PHENTOLAMINE

First approved in 1952

Details

Stereochemistry	ACHIRAL
Molecular Formula	C17H19N3O
Molecular Weight	281.3523
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CC1=CC=C(C=C1)N(CC2=NCCN2)C3=CC(O)=CC=C3

InChI

InChIKey=MRBDMNSDAVCSSF-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022159s000_Lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.drugbank.ca/drugs/DB00692 | https://www.drugs.com/pro/phentolamine.html | http://reference.medscape.com/drug/regitine-oraverse-phentolamine-342392 | https://www.ncbi.nlm.nih.gov/pubmed/26180030

Phentolamine (trade name Regitine) is a reversible nonselective α-adrenergic antagonist used for the control of hypertensive emergencies, most notably due to pheochromocytoma. Phentolamine produces its therapeutic actions by competitively blocking alpha-adrenergic receptors (primarily excitatory responses of smooth muscle and exocrine glands), leading to a muscle relaxation and a widening of the blood vessels. This widening of the blood vessels results in a lowering of blood pressure. The action of phentolamine on the alpha-adrenergic receptors is relatively transient and the blocking effect is incomplete. The drug is more effective in antagonizing responses to circulating epinephrine and/or norepinephrine than in antagonizing responses to mediator released at the adrenergic nerve ending. Phentolamine also stimulates β-adrenergic receptors and produces a positive inotropic and chronotropic effect on the heart and increases cardiac output. Phentolamine is indicated for the prevention or control of hypertensive episodes that may occur in a patient with pheochromocytoma as a result of stress or manipulation during preoperative preparation and surgical excision. Phentolamine is indicated for the prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. Phentolamine is also indicated for the diagnosis of pheochromocytoma by the Phentolamine blocking test. Acute and prolonged hypotensive episodes, tachycardia, and cardiac arrhythmias have been reported. In addition, weakness, dizziness, flushing, orthostatic hypotension, nasal stuffiness, nausea, vomiting, and diarrhea may occur.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Adrenergic receptor alpha 64 Target ID: CHEMBL2095203 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6124636	Antagonist 2778	3.7 nM [Kd]
Adrenergic receptor alpha-1 169 Target ID: CHEMBL2094251 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2886664	Antagonist 2778	16.6 nM [Kd]
Adrenergic receptor alpha-2 113 Target ID: CHEMBL2095158 Sources: https://www.ncbi.nlm.nih.gov/pubmed/6330361	Antagonist 2778	5.0 nM [Ki]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Pheochromocytoma 14 Sources: https://www.drugs.com/pro/phentolamine.html	Primary		Approved 8429	REGITINE Approved Use Phentolamine Mesylate for Injection is indicated for the prevention or control of hypertensive episodes that may occur in a patient with pheochromocytoma as a result of stress or manipulation during preoperative preparation and surgical excision. Phentolamine Mesylate for Injection is indicated for the prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. Phentolamine Mesylate for Injection is also indicated for the diagnosis of pheochromocytoma by the phentolamine blocking test. Launch Date -5.6557437E11
Dental pain 3 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/022159s000_Lbl.pdf	Primary		Approved 8429	REGITINE Approved Use Phentolamine Mesylate for Injection is indicated for the prevention or control of hypertensive episodes that may occur in a patient with pheochromocytoma as a result of stress or manipulation during preoperative preparation and surgical excision. Phentolamine Mesylate for Injection is indicated for the prevention or treatment of dermal necrosis and sloughing following intravenous administration or extravasation of norepinephrine. Phentolamine Mesylate for Injection is also indicated for the diagnosis of pheochromocytoma by the phentolamine blocking test. Launch Date -5.6557437E11

