Phenoxybenzamine

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Phenoxybenzamine
Phenoxybenzamine.png
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 cat.
Legal status
?
Routes Oral
Pharmacokinetic data
Half-life 24 hours
Identifiers
CAS number 59-96-1 YesY
ATC code C04AX02
PubChem CID 4768
DrugBank DB00925
ChemSpider 4604 YesY
UNII 0TTZ664R7Z YesY
KEGG D08358 YesY
ChEMBL CHEMBL753 YesY
Chemical data
Formula C18H22ClNO 
Mol. mass 303.826 g/mol
 YesY (what is this?)  (verify)

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

Uses[edit]

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[edit]

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[edit]

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 like the competitive antagonist phentolamine blocks alpha receptors (but does not differentiate between alpha-1 and alpha-2. It was used as an antihypertensive (because of the block of alpha-receptor-mediated vasoconstriction). Upon use, it binds reversibly and its action is short-acting only, and it causes a reflex tachycardia. The block on alpha-2 receptors further potentiated beta-effects of increasing cardiac output. Phenoxybenzamine has a longer-lasting action by binding covalently to the alpha receptors. Its current only clinical use is in preparing patients with phaeochromocytoma for surgery; its irreversible antagonism and the result 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 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.

It also has partial agonist/antagonist properties at the serotonin 5-HT2A receptor. Due to its 5-HT2A antagonism, it is useful in the treatment of carcinoid tumor, a neoplasm that secretes large amounts of serotonin and causes diarrhea, bronchoconstriction, and flushing.[7]

Chemistry[edit]

Phenoxybenzamine can be synthesized by reacting phenol with propylenoxide, which forms 1-phenoxy-2-propanol, the chlorination of which with thionyl chloride gives 1-phenoxy-2-propylchloride.[8] Reacting this with 2-aminoethanol leads to formation of 1-phenoxy-2-(2-hydroxyethyl)aminopropane. Alkylation of the secondary amino group gives N-(2-hydroxyethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine, the hydroxyl group of which is chlorinated using thionyl chloride, giving phenoxybenzamine.

Phenoxybenzamine synthesis.png

References[edit]

  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. 
  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. 
  3. ^ 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. 
  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. 
  7. ^ Katzung, Trevor et al. Pharmacology Board Review. p.153. Mcgraw Hill, 2007.
  8. ^ J.F. Kerwin, G.E. Ullyot, U.S. Patent 2,599,000 (1952)