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a complex consisting of an organic base in association with hydrogen chloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/05/24 22:04:58」(JST)

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Phenoxybenzamine (marketed under the trade name Dibenzyline) is a non-selective, irreversible alpha blocker.

Uses

It is used in the treatment of hypertension, and specifically that caused by pheochromocytoma. It has a slower onset and a longer lasting effect compared with other alpha blockers.

It was also the first alpha blocker to be used for treatment of benign prostatic hyperplasia,^[1] although it is currently seldom used for that indication due to unfavourable side effects.

It has been used in the treatment of hypoplastic left heart syndrome.^[2]

It is also used in complex regional pain syndrome type 1 due to its anti-adrenergic affects. It has shown to be beneficial if used in the first 3 months of the CRPS diagnosis.

Investigational

Phenoxybenzamine has long been known to block ejaculation without affecting semen quality or ability to achieve orgasm, which could make it an effective male contraceptive. This effect is completely reversible, and is believed to be the result of alpha-1 adrenoceptor blockade in the longitudinal muscles of the vas deferens.^[3]^[4]^[5] As of 2008, research was underway to identify possible drug candidates that share this effect but act specifically on the reproductive tract, unlike phenoxybenzamine.^[3]

Pharmacology

Phenoxybenzamine is used as an anti-hypertensive due to its efficacy in reducing the vasoconstriction caused by epinephrine (adrenaline) and norepinephrine. Phenoxybenzamine forms a permanent covalent bond with adrenergic receptors. Based on known information about the structures of these receptors, it likely involves attack by the cysteine at position 3.36 in transmembrane helix 3 to form a stable linkage.^[6] Thus, it remains permanently bound to the receptor, preventing adrenaline and noradrenaline from binding. This causes vasodilatation in blood vessels, due to its antagonistic effect at the alpha-1 adrenoceptor found in the walls of blood vessels, resulting in a drop in blood pressure. A side effect of phenoxybenzamine is reflex tachycardia.

As a non-selective alpha receptor antagonist, it will also affect both the postsynaptic alpha 1 and presynaptic alpha 2 receptors in the nervous system, and so reduce sympathetic activity. This results in further vasodilation, pupil constriction, an increase in GI tract motility and secretions, and glycogen synthesis.

Clinically, non-selective alpha antagonists block alpha receptors (but do not differentiate between alpha-1 and alpha-2). They are used as antihypertensives because they block alpha-receptor-mediated vasoconstriction. The block on alpha-2 receptors further potentiates beta-effects, increasing cardiac output.

Phenoxybenzamine has a long-lasting action, binding covalently to the alpha receptors. Its only current clinical use is in preparing patients with phaeochromocytoma for surgery; its irreversible antagonism and the resultant depression in the maximum of the agonist dose-response curve are desirable in a situation where surgical manipulation of the tumour may release a large bolus of pressor amine into the circulation. Typically, phenoxybenzamine is not used in the long term, as new receptors are made to upregulate alpha stimulation. The main limiting side-effects of alpha antagonists is that the baroreceptor reflex is disrupted and thus this can cause postural hypotension.

Phenoxybenzamine also has irreversible antagonist/weak partial agonist properties at the serotonin 5-HT_2A receptor.^[7]^[8]^[9]^[10] Due to its 5-HT_2A receptor antagonism, phenoxybenzamine is useful in the treatment of carcinoid tumor, a neoplasm that secretes large amounts of serotonin and causes diarrhea, bronchoconstriction, and flushing.^[8]

