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From the Department of Urology, University Hospital of Cleveland, Case Western Reserve University, Cleveland VA Medical Center, Cleveland, Ohio.
| Correspondence to: Allen D. Seftel, MD, mail stop LKS-5046, University Hospital of Cleveland, Department of Urology, 11100 Euclid Avenue, Cleveland, OH 44106 (e-mail: adseftel{at}aol.com). |
| Received for publication January 10, 2002; accepted for publication April 1, 2002. |
Physiology of Penile Erection
ED treatments have evolved as a result of a better understanding of the
physiology and pharmacology of erectile mechanisms. Penile erection occurs as
a function of trabecular smooth muscle relaxation and a subsequent increase in
blood flow to lacunar spaces, which results in engorgement of the penis and
restriction of venous drainage. Relaxation of the smooth muscle in the corpus
cavernosum relies on the coordination of several central and peripheral
nervous system signaling pathways. A change from primarily sympathetic to
parasympathetic activity in the penis causes nitric oxide, the principal
mediator of penile erections, to be released from endothelial cells lining the
blood vessels and sinusoids of the corpus cavernosum and from nonadrenergic,
noncholinergic nitric oxide-producing neurons
(Sáenz de Tejeda et al,
1988; Rajfer et al,
1992; Sáenz de Tejeda,
2000; Traish et al,
2000). Nitric oxide then diffuses across smooth muscle cell
membranes and activates soluble guanylate cyclase, causing accumulation of
cyclic guanosine monophosphate (cGMP) and resulting in a cascade of events
that leads to the relaxation of smooth muscle and to an erection
(Ignarro et al, 1990;
Sáenz de Tejada,
2000).
Recently, Mills and colleagues (2001) hypothesized that the nitric oxide/protein kinase G pathway controls erection by not only lowering Ca2+ but also by inhibiting the Rho-kinase pathway. Detumescence is initiated by sympathetic stimulation, which is followed by ejaculation, contraction of cavernosal smooth muscle, and a return to penile flaccidity (Diederichs et al, 1990; Sáenz de Tejada, 2000; Sáenz de Tejada et al, 2000; Traish et al, 2000). Maintenance of the flaccid state appears to be due mainly to the action of vasoconstrictive agents such as norepinephrine and endothelins (Traish et al, 1995; Dai et al, 2000). Endothelin effects in the vascular tissue are mediated by 2 receptors, endothelin-A and endothelin-B. Binding of endothelin-1 to endothelin-A promotes contraction of vascular muscle, whereas binding of endothelin to endothelin-B results in vasodilation (Sáenz de Tejada et al, 1991; Dai et al, 2000; Sáenz de Tejada, 2002).
Pathophysiology of ED
Understanding the pathophysiology of ED has been one of the challenges of
effective treatment. Two hypotheses are currently believed most likely to play
a role in the pathology of ED. The first considers metabolic imbalances
between contractile (norepinephrine, endothelin, and prostanoids) and
relaxatory factors (vasoactive intestinal polypeptide and nitric oxide) in the
corpus cavernosum as the reason for ED
(Lerner et al, 1993; Taub et al, 1993;
Moreland, 2000). The other
focuses on a structural basis of the condition, such as an imbalance between
trabecular smooth muscle and connective tissue
(Moreland, 1998) and a
possible role for corpus cavernosum hypoxemia in tissue fibrosis
(Nehra et al, 1996; Moreland, 1998). The greater
prevalence and severity of ED that occurs with aging may be a consequence of a
shifting in the structural or metabolic balance in some men
(Lerner et al, 1993; Moreland, 1998;
Wespes, 2000). In addition,
any condition, disease, medication, or injury/surgery that will affect the
ability to initiate erections or to fill the lacunar space, to store blood, or
both, may cause ED (Rosen et al,
1998).
The etiology of ED involves multiple organic and psychogenic factors that often coexist. Psychogenic factors are the most common causes of intermittent erectile failure in younger populations, but they are usually secondary to or they may coexist with organic factors in older populations (Rosen et al, 1998; Melman and Gingell, 1999). Other factors contributing to ED include vasculogenic, neurogenic, endocrinologic, structural (traumatic), and pharmacologic causes, as well as lifestyle factors such as obesity, a sedentary lifestyle, and alcohol and tobacco use. Many of the conditions that contribute to ED are chronic and systemic, involving multiple avenues of damage. These conditions include cardiovascular disease, hypertension, diabetes mellitus, and depression (Feldman, 1994; Araujo et al, 1998; Sullivan et al, 1999; McVary et al, 2001). The unifying theme in many of the diseases linked to ED is a damaged or malfunctioning endothelium, referred to as endothelial dysfunction (Cooke, 1997; Laight et al, 1999). For instance, altered activity of endothelin, the peptide released by the endothelium, has been linked to risk factors for ED that include atherosclerotic disease and diabetes (McAuley et al, 2000; Ihling et al, 2001; Kinlay et al, 2001). Isoforms of nitric oxide synthase, which plays a major role in penile smooth muscle relaxation by regulating nitric oxide levels, have also been localized to the endothelium (Stanarius et al, 2001). Any damage to this tissue will therefore affect erectile function.
