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{{Short description|Chemical compound}}
{{drugbox
{{pp-pc}}
| Verifiedfields = changed
{{Use dmy dates|date=November 2017}}
| Watchedfields = changed
{{Use American English|date=November 2017}}
| verifiedrevid = 419225254

| IUPAC_name = 1--<BR>4-piperidinyl]-1,3-dihydro-<BR>2''H''-benzimidazole-2-one
{{infobox drug
| image = Pimozide skeletal.svg
| Watchedfields = changed
| width = 300
| verifiedrevid = 464206733
| IUPAC_name = 1--4-piperidinyl]-1,3-dihydro-2''H''-benzimidazole-2-one
| image = Pimozide.svg
| width = 200
| image2 = Pimozide-based-on-xtal-3D-bs-17.png


<!--Clinical data--> <!--Clinical data-->
| tradename = Orap | tradename = Orap
| Drugs.com = {{drugs.com|monograph|pimozide}} | Drugs.com = {{drugs.com|monograph|pimozide}}
| MedlinePlus = a686018 | MedlinePlus = a686018
| licence_US = Pimozide
| pregnancy_category = Teratogenic data in rats exist : drug should only be used when the benefit clearly exceeds the potential harm to the unborn
| pregnancy_AU = B1
| legal_status = Rx-only, not a controlled narcotic
| pregnancy_US = C
| routes_of_administration = oral only
| legal_AU = S4
| legal_BR = C1
| legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=] |language=pt-BR |publication-date=2023-04-04}}</ref>
| legal_US = Rx-only
| routes_of_administration = Oral
| class = ]


<!--Pharmacokinetic data--> <!--Pharmacokinetic data-->
| bioavailability = at least 40 to 50% | bioavailability = 40-50%
| metabolism = ], ] and ]
| metabolism = hepatic, by cytochrome P450, isoenzymes 3A, and 1A2; metabolites are inactive
| elimination_half-life = 2 to 3 days (average in one study 55 hours) | elimination_half-life = 55 hours (adults), 66 hours (children)
| excretion = urine, and to a lesser extent in feces | excretion = Urine


<!--Identifiers--> <!--Identifiers-->
| CASNo_Ref = {{cascite|correct|CAS}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 2062-78-4
| CAS_number_Ref = {{cascite|correct|??}}
| ATC_prefix = N05
| CAS_number = 2062-78-4
| ATC_suffix = AG02
| ATC_prefix = N05
| PubChem = 16362
| ATC_suffix = AG02
| IUPHAR_ligand = 90
| PubChem = 16362
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| IUPHAR_ligand = 90
| DrugBank = DB01100
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| DrugBank = DB01100
| ChemSpiderID = 15520
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| UNII_Ref = {{fdacite|correct|FDA}}
| ChemSpiderID = 15520
| UNII = 1HIZ4DL86F
| UNII_Ref = {{fdacite|correct|FDA}}
| KEGG_Ref = {{keggcite|correct|kegg}}
| UNII = 1HIZ4DL86F
| KEGG = D00560
| KEGG_Ref = {{keggcite|correct|kegg}}
| ChEBI_Ref = {{ebicite|correct|EBI}}
| KEGG = D00560
| ChEBI = 8212
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEBI = 8212
| ChEMBL = 1423
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1423


<!--Chemical data--> <!--Chemical data-->
| C=28 | H=29 | F=2 | N=3 | O=1 |C=28 |H=29 |F=2 |N=3 |O=1
| smiles = Fc1ccc(cc1)C(c2ccc(F)cc2)CCCN5CCC(N4c3ccccc3NC4=O)CC5
| molecular_weight = 461.56
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| smiles = Fc1ccc(cc1)C(c2ccc(F)cc2)CCCN5CCC(N4c3ccccc3NC4=O)CC5
| InChI = 1/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34) | StdInChI = 1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YVUQSNJEYSNKRX-UHFFFAOYSA-N
| StdInChI = 1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = YVUQSNJEYSNKRX-UHFFFAOYSA-N
}} }}


'''Pimozide''' ('''Orap''') is an ] ] of the ] class. It was discovered at ] in 1963. It has a high potency compared to ] (ratio 50-70:1). On a weight basis it is even more potent than ]. It also has special neurologic indications for ] and resistant ]. The side effects include ], ], and, more rarely, ] and prolongation of the ]. '''Pimozide''' (sold under the brand name '''Orap''') is a neuroleptic ] of the ] class. It was discovered at ] in 1963. It has a high potency compared to ] (ratio 50-70:1). On a weight basis it is even more potent than ]. It also has special indication for ] and resistant ].


