Continuing Education Activity

Prostaglandin E1 (PGE1) is a medication used to manage erectile dysfunction and ductus arteriosus in neonates. It is a smooth muscle relaxant and vasodilator. This article outlines the indications, mechanism of action, and contraindications of taking alprostadil as a valuable agent in treating erectile dysfunction and neonatal congenital heart defects. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the treatment of patients with the conditions as mentioned above.

Objectives:

• Identify the mechanism of action of PGE1 (alprostadil).
• Describe the adverse effects of PGE1 (alprostadil).
• Review the toxicity of PGE1 (alprostadil).
• Outline interprofessional team strategies for improving care coordination and communication to improve PGE1 (alprostadil) therapy and improve outcomes.

Indications

Prostaglandin E1 (PGE1) is an endogenous prostaglandin used as a medication. Its synthetic form, alprostadil, is a vasodilator and smooth muscle relaxant used for several medical purposes.[1]

• Labeled indications
  • Temporary patency of ductus arteriosus in ductal-dependent congenital heart disease obstructing pulmonary circulation in neonates. The patent ductus arteriosus allows the neonate to adequately oxygenate the blood and is a temporary measure until surgical intervention can correct the defect.[2]
  • Diagnosis and second-line treatment of erectile dysfunction due to vascular, psychological, or neurological etiologies.[3]
• Off-label indications
  • Treatment of Raynaud phenomenon due to systemic sclerosis after standard oral therapies such as calcium-channel blockers and phosphodiesterase (PDE-5) inhibitors have proven insufficient. However, some studies indicate that alprostadil has the same efficacy as a placebo[4]
  • Prevention of contrast-induced nephropathy[5]
  • Treatment for stenosis of the lumbar spinal canal[6]

Mechanism of Action

In the treatment of erectile dysfunction, prostaglandin E1 (PGE1) works by increasing cAMP production, reducing the influx of calcium within the penile vascular smooth muscle. The result is a relaxation of trabecular smooth muscle by arterial dilation. Blood becomes entrapped in the penis, which eventually leads to an erection.[2]

PGE1 can also serve as a treatment for maintaining the patency of ductus arteriosus heart defects in neonates by a similar mechanism. PGE1 dilates the ductus smooth muscle so that it remains open and blood flow may be maintained. Ductal patency allows for oxygenated blood flow until the congenital anomaly can be surgically corrected.[3]

Administration

For Erectile Dysfunction (Adult Administration)

Prostaglandin E1 (PGE1) can be administered via intracavernous or intraurethral routes. Dosages for individual persons require titration to achieve the most efficacious results.

Intracavernous administration involves an injection directly into the penis using a 27- to 30-gauge 1/2-inch needle syringe. Strong recommendations are that a healthcare professional administers the first dose; afterward, self-administration is permissible with adequate patient training. After sterilization of the injection site, the penis should be held firmly away from the body in preparation for injection. The injection should be given perpendicular to the base of the penis, avoiding any visible veins. Repeated administrations should be on alternate sides of the penis. Pressure should be applied to the injection site to cease bleeding if any. Studies have shown that efficacy is dose-dependent.[7] 

Dosing is as follows:

• For vasculogenic/psychogenic/mixed etiology: The initial dose is 2.5 mcg once intracavernous; within one hour, the patient may dose 5 mcg if there was a partial response or 7.5 mcg with no response to the first injection. After 24 hours, the patient may increase the dose by 5 or 10 mcg for a single dose and continue this process every 24 hours until achieving a response. Maximum dosing is twice per 24 hours during the initial titration, and then one dose per 24 hours to a maximum of 60 mcg. Patients should use the lowest effective dose.

• For pure neurological etiology: The initial dose is 1.25 mcg once intracavernous; within one hour, the patient may dose 2.5 mcg. After 24 hours, the patient may increase the dose by 5 mcg for a single dose and continue this process every 24 hours until achieving a response. Maximum dosing is twice per 24 hours during the initial titration, and then one dose per 24 hours to a maximum of 60 mcg. Patients should use the lowest effective dose.

When utilizing the urethral suppository via the intraurethral route, the pellet must be inserted immediately following urination. The applicator stem will get inserted into the urethra to deposit the medicinal pellet. To deposit the pellet, a user would press the button at the top of the applicator. Following administration, the user removes the applicator. A study on the drug’s efficacy indicated an increase in dosage (ranging between the lowest effective dose of 125 mcg and a maximum of 1000 mcg) also increased the maximum response. For this reason, the recommended initial starting dose is 500 mcg. There are no reported instances of increased adverse effects with increasing dosage.[8][9]

Transurethral suppository dosing:

• Insert 125 or 250 mcg into the urethra with a maximum of two doses per 24 hours.

For both formulations, the maximum time of an achieved erection should not exceed one hour.

For Ductus Arteriosus (Pediatric Administration)

PGE1 administration for pediatric patients is via continuous IV infusion through a vein or at the site of the ductal opening using a catheter placed in the umbilical artery. The typical concentration of the infusion is 10 to 20 mcg/mL. Initial dosing requires titration by micrograms per kilogram of body weight per minute.[10]

Dosing for PDA in infants:

• Initial dose: 0.05 to 0.1 mcg/kg/min continuous IV infusion
• Maintenance/maximum dose: 0.01 to 0.4 mcg/kg/min continuous IV infusion

No renal dosing adjustment is necessary for any of the above regimens, including dialysis. Hepatic dosing is undefined.

