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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 (CRPS) 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 pheochromocytoma 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]

stereoisomerism

Phenoxybenzamine contains a stereocenter, so there are two enantiomers, the ( R ) - form and the ( S ) - form. All commercial preparations contain the drug as racemate.^[11]

Enantiomers of phenoxybenzamine
CAS-Nummer: 71799-91-2	CAS-Nummer: 71799-90-1

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.
^ F. v. Bruchhausen, G. Dannhardt, S. Ebel, A. W. Frahm, E. Hackenthal, U. Holzgrabe (Hrsg.): Hagers Handbuch der Pharmazeutischen Praxis: Band 9: Stoffe P-Z, Springer Verlag, Berlin, Aufl. 5, 2014, S. 140, ISBN 978-3-642-63389-8.

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. 傍神経節腫：限局性疾患の治療 paragangliomas treatment of locoregional disease
3. 小児における褐色細胞腫 pheochromocytoma in children
4. 褐色細胞腫の臨床症状および診断 clinical presentation and diagnosis of pheochromocytoma
5. 小児における高血圧緊急症および高血圧性急迫症のマネージメント management of hypertensive emergencies and urgencies in children

English Journal

Involvement of Neurotransmitters in the Action of the Nociceptin/Orphanin FQ Peptide-Receptor System on Passive Avoidance Learning in Rats.

Palotai M1, Adamik A, Telegdy G.
Neurochemical research.Neurochem Res.2014 Jun 4. [Epub ahead of print]
The nociceptin/orphanin FQ peptide (NOP) receptor and its endogenous ligand plays role in several physiologic functions of the central nervous system, including pain, locomotion, anxiety and depression, reward and drug addiction, learning and memory. Previous studies demonstrated that the NOP-recept
PMID 24893797

Analysis of the mechanism of reactivation of latently infecting pseudorabies virus by acetylcholine.

Tanaka S1, Mannen K.
The Journal of veterinary medical science / the Japanese Society of Veterinary Science.J Vet Med Sci.2014 Jun 2;76(5):719-22. Epub 2014 Jan 10.
In this study, the effect of cholinergic or adrenergic inhibitors on the reactivation of latent Pseudorabies virus (PRV) was analyzed to clarify the mechanism of the reactivation of latent PRV by acetylcholine. For acetylcholine inhibition, latently infected mice were injected with scopolamine or su
PMID 24419873

Orexin A-induced anxiety-like behavior is mediated through GABA-ergic, α- and β-adrenergic neurotransmissions in mice.

Palotai M1, Telegdy G2, Jászberényi M1.
Peptides.Peptides.2014 May 27. pii: S0196-9781(14)00149-1. doi: 10.1016/j.peptides.2014.05.003. [Epub ahead of print]
Orexins are hypothalamic neuropeptides, which are involved in several physiological functions of the central nervous system, including anxiety and stress. Several studies provide biochemical and behavioral evidence about the anxiogenic action of orexin A. However, we have little evidence about the u
PMID 24874709

Japanese Journal

Enhancement of 5-hydroxytryptamine-induced contraction of the guinea pig ileum by a new sulfur compound, tripropylsulfonium bromide.

Yoshimura Masahiro [他],TAKAMURA Shozo,ISHIKAWA Tamako,YOSHIDA Junko,YAMADA Kuniko,MIYOSHI Fumihisa,TOKUNO Kenji,OHASHI Tsutomu
The Japanese Journal of Pharmacology 28(3), 359-366, 1978
… The "TPS effect" remained unaffected in the presence of dibenzyline (1×10<SUP>-7</SUP> …
NAID 130000839386

腎静脈系の収縮の形態学--Dibenzyline,Acetylcholine,Isoproterenol投与後の光顕的・電顕的・組織化学的変化について

佐々木正典
日大医学雑誌 36(11・12), p1055-1065, 1977-12
NAID 40002797770

Phenoxybenzamine(Dibenzyline)の心臓外科への応用その特性と効果 (ショック研究会(特集))