Role of Phosphodiesterases and Phosphodiesterase Inhibitors in Penile
Erection
Phosphodiesterases (PDEs) are a superfamily of hydrolytic enzymes that play
a critical role in regulating physiological processes by terminating signal
transduction through their hydrolytic action on cyclic nucleotides. Since the
discovery of the first PDE in the 1950s
(Sutherland and Rall, 1958),
11 PDE subfamilies with different cyclic adenosine monophosphate (cAMP) or
cGMP specificities and tissue localizations have been identified in mammalian
tissues (for a review, see Francis et al,
2000). The interest in PDEs as targets for pharmacological
treatment has evolved with the development of selective PDE inhibitors.
Selectivity and tissue localization for the different PDEs determine the
side-effect profiles and safety of the PDE inhibitors. Among the clinically
useful PDE inhibitors is sildenafil (Pfizer, New York, NY), a PDE5 inhibitor
that was introduced in 1998 for the treatment of ED. Two other PDE5
inhibitors, vardenafil (Bayer, West Haven, Conn) and tadalafil (Lilly ICOS,
Indianapolis, Ind), are being reviewed for marketing approval for the
treatment of ED and will be discussed later. PDE5 is the main cGMP-catalyzing
enzyme in human trabecular smooth muscle. To date, 3 isoforms of PDE5 (PDE5
A1, A2, and A3) have been cloned from human penile tissue
(Lin et al, 2000). PDE5 is
also expressed in vascular smooth muscle, lung, and platelets, as well as in a
wide variety of other tissues (Ito et al,
1996; Lin et al,
2000), but it is not present in cardiac muscle cells
(Ito et al, 1996). Human
corpus cavernosum also contains PDE types 2, 3, and 4 enzymes
(Boolell et al, 1996;
Taher et al, 1997). PDE5
inhibitors are contingent on the presence of cGMP in the smooth muscle cell.
In the presence of sexual stimulation, the PDE inhibitors will reinforce the
normal cellular signals that increase cyclic nucleotide concentrations by
blocking cyclic nucleotide hydrolysis, thereby facilitating the initiation and
maintenance of an erection.
Oral Therapy for ED
Over the past 20 years, treatment options for ED have become more effective
and, despite the effectiveness of intracavernous injections, vacuum devices,
surgery, and other treatments, there has been a trend toward the development
of less invasive modalities. The introduction of sildenafil, a PDE5 inhibitor,
heralded the beginning of oral treatment for ED. Sublingual apomorphine
(Uprima), which was recently approved for marketing in Europe, introduced
central control as a mechanism for reducing symptoms of ED.
PDE5 Inhibitors: Sildenafil— The first selective PDE5 inhibitor, sildenafil, enhances the proerectile effect of nitric oxide by decreasing the rate of catabolism of cGMP, thereby reinforcing the physiological signal that facilitates smooth muscle relaxation and erection (Ballard et al, 1998; Pfizer, 2000). Sildenafil is more selective for PDE5 inhibition than many other PDE isozymes, but it is only about 10 times more selective for PDE5 than it is for PDE6. This collateral inhibition of PDE6, an enzyme found in the retina, is believed to be the basis for abnormal changes in color vision that are observed with higher doses or plasma levels of sildenafil (Morales et al, 1998; Gonzalez et al, 1999; Pfizer, 2000). Sildenafil is rapidly absorbed, reaching maximum plasma concentrations within 30 to 120 minutes (median, 60 minutes) of oral dosing in the fasted state (Pfizer, 2000); however, a high-fat meal has been found to reduce the rate and extent of absorption (Pfizer, 2000). The elimination half-life of sildenafil and its major active metabolite is approximately 4 hours, and no more than one dose should be taken in a 24-hour period (Pfizer, 2000).
