3-((4,5-Dihydro-1H-imidazol-2-yl)-methyl)(4-methyl-phenyl)amino)phenol

/SIGNS AND SYMPTOMS/ Phentolamine may cause acute and prolonged hypotension, tachycardia, cardiac arrhythmias, and angina, especially after parenteral administration. Myocardial infarction and cerebrovascular spasm or occlusion, usually in association with marked hypotension and a shock-like state, have been reported occasionally following parenteral administration of phentolamine. Deaths have occurred after IV administration of phentolamine for the diagnosis of pheochromocytoma.

/SIGNS AND SYMPTOMS/ Overdosage with Regitine is characterized chiefly by cardiovascular disturbances, such as arrhythmias, tachycardia, hypotension, and possibly shock. In addition, the following might occur: excitation, headache, sweating, pupillary contraction, visual disturbances; nausea, vomiting, diarrhea; hypoglycemia.

/SIGNS AND SYMPTOMS/ Phentolamine may cause acute and prolonged hypotension, tachycardia, cardiac arrhythmias, and angina, especially after parenteral administration. Myocardial infarction and cerebrovascular spasm or occlusion, usually in association with marked hypotension and a shock-like state, have been reported occasionally following parenteral administration of phentolamine. Deaths have occurred after IV administration of phentolamine for the diagnosis of pheochromocytoma.

/SIGNS AND SYMPTOMS/ Intracavernous injection /not approved in the US/ of combined phentolamine and papaverine for the treatment of impotence occasionally has caused priapism. Priapism is a medical emergency that could result in penile tissue damage and permanent loss of potency if not treated immediately, and therefore, patients should be advised to report promptly to their physician or, if unavailable, to seek alternative immediate medical attention if an erection that persists longer than 4 hours or that is extremely painful occurs. ...

Benchmark Dataset for the Liver Toxicity Knowledge Base (LTKB)

phentolamine

Regitine®

Vasodilators

Not Applicable

no-DILI-concern

/LABORATORY ANIMALS: Acute Exposure/ OraVerse, an injectable formulation of phentolamine mesylate), was recently approved by the U.S. Food and Drug Administration (FDA) for reversal of anesthesia of the lip and tongue and associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. Because phentolamine mesylate had not been approved previously for submucosal administration, 2 Good Laboratory Practices (GLP) studies in dogs designed to investigate systemic toxicity and the local effects of single and repeated dosing of OraVerse on the inferior alveolar nerve and branches of the superior alveolar nerve and adjacent soft tissues after local administration were conducted. Systemic toxicity was measured by preinjection and postinjection clinical examinations, clinical chemistry, and gross and microscopic examinations of major organs after necropsy. No evidence of systemic toxicity was detected. Local nerve and adjacent tissue damage was assessed by conventional histopathology. Nerve degeneration was evident in 1 animal. Mild perineural inflammation adjacent to the inferior alveolar nerve and inflammatory exudates were observed in submucosal tissues in several animals. No changes were observed in the nerves at injection sites of dogs from any dose group that were considered directly related to the test articles.

/LABORATORY ANIMALS: Acute Exposure/ The aim of this study was to assess the effects of acute systemic, nonselective alpha-adrenergic blockade on aqueous flow. This study used pentobarbital-anesthetized rabbits (n=7), in which the following parameters were measured: mean arterial pressure, carotid blood flow, heart rate, intraocular pressure (IOP), orbital venous pressure (OVP), ciliary blood flow, and aqueous flow (AqFlow). Measurements were made before and after an intravenous administration of phentolamine (0.1 mg/kg). Phentolamine caused significant decreases in IOP -23%+/-2%; P<0.01), OVP (-28%+/-12%; P<0.05), and AqFlow (-33%+/-6%; P<0.01). The other parameters were not significantly altered. The rapidity of the OVP and IOP responses were noteworthy, being essentially complete 60 s after the phentolamine injection. A subpressor dose of phentolamine has complex effects on ocular hydrodynamics. The initial IOP decrease is too fast to be explained by aqueous dynamics or ocular rigidity, and so is most likely a result of the disgorgement of choroidal blood volume caused by decreased venous pressure outside the eye. The more prolonged ocular hypotensive effect is explained by the decrease in AqFlow, and perhaps a decrease in episcleral venous pressure or increase in uveoscleral outflow. However, the inhibition of aqueous production is odd, as lost prejunctional inhibition of norepinephrine release and unopposed beta-receptor activation should have increased aqueous production.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ ... Phentolamine mesylate was administered to rats by oral gavage at daily doses of 10, 50, and 150 mg/kg for 24 months. A dose-related increase in mortality, ascribed to an exaggerated pharmacologic effect, was seen at high doses. Systemic exposure as measured by plasma drug concentration increased with dose and duration of dosing and slight drug accumulation occurred, particularly in high-dose males. In the treated groups, 10 males and 1 female were diagnosed with hibernomas, neoplasms of brown adipose tissue, which appeared in the thoracic cavity or retroperitoneal area as circumscribed, tan to reddish-brown lobulated masses. Histologically, the masses were well circumscribed with variably sized lobules defined by a rich capillary network and consisted of closely apposed oval to polygonal cells with large amounts of cytoplasm and a centrally located nucleus. The cytoplasm's appearance varied from multivacuolated to univacuolated to granular eosinophilic. In a few cases, neoplastic emboli were observed in capsular vessels. Ultrastructurally, the neoplastic cells contained numerous mitochondria with transverse parallel cristae that occupied over 60% of the cytoplasm and lipid droplets.

Treatment. There is no specific antidote. A decrease in blood pressure to dangerous levels or other evidence of shocklike conditions should be treated vigorously and promptly. The patient's legs should be kept raised and a plasma expander should be administered. If necessary, intravenous infusion of norepinephrine, titrated to maintain blood pressure at the normotensive level, and all available supportive measures should be included. Epinephrine should not be used, since it may cause a paradoxical reduction in blood pressure.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

LD50 Rat oral 1250 mg/kg

LD50 Mouse oral 1000 mg/kg

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including phentolamine mesylate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Phentolamine mesylate/

Treatment of hypertension and hypertensive emergencies, pheochromocytoma, vasospasm of Raynaud disease and frostbite, clonidine withdrawal syndrome, impotence, and peripheral vascular disease

To relieve pseudo-obstruction of the bowel in patients with pheochromocytoma; to prevent dermal necrosis after inadvertent extravasation of an alpha-receptor antagonist; for treatment of hypertensive crisis that follow the abrupt withdrawal of clonidine or that may result from the ingestion of tyramine-containing food during the use of nonselective MAO inhibitors.

THERAPEUTIC CATEGORY: Antihypertensive in treatment of pheochromocytoma; diagnostic aid (pheochromocytoma). In treatment of male erectile dysfunction.

MEDICATION

For injection, powder, lyophilized, for suspension: vials each containing 5 mg of phentolamine mesylate for injection, USP, and 25 mg of mannitol, USP, inlyophilized form, Regitine (Novartis).

For injection, solution for submucosal use: 0.4 mg/1.7 mL solution per cartridge, OraVerse (Novalar).

Parenteral: For injection: 5 mg Phentolamine Mesylate for Injection (Available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name). /Phentolamine mesylate/