太田喜義
麻酔 22(2), 160-168, 1973-02
NAID 40018518333

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関連記事	「DIBENZYLINE」

「DIBENZYLINE」

Phenoxybenzamine
Clinical data
Trade names	Dibenzyline
AHFS/Drugs.com	Monograph
MedlinePlus	a682059
Pregnancy; category	AU: B2; US: C (Risk not ruled out); ;
Routes of; administration	Oral
ATC code	C04AX02 (WHO);
Pharmacokinetic data
Biological half-life	24 hours
Identifiers
	IUPAC name (RS)-N-Benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine;
CAS Number	59-96-1 ;
PubChem CID	4768;
IUPHAR/BPS	7268;
DrugBank	DB00925 ;
ChemSpider	4604 ;
UNII	0TTZ664R7Z;
KEGG	D08358 ;
ChEMBL	CHEMBL753 ;
ECHA InfoCard	100.000.406
Chemical and physical data
Formula	C18H22ClNO
Molar mass	303.83 g·mol−1
3D model (JSmol)	Interactive image;
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 ;
(verify)

　　[★] 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.

[Hager-11] F. v. Bruchhausen, G. Dannhardt, S. Ebel, A. W. Frahm, E. Hackenthal, U. Holzgrabe (Hrsg.): Hagers Handbuch der Pharmazeutischen Praxis: Band 9: Stoffe P-Z, Springer Verlag, Berlin, Aufl. 5, 2014, S. 140, ISBN 978-3-642-63389-8.

v t e Peripheral vasodilators (C04)
Phenylethanolamine derivatives	Isoxsuprine Buphenine Bamethan
Alpha blockers	Non-selective Tolazoline Phentolamine Selective α₁-blockers Alfuzosin Doxazosin Prazosin Silodosin Tamsulosin Terazosin
Niacin and derivatives	Niacin Nicotinyl alcohol Inositol nicotinate Ciclonicate
Purine derivatives	Pentifylline Xantinol nicotinate Pentoxifylline Etofylline nicotinate
Ergot alkaloids	Ergoloid Nicergoline Dihydroergocristine
Other peripheral vasodilators	Cyclandelate Phenoxybenzamine Vincamine Moxisylyte Bencyclane Vinburnine Sulcotidil Buflomedil Naftidrofuryl Butalamine Visnadine Cetiedil Cinepazide Ifenprodil Azapetine Fasudil

