Erectile Dysfunction Review
August 1, 2017
August 31, 2019
Tammie Lee Demler, BS Pharm, PharmD, MBA, BCPP
Director of Pharmacy Services and Pharmacy Residency Training
New York State Office of Mental Health at the Buffalo Psychiatric Center
Psychiatric Pharmacy Practice Residency Program
Clinical Associate Professor
University of Buffalo School of Pharmacy and Pharmaceutical Sciences
Buffalo, New York
FACULTY DISCLOSURE STATEMENTS:
Dr. Demler has no actual or potential conflicts of interest in relation to this activity. Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Credits: 2.0 hours (0. 20 ceu)
Type of Activity: Knowledge
This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.
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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.
To educate pharmacists about erectile dysfunction (ED), including potential causes and available treatment options.
After completing this activity, the participant should be able to:
- Describe the prevalence, risk factors, and available treatments for ED.
- Identify potential drug-induced causes of ED and appropriate pharmacologic therapies.
- Discuss potential drug interactions and adverse reactions associated with ED pharmacotherapy.
- Review general patient education about the medications used to treat ED.
ABSTRACT: Greater life expectancy, along with recognition of the importance of continued sexual activity in an increasingly aging population, has fostered a higher demand for safe, effective, and convenient pharmacologic interventions for erectile dysfunction. It was previously assumed that with advanced age came a natural and expected loss of sexual interest and ability; this assumption is now understood to be neither inevitable nor unavoidable. Older adults are looking for ways to preserve and enhance sexual activity as they age. A variety of pharmacotherapeutic and nonpharmacologic interventions are available for erectile dysfunction, a condition that challenges males seeking to achieve the goal of preserving sexual function as they grow older. Patient education is an important component of treatment for erectile dysfunction.
Erectile dysfunction (ED) is a common problem in older men, affecting more than 75% of those greater than 70 years of age in the United States.1 Along with advances in care and treatments that extend our ever-increasing lifespan comes the unintended consequence of new health complications that also must be addressed. One fear commonly reported by older Americans involves potential cognitive changes, but physical changes are also listed among the top 10 concerns.2 For American men, concerns include sexual health and physical changes related to ED, which ranks higher than cancer or death on the list of fears.3 It is projected that ED will affect more than 300 million men worldwide by the year 2025.4
ED has been reported as the most common sexual complaint of males presenting to their healthcare providers, and it is considered one of the most widely studied sexual dysfunctions (SDs) in men.5 In addition to age-related changes, older men are also more likely to have chronic comorbid conditions that increase the risk and/or severity of ED. While ED is more likely to occur with increasing age, sexual desire often remains unchanged. In cases of diminished desire, other factors, such as depression or other general health problems, should be considered. A significant age-related decline in the rate of sexual activity was noted by Lindau and colleagues, who conducted a study of more than 1,400 U.S. men; sexual activity was reported to have decreased from a rate of slightly over 80% in men aged 57 to 64 years to roughly half that rate in those aged 75 to 85 years.6
ED, which was previously termed impotence, is defined as the inability to maintain or achieve an erection sufficient for sexual performance. A normal erection requires the parasympathetic and sympathetic nervous systems to trigger the required vascular smooth-muscle actions that facilitate a cascade of cellular actions ultimately producing nitric oxide (NO) with a subsequent influx of arterial blood into the corpus cavernosum, causing an erection.
Physical and mental wellness, including healthy relationships and sexuality, influence a person’s perceptions of overall quality of life. Sexual activity in older adults can potentially lead to improved mental health and may provide cardiovascular and immunologic benefits, among others.7 Although age-related changes are a factor in ED, the condition is not limited to the older population. In studies, up to 61% of men aged 40 to 69 years have reported ED; however, older men continue to describe more severe symptoms. Increased awareness and societal acceptance of discussing ED has allowed for enhanced diagnosis, treatment, and restoration of sexual function in many men who might not otherwise have sought care. Previously, ED was treated behind closed doors and was not widely discussed, primarily because of the stigma that the disorder was “all in one’s head” or a mark of physical weakness. Roughly 10% to 20% of ED cases are believed to have a solely psychogenic cause; however, psychogenic features are often present in patients diagnosed with a physical cause.8
Mixtures of self-administered injectable drugs were among the first available treatments for ED. As might be expected, these therapies were not favored, and many patients opted to live with the dysfunction rather than use these agents. Newer oral medications have become available and are routinely prescribed (discussed at length in this article).
