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词条 Pimozide
释义

  1. Medical uses

  2. Efficacy

  3. Contraindications

  4. Side effects

  5. Overdose

  6. Pharmacology

  7. History

  8. See also

  9. Notes

  10. References

  11. External links

{{pp-pc1}}{{Use dmy dates|date=November 2017}}{{Use American English|date=November 2017}}{{drugbox
| Watchedfields = changed
| verifiedrevid = 464206733
| IUPAC_name = 1-[1-[4,4-Bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one
| image = Pimozide.svg
| width = 200
| tradename = Orap
| Drugs.com = {{drugs.com|monograph|pimozide}}
| MedlinePlus = a686018
| licence_US = Pimozide
| pregnancy_AU = B1
| pregnancy_US = C
| legal_AU = S4
| legal_US = Rx-only
| routes_of_administration = Oral
| bioavailability = 40-50%
| metabolism = CYP3A4, CYP1A2 and CYP2D6
| elimination_half-life = 55 hours (adults), 66 hours (children)
| excretion = Urine
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 2062-78-4
| ATC_prefix = N05
| ATC_suffix = AG02
| PubChem = 16362
| IUPHAR_ligand = 90
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01100
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 15520
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1HIZ4DL86F
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00560
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 8212
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1423
|C=28 |H=29 |F=2 |N=3 |O=1
| molecular_weight = 461.56 g/mol
| smiles = Fc1ccc(cc1)C(c2ccc(F)cc2)CCCN5CCC(N4c3ccccc3NC4=O)CC5
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| 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 (sold under the brand name Orap) is an antipsychotic 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 neurologic indications for Tourette syndrome and resistant tics. The side effects include akathisia, tardive dyskinesia, and, more rarely, neuroleptic malignant syndrome and prolongation of the QT interval.

Medical uses

Pimozide is used in its oral preparation in schizophrenia and chronic psychosis (on-label indications in Europe only), Tourette syndrome,[1] and resistant tics (Europe, USA and Canada).

There have been numerous studies showing Pimozide can be used successfully to treat Delusional parasitosis and traditionally was the drug of choice. However, newer medications have become prevalent recently as the preferred medication. 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. It should be noted that 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.[1][2]

Efficacy

A 2013 systematic review compared pimozide with other antipsychotics for schizophrenia or related psychoses:

Pimozide versus any other antipsychotic[3]
Summary
Enough overall consistency over different outcomes and time scales is present to confirm that pimozide is a drug with effectiveness similar to that of other, more commonly used antipsychotic drugs such as chlorpromazine for people with schizophrenia.[3]

Pimozide has been used in the treatment of delusional disorder and paranoid personality disorder.[4] It has also been used for delusional parasitosis.[5]

Contraindications

It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.[8] Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or torsades de pointes.[8] 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.[8] It is also contraindicated in individuals being cotreated with SSRIs or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.[8] Likewise its use is contraindicated in individuals receiving treatment with CYP3A4, CYP1A2, or CYP2D6 inhibitors.[8]

Side effects

Very common (>10% frequency) side effects include:[13][8][15][16]

  • Akinesia
  • Constipation
  • Dizziness
  • Dry mouth
  • Hyperhidrosis
  • Nocturia
  • Somnolence
  • Speech disorder

Overdose

Pimozide overdose presents with severe extrapyramidal symptoms, hypotension, sedation, QT interval prolongation and ventricular arrhythmias including torsades de pointes.[8] Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.[8] Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.[8]

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.[6]

Binding profile[7]
Protein Ki (nM)[8] 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.[9]
α1A 197.7 Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.[6]
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.[10] 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.[10]
D3 0.25
D4 1.8
hERG 18 May be responsible for pimozide's high liability for prolonging the QT interval.[10]
H1 692 Likely responsible for why pimozide tends to produce so little sedation.
σ 508
Pharmacokinetic data[11][12][13][14]
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
{{clear}}

History

In 1985 the pimozide was approved by the FDA for marketing as an orphan drug for the treatment of Tourette's syndrome.[15]