Sildenafil has been reported to significantly improve the symptoms of ED with varying etiologies and levels of severity (Dinsmore et al, 1999), and the postmarketing data are consistent with the results of clinical trials (for a review, see Sadovsky et al, 2001). The specific etiology of ED may have an effect on sildenafil's efficacy and safety. In ED following radical retropubic prostatectomy, the efficacy of sildenafil is significantly reduced overall, with only 31% of patients reporting satisfaction with treatment (Blander et al, 2000). Patients who undergo non—nerve-sparing procedures respond poorly to sildenafil compared with those who have undergone a nerve-sparing procedure (Feng et al, 2000). Among patients with ED secondary to radiotherapy, good results with sildenafil have been reported, with approximately 70% of patients reporting a significant improvement in their erections (Zelefsky et al, 1999). However, no data on the subsequent rate of satisfactory intercourse have been provided. Sildenafil is reported effective and well tolerated in patients with diabetes (Rendell et al, 1999; Sadovsky et al, 2001) and in those with cardiovascular disease, including those taking beta-blockers, angiotensin-converting enzyme inhibitors, calcium-channel blockers, or a combination of these (Olsson and Persson, 2001). Evidence also exists that sildenafil is effective in men with parkinsonism (Zesiewicz et al, 1999) and spina bifida (Palmer et al, 2000).
Sildenafil is generally well tolerated, with most adverse events being transient, and mild to moderate in severity (Goldstein et al, 1998; Morales et al, 1998; Padma-Nathan et al, 1998). The majority of sildenafil-associated adverse events are vasodilatory in nature (eg, headache, flushing, nasal congestion), with gastrointestinal (dyspepsia) and visual (abnormal color vision) adverse events reported less frequently (Morales et al, 1998), although they have been greater in fixed-dose studies (Pfizer, 2000). Sildenafil can potentiate the vasodilatory properties of nitrates; therefore, its administration is contraindicated in patients who use nitric oxide donors or nitrates in any form (Pfizer, 2000).
Dopamine Agonists: Sublingual Apomorphine (Uprima)— Apomorphine (TAP Pharmaceuticals, Abbott Park, Ill), enhances central proerectile mechanisms by binding to dopamine receptors in the paraventricular nucleus of the hypothalamus. In clinical trials, apomorphine was found to be effective in patients with ED of various etiologies and levels of severity, albeit with substantially less efficacy than any of the PDE5 inhibitors (Padma-Nathan et al, 1998, 2001; Heaton, 2000, 2001; Porst et al, 2001). In a trial in which men received apomorphine at doses of 2 or 4 mg, approximately 51% of patients using apomorphine 4 mg reported erections sufficient to have intercourse, compared with 26% of those receiving placebo. The adverse events reported most frequently during clinical trials with sublingual apomorphine were nausea, headache, and dizziness (Heaton, 2000; Mulhall et al, 2001). The sublingual formulation of this drug permits rapid absorption and a rapid onset of action, with an average median time of 16 to 23 minutes after dosing to attain an erection with sexual stimulation (Heaton, 2000; Mulhall et al, 2001). Overall, sublingual apomorphine meets the criteria to be a first-line treatment for ED.
Alpha-Adrenoreceptor Antagonists: Yohimbine and
Phentolamine—
Because the stimulation of adrenoreceptors is considered the main mechanism
of cavernosal smooth muscle contraction, antagonizing antierectile mechanism
with alpha-adrenergic receptor antagonists is a potential treatment for ED.
Yohimbine, a naturally occurring alkaloid agent derived from the bark of an
African tree, has been used as an aphrodisiac and erectogenic drug for many
years. However, the use of yohimbine for the treatment of ED remains
controversial, because the drug has not been assessed in rigorous clinical
trials (Morales, 2000).
Phentolamine is an 
1- and 2-adrenergic receptor antagonist.
Clinical trials have demonstrated that oral phentolamine (Vasomax, The
Woodlands, Tex) may have a beneficial effect on erectile function
(Goldstein et al, 2001).
However, clinical trials with phentolamine mesylate-based drugs have been
reportedly suspended by the US Food and Drug Administration until some safety
issues are resolved. It should be noted that this ban has been lifted by the
United Kingdom, and patients there may be recruited again into clinical
trials.
Oral Therapies In Development
Tadalafil—
Tadalafil is a potent and selective PDE5 inhibitor being reviewed for the
treatment of ED. Tadalafil is rapidly absorbed, with a mean time to maximum
drug concentration (tmax) of 2 hours and a half-life of 17.5 hours
(Porst, 2002). The rate and
extent of absorption of tadalafil are not affected by food. In a trial in
which men with mild to severe ED took tadalafil as needed at doses ranging
from 2 to 25 mg, tadalafil significantly improved erections in up to 81% of
men, compared with 17% of those taking placebo. Men with psychogenic, organic,
and mixed ED were included in this trial, and the distribution of ED severity
among patients was comparable to that of the general population
(Padma-Nathan et al, 2001). Tadalafil was well tolerated in this study. The most commonly reported adverse
events were headache and dyspepsia. Most adverse events were mild to moderate
in intensity and attenuated with further treatment. Of interest, no
abnormalities of color vision were reported, which is consistent with a much
higher selectivity of tadalafil for PDE5 than for the retinal enzyme PDE6
(Padma-Nathan et al, 2001). It
is important that during this at-home study, tadalafil could be taken without
restriction on food intake at any time prior to sexual activity
(Padma-Nathan et al,
2001).