v t e Adrenergic receptor modulators
α₁	Agonists: 6-FNE Amidephrine Anisodine Buspirone Cirazoline Corbadrine Desglymidodrine Dexisometheptene Dipivefrine Dopamine Droxidopa (L-DOPS) Ephedrine Epinephrine Etilefrine Etilevodopa Ethylnorepinephrine Indanidine Isometheptene L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Melevodopa Metaraminol Methoxamine Methyldopa Midodrine Naphazoline Norepinephrine Octopamine (drug) Oxymetazoline Phenylephrine Phenylpropanolamine Pseudoephedrine Synephrine Tetryzoline Tiamenidine XP21279 Xylometazoline Antagonists: Abanoquil Adimolol Ajmalicine Alfuzosin Amosulalol Anisodamine Arotinolol Atiprosin Atypical antipsychotics (e.g., brexpiprazole, clozapine, olanzapine, quetiapine, risperidone) Benoxathian Buflomedil Bunazosin Carvedilol Corynanthine Dapiprazole Domesticine Doxazosin Ergolines (e.g., ergotamine, dihydroergotamine, lisuride, terguride) Etoperidone Eugenodilol Fenspiride Hydroxyzine Indoramin Ketanserin L-765,314 Labetalol mCPP Mepiprazole Metazosin Monatepil Moxisylyte Naftopidil Nantenine Neldazosin Niaprazine Nicergoline Niguldipine Pardoprunox Pelanserin Perlapine Phendioxan Phenoxybenzamine Phentolamine Phenylpiperazine antidepressants (e.g., hydroxynefazodone, nefazodone, trazodone, triazoledione) Piperoxan Prazosin Quinazosin Quinidine Ritanserin Silodosin Spiperone Talipexole Tamsulosin Terazosin Tiodazosin Tolazoline Tetracyclic antidepressants (e.g., amoxapine, maprotiline, mianserin) Tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine) Trimazosin Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Urapidil WB-4101 Zolertine
α₂	Agonists: (R)-3-Nitrobiphenyline 4-NEMD 6-FNE Amitraz Apraclonidine Brimonidine Cannabivarin Clonidine Corbadrine Detomidine Dexmedetomidine Dihydroergotamine Dipivefrine Dopamine Droxidopa (L-DOPS) Etilevodopa Ephedrine Ergotamine Epinephrine Etilefrine Ethylnorepinephrine Guanabenz Guanfacine Guanoxabenz L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Lofexidine Medetomidine Melevodopa Methyldopa Mivazerol Naphazoline Norepinephrine Oxymetazoline Phenylpropanolamine Piperoxan Pseudoephedrine Rezatomidine Rilmenidine Romifidine Talipexole Tasipimidine Tetrahydrozoline Tiamenidine Tizanidine Tolonidine Urapidil Vatinoxan XP21279 Xylazine Xylometazoline Antagonists: 1-PP Adimolol Amesergide Aptazapine Atipamezole Atypical antipsychotics (e.g., asenapine, brexpiprazole, clozapine, lurasidone, paliperidone, quetiapine, risperidone, zotepine) Azapirones (e.g., buspirone, gepirone, ipsapirone, tandospirone) BRL-44408 Buflomedil Cirazoline Efaroxan Esmirtazapine Fenmetozole Fluparoxan Idazoxan mCPP Mianserin Mirtazapine NAN-190 Olanzapine Pardoprunox Phentolamine Phenoxybenzamine Piperoxan Piribedil Rauwolscine Rotigotine SB-269970 Setiptiline Spiroxatrine Sunepitron Tolazoline Typical antipsychotics (e.g., chlorpromazine, fluphenazine, loxapine, thioridazine) Yohimbine
β	Agonists: Abediterol Alifedrine Amibegron Arbutamine Arformoterol Arotinolol BAAM Bambuterol Befunolol Bitolterol Broxaterol Buphenine Carbuterol Carmoterol Cimaterol Clenbuterol Colterol Corbadrine Denopamine Dipivefrine Dobutamine Dopamine Dopexamine Droxidopa (L-DOPS) Ephedrine Epinephrine Etafedrine Etilefrine Etilevodopa Ethylnorepinephrine Fenoterol Formoterol Hexoprenaline Higenamine Indacaterol Isoetarine Isoprenaline Isoxsuprine L-DOPA (levodopa) L-Phenylalanine L-Tyrosine Levosalbutamol Mabuterol Melevodopa Methoxyphenamine Methyldopa Mirabegron Norepinephrine Orciprenaline Oxyfedrine PF-610355 Phenylpropanolamine Pirbuterol Prenalterol Ractopamine Procaterol Pseudoephedrine Reproterol Rimiterol Ritodrine Salbutamol Salmeterol Solabegron Terbutaline Tretoquinol Tulobuterol Vilanterol Xamoterol XP21279 Zilpaterol Zinterol Antagonists: Acebutolol Adaprolol Adimolol Afurolol Alprenolol Alprenoxime Amosulalol Ancarolol Arnolol Arotinolol Atenolol Befunolol Betaxolol Bevantolol Bisoprolol Bopindolol Bornaprolol Brefonalol Bucindolol Bucumolol Bufetolol Bufuralol Bunitrolol Bunolol Bupranolol Butaxamine Butidrine Butofilolol Capsinolol Carazolol Carpindolol Carteolol Carvedilol Celiprolol Cetamolol Cicloprolol Cinamolol Cloranolol Cyanopindolol Dalbraminol Dexpropranolol Diacetolol Dichloroisoprenaline Dihydroalprenolol Dilevalol Diprafenone Draquinolol Ecastolol Epanolol Ericolol Ersentilide Esatenolol Esprolol Eugenodilol Exaprolol Falintolol Flestolol Flusoxolol Hydroxycarteolol Hydroxytertatolol ICI-118,551 Idropranolol Indenolol Indopanolol Iodocyanopindolol Iprocrolol Isoxaprolol Isamoltane Labetalol Landiolol Levobetaxolol Levobunolol Levomoprolol Medroxalol Mepindolol Metipranolol Metoprolol Moprolol Nadolol Nadoxolol Nebivolol Nifenalol Nipradilol Oxprenolol Pacrinolol Pafenolol Pamatolol Pargolol Penbutolol Pindolol Practolol Primidolol Procinolol Pronethalol Propafenone Propranolol Ridazolol Ronactolol Soquinolol Sotalol Spirendolol SR 59230A Sulfinalol Talinolol Tazolol Tertatolol Tienoxolol Tilisolol Timolol Tiprenolol Tolamolol Toliprolol Xibenolol Xipranolol

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dibenzyline