C_max

Value	Dose	Co-administered	Analyte	Population
67.05 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24452521	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENTOLAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
197.59 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24452521	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENTOLAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
3.32 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/24452521	60 mg single, oral dose: 60 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENTOLAMINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
80 mg 10 times / month multiple, oral Highest studied dose Dose: 80 mg, 10 times / month Route: oral Route: multiple Dose: 80 mg, 10 times / month Sources: https://pubmed.ncbi.nlm.nih.gov/12152116 Page: p.268	unhealthy, 26–83 n = 691 Health Status: unhealthy Condition: Erectile dysfunction Age Group: 26–83 Sex: M Population Size: 691 Sources: https://pubmed.ncbi.nlm.nih.gov/12152116 Page: p.268	Disc. AE: Rhinitis, Vomiting... AEs leading to discontinuation/dose reduction: Rhinitis Vomiting Nausea Diarrhea Headache Dizziness Tachycardia Sources: https://pubmed.ncbi.nlm.nih.gov/12152116 Page: p.268
40 mg 1 times / day multiple, oral Studied dose Dose: 40 mg, 1 times / day Route: oral Route: multiple Dose: 40 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/12161768 Page: S51	unhealthy, 28–80 n = 119 Health Status: unhealthy Condition: Erectile dysfunction Age Group: 28–80 Sex: M Population Size: 119 Sources: https://pubmed.ncbi.nlm.nih.gov/12161768 Page: S51	Disc. AE: Dyspnea, Tachycardia... AEs leading to discontinuation/dose reduction: Dyspnea (0.84%) Tachycardia (0.84%) Epistaxis (0.84%) Cephalgia (0.84%) Flushing (serious, 0.84%) Chest pain (serious, 0.84%) Shortness of breath (serious, 0.84%) Tachycardia (serious, 0.84%) Sources: https://pubmed.ncbi.nlm.nih.gov/12161768 Page: S51
5 mg single, intravenous\|intramuscular Recommended Dose: 5 mg Route: intravenous\|intramuscular Route: single Dose: 5 mg Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fe1e10f5-4ff3-4616-9534-489648d88d33&type=display	unhealthy Health Status: unhealthy Condition: Pheochromocytoma Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fe1e10f5-4ff3-4616-9534-489648d88d33&type=display	Disc. AE: Myocardial infarction, Cerebrovascular spasm... AEs leading to discontinuation/dose reduction: Myocardial infarction Cerebrovascular spasm Cerebral vascular occlusion Hypotension Sources: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=fe1e10f5-4ff3-4616-9534-489648d88d33&type=display

AEs

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:8081	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:8081
ChemicalBook	CB6665216	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6665216
MolPort	MolPort-000-771-097	https://www.molport.com/shop/molecule-link/MolPort-000-771-097
MolPort	MolPort-001-783-569	https://www.molport.com/shop/molecule-link/MolPort-001-783-569
ZINC	ZINC000000020251	http://zinc15.docking.org/substances/ZINC000000020251
eMolecules	31790003	https://www.emolecules.com/cgi-bin/more?vid=31790003
eMolecules	975745	https://www.emolecules.com/cgi-bin/more?vid=975745

