Phenoxybenzamine
Encyclopedia
Phenoxybenzamine is a non-selective, irreversible alpha antagonist
Alpha blocker
Alpha-1 blockers constitute a variety of drugs which block α1-adrenergic receptors in arteries and smooth muscles.-Pharmacology:...

.

Uses

It is used in the treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, and specifically that caused by pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...

. It has a slower onset and a longer lasting effect compared with other alpha blockers.

It was also the first alpha blocker
Alpha blocker
Alpha-1 blockers constitute a variety of drugs which block α1-adrenergic receptors in arteries and smooth muscles.-Pharmacology:...

 to be used for treatment of benign prostatic hyperplasia
Benign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....

, 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
Hypoplastic left heart syndrome
Hypoplastic left heart syndrome , is a rare congenital heart defect in which the left ventricle of the heart is severely underdeveloped.-Causes:...

.

It is also used in Complex Regional Pain Syndrome
Complex regional pain syndrome
Complex regional pain syndrome is a chronic progressive disease characterized by severe pain, swelling and changes in the skin. It often affects an arm or a leg and may spread to another part of the body.Though treatment is often unsatisfactory, early multimodal therapy can cause dramatic...

 Type 1 due to its anti-adrenergic affects. It has shown to be beneficial if used in the first 3 months of CRPS diagnosis.

Investigational

Phenoxybenzamine has long been known to block ejaculation
Ejaculation
Ejaculation is the ejecting of semen from the male reproductory tract, and is usually accompanied by orgasm. It is usually the final stage and natural objective of male sexual stimulation, and an essential component of natural conception. In rare cases ejaculation occurs because of prostatic disease...

 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
Vas deferens
The vas deferens , also called ductus deferens, , is part of the male anatomy of many vertebrates; they transport sperm from the epididymis in anticipation of ejaculation....

. As of 2008, research was underway to identify possible drug candidates that share this effect but act specifically on the reproductive tract, unlike phenoxybenzamine.

Chemistry

Phenoxybenzamine, N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine, is synthesized by reacting phenol
Phenol
Phenol, also known as carbolic acid, phenic acid, is an organic compound with the chemical formula C6H5OH. It is a white crystalline solid. The molecule consists of a phenyl , bonded to a hydroxyl group. It is produced on a large scale as a precursor to many materials and useful compounds...

 with propylenoxide, which forms 1-phenoxy-2-propanol, the chlorination of which with thionyl chloride
Thionyl chloride
Thionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...

 gives 1-phenoxy-2-propylchloride. 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
Thionyl chloride
Thionyl chloride is an inorganic compound with the formula SOCl2. It is a reactive chemical reagent used in chlorination reactions. It is a colorless, distillable liquid at room temperature and pressure that decomposes above 140 °C. Thionyl chloride is sometimes confused with sulfuryl...

, giving phenoxybenzamine
  • J.F. Kerwin, G.E. Ullyot, (1952).

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. 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.

It will also affect the postsynaptic alpha 1 and 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.

It also has partial agonist
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...

/antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 properties at the serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 5-HT2A receptor
5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...

. 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.
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