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
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.
Safety
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.
Tachyphylaxis
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.
Conclusions
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:
http://aha.agora.com/abstractviewer/av_view.asp. 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.