== Uses == == Medical uses ==
Pimozide is used in its oral preparation in ] and chronic ] (on-label indications in Europe only), Tourette syndrome and resistant ] (Europe, USA and Canada). In Germany the 1&nbsp;mg tablet is indicated for the treatment of some forms of reactive depression.


Pimozide is used for Tourette syndrome,<ref name="Pimozide_1985"/> and resistant ] (Europe, United States, and Canada) and in Europe for ], chronic ], ], and ].<ref>{{cite book | vauthors = Munro A | date = 1999 | title = Delusional disorder | location = Cambridge | publisher = Cambridge University Press | isbn = 0-521-58180-X }}</ref>
== Off-label use ==


== Efficacy ==
Pimozide has been used in the treatment of ] and ].<ref>Munro, A. (1999) ''Delusional disorder''. Cambridge: Cambridge University Press. ISBN 0-521-58180-X</ref>


A 2013 ] compared pimozide with other antipsychotics for schizophrenia or related psychoses: Pimozide versus any other antipsychotic<ref name=Mot2013>{{cite journal | vauthors = Mothi M, Sampson S | title = Pimozide for schizophrenia or related psychoses | journal = The Cochrane Database of Systematic Reviews | volume = 11 | issue = 11 | pages = CD001949 | date = November 2013 | pmid = 24194433 | doi = 10.1002/14651858.CD001949.pub3 | url = http://www.cochrane.org/CD001949/SCHIZ_pimozide-for-schizophrenia-or-related-psychoses | url-status = live | df = dmy-all | archive-url = https://web.archive.org/web/20171127123319/http://www.cochrane.org/CD001949/SCHIZ_pimozide-for-schizophrenia-or-related-psychoses | archive-date = 27 November 2017 }}</ref>
It has been used for ].<ref name="pmid12639456">{{cite journal |author=van Vloten WA |title=Pimozide: use in dermatology |journal=Dermatol. Online J. |volume=9 |issue=2 |pages=3 |year=2003 |month=March |pmid=12639456 |doi= |url=http://dermatology.cdlib.org/92/reviews/pimozide/vanvloten.html }}</ref>


In one case a series of 33 patients with delusional parasitosis (median age, 60 years), pimozide was prescribed for 24 patients, 18 of whom took the drug. The dose ranged from 1 to 5&nbsp;mg daily. No information regarding initial dosing was specified, although the dose was continued for 6 weeks prior to tapering. Of those patients receiving pimozide, 61% (11/18) experienced improvement in or full remission of symptoms. The use of pimozide for the treatment of delusional parasitosis is based primarily on data from case series/reports that demonstrate some efficacy in the majority of patients. Currently, ]s such as ] or ] are used as first line treatment. However, patients who experience negative side-effects with the first line medications are typically given pimozide.<ref>{{cite journal | vauthors = Generali JA, Cada DJ | title = Pimozide: parasitosis (delusional) | journal = Hospital Pharmacy | volume = 49 | issue = 2 | pages = 134–135 | date = February 2014 | pmid = 24623867 | pmc = 3940679 | doi = 10.1310/hpj4902-134 }}</ref><ref>{{cite journal | vauthors = Meehan WJ, Badreshia S, Mackley CL | title = Successful treatment of delusions of parasitosis with olanzapine | journal = Archives of Dermatology | volume = 142 | issue = 3 | pages = 352–355 | date = March 2006 | pmid = 16549712 | doi = 10.1001/archderm.142.3.352 | doi-access = }}</ref>
Use as a ] inhibitor has been described.<ref name="pmid19015342">{{cite journal |author=Lieberman LA, Higgins DE |title=A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection |journal=Antimicrob. Agents Chemother. |volume=53 |issue=2 |pages=756–64 |year=2009 |month=February |pmid=19015342 |pmc=2630664 |doi=10.1128/AAC.00607-08 |url=http://aac.asm.org/cgi/pmidlookup?view=long&pmid=19015342}}</ref>


== Pharmacology == == Contraindications ==
=== Pharmacokinetics ===


It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.<ref name = EMC /> Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or ].<ref name = EMC /> Likewise its use is also advised against in individuals with uncorrected ] and ] or clinical significant cardiac disorders (e.g. a recent ] or ].<ref name =EMC /> It is also contraindicated in individuals being cotreated with ] (SSRI) or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.<ref name = EMC /> Likewise its use is contraindicated in individuals receiving treatment with ], ], or ] inhibitors.<ref name = EMC />
Plasma levels of pimozide can vary widely between patients, and in insufficient response ] may be required to ascertain that the patient is developing adequate plasma levels before withdrawing the drug and attempting other antipsychotics.

