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CLINICAL CORNER |
From the Division of Urology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Address correspondence and reprint requests to Culley C. Carson, MD, Division of Urology, School of Medicine, University of North Carolina at Chapel Hill, 427 Burnet-Womack Building, Campus Box 7235, Chapel Hill, NC 27599-7235. E-mail: Carson{at}med.unc.edu
ABSTRACT
OBJECTIVE: Erectile dysfunction (ED) is a common condition of aging men. Indeed as many as 50% of men over age 40 will suffer some degree of ED. This erectile dysfunction has substantial impact on interaction with their partners, families, and employment. ED may be a harbinger of more serious vascular events and is commonly associated with depression.
METHODS: Evaluation of ED begins with a careful history, asking the patient about his sexual function during clinical visits. Once identified, ED must be carefully considered with full history, careful physical examination, and laboratory studies to include markers of vascular risk factors, diabetes, and hypogonadism.
RESULTS: The treatment of ED was revolutionized by the introduction of phosphodiesterase type 5 (PDE5) inhibitors in 1998. Currently, 3 PDE5 inhibitors are available internationally with excellent expected results and somewhat unique profiles. Although these agents are safe in all patients who do not have severe cardiac disease or who are taking nitrate medications, they require some patient instruction and counseling to optimize results. In that small group of patients who do not respond to these oral medications, additional alternatives are available for patients motivated to pursue treatment of their ED.
CONCLUSION: Currently available safe and effective alternatives for the treatment of ED can improve the lives of patients and partners and increase their quality of life.
Key Words: erectile dysfunction, • sildenafil, • antidepressants.
Abbreviations: ED = erectile dysfunction;; NHSLS = National Health and Social Life Survey;; NANC = nonadrenergic-noncholinergic;; NO = neurotransmitters nitric oxide;; Ach = acetylcholine;; cGMP = cyclic guanosine monophosphate;; PDE5 = phosphodiesterase type 5.
INTRODUCTION
Erectile dysfunction (ED), the term used to replace "impotence," is a ubiquitous condition occurring in men throughout the world. This condition, defined as the consistent or recurrent inability of a man to obtain and/or maintain a penile erection that is satisfactory for sexual performance, has undergone revolutionary improvement in diagnosis and treatment as a result of basic science and clinical advances over the past 2 decades (1,2). Indeed, the true revolution in ED management occurred with the introduction of sildenafil in 1998. This first in a class of effective, oral, easily administered medications to treat most men with ED not only improved our management, but also permitted more men to be evaluated and treated by their physicians. In addition, the treatment of ED was moved from the office of specialists to the offices of internists, family practitioners, and all physicians treating men with conditions that pose risks of ED. Erectile dysfunction, which is often attributed to aging and was rarely evaluated and treated, can now be treated for most patients.
