Phentolamine

Phentolamine
Names
Trade namesRegitine, Oraverse
IUPAC name
  • 3-[(4,5-Dihydro-1H-imidazol-2-ylmethyl)(4-methylphenyl)amino]phenol
Clinical data
Drug classAlpha blocker[1]
Main usesHigh blood pressure in pheochromocytoma, following norepinephrine entry into soft tissues, hypertensive emergencies[1][2]
Side effectsAbdominal pain, nausea, diarrhea, flushing, stuffy nose, low blood pressure with standing[1]
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Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		intravenous (IV) or intramuscular (IM)
    Onset of actionIV < 2min; IM < 20 min[1]
    Duration of actionIV up to 30 min; IM up to 4 hrs[1]
    Typical dose5 mg[1]
    External links
    AHFS/Drugs.comMonograph
    Legal
    Legal status
    Pharmacokinetics
    MetabolismLiver
    Elimination half-life19 minutes
    Chemical and physical data
    FormulaC17H19N3O
    Molar mass281.359 g·mol−1
    3D model (JSmol)
    SMILES
    • Oc3cc(N(c1ccc(cc1)C)CC/2=N/CCN\2)ccc3
    InChI
    • InChI=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) checkY
    • Key:MRBDMNSDAVCSSF-UHFFFAOYSA-N checkY

    Phentolamine, sold under the brand name Regitine among others, is a medication used to treat high blood pressure in pheochromocytoma, following norepinephrine entry into soft tissues, and hypertensive emergencies.[1][2] It is given by injection.[1] When injected into a vein effects occur within 2 minutes and last up to 30 minutes.[1]

    Common side effects include abdominal pain, nausea, diarrhea, flushing, stuffy nose, and low blood pressure with standing.[1] Other side effects may include myocardial infarction and priapism.[1] Safety in pregnancy is unclear.[3] It is a alpha blocker.[1]

    Phentolamine was approved for medical use in the United States in 1952.[1] In the United States it costs about 460 USD per dose as of 2021.[4] In the United Kingdom it is available together with aviptadil for the treatment of erectile dysfunction.[5]

    Medical uses

    The primary application for phentolamine is for the control of hypertensive emergencies, most notably due to pheochromocytoma.[6]

    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.[7][8] It is important to note that 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.[9][10]

    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.[11]

    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 (reflex sympathetic dystrophy).[12]

    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.[13]

    Dosage

    It is frequently given at a dose of 5 mg.[1] This dose may be repeated.[1]

    To treat extravasation of norepinephrine or dopamine 5 to 10 mg is mixed with 10 ml of normal saline and injected into the tissues were this occurred.[1]

    Side effects

    Mechanism

    Its primary action is vasodilation due to α1 blockade.[15]

    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.[16]

    Chemistry

    Phentolamine can be synthesized by alkylation of 3-(4-methylanilino)phenol using 2-chloromethylimidazoline:[17][18]

    References

    1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Phentolamine Monograph for Professionals". Drugs.com. Archived from the original on 21 January 2021. Retrieved 28 October 2021.
    2. 1 2 "DailyMed - PHENTOLAMINE MESYLATE injection". dailymed.nlm.nih.gov. Archived from the original on 28 October 2021. Retrieved 28 October 2021.
    3. ↑ "Phentolamine Use During Pregnancy". Drugs.com. Archived from the original on 27 October 2020. Retrieved 28 October 2021.
    4. ↑ "Phentolamine Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 28 October 2021.
    5. ↑ BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 866. ISBN 978-0857114105.
    6. ↑ Tuncel M, Ram VC (2003). "Hypertensive emergencies. Etiology and management". American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions. 3 (1): 21–31. doi:10.2165/00129784-200303010-00003. PMID 14727943. S2CID 1993954.
    7. ↑ Schurr, James W.; Gitman, Brenda; Belchikov, Yuly (2014). "Controversial Therapeutics: The β-Adrenergic Antagonist and Cocaine-Associated Cardiovascular Complications Dilemma". Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 34 (12): 1269–1281. doi:10.1002/phar.1486. ISSN 1875-9114. PMID 25224512.
    8. ↑ Freeman, Kalev; Feldman, James A. (2008). "Cocaine, Myocardial Infarction, and β-Blockers: Time to Rethink the Equation?". Annals of Emergency Medicine. 51 (2): 130–134. doi:10.1016/j.annemergmed.2007.08.020. ISSN 0196-0644. PMID 17933425.
    9. ↑ Hollander JE, Henry TD (February 2006). "Evaluation and management of the patient who has cocaine-associated chest pain". Cardiology Clinics. 24 (1): 103–14. doi:10.1016/j.ccl.2005.09.003. PMID 16326260.
    10. ↑ Chan GM, Sharma R, Price D, Hoffman RS, Nelson LS (September 2006). "Phentolamine therapy for cocaine-association acute coronary syndrome (CAACS)". Journal of Medical Toxicology. 2 (3): 108–11. doi:10.1007/BF03161019. PMC 3550159. PMID 18072128.
    11. ↑ Bella AJ, Brock GB (2004). "Intracavernous pharmacotherapy for erectile dysfunction". Endocrine. 23 (2–3): 149–55. doi:10.1385/ENDO:23:2-3:149. PMID 15146094. S2CID 13056029.
    12. ↑ Rowbotham MC (June 2006). "Pharmacologic management of complex regional pain syndrome". The Clinical Journal of Pain. 22 (5): 425–9. doi:10.1097/01.ajp.0000194281.74379.01. PMID 16772796. S2CID 17837280.
    13. ↑ Malamed S (January 2009). "What's new in local anaesthesia?". SAAD Digest. 25: 4–14. PMID 19267135.
    14. ↑ "Common Side Effects of Phentolamine Mesylate for Injection (Phentolamine Mesylate)". Drug Center - RxList. Archived from the original on 2020-09-24. Retrieved 2021-04-14.
    15. ↑ Brock G (2000). "Oral phentolamine (Vasomax)". Drugs of Today. Barcelona, Spain. 36 (2–3): 121–4. doi:10.1358/dot.2000.36.2-3.568785. PMID 12879109.
    16. ↑ Shen H (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. p. 14. ISBN 978-1-59541-101-3.
    17. ↑ US 2503059, Miescher K, Marxer A, Urech E, "2-(N:N-diphenyl-aminomethyl) imidazolines", issued 1950, assigned to Ciba Pharmaceuticals Products, Inc. 
    18. ↑ Urech E, Marxer A, Miescher K (1950). "2-Aminoalkylimidazoline". Helv. Chim. Acta. 33 (5): 1386–407. doi:10.1002/hlca.19500330539.
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