=== Pharmacodynamics ===

Pimozide blocks the following postsynaptic receptors according to Bezchlinyk-Butler and Jeffries:

* Extremely strong: ]
* Strong: ], ], ]
* Moderate: ], ], ]
* Weak: ], ]
* Extremely weak: ]

Pimozide also inhibits moderately the ] (DAT), accounting for the stimulant properties of the drug. The inhibition of dopamine-reuptake may also explain the synergistic effects of pimozide in the treatment of ADHD when given together with a stimulant.

== Contraindications and precautions ==

* Contraindicated in patients taking citalopram ] (Celexa) and escitalopram ] (Lexapro) due to prolongation of the QTc interval, as per the FDA.
* Patients with prominent agitation or anxiety
* Depressed patients
* Severe intoxication with alcohol, opiates, and psychoactive drugs (e.g. antidepressants, benzodiazepines)
* Preexisting ]
* Comedication with ], ] and vetoconazol (see below under interactions)
* Caution: Anticonvulsive treatment in epileptic patients should not be interrupted. Pimozide may in principle lower the seizure-threshold.
* Caution: Patients under 18 yrs. of age. Side effects may be particularly frequent and severe. Treatment should be started with low initial dose and the dose increased very slowly.


== Side effects == == Side effects ==


Very common (>10% frequency) side effects include:<ref name = MSR /><ref name = EMC /><ref name = MD /><ref name = DM />
{{see|Typical antipsychotic}}


* ]
Pimozide can have severe, potentially fatal side effects. As with other ] antagonists pimozide can cause various ]s, including ] and ]. The frequency of extrapyramidal side effects is quite high. ] may also occur.
* Constipation
* Dizziness
* Dry mouth
* ]
* ]
* ]
* Speech disorder


== Overdose ==
In particular, pimozide is known for causing the unpleasant extrapyramidal side effect ] (commonly referred to as "restless pacing") in a large percentage of those who take it. This "restlessness" can sometimes be treated with ] drugs (mainly ]), ] or ]s, particularly ] (Klonopin). Unfortunately, in many cases this side effect can be so intense that even large doses of these drugs are unable to counter it, and often is so extreme that self-destructive behaviour, including attempting ], may occur.


Pimozide overdose presents with severe ], ], ], QT interval prolongation and ventricular arrhythmias including ].<ref name = EMC /> Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.<ref name = EMC /> Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.<ref name = EMC />
Pimozide has no significant sedative properties, but behaves in some patients as a mild stimulant. If the drug is given shortly before bedtime, ] may result. Excitement, agitation, irritability, tension, anxiety, and nightmares have all been seen.


== Pharmacology ==
The drug can also cause depression in quite a number of patients, severe enough to result in suicide.


Pimozide acts as an ] of the ], ], and ] and the ]. It is also a ] ].
Pimozide has few but nonetheless existing anticholinerg side effects (e.g. dry mouth, obstipation, urinary hesitancy), rarely of clinical importance.


Similarly to other typical antipsychotics pimozide has a high affinity for the ] and this likely results in its sexual (due to ]) and extrapyramidal side effects as well as its therapeutic efficacy against the positive symptoms of ].<ref name="Maudsley">{{cite book |isbn = 978-0-470-97948-8 |title = The Maudsley prescribing guidelines in psychiatry | vauthors = Taylor D, Paton C, Shitij K |year = 2012 |publisher = Wiley-Blackwell |location = West Sussex }}</ref>
Pimozide may rarely cause seizures of the grand-mal-type. Patients with epilepsia should be counselled to maintain anticonvulsive therapy.


