VA Class:AU200

AHFS Class:

• Non-selective alpha-Adrenergic Blocking Agents 12:16.04.04

Generic Name(s):

• Phentolamine Mesylate

Phentolamine is an imidazoline α-adrenergic blocking agent.

Phentolamine is used mainly in the diagnosis of pheochromocytoma and to control or prevent paroxysmal hypertension immediately prior to or during pheochromocytomectomy.

Diagnosis of Pheochromocytoma

Although no single chemical or pharmacological test is completely reliable, determinations of blood concentrations of catecholamines and/or urinary excretion of catecholamines or their metabolites are the safest and most reliable methods for the diagnosis of pheochromocytoma. The phentolamine test may be used when additional confirmatory evidence of pheochromocytoma is required and the potential benefits of the test outweigh the possible risks. (See Cautions: Adverse Effects.) The phentolamine test is more reliable in detecting pheochromocytomas in patients with sustained hypertension than in those with paroxysmal hypertension and is of no value in patients who are not hypertensive at the time of the test. Sudden and marked reduction in blood pressure following parenteral administration of phentolamine to a hypertensive patient suggests the presence of a pheochromocytoma. However, false-negative and false-positive responses to the phentolamine test occur frequently. (See Cautions: Precautions and Contraindications.)

Hypertension in Pheochromocytoma

In patients with pheochromocytomas, phentolamine may be administered immediately prior to or during pheochromocytomectomy to prevent or control paroxysmal hypertension resulting from anesthesia, stress, or operative manipulation of the tumor. For information regarding pheochromocytoma crisis, see Uses: Hypertensive Crises.

Although phentolamine has also been used for the medical management of patients with pheochromocytomas until surgery is performed and for prolonged treatment of hypertension caused by a pheochromocytoma not amenable to surgery, most clinicians consider phenoxybenzamine the drug of choice because it has a longer duration of action.

Hypertensive Crises

Phentolamine mesylate also has been used to treat hypertensive crises or emergencies† (severe elevations in blood pressure exceeding 180/120 mm Hg accompanied by new or worsening target organ dysfunction) induced by catecholamine excess (e.g., pheochromocytoma, drug interactions with a monoamine oxidase [MAO] inhibitor, amphetamine overdosage, cocaine toxicity, clonidine withdrawal)†.1200

Phentolamine is not used in the treatment of essential hypertension because most patients become refractory to the antihypertensive effect of the drug and because of the high incidence of adverse GI effects. Although phentolamine has been used as adjunctive therapy in the treatment of peripheral vasospastic disorders†, the efficacy of the drug has not been established and the frequency of adverse effects limits its usefulness.

Extravasation of Catecholamines

Phentolamine mesylate is used for the prevention and treatment of dermal necrosis and sloughing following IV administration or extravasation of norepinephrine.177,200 Phentolamine mesylate has also been used to prevent necrosis after extravasation of dopamine†.

Myocardial Infarction

Phentolamine mesylate has been used IV to decrease the impedance to left ventricular ejection and the size of infarction in patients with myocardial infarction (MI) associated with left ventricular failure†. However, the manufacturers state that the drug is contraindicated in patients with MI and investigators do not recommend this therapy for routine use, since left ventricular function and the ECG must be monitored continuously.

Erectile Dysfunction

Self-injection of small doses of phentolamine mesylate combined with papaverine hydrochloride into a corpus cavernosum of the penis has been effective for the treatment of erectile dysfunction† (impotence).103,105,106,107,108,110,112,113,114,115,118,119,120,121,122,123,124,125,126,127 Injection into a single cavernosum can increase tumescence (in both cavernosa because of cross circulation) and produce erection probably secondary to drug-induced increased arterial inflow and sinusoidal relaxation and decreased venous outflow (from increased venous resistance).105,106,108,110,116,117,124,127 The goal of such therapy is to provide an erection of adequate rigidity and duration to be sexually functional while avoiding prolonged erection or priapism.142,153,154,155,156,158 Intracavernosal papaverine (alone or combined with phentolamine and/or alprostadil) is one of the most effective and well-studied agents for the treatment of erectile dysfunction and has been in widespread clinical use.125,128 The combination has been effective in patients with neurogenic103,105,106,108,110,112,113,115,116,118,119,120,122,123,124,127 and/or limited vasculogenic impotence103,105,106,108,110,112,113,115,116,120,122,123,124,127 or with psychogenic impotence,105,106,108,123,124,127 but efficacy in those with a vasculogenic component of their impotence may be variable depending on the extent and type of vascular dysfunction.103,108,110,115,120,123,124 Erection, which can be potentiated by sexual arousal, usually occurs within 10 minutes after injection of the drugs and may persist for one to several hours;105,106,108,113,114,116,118,119,124 tolerance to the beneficial vascular effects of the drugs may occur during long-term use and may require an increase in dosage.105,114,124 Occasionally, priapism may occur.103,105,106,107,108,110,113,115,116,124,125,126,127 (See Cautions: Adverse Effects.)