Prevalence of ED
The Massachusetts Male Aging Study published results of its landmark epidemiologic evaluation of a group of suburban Boston men to identify the prevalence of ED (3). This 1994 classic study interviewed 1,290 men aged 40 to 70 with a self-administered sexual activity questionnaire. Patients were queried regarding the ability to obtain and maintain an erection, frequency of erections, satisfactory of sexual relationships with the subject’s partner, and risk factors for vascular disease and ED. This study reports that 52% of men age 40 to 70 had some degree of ED, with 10% having complete ED. As patients aged, there was an increase in the prevalence of ED, so that 68% of men age 60 to 70 experienced ED of some degree. Risk factors were assessed, and it was identified that after adjusting for age factors directly related to the prevalence of ED included heart disease, hypertension, diabetes mellitus, low serum levels of high density lipoprotein C, depression, and lifestyle factors such as cigarette smoking. Indeed, cigarette smoking was demonstrated to increase ED beyond other risk factors for given ages (4). In reviewing men with complete ED, there was a rapid increase in complete ED in the 40-year-old group (5.1%) to the 70-year-old men (15%). A subsequent evaluation of this same population of men 8 years later investigated incidence of ED (4). Incidence in ED cases per 100 man years demonstrated an incidence of 1.24 in men in the decade of their 40s, 2.98 in the decade of the 50s, and 4.64 in the decade of the 60s. In further evaluating these men who had been followed up for 8 years, continuing or initiating smoking was most highly correlated with loss of erectile function, whereas exercise (more than 20 minutes 3 times weekly) was associated with preservation of erectile function. In investigation of ethnic prevalence of ED, Carson et al. reported no difference among white, African American, and Hispanic men in a large epidemiologic study (5). When age and risk factors were adjusted, there was no statistically significant difference among ethnic groups. In further evaluating these patients, however, ejaculatory dysfunction appeared to be most prevalent in the Hispanic men and least prevalent in the white men. Laumann et al. evaluated 1,410 men age 18 to 59 in the National Health and Social Life Survey (NHSLS) (6). They reported a lower prevalence of ED of 5% but also reported that 21% of men had some form of ejaculatory dysfunction, most often premature ejaculation in younger men, and 5% of men suffered from low sexual desire. This study, likewise, demonstrated a high bother score for ED. The NHSLS study reported that low physical satisfaction, low emotional satisfaction, and low general happiness were more prevalent in those men with ED than any other group, and low desire was significantly higher in these categories than in patients with no problems with sexual function. They demonstrated an increase in ED influenced by health-related and psychological factors. Stress-induced events appear to influence and increase sexual dysfunction. As a result of these epidemiologic studies, it has been estimated that as many as 30 million American men may suffer from ED. Current estimates, however, demonstrate that only 3 million are currently being treated. Despite the prevalence, increased with risk factors, ED is poorly identified and treated in the US population. Physician-patient communication is the critical beginning of ED treatment. Marwick and associates surveyed patients’ expectations and experience in discussion of sexual issues with their physicians (7). Seventy-one percent of patients stated that they believe that their physicians would not recognize ED as a medical problem, while 68% of patients feared that discussing sexuality with their physician would embarrass their physicians. It is clear from these data that physicians must initiate conversations to identify patients for adequate treatment initiation. A study performed by American Association for Retired Persons reported that fewer than 10% of men over age 45 who had sexual problems received treatment, and only half of those patients who had ever tried oral medications continued with their treatment (8). Other international studies have demonstrated similar disturbing results.
Erectile Function
ED is generally a multifactorial condition that mirrors the diseases of aging, most commonly those with associated psychological, neurological, and most importantly vascular abnormalities (9). For an erection to occur, blood supply and nerves to the penis must be functional and there must be an adequate supply of androgenization for erection to occur. Testosterone levels have been demonstrated to be associated with receptors in the midbrain as well as in the smooth muscle cells of the corpus cavernosum of the penis. Therefore, hormonal levels are important not only for libido and central nervous system function, but also for local penile function. Erectile function begins in the central nervous system with tactile or psychological stimulation and excitatory impulses through the parasympathetic pathway with nerve endings in the corpus cavernosum. Nonadrenergic-noncholinergic (NANC) nerves in the penis release neurotransmitters nitric oxide (NO) and acetylcholine (Ach) to stimulate relaxation of corpus cavernosum smooth muscle and produce erections. NO, the principal neurotransmitter involved in smooth muscle relaxation and ultimately erectile function, enters the smooth muscle cells and activates soluble guanylate cyclase increasing the intracellular level of cyclic guanosine monophosphate (cGMP). Cyclic GMP activates a specific protein kinase that is responsible for phosphorylation proteins and changes in ion channels. This results in the opening of potassium channels, the exit of calcium from the cell, and ultimately corpus cavernosum smooth muscle relaxation. As this smooth muscle relaxation proceeds, penile arteries relax and arterial flow to the penis increases. The lacunar spaces of the corpus cavernosum fill with arterialized blood and expand, increasing volume and pressure within the penis. This pressure decreases venous outflow, trapping blood in the penis and producing an erection. At the same time, muscles in the perineum contract to increase pressure within the penis to a level beyond that of the abdominal aorta. Failure of increased arterial flow and failure of venous occlusion will result in significant ED. As stimulation declines, NO diminishes and cyclic GMP decreases in concentration by metabolism from the enzyme phosphodiesterase type 5 (PDE5). Although there are other phosphodiesterases in the smooth muscle cells of the corpus cavernosum and a secondary dilation pathway through cyclic adenosine monophosphate, the nitric oxide cGMP PDE5 cascade is the most important and active events for producing erection. The new oral medications facilitate erectile function through the inhibition of PDE5, increasing the concentration and duration of cGMP in the corpus cavernosum smooth muscle and thus increasing smooth muscle relaxation and ultimately erectile function (Figure 1).