{| class="wikitable sortable"
Particularly disturbing is a relatively high incidence of the ], which may lead to ], ] and death via ].
|+ <big>Binding profile</big><ref group = Note>A lower K<sub>i</sub> value indicates a stronger binding</ref>
! Protein !! K<sub>i</sub> (nM)<ref>{{cite web |title = PDSP K<sub>i</sub> Database |work = Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J |author1-link=Bryan Roth|url = http://pdsp.med.unc.edu/pdsp.php |publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health |access-date = 4 December 2013 |date = 12 January 2011 |url-status = dead |archive-url = https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archive-date = 8 November 2013 |df = dmy-all }}</ref> !! Notes
|-
| ] || 650 ||
|-
| ] || 48.4 || This receptor is believed to be responsible for the atypicality of other antipsychotics like ], ] and ]. Pimozide's affinity towards this receptor is low compared to its affinity for the D<sub>2</sub> receptor and hence this receptor unlikely contributes to its effects to any meaningful extent.
|-
| ] || 2,112 ||
|-
| ] || 71 ||
|-
| ] || 0.5 || Relatively high affinity for this receptor may explain its supposed antidepressant-like effects in animal models of depression.<ref>{{cite journal | vauthors = Mahesh R, Pandey DK, Bhatt S, Gautam BK |title = Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression |journal = Indian Journal of Pharmaceutical Education and Research |volume = 45 |issue = 1 |pages = 46–53 |date = January–March 2011 }}</ref>
|-
| ] || 197.7 || Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.<ref name = Maudsley />
|-
| ] || 1,593 ||
|-
| ] || 821 ||
|-
| ] || 376.5 ||
|-
| ] || 1,955 || This receptor is believed to be responsible for the interference with glucose ] seen with some of the ] such as ] and ].<ref name="GG">{{cite book |isbn = 978-0-07-162442-8 |title = Goodman and Gilman's The Pharmacological Basis of Therapeutics |edition = 12th | vauthors = Brunton L, Chabner B, Knollman B |year = 2010 |publisher = McGraw-Hill Professional |location = New York |title-link = Goodman and Gilman's The Pharmacological Basis of Therapeutics }}</ref> Pimozide's low affinity for this receptor likely contributes to the comparatively mild effects on glucose homeostasis.
|-
| ] || >10,000 ||
|-
| ] || 0.33 || Likely the receptor responsible for the therapeutic effects against the positive symptoms of schizophrenia of antipsychotics like pimozide as well as the prolactin-elevating and extrapyramidal side effect-generating effects of typical antipsychotics like pimozide.<ref name = GG />
|-
| ] || 0.25 ||
|-
| ] || 1.8 ||
|-
| ] || 18 || May be responsible for pimozide's high liability for prolonging the QT interval.<ref name = GG />
|-
| ] || 692 || Likely responsible for why pimozide tends to produce so little sedation.<ref name =" GG" />
|-
| ] || 508 ||
|}


{| class="wikitable" align="left"
There is also specific information of carcinogenity both in animals and humans. The carcinogenity in animals has been proven and the carcinogenity in man is strongly suspected (breast cancer and probably liver tumors).
|+ <big>Pharmacokinetic data</big><ref name=MSR>{{cite web |title = Oral (pimozide) dosing, indications, interactions, adverse effects, and more |work = Medscape Reference |publisher = WebMD |access-date = 4 December 2013 |url = http://reference.medscape.com/drug/orap-pimozide-342982#showall |url-status = live |archive-url = https://web.archive.org/web/20131204215602/http://reference.medscape.com/drug/orap-pimozide-342982#showall |archive-date = 4 December 2013 |df = dmy-all }}</ref><ref name=EMC>{{cite web |title = Oral 4 mg tablets. - Summary of Product Characteristics |work = electronic Medicines Compendium |publisher = Janssen-Cilag Ltd |date = 2 April 2013 |access-date = 4 December 2013 |url = http://www.medicines.org.uk/emc/medicine/6753/SPC/Orap+4+mg+tablets./ |url-status = dead |archive-url = https://web.archive.org/web/20160303230421/http://www.medicines.org.uk/emc/medicine/6753/SPC/Orap+4+mg+tablets./ |archive-date = 3 March 2016 }}</ref><ref name = MD>{{cite book |title = Pimozide | vauthors = Brayfield A |work = Martindale: The Complete Drug Reference |publisher = Pharmaceutical Press |location = London, UK |url = https://www.medicinescomplete.com/mc/martindale/current/7087-n.htm |access-date = 4 December 2013 |date = 12 February 2013 }}</ref><ref name=DM>{{cite web |title = ORAP (pimozide) tablet |work = DailyMed |publisher = Teva Select Brands |date = July 2012 |url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd9729c3-545f-4d34-9bc7-72b61e028fc4 |access-date = 4 December 2013 |url-status = live |archive-url = https://web.archive.org/web/20130703154327/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd9729c3-545f-4d34-9bc7-72b61e028fc4 |archive-date = 3 July 2013 |df = dmy-all }}</ref>
! Pharmacokinetic parameter !! Value
|-
| Time to peak plasma concentration (T<sub>max</sub>) || 6-8 hr
|-
| Peak plasma concentration (C<sub>max</sub>) || 4-19&nbsp;ng/mL
|-
| Elimination half-life (t<sub>1/2</sub>) || 55 hours (adults), 66 hours (children)
|-
| Metabolising enzymes || ], ] and ]
|-
| Excretion pathways || Urine
|}
{{clear}}