Because of their convenience (e.g., ease of administration, patient and partner acceptance, and effectiveness in a broad range of patients), most experts (e.g., the American Urological Association [AUA]) currently recommend that selective phosphodiesterase (PDE) type 5 inhibitor therapy (sildenafil, tadalafil, vardenafil) be offered as first-line treatment of erectile dysfunction unless contraindicated.178 Intracavernosal therapy with papaverine and/or phentolamine generally is reserved for patients who do not respond to psychotherapy/behavioral therapy, vacuum constriction devices, and/or selective PDE type 5 inhibitors, and in whom attempts at identifying and modifying any drug-related (e.g., certain antihypertensive agents) or other potential reversible medical cause of erectile dysfunction have proved inadequate.110,125,167,168,169 Intracavernosal therapy or vacuum constriction devices generally are considered or attempted before resorting to more invasive (e.g., surgical) therapies.125,178 Ultimately, the choice of therapy for erectile dysfunction should be individualized, taking into account differences in response, tolerability and safety, administration considerations, cost and patient reimbursement factors, experience and judgment of the clinician, and individual patient and partner preference, expectations, and satisfaction.167,168,169,170,171,172,173,174,178

Intracavernosal vasoactive therapy (e.g., papaverine, papaverine and phentolamine, alprostadil) is the most effective treatment for erectile dysfunction;178 however, it is invasive and associated with the highest risk of priapism.178 Clinician preference and experience often guide the initial treatment choice when intracavernosal therapy is indicated.178

Additional study of the long-term safety and efficacy of intracavernous injection of vasoactive drugs for the treatment of erectile dysfunction is necessary and ongoing,103,105,110,112,113,116,118,124 particularly regarding the relative efficacy of single- versus multiple-drug therapy and the relative complications (e.g., penile scarring, penile fibrosis) and safety of each approach.103,108,112,113,115,124,125,127,128 Additional study also is needed to identify optimal patient education and follow-up support that might improve compliance and decrease dropout rates.125,128 Patients should be instructed to visit their clinician regularly (e.g., at 3-month intervals) for assessment of therapeutic benefit, including the need for possible dosage adjustment, and of potential adverse effects of their therapy.142,152,156,163

Vasoactive therapy for erectile dysfunction should not be used in patients who might have conditions predisposing to priapism (e.g., sickle cell anemia or trait, multiple myeloma, leukemia), in those with anatomic deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie's disease), or in men for whom sexual activity is inadvisable or contraindicated.142,145,148,151,154,160,163 In addition, vasoactive therapy should be discontinued in any patient who develops penile angulation, cavernosal fibrosis, or Peyronie's disease during therapy with the drug.142,163 One manufacturer also states that patients with penile implants should not be treated with vasoactive therapy for impotence.142

Because of the risk of priapism and other potential complications (e.g., adverse morphologic penile effects such as fibrosis) associated with intercavernosal vasoactive therapy, such therapy is not recommended for simply enhancing erections in men who are not impotent†.158

Cocaine-induced Acute Coronary Syndrome

Phentolamine has been used as an adjunct in the management of cocaine overdose† to reverse coronary vasoconstriction.196

Other Uses

IV phentolamine has been used effectively to treat ventricular or supraventricular premature contractions†.

Reconstitution and Administration

Phentolamine mesylate may be administered by IM or IV injection. Phentolamine mesylate injection is reconstituted by adding 1 mL of sterile water for injection to the vial containing 5 mg of lyophilized drug. The resulting solution contains 5 mg of phentolamine mesylate per mL.

Phentolamine mesylate also has been administered by intracavernous injection† for the treatment of erectile dysfunction.103,105,106,107,108,110,112,113,114,115 (See Uses: Erectile Dysfunction.) Patients receiving the drug via intracavernosal injection should be advised of the potential for prolonged erections (priapism) and advised of steps to take in the event that this potentially serious adverse effect occurs.178,179 (See Adverse Effects: Adverse Intracavernosal Effects, in Cautions.)

Dosage

Diagnosis of Pheochromocytoma

For the diagnosis of pheochromocytoma, phentolamine mesylate may be administered IM or preferably IV. The usual adult IV or IM dose is 5 mg. Children may receive 1 mg IV or 3 mg IM. Alternatively, some clinicians have recommended an IV pediatric dose of 0.1 mg/kg or 3 mg/m². Before the drug is injected, the patient should rest in a supine position (preferably in a quiet, darkened room) until the blood pressure is stabilized and a basal level is established by blood pressure readings taken every 10 minutes for at least 30 minutes. When phentolamine mesylate is administered IV, injection of the drug should be delayed until the effect of the venipuncture on the blood pressure has passed; the drug should then be rapidly injected. In patients with a pheochromocytoma which is secreting epinephrine or norepinephrine, the response to IV injection of phentolamine mesylate is an immediate, marked decrease in both systolic and diastolic blood pressure. The maximum effect is usually obtained within 2 minutes after IV injection of the drug, and the blood pressure usually returns to pretest levels within 15-30 minutes. Therefore, blood pressure should be recorded immediately after the injection, at 30-second intervals for the first 3 minutes, and at 1-minute intervals for the next 7 minutes. Following IM injection, the maximum effect usually occurs within 20 minutes and persists for about 30-45 minutes. Blood pressure returns to pretest levels after 3-4 hours. After IM administration of phentolamine mesylate, blood pressure determinations should be made at 5-minute intervals for 30-45 minutes.

