Continuing Education Activity

Alprostadil is a medication used in the management and treatment of erectile dysfunction in males and for temporary patency of ductus arteriosus in newborns with congenital heart diseases before surgical intervention. It is in the prostaglandin analog class of medications. This activity reviews the indications, action, and contraindications for alprostadil as a valuable agent in the therapy of erectile dysfunction in males and presurgical management for newborns with congenital heart diseases with ductus arteriosus dependent circulation. This activity will also highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of those conditions.

Objectives:

• Review the indications for alprostadil.
• Describe the adverse effects and contraindications of alprostadil.
• Identify the appropriate monitoring and toxicity of alprostadil.
• Summarize interprofessional team strategies for enhancing care coordination and communication to advance the management of conditions that can be treated with alprostadil and improve patient outcomes.

Indications

Over 150 million people worldwide are affected by erectile dysfunction. Alprostadil is an approved second-line treatment for erectile dysfunction (oral phosphodiesterase-5 inhibitors like sildenafil are first-line therapy).[1] Another option is using alprostadil in combination with other medications, the combination of papaverine, phentolamine, and alprostadil, known as "trimix," is particularly effective when used for intracavernous injection as a treatment for erectile dysfunction (ED). However, it is only available from compounding pharmacies authorized to produce such extemporaneous dosage forms as it is otherwise not produced commercially.[2]

Alprostadil can also be a therapeutic option for the temporary ductus arteriosus patency maintenance in heart conditions where duct patency is mandated for survival until the defect is corrected surgically. The defects are both cyanotic (e.g., TGA - transposition of great vessels, TOF - tetralogy of Fallot, tricuspid atresia, pulmonary stenosis, etc.) and acyanotic (e.g., coarctation of the aorta, interruption of the aortic arch).[3][4] Alprostadil IV is FDA-approved for the temporary maintenance of patency of ductus arteriosus in neonates with ductal-dependent congenital heart disease until surgery. Alprostadil causes vasodilation by a direct effect on vascular and ductus arteriosus smooth muscle. In infants exhibiting restricted systemic blood flow, alprostadil can increase systemic blood pressure, and decrease the pulmonary artery pressure to aortic pressure ratio. Diabetic peripheral neuropathy (DPN) is the most common chronic complication of diabetes. Lipo-PGE1 can effectively improve the neural function of patients with DPN.[5]

Topical alprostadil has also shown promising results for the treatment of FSAD (female sexual arousal disorder) when used in a clinic on females with female sexual arousal disorder, but additional studies are necessary to define further a proper role of topical alprostadil in the treatment of FSAD.[6] Alprostadil is widely used to manage ischemic changes in patients with Raynaud phenomena.[7] Prostaglandin E1 analogs have shown to be efficacious as a modality for conservative treatment for patients with lumbar spinal canal stenosis.[8] Contrast-induced nephropathy (CIN) is one of the top five leading causes of hospital-acquired acute renal injury, using alprostadil has been shown to reduce the precontrast serum creatinine (SCr), blood urea nitrogen (BUN) levels, and a decrease in the incidence of contrast-induced nephropathy (CIN).[9]

Mechanism of Action

Alprostadil is a synthetic analog of prostaglandin E1 (PGE1) and shows a multifariousness of pharmacologic actions. Alprostadil binds as an agonist to prostaglandin receptors, e.g., EP2 which in turns activates adenylate cyclase leading to accumulation of 3'5'-cAMP (cyclic adenosine monophosphate) which is responsible for the pharmacologic effects of the medication including smooth muscle relaxation, causing vasodilation (increasing peripheral blood flow; helps in erectile dysfunction) and bronchodilation, and inhibits platelet aggregation.[10]

Administration

1. Intracavernous alprostadil is useful for its vasodilating properties, which act by relaxing the smooth muscle of the corpus cavernosum, hence increasing the diameter of the cavernous arteries leading to an erection. After intracavernous administration of alprostadil, it is either metabolized locally or via the lungs after being absorbed systematically. Short-term trials have shown that using alprostadil by an intracavernous route is equal to if not superior in inducing erection as compared to other drugs used via intracavernous routes such as papaverine or the combination therapy of papaverine and phentolamine, linsidomine, and topical nitroglycerine (glyceryl trinitrate). If used in therapeutic dosages, most patients tolerate intracavernous alprostadil well. Some potentially severe side effects of intracavernous alprostadil are priapism (4%) and fibrosis (8%).[11]
2. Topical alprostadil therapy is associated with a high rate of discontinuation, as are intracavernosal or transurethral therapies, which are inconvenient and invasive.[12]  Several studies, including four double-blind, placebo-controlled, phase II trials, show that alprostadil topical cream is efficacious and well-tolerated in ED patients with mild-to-severe symptoms, in those undergoing treatment for cardiovascular diseases and diabetes mellitus and in otherwise healthy ED patients. Thus, alprostadil topical cream is a potential first-choice alternative for ED patients who do not respond or who cannot tolerate or do not accept PDE-5 inhibitor therapy.
3. Intraurethral suppository/medicated urethral system for erection (muse) - alprostadil can be used as an intraurethral suppository or medicated urethral system for erection, but have shown to be less efficient in inducing cavernous smooth muscle relaxation and also have more side effects such as penile pain/burning, hypotension, and urethral bleeding. This is why self-injection therapy with alprostadil is still considered the first-line therapy/gold standard for the management of erectile dysfunction. The intraurethral suppository is usually only for patients who have refractory erectile dysfunction.[13]
4. Alprostadil cream is an option with vacuum devices with an elastic ring placed at the base of the penis to achieve sufficient rigidity to maintain an erection for satisfactory penetration.[14]
5. Intravenous prostacyclin (PGI2) analogs have shown to be more effective than aspirin for dealing with the rest pain and healing the ischaemic ulcers in Buerger disease.[15]