See also

{{Portal|Medicine}}
  • Amisulpride
  • Pipamperone

Notes

1. ^{{cite journal|last1=Generali|first1=Joyce A.|last2=Cada|first2=Dennis J.|title=Pimozide: Parasitosis (Delusional)|journal=Hospital Pharmacy|date=February 2014|volume=49|issue=2|pages=134–135|doi=10.1310/hpj4902-134|pmid=3940679|pmc=3940679|accessdate=}}
2. ^{{cite journal|last1=Meehan|first1=William|title=Successful Treatment of Delusions of Parasitosis With Olanzapine|journal=Arch Dermatol|date=20 March 2006|doi=10.1001/archderm.142.3.352|url=https://jamanetwork.com/journals/jamadermatology/fullarticle/403426|accessdate=20 March 2018}}
3. ^1 {{cite journal |last1 = Mothi |first1 = M |last2 = Sampson |first2 = S |first3 = |last3 = |title = Pimozide for schizophrenia or related psychoses |journal = Cochrane Database of Systematic Reviews |date = 2013 |volume = 11 |url = http://www.cochrane.org/CD001949/SCHIZ_pimozide-for-schizophrenia-or-related-psychoses |pages = CD001949.pub3 |doi = 10.1002/14651858.CD001949.pub3 |deadurl = no |archiveurl = https://web.archive.org/web/20171127123319/http://www.cochrane.org/CD001949/SCHIZ_pimozide-for-schizophrenia-or-related-psychoses |archivedate = 27 November 2017 |df = dmy-all }}
4. ^Munro, A. (1999)Delusional disorder. Cambridge: Cambridge University Press. {{ISBN|0-521-58180-X}}.
5. ^{{cite journal |author = van Vloten WA |title = Pimozide: use in dermatology |journal = Dermatol. Online J. |volume = 9 |issue = 2 |pages = 3 |date = March 2003 |pmid = 12639456 |doi = |url = http://dermatology.cdlib.org/92/reviews/pimozide/vanvloten.html |deadurl = no |archiveurl = https://web.archive.org/web/20030819211712/http://dermatology.cdlib.org/92/reviews/pimozide/vanvloten.html |archivedate = 19 August 2003 |df = dmy-all }}
6. ^1 {{cite book |isbn = 978-0-470-97948-8 |title = The Maudsley prescribing guidelines in psychiatry |last1 = Taylor |first1 = D |last2 = Paton |first2 = C |last3 = Shitij |first3 = K |year = 2012 |publisher = Wiley-Blackwell |location = West Sussex |pages = }}
7. ^A lower Ki value indicates a stronger binding
8. ^{{cite web |title = PDSP Ki Database |work = Psychoactive Drug Screening Program (PDSP) |last1 = Roth |first1 = BL |last2 = Driscol |first2 = J |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 |accessdate = 4 December 2013 |date = 12 January 2011 |deadurl = yes |archiveurl = https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php |archivedate = 8 November 2013 |df = dmy-all }}
9. ^{{cite journal |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 |url = http://www.ijperonline.com/jan_mar_2011/49-56.pdf |format = PDF }}
10. ^1 2 {{cite book |isbn = 978-0-07-162442-8 |title = Goodman and Gilman's The Pharmacological Basis of Therapeutics |edition = 12th |last1 = Brunton |first1 = L |last2 = Chabner |first2 = B |last3 = Knollman |first3 = B |year = 2010 |publisher = McGraw-Hill Professional |location = New York }}
11. ^1 {{cite web |title = Oral (pimozide) dosing, indications, interactions, adverse effects, and more |work = Medscape Reference |publisher = WebMD |accessdate = 4 December 2013 |url = http://reference.medscape.com/drug/orap-pimozide-342982#showall |deadurl = no |archiveurl = https://web.archive.org/web/20131204215602/http://reference.medscape.com/drug/orap-pimozide-342982#showall |archivedate = 4 December 2013 |df = dmy-all }}
12. ^1 2 3 4 5 6 7 8 9 {{cite web |title = Oral 4 mg tablets. - Summary of Product Characteristics |work = electronic Medicines Compendium |publisher = Janssen-Cilag Ltd |date = 2 April 2013 |accessdate = 4 December 2013 |url = http://www.medicines.org.uk/emc/medicine/6753/SPC/Orap+4+mg+tablets./ |deadurl = yes |archiveurl = https://web.archive.org/web/20160303230421/http://www.medicines.org.uk/emc/medicine/6753/SPC/Orap+4+mg+tablets./ |archivedate = 3 March 2016 }}
13. ^1 {{cite book |title = Pimozide |author = Brayfield, A |work = Martindale: The Complete Drug Reference |publisher = Pharmaceutical Press |location = London, UK |url = http://www.medicinescomplete.com.elibrary.jcu.edu.au/mc/martindale/current/7087-n.htm |accessdate = 4 December 2013 |date = 12 February 2013 }}
14. ^1 {{cite web |title = ORAP (pimozide) tablet [Teva Select Brands] |work = DailyMed |publisher = Teva Select Brands |date = July 2012 |url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd9729c3-545f-4d34-9bc7-72b61e028fc4 |accessdate = 4 December 2013 |deadurl = no |archiveurl = https://web.archive.org/web/20130703154327/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=fd9729c3-545f-4d34-9bc7-72b61e028fc4 |archivedate = 3 July 2013 |df = dmy-all }}
15. ^1 {{cite journal |journal = Drug Intell Clin Pharm |date = June 1985 |volume = 19 |number = 6 |pages = 421–4 |title = Pimozide: use in Tourette's syndrome |last1 = Colvin |first1 = CL |last2 = Tankanow |first2 = RM |pmid = 3891283 }}

References

{{Reflist}}

External links

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| title = Pharmacodynamics
| titlestyle = background:#ccccff
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