In the phentolamine test, a typical blood pressure response in patients with pheochromocytomas is a decrease in blood pressure of 60 mm Hg systolic and 25 mm Hg diastolic within 2 minutes after IV administration of the drug or within 20 minutes after IM administration. A blood pressure decrease of at least 35 mm Hg systolic and 25 mm Hg diastolic is considered a positive response and a positive test for pheochromocytoma. A negative response is indicated when the blood pressure is unchanged, elevated, or lowered less than 35 mm Hg systolic and 25 mm Hg diastolic.

Hypertension in Pheochromocytoma

To reduce elevated blood pressure prior to surgical removal of a pheochromocytoma, 5 mg of phentolamine mesylate is given IM or IV 1-2 hours preoperatively to adults or 1 mg, 0.1 mg/kg, or 3 mg/m² is given IM or IV to children; the dose may be repeated if necessary. During surgery for pheochromocytoma, 5 mg of phentolamine mesylate may be given IV to adults as needed to prevent or control paroxysms of hypertension, tachycardia, respiratory depression, convulsions, or other effects of excessive epinephrine secretion due to manipulation of the tumor. For children, the IV dose of phentolamine mesylate during surgery is 1 mg, 0.1 mg/kg, or 3 mg/m². Postoperatively, norepinephrine may be administered to control hypotension which commonly follows removal of a pheochromocytoma; however, this hypotension is more often prevented by administration of blood, plasma, or 5% albumin in 0.9% sodium chloride injection to correct the reduced blood volume which may occur.

Hypertensive Crisis

For hypertensive crisis resulting from catecholamine excess†, some experts recommend 5 mg administered as a rapid IV (“bolus”) injection.1200 Experts state that this dosage may be repeated every 10 minutes as necessary to achieve the desired blood pressure target.1200

If IV phentolamine is used in the management of a hypertensive crisis, patients who have hypertensive crisis with a compelling condition (e.g., aortic dissection, severe preeclampsia or eclampsia, pheochromocytoma crisis) should have their systolic blood pressure reduced to less than 140 mm Hg during the first hour and, in patients with acute aortic dissection, to less than 120 mm Hg within the first 20 minutes.1200 The initial goal of such therapy in adults without a compelling condition is to reduce systolic blood pressure by no more than 25% within the first hour, followed by further blood pressure reduction if stable to 160/110 or 160/100 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.1200 If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal can be implemented in the next 24-48 hours.1200

Extravasation of Catecholamines

To treat dermal necrosis and sloughing following IV administration or extravasation of norepinephrine, 5-10 mg of phentolamine mesylate diluted in 10 mL of 0.9% sodium chloride injection is injected into the affected area within 12 hours.177,200 Immediate and conspicuous local hyperemic changes occur if the area is infiltrated within 12 hours, but such treatment is ineffective when given more than 12 hours after extravasation.177

To prevent dermal necrosis and sloughing from IV administration or extravasation of norepinephrine, 10 mg of phentolamine mesylate may be added to each liter of IV fluids containing norepinephrine (the pressor effect of norepinephrine is unaffected).200

To prevent tissue necrosis and sloughing following extravasation of dopamine injection, 10-15 mL of 0.9% sodium chloride injection containing 5-10 mg of phentolamine mesylate should be infiltrated (using a syringe with a fine hypodermic needle) liberally throughout the affected area, which is identified by coldness, hardness, and a pallid appearance. In children, phentolamine mesylate dosages of 0.1-0.2 mg/kg, up to a maximum of 10 mg per dose, may be administered. Immediate and conspicuous local hyperemic changes occur if the area is infiltrated within 12 hours.

Myocardial Infarction

For the treatment of left ventricular failure secondary to acute myocardial infarction (MI)†, the adult IV dosage of phentolamine mesylate as an infusion has ranged from 0.17-0.4 mg/minute. Left ventricular function and the ECG must be monitored continuously.

Erectile Dysfunction

When used for the treatment of erectile dysfunction† (impotence), self-injection into the corpus cavernosum of the penis of small doses of phentolamine mesylate (0.08-1.25 mg, but usually 0.5-1 mg) combined with papaverine hydrochloride (2.5-37.5 mg, but usually titrated up to 30 mg) have been effective. Erection, which can be potentiated by sexual arousal, usually occurs within 10 minutes after injection of the drugs and may persist for one to several hours; tolerance to the beneficial vascular effects of the drugs may occur during long-term use and may require an increase in dosage. Occasionally, priapism may occur. (See Cautions: Adverse Effects.)

