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the most commonly used diphenylbutyl piperidine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/07/04 19:48:04」(JST)

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Pimozide (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 and resistant tics (Europe, USA and Canada).

Pimozide has been used in the treatment of delusional disorder and paranoid personality disorder.^[1] It has also been used for delusions of parasitosis.^[2]

Use as a Listeria monocytogenes inhibitor has been described.^[3]

Side effects

Very common (>10% frequency) side effects include:^[4]^[5]^[6]^[7]

Akinesia
Dizziness
Somnolence
Hyperhidrosis
Nocturia
Speech disorder
Dry mouth
Constipation

Contraindications

It is contraindicated in individuals with either acquired, congenital or a family history of QT interval prolongation.^[5] Its use is advised against in individuals with people with either a personal or a family history of arrhythmias or torsades de pointes.^[5] 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.^[5] It is also contraindicated in individuals being cotreated with SSRIs or in those with a known hypersensitivity to pimozide or other diphenylbutyl-piperidine derivatives.^[5] Likewise its use is contraindicated in individuals receiving treatment with CYP3A4, CYP1A2, or CYP2D6 inhibitors.^[5]

Overdose

Pimozide overdose presents with severe extrapyramidal symptoms, hypotension, sedation, QT interval prolongation and ventricular arrhythmias including torsades de pointes.^[5] Gastric lavage, establishment of a patent airway and, if necessary, mechanically assisted respiration is the recommended treatment for pimozide overdose.^[5] Cardiac monitoring should be continued for at least 4 days due to the long half-life of pimozide.^[5]

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.^[8]

Binding profile^{[Note 1]}
Protein	K_i (nM)^[9]	Notes
5-HT_1A	650
5-HT_2A	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-HT_2C	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.^[10]
α_1A	197.7	Low affinity towards this receptor may explain why pimozide has a lower liability for producing orthostatic hypotension.^[8]
α_2A	1,593
α_2B	821
α_2C	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.^[11] 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.^[11]
D₃	0.25
D₄	1.8
hERG	18	May be responsible for pimozide's high liability for prolonging the QT interval.^[11]
H₁	692	Likely responsible for why pimozide tends to produce so little sedation.^[11]
σ	508

Pharmacokinetic data^[4]^[5]^[6]^[7]
Pharmacokinetic parameter	Value
Time to peak plasma concentration (T_max)	6-8 hr
Peak plasma concentration (C_max)	4-19 ng/mL
Elimination half-life (t_1/2)	55 hours (adults), 66 hours (children)
Metabolising enzymes	CYP3A4, CYP1A2 and CYP2D6
Excretion pathways	Urine

Notes

^ Lower the K_i value is the stronger the binding

References

^ Munro, A. (1999)Delusional disorder. Cambridge: Cambridge University Press. ISBN 0-521-58180-X.
^ van Vloten WA (March 2003). "Pimozide: use in dermatology". Dermatol. Online J. 9 (2): 3. PMID 12639456.
^ Lieberman LA, Higgins DE (February 2009). "A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection". Antimicrob. Agents Chemother. 53 (2): 756–64. doi:10.1128/AAC.00607-08. PMC 2630664. PMID 19015342.
^ ^a ^b "Oral (pimozide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 4 December 2013.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Oral 4 mg tablets. - Summary of Product Characteristics". electronic Medicines Compendium. Janssen-Cilag Ltd. 2 April 2013. Retrieved 4 December 2013.
^ ^a ^b Brayfield, A (12 February 2013). Pimozide. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). Retrieved 4 December 2013.
^ ^a ^b "ORAP (pimozide) tablet [Teva Select Brands]". DailyMed. Teva Select Brands. July 2012. Retrieved 4 December 2013.
^ ^a ^b Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.
^ Roth, BL; Driscol, J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 4 December 2013.
^ "Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression" (PDF). Indian Journal of Pharmaceutical Education and Research 45 (1): 46–53. January–March 2011.
^ ^a ^b ^c ^d 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.

