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Erectile Dysfunction Julio R The Consultant ImprovingR patient care through drug education September 2004 Volume XIII Number 8 Erectile Dysfunction Julio R. Lopez, Pharm.D. OVERVIEW The medical management of male erectile dysfunction has The Bottom Line undergone significant changes in recent years. The introduction • Erectile dysfunction (ED) is a common of phosphodiesterase type 5 inhibitors (PDE5) such as sildenafil condition. The cause is frequently physical, ® (Viagra ) changed the approach to treatment, making this the such as a medical condition, an injury or an preferred drug class for erectile dysfunction (ED). What was adverse effect from a medication, and may once a condition managed with surgical implants, vacuum also include psychological factors. pumps or penile injections is now typically approached with • Sildenafil, vardenafil, and tadalafil are oral therapy using drugs in the PDE5 class. Sildenafil, the first oral PDE5 inhibitors currently approved for PDE5 inhibitor approved by the FDA, was marketed in the use in ED. These drugs improve sexual United States in 1998. The new drug was quickly incorporated function in about 50-75% of men with ED. into practice, shifting utilization away from alprostadil injection • There is no evidence that one PDE5 drug or intraurethral suppository. The number of men seeking is more effective than another. The 3 drugs sildenafil prescriptions rose rapidly. By 2001 there had been an share similar precautions, but differ in onset 87% increase in prescriptions, to an estimated 145 million and duration of action. 1 annually. • PDE5 inhibitors can be effective in elderly Erectile dysfunction is a common problem. It is estimated men; those with cardiovascular disease, that most men 45 years of age or older experience the inability to diabetes or antidepressant-induced ED; and achieve an erection sufficient for sexual intercourse at least some in men who have undergone prostatectomy. of the time.2 The prevalence of ED increases with age so that by • PDE5 drugs can lower blood pressure. age 50, for example, about 50% of men have experienced erectile Cautious use is warranted in patients with dysfunction. Clearly, this is a large number of men and the cardiovascular disease. These drugs are potential use of drugs to treat ED is equally large. safe, however, in most men with controlled This article will review new data on the drugs used to treat hypertension or stable heart disease. erectile dysfunction. Information on sildenafil as well as the two • PDE5 drugs interact with many other new drugs, tadalafil (Cialis®) and vardenafil (Levitra®), will be drugs and all medication use should be presented. Issues surrounding the use of these drugs will be dis- carefully reviewed before these agents are used. Concurrent use of PDE5 drugs and nitrates or nitrites is contraindicated. Continuing Education Objectives ACPE# 428-000-04-008-H01 CA BRN # 13118 • Describe the clinical efficacy of PDE5 drugs in the general cussed, including social issues such as market- population of men with ED and in men with medical condi- tions such as diabetes and heart disease. ing, the availability of ED drugs through non- conventional sources, and rationing via health • Discuss side effects of PDE5 drugs, and in particular how they relate to cardiovascular risks and benefits. care policy-making. Lastly, common questions regarding the off-label use of PDE5 drugs will be • Provide dosing information for PDE5 drugs and understand pharmacokinetic differences among the agents. answered, including uses other than sexual disorders. (See Insets, pages 3, 4, 6 and 7.) • List potentially dangerous drug interactions with PDE5 drugs. 1 Table 1. Commonly Used Drugs That May Cause Erectile Dysfunction Pathophysiology of Erectile Dysfunction Cardiovascular Drugs Beta blockers, centrally-acting sympatholytic ED is the inability to achieve sufficient penile engorge- drugs such as methyldopa and clonidine, thiazide ment to perform sexual intercourse. There are many rea- diuretics, spironolactone (high doses), digoxin sons why this happens.3 The physiology of normal pe- nile erection is complex and involves higher brain func- CNS Drugs tion, sympathetic and parasympathetic nervous system SSRI antidepressants, tricyclic antidepressants, pathways, and perhaps most importantly, a healthy pe- phenothiazines, atypical antipsychotics nile vascular system. With sexual stimulation, parasym- Endocrine Agents pathetic impulses via the cavernosal nervous system Drugs with estrogenic activity, antiandrogens used cause a release of nitric oxide, which in turn increases in prostate cancer, finasteride, dutasteride, intracellular cyclic guanosine monophosphate (cGMP) in anabolic steroids vascular smooth muscle within the corpus cavernosa. Miscellaneous