== History ==
Because of these serious side effects, Pimozide should only be used after the patient has received full information about the drug and agrees to treatment with it despite the risks (fully ]).


In 1985 pimozide was approved by the FDA for marketing as an ] for the treatment of Tourette's syndrome.<ref name="Pimozide_1985">{{cite journal | vauthors = Colvin CL, Tankanow RM | title = Pimozide: use in Tourette's syndrome | journal = Drug Intelligence & Clinical Pharmacy | volume = 19 | issue = 6 | pages = 421–424 | date = June 1985 | pmid = 3891283 | doi = 10.1177/106002808501900602 | s2cid = 19179304 }}</ref>
Given to a non-psychotic patient, Pimozide can result in severe disabilities, both mental and physical. Loss of ability to lead a conversation is a common side effect. Due to that specific side effect, patients who have been wrongly given Pimozide cannot explain their need to stop taking the medication. Pimozide should be prescribed only after a complete medical examination and consensus between the patient and doctor.


== See also ==
There have been reported cases of irreversible ] in healthy patients treated with Pimozide.


{{Portal|Medicine}}
== Interactions ==


* ]
* Central Depressants: Action of the other drug may be increased.
* ]
* Drugs competing for the same cytochrome subenzymes: Risk of mutual and uncontrollable increased action. ], ], ] and ] all lead to increased pimozide plasma levels and to a higher incidence of (potentially serious) side effects of pimozide.
* ]
* Grapefruit juice: Elimination of Pimozide is inhibited. Avoid drinking grapefruit juice during treatment with Pimozide.
* ]


== Dosage == == Notes ==


{{reflist|group=Note}}
Due to its long halflife pimozide is usually given once a day (preferably in the morning, because pimozide may have a rather stimulating effect).


== References ==
Recommended dose ranges are as follows:
* Acute psychotic disorders: usually 2 to 12&nbsp;mg daily starting with low doses, then slowly increasing. More than 20&nbsp;mg daily should be avoided, because the benefit-risk ratio is unclear
* Chronic psychotic disorders: for maintenance of acute results 6&nbsp;mg daily is the usual dose
* Tics: 1 to 16&nbsp;mg daily in slowly increasing doses
* Reactive Depression: 1 to 2&nbsp;mg daily
* ADHD: not clearly established, start with very small doses (e.g. 0.5 to 1.0&nbsp;mg) and increase slowly according to the clinical reaction and the side effects encountered.


{{Reflist}}
== Animal toxicity and human overdose ==

The precise lethal dose in humans is unknown. The oral LD50 is 228&nbsp;mg/kg in mice, 5120&nbsp;mg/kg in rats, 188&nbsp;mg/kg in guinea pigs, and 40&nbsp;mg/kg in dogs.

Generally human overdoses show exaggerations of the pharmacologic effect of Pimozide. These are : ECG-abnormalities, severe extrapyramidal reactions, hypotension, and comatose state with respiratory depression.

Treatment is largely symptomatic. No specific antidote exists. Induction of emesis, gastric lavage and the repeated application of activated charcoal can all be helpful. Monitor and stabilize, if necessary, the vital functions. Hospitialization and/or admittance to intensive care treatment is in most cases necessary. Due to the long halflife of Pimozide, the symptoms of overdose may last for several days.

