View source for Phentolamine

{{Short description|Medication; α-adrenergic antagonist}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 464200826
| image = Phentolamine.svg
| width = 150
| image2 = Phentolamine-space-filling.png

<!--Clinical data-->| tradename = Regitine, Oraverse, Ryzumvi
| Drugs.com = {{drugs.com|monograph|phentolamine-mesylate}}
| legal_US = Rx-only
| routes_of_administration = [[Intravenous therapy|intravenous]], [[Intramuscular injection|intramuscular]], [[Ophthalmic drug administration|eye drops]]
| ATC_prefix = C04
| ATC_suffix = AB01
| ATC_supplemental = {{ATC|V03|AB36}}, {{ATC|G04|BE05}}

<!--Pharmacokinetic data-->| bioavailability = 
| protein_bound = 
| metabolism = [[Liver]]
| elimination_half-life = 19 minutes

<!--Identifiers-->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 50-60-2
| PubChem = 5775
| IUPHAR_ligand = 502
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00692
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5571
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = Z468598HBV
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 8081
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08362
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 597

<!--Chemical data-->| IUPAC_name = 3-[(4,5-Dihydro-1''H''-imidazol-2-ylmethyl)(4-methylphenyl)amino]phenol
| C = 17
| H = 19
| N = 3
| O = 1
| smiles = Oc3cc(N(c1ccc(cc1)C)CC/2=N/CCN\2)ccc3
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C17H19N3O/c1-13-5-7-14(8-6-13)20(12-17-18-9-10-19-17)15-3-2-4-16(21)11-15/h2-8,11,21H,9-10,12H2,1H3,(H,18,19)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = MRBDMNSDAVCSSF-UHFFFAOYSA-N
}}

'''Phentolamine''', sold under the brand name '''Regitine''' among others, is a reversible<ref name="isbn0-7817-4266-8">{{cite book | vauthors = Jewell JR, Longworth DL, Stoller JK, Casey D |title=The Cleveland Clinic internal medicine case reviews |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2003 |isbn=0-7817-4266-8 |page=32}}</ref> nonselective α-[[adrenergic antagonist]].<ref>{{MeshName|Phentolamine}}</ref>

==Mechanism==
Its primary action is [[vasodilation]] due to α<sub>1</sub> blockade.<ref name="pmid12879109">{{cite journal | vauthors = Brock G | title = Oral phentolamine (Vasomax) | journal = Drugs of Today | location = Barcelona, Spain | volume = 36 | issue = 2–3 | pages = 121–4 | date = 2000 | pmid = 12879109 | doi = 10.1358/dot.2000.36.2-3.568785 }}</ref>

Non-selective α-blockers can cause a much more pronounced reflex [[tachycardia]] than the selective [[Alpha-1 blocker|α<sub>1</sub> blockers]]. Like the selective α<sub>1</sub> blockers, phentolamine causes a relaxation of systemic vasculature, leading to [[hypotension]]. This hypotension is sensed by the [[Baroreflex|baroreceptor reflex]], which results in increased sympathetic nerve firing on the heart, releasing [[norepinephrine]]. In response, the [[Beta-1 adrenergic receptor|β<sub>1</sub> adrenergic receptors]] on the heart increase their [[Heart rate|rate]], [[Myocardial contractility|contractility]], and [[Dromotropic|dromotropy]], which help to offset the decrease in systemic blood pressure. Unlike the α<sub>1</sub> selective blockers, phentolamine also inhibits the α<sub>2</sub> receptors, which function predominantly as [[Chemical synapse|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.<ref name=pharmnemonics>{{cite book | vauthors = Shen H | title=Illustrated Pharmacology Memory Cards: PharMnemonics | year=2008 | publisher=Minireview | isbn=978-1-59541-101-3 | page=14}}</ref>

==Uses==
The primary application for phentolamine is for the control of [[hypertensive emergency|hypertensive emergencies]], most notably due to [[pheochromocytoma]].<ref name="pmid14727943">{{cite journal | vauthors = Tuncel M, Ram VC | s2cid = 1993954 | title = Hypertensive emergencies. Etiology and management | journal = American Journal of Cardiovascular Drugs | volume = 3 | issue = 1 | pages = 21–31 | date = 2003 | pmid = 14727943 | doi = 10.2165/00129784-200303010-00003 }}</ref>