This causes vasodilation of the arteries and venules of alcohol, opioids the corpora cavernosa, allowing it to fill with blood. As the cavernosal sinusoids fill with blood, they compress the veins that drain these spaces, preventing outflow of blood. Elongation and rigidity of the penis occur. Once independent studies that compared each drug to pla- orgasm occurs, there is activation of the sympathetic ner- cebo. For example, patient selection criteria may have vous system leading to emptying of the corpus been different and the measurements of efficacy may cavernosum and penile detumescence. have used different self-reporting erectile dysfunction scales. In general, sildenafil is reported to have efficacy Any impairment of this system can lead to ED. This in- between 50% and 70% of the time when taken in doses cludes damage to the nervous system, as may occur with ranging from 25 to 200 mg. Indeed, in the pooled results diabetes or prostate surgery; vascular damage due to of 14 trials, 57% of intercourse attempts were successful atherosclerosis; or the effects of drugs and other agents among men taking sildenafil, compared to 21% among that impair both neural and vascular function such as men taking placebo.5 Vardenafil has been studied in overuse of alcohol. In particular, ED is commonly asso- doses ranging from 5 to 20 mg. Improvement in ED suf- ciated with cardiovascular disease and may be an early ficient to allow penetration was seen in 65% to 80% of 4 indicator of vascular disease. Many drugs are associ- patients, as compared to 52% with placebo.6 In the two ated with causing ED; some of the more commonly used U.S. studies used for the marketing approval of tadalafil, agents are listed in Table 1. If drug-related ED is sus- men taking tadalafil achieved erections sufficient for pected, other therapeutic options should be considered. penetration in 62% and 77% of attempts, compared to If the suspect drug is necessary, addition of a PDE5 drug 39% and 43% of attempts for men taking placebo.7 A may be appropriate. summary of five tadalafil studies conducted outside the U.S. reported a response rate of 75% based on ability to Phosphodiesterase Inhibitors complete intercourse.8 In summary, half to three quar- PDE5 drugs increase the normal response of the penile ters of patients with ED will get clinical benefit from vasculature to nitric oxide. They do so by inhibiting PDE5 drugs, with no apparent difference in efficacy rates phosphodiesterase, the enzyme that breaks down intrac- among the 3 drugs. As expected, the use of PDE5 drugs has been associated with improved well being and ellular cGMP. PDE5 drugs can overcome ED that results 9 from psychogenic causes (e.g., stress, anxiety) or neural sexual partner relationships. While there is no direct damage as long as the smooth muscle in the penile vas- comparative data among the PDE5 drugs, there is some culature is at least partially preserved. Sexual stimula- data comparing sildenafil to alprostadil and surgical im- tion is necessary to initiate an erection. plants. These data suggest that alprostadil and sildenafil are equivalent in efficacy but that penile implants are 10 Efficacy in the General Population superior for long term management of ED. The first commercially available drug in this class was Efficacy in Special Populations sildenafil. More recently, tadalafil and vardenafil have been marketed. Clinical trials directly comparing the Of particular interest is the use of PDE5 drugs in special three PDE5 agents have not been published. There are populations that are traditionally more difficult to treat many limitations when comparing the drugs by using or at higher risk of adverse events. Elderly patients are at higher risk of adverse events and drug interactions 2 Do sildenafil or similar drugs work in women with sexual dysfunction? because of an increased prevalence of heart disease and the concurrent use of other medications. A review of the Female sexual dysfunction appears to be elderly patients (defined as older than 65 years) included much more complex than male erectile dysfunc- in five clinical trials evaluating sildenafil shows that tion. Vascular events parallel to those that oc- sildenafil is effective in this age group, with an incidence cur in men lead to clitoral enlargement and of side effects similar to that seen in younger patients.16 vaginal lubrication. However, this plays a lim- Vardenafil and tadalafil are also equally effective in eld- ited role in female sexual dysfunction, as loss of erly men as compared to younger men.17,18 libido and anorgasmia are more prevalent. Treatment with PDE5 drugs, particularly Sildenafil has also been studied in patients with heart sildenafil, has resulted in reversal of failure and stable coronary artery
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