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Evaluation of Erectile Dysfunction
Evaluation of ED begins with a carefully crafted history and focused physical examination. This should include a sexual and psychosocial history with information on ED onset, duration, progression, associated medications and risk factors (11). Because many patients and partners are uncomfortable in discussing sexual function, it is important that patients be placed at ease and each portion of the history and physical examination is carefully explained. Initial history can be facilitated through the use of self-administered questionnaires. The most clinically useful of these is the Sexual Health Inventory for Men (12). Once the history has been completed, targeted physical examination should evaluate secondary sex characteristics, genitalia for testicular size, and the presence of Peyronie’s disease and other abnormalities, and an examination of the prostate gland for possible prostatic malignancy or prostatitis. This should be followed by laboratory testing to include studies for diabetes, hypercholesterolemia, and hypogonadism. Because the first symptom of diabetes, hypercholesterolemia, and hypogonadism can be ED, a high index of suspicion for these associated conditions should accompany all examinations of patients with ED.
Depression as a Common Cause of Erectile Dysfunction
Depression has been demonstrated in a number of studies to be associated with ED. Indeed, the Massachusetts Male Aging Study documented depression as the second most common risk factor for ED (3). It is well known that vascular disease is a primary and independent risk factor for ED. Recent studies have demonstrated a link of ischemic heart disease with ED. Many of the conditions that result in ischemic heart disease likewise change lifestyle to increase the chances of depressive illness. These include sedentary lifestyle, smoking, obesity, and diabetes (13). Similarly, as patients age, the risk of depression likewise increases. The study by Tan and Pu suggested the term "DEC syndrome" to refer to those patients with depression, ED, and coronary heart disease because these conditions often coexist (14). Other studies have failed to demonstrate a strong link between ED and depression, but patient numbers were small enough to preclude clear conclusions (15,16).
Medications used for the treatment of depression are likewise associated with decreased erectile function (17). Indeed, the selective serotonin reuptake inhibitors (SSRIs) are significant culprits in causing ED. Shabsigh et al. reported that men with ED and depressive symptoms were less likely to continue depression treatment with SSRI drugs than those in whom ED was either absent or treated (18). The SSRI antidepressants are associated with many sexual side effects, most commonly ejaculatory dysfunction with delayed ejaculation (18,19). Paroxetine of the SSRI agents has been demonstrated to be most commonly associated with ED (20). Clayton et al. evaluated antidepressant monotherapy and associated sexual dysfunction in men and women (21). This questionnaire-based study demonstrated that bupropion was associated with the lowest risk for ED followed by nefazodone. While bupropion was associated with a 22% risk of sexual dysfunction, SSRI antidepressants were associated with rates from 36% to 43%, with odds of sexual dysfunction four to six times greater with SSRIs than with bupropion. Similarly, Masand et al. demonstrated an improvement in sexual function when combining bupropion with SSRI antidepressants in patients complaining of SSRI-associated sexual dysfunction (22). Further investigations by Clayton et al. have supported this conclusion, demonstrating that bupropion SR may reverse the SSRI-induced sexual dysfunction (23).