It also has usefulness in the treatment of [[cocaine]]-induced cardiovascular complications, where one would generally avoid [[Beta blocker|β-blocker]]s (e.g. [[metoprolol]]), as they can cause unopposed α-adrenergic mediated [[Coronary vasospasm|coronary vasoconstriction]], worsening myocardial ischemia and hypertension.<ref>{{cite journal | vauthors = Schurr JW, Gitman B, Belchikov Y | title = Controversial therapeutics: the β-adrenergic antagonist and cocaine-associated cardiovascular complications dilemma | journal = Pharmacotherapy | volume = 34 | issue = 12 | pages = 1269–1281 | date = December 2014 | pmid = 25224512 | doi = 10.1002/phar.1486 | s2cid = 5282953 }}</ref><ref>{{cite journal | vauthors = Freeman K, Feldman JA | title = Cocaine, myocardial infarction, and beta-blockers: time to rethink the equation? | journal = Annals of Emergency Medicine | volume = 51 | issue = 2 | pages = 130–134 | date = February 2008 | pmid = 17933425 | doi = 10.1016/j.annemergmed.2007.08.020 }}</ref> Phentolamine is not a first-line agent for this indication. Phentolamine should only be given to patients who do not fully respond to [[benzodiazepine]]s, [[Nitroglycerin (medication)|nitroglycerin]], and [[calcium channel blocker]]s.<ref name="pmid16326260">{{cite journal | vauthors = Hollander JE, Henry TD | title = Evaluation and management of the patient who has cocaine-associated chest pain | journal = Cardiology Clinics | volume = 24 | issue = 1 | pages = 103–114 | date = February 2006 | pmid = 16326260 | doi = 10.1016/j.ccl.2005.09.003 }}</ref><ref name="pmid18072128">{{cite journal | vauthors = Chan GM, Sharma R, Price D, Hoffman RS, Nelson LS | title = Phentolamine therapy for cocaine-association acute coronary syndrome (CAACS) | journal = Journal of Medical Toxicology | volume = 2 | issue = 3 | pages = 108–111 | date = September 2006 | pmid = 18072128 | pmc = 3550159 | doi = 10.1007/BF03161019 }}</ref>

When given by injection, it causes blood vessels to [[vasodilation|dilate]], thereby increasing blood flow. When injected into the penis (intracavernosal), it increases blood flow to the penis, which results in an erection.<ref name="pmid15146094">{{cite journal | vauthors = Bella AJ, Brock GB | s2cid = 13056029 | title = Intracavernous pharmacotherapy for erectile dysfunction | journal = Endocrine | volume = 23 | issue = 2–3 | pages = 149–55 | date = 2004 | pmid = 15146094 | doi = 10.1385/ENDO:23:2-3:149 }}</ref>

It may be stored in [[crash cart]]s to counteract severe peripheral vasoconstriction secondary to [[extravasation]] of peripherally placed [[vasopressor]] infusions, typically of [[Norepinephrine (medication)|norepinephrine]]. [[Epinephrine (medication)|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).<ref name="pmid16772796">{{cite journal | vauthors = Rowbotham MC | s2cid = 17837280 | title = Pharmacologic management of complex regional pain syndrome | journal = The Clinical Journal of Pain | volume = 22 | issue = 5 | pages = 425–9 | date = June 2006 | pmid = 16772796 | doi = 10.1097/01.ajp.0000194281.74379.01 }}</ref>

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.<ref name="pmid19267135">{{cite journal | vauthors = Malamed S | title = What's new in local anaesthesia? | journal = SAAD Digest | volume = 25 | pages = 4–14 | date = January 2009 | pmid = 19267135 }}</ref>

Phentolamine is also used [[Ophthalmic drug administration|ophthalmically]] under the brand name Ryzumvi to reverse the effects of pharmacologically-induced [[mydriasis]].<ref>{{Cite web |date=2023-09-27 |title=FDA approves RYZUMVI (Phentolamine Ophthalmic Solution) for the treatment of pharmacologically-induced mydriasis |url=https://www.ophthalmologytimes.com/view/fda-approves-ryzumvi-phentolamine-ophthalmic-solution-for-the-treatment-of-pharmacologically-induced-mydriasis |access-date=2025-02-21 |website=Ophthalmology Times |language=en}}</ref>

==Chemistry==
Phentolamine can be synthesized by alkylation of 3-(4-methylanilino)phenol using 2-chloromethylimidazoline:<ref>{{cite patent | inventor = Miescher K, Marxer A, Urech E | assign1 = Ciba Pharmaceuticals Products, Inc. | country = US | number = 2503059 | title = 2-(N:N-diphenyl-aminomethyl) imidazolines | gdate = 1950 }}</ref><ref>{{cite journal | vauthors = Urech E, Marxer A, Miescher K  | title = 2-Aminoalkylimidazoline. | journal = Helv. Chim. Acta | date = 1950 | volume = 33 | issue = 5 | pages = 1386–407 | doi = 10.1002/hlca.19500330539 }}</ref>

:[[File:Phentolamine synthesis.png|400px|left]]{{clear left}}

== Adverse effects ==
* [[Orthostatic hypotension]].<ref>{{cite web|url=http://www.rxlist.com/phentolamine-mesylate-for-injection-side-effects-drug-center.htm|title=Common Side Effects of Phentolamine Mesylate for Injection (Phentolamine Mesylate) | work = Drug Center - RxList }}</ref>

==References==
{{reflist}}

{{Antihypertensives and diuretics}}
{{Peripheral vasodilators}}
{{Drugs for erectile dysfunction and PE}}
{{Alpha blockers}}
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