Adverse Effects

Phentolamine may cause acute and prolonged hypotension, tachycardia, cardiac arrhythmias, and angina, especially after parenteral administration. Myocardial infarction (MI) 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.

Weakness, dizziness, flushing, orthostatic hypotension, and nasal congestion have been reported in patients receiving phentolamine. Adverse GI effects are common and include abdominal pain, nausea, vomiting, diarrhea, and exacerbation of peptic ulcer; these adverse effects generally prevent long-term administration of phentolamine.

Adverse Intracavernosal Effects

Intracavernous injection† of combined phentolamine and papaverine for the treatment of impotence occasionally has caused priapism.103,105,106,107,108,110,113,115,116,120,124,125,126,127 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.142,152,161,162,163 Management of priapism should be according to established medical practice, and has included aspiration of cavernosal blood105,110,113,115,116,120,124 and/or intracavernous injection of small doses of an α-adrenergic agonist (e.g., metaraminol, phenylephrine),103,105,106,107,108,109,110,111,113,115,120,124 or dopamine.144,145,146,148,150,157,159,161,179 Rarely, more radical therapy for priapism (e.g., cavernospongiosus or Winter's shunt) may be necessary,104,105,106,110,124,179 such as in patients with persistent priapism (e.g., for longer than 24 hours).104,110,125

Other complications of intracavernous injection of combined phentolamine and papaverine have included transient pain,105,108,110,124 including referred pain to the glans,108,110 burning,103 and paresthesia.105,110,124 Penile ecchymosis has occurred in many patients,105,110,113,124 and superficial hematoma103,110 and bruising of the penis108 also have occurred. Fibrotic changes (e.g., induration, lumpy areas of the penis but not necessarily at the injection site), including bilateral fibrosis of the corpora cavernosa, also have been reported.105,110,114,124 Embolus in the glans has been reported rarely,105,108,124 and the development of priapism, deep vein thrombosis, and fatal pulmonary embolus occurred in one patient.105,124 Adverse systemic effects of the drugs (e.g., facial flushing,110 dizziness,103,110 decreased systemic blood pressure,105,108,110,120,124 metallic taste)103 also have occurred.103,105,108,110

The risk of priapism, although reportedly uncommon, can be reduced by careful patient instruction and dosage titration.112,127,128,133,134,135,141 Alternatively, switching to another therapy (e.g., alprostadil) may provide better patient tolerance.127,128,133,137,138,139,140 Some clinicians also have used alprostadil in combination with papaverine and phentolamine in an attempt to potentiate their therapeutic activity, reduce the dose of each drug required, and decrease the risk of local pain, penile corporal fibrosis, fibrotic nodules, hypotension, and priapism associated with higher dosages.125,129,130,131,132,133,135,136,140,178 However, additional study is needed to elucidate the long-term safety and benefits of such combined therapy.125,131,140

Precautions and Contraindications

If severe hypotension or other signs and symptoms of shock occur following administration of phentolamine, treatment must be vigorous and prompt. Therapy should include supportive measures and norepinephrine may be administered if necessary; epinephrine should not be given since it may cause a paradoxical fall in blood pressure. The manufacturer states that if cardiac arrhythmias occur during therapy with phentolamine, administration of digitalis glycosides should be deferred until the cardiac rhythm returns to normal.

False-negative responses to the phentolamine test may occur, especially in patients with paroxysmal hypertension or with a pheochromocytoma which is not secreting enough epinephrine or norepinephrine to elevate the blood pressure or to sustain an elevation. False-positive reactions occur more commonly than do false-negative responses and have occurred in patients with essential hypertension, in patients who have received sedatives, opiates, or antihypertensive drugs, and in patients with uremia. When practical, sedatives, analgesics, and all other medication should be withdrawn at least 24 hours (but preferably 48-72 hours) prior to the phentolamine test. Antihypertensive drugs should be withdrawn and the test should not be performed until blood pressure returns to pretreatment hypertensive levels; rauwolfia drugs (no longer commercially available in the US) should be withdrawn at least 4 weeks prior to testing.

The possibility that intracavernosal therapy for impotence could result in persistent priapism requiring medical and/or surgical intervention should be considered.103,105,106,107,108,110,113,115,116,120,124,125,126,127,128 (See Cautions: Adverse Effects.) Patients should be advised to contact their clinician if they develop a persistent (e.g., longer than 4 hours) erection during such therapy.132,133 The possibility that intracavernosal therapy may be problematic in patients receiving anticoagulants or who cannot tolerate transient hypotension and, because of the self-injection techniques involved, in those with poor manual dexterity, poor vision, or severe psychiatric disease also should be considered.125 For additional precautions and contraindications associated with vasoactive therapy in impotence, see Uses.

Phentolamine should be used with caution in patients with gastritis or peptic ulcer. Although the manufacturer states that phentolamine is contraindicated in patients with MI or a history of MI, coronary insufficiency, angina, or other evidence suggestive of coronary artery disease, results of some studies indicate that the drug may have a beneficial effect in patients with MI. (See Uses: Other Uses.) The drug is contraindicated in patients who are hypersensitive to phentolamine or to related drugs.