In those patients with sexual dysfunction associated with depression, SSRIs, or a combination or both, PDE5 inhibitors appear to be effective treatment for ED. Nurenberg et al. reviewed the effect of sildenafil citrate in patients with depression and antidepressant therapies (24). They demonstrated statistically significant improvement in erectile function in patients treated with sildenafil as needed and maintained on SSRI for treatment of depression. Indeed, in this questionnaire-based study, erectile function, arousal, ejaculation, orgasm, and overall satisfaction were statistically better with sildenafil than in patients treated with placebo while maintaining SSRI treatment for depression. In a study of ejaculatory dysfunction caused by SSRI, Seidman et al. demonstrated that high-dose sildenafil citrate improved ejaculatory function and indeed reduced ejaculatory latency in patients with sexual dysfunction characterized by ejaculatory delay (25). Rosen et al., in review of the prevalence of ED in patients with SSRI, report that up to 90% of men on antidepressant therapy may suffer sexual side effects (17). In patients with depression not requiring SSRIs and with ED, sildenafil citrate has also been demonstrated to be effective. Seidman et al. investigated a group of patients with significant but untreated depressive symptoms and ED (26). A 12-week randomized, double-blind, placebo-controlled trial was carried out that demonstrated marked improvement in erectile function at the 12-week level. In addition, depression scores as measured by the Hamilton Depression Scale decreased by as much as 50% in treatment responders. Other data support the use of sildenafil citrate for the treatment of ED in patients with chronic diseases associated with ED. Raffaele et al. report the use of patients with significant idiopathic Parkinson’s disease and sexual dysfunction (27). In a double-blind, placebo-controlled study using the Beck Depression Inventory and Hamilton Depression Scale in addition to the International Index of Erectile Function (IIEF), there was a highly statistically significant improvement in erectile function with sildenafil treatment and a secondary improvement in depressive symptoms in these patients.
Treatment with PDE5 inhibitors has been demonstrated to decrease ED in depressed men as well as improve their depression status (28). In a study of 152 men with ED and mild untreated depression, sildenafil given for 12 weeks was associated with marked improvement in erectile function but also significant improvements in depressive symptoms using standard depression inventories as well as quality of life (26). Shabsigh et al. reported that men with ED and depressive symptoms were less likely to continue depression treatment with SSRI drugs than those in whom ED was either absent or treated. Similarly, medications to treat depression are associated with sexual side effects (18). The SSRI antidepressants are most associated with ejaculatory dysfunction with delayed ejaculation (19). Of the SSRI agents, paroxetine has been demonstrated to be the most commonly associated with ED (20).
It is apparent, therefore, that patients with depressive illnesses are at higher risk of ED irrespective of the etiology of depression. SSRI antidepressants are also responsible for sexual dysfunction, most commonly ejaculatory dysfunction, with delayed ejaculation being most common (15). ED is also associated with these medications and can be ameliorated by addition of or switching to bupropion. The use of sildenafil citrate has been demonstrated in many studies to improve ED in patients with depression whether treated or untreated. Although data for other PDE5 inhibitors are not available, these agents may also be effective in improving ED in patients with depressive illness.
Treatment of Erectile Dysfunction
A stepwise care approach to the management of ED permits adequate and effective treatment of ED in the most conservative and noninvasive fashion possible (29). Because oral medications are the principal method for the treatment of most men with ED, these can be considered first-line therapy. Other elements of first-line therapy that should precede the prescription of oral medications include lifestyle modification, modification of drug therapy, especially antihypertensive medication, psychosocial counseling, smoking cessation, and androgen replacement therapy if indicated. Oral PDE5 inhibitors can then be administered once underlying healthcare and lifestyle considerations have been optimized. Men with documented deficiencies in androgen levels should have normalized androgen levels in association with oral medication treatment. It has been demonstrated that eugonadal men respond better to sildenafil than those who are hypogonadal.