Pathophysiology of ED
The pathophysiology of ED is multifactorial, including vascular, neurologic, and hormonal causes, as well as causes related to injury or surgery. ED may also be due to mental-health conditions such as depression, anxiety, and dementia. Sexual problems may be a symptom or consequence of a serious underlying illness, such as diabetes, infection, a urogenital-tract condition, or cancer; therefore, sexual problems should be prioritized in the management of overall male health. To determine the origin of SD, the American Urological Association (AUA) recommends diagnostic tests including, among others, CBC with differential, lipid panel, fasting serum glucose, thyroid-stimulating hormone levels, prostate-specific antigen, and morning total testosterone. Luteinizing hormone, prolactin levels, sex hormone–binding globulin, and urinalysis are also recommended to diagnose potential comorbidities in older men with ED.9 Insurance-coverage limitations often pose a barrier to many of the available diagnostic tests, so such testing may not be practical or possible for most patients.
Common ED Causes and Contributors
Vascular-Supply Compromise and Atherosclerosis: The accumulation of plaque inside arteries that carry oxygen-rich blood to organs and other areas of the body often progresses to the point that the receiving organs and tissues become severely compromised by this arteriolar narrowing. Healthcare professionals commonly associate atherosclerosis with increased risk of heart attack and stroke; however, few consider the impact on the penile arteries and the resulting ED in many men. Although this plaque is composed mostly of fat and cholesterol, poor diet is not the only cause. Risk factors include not only modifiable lifestyle habits such as smoking and reduced physical activity, but also factors that cannot be changed, such as age and family history of heart disease.
Because atherosclerosis is sometimes asymptomatic, patients with ED should have a workup for cardiovascular (CV) disease (CVD); if CVD is detected, lifestyle modifications should be immediately implemented and metabolic medications considered, as appropriate.4 Men with coronary artery disease (CAD) experience an increased rate of ED compared with men without CAD, and ED generally presents earlier than CAD symptom onset in older men; additionally, those with ED have a 75% increased risk of developing peripheral vascular disease.10 This CAD/ED correlation has been the focus of an expert panel known as the Princeton Consensus Conference, a multispecialty collaborative with a shared mission of optimizing sexual function and preserving CV health. In 2010, this panel assessed the evaluation and management of CV risk in men with ED with no known CVD; it also updated previous recommendations for the evaluation of cardiac risk associated with sexual activity in men with known CVD. Emphasis was placed on the identification of men with ED who may require an additional CV workup.10
The recommendations of the 2010 Princeton Consensus Conference expand on those established in the first two conferences; one recommendation emphasizes that the patient’s exercise ability be determined and stress testing be employed to ensure that the patient’s CV health is sufficient for the physical demands of sexual activity before ED treatment is prescribed.10 Another recommendation stresses the connection between ED and CVD, noting that CVD may be asymptomatic and the reduction of CV risks could be beneficial.10 Because cardiometabolic conditions such as hypertension, diabetes, and hyperlipidemia can complicate CV health, they also should be assessed, and efforts to control these comorbid diseases must be a priority. Sexual activity may not be appropriate for men with significant CV conditions.