Mutagenicity and Carcinogenicity

Studies to determine the mutagenic and carcinogenic potentials of phentolamine mesylate have not been performed to date.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and mice using oral phentolamine mesylate dosages 24-30 times the usual daily human dosage (based on a 60-kg individual) have shown slightly decreased fetal growth and slight fetal skeletal immaturity (manifested by an increased incidence of incomplete or unossified calcanei and phalangeal nuclei of the hind limb and of incompletely ossified sternebrae). In rats receiving oral dosages 60 times the usual human daily dosage (based on a 60-kg individual), a slightly decreased rate of implantation occurred. In rabbits receiving oral dosages 20 times the usual human daily dosage (based on a 60-kg individual), embryonic and fetal development were not affected. No teratogenic or embryotoxic effects were observed in reproduction studies in rats, mice, and rabbits. At least one human death has been reported following the phentolamine test during pregnancy. There are no adequate and well-controlled studies using phentolamine in pregnant women, and the drug should be used during pregnancy only when the potential benefits outweigh the possible risks to the fetus.

Fertility

Studies to determine the potential effects of phentolamine mesylate on fertility have not been performed to date.

Lactation

It is not known whether phentolamine mesylate is distributed into milk. Because of the potential for serious adverse reactions to phentolamine mesylate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Pharmacology

Phentolamine inhibits responses to adrenergic stimuli by competitively blocking α-adrenergic receptors (primarily excitatory responses of smooth muscle and exocrine glands), but the action of the drug is relatively transient and α-adrenergic blockade is incomplete. Phentolamine has greater α-adrenergic blocking effects than does tolazoline. Phentolamine is more effective in antagonizing responses to circulating epinephrine and/or norepinephrine than in antagonizing responses to mediator released at the adrenergic nerve ending. The drug causes peripheral vasodilation and decreases peripheral resistance, primarily by direct relaxation of vascular smooth muscle, but α-adrenergic blockade also contributes to vasodilation. Phentolamine also stimulates β-adrenergic receptors and produces a positive inotropic and chronotropic effect on the heart and increases cardiac output.

Blood pressure response to phentolamine depends on the relative contributions of its vasodilating and cardiac stimulating effects. IV infusion of phentolamine mesylate 0.3 mg/minute may increase blood pressure because of a predominant inotropic effect, but with higher rates of administration vasodilation may predominate, decreasing blood pressure and masking the inotropic effect. Pulmonary vascular resistance and pulmonary arterial pressure are decreased. Cerebral blood flow is generally maintained. Usual doses of phentolamine lower blood pressure when it is maintained by circulating epinephrine or norepinephrine, but have little effect on the blood pressure of healthy individuals or patients with essential hypertension.

When phentolamine is administered IV to patients with acute myocardial infarction (MI) associated with hypertension and/or left ventricular failure, improvement in left ventricular performance results, with cardiac output, stroke index, heart rate, and cardiac index being increased and left ventricular filling pressure being decreased. In one study, IV phentolamine increased coronary blood flow in patients with recent MI. In animal studies, the drug prolonged the action potential duration and the effective refractory period and decreased conduction velocity.

Phentolamine dilates bronchial smooth muscle, presumably through stimulation of β-adrenergic receptors. The drug stimulates the smooth muscle of the GI tract, an effect which is blocked by atropine, and has a histamine-like effect which stimulates gastric secretion of both acid and pepsin. Large IV doses (40-50 mg) cause relaxation of the ureters.

Pharmacokinetics

The pharmacokinetics of phentolamine have not been determined. Phentolamine is only about 20% as active after oral administration as after parenteral administration. About 10% of a parenteral dose can be recovered in the urine as active drug; the fate of the remainder is not known. It is not known whether the drug crosses the placenta or appears in milk.

Chemistry and Stability

Chemistry

Phentolamine is an imidazoline α-adrenergic blocking agent that is related structurally to tolazoline. Phentolamine mesylate occurs as a white or off-white, crystalline powder and has solubilities of approximately 1 g/mL in water and 250 mg/mL in alcohol at 25°C. The pK_a of phentolamine mesylate is 8.01. Following reconstitution of the commercially available lyophilized powder with sterile water for injection to a concentration of 5 mg/mL, phentolamine mesylate injection has a pH of 4.5-6.5.

Stability

Phentolamine mesylate powder for injection should be stored at 15-30°C.

Following reconstitution of the commercially available lyophilized powder with sterile water for injection to a concentration of 5 mg/mL, phentolamine mesylate injection is stable for 48 hours at room temperature or 1 week at 2-8°C; however, the manufacturer recommends that the reconstituted injection be used immediately and not stored.