External links

Pimozide (A medical white paper on its use)

UpToDate Contents

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1. 第1世代抗精神病剤：薬理学、投与、および副作用の比較 first generation antipsychotic medications pharmacology administration and comparative side effects
2. 寄生虫妄想症の治療 treatment of delusional parasitosis
3. トゥレット症候群 tourette syndrome
4. 統合失調症に対する薬物療法：副作用マネージメント pharmacotherapy for schizophrenia side effect management
5. シデナム舞踏病 sydenham chorea

English Journal

Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia.

Kiel MJ1, Velusamy T1, Rolland D1, Sahasrabuddhe AA1, Chung F1, Bailey NG1, Schrader A2, Li B3, Li JZ4, Ozel AB4, Betz BL1, Miranda RN5, Medeiros LJ5, Zhao L6, Herling M2, Lim MS1, Elenitoba-Johnson KS7.
Blood.Blood.2014 May 13. pii: blood-2014-03-559542. [Epub ahead of print]
The comprehensive genetic alterations underlying the pathogenesis of T-Prolymphocytic Leukemia (T-PLL) are unknown. To address this, we performed whole genome sequencing (WGS), whole exome sequencing (WES), high-resolution copy number analysis and Sanger resequencing of a large cohort of T-PLL. WGS
PMID 24825865

A selective USP1-UAF1 inhibitor links deubiquitination to DNA damage responses.

Liang Q1, Dexheimer TS2, Zhang P1, Rosenthal AS2, Villamil MA1, You C3, Zhang Q4, Chen J1, Ott CA1, Sun H2, Luci DK2, Yuan B3, Simeonov A2, Jadhav A2, Xiao H5, Wang Y3, Maloney DJ2, Zhuang Z1.
Nature chemical biology.Nat Chem Biol.2014 Apr;10(4):298-304. doi: 10.1038/nchembio.1455. Epub 2014 Feb 16.
Protein ubiquitination and deubiquitination are central to the control of a large number of cellular pathways and signaling networks in eukaryotes. Although the essential roles of ubiquitination have been established in the eukaryotic DNA damage response, the deubiquitination process remains poorly
PMID 24531842

Evaluating state dependence and subtype selectivity of calcium channel modulators in automated electrophysiology assays.

Kuryshev YA1, Brown AM, Duzic E, Kirsch GE.
Assay and drug development technologies.Assay Drug Dev Technol.2014 Mar;12(2):110-9. doi: 10.1089/adt.2013.552. Epub 2014 Feb 28.
Voltage-gated Ca2+ channels play essential roles in control of neurosecretion and muscle contraction. The pharmacological significance of Cav channels stem from their identification as the molecular targets of calcium blockers used in the treatment of cardiovascular diseases, such as hypertension, a
PMID 24579774

Japanese Journal

Haloperidol, spiperone, pimozide and aripiprazole reduce intracellular dopamine content in PC12 cells and rat mesencephalic cultures: Implication of inhibition of vesicular transport.

Matsuo Takaaki,Izumi Yasuhiko,Wakita Seiko,Kume Toshiaki,Takada-Takatori Yuki,Sawada Hideyuki,Akaike Akinori
European journal of pharmacology 640(1-3), 68-74, 2010-08-25
… Pretreatment with haloperidol, spiperone, pimozide, aripiprazole and risperidone markedly inhibited high potassium-evoked dopamine release. … Haloperidol, spiperone, pimozide, chlorpromazine, aripiprazole and olanzapine evoked dopamine release, while sulpiride and risperidone had no effect. … In addition, haloperidol, spiperone, pimozide, aripiprazole and risperidone reduced intracellular dopamine content in a concentration-dependent manner. …
NAID 120002426867

Swelling-Activated Cl^- Current in Isolated Rabbit Articular Chondrocytes : Inhibition by Arachidonic Acid