Obesity: Older adults generally have an increased and altered distribution of body fat. ED is much more common in men with the highest body weight, total body-fat percentage, and trunk fat, as well as a BMI greater than 30.11 Obesity not only contributes to the underlying physiological metabolic factors of ED, but may also have a psychological impact stemming from a negative body image that lessens sexual confidence; therefore, it requires a comprehensive workup.11
Benign Prostatic Hyperplasia: Symptomatic benign prostatic hyperplasia (BPH), which is common in men older than 60 years, is dependent on circulating androgens (testosterone). Lower urinary tract symptoms (LUTS) associated with BPH are common in older men. LUTS/BPH is also accompanied by SD in 40% to 70% of men; however, urologists and primary care physicians may underestimate the prevalence of SD in men with LUTS/BPH.12 BPH is associated with urinary frequency, decreased flow, urgency, hesitancy, and irritation from incomplete bladder emptying. The treatment of BPH includes the use of medications, such as 5-alpha-reductase inhibitors, that can worsen and further complicate ED symptoms.
In 2003, the AUA issued updated guidelines that recommended alpha-blockers and 5-alpha-reductase inhibitors as alternatives to surgical intervention for BPH.13 Alpha-adrenergic antagonists quickly relieve urinary voiding symptoms, but they do not slow or prevent disease progression; 5-alpha-reductase inhibitors reduce urinary voiding symptoms more slowly. However, these agents decrease complications and symptom progression in patients with larger prostates (i.e., 30-49 g). Recently, it was recognized that phosphodiesterase type 5 (PDE5) inhibitors may be used with good effect in patients with ED who also have moderate-to-severe symptoms of BPH. PDE5 inhibitors are considered less effective than alpha-adrenergic antagonists for BPH, however, because of less robust improvements in urinary flow rates and residual urine volume measured after voiding. The AUA practice guidelines on BPH (2010) and overactive bladder (2012), both of which were validated in 2014, do not discuss the appropriateness of PDE5 inhibitors as a treatment for LUTS; however, the 2014 European Association of Urology guidelines on the management of non-neurogenic LUTS recommend a PDE5 inhibitor with or without an alpha-1 blocker for moderate-to-severe LUTS in patients with or without ED.14
Urinary Incontinence: Urinary incontinence (UI) has significant quality-of-life consequences for both sexes, but for men, this condition is another potential source of increased risk of impaired sexual function. Estimates of prevalence vary significantly by incontinence type; however, UI is more common in women, and there are fewer studies assessing its incidence and epidemiology in men. UI has a more sudden and later onset in men, with an overall prevalence of roughly 4.5% and an increase to 16% in men aged 75 years and older. LUTS, BPH, hypertension, and depression are associated factors. In addition to the adverse physiological impact of UI on sexual function, many of the medications used to treat UI further complicate the resolution of ED.15
Prostate Cancer: The prevalence of prostate cancer in men over a lifetime is one in six cases, and the incidence increases in certain ethnic populations. Treatments for prostate cancer are more likely than the disease itself to be associated with ED. Hormone-based cancer therapy can affect libido, radiation therapy can damage the penile arteries, and the trauma resulting from the removal of cancerous tissues during surgery can impair the nerves and surrounding tissue.1
Androgen Deficiency: Androgen is known to play a role in achieving an erection; however, the link between low testosterone levels and ED lacks sufficient clinical evidence for supplementation to be established as a routine first-line intervention. Testosterone therapy has been associated with an increased risk of CV complications and events; however, studies have demonstrated that for men with low testosterone who also have low bone mineral density and decreased sexual function, supplementation may be a good option.16
Neurologic Disorders: Parkinson’s disease, multiple sclerosis, stroke, and Alzheimer’s disease are commonly reported causes of ED, and other neurologic disorders caused by peripheral neuropathy and trauma to the spinal and or pelvic nerves also have been reported as causes.17
Drug-Induced ED: Many drugs prescribed for medical and psychiatric conditions can contribute to, or even cause, ED (TABLE 1). Antihypertensive agents, diuretics, and many psychiatric medications have been implicated. Debate is ongoing over which drugs should be considered essential and need to be continued regardless of their impact on sexual function and which others could be replaced, according to patient preference, with an alternative that has less impact on sexual function. In cases where medications with an adverse effect (AE) of ED have been identified as nonessential, discontinuation should be considered to improve the patient’s quality of life.4
