Phentolamine

Identification

Summary

Phentolamine is an alpha-adrenergic blocker used to treat hypertensive episodes, diagnose pheochromocytoma, treat norepinephrine administration site reactions, and reverse soft tissue anesthesia and mydriasis.

Brand Names
Oraverse
Generic Name
Phentolamine
DrugBank Accession Number
DB00692
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.1,4 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.8,7,5 Phentolamine is administered intravenously, intramuscularly, submucosally, and topically.

Type
Small Molecule
Groups
Approved
Structure
Weight
Average: 281.3523
Monoisotopic: 281.152812245
Chemical Formula
C17H19N3O
Synonyms
  • 2-(N-(m-hydroxyphenyl)-p-toluidinomethyl)imidazoline
  • 3-((4,5-DIHYDRO-1H-IMIDAZOL-2-YLMETHYL)(4-METHYLPHENYL)AMINO)PHENOL
  • Fentolamina
  • Phentolamin
  • Phentolamine
  • Phentolaminum
External IDs
  • C 7337
  • C 7337 Ciba

Pharmacology

Indication

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.8

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.7

Phentolamine ophthalmic solution is used to treat pharmacologically-induced mydriasis produced by adrenergic agonists (e.g., phenylephrine) or parasympatholytic (e.g., tropicamide) agents.5

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Reversal ofMydriasis••••••••••••
Reversal ofMydriasis••••••••••••
Prophylaxis ofNecrosis caused by norepinephrine extravasation••••••••••••
Diagnostic agentPheochromocytoma••••••••••••
Reversal ofSoft tissue anesthesia (numbness)••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Phentolamine produces an alpha-adrenergic block of a relatively short duration.7 Phentolamine induces vasodilatation of vascular smooth muscle and pupils.7,5 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.5 Phentolamine also has direct but less marked positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle;8 however, phentolamine is not believed to affect contractile or adenyl cyclase function.1 Large doses can lead to a mild sympatholytic action.1

Some evidence suggests that phentolamine also stimulates beta-adrenergic receptors, thereby causing peripheral vasodilation.1 Phentolamine was shown to stimulate insulin secretion, possibly related to its blocking actions on ATP-sensitive K+ channels.1,3

Mechanism of action

Phentolamine is a reversible, competitive antagonist at alpha-1 and alpha-2 adrenergic receptors.2,5 It causes vasodilation of vascular smooth muscles.7 Pupil dilation is primarily controlled by the radial iris dilator muscles surrounding the pupil, which are activated by the alpha-1 adrenergic receptors. Phentolamine reversibly binds to these receptors and reduces pupil diameter. By blocking alpha-1 adrenergic receptors, phentolamine can also be used to reverse mydriasis induced by muscarinic antagonists.5

TargetActionsOrganism
AAlpha-1 adrenergic receptors
antagonist
Humans
UAlpha-2 adrenergic receptors
antagonist
Humans
UATP-sensitive inward rectifier potassium channel 11
blocker
Humans
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.7

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.5

Volume of distribution

While there is limited information on phentolamine distribution, the drug is reported to cross the blood-brain barrier.2

Protein binding

Not Available

Metabolism
Not Available
Route of elimination

Approximately 13% of a single intravenous dose appears in the urine as unchanged drug.8

Half-life

Phentolamine has a half-life of 19 minutes following intravenous administration.8 The terminal elimination half-life of phentolamine was approximately two to three hours following submucosal administration.7

Clearance

Not Available

Adverse Effects
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Toxicity

The oral LD50 of phentolamine mesylate, a salt of phentolamine, was 1250 mg/kg in rats and 1000-1100 mg/kg in mice.6,8

