Alprostadil


Article Author:
Ashish Jain


Article Editor:
Omar Iqbal


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


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Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
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Heba Mahdy
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Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
10/12/2019 2:30:48 PM

Indications

Over 150 million people worldwide are affected by erectile dysfunction.[1] 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. However, it is only available from pharmacies authorized to produce such mixtures 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 (eg., 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 further define 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 cause of hospital-acquired acute renal injury, using alprostadil has 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 and shows a multifariousness of pharmacologic actions. Alprostadil binds as an agonist to prostaglandin receptor 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 - PDE-5 inhibitor 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 in patients with mild-to-severe symptoms, in those undergoing treatment for cardiovascular diseases and diabetes and in otherwise healthy ED patients. Thus, alprostadil topical cream is a potential first-choice alternative for ED in 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) - 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. That 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 suffering from 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 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.
  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 infection. 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, 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, 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. Nursing can also give counsel, and determine compliance and regimen effectiveness on followup 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.


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Alprostadil - Questions

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A 60-year-old male patient comes in for an annual exam. He complains about having difficulty with maintaining and achieving an erection. He has uncontrolled hypertension and diabetes mellitus. He has been taking his medication but tends to often forget. The provider determines the etiology to be vasculogenic and goes ahead and prescribes medication. Which medication used in the treatment of male impotence?



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A 60-year-old male patient comes in for a regular check-up with his wife. He hesitates to share his issue with achieving and maintaining an erection. The patient has had an inferior wall myocardial infarction. He is currently on aspirin, atenolol, and atorvastatin. The provider explains to the patient that he will most likely need a medication that helps dilate his blood vessels. After ruling out psychogenic causes, the provider prescribes which of the following treatments for this patient's impotence?



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A full-term newborn male is noted to be cyanotic 3 days after delivery. Auscultation reveals a continuous murmur heard in both systole and diastole, specifically in the right upper sternal border. The provider diagnoses a patent ductus arteriosus, a connection from the pulmonary artery to the aorta which should have closed after birth. When starting medication in the neonate to maintain the ductus patent, what complication can arise?



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A 65-year-old male presents to the emergency department with the chief complaints of pain in his penis and prolonged penile erection for the last 2 hours. He has a history of diabetes mellitus, hypertension, depression, and erectile dysfunction. He has been taking a drug as an intracavernous injection for erectile dysfunction. What is the mechanism of action of the drug the patient might be using?



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A 2-day-old male newborn is found to have cyanosis after birth. His mother, a 35-year-old school teacher has a known history of type II diabetes but is not on any medications. Her blood glucose was well controlled throughout pregnancy. On examination, the newborn has a holosystolic murmur on the left sternal border. Echocardiography confirms the transposition of great arteries. Before the surgical correction, which of the following is the best step in the management of this patient?



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A 56-year-old Caucasian male with a history of hypertension, diabetes, coronary artery disease, and hypercholesterolemia presents to the hospital with a chief complaint of intermittent abdominal pain. The patient is compliant with his medications. His vitals reveal BP=146/80mmHg, RR=18/min, and temperature of 37 C. The pain occurs after having a meal and is proportionately worse as compared to now. A contrast-enhanced CT scan is ordered. Which of the following medications would be most beneficial in decreasing the chances of contrast-induced nephropathy?



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Alprostadil - References

References

Neves-Zaph SR, Phosphodiesterase Diversity and Signal Processing Within cAMP Signaling Networks. Advances in neurobiology. 2017;     [PubMed]
Hanchanale V,Eardley I, Alprostadil for the treatment of impotence. Expert opinion on pharmacotherapy. 2014 Feb;     [PubMed]
Coceani F,Olley PM,Bishai I,Bodach E,Heaton J,Nashat M,White E, Prostaglandins and the control of muscle tone in the ductus arteriosus. Advances in experimental medicine and biology. 1977;     [PubMed]
Aykanat A,Yavuz T,Özalkaya E,Topçuoğlu S,Ovalı F,Karatekin G, Long-Term Prostaglandin E1 Infusion for Newborns with Critical Congenital Heart Disease. Pediatric cardiology. 2016 Jan;     [PubMed]
Wu JD,Tao S,Jin X,Jiang LL,Shen Y,Luo Y,Zhang P,Lee KO,Ye L,Ma JH, PGE1 improves diabetic peripheral neuropathy in patients with type 2 diabetes. Prostaglandins     [PubMed]
Kielbasa LA,Daniel KL, Topical alprostadil treatment of female sexual arousal disorder. The Annals of pharmacotherapy. 2006 Jul-Aug;     [PubMed]
Marasini B,Massarotti M,Bottasso B,Coppola R,Del Papa N,Maglione W,Comina DP,Maioli C, Comparison between iloprost and alprostadil in the treatment of Raynaud's phenomenon. Scandinavian journal of rheumatology. 2004;     [PubMed]
Yoshihara H, Prostaglandin E1 Treatment for Lumbar Spinal Canal Stenosis: Review of the Literature. Pain practice : the official journal of World Institute of Pain. 2016 Feb;     [PubMed]
Zhang JZ,Kang XJ,Gao Y,Zheng YY,Wu TT,Li L,Liu F,Yang YN,Li XM,Ma YT,Xie X, Efficacy of alprostadil for preventing of contrast-induced nephropathy: A meta-analysis. Scientific reports. 2017 Apr 21;     [PubMed]
Vieillard V,Eychenne N,Astier A,Yiou R,Deffaux C,Paul M, Physicochemical stability study of a new Trimix formulation for treatment of erectile dysfunction. Annales pharmaceutiques francaises. 2013 Sep;     [PubMed]
Lea AP,Bryson HM,Balfour JA, Intracavernous alprostadil. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in erectile dysfunction. Drugs     [PubMed]
Becher E, Topical alprostadil cream for the treatment of erectile dysfunction. Expert opinion on pharmacotherapy. 2004 Mar;     [PubMed]
Porst H, Transurethral alprostadil with MUSE (medicated urethral system for erection) vs intracavernous alprostadil--a comparative study in 103 patients with erectile dysfunction. International journal of impotence research. 1997 Dec;     [PubMed]
Mantovani F, Alprostadil plus Vacuum (VITARUM) in severe erectile dysfunction (ED). Archivio italiano di urologia, andrologia : organo ufficiale [di] Societa italiana di ecografia urologica e nefrologica. 2017 Jun 30;     [PubMed]
Cacione DG,Macedo CR,Baptista-Silva JC, Pharmacological treatment for Buerger's disease. The Cochrane database of systematic reviews. 2016 Mar 11;     [PubMed]
Porst H, [Transurethral alprostadil administration with MUSE (     [PubMed]
Yücel ÖB,Pazır Y,Kadıoğlu A, Penile Prosthesis Implantation in Priapism. Sexual medicine reviews. 2018 Apr;     [PubMed]
Podolej GS,Babcock C, Emergency Department Management Of Priapism. Emergency medicine practice. 2017 Jan;     [PubMed]
Shamloul R,Ghanem H, Erectile dysfunction. Lancet (London, England). 2013 Jan 12;     [PubMed]

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