Pharmacotherapy for ED
PDE5 Inhibitors: These oral agents, which are considered first-line therapy, facilitate the release of NO from penile corpus cavernosal neurons and enhance the relaxation of smooth muscle, allowing increased blood flow to tissues involved in an erection. Currently available PDE5 inhibitors are sildenafil, tadalafil, vardenafil, and avanafil (TABLE 2). The endogenous production of NO diminishes with advancing age and further decreases in the presence of comorbidities including medical complications of diabetes and atherosclerosis, as well as the hormonal deficits seen in hypogonadism. There are presently no studies comparing these agents, so patient preference and the insurance formulary may determine the selection of prescribed medication. Of note is the difference in reported half-lives of these agents: Tadalafil has a half-life of 17 to 21 hours compared with 4 to 6 hours for sildenafil and vardenafil, potentially allowing for more sexual spontaneity.4
The magnitude of vasodilation is significant and is the reason that concomitant use of nitrates (also potent vasodilators) is contraindicated, given the potentially severe hypotension that may occur and lead to myocardial infarction (MI), stroke, or death with concurrent use. These agents are associated with other notable drug interactions, some of which require dose adjustments or avoidance of certain drug combinations including, but not limited to, nitrates. Because of the class effect of vasodilation, flushing and headache are common side effects reported by patients using PDE5 inhibitors. For patients who are newly prescribed these agents, the success of drug therapy may be associated with a long-lasting erection. However, it is critical to educate the patient that prolonged erections (lasting >4 hours) and priapism (an abnormal, more or less persistent, often painful penile erection) have been associated with PDE5 inhibitor use. If these conditions are not treated promptly, irreversible damage to the erectile tissue may occur. A patient with an erection lasting more than 4 hours, whether painful or not, should seek emergency medical attention. Patients who have penile structural abnormalities or conditions that may predispose them to priapism (e.g., leukemia, multiple myeloma, history of priapism) should use these ED treatments with caution.4
Sexual activity is not safe for every patient; therefore, a thorough workup is indicated prior to recommending the use of PDE5 inhibitors. Some patients for whom this therapy may not be appropriate include those with low systolic blood pressure (BP), recent stroke or MI, unstable angina, hypotension, or specific types of optic neuropathy. The most commonly reported side effects are associated with the resulting vasodilation in other bodily tissues and include hyperemia of the eyes, nasal congestion, flushing, dyspepsia, and myalgia. In studies, these effects were mild-to-moderate, transient, and unrelated to age.4 Patients should stop taking these agents and seek medical care if a sudden loss of vision occurs in one or both eyes; this could be a sign of nonarteritic anterior ischemic optic neuropathy. In most preclinical trials evaluating these effects, however, most visual or aural changes (tinnitus) were transient and reversible upon discontinuation. The proposed mechanism of action is not fully understood; however, in addition to changes in blood flow, these agents have a minor inhibitory effect on another form of phosphodiesterase, PDE6, which is present exclusively in the retinal rod and cone photoreceptors; at higher doses, these agents may be associated with blue visual tints and a perception of increased brightness of lights.18-21
Alprostadil: Alprostadil causes direct relaxation of the vascular smooth muscle, making it a viable option for patients with ED; it is available as a solution for injection that may be administered as needed up to three times per week.1 Although this medication is a second-line option for patients seeking an ED treatment, the fact that it requires self-injection into the corpus cavernosum has made it a much less desirable choice for most patients. Common side effects are irritation, pain, and injection-site redness; other effects may include inhibited platelet aggregation, enhanced relaxation of bronchial muscle, and delayed gastric emptying time. Another administration option for alprostadil is Muse, a medicated pellet that is administered intraurethrally via plunger, delivering the dose to the tip and surrounding skin of the penis. Many patients stop using alprostadil because of the pain experienced upon administration.1
Testosterone: Testosterone, the main sex hormone in the male body, plays many roles in overall health. Testosterone levels naturally drop with age, which can result in decreased libido, reduced sperm count, and, for some men, secondary ED. Although testosterone is not approved specifically for ED, the treatment of an underlying testosterone deficit may help resolve the associated symptoms.