Oral Agents for the Treatment of Erectile Dysfunction
A number of therapeutic agents have been used for ED before phosphodiesterase-inhibiting medications. These agents such as alpha-blockers, apomorphine, trazodone hydrochloride, yohimbine, and other herbal medication demonstrated poor responses in comparison with placebo in double-blind studies (30).
Before the introduction of effective oral agents for the treatment of ED and in current patients with severe vascular disease who are unresponsive to PDE5 inhibitors, intracavernosal injection therapy may be an option for treatment. Injection of vasoactive agents such as alprostadil (PGE1), papaverine, or other similar agents may produce excellent erectile responses (31). These second-line treatment alternatives can be effective, especially in severe diabetics and patients after non-nerve-sparing radical prostatectomy. Intracavernosal injection of alprostadil is relatively safe and highly effective in a majority of patients (up to 94% in some studies), producing more reliable, rapid, and predictable erections (32). One potential caveat is the high rate of discontinuation because of side effects such as injection site pain, prolonged erections, and scar tissue formation in the corpus cavernosum. Other ways of administering alprostadil include transurethral and topical administration, including the medicated urethral system for erection (Muse). In a comparison study, intracavernosal injection therapy resulted in better efficacy of penetration, higher patient and partner satisfaction, and fewer withdrawals than did transurethral alprostadil therapy (31). Adverse events include penile pain and burning, occasional symptomatic hypotension, and syncope.
PDE5 Inhibitors
The PDE5 inhibitors block the breakdown of cGMP through inactivation of the PDE5 isoenzyme (Figure 1). Sildenafil citrate, the first PDE5 inhibitor, has been available for more than 5 years with excellent clinical success and low morbidity (34). Two new PDE5 inhibitors, tadalafil and vardenafil, are currently available and approved for use through the Food and Drug Administration (FDA). These agents, available in most Western countries, have a mechanism similar to sildenafil as PDE5 inhibitors. These other oral PDE5 inhibitors, however, differ in regard to selectivity and pharmacokinetic characteristics (Table 1).
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Oral Agents
Sildenafil citrate is the first orally active inhibitor of PDE5 to be approved and widely used for the treatment of ED. Worldwide clinical trials have established efficacy and safety of sildenafil in men with ED of all etiologies, ages, and ethnic populations. Placebo-controlled double-blind studies were performed from 8 to 12 weeks with flexible dosing of sildenafil at 25, 50, and 100 mg (34). Measurement of outcomes was carried out using the IIEF as well as the Sexual Event Profile (SEP) questionnaire (12). These standard questionnaires demonstrated satisfactory outcomes that were statistically significantly and clinically significantly improved over baseline and placebo for all doses of sildenafil in a dose-response escalation pattern. Pivotal studies demonstrated improved erections in more than 60% of patients, compared with less than 20% with placebo. In an analysis of 11 double-blind, placebo-controlled, flexible-dose trials evaluating sildenafil as a treatment for ED, Carson et al. reported the results of a 4-year update on patients in various subpopulations. Long-term extension studies were also included in this analysis (34). The 11 studies included 2,667 men aged 23 to 89 years with a broad spectrum of etiologies not receiving concomitant nitrate therapy. Using the International Index of Erectile Function and the Global Efficacy Question ("Did treatment improve your erections?") and a SEP Log patient recorded, erectile function was demonstrated to be significantly improved in comparison with placebo for all efficacy parameters analyzed, regardless of patient age, race, body mass index, etiology of ED, severity, duration of ED, or the presence of various comorbidities or medications. In three open-label extension studies, long-term effectiveness was assessed. Of those who continued therapy 1 to 3 years with sildenafil, more than 95% of patients reported satisfaction with treatment and erectile function throughout the 3 years of study (34).