Isoya Eiji,Toyoda Futoshi,Imai Shinji [他],OKUMURA Noriaki,KUMAGAI Kousuke,OMATSU KANBE Mariko,KUBO Mitsuhiko,MATSUURA Hiroshi,MATSUSUE Yoshitaka
Journal of pharmacological sciences 109(2), 293-304, 2009-02-20
… ICl,swell was potently inhibited by the Cl− channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid, glibenclamide, and tamoxifen, but was little affected by pimozide. …
NAID 10025734699

皮膚寄生虫症妄想の１例

平野愛,夏秋優,今田微香,伊藤孝明,山西清文
皮膚の科学 6(2), 183-186, 2007
66歳，女性。そう痒を伴う顔面の丘疹と下肢の関節痛を主訴に受診した。血液検査所見に異常は無く，梅毒血清反応も陰性であったが，患者は自分が梅毒に感染しており，症状は梅毒によるものだと信じていた。患者は整形外科や内科も受診したが，皮疹と関節痛の原因は明らかにならず，症状の改善もなかった。その後，皮膚から虫が出たと訴えて再度当科を受診したが，患者が持参したものは実際にはゴミや鱗屑であった。このことから， …
NAID 130004547234

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Pimozide
Systematic (IUPAC) name
	1-[1-[4,4-bis(4-fluorophenyl)butyl]-; 4-piperidinyl]-1,3-dihydro-; 2H-benzimidazole-2-one
Clinical data
Trade names	Orap
AHFS/Drugs.com	monograph
MedlinePlus	a686018
Licence data	US FDA:link
Pregnancy; category	AU: B1; US: C (Risk not ruled out);
Legal status	AU: Prescription Only (S4); US: ℞-only;
Routes of; administration	oral
Pharmacokinetic data
Bioavailability	40-50%
Metabolism	CYP3A4, CYP1A2 and CYP2D6
Biological half-life	55 hours (adults), 66 hours (children)
Excretion	Urine
Identifiers
CAS Registry Number	2062-78-4
ATC code	N05AG02
PubChem	CID: 16362
IUPHAR/BPS	90
DrugBank	DB01100
ChemSpider	15520
UNII	1HIZ4DL86F
KEGG	D00560
ChEBI	CHEBI:8212
ChEMBL	CHEMBL1423
Chemical data
Formula	C28H29F2N3O
Molecular mass	461.56
	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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英: pimozide
商: オーラップ
関: 抗精神病薬

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[9] Lower the K_i value is the stronger the binding

[1] Munro, A. (1999)Delusional disorder. Cambridge: Cambridge University Press. ISBN 0-521-58180-X.

[pmid12639456-2] van Vloten WA (March 2003). "Pimozide: use in dermatology". Dermatol. Online J. 9 (2): 3. PMID 12639456.

[pmid19015342-3] Lieberman LA, Higgins DE (February 2009). "A small-molecule screen identifies the antipsychotic drug pimozide as an inhibitor of Listeria monocytogenes infection". Antimicrob. Agents Chemother. 53 (2): 756–64. doi:10.1128/AAC.00607-08. PMC 2630664. PMID 19015342.

[MSR-4] "Oral (pimozide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 4 December 2013.

[EMC-5] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j "Oral 4 mg tablets. - Summary of Product Characteristics". electronic Medicines Compendium. Janssen-Cilag Ltd. 2 April 2013. Retrieved 4 December 2013.

[MD-6] Brayfield, A (12 February 2013). Pimozide. Martindale: The Complete Drug Reference (London, UK: Pharmaceutical Press). Retrieved 4 December 2013.

[DM-7] "ORAP (pimozide) tablet [Teva Select Brands]". DailyMed. Teva Select Brands. July 2012. Retrieved 4 December 2013.

[Maudsley-8] Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8.

[10] Roth, BL; Driscol, J (12 January 2011). "PDSP K_i Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 4 December 2013.

[11] "Anti-depressant like Effect of Pimozide in Acute and Chronic Animal Models of Depression" (PDF). Indian Journal of Pharmaceutical Education and Research 45 (1): 46–53. January–March 2011.

[GG-12] 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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