Phentolamine

Absorption

The peak concentrations of phentolamine are achieved within 10 to 20 minutes following submucosal administration. The Cmax was higher in children with greater weights.
Following topical ocular administration of phentolamine ophthalmic solution 0.75%, the peak concentration levels were achieved between 15 minutes and one hour after dosing with the median value of 0.45 ng/mL.

Toxicity

The oral LD50 of phentolamine mesylate, a salt of phentolamine, was 1250 mg/kg in rats and 1000-1100 mg/kg in mice.
No deaths due to acute poisoning with phentolamine have been reported. Overdosage with phentolamine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. Other possible signs and symptoms include excitation, headache, sweating, pupillary contraction, visual disturbances, nausea, vomiting, diarrhea, and hypoglycemia. There is no specific antidote: Treatment consists of appropriate monitoring and supportive care. A plasma expander and norepinephrine may be administered to manage decreased blood pressure.

Description

Phentolamine is also a derivative of imidazoline that exhibits a direct α-adrenoblocking, muscle-relaxant effect on smooth muscle as well as cholinomimetic, histamine, and sympathomimetic effects. The chemical variation of its structure permits a few of its properties to be more expressed. For example, the aforementioned tolazoline, 2-benzyl-2-imidazoline, a structural analog of phentolamine, has more of an expressed muscle-relaxant effect on smooth muscle than an α-adrenoblocking effect.

Originator

Regitine, Ciba, US ,1952

The Uses of Phentolamine

Anti-adrenergic.
Phentolamine is used to prevent or control hypertensive episodes that occurin patients with pheochromocytoma. It also has been used incombination with papaverine to treat impotence.

The Uses of Phentolamine

Phentolamine is used for peripheral blood circulation disorders, in particular in the beginning stages of gangrene, for treatment of trophic ulcers of the extremities, bedsores, and frostbite.

Background

Phentolamine is a reversible, non-selective alpha-adrenergic blocker that induces vasodilation. While initially introduced to the market for the treatment of hypertension, this clinical use was halted due to cardiovascular and gastrointestinal adverse effects with the prolonged use of large oral doses of phentolamine. It has several therapeutic uses, including the treatment of hypertensive episodes, prevention of norepinephrine-induced extravasation, diagnosis of pheochromocytoma, reversal of soft-tissue anesthesia, and treatment of pharmacologically-induced mydriasis. Phentolamine is administered intravenously, intramuscularly, submucosally, and topically.

Indications

When used intravenously or intramuscularly, phentolamine is used to prevent or control hypertensive episodes that may occur in a patient with pheochromocytoma due to stress or manipulation during preoperative preparation and surgical excision. It is also used to prevent or treat dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. It may be used to diagnose pheochromocytoma by the phentolamine-blocking test.
Submucosal injection of phentolamine is indicated for the reversal of soft-tissue anesthesia (e.g. anesthesia of the lip and tongue) and the associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor in patients three years old and older.
Phentolamine ophthalmic solution is used to treat pharmacologically-induced mydriasis produced by adrenergic agonists (e.g., phenylephrine) or parasympatholytic (e.g., tropicamide) agents.

Definition

ChEBI: A substituted aniline that is 3-aminophenol in which the hydrogens of the amino group are replaced by 4-methylphenyl and 4,5-dihydro-1H-imidazol-2-ylmethyl groups respectively. An alpha-adrenergic antagonist, it is used fo the treatment of hypertension.

Indications

Human erectile tissue has a population of membrane receptors that are predominantly of the -adrenoceptor subtype. Phentolamine (Vasomax) is a nonselective - adrenoceptor blocking agent (see Chapter 11), and like other such agents, it has been used to treat ED. Nonselective adrenoceptor antagonists may provoke a reflex that increases both sympathetic outflow and the release of norepinephrine.

Manufacturing Process

199.24 parts of N-(p-methylphenyl)-m'-hydroxyphenylamine and 77.52 parts of 2-chloromethylimidazoline hydrochloride are heated for sixteen hours in an oil bath having a temperature of 150°C, while stirring and introducing a current of nitrogen. The viscous contents of the flask are then cooled to about 100°C, mixed with 400 parts by volume of hot water, and stirred for a short time.
After further cooling to about 60°C, 200 parts by volume of water and 500 parts by volume of ethyl acetate at 60°C are added, and the aqueous layer is separated. The excess of starting material may be recovered from the ethyl acetate.
The aqueous portion is chilled in a cooling chamber at -10°C, whereupon the hydrochloride of 2-[N-(p-methylphenyl)-N-(m'-hydroxyphenyl)-aminomethyl]imidazoline crystallizes. Upon being concentrated and cooled the mother liquor yields a further quantity of the hydrochloride. The combined quantities of hydrochloride are treated with a small quantity of cold water, dried with care, and washed with ethyl acetate. The product is then crystallized from a mixture of alcohol and ethyl acetate, and there is obtained a hydrochloride melting at 239°-240°C.

brand name

Regitine (Novartis) [Name previously used: Phentolamine Methanesulfonate.].

Therapeutic Function

Adrenergic blocker

General Description

Phentolamine isthe more effectiveα -blocker.

Mechanism of action

Its mechanism of action is as an α-adrenergic antagonist of both α1- and α2-receptors, causing vasodilation and reduction in peripheral resistance. When administered by intracavernosal injection, it is thought to cause relaxation of the cavernous smooth muscles and vasodilation of the penile arteries. This results in increased arterial blood flow into the corpus cavernosa as well as swelling and elongation of the penis. Venous outflow also is reduced, possibly as a result of increased venous resistance. Phentolamine is slowly released into venous circulation with minimal, if any, systemic effects. Time to peak effect is within 10 minutes, and duration of action when used with papaverine is 1 to 6 hours.

Pharmacokinetics

Phentolamine produces an alpha-adrenergic block of a relatively short duration. Phentolamine induces vasodilatation of vascular smooth muscle and pupils. When used in an ophthalmic solution, the onset of pupil dilation generally occurred in 30 minutes, with the maximal effect seen in 60 to 90 minutes. Pupil dilation lasted for at least 24 hours. Phentolamine also has direct but less marked positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle; however, phentolamine is not believed to affect contractile or adenyl cyclase function. Large doses can lead to a mild sympatholytic action.
Some evidence suggests that phentolamine also stimulates beta-adrenergic receptors, thereby causing peripheral vasodilation. Phentolamine was shown to stimulate insulin secretion, possibly related to its blocking actions on ATP-sensitive K+ channels.

Clinical Use

Phentolamine has been used orally and intracavernosally in the treatment of ED. Following oral administration, phentolamine has a plasma half-life of about 30 minutes and a duration of action of 2 to 4 hours. An intracavernosal injection of phentolamine results in the drug reaching maximum serum levels in about 20 to 30 minutes. It is rapidly metabolized. Phentolamine has been used in combination with papaverine, chlorpromazine, and vasoactive peptides in the treatment of ED.

Side Effects

Side effects of phentolamine are dose related. It may cause orthostatic hypotension, reflex tachycardia, cardiac arrhythmias, and rarely, myocardial infarction. Phentolamine also may reduce sperm motility in vitro.

Safety Profile

Poison by subcutaneous, intravenous, and intraperitoneal routes. Moderately toxic by ingestion. Experimental reproductive effects. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Phentolamine, 2-[[N-(3??-hydroxyphenyl)-para-toluidion]methyl]-2- imidazoline (12.2.8), is synthesized by alkylation of 3-(4-methylanilino)phenol using 2-chloromethylimidazoline [36, 37].

Metabolism

Not Available