Phentolamine

Medical uses

The primary application for phentolamine is for the control of hypertensive emergencies, most notably due to pheochromocytoma.

It also has usefulness in the treatment of cocaine-induced cardiovascular complications, where one would generally avoid β-blockers (e.g., metoprolol), as they can cause unopposed α-adrenergic mediated coronary vasoconstriction, worsening myocardial ischemia and hypertension. Phentolamine is not a first-line agent for this indication. Phentolamine should only be given to patients who do not fully respond to benzodiazepines, nitroglycerin, and calcium channel blockers.

When given by injection, it causes blood vessels to dilate, thereby increasing blood flow. When injected into the penis (intracavernosal), it increases blood flow to the penis, which results in an erection.

It may be stored in crash carts to counteract severe peripheral vasoconstriction secondary to extravasation of peripherally placed vasopressor infusions, typically of norepinephrine. Epinephrine infusions are less vasoconstrictive than norepinephrine as they primarily stimulate β receptor more than α receptors, but the effect remains dose-dependent.

Phentolamine also has diagnostic and therapeutic roles in complex regional pain syndrome (CRPS).

Phentolamine is marketed in the dental field as a local anesthetic reversal agent. Branded as OraVerse, it is a phentolamine mesylate injection designed to reverse the local vasoconstrictor properties used in many local anesthetics to prolong anesthesia.

Phentolamine is also used ophthalmically under the brand name Ryzumvi to reverse the effects of pharmacologically-induced mydriasis.

Side effects

A possible adverse effect of phentolamine is orthostatic hypotension.

Pharmacology

Mechanism of action

Phentolamine acts as a reversible dual or non-selective α1- and α2-adrenergic receptor antagonist. Its primary action is vasodilation due to α1-adrenergic receptor blockade. Reportedly, phentolamine may also stimulate β-adrenergic receptors.

Non-selective α-blockers can cause a much more pronounced reflex tachycardia than the selective α1 blockers. Like the selective α1 blockers, phentolamine causes a relaxation of systemic vasculature, leading to hypotension. This hypotension is sensed by the baroreceptor reflex, which results in increased sympathetic nerve firing on the heart, releasing norepinephrine. In response, the β1 adrenergic receptors on the heart increase their rate, contractility, and dromotropy, which help to offset the decrease in systemic blood pressure. Unlike the α1 selective blockers, phentolamine also inhibits the α2 receptors, which function predominantly as presynaptic negative feedback for norepinephrine release. By abolishing this negative feedback phentolamine leads to even less regulated norepinephrine release, which results in a more drastic increase in heart rate.

Chemistry

Phentolamine can be synthesized by alkylation of 3-(4-methylanilino)phenol using 2-chloromethylimidazoline:

:[[File:Phentolamine synthesis.png|400px|left|class=skin-invert-image]]

References

References

1. {{MeshName. Phentolamine
2. (2003). "The Cleveland Clinic internal medicine case reviews". Lippincott Williams & Wilkins.
3. (2003). "Hypertensive emergencies. Etiology and management". American Journal of Cardiovascular Drugs.
4. (December 2014). "Controversial therapeutics: the β-adrenergic antagonist and cocaine-associated cardiovascular complications dilemma". Pharmacotherapy.
5. (February 2008). "Cocaine, myocardial infarction, and beta-blockers: time to rethink the equation?". Annals of Emergency Medicine.
6. (February 2006). "Evaluation and management of the patient who has cocaine-associated chest pain". Cardiology Clinics.
7. (September 2006). "Phentolamine therapy for cocaine-association acute coronary syndrome (CAACS)". Journal of Medical Toxicology.
8. (2004). "Intracavernous pharmacotherapy for erectile dysfunction". Endocrine.
9. (June 2006). "Pharmacologic management of complex regional pain syndrome". The Clinical Journal of Pain.
10. (January 2009). "What's new in local anaesthesia?". SAAD Digest.
11. (2023-09-27). "FDA approves RYZUMVI (Phentolamine Ophthalmic Solution) for the treatment of pharmacologically-induced mydriasis".
12. "Common Side Effects of Phentolamine Mesylate for Injection (Phentolamine Mesylate)". Drug Center - RxList.
13. (1 June 2011). "Phentolamine: Uses, Interactions, Mechanism of Action".
14. (2000). "Oral phentolamine (Vasomax)". Drugs of Today.
15. (September 1976). "Phentolamine". Am Heart J.
16. (2008). "Illustrated Pharmacology Memory Cards: PharMnemonics". Minireview.
17. "2-(N:N-diphenyl-aminomethyl) imidazolines".
18. (1950). "2-Aminoalkylimidazoline.". Helv. Chim. Acta.