref>{{cite journal|title=MPP(+)-like neurotoxicity of a pyridinium metabolite derived from haloperidol: in vivo microdialysis and in vitro mitochondrial studies.|journal=J Pharmacol Exp Ther. 1994 Jan;268(1):380-7|pmid=8301579|url=http://www.ncbi.nlm.nih.gov/pubmed/8301579}}</ref> Prolonged, high dose (2 & 5mg\kg) administration of haloperidol in a murine model elevates striatal nitric oxide, TNF-a, and caspase-3.<ref>{{cite journal|title=Activation of striatal inflammatory mediators and caspase-3 is central to haloperidol-induced orofacial dyskinesia.|journal=Eur J Pharmacol. 2008 Aug 20;590(1-3):241-5. Epub 2008 Jun 14|pmid=18590723|url=http://www.ncbi.nlm.nih.gov/pubmed/18590723}}</ref>

HPP+ and RHPP+ have been found in the brains of patients taking Haldol at autopsy.<ref>{{cite journal|title=Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem.|journal=Life Sci. 1997;60(8):529-34.|pmid=9042387|url=http://www.ncbi.nlm.nih.gov/pubmed/9042387}}</ref> A short term 6 week trial failed to find statistically significant correlation between HPP+, RHPP+ and extrapyramidal symptoms.<ref>{{cite journal|title=Disposition of haloperidol pyridinium and reduced haloperidol pyridinium in schizophrenic patients: no relationship with clinical variables during short-term treatment.|journal=J Clin Psychopharmacol. 2000 Apr;20(2):210-9.|pmid=10770460|url=http://www.ncbi.nlm.nih.gov/pubmed/10770460}}</ref> A long term retrospective study found significant positive correlation between levels of HPP+ and severity of tardive dyskinesia.<ref>{{cite journal|title=Serum concentrations of haloperidol pyridinium metabolites and the relationship with tardive dyskinesia and parkinsonism: a cross-section study in psychiatric patients.|journal=Pharmacopsychiatry. 2005 Jul;38(4):171-7|url=http://www.ncbi.nlm.nih.gov/pubmed/16025420}}</ref>

==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 salt|lithium]]: rare cases of the following symptoms have been noted: [[encephalopathy]], early and late extrapyramidal side effects, other neurologic symptoms, and coma.<ref>{{cite web|url=http://www.ncbi.nlm.nih.gov/pubmed/6415823|title=Toxic irreversible encephalopathy induced by lithium carbonate and haloperidol. A report of 2 cases.}}</ref>
* [[Guanethidine]]: antihypertensive action antagonized
* [[Epinephrine]]: action antagonized, paradoxical decrease in blood pressure may result
* [[Amphetamine]] and [[methylphenidate]]: counteracts increased action of norepinephrine and dopamine in patients with [[narcolepsy]] or [[ADD]]/[[ADHD]]

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

* Acute problems: single doses of 1 to 5&nbsp;mg (up to 10&nbsp;mg) oral or IM, usually repeated every four to six hours, not exceeding an oral dose of 100&nbsp;mg daily. Doses used for IV injection are usually five to 10&nbsp;mg as a single dose; not exceeding 50&nbsp;mg daily. The British National Formulary recommends a maximum daily dose of 30&nbsp;mg total (IM and oral) with a maximum of 18&nbsp;mg by the IM route.

: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&nbsp;mg increased the risk of side effects without improving efficacy.<ref>P Oosthuizen, RA Emsley, J Turner et al. Determining the optimal dose of haloperidol in first-episode psychosis. Journal of Psychopharmacology. 2001, 15: 251–255.</ref> Patients responded with doses under even 2&nbsp;mg in first episode psychosis.<ref>J Tauscher, S Kapur. CNS Drugs. 2001, 15, 9: 671–678(8)</ref>
* Chronic conditions: 0.5 to 20&nbsp;mg daily oral doses are recommended, 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 to 500&nbsp;mg daily have been conducted (in most cases with an anticholinergic, anti-Parkinsonian 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 arrhythmia]]s) 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 IM 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 the 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, decreased [[perspiration]])
* 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. [[Epinephrine]] is avoided for treatment of hypotension and shock, because its action might be reversed. In the case of a severe overdose, antidotes such as [[bromocryptine]] or [[ropinirole]] may be used to treat the extrapyramidal effects caused by haloperidol, acting as dopamine receptor agonists.

