Phenoxybenzamine

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Phenoxybenzamine
Phenoxybenzamine2DCSD.svg
Clinical data
Trade namesDibenzyline
AHFS/Drugs.comMonograph
MedlinePlusa682059
Pregnancy
category
  • AU: B2
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code
Pharmacokinetic data
Elimination half-life24 hours
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.406 Edit this at Wikidata
Chemical and physical data
FormulaC18H22ClNO
Molar mass303.83 g·mol−1
3D model (JSmol)
ChiralityRacemic mixture
  (verify)

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

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 (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[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 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-HT2A receptor.[7][8][9][10] Due to its 5-HT2A 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[edit]

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

Enantiomers of phenoxybenzamine
(R)-Phenoxybenzamin Structural Formula V1.svg
(R)-Phenoxybenzamine
CAS number: 71799-91-2
(S)-Phenoxybenzamin Structural Formula V1.svg
(S)-Phenoxybenzamine
CAS number: 71799-90-1

See also[edit]

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