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.7,8

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbaloparatideThe risk or severity of adverse effects can be increased when Phentolamine is combined with Abaloparatide.
AcebutololAcebutolol may increase the orthostatic hypotensive activities of Phentolamine.
AceclofenacThe therapeutic efficacy of Phentolamine can be decreased when used in combination with Aceclofenac.
AcemetacinThe therapeutic efficacy of Phentolamine can be decreased when used in combination with Acemetacin.
Acetylsalicylic acidAcetylsalicylic acid may decrease the antihypertensive activities of Phentolamine.
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Phentolamine mesylateY7543E5K9T65-28-1OGIYDFVHFQEFKQ-UHFFFAOYSA-N
International/Other Brands
Regitin (Novartis) / Regitina (Novartis) / Vigamed (Grupo Cimed)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OraverseInjection, solution0.235 mg/1mLSubmucosalSeptodont, Inc.2011-06-01Not applicableUS flag
OraverseSolution0.4 mg / 1.7 mLSubmucosalSeptodont2014-09-17Not applicableCanada flag
OraVerseInjection, solution0.4 mg/1.7mLSubmucosalNovalar Pharmaceuticals2008-05-23Not applicableUS flag
Phentolamine MesylateInjection5 mg/1mLIntramuscular; Intravenous; ParenteralSandoz Inc2012-06-012013-07-31US flag
Phentolamine Mesylate Injection Sandoz StandardSolution5 mg / mLIntramuscular; IntravenousSandoz Canada Incorporated2001-06-15Not applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Phentolamine MesylateInjection, powder, for solution5 mg/1mLIntramuscular; IntravenousWest-Ward Pharmaceuticals Corp1998-05-15Not applicableUS flag
Phentolamine MesylateInjection5 mg/1Intramuscular; IntravenousPrecision Dose Inc.2017-07-15Not applicableUS flag
Phentolamine MesylateInjection, powder, for solution5 mg/1mLIntramuscular; IntravenousBedford Pharmaceuticals1998-05-152015-09-30US flag
Phentolamine MesylateInjection5 mg/1Intramuscular; IntravenousTAGI Pharma, Inc.2017-07-15Not applicableUS flag
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
Phentolamine MesylatePhentolamine mesylate (5 mg/1mL)InjectionIntramuscular; Intravenous; ParenteralSandoz Inc2012-06-012013-07-31US flag

Categories

ATC Codes
V03AB36 — PhentolamineC04AB01 — Phentolamine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as alkyldiarylamines. These are tertiary alkylarylamines having two aryl and one alkyl groups attached to the amino group.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Amines
Direct Parent
Alkyldiarylamines
Alternative Parents
m-Aminophenols / Aniline and substituted anilines / Aminotoluenes / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Imidolactams / Imidazolines / Propargyl-type 1,3-dipolar organic compounds / Carboximidamides / Carboxamidines
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Substituents
1-hydroxy-2-unsubstituted benzenoid / 1-hydroxy-4-unsubstituted benzenoid / 2-imidazoline / Alkyldiarylamine / Amidine / Aminophenol / Aminotoluene / Aniline or substituted anilines / Aromatic heteromonocyclic compound / Azacycle
show 15 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
tertiary amino compound, substituted aniline, imidazoles, phenols (CHEBI:8081)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
Z468598HBV
CAS number
50-60-2
InChI Key
MRBDMNSDAVCSSF-UHFFFAOYSA-N
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)
IUPAC Name
3-{[(4,5-dihydro-1H-imidazol-2-yl)methyl](4-methylphenyl)amino}phenol
SMILES
CC1=CC=C(C=C1)N(CC1=NCCN1)C1=CC(O)=CC=C1