References

^ Caine M, Perlberg S, Meretyk S (1978). "A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction". British journal of urology 50 (7): 551–4. doi:10.1111/j.1464-410X.1978.tb06210.x. PMID 88984.
^ Guzzetta NA (August 2007). "Phenoxybenzamine in the treatment of hypoplastic left heart syndrome: a core review". Anesth. Analg. 105 (2): 312–5. doi:10.1213/01.ane.0000275185.44796.92. PMID 17646482.
^ ^a ^b Aitken RJ, Baker MA, Doncel GF, Matzuk MM, Mauck CK, Harper MJ (April 2008). "As the world grows: contraception in the 21st century". J Clin Invest 118 (4): 1330–43. doi:10.1172/JCI33873. PMC 2276786. PMID 18382745.
^ Kjaergaard N, Kjaergaard B, Lauritsen JG (June 1988). "Prazosin, an adrenergic blocking agent inadequate as male contraceptive pill". Contraception 37 (6): 621–9. doi:10.1016/0010-7824(88)90008-X. PMID 2899490.
^ Homonnai ZT, Shilon M, Paz GF (May 1984). "Phenoxybenzamine—an effective male contraceptive pill". Contraception 29 (5): 479–91. doi:10.1016/0010-7824(84)90022-2. PMID 6430643.
^ Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamäki A (2001). "Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors". J. Biol. Chem. 276 (33): 31279–84. doi:10.1074/jbc.M104167200. PMID 11395517.
^ Doggrell, S. A. (1995). "Increase in affinity and loss of 5-hydroxytryptamine2A-receptor reserve for 5-hydroxytryptamine on the aorta of spontaneously hypertensive rats". Journal of Autonomic Pharmacology 15 (5): 371–377. doi:10.1111/j.1474-8673.1995.tb00403.x. ISSN 0144-1795.
^ ^a ^b Anthony Trevor; Bertram Katzung; Susan Masters (2008). Katzung & Trevor's Pharmacology Examination and Board Review: Eighth Edition. McGraw Hill Professional. pp. 153,500. ISBN 978-0-07-148869-3.
^ B. Olivier; I. van Wijngaarden; W. Soudijn (10 July 1997). Serotonin Receptors and their Ligands. Elsevier. pp. 206–. ISBN 978-0-08-054111-2.
^ Timothy S. Gaginella; James J. Galligan (25 July 1995). Serotonin and Gastrointestinal Function. CRC Press. pp. 56–. ISBN 978-0-8493-8387-8.

UpToDate Contents

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1. 成人における褐色細胞腫の治療 treatment of pheochromocytoma in adults
2. 褐色細胞腫を有する成人に対する麻酔 anesthesia for the adult with pheochromocytoma
3. 成人における複合性局所疼痛症候群：予防およびマネージメント complex regional pain syndrome in adults prevention and management
4. 褐色細胞腫の臨床症状および診断 clinical presentation and diagnosis of pheochromocytoma
5. Pheochromocytoma and paraganglioma in children

English Journal

Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate.

Karube K, Tsuzuki S, Yoshida N, Arita K, Kato H, Katayama M, Ko YH, Ohshima K, Nakamura S, Kinoshita T, Seto M.SourceDivision of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
Cancer letters.Cancer Lett.2013 Jun 1;333(1):47-55. doi: 10.1016/j.canlet.2012.12.022. Epub 2013 Jan 21.
NK cell neoplasms are lymphoid malignancies with an aggressive clinical course. In the present study, we analyzed gene expression profiling of NK cell neoplasms and attempted to identify important molecular pathways and new effective drugs. Pathway analysis of gene expression profiles suggested the
PMID 23348693

Assessment of the 18F-Labeled PET Tracer LMI1195 for Imaging Norepinephrine Handling in Rat Hearts.

Higuchi T, Yousefi BH, Kaiser F, Gärtner F, Rischpler C, Reder S, Yu M, Robinson S, Schwaiger M, Nekolla SG.SourceNuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine.J Nucl Med.2013 May 13. [Epub ahead of print]
A novel 18F-labeled tracer, LMI1195 (N-[3-bromo-4-(3-18F-fluoro-propoxy)-benzyl]-guanidine), is being developed for sympathetic nerve imaging; its high specificity for neural uptake-1 mechanism has previously been demonstrated in cell associative studies and in rabbit and nonhuman primate studies as
PMID 23670901

Ephedrine induced thioredoxin-1 expression through β-adrenergic receptor/cyclic AMP/protein kinase A/dopamine- and cyclic AMP-regulated phosphoprotein signaling pathway.

Jia JJ, Zeng XS, Li Y, Ma S, Bai J.SourceFaculty of Environmental Science and Engineering, Kunming University of Science and Technology, Kunming 650500, China.
Cellular signalling.Cell Signal.2013 May;25(5):1194-201. doi: 10.1016/j.cellsig.2013.02.007. Epub 2013 Feb 14.
Ephedrine (Eph) is one of alkaloids that has been isolated from the ancient herb ephedra (ma huang) and is used as the treatment of asthma, hypotension and fatigue. However, its molecular mechanism remains unknown. Thioredoxin-1 (Trx-1) is a redox regulating protein, which has various biological act
PMID 23416460

Japanese Journal

Identification of novel small-molecule inhibitors of glioblastoma cell growth and invasion by high-throughput screening

