New Oral Agents for Erectile Dysfunction

by Laurence A. Levine, MD

Erectile dysfunction (ED) is a common and increasingly prevalent disorder. It affects an estimated 30 million men in the United States, and over 617,000 new cases are expected annually in men between the ages of 40 and 69. The availability of sildenafil citrate, the first effective oral agent for ED, has dramatically increased the number of men seeking treatment for this disorder and shifted much of the management of ED to primary care physicians. In the near future 2 other oral erectogenic agents will likely become available. Vardenafil is a phosphodiesterase type 5 (PDE5) inhibitor with a pharmacokinetic profile and molecular configuration nearly identical to that of sildenafil. A new drug application (NDA) for vardenafil was submitted to the FDA in September 2001. The other new PDE5 inhibitor is tadalafil. It has a unique chemical structure and a pharmacokinetic and pharmacodynamic profile that differs from both sildenafil and vardenafil. The manufacturer of tadalafil submitted an NDA for it in June 2001.

The availability of these new PDE5 inhibitors will greatly expand our treatment armamentarium for ED but also raises important questions for physicians. First, how do we choose among the 3 drugs? And, second, how do the new drugs differ from sildenafil, the established benchmark in ED treatment? Over 11,000 patient-years of experience with sildenafil exist as well as a tremendous amount of reassuring safety and efficacy data. This makes most physicians feel comfortable prescribing sildenafil as first-line therapy for ED. However, for many patients who do not have a reasonable response to sildenafil, the opportunity to try a different oral agent will be a welcome option and an alternative to second-line therapy with a vacuum constriction device, an injected agent, or intraurethral alprostadil (MUSE).

To help us select the most appropriate PDE5 inhibitor for our patients with ED, and in the absence of carefully controlled head-to-head trials, it is important to examine some of the distinguishing characteristics of these agents, including selectivity, onset and duration of action, and safety and efficacy (see also the table below).

Selectivity is an important issue, because there are as yet no pure PDE5 inhibitors. In addition to inhibiting PDE5, both sildenafil and vardenafil also produce modest PDE6 effects at the upper limits of the dosage range, whereas these effects are absent with tadalafil. In contrast, only tadalafil has definite PDE11 effects at therapeutic doses, although the significance of this is not yet clear. We know that PDE6 inhibition affects the cones in the retina and results in the “blue” vision experienced by some patients taking sildenafil and vardenafil. However, no adverse visual effects have been reported with sildenafil, and vardenafil studies in this area will likely be forthcoming.

PDE11 has only recently been described and is present in the pituitary, pancreas, skeletal muscle, heart, testes, and corpus cavernosum. However, the effects on these tissues of chronic or intermittent PDE11 inhibition are not known and require further study.

Onset of Action
None of the PDE5 inhibitors works immediately. Most studies indicate that all 3 agents have an average onset of action of about 30 to 60 minutes, although there have been reports that tadalafil may be effective in as little as 15 or 16 minutes. However, this rapid onset of effect occurred in less than 20% of patients in one small study and is similar to results observed in the sildenafil trials. In general, the speed of onset of a drug varies from person to person and will be determined by an individual’s internal chemistry.

If, however, onset of action becomes a critical concern for any individual patient, he should be advised to avoid taking the drug on a full stomach and particularly after a fatty meal, which further delays gastric emptying and drug absorption. This is certainly true for patients taking sildenafil and vardenafil, although it may not be the case for tadalafil. One possible benefit of tadalafil is the reported lack of a food effect, which is most likely due to the drug’s delayed metabolism. As a result, slow gastric emptying has less effect on the time to maximum concentration (Tmax).

Duration of Action
The duration of action is an exciting area of comparison among the oral agents because it is where the most significant differences are found. The reported duration of action (t_) of sildenafil and vardenafil is approximately 4 to 5 hours, whereas for tadalafil it is between 17 and 21 hours. There is no doubt that an oral erectogenic agent with a long duration of action provides some men with additional confidence, allowing them to take the drug long before they anticipate having sexual relations. However, on the downside, taking a drug long before sexual relations are to occur may result in some waste as well as some blunting of response over time.

Patterns of Sexual Behavior
When evaluating the onset and duration of action of the PDE5 inhibitors it is also important to consider how these features conform to the normal sexual patterns of patients. In a recent study of sexually active men aged 40 to 69 years both with and without ED, investigators found that the average frequency of sexual intercourse was 1 episode per week and that the average time for foreplay was approximately 14 minutes; the vast majority (> 70%) of men studied reported that they had sex only once in a 24-hour period. Based on these statistics, it will be relatively easy to select a drug with onset and duration of action that satisfies patients’ needs.