===Prognosis===
In general, the prognosis of overdose is good, and lasting damage is not known, provided the patient has survived the initial phase. An overdose of haloperidol can be fatal.<ref>{{cite web|url=http://www.drugs.com/mtm/haloperidol.html|title=Haloperidol at Drugs.com}}</ref>

==Other formulations==
[[Image:Haloperidol decanoate highlighting ester group.svg|thumb|[[Skeletal formula]] of haloperidol decanoate: The decanoate group is highlighted in {{color|blue|blue}}.]]
The [[decanoate]] ester of haloperidol (haloperidol decanoate, trade names Haldol decanoate, Halomonth, Neoperidole) has a much longer duration of action, so is often used in people known to be noncompliant with oral medication. A dose of 25 to 250&nbsp;mg is given by intramuscular injection once every two to four weeks.<ref>Goodman and Gilman's ''Pharmacological Basis of Therapeutics, 10th edition'' (McGraw-Hill, 2001).</ref>

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.<ref>{{cite web|url=http://www.lcrx.com/veterinary_avian.html|title=Veterinary:Avian at Lloyd Center Pharmacy}}</ref>

==Dose forms==
* Liquid: 2.0 and 10&nbsp;mg/ml
* Tablets: 0.5, 1.0, 2.0, 5.0, 10, and 20&nbsp;mg
* Injection: 5&nbsp;mg (1 ml)
* Depot injection forms
* The original brand Haldol and many generics are available

==See also==
* [[Biological psychiatry]]

==References==
{{Reflist|2}}

==External links==
* [http://www.rxlist.com/cgi/generic/haloper.htm Rx-List.com - Haloperidol]
* [http://www.nlm.nih.gov/medlineplus/druginfo/meds/a682180.html Medline plus - Haloperidol]
* [http://www.kompendium.ch/MonographieTxt.aspx?lang=de&MonType=fi Swiss scientific information on Haldol]
*{{cite web
| url = http://www.who.int/medicines/publications/essentialmedicines/Updated_sixteenth_adult_list_en.pdf
| title = WHO Model List of Essential Medicines
| edition = 16th list (updated)
| publisher = World Health Organization
| accessdate = 2010-09-14
| format = PDF
| month = March
| year = 2010
}}
* [http://druginfo.nlm.nih.gov/drugportal/dpdirect.jsp?name=Haloperidol U.S. National Library of Medicine: Drug Information Portal - Haloperidol]

{{Antipsychotics}}
{{Dopaminergics}}
{{Serotonergics}}

[[Category:Antiemetics]]
[[Category:Organofluorides]]
[[Category:Organochlorides]]
[[Category:Alcohols]]
[[Category:Piperidines]]
[[Category:Butyrophenone antipsychotics]]
[[Category:Janssen Pharmaceutica]]
[[Category:Belgian inventions]]

[[bar:Haloperidol]]
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[[de:Haloperidol]]
[[et:Haloperidool]]
[[el:Αλοπεριδόλη]]
[[es:Haloperidol]]
[[fa:هالوپریدول]]
[[fr:Halopéridol]]
[[ko:할로페리돌]]
[[it:Aloperidolo]]
[[hu:Haloperidol]]
[[nl:Haloperidol]]
[[ja:ハロペリドール]]
[[no:Haloperidol]]
[[pl:Haloperidol]]
[[pt:Haloperidol]]
[[ro:Haloperidol]]
[[ru:Галоперидол]]
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[[zh:氟哌啶醇]]

Latest revision as of 22:55, 14 January 2013

Linopirdine is a putative cognition-enhancing drug with a novel mechanism of action. Linopirdine blocks the KCNQ2\3 heteromer M current with an IC50 of 2.4nM,[1] disinhibiting acetylcholine release, and increases hippocampal CA3-schaffer collateral glutamate release onto CA1 pyramidal neurons.[2] Linopirdine is able to nearly completely reverse the senescence-related decline in cortical c-FOS, this effect is blocked by atropine and MK-801, suggesting Linopirdine can compensate for the age related decline in acetylcholine release.[3] Linopirdine also blocks homomeric KCNQ1 and KCNQ4 voltage gated potassium channels which contribute to vascular tone with substantially less selectivity than KCNQ2/3.,[1]

  1. ^ a b Schnee ME, Brown BS (1998) Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons. J Pharmacol Exp Ther 286 (2):709-17. PMID: 9694925
  2. ^ Sun J, Kapur J (2012) M-type potassium channels modulate Schaffer collateral-CA1 glutamatergic synaptic transmission. J Physiol 590 (Pt 16):3953-64. DOI:10.1113/jphysiol.2012.235820 PMID: 22674722
  3. ^ Dent GW, Rule BL, Zhan Y, Grzanna R (2001) The acetylcholine release enhancer linopirdine induces Fos in neocortex of aged rats. Neurobiol Aging 22 (3):485-94. PMID: 11378256
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