Following reconstitution of phentolamine mesylate lyophilized powder with 2 mL of commercially available papaverine hydrochloride injection (containing 30 mg/mL) and further dilution in 8 mL of the papaverine injection to provide an admixture containing 0.5 mg of phentolamine mesylate per mL and 30 mg of papaverine hydrochloride per mL, the resultant admixture had a pH of 3.6 and was stable for at least 30 days when stored in the papaverine vial at 5 or 25°C.100 It should be noted, however, that the manufacturer of papaverine hydrochloride injection recommends that the injection not be refrigerated since solubility of the drug is reduced at cold temperatures, possibly resulting in precipitation or crystallization.101,102 In addition, the possibility of microbial contamination of such admixtures during prolonged storage should be considered.100

Only references cited for selected revisions after 1984 are available electronically.

100. Tu YH, Allen LV Jr, Wang DP. Stability of papaverine hydrochloride and phentolamine mesylate in injectable mixtures. Am J Hosp Pharm . 1987; 44:2524-7. [PubMed 2446497]

101. Romankiewicz JA, McManus J, Gotz VP et al. Medications not to be refrigerated. Am J Hosp Pharm . 1979; 36:1541-5. [PubMed 517543]

102. Stillwell S (Eli Lilly and Company, Indianapolis, IN): Personal communication; 1986 Sept 10.

103. Sidi AA, Cameron JS, Duffy LM et al. Intracavernous drug-induced erections in the management of male erectile dysfunction: experience with 100 patients. J Urol . 1986; 135:704-6. [PubMed 2421014]

104. Lindoro J, Castro JC, Cruz F et al. Treatment of priapism. Lancet . 1984; 2:1348. [PubMed 6150362]

105. Anon. Intracavernous injections for impotence. Med Lett Drugs Ther . 1987; 29:95-6. [PubMed 3670212]

106. Robinette MA, Moffat MJ. Intracorporal injection of papaverine and phentolamine in the management of impotence. Br J Urol . 1986; 58:692-5. [PubMed 3801830]

107. Ellis LR, Nellans RE, Kramer-Levien DJ et al. Evaluation of the first 300 patients treated at an outpatient center for male sexual dysfunction. West J Med . 1987; 147:296-300. [PubMedCentral][PubMed 3673062]

108. Nellans RE, Ellis LR, Kramer-Levien D. Pharmacological erection: diagnosis and treatment applications in 69 patients. J Urol . 1987; 138:52-4. [PubMed 2439712]

109. Fernandez JA, Basha MA, Wilson GC. Emergency treatment of papaverine priapism. J Emerg Med . 1987; 5:289-91. [PubMed 3624835]

110. Lue TF, Tanagho EA. Physiology of erection and pharmacological management of impotence. J Urol . 1987; 137:829-36. [PubMed 3553617]

111. Mizutani M, Nakano H, Sagami K et al. Treatment of post-traumatic priapism by intracavernous injection of α-stimulant. Urol Int . 1986; 41:312-4. [PubMed 3787856]

112. Sidi AA, Cameron JS, Dykstra DD et al. Vasoactive intracavernous pharmacotherapy for the treatment of erectile impotence in men with spinal cord injury. J Urol . 1987; 248:539-42.

113. Gasser TC, Roach RM, Larsen EH et al. Intracavernous self-injection with phentolamine and papaverine for the treatment of impotence. J Urol . 1987; 137:678-80. [PubMed 3550149]

114. Larsen EH, Gasser TC, Bruskewitz RC. Fibrosis of corpus cavernosum after intracavernous injection of phentolamine/papaverine. J Urol . 1987; 137:292-3. [PubMed 3806824]

115. Trapp JD. Pharmacologic erection program for the treatment of male impotence. South Med J . 1987; 60:426-7.

116. Zorgniotti AW, Lefleur RS. Auto-injection of the corpus cavernosum with a vasoactive drug combination for vasculogenic impotence. J Urol . 1985; 133:39-41. [PubMed 2578067]

117. Juenemann KP, Lue TF, Fournier GR Jr et al. Hemodynamics of papaverine- and phentolamine-induced penile erection. J Urol . 1986; 136:158-61. [PubMed 3712604]

118. Wyndaele JJ, de Meyer JM, de Sy WA et al. Intracavernous injection of vasoactive drugs, an alternative for treating impotence in spinal cord injury patients. Paraplegia . 1986; 24:271-5. [PubMed 3774363]

119. Al-Juburi AZ, O'Donnell PD. Penile self-injection for impotence in patients after radical cystectomy-ileal loop. Urology . 1987; 30:29-30. [PubMed 3603906]

120. Kiely EA, Williams G, Goldie L. Assessment of the immediate and long-term effects of pharmacologically induced penile erections in the treatment of psychogenic and organic impotence. Br J Urol . 1987; 59:164-9. [PubMed 3828713]

121. Puyau FA, Lewis RW, Balkin P et al. Dynamic corpus cavernosography: effect of papaverine injection. Radiology . 1987; 164:179-82. [PubMed 3588901]

122. Zorgniotti AW. Corpus cavernosum blockade for impotence: practical aspects and results in 250 cases. J Urol . 1986; 135:306A.