References

General References
  1. Gould L, Reddy CV: Phentolamine. Am Heart J. 1976 Sep;92(3):397-402. doi: 10.1016/s0002-8703(76)80121-4. [Article]
  2. Raja SN, Treede RD, Davis KD, Campbell JN: Systemic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiology. 1991 Apr;74(4):691-8. doi: 10.1097/00000542-199104000-00012. [Article]
  3. Proks P, Ashcroft FM: Phentolamine block of KATP channels is mediated by Kir6.2. Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11716-20. doi: 10.1073/pnas.94.21.11716. [Article]
  4. Brock G: Oral phentolamine (Vasomax). Drugs Today (Barc). 2000 Feb-Mar;36(2-3):121-4. doi: 10.1358/dot.2000.36.2-3.568785. [Article]
  5. FDA Approved Drug Products: RYZUMVI (phentolamine ophthalmic solution) 0.75%, for topical ophthalmic use [Link]
  6. Oraverse: Phentolamine mesylate MSDS [Link]
  7. DailyMed Label: ORAVERSE (phentolamine mesylate) submucosal injection, solution [Link]
  8. DailyMed Label: PHENTOLAMINE MESYLATE intravenous or intramuscular injection, powder, for solution [Link]
Human Metabolome Database
HMDB0014830
PubChem Compound
5775
PubChem Substance
46506535
ChemSpider
5571
BindingDB
31046
RxNav
8153
ChEBI
8081
ChEMBL
CHEMBL597
ZINC
ZINC000000020251
Therapeutic Targets Database
DAP000299
PharmGKB
PA450926
Guide to Pharmacology
GtP Drug Page
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Phentolamine

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentAnesthesia, Reversal / Dental Local Anesthesia / Local Anaesthesia therapy1
4CompletedTreatmentLocal Anaesthesia therapy1
4Not Yet RecruitingPreventionPre-eclampsia Aggravated / Pre-Eclampsia; Complicating Pregnancy1
4RecruitingBasic ScienceVasoconstriction / Vasodilation1
3CompletedTreatmentDental Local Anesthesia2

Pharmacoeconomics

Manufacturers
  • Novalar pharmaceuticals inc
  • Bedford laboratories div ben venue laboratories inc
  • Novartis pharmaceuticals corp
  • Sanofi aventis us llc
  • Glaxosmithkline
  • Perrigo co
  • Ranbaxy laboratories ltd
  • Mcneil consumer healthcare
Packagers
  • Bedford Labs
  • Ben Venue Laboratories Inc.
  • Novalar Pharmaceuticals Inc.
  • Novartis AG
  • Novocol Pharmaceutical Canada
Dosage Forms
FormRouteStrength
Injection, solutionSubmucosal0.235 mg/1mL
Injection, solutionSubmucosal0.4 mg/1.7mL
Injection, solutionSubmucosal400 MICROGRAMMI/1.7ML
SolutionSubmucosal0.4 mg / 1.7 mL
InjectionIntramuscular; Intravenous5 mg/1
InjectionIntramuscular; Intravenous; Parenteral5 mg/1mL
Injection, powder, for solutionIntramuscular; Intravenous5 mg/1mL
PowderNot applicable1 g/1g
SolutionIntramuscular; Intravenous5 mg / mL
Injection, powder, lyophilized, for suspensionIntramuscular; Intravenous5 mg/1mL
SolutionIntramuscular; Intravenous10 mg / mL
Powder, for solutionIntramuscular; Intravenous5 mg / amp
Prices
Unit descriptionCostUnit
Phentolamine 5 mg vial84.0USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6764678No2004-07-202021-05-11US flag
US7569230No2009-08-042023-10-17US flag
US6872390No2005-03-292021-05-11US flag
US7229630No2007-06-122023-06-20US flag
US7575757No2009-08-182025-04-21US flag
US11844858No2014-01-312034-01-31US flag
US9795560No2014-01-312034-01-31US flag
US11090261No2014-01-312034-01-31US flag
US10278918No2014-01-312034-01-31US flag
US10772829No2014-01-312034-01-31US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)181https://www.spectrumchemical.com/media/sds/P1687_AGHS.pdf
logP3.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.272 mg/mLALOGPS
logP2.91ALOGPS
logP2.52Chemaxon
logS-3ALOGPS
pKa (Strongest Acidic)9.78Chemaxon
pKa (Strongest Basic)9.02Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area47.86 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity84.25 m3·mol-1Chemaxon
Polarizability31.37 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9293
Blood Brain Barrier+0.838
Caco-2 permeable-0.6104
P-glycoprotein substrateSubstrate0.772
P-glycoprotein inhibitor INon-inhibitor0.9329
P-glycoprotein inhibitor IIInhibitor0.8031
Renal organic cation transporterInhibitor0.7497
CYP450 2C9 substrateNon-substrate0.6892
CYP450 2D6 substrateNon-substrate0.5668
CYP450 3A4 substrateNon-substrate0.6313
CYP450 1A2 substrateNon-inhibitor0.9046
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8931
CYP450 2C19 inhibitorNon-inhibitor0.8454
CYP450 3A4 inhibitorNon-inhibitor0.831
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7661
Ames testNon AMES toxic0.6266
CarcinogenicityNon-carcinogens0.8555
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.4366 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.6149
hERG inhibition (predictor II)Inhibitor0.59
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-0002-2950000000-98d994688cae92ea0a0b
MS/MS Spectrum - , positiveLC-MS/MSsplash10-03di-4890000000-37817fa5f0f18f71350d
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-1090000000-12d07807548bcd134d5d
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001j-0590000000-4d7583077dbb88038013
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-001i-2090000000-c7886ddd4668eef3ea15
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0002-0900000000-89d9747479428d981279
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00e9-3920000000-05cbaff72692987bff19
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-00xs-0900000000-7279342f89428b40ac3a
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-182.5343984
predicted
DarkChem Lite v0.1.0
[M-H]-182.4186984
predicted
DarkChem Lite v0.1.0
[M-H]-162.72264
predicted
DeepCCS 1.0 (2019)
[M+H]+183.3238984
predicted
DarkChem Lite v0.1.0
[M+H]+182.7420984
predicted
DarkChem Lite v0.1.0
[M+H]+165.08067
predicted
DeepCCS 1.0 (2019)
[M+Na]+183.0052984
predicted
DarkChem Lite v0.1.0
[M+Na]+182.4973984
predicted
DarkChem Lite v0.1.0
[M+Na]+171.1738
predicted
DeepCCS 1.0 (2019)