== Chemistry ==
Pimozide is a diphenylbutylpiperidine derivative.
]
]
]
*Janssen, P. A. J.; Soudijn,W.; VanWijngaarden, I.; Dreese A.; Arzneimittel-Forsch. 1968, 18, 282.
*P. Meisel, H.-J. Heidrich, H.-J. Hansch, E. Kretzschman, S. Henker, G. Laban, Ger. (Dem.) {{Cite patent|DD|243284}} (1987).
*P.A.J. Janssen, {{US Patent|3196157}} (1965).
*P. Janssen, {{Cite patent|DE|1470124}} (1963).

(See also: ])

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


== External links == == External links ==
* (A medical white paper on its use)
* (patient information)


{{Antipsychotics}} {{Antipsychotics}}
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Latest revision as of 21:53, 16 September 2024

Chemical compound

Pharmaceutical compound
Pimozide
Clinical data
Trade namesOrap
AHFS/Drugs.comMonograph
MedlinePlusa686018
License data
Pregnancy
category
  • AU: B1
Routes of
administration		Oral
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40-50%
MetabolismCYP3A4, CYP1A2 and CYP2D6
Elimination half-life55 hours (adults), 66 hours (children)
ExcretionUrine
Identifiers
IUPAC name
  • 1--4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.016.520 Edit this at Wikidata
Chemical and physical data
FormulaC28H29F2N3O
Molar mass461.557 g·mol
3D model (JSmol)
SMILES
  • Fc1ccc(cc1)C(c2ccc(F)cc2)CCCN5CCC(N4c3ccccc3NC4=O)CC5
InChI
  • InChI=1S/C28H29F2N3O/c29-22-11-7-20(8-12-22)25(21-9-13-23(30)14-10-21)4-3-17-32-18-15-24(16-19-32)33-27-6-2-1-5-26(27)31-28(33)34/h1-2,5-14,24-25H,3-4,15-19H2,(H,31,34)
  • Key:YVUQSNJEYSNKRX-UHFFFAOYSA-N
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Pimozide (sold under the brand name Orap) is a neuroleptic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine (ratio 50-70:1). On a weight basis it is even more potent than haloperidol. It also has special indication for Tourette syndrome and resistant tics.

Medical uses

Pimozide is used for Tourette syndrome, and resistant tics (Europe, United States, and Canada) and in Europe for schizophrenia, chronic psychosis, delusional disorder, and paranoid personality disorder.

Efficacy

A 2013 systematic review compared pimozide with other antipsychotics for schizophrenia or related psychoses: Pimozide versus any other antipsychotic

In one case a series of 33 patients with delusional parasitosis (median age, 60 years), pimozide was prescribed for 24 patients, 18 of whom took the drug. The dose ranged from 1 to 5 mg daily. No information regarding initial dosing was specified, although the dose was continued for 6 weeks prior to tapering. Of those patients receiving pimozide, 61% (11/18) experienced improvement in or full remission of symptoms. The use of pimozide for the treatment of delusional parasitosis is based primarily on data from case series/reports that demonstrate some efficacy in the majority of patients. Currently, atypical antipsychotics such as olanzapine or risperidone are used as first line treatment. However, patients who experience negative side-effects with the first line medications are typically given pimozide.

Contraindications

It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation. Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or torsades de pointes. Likewise its use is also advised against in individuals with uncorrected hypokalaemia and hypomagnesaemia or clinical significant cardiac disorders (e.g. a recent myocardial infarction or bradycardia. It is also contraindicated in individuals being cotreated with selective serotonin reuptake inhibitors (SSRI) or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives. Likewise its use is contraindicated in individuals receiving treatment with CYP3A4, CYP1A2, or CYP2D6 inhibitors.

Side effects

Very common (>10% frequency) side effects include:

Overdose

Pimozide overdose presents with severe extrapyramidal symptoms, hypotension, sedation, QT interval prolongation and ventricular arrhythmias including torsades de pointes. Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose. Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.

Pharmacology

Pimozide acts as an antagonist of the D2, D3, and D4 receptors and the 5-HT7 receptor. It is also a hERG blocker.