123. Williams G. Impotence: treatment by autoinjection of vasoactive drugs. BMJ . 1987; 295:1279. [PubMedCentral][PubMed 3120975]

124. Anon. Intracavernous injections for impotence. Med Lett Drugs Ther . 1990; 32:116-7. [PubMed 2255296]

125. NIH Consensus Development Panel on Impotence. Impotence. JAMA . 1993; 270:83-90. [PubMed 8510302]

126. Anon. Vasodilators provide new therapy for erectile dysfunction. F-D-C Rep . 1992; 54:16-7.

127. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. N Engl J Med . 1989; 321:1648-59. [PubMed 2685600]

128. Kirby RS. Impotence: diagnosis and management of male erectile dysfunction. BMJ . 1994; 308:957-61. [PubMedCentral][PubMed 8173405]

129. Bennett AH, Carpenter AJ, Barada JH. An improved vasoactive drug combination for a pharmacological erection program. J Urol . 1991; 146:1564-5. [PubMed 1719248]

130. Montorsi F, Guazzoni G, Bergamaschi F et al. Four-drug intracavernous therapy for impotence due to corporeal veno-occlusive dysfunction. J Urol . 1993; 149:1291-5. [PubMed 7683061]

131. Montorsi F, Guazzoni G, Bergamaschi F et al. Effectiveness and safety of multidrug intracavernous therapy for vasculogenic impotence. Urology . 1993; 42:554-8. [PubMed 7694416]

132. von Heyden B, Donatucci CF, Kaula N et al. Intracavernous pharmacotherapy for impotence: selection of appropriate agent and dose. J Urol . 1993; 149:1288-90. [PubMed 8479018]

133. Reviewers' comments on papaverine (personal observations).

134. Biering-Sorensen F, Sonksen J. Penile erection in men with spinal cord or cauda equina lesions. Semin Neurol . 1992; 12:98-105. [PubMed 1502437]

135. Govier FE, McClure RD, Weissman RM et al. Experience with triple-drug therapy in a pharmacological erection program. J Urol . 1993; 150:1822-4. [PubMed 8230514]

136. Montorsi F, Guazzoni G, Bergamaschi F et al. Clinical reliability of multi-drug intracavernous vasoactive pharmacotherapy for diabetic impotence. Acta Diabetol . 1994; 31:1-5. [PubMed 8043890]

137. McGuffey E, Kramer L. Drugs for impotence. Am Pharm . 1992; NS32:23. [PubMed 1285547]

138. von Heyden B, Donatucci CF, Marshall GA et al. A prostaglandin El dose-response study in man. J Urol . 1993; 150:1825-8. [PubMed 8230515]

139. Mahmoud KZ, El Dakhli MR, Fahmi IM et al. Comparative value of prostaglandin El and papaverine in treatment of erectile failure: double-blind crossover study among Egyptian patients. J Urol . 1992; 147:623-6. [PubMed 1538443]

140. Allen RP, Engel RM, Smolev JK et al. Objective double-blind evaluation of erectile function with intracorporeal papaverine in combination with phentolamine and/or prostaglandin El. J Urol . 1992; 148:1181-3. [PubMed 1404632]

141. Lomas GM, Jarow JP. Risk factors for papaverine-induced priapism. J Urol . 1992; 147:1280-1. [PubMed 1569668]

142. The Upjohn Company. Caverject^® (alprostadil) injection for intracavernosal use prescribing information. Kalamazoo, MI; 1995 Jul.

143. Martinez-Pineiro L, Lopez-Tello J, Dorrego JMA et al. Preliminary results of a comparative study with intracavernous sodium nitroprusside and prostaglandin E1 in patients with erectile dysfunction. J Urol . 1995; 153:1487-90. [PubMed 7714974]

144. Whitehead ED. Impotence: should primary care physicians give penile injections? Geriatrics . 1995; 50:14. Letter. (IDIS 341817)

145. von Heyden B, Donatucci CF, Marshall GA et al. A prostaglandin E1 dose-response study in man. J Urol . 1993; 150:1825-8. [PubMed 8230515]

146. Montorsi F, Guazzoni G, Bergamaschi F et al. Four-drug intracavernous therapy for impotence due to corporeal veno-occlusive dysfunction. J Urol . 1993; 149:1291-5. [PubMed 7683061]

147. von Heyden B, Donatucci CF, Kaula N et al. Intracavernous pharmacotherapy for impotence: selection of appropriate agent and dose. J Urol . 1993; 149:1288-90. [PubMed 8479018]

148. Gerber GS, Levine LA. Pharmacological erection program using prostaglandin E1. J Urol . 1991; 146:786-9. [PubMed 1875494]

149. Artoux MJ, McQueen KD. Alprostadil in impotence. DICP . 1991; 25:363-6. [PubMed 1926907]

150. Whitehead ED, Klyde BJ, Zussman S et al. Treatment alternatives for impotence. Postgrad Med . 1990; 88:139-52. [PubMed 2199954]

151. Godschalk MF, Chen J, Katz PG et al. Prostaglandin E1 as treatment for erectile failure in elderly men. J Am Geriatr Soc . 1994; 42:1263-5. [PubMed 7983289]

152. Linet OI, Neff LL. Intracavernous prostaglandin E1 in erectile dysfunction. Clin Investig . 1994; 72:139-49. [PubMed 8186662]

153. Linet OI, Ogrinc FG. Dose-escalating study with maintenance phase using alprostadil (prostaglandin E1, PGE1) sterile powder in patients with erectile dysfunction. Technical Report No. 9124-93-006. The Upjohn Company: Kalamazoo, MI; 1993 Dec 3.