In reviewing the most difficult patients to treat, including diabetics and patients after radical prostatectomy, sildenafil was demonstrated to improve erectile function in all groups (34). Patients with most significant responses included younger patients, patients with depression, and patients with lower body mass index. The most difficult to treat patients with most limited responses included those patients with diabetes, ischemic heart disease, radical prostatectomy, and age over 65.
The optimum administration of sildenafil is important for obtaining and maintaining the optimal results. Because absorption of sildenafil is reduced after high-fat meals, a 2-hour fasting is best to obtain optimum response without delaying onset. Because many patients have had ED for long periods of time and may have partner issues, it is of critical importance to encourage patients to use adequate numbers of trials to assess adequacy of treatment. Indeed, it often requires six to eight clinical trials for optimum response in patients with both mild to moderate and severe ED (35). Because sildenafil and other PDE5 inhibitors do not produce but only facilitate erections, it is important to counsel patients that sexual stimulation to produce release of NO is required to achieve pharmacologic effect of these agents. Although onset of action can vary from 15 to 60 minutes, it is important, especially in patients with reduced absorption or severe ED, to counsel them that optimal response will be had at 60 minutes after administration (36). Dose escalation is likewise critical in the optimization of response to sildenafil. Although the starting dose of 50 mg is adequate for some patients, more than half of patients require 100 mg and ultimate dose escalation to achieve optimal results. Patients should be counseled, therefore, to try a starting dose of at least four times, to realistically evaluate efficacy and tolerability, and if responses are insufficient to obtain satisfactory sexual performance, patients should be advised to titrate to higher doses (35). Tolerability of sildenafil is quite satisfactory. The most common side effects include headache, facial flushing, blue vision, and dyspepsia. Blue vision, caused by the interaction of PDE6 with sildenafil, is less pronounced or absent with other PDE5 inhibitors (37).
Patients with minimal organic comorbidities and predominantly psychogenic ED appear to respond best to sildenafil for ED (37). Initial concern regarding the cardiac effects of sildenafil have now been ameliorated by a number of recent studies that clearly show that sildenafil neither worsens or adversely impacts the cardiac profile of patients with significant heart disease (38). In investigating patients with coronary artery disease and angina, Arruda-Olsen et al. demonstrated an enhanced cardiac profile in a group of men with symptomatic ischemic heart disease undergoing stress test (39). Fox et al. reviewed a group of men with symptomatic ischemic heart disease and compared them with a placebo group undergoing treadmill testing (40). The sildenafil group demonstrated statistically significant improvement in time to symptomatic angina and exercise tolerance compared with those patients treated with placebo. Although none of the oral agents for ED are contraindicated in patients with cardiac disease, guidelines have been established to assist the clinician in identifying those patients placed at risk by the exercise associated with sexual activity (38). Thus, patients with symptomatic and severe cardiac disease should be carefully evaluated before initiating treatment for sexual function with any oral or local agent. A review of the Princeton guidelines may be helpful in identifying those patients who should be carefully evaluated by a cardiologist before initiation of treatment (38).
Two new novel agents have been developed, approved, and are marketed worldwide for the treatment of ED. These PDE5 inhibitors: vardenafil and tadalafil are similar in their pharmacologic action to sildenafil but have unique pharmacologic properties.