BioScience Trends 6(4), 192-200, 2012
NAID 130004572577

生体鼻腔粘膜収縮の機序　ａｃｏｕｓｔｉｃ　ｒｈｉｎｏｍｅｔｒｙを用いて:acoustic rhinometryを用いて

日本耳鼻咽喉科学会会報 97(11), 2075-2084, 1994
NAID 130000805503

副腎再生高血圧症:血管結合織蛋白質とコルチコステロンの高血圧に果す役割

日本泌尿器科學會雑誌 81(1), 49-53, 1990
NAID 110003084725

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★リンクテーブル★

リンク元	「フェノキシベンザミン」
関連記事	「hydrochloride」「phenoxybenzamine」

「フェノキシベンザミン」

Phenoxybenzamine
Systematic (IUPAC) name
	(RS)-N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine
Clinical data
Trade names	Dibenzyline
AHFS/Drugs.com	monograph
MedlinePlus	a682059
Pregnancy	C (U.S.);
Administration	Oral
Pharmacokinetic data
Biological half-life	24 hours
Identifiers
CASRN	59-96-1
ATC code	C04AX02 (WHO)
PubChem	CID 4768
IUPHAR/BPS	7268
DrugBank	DB00925
ChemSpider	4604
UNII	0TTZ664R7Z
KEGG	D08358
ChEMBL	CHEMBL753
Chemical data
Formula	C18H22ClNO
Molar mass	303.826 g/mol
Chirality	Racemic mixture
	SMILES ClCCN(C(COc1ccccc1)C)Cc2ccccc2 ;
	InChI InChI=1S/C18H22ClNO/c1-16(15-21-18-10-6-3-7-11-18)20(13-12-19)14-17-8-4-2-5-9-17/h2-11,16H,12-15H2,1H3 ; Key:QZVCTJOXCFMACW-UHFFFAOYSA-N ;
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　　[★]

英: phenoxybenzamine
化: 塩酸フェノキシベンザミン phenoxybenzamine hydrochloride
商: Dibenzyline

交感神経拮抗薬

α受容体拮抗薬

非競合的拮抗薬 (⇔競合的拮抗薬フェントラミン)
使うことはまれ

適応：褐色細胞腫の高血圧、末梢循環障害、神経性膀胱機能不全
副作用：起立性低血圧

「hydrochloride」

　　[★] 塩酸塩、ハイドロクロライド　

「phenoxybenzamine」

　　[★] フェノキシベンザミン

[1] Caine M, Perlberg S, Meretyk S (1978). "A placebo-controlled double-blind study of the effect of phenoxybenzamine in benign prostatic obstruction". British journal of urology 50 (7): 551–4. doi:10.1111/j.1464-410X.1978.tb06210.x. PMID 88984.

[pmid17646482-2] Guzzetta NA (August 2007). "Phenoxybenzamine in the treatment of hypoplastic left heart syndrome: a core review". Anesth. Analg. 105 (2): 312–5. doi:10.1213/01.ane.0000275185.44796.92. PMID 17646482.

[Aitken-3] Aitken RJ, Baker MA, Doncel GF, Matzuk MM, Mauck CK, Harper MJ (April 2008). "As the world grows: contraception in the 21st century". J Clin Invest 118 (4): 1330–43. doi:10.1172/JCI33873. PMC 2276786. PMID 18382745.

[4] Kjaergaard N, Kjaergaard B, Lauritsen JG (June 1988). "Prazosin, an adrenergic blocking agent inadequate as male contraceptive pill". Contraception 37 (6): 621–9. doi:10.1016/0010-7824(88)90008-X. PMID 2899490.

[5] Homonnai ZT, Shilon M, Paz GF (May 1984). "Phenoxybenzamine—an effective male contraceptive pill". Contraception 29 (5): 479–91. doi:10.1016/0010-7824(84)90022-2. PMID 6430643.

[6] Frang H, Cockcroft V, Karskela T, Scheinin M, Marjamäki A (2001). "Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors". J. Biol. Chem. 276 (33): 31279–84. doi:10.1074/jbc.M104167200. PMID 11395517.

[Doggrell1995-7] Doggrell, S. A. (1995). "Increase in affinity and loss of 5-hydroxytryptamine2A-receptor reserve for 5-hydroxytryptamine on the aorta of spontaneously hypertensive rats". Journal of Autonomic Pharmacology 15 (5): 371–377. doi:10.1111/j.1474-8673.1995.tb00403.x. ISSN 0144-1795.

[TrevorKatzung2008-8] Anthony Trevor; Bertram Katzung; Susan Masters (2008). Katzung & Trevor's Pharmacology Examination and Board Review: Eighth Edition. McGraw Hill Professional. pp. 153,500. ISBN 978-0-07-148869-3.

[OlivierWijngaarden1997-9] B. Olivier; I. van Wijngaarden; W. Soudijn (10 July 1997). Serotonin Receptors and their Ligands. Elsevier. pp. 206–. ISBN 978-0-08-054111-2.

[GaginellaGalligan1995-10] Timothy S. Gaginella; James J. Galligan (25 July 1995). Serotonin and Gastrointestinal Function. CRC Press. pp. 56–. ISBN 978-0-8493-8387-8.

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案内

phenoxybenzamine hydrochloride