Adverse Effects

Prostaglandin E1 (PGE1) is a second-line treatment for erectile dysfunction when oral therapies are not the most effective option. Overall, it is both safe and effective. The side effects are listed below by route of administration.[11]

Following Intracavernosal Injection

Adverse events following intracavernous injection include penile pain (greater than 10%), hypertension, dizziness, headache, penile disease, penile rash or swelling, Peyronie disease (1 to 10%), an erection lasting more than four hours (4%), localized injection site bruising, or hematoma (less than 1%), balanitis, hemorrhage at the site of injection, priapism (0.4%).

Following Intraurethral Injection

Adverse events with this formulation include penile pain, urethral burning (greater than 10%), dizziness, headache, central nervous system-related pain, testicular pain, minor urethral bleeding, vulvovaginal pruritus in female partners (2 to 10%), leg pain, perineal pain, tachycardia (less than 2%). 

Following Intravenous Injection

Flushing, apnea, fever (greater than 10%), bradycardia/tachycardia, cardiac episode, edema, hypertension/hypotension, seizure, headache, dizziness, hypokalemia, diarrhea, disseminated intravascular coagulation (DIC), sepsis, local pain not at the injection site, back pain, upper respiratory tract infection, flu-like symptoms, cough, congestion, sinusitis (1-10%), anemia, bradypnea, cardiac failure, gastroesophageal reflux disease (GERD), hemorrhage (cerebral hemorrhage), hyperbilirubinemia, stiffness, shock, lethargy, jitteriness, hyperemia, irritability, hyperkalemia, thrombocytopenia, hypoglycemia, neck hyperextension, hypothermia, peritonitis, second-degree atrioventricular block, supraventricular tachycardia, ventricular fibrillation, hematuria or anuria, bronchial wheezing (less than 1%). 

U.S. Boxed Warnings

When using the pediatric IV formulation, infants born with congenital heart defects and weighing less than two kilograms at birth may experience apnea. Symptoms are most likely to be seen within an hour of the initial infusion. The recommendation is that infants who meet these criteria receive careful monitoring and treatment where emergency respiratory assistance can are readily available for rapid deployment.[12]  

Other Concerns

• Hypotension/syncope
• Penile fibrosis
• Priapism/prolonged erection
• Cardiovascular disease

Contraindications

For Intracavernosal Injection

Contraindications include documented hypersensitivity to the drug or any of its ingredients, predisposing conditions related to priapism or penile deformities, and penile implants.

For Intraurethral Suppository

COntraindications include documented hypersensitivity to the drug or any of its ingredients, urethral deformities, urethritis, and predisposing hematological conditions such as thrombosis or hyper-viscosity syndrome that could cause priapism, warning against sexual activity, sexual intercourse with a pregnant woman without using a condom.

For Intravenous Injection

Caution is advised in patients under 2 kg, those with respiratory distress syndrome, and patients should be monitored for sensitivity to the drug or any of its components.

Monitoring

When starting prostaglandin E1 (PGE1) and during treatment with this drug, the clinical team should monitor vital signs such as blood pressure, heart rate, temperature, respiration, signs of penile pain, fibrosis, and infection. They should also evaluate the effectiveness following dosing and the duration of an achieved erection.

For IV injection to address PDA, the infant's respiratory status requires monitoring.[13]

Toxicity

Phosphodiesterase 5 inhibitors in combination with prostaglandin E1 (PGE1) may enhance the toxic effects of PGE1. Two common side effects of taking PGE1 are prolonged erection or priapism, requiring emergent treatment. There are dosage forms that contain benzyl alcohol, which can potentially cause fatal toxicity in infants, known as “gasping syndrome” when introduced in high amounts.

Enhancing Healthcare Team Outcomes

The use of prostaglandin E1 (PGE1) for erectile dysfunction and its side effects requires thorough discussion with patients. There are relatively common pre-existing conditions such as cardiovascular disease that are contraindicated or cautioned with PGE1. The healthcare team should be aware of all up-to-date information about PGE1 to prescribe the medication to the appropriate patient population. While some brands of PGE1 used for erectile dysfunction can be self-administered, the first dose should be administered by a healthcare professional. In particular, patient education about intracavernosal injection requires an interprofessional team of healthcare providers, including physicians, nurses, and pharmacists. Clinicians and pharmacists need to discuss their patient's sexual health before prescribing sexual performance-enhancing medications. Finally, because dosing may require titration, the healthcare team may need to adjust the dose repeatedly to obtain the most effective dose. Though the efficacy appears to be dose-dependent, the recommended maximum dosages should not be surpassed. Nursing can play a vital role in monitoring patient compliance, administration technique, and watching for adverse events. The pharmacist should also perform complete medication reconciliation and report back to the rest of the healthcare team.

For pediatric patients, the use of PGE1 for congenital heart defects comes with a U.S. Boxed Warning. An interprofessional healthcare team should monitor neonates receiving this medication, as symptoms are not always immediately apparent. Neonatal nursing is crucial in administering medication and monitoring these patients and will alert the treating physician promptly regarding any concerns.

In summary, PGE-1 therapy requires an interprofessional healthcare team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]