Vardenafil is unique in its high biochemical potency. Pharmacokinetic findings from randomized, double-blind, placebo-controlled studies with oral doses of 10, 20, or 40 mg of vardenafil demonstrated a similar plasma concentration curve to sildenafil with time to maximum plasma concentration (Tmax) of 0.7 to 0.9 hours (41). Because of this rapid Tmax, vardenafil absorption is mildly delayed with high-fat meals. Although this delay is somewhat less than with sildenafil, patients must be counseled to avoid meals greater than 30% fat within 2 hours of vardenafil administration. In a real-time clinical monitoring study using the RigiScan instrument, significant differences in penile rigidity were obtained between placebo and vardenafil using visual sexual stimulation (42). Of interest, however, there was little difference between 20 and 40 mg and no distinct dose escalation curve. In a fixed-dose, parallel-group, double-blind study providing pivotal data on 5, 10, and 20 mg of vardenafil, Hellstrom et al. studied a group of men with various etiologies of ED at a multicenter study (43). Severe ED patients with spinal cord injury, diabetes, and radical prostatectomy were included in this study. Eight hundred five men were randomized for a 26-week treatment. All three doses of vardenafil demonstrated statistically significant superiority to placebo, using all efficacy variables including the IIEF erectile function domain score and the SEP questions 2 and 3. Adverse events were similar to those reported for sildenafil and included headache, flushing, but a significantly reduced incidence of blue-tinted vision. In subpopulation studies investigating patients with severe ED, vardenafil was likewise of high efficacy and tolerable adverse event profile. Patients with diabetes and post-nerve-sparing radical prostatectomy responded with a statistically significantly improved erectile function over both baseline and placebo.
In timed onset studies, stopwatch and patient diary studies including the questionnaire endpoints were used to evaluate onset of action (44). At 25 minutes, 48% of men on vardenafil responded compared with only 30% of those taking placebo (p < .0001). At 16 minutes, 34% of patients responded to vardenafil compared with 24% placebo. The safety and tolerability of vardenafil appears to be similar to that of sildenafil. Adverse events include headache, flushing, rhinitis, and dyspepsia, all adverse events typical of PDE5 agents. These adverse events are usually mild to moderate in intensity and diminish with use of medication. Although adverse events occurred, only 3.2% of patients discontinued medication as a result of adverse events. Abnormal vision was reported in only 0.7% of patients in pivotal studies.
Cardiac safety was likewise investigated in multiple studies (45,46). In a fashion similar to those studies reported with sildenafil, vardenafil did not alter cardiac status and increased the exercise time in stress test studies compared with placebo (46). Indeed, there are no data from multiple pivotal studies that indicate an increase in cardiac events or danger of patients taking vardenafil compared with age-adjusted populations or those patients treated with placebo (45).
Vardenafil is a potent selective PDE5 inhibitor that has been demonstrated to improve erectile function in men of broad and varied etiologies including diabetics and post-prostatectomy patients (47). Vardenafil is well tolerated, with a safety profile no different from the other PDE5s in its class. A recent trial demonstrated that, in a group of sildenafil nonresponders, vardenafil was effective in more than 60% of men (48). Adverse events, mostly mild, occurred in some patients and were similar to those seen with sildenafil. Cardiovascular adverse events are similar to those of placebo, and there were no significant changes in vital signs in patients on a variety of medications including antihypertensive agents. In the FDA approval in the United States, however, vardenafil is contraindicated in patients taking any alpha-blocker medication for any indication.
Tadalafil is another new and novel PDE5 inhibitor with unique profile. In five randomized, double-blind, placebo-controlled, parallel design studies involving 1,112 men with ED of various etiologies and severities including patients with hypertension, coronary artery disease, diabetes, and depression, patients were randomized to placebo, 5 mg, 10 mg, or 20 mg of tadalafil (49). Tadalafil was demonstrated in these studies to significantly improve erectile response compared with placebo. The rate of successful intercourse attempts was 61% with 10 mg, 75% with 20 mg, compared with 32% of those patients receiving placebo (50). In difficult-to-treat patients, tadalafil was likewise effective. A study of 216 diabetic men with ED was reported by Sanezdetejada et al. and demonstrated improved erectile function using 10 and 20 mg of tadalafil compared with placebo (51). Positive responses to SEP 2 question (ability to attain an erection) was 22.2% and 22.6% with 10 and 20 mg, respectively, compared with a decline of 4.1% for those patients with placebo. The Global Efficacy Question was responded to positively by 25% of men taking placebo compared with 64% of men taking 20 mg of tadalafil. Onset is likewise within 30 minutes in more than 30% of men (52). The safety and tolerability of tadalafil is similar to that of the other PDE5 inhibitors. The major difference is the inhibition of PDE11 with tadalafil, which is minimal with the other PDE5 inhibitors. The impact of this PDE11 inhibition is as yet unknown, and studies of hormone profile and spermatogenic function have demonstrated no impact of tadalafil compared with placebo. Adverse events including headache, rhinitis, and dyspepsia are also seen in patients with tadalafil, but patients with tadalafil also complain of increased back pain at levels of approximately 6% to 9% (49). This back pain is usually self-limiting, mild, and results in rare discontinuation (49,50).