Because of significant potential adverse effects, including an increased risk of CV events such as heart attack and stroke, the use of testosterone should be limited to conditions in which the benefit outweighs the risks. Testosterone can increase the chance of a heart attack or stroke. Because of these risks, the FDA advises that only men whose low testosterone is due to certain health issues should use testosterone. Safety is often benchmarked and monitored via blood tests, physical examinations (to detect acne, edema, and changes in male genitalia), and behavioral mood evaluations.4
The addition of testosterone to other ED treatments (such as PDE5 inhibitors) may help older patients or those who have hypogonadism, thus enhancing the efficacy of overall ED intervention. Adequate physiological testosterone levels are necessary to maintain healthy erectile tissue and its nerves. Testosterone also enhances the availability of NO in penile cavernous smooth muscle, thereby increasing the efficacy of PDE5 inhibition.4
Testosterone is available as a mucoadhesive that dissolves under the gums (Striant); transdermal patch (Androderm); cream; gel (e.g., AndroGel); oral capsule; pellet implants (Testopel); solution for IM injection; transdermal solution (Axiron); and nasal gel.4
Other Products: Increasing numbers of non–FDA-approved products are available, and many of them have adverse effects. These agents include—but are not limited to—yohimbine, maca, horny goatweed, and gingko biloba.4
Some nonpharmacologic treatment options for ED include devices and prostheses. An external vacuum cylinder can be fitted over the penis to allow air to be pumped out, resulting in engorgement of the penis with blood.4 Adverse events associated with use of vacuum cylinders include pain, petechiae, bruising, and numbness. Inflatable, semirigid, or surgically implanted prosthetic devices also may be used to produce an erection. These nonpharmacologic options may be useful for patients who are unable to or prefer not to take pharmacologic agents. These alternatives are most successfully employed with a partner’s support and may ultimately be a treatment of choice for those with comorbidities restricting other therapies.4
Pharmacist’s Role in Patient Education
Patients should be encouraged to share concerns about and goals for sexual health as they age. Significant adverse outcomes may be associated with unaddressed ED symptoms, including, but not limited to, decreased adherence to medication the patient associates with the cause of the ED. Since medication used by the patient for other conditions may be responsible for drug-induced ED, a thorough medication review should be conducted.4 The role of the pharmacist in this review is important because, often, an alternative treatment with less potential for the complication of ED can be recommended. The prioritization of essential agents and the identification of nonessential medication that could be discontinued without negative impact are key. For example, in cases of BP disorders, changing to a different class of drugs—i.e., alpha-adrenergic blockers (e.g., doxazosin)—can preserve erectile function, and some angiotensin II blockers (ARBs) may have a positive effect on ED. For mental-health agents, changing an antidepressant drug to a less offending agent provides continued depression coverage without the temptation for the patient to self-discontinue the medication.4
Patients should be encouraged to implement modifiable risk factors to improve general overall health, including increased exercise, weight loss, smoking cessation, and reduced alcohol intake. If all possible lifestyle modifications have been made and diagnosis indicates that potential curative therapies will fail, symptomatic treatments should be selected according to efficacy, safety, cost, and patient preference.4
It has been reported that the first use of PDE5 inhibitors may be less effective than subsequent responses seen with continued, repeated use. Patients who have failed a trial of a PDE5 inhibitor should be educated about other therapeutic options, including the use of a different PDE5 inhibitor.22 Patients must be informed that successful ED outcomes are possible only when the drug is administered at appropriate dosing intervals and with sufficient sexual stimulation. The prescribed dosing regimen that allows on-demand use may be optimal for some patients; however, many patients have better results with agents approved for daily use, such as tadalafil.20
Patients must understand the danger of priapism and that visual and hearing changes, although common and often benign, must be reported and evaluated in order to rule out more serious conditions. Patients should be advised that headache is common and usually is not a serious side effect. Managing headaches may require a lower dose of the PDE5 inhibitor and the supplemental prn use of OTC pain relievers. Limiting or avoiding alcohol can further reduce risk of headache, hypotension, and other more serious consequences.18-21
It is important that healthcare providers always consider the impact of sexuality in the overall health and quality of life of their patients. It also should be remembered that the critical first step in ensuring optimal treatment is to encourage patients to report sexual dysfunction early. All healthcare providers dealing with the health problems of older adult males should be aware of current pharmacologic and nonpharmacologic treatments available and the role these therapies play in the management of ED.
