Bi-Mix

Papaverine hydrochloride is a benzylisoquinoline alkaloid originally isolated from opium. It has no narcotic or analgesic activity and is not a controlled substance. Drug class: vasodilator (non-selective phosphodiesterase inhibitor). In the US it is available as papaverine hydrochloride injection 30 mg/mL for intramuscular or slow intravenous use. Lake Hills Pharmacy uses it as a component of compounded intracavernosal preparations.

Papaverine injection labeling lists relief of conditions accompanied by smooth-muscle spasm: vascular spasm associated with acute myocardial infarction, angina, peripheral and pulmonary embolism, peripheral vascular disease with a vasospastic element and certain cerebral angiospastic states, and visceral spasm such as ureteral, biliary or gastrointestinal colic.

Intracavernosal use for erectile dysfunction is not a labeled use; the label notes that intracorporeal injection for impotence is not approved and has been associated with persistent priapism. Prescribers use papaverine in compounded intracavernosal preparations, alone or combined with phentolamine and alprostadil.

Papaverine inhibits phosphodiesterase isoenzymes non-selectively, raising intracellular cAMP and cGMP, and may also inhibit calcium influx. The result is direct relaxation of vascular, bronchial, gastrointestinal, biliary and urogenital smooth muscle. In the corpora cavernosa it relaxes trabecular smooth muscle and cavernosal arteries, increasing arterial inflow and compressing subtunical venules to restrict outflow. It is not selective for PDE5.

Papaverine is highly protein bound (about 90%) and is metabolized in the liver, chiefly by O-demethylation followed by glucuronide conjugation; metabolites are excreted in the urine. The plasma half-life is short, roughly 0.5 to 2 hours, with wide individual variation. After intracavernosal injection most of the effect is local, but some of the dose reaches the systemic circulation.

• Hypersensitivity to papaverine.
• Complete atrioventricular heart block (intravenous use).
• For intracavernosal use, conditions predisposing to priapism (sickle cell anemia or trait, multiple myeloma, leukemia), anatomic deformation of the penis and penile implants are treated as contraindications, consistent with intracavernosal alprostadil labeling.

• Hepatic hypersensitivity: eosinophilia, elevated liver enzymes and jaundice have been reported, including with intracavernosal use. Stop the drug if liver abnormalities appear.
• Priapism and penile fibrosis can follow intracavernosal injection; papaverine-containing mixtures carry a higher priapism risk than alprostadil alone.
• Cardiac: when conduction is depressed, papaverine can produce transient ectopic rhythms. Intravenous doses are given slowly over 1 to 2 minutes; rapid injection can cause arrhythmia.
• Use with caution in glaucoma.

• Levodopa: papaverine may reduce its antiparkinsonian effect.
• PDE5 inhibitors, nitrates, alpha-blockers and other antihypertensives or vasodilators: additive hypotension.
• Other intracavernosal or erectile dysfunction therapies: increased risk of priapism.

Local (intracavernosal): penile pain, hematoma, ecchymosis, fibrosis, nodules and priapism. Systemic: flushing, dizziness, hypotension, tachycardia, headache, sweating, drowsiness, nausea, abdominal discomfort, constipation or diarrhea, rash, and hepatic hypersensitivity.

Adequate human data are lacking. Intracavernosal use applies to men and the drug is not used for this purpose in pregnancy. Whether papaverine is excreted in human milk is unknown.

Liver tests periodically during ongoing use and whenever symptoms suggest hepatotoxicity; penile examination for fibrosis, nodules or curvature at follow-up; blood pressure and heart rate; and the duration of each erection, with prompt treatment of any erection lasting more than 4 hours.

• Papaverine Hydrochloride Injection, USP, manufacturer prescribing information.
• Erectile Dysfunction: AUA Guideline (2018), American Urological Association.
• Martindale: The Complete Drug Reference, papaverine monograph.

Phentolamine mesylate is an imidazoline, competitive, non-selective alpha-1 and alpha-2 adrenergic antagonist. US products include phentolamine mesylate for injection (5 mg vial, intravenous or intramuscular; the original brand was Regitine), OraVerse (dental submucosal injection) and Ryzumvi (phentolamine ophthalmic solution 0.75%). Lake Hills Pharmacy uses it as a component of compounded intracavernosal preparations.

• Injection: prevention or control of hypertensive episodes in pheochromocytoma, such as before and during surgical excision; prevention or treatment of dermal necrosis and sloughing after intravenous extravasation of norepinephrine; and the phentolamine blocking test in the diagnosis of pheochromocytoma.
• OraVerse: reversal of soft-tissue anesthesia and the associated functional deficits after a dental procedure using a local anesthetic with a vasoconstrictor.
• Ryzumvi: treatment of pharmacologically induced mydriasis produced by adrenergic agonists or parasympatholytic agents.
• Intracavernosal use is not labeled. Prescribers use phentolamine in compounded combinations with papaverine, alprostadil or both for erectile dysfunction.

Phentolamine blocks postsynaptic alpha-1 and presynaptic alpha-2 receptors, causing arterial and venous vasodilation. Alpha-2 blockade increases norepinephrine release, which with baroreflex activation produces tachycardia. In the penis it opposes the adrenergic tone that maintains flaccidity, complementing smooth-muscle relaxants such as papaverine and alprostadil. In the eye it relaxes the iris dilator muscle.

After intravenous injection the effect is immediate and the plasma half-life is about 19 minutes; after intramuscular injection the effect peaks within about 20 minutes and lasts 3 to 4 hours. Phentolamine is extensively metabolized, and about 13% of an intravenous dose is excreted unchanged in the urine. Intracavernosal injection acts mainly locally, with some systemic absorption.

• Hypersensitivity to phentolamine or related compounds.
• Myocardial infarction, history of myocardial infarction, coronary insufficiency, angina or other evidence of coronary artery disease.

• Myocardial infarction, cerebrovascular spasm and cerebrovascular occlusion have been reported after administration, usually in association with marked hypotension.
• Tachycardia and cardiac arrhythmias can occur; use with caution in patients with cardiac disease.
• Hypotension: if severe, treat with norepinephrine; epinephrine should not be used, because its beta effect can lower blood pressure further when alpha receptors are blocked.
• Intracavernosal use carries the risks of priapism, penile fibrosis and hematoma.

• PDE5 inhibitors, nitrates, alpha-blockers and other antihypertensives: additive hypotension.
• Epinephrine: paradoxical fall in blood pressure.
• Other intracavernosal or erectile dysfunction therapies: increased risk of priapism.

Hypotension including orthostatic hypotension, tachycardia, arrhythmia, angina, flushing, dizziness, weakness, nasal congestion, nausea, vomiting and diarrhea. Intracavernosal use adds penile pain, hematoma, fibrosis and priapism. OraVerse commonly causes injection-site pain; Ryzumvi causes conjunctival redness and instillation-site discomfort.

Adequate human data are lacking. Intracavernosal use applies to men. Whether phentolamine is excreted in human milk is unknown.

Blood pressure and heart rate, symptoms of myocardial ischemia in patients with cardiovascular risk, penile examination for fibrosis at follow-up, and the duration of each erection, with prompt treatment of any erection lasting more than 4 hours.

• Phentolamine Mesylate for Injection, USP, manufacturer prescribing information.
• OraVerse (phentolamine mesylate) Injection Prescribing Information, Septodont.
• Ryzumvi (phentolamine ophthalmic solution) 0.75% Prescribing Information.
• Erectile Dysfunction: AUA Guideline (2018), American Urological Association.