The principal difference between tadalafil and other PDE5 inhibitors is its pharmacologic profile. Tadalafil, like other PDE5s, is metabolized by the cytochrome P4503A4 pathway in the liver, but has a Tmax of 2 hours compared with 1 hour for both sildenafil and vardenafil. Onset of action is from 16 to 60 minutes as a result of a 2-hour Tmax (52). There is minimal to no effect of fatty foods with tadalafil. The serum half-life (T1/2) for tadalafil, however, is distinctly different from the other agents in its class. In healthy young men, the T1/2 for tadalafil is 17
hours compared with 4 to 5 hours for sildenafil and vardenafil, respectively (53). The difference in half-life results in ability to obtain and maintain an erection as a result of medication effect for as long as 36 hours after administration (53).
Clinical trials for tadalafil demonstrate excellent improved sexual activity with opportunities for sexual activity for as long as 36 hours after administration (53). Efficacy is similar to both vardenafil and sildenafil, and side effects are class related except for back pain. Interaction with food and alcohol is minimal, and discontinuation from adverse events is rare. Safety is similar to that of other PDE5 agents, with no significant cardiac or reproductive side effects (34,46,54). As a result of additive effects with alpha-blocking medications, additive effects with causing hypotension with alpha-blocking antihypertensives, only tamsulosin may be used as an alpha-blocker in conjunction with tadalafil (55).
CONCLUSIONS
With the advent of sildenafil and the addition of newer, well-tolerated effective PDE5 agents, oral pharmacotherapy is first-line treatment for patients with ED. Although no patients taking nitrate medications and some patients with alpha-blockers cannot take selected PDE5 inhibitors, these agents are effective and well tolerated in the treatment of most patients with ED. Sildenafil citrate is clearly effective and has more than a 4-year clinical and trial experience internationally. Its effectiveness, safety, and tolerability have been confirmed in thousand of patients taking thousands of pills over the past 5 years. Newer PDE5 inhibitors including vardenafil and tadalafil are effective and safe and have slightly different profiles (Table 2). These additions to the oral pharmacotherapy market provide options for those patients who cannot tolerate or fail to respond to sildenafil or for patients who prefer a pharmacokinetic profile of longer duration. No currently available head-to-head studies have been performed to evaluate the place of individual drug and the preference by patients of the various pharmacokinetic profiles. Clearly, the market will define many of these differences and preferences for our patients.
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Received for publication February 20, 2004.
REFERENCES
This article has been cited by other articles:
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  A. Grinshpoon, A. Margolis, A. Weizman, and A. M. Ponizovsky Sildenafil citrate in the treatment of sexual dysfunction and its effect on quality of life in alcohol dependent men: preliminary findings Alcohol Alcohol., July 1, 2007; 42(4): 340 - 346. [Abstract] [Full Text] [PDF]
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|
|
|
 |
|
 D. H. W. Lau, C. S. Thompson, J. F. Bellringer, P. J. Thomas, F. H. Mumtaz, R. J. Morgan, and D. P. Mikhailidis Doxazosin and Serotonin (5-HT) Receptor (1A, 2A, and 4) Antagonists Inhibit 5-HT-Mediated Human Cavernosal Contraction J Androl, September 1, 2006; 27(5): 679 - 685. [Abstract] [Full Text] [PDF]
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