- Mola JR. Erectile dysfunction in the older adult male. Urol Nurs. 2015;35:87-93.
- American Psychological Association. Older adults’ health and age-related changes. www.apa.org/pi/aging/resources/guides/older. aspx. Accessed May 12, 2017.
- Scott PS. Men and aging: 5 things men fear most about aging. www.caring.com/articles/5-things-men-fear-about-aging. Accessed May 12, 2017.
- Albersen M, Orabi H, Lue TF. Evaluation and treatment of erectile dysfunction in the aging male: a mini-review. Gerontology. 2012;58:3-14.
- Ückert S, Mayer ME, Stief CG, Jonas U. The future of the oral pharmacotherapy of male erectile dysfunction: things to come. Exp Opin Emerg Drugs. 2007;12:219-228.
- Lindau, ST, Schumm LP, Laumann EO, et al. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357:762-774.
- Brody S. The relative health benefits of different sexual activities. J Sex Med. 2010;7(4 pt 1):1336-1361.
- Hatzimouratidis K, Eardley I, Giuliano F, et al. Guidelines on male sexual dysfunction: erectile dysfunction and premature ejaculation. European Association of Urology; 2015. http://uroweb.org/ wp-content/uploads/14-Male-Sexual-Dysfunction_LR1.pdf. Accessed May 12, 2017.
- Heidelbaugh JJ. Management of erectile dysfunction. Am Fam Physician. 2010;81:305-312.
- Nehra A, Jackson G, Miner M, et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012;87:766-778.
- Garimella PS, Paudel ML, Ensrud KE, et al. Association between body size and composition and erectile dysfunction in older men: Osteoporotic Fractures in Men Study. J Am Geriatr Soc. 2013;61:46-54.
- Wei JT, Miner MM, Steers WD, et al. Benign prostatic hyperplasia evaluation and management by urologists and primary care physicians: practice patterns from the observational BPH registry. J Urol. 2011;186:971-976.
- AUA Practice Guidelines Committee. AUA guideline on management of benign prostatic hyperplasia (2003). Chapter 1: diagnosis and treatment recommendations. J Urol. 2003;170(2 pt 1):530547.
- Phosphodiesterase type 5 inhibitors for the treatment of BPH/ LUTS and penile rehabilitation: evidence summary and recommendations. www.pbm.va.gov/PBM/clinicalguidance/clinicalrecommendations/PDE5I_BPH_LUTS_Evidence_Summary_and_Recommendations.pdf. Accessed May 26, 2017.
- Cook K, Sobeski LM. Urinary incontinence in the older adult. Pharmacother Self-Assessment Prog: Spec Pop. 2013;3-19.
- Cheetham TC, An J, Jacobsen SJ, et al. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA Intern Med. 2017;177(4):491-499.
- Gareri P, Castagna A, Francomano D, et al. Erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. Int J Endocrinol. 2014;2014:878670.
- Viagra (sildenafil citrate) package insert. New York, NY: Pfizer, Inc; 2006.
- Vardenafil HCl package insert. Indianapolis, IN: Eli Lilly & Co; December 2008.
- Cialis (tadalafil) package insert. Indianapolis, IN: Eli Lilly & Co; 2005.
- Stendra (avanafil) package insert. Cranford, NJ: Mist Pharmaceuticals, LLC; 2015.
- American Urological Association. Erectile dysfunction. www. auanet.org/guidelines/erectile-dysfunction-(2005-reviewed-andvalidity-confirmed-2011). Accessed June 26, 2017.