154. Linet OI, Ogrinc FG. Long-term safety study with alprostadil sterile powder (alprostadil S.Po.; prostaglandin E₁, PGE₁) in patients with erectile dysfunction. Technical Report No. 9124-93-007. The Upjohn Company: Kalamazoo, MI; 1993 Dec 10.

155. Linet OI, Ogrinc FG. Dose-escalating study with maintenance phase using alprostadil (prostaglandin E₁, PGE₁) sterile powder (S.Po.) in elderly patients with erectile dysfunction. Technical Report No. 9124-95-002. The Upjohn Company: Kalamazoo, MI; 1995 Jan 17.

156. Linet OI. Clinical pharmacology of alprostadil. In: Goldstein I, Lue TF, eds. The role of alprostadil in the diagnosis and treatment of erectile dysfunction. Princeton: Excerpta Medica; 1993:28-39.

157. Waldhauser M, Schramek P. Efficiency and side effects of prostaglandin E1 in the treatment of erectile dysfunction. J Urol . 1988; 140:525-7. [PubMed 3045341]

158. The Upjohn Company, Kalamazoo, MI: Personal communication.

159. Ravnik-Oblak M, Oblak C, Vodusek DB et al. Intracavernous injection of prostaglandin E₁ in impotent diabetic men. Int J Impotence Res . 1990; 2:143-49.

160. Lue TF, Tanagho EA. Physiology of erection and pharmacological management of impotence. J Urol . 1987; 137:829-36. [PubMed 3553617]

161. Krane RJ, Goldstein I, Saenz de Tejada I. Impotence. N Engl J Med . 1989; 321:1648-59. [PubMed 2685600]

162. Kirby RS. Impotence: diagnosis and management of male erectile dysfunction. BMJ . 1994; 308:957-61. [PubMedCentral][PubMed 8173405]

163. Bénard F, Lue TF. Self-administration in the pharmacological treatment of impotence. Drugs . 1990; 39:394-8. [PubMed 2184008]

165. Koestenblatt CP. Dear Pharmacist letter. Summit, NJ: CibaGeneva Pharmaceuticals; 1996 July 8.

166. Novartis, East Hanover, NJ: Personal communication.

167. The Process of Care Consensus Panel. Position paper: the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res . 1999; 11:59-70.

168. Sarramon JP. Editorial comments on the process of care model for evaluation and treatment of erectile dysfunction. Int J Impotence Res . 1999; 11:73.

169. Padma-Nathan H. A new era in the treatment of erectile dysfunction. Am J Cardiol . 1999; 84:18-23N. [PubMed 10404845]

170. Goldstein I, Lue TF, Padma-Nathan H et al. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med . 1998; 338:1397-404. [PubMed 9580646]

171. Goldstein I, Rosen RC, Steers WD. Sildenafil in the treatment of erectile dysfunction. N Engl J Med . 1998; 339:701-2.

172. Standing Medical Advisory Committee, United Kingdom Department of Health. The use of sildenafil in the treatment of erectile dysfunction. London; November 9,1998. From the United Kingdom Department of Health Web Site. [Web]

173. Lipshultz LI, Kim ED. Treatment of erectile dysfunction in men with diabetes. JAMA . 1999; 281:465-6. [PubMed 9952210]

174. Pfizer Inc, New York, NY: Personal communication on sildenafil.

176. Catalano DJ. Dear health care professional letter regarding discontinuation of Regitine^®. East Hanover, NJ: Novartis; 2000 May 31.

177. Bedford Laboratories. Phentolamine mesylate for injection, USP prescribing information. Bedford, OH; 1999 May.

178. Erectile Dysfunction Guideline Update Panel, American Urological Association Education and Research. Management of erectile dysfunction: An update. 2005. Available from website. Accessed 2005 Oct. 20. [Web]

179. Priapism Guideline on the Management of Priapism Panel, American Urological Association Education and Research. An update. 2003. Available from website. Accessed 2005 Oct. 20. [Web]

196. Vanden Hoek TL, Morrison LJ, Shuster M et al. Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation . 2010; 122(18 Suppl 3):S829-61.

200. West-Ward Pharmaceuticals. Phentolamine mesylate for injection prescribing information. Eatontown, NJ; 2015 Sept.

1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]