The safety of PDE5 inhibitors is an important concern, since many men with ED also have cardiovascular disease. A careful assessment of cardiovascular status before prescribing treatments for ED and/or advising the patient to resume sexual activity is recommended.
To date, there is no evidence that any of the PDE5 inhibitors has any direct adverse cardiovascular effects. In fact, the reverse may be true, as recent studies suggest that sildenafil may delay exercise-induced ischemia and angina.

Other safety issues specific to tadalafil also need to be considered. Because of the drug’s prolonged duration of action (ie, approximately 17 hours in a healthy man and up to 21 hours in an elderly patient), it will take up to 4 days for tadalafil to be completely eliminated from the body. This could potentially extend the duration of adverse effects or delay intervention with nitroglycerin during a cardiac event.

In addition, because tadalafil inhibits PDE11, additional studies examining the effects of tadalafil on spermatogenesis as well as on pituitary and cardiac function are also needed. These studies are expected to be forthcoming. The effects of tadalafil on sperm function are also being investigated. Studies to date have demonstrated no long-term effects of sildenafil on sperm function.

Adverse Effects
In general, the PDE5 inhibitors are well tolerated and have similar mild to moderate adverse effects profiles. In clinical trials, the most commonly reported adverse events were vasodilation, resulting in headache, nasal congestion, facial flushing, and dyspepsia. There appears to be a greater incidence of myalgia and low back pain with tadalafil, although the etiology of the myalgia remains unclear.

None of the PDE5 inhibitors has any significant drug interactions except for an absolute contraindication for the concomitant use of organic nitrates. Sildenafil and all agents in this class potentiate nitrate-induced vasodilation. In addition, they are all metabolized by the cytochrome P450 3A4 isoenzyme system, and concomitant administration of inhibitors of this pathway (eg, cimetidine, ketoconazole, erythromycin, and protease inhibitors) will prolong duration of action and raise serum concentrations of the drugs.

The issue of tachyphylaxis with the PDE5 inhibitors, or the loss of clinical effectiveness with chronic use, has generated considerable interest. In this case, there is concern that the penis will begin to produce more PDE5 in response to chronic PDE5 inhibition. For biochemical tachyphylaxis to occur, however, cavernosal tissue needs to be exposed to PDE5 inhibitors for approximately 4 to 5 days. (Dr. Levine, please confirm). Although this is not likely to occur with sildenafil or vardenafil due to their short half-lives, the extended half-life and delayed clearance of tadalafil may pose a problem.

Clinical Efficacy
Once the safety of the drug has been established, clinical efficacy is clearly the most important factor for the clinician to consider when selecting a drug. Evidence suggests that all 3 PDE5 inhibitors improve the quality of erections and enable successful intercourse in men with ED of all etiologies, even those with severe ED. The question as to whether men with certain comorbidities (eg, diabetes, post–radical prostatectomy, and hypertension) would be more successfully treated with one particular agent awaits further study and experience. To clearly define one drug’s benefit or superiority over another requires carefully designed, head-to-head studies with well-defined efficacy measures.

New oral treatments for ED will soon be available. How physicians will choose which drug to prescribe will be much the same as electing among other classes of drugs with multiple options, such as NSAIDs, alpha-blockers, or SSRIs. The selection process will take into account physicians’ previous experiences with sildenafil and patient satisfaction and preferences as well as the recognition that similar drugs may have significantly different effects in the same individual. Ultimately, however, choosing a drug for our patients with ED will end up being a ” tincture” of time, trial and error and experience.

Suggested Readings
Fox KM, Thadani U, Ma PTS, et al. Time to onset of limiting angina during treadmill exercise in men with erectile dysfunction and stable chronic angina: Effect of sildenafil citrate. In: Abstracts of the American Heart Association Scientific Sessions 2001; November 11-14, 2001; Anaheim, Calif. Available at: Accessed June 14, 2002.
Johannes CB, Araujo AB, Feldman HA, et al. Incidence of erectile dysfunction in men 40 to 69 years old: Longitudinal results from the Massachusetts Male Aging Study. J Urol 2000;163:460-463.
Muirhead G, Harness J, Purvis K. The effects of Viagra (sildenafil) on human sperm function in healthy volunteers. ESSIR Oct 2001.
Padma Nathan H, Eardley I, Maytom M. Long-term efficacy of Viagra (sildenafil citrate): Results after 2-3 years of treatment. ESIR Oct 2001.
Sasche et al. Safety, tolerability and pharmacokinetics of BAY 38-9456 in patients with erectile dysfunction. AUA May 2001.
Zrenner E, et al. The effects of long-term sildenafil treatment on ocular safety in patients with erectile dysfunction. Invest Ophthalmol Vis Sci. 2000;41:S592.

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of BU School of Medicine