Similarly to other typical antipsychotics pimozide has a high affinity for the dopamine D2 receptor and this likely results in its sexual (due to prolactin hypersecretion) and extrapyramidal side effects as well as its therapeutic efficacy against the positive symptoms of schizophrenia.

Binding profile
Protein Ki (nM) Notes
5-HT1A 650
5-HT2A 48.4 This receptor is believed to be responsible for the atypicality of other antipsychotics like clozapine, olanzapine and quetiapine. Pimozide's affinity towards this receptor is low compared to its affinity for the D2 receptor and hence this receptor unlikely contributes to its effects to any meaningful extent.
5-HT2C 2,112
5-HT6 71
5-HT7 0.5 Relatively high affinity for this receptor may explain its supposed antidepressant-like effects in animal models of depression.
α1A 197.7 Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.
α2A 1,593
α2B 821
α2C 376.5
M3 1,955 This receptor is believed to be responsible for the interference with glucose homeostasis seen with some of the atypical antipsychotics such as clozapine and olanzapine. Pimozide's low affinity for this receptor likely contributes to the comparatively mild effects on glucose homeostasis.
D1 >10,000
D2 0.33 Likely the receptor responsible for the therapeutic effects against the positive symptoms of schizophrenia of antipsychotics like pimozide as well as the prolactin-elevating and extrapyramidal side effect-generating effects of typical antipsychotics like pimozide.
D3 0.25
D4 1.8
hERG 18 May be responsible for pimozide's high liability for prolonging the QT interval.
H1 692 Likely responsible for why pimozide tends to produce so little sedation.
σ 508
Pharmacokinetic data
Pharmacokinetic parameter Value
Time to peak plasma concentration (Tmax) 6-8 hr
Peak plasma concentration (Cmax) 4-19 ng/mL
Elimination half-life (t1/2) 55 hours (adults), 66 hours (children)
Metabolising enzymes CYP3A4, CYP1A2 and CYP2D6
Excretion pathways Urine

History

In 1985 pimozide was approved by the FDA for marketing as an orphan drug for the treatment of Tourette's syndrome.

See also

Notes

  1. A lower Ki value indicates a stronger binding

References

  1. 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.
  2. ^ Colvin CL, Tankanow RM (June 1985). "Pimozide: use in Tourette's syndrome". Drug Intelligence & Clinical Pharmacy. 19 (6): 421–424. doi:10.1177/106002808501900602. PMID 3891283. S2CID 19179304.
  3. Munro A (1999). Delusional disorder. Cambridge: Cambridge University Press. ISBN 0-521-58180-X.
  4. Mothi M, Sampson S (November 2013). "Pimozide for schizophrenia or related psychoses". The Cochrane Database of Systematic Reviews. 11 (11): CD001949. doi:10.1002/14651858.CD001949.pub3. PMID 24194433. Archived from the original on 27 November 2017.
  5. Generali JA, Cada DJ (February 2014). "Pimozide: parasitosis (delusional)". Hospital Pharmacy. 49 (2): 134–135. doi:10.1310/hpj4902-134. PMC 3940679. PMID 24623867.
  6. Meehan WJ, Badreshia S, Mackley CL (March 2006). "Successful treatment of delusions of parasitosis with olanzapine". Archives of Dermatology. 142 (3): 352–355. doi:10.1001/archderm.142.3.352. PMID 16549712.
  7. ^ "Oral 4 mg tablets. - Summary of Product Characteristics". electronic Medicines Compendium. Janssen-Cilag Ltd. 2 April 2013. Archived from the original on 3 March 2016. Retrieved 4 December 2013.
  8. ^ "Oral (pimozide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Archived from the original on 4 December 2013. Retrieved 4 December 2013.
  9. ^ Brayfield A (12 February 2013). Pimozide. London, UK: Pharmaceutical Press. Retrieved 4 December 2013. {{cite book}}: |work= ignored (help)
  10. ^ "ORAP (pimozide) tablet [Teva Select Brands]". DailyMed. Teva Select Brands. July 2012. Archived from the original on 3 July 2013. Retrieved 4 December 2013.
  11. ^ Taylor D, Paton C, Shitij K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
  12. Roth BL, Driscol J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 4 December 2013.
  13. Mahesh R, Pandey DK, Bhatt S, Gautam BK (January–March 2011). "Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression". Indian Journal of Pharmaceutical Education and Research. 45 (1): 46–53.
  14. ^ Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.

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