Targets

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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...

Components:
References
  1. Raja SN, Treede RD, Davis KD, Campbell JN: Systemic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiology. 1991 Apr;74(4):691-8. doi: 10.1097/00000542-199104000-00012. [Article]
  2. Goldstein I: Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction. Int J Impot Res. 2000 Mar;12 Suppl 1:S75-80. [Article]
  3. Traish A, Gupta S, Gallant C, Huang YH, Goldstein I: Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. Int J Impot Res. 1998 Dec;10(4):215-23. doi: 10.1038/sj.ijir.3900351. [Article]
  4. FDA Approved Drug Products: RYZUMVI (phentolamine ophthalmic solution) 0.75%, for topical ophthalmic use [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...

Components:
References
  1. Raja SN, Treede RD, Davis KD, Campbell JN: Systemic alpha-adrenergic blockade with phentolamine: a diagnostic test for sympathetically maintained pain. Anesthesiology. 1991 Apr;74(4):691-8. doi: 10.1097/00000542-199104000-00012. [Article]
  2. Goldstein I: Oral phentolamine: an alpha-1, alpha-2 adrenergic antagonist for the treatment of erectile dysfunction. Int J Impot Res. 2000 Mar;12 Suppl 1:S75-80. [Article]
  3. Traish A, Gupta S, Gallant C, Huang YH, Goldstein I: Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. Int J Impot Res. 1998 Dec;10(4):215-23. doi: 10.1038/sj.ijir.3900351. [Article]
  4. FDA Approved Drug Products: RYZUMVI (phentolamine ophthalmic solution) 0.75%, for topical ophthalmic use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Blocker
General Function
Voltage-gated potassium channel activity
Specific Function
This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage ...
Gene Name
KCNJ11
Uniprot ID
Q14654
Uniprot Name
ATP-sensitive inward rectifier potassium channel 11
Molecular Weight
43540.375 Da
References
  1. Proks P, Ashcroft FM: Phentolamine block of KATP channels is mediated by Kir6.2. Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11716-20. doi: 10.1073/pnas.94.21.11716. [Article]

Drug created at June 13, 2005 13:24 / Updated at March 18, 2024 16:48