Adverse Effects

When used as an intraurethral suppository (medicated urethral system for erection)[16]:

• Urethral strictures 
• Hypotension
• Syncope
• Penile/urethral pain
• Priapism/prolonged erection
• Penile fibrosis
• Headache
• Dizziness

Side effects of alprostadil on intracavernosal use:

• Hypotension/hypertension
• Dizziness
• Headache
• Prolonged erection/priapism is less common
• Rash on the penis
• Swelling of the penis
• Penile infections
• Injuries to the penis including hematoma formation at the site of the injection

Side effects of prostaglandin E1 analog (alprostadil) on intravenous use:

• Flushing
• Hypotension/hypertension
• Tachycardia/bradycardia
• Dizziness
• Headache
• Electrolyte imbalances such as hypokalemia
• Nausea/vomiting
• Gastrointestinal upset
• Infection at the injection site or even sepsis
• Pain at the injection site
• Cough
• Flu-like symptoms
• GERD
• Bronchoconstriction

Contraindications

1. Known hypersensitivity to alprostadil or components of the dosage form.
2. Sickle cell disease or trait, multiple myeloma, leukemia, polycythemia vera, thrombocythemia as these conditions are known to precipitate priapism, and alprostadil can also predispose to prolonged erection or priapism.
3. Peyronie disease of the penis, as alprostadil, is known to cause penile fibrosis and may worsen the condition.
4. Alprostadil intraurethral suppository; "medicated urethral system for erection" should be avoided in patients with urethral strictures as using it can cause further injuries to the penis.
5. Clinicians should avoid using alprostadil as an intraurethral suppository in patients with urethritis.

Monitoring

When starting alprostadil for a patient complaining of erectile dysfunction, certain things are to be kept in mind to prevent and for the early identification of adverse effects for better overall outcomes. Alprostadil is known to cause hemodynamic instability causing hypotension/hypertension, and flushing. It is advisable to monitor blood pressure, heart rate, and temperature before and after the use of the drug. Alprostadil is also known to cause penile pathologies such as stricture formation, fibrosis, and hematoma formation at the site of injection. Regular examination by a physician and timely attention by one on the onset of discomfort can bring about better possible outcomes. For a better understanding of drug-to-effect response, monitoring the duration of erection can be essential for tailoring management for the patient.

Toxicity

The use of alprostadil for the treatment of erectile dysfunction in men has correlations with prolonged erection, and sometimes priapism. The incidence of priapism as an adverse effect of alprostadil is more common with the intraurethral suppository, and priapism is a genitourinary emergency that requires detailed evaluation. The evaluation is primarily based on physical exam and possibly with the help of penile ultrasonography and penile blood gas analysis. Some of the management techniques include aspiration of cavernosal blood, cold saline irrigation, and penile injections with sympathomimetic agents.[17] Penile prosthesis implantation for priapism is also commonly used.[18]

Enhancing Healthcare Team Outcomes

Managing erectile dysfunction with alprostadil as an intracavernosal injection or as an intraurethral suppository requires an interprofessional team of healthcare providers, including a nurse, pharmacist, and several physicians in different specialties. Apart from classical causes of erectile dysfunction such as diabetes mellitus, hypertension, other common lifestyle factors such as obesity, limited or absence of physical exercise, lower urinary tract system infections are also linked to the development of erectile dysfunction requiring attention. Without proper management and patient education, the morbidity associated with the treatment itself can be dreadful. Patient education for the use of alprostadil as an intracavernosal injection form or as an intraurethral suppository is a must and is an essential aspect of the management. The patient should be monitored timely for the adverse effects of the drug, such as prolonged erection/priapism, penile fibrosis, urethritis, and penile fibrosis or stricture formation, and circulatory disturbances causing hypotension. Consult with a radiologist, urologist, to assess any penile pathology before starting alprostadil. Consult with a psychiatrist to evaluate for possible psychiatric issues that might cause erectile dysfunction. Consult a sex therapist for holistic management of erectile dysfunction. Consult a cardiologist as studies have shown an association of cardiovascular diseases with erectile dysfunction (ED), whereas ED can be a strong indicator of CAD (coronary artery disease), and the recommendation is for cardiovascular assessment of a noncardiac patient in a patient coming with the chief complaint of erectile dysfunction.[19] Also, using alprostadil can cause circulatory issues causing hypotension.

Pharmacists should be ready to counsel patients on the proper use of the intracavernous and suppository formulations since they require the patient to have solid administration technique skills. If the pharmacist has any concerns about the patient's ability to self-administer the drug, or there are drug interactions on the medication review, they should contact the prescribing physician promptly. Nurses can also give counsel, and determine adherence and regimen effectiveness on follow-up visits, and check for any adverse medication effects, reporting any concerns to the physician. Only with this type of interprofessional team approach can alprostadil therapy be most effective. [Level V]

Patients discussing reproductive health, particularly men, can be challenging, and it is essential to be empathetic and maintain a professional attitude while establishing a rapport. Creating a positive and respectful approach for patient and provider, allows there to be an open discussion for subject matters such as erectile dysfunction.