PubMed

Title	Date	PubMed
Use of phentolamine in acute myocardial infarction associated with hypertension and left ventricular failure.	1973 Apr	4696794
[Effect of several neuroleptic, adreno-, sympatho- and cholinolytic substances on the development of experimental cerebral edema induced by nicotine].	1977 May-Jun	20324
A study of the sympathomimetic action of guanethidine on the isolated anococcygeus muscle of the rat.	1978 Feb	623942
Three cases of sinoatrial block induced by anticonvulsants.	1978 Jul	731879
Central action of narcotic analgesics. Part III. The role of endogenous noradrenaline in hyperactivity induced by morphine or fentanyl in mice.	1978 Jul-Aug	216979
Oral therapy with phentolamine in chronic congestive heart failure.	1979 Apr	446138
Chronic treatment with antidepressant drugs: potentiation of apomorphine-induced aggressive behaviour in rats.	1979 Aug	575199
Effects of pretreatment with 6-hydroxydopamine or noradrenergic receptor blockers on the clonidine-induced distruption of conditioned avoidance responding.	1979 Sep 1	499336
Noradrenergic influences on sound-induced seizures.	1980 Aug	6104728
Effects of clonidine on canine cardiac neuroeffector structures controlling heart rate.	1980 Oct	7426836
Noninvasive assessment of load reduction in chronic congestive heart failure patients.	1981 Aug	7258732
Hypertensive crisis resulting from avocados and a MAO inhibitor.	1981 Nov	7297422
Mediation of renin release in essential hypertension by alpha-adrenoreceptors.	1981 Nov-Dec	6173514
[Acute and chronic cardiac decompensation: is vasodilator therapy useful?].	1982 Jan 14	7058000
Alpha-adrenoceptor blockade by phentolamine causes beta-adrenergic vasodilation by increased catecholamine release due to presynaptic alpha-blockade.	1982 Jan-Feb	6176798
The effects of cigarette smoke and nicotine on platelet thrombus formation in stenosed dog coronary arteries: inhibition with phentolamine.	1982 Mar	7055868
Some functional changes in experimentally induced cardiac overload.	1983	6230880
Contribution of alpha-adrenoceptor activation to the pathogenesis of norepinephrine cardiomyopathy.	1983 Apr	6131755
Role of autonomic nervous system in the pathogenesis of angina pectoris.	1983 Feb	6305298
A nonhuman primate model for evaluating the potential of antihypertensive drugs to cause orthostatic hypotension.	1983 May	6876810
Involvement of adenosine receptor activities in aggressive responses produced by clonidine in mice.	1984	6093179
Pharmacological, hemodynamic and autonomic nervous system mechanisms responsible for the blood pressure and heart rate lowering effects of pergolide in rats.	1984 Mar	6707926
[Hemodynamic and respiratory effects of phentolamine in pulmonary hypertension secondary to chronic obstructive syndrome].	1985 Jan 19	3975579
Ventricular tachycardia induced by clonidine withdrawal.	1985 Jun	4005090
Sympathetic mechanisms in poststenotic myocardial ischemia.	1986	2429111
Antagonism of cocaine-induced hepatotoxicity by the alpha adrenergic antagonists phentolamine and yohimbine.	1987 Aug	2886651
Prostaglandins inhibit endogenous pain control mechanisms by blocking transmission at spinal noradrenergic synapses.	1988 Apr	2833584
Complications of phenylpropanolamine.	1989 Apr	2650503
Propranolol antagonizes hypotension induced by alpha-blockers but not by sodium nitroprusside or methacholine.	1989 Feb	2565755
Treatment of peripheral ischemia secondary to lidocaine containing epinephrine.	1989 Jul	2764457
Presynaptic alpha 2-autoreceptors in brain cortex: alpha 2D in the rat and alpha 2A in the rabbit.	1993 Jul	8397342
Sodium bicarbonate alleviates penile pain induced by intracavernous injections for erectile dysfunction.	1993 May	8386779
Comparison of a mixture of papaverine, phentolamine and prostaglandin E1 with other intracavernous injections.	1994	7713130
Reasons for high drop-out rate with self-injection therapy for impotence.	1994 Sep	7735362
KMD-3213, a novel, potent, alpha 1a-adrenoceptor-selective antagonist: characterization using recombinant human alpha 1-adrenoceptors and native tissues.	1995 Aug	7651358
Effects of chronic NO synthase inhibition in rats on renin-angiotensin system and sympathetic nervous system.	1995 Jun	7541960
Contribution of peripheral alpha 1A-adrenoceptors to pain induced by formalin or by alpha-methyl-5-hydroxytryptamine plus noradrenaline.	1996 Apr 22	8773445
Cocaine-associated myocardial infarction.	1996 Aug	8795497
Neural mechanism of pressor action of nitric oxide synthase inhibitor in anesthetized monkeys.	1996 Sep	8794814
[The vasodilation and its mechanism of C-type natriuretic peptide].	2001 May	21171413
Limited clinical value of bacterial cocaine esterase in cocaine toxicity.	2010 May	20417385
Phentolamine mesylate for accelerating recovery from lip and tongue anesthesia.	2010 Oct	20831927
Cell membrane chromatography competitive binding analysis for characterization of α1A adrenoreceptor binding interactions.	2011 Jul	21544540
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003
Characterization of a β-adrenergic-like octopamine receptor from the rice stem borer (Chilo suppressalis).	2012 Aug 1	22786641
Insights into the mechanisms mediating hyperglycemic and stressogenic outcomes in rats treated with monocrotophos, an organophosphorus insecticide.	2012 Mar 29	22305719
Palmitate increases the susceptibility of cells to drug-induced toxicity: an in vitro method to identify drugs with potential contraindications in patients with metabolic disease.	2012 Oct	22700542
Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model.	2013 Dec	24052561
Comparative pathophysiology, toxicology, and human cancer risk assessment of pharmaceutical-induced hibernoma.	2013 Dec 15	24141031
Acute effects of a sarin-like organophosphorus agent, bis(isopropyl methyl)phosphonate, on cardiovascular parameters in anaesthetized, artificially ventilated rats.	2013 Oct 1	23769715

Patents

Sample Use Guides

In Vivo Use Guide

Prevention or control of hypertensive episodes in the patient with pheochromo-cytoma. For preoperative reduction of elevated blood pressure, 5 mg of Phentolamine mesylate (1 mg for children) is injected intravenously or intramuscularly 1 or 2 hours before surgery, and repeated if necessary. During surgery, Phentolamine mesylate (5 mg for adults, 1 mg for children) is administered intravenously as indicated, to help prevent or control paroxysms of hypertension, tachycardia, respiratory depression, convulsions, or other effects of epinephrine intoxication.

Route of Administration: Other

In Vitro Use Guide

Cancer cell lines, PC-3, DU-145, NCI/ADR-RES, and SKOV3 were used for activity evaluation. Cells were seeded in 96-well plates. After 24 hr, cells were fixed with 10% trichloroacetic acid (TCA) representing cell population at time zero (T0). After additional incubation of 0.1% DMSO or phentolamine for 48 hr, cells were fixed with 10% TCA and SRB at 0.4% (w/v) in 1% acetic acid was added to stain cells. Unbound SRB was washed out. SRB bound cells were solubilized with 10mM Trizma base.

Name

Type

Language

PHENTOLAMINE

Official Name

English

PHENTOLAMINE [MI]

Common Name

English

Phentolamine [WHO-DD]

Common Name

English

3-((4,5-DIHYDRO-1H-IMIDAZOL-2-YLMETHYL)(4-METHYLPHENYL)AMINO)PHENOL

Systematic Name

English

PHENTOLAMIN

Common Name

English

phentolamine [INN]

Common Name

English

PHENTOLAMINE [HSDB]

Common Name

English

PHENTOLAMINE [VANDF]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QV03AB36