Studies specifically designed to assess the period of responsiveness of
tadalafil demonstrated that, for the majority of patients, tadalafil had an
onset of action within 30 minutes and allowed successful intercourse for at
least 24 hours after dosing (Padma-Nathan,
2001). The unique pharmacokinetic properties of tadalafil, as well
as the lack of food and alcohol interaction, are potentially valuable features
in an ED therapy, because it may improve ease of use and eliminate planning in
a couple's sexual
activity.
,
|
|
Vardenafil— Vardenafil is another PDE5 inhibitor that has shown superior PDE5 selectivity and potency compared with that of sildenafil (Porst et al, 2001). Vardenafil is rapidly absorbed, with a tmax of 0.7 hours and a half-life similar to that of sildenafil; approximately 4 hours (Pfizer, 2000; Klotz et al, 2001). Vardenafil's efficacy and safety have been evaluated in an at-home trial in which men with mild to severe ED took the study drug about 1 hour prior to intended intercourse. Eighty percent of patients taking vardenafil 20 mg reported an improvement in their erection at the end of treatment, versus 30% of those who received placebo. The most common adverse events associated with vardenafil included headache, flushing, dyspepsia, and rhinitis (Porst et al, 2001).
New Drug Targets for the Treatment of ED: RhoA/Rho Kinase and
Endothelins
Although the precise role of Rho-kinase in the maintenance of penile
erection remains to be elucidated, Rho-kinase antagonists such as Y-27632 have
been shown to stimulate erection in rats and to inhibit the contraction of
corpus cavernosum in humans and rabbits (Chitaley et al,
2001a,b;
Rees et al, 2001).
Endothelin-1 is a potent endothelial-derived vasoconstrictor, with a possible
role in penile flaccidity and ED pathophysiology
(Sullivan et al, 1997; Dai et al, 2000). Endothelin-1
and Rho-kinase antagonists may therefore prove beneficial in ED treatment.
Challenges in Oral Therapy for ED
The rate of dissatisfaction and discontinuation of ED therapy prior to the
availability of sildenafil was usually high
(NIH Consensus Conference,
1993). Even with the availability of sildenafil, which is a highly
effective and easily administered oral agent, a similar pattern of lack of
satisfaction and of treatment adherence has been observed, with
discontinuation rates ranging from 14% to almost 50% (Table). Also, some
patients decline to fill a prescription for sildenafil out of fear of adverse
effects (Hatzichristou et al,
2000; El-Galley et al,
2001). Whereas some new data show that the persistency with
sildenafil treatment has increased for patients starting treatment in the year
2000, compared with those who started in 1998, relatively few patients remain
on sildenafil treatment after 1 year or more (Figure;
NDC Health, 2001).
The highly publicized release of sildenafil in 1998 may have unrealistically raised patients' expectations. Shortly after sildenafil became available, treatment responses and overall satisfaction rates were measured in a short-term study involving 308 patients. Almost half the patients (49%) indicated that sildenafil did not meet their expectations, even though 65% of patients reported being satisfied with the level of sexual function it allowed them to achieve (Jarow et al, 1999). However, this percentage fell to 41% for men who were more severely affected. This result was consistent with those of other sildenafil studies, which indicated a lower level of efficacy in men with severe ED at baseline (Rendell et al, 1999; Hatzichristou et al, 2000). Similarly, sildenafil efficacy and satisfaction with sildenafil treatment were considered inadequate by 39% of patients in another cohort who took the drug for 2 months in 1998 (Virag, 1999). Sildenafil was subsequently chosen as the sole treatment for ED by 32% of those patients (Virag, 1999).
Another factor that may influence the success of oral therapy is prior response to other medical therapies for ED. For instance, McMahon and colleagues (2000) assessed the response to sildenafil in 304 men, the majority of whom had previously been treated for ED, mostly by intracavernous injections. The overall response rate for men taking sildenafil was 68%, and adverse events were reported by 54% of patients. After a mean of 1.3 months, 9% of sildenafil responders discontinued treatment because of intolerable adverse events. Among sildenafil responders, 48.5% discontinued the previous therapy and elected to use sildenafil instead, 32% decided to alternate between sildenafil and the previous treatment, and 19.5% simply discontinued sildenafil. Twenty percent of patients who discontinued sildenafil and returned to intracavernous injections cited a delayed response to the former as their main reason for doing so (McMahon et al, 2000). Sildenafil acts within 1 hour of intake, whereas intracavernous injections provide a response within minutes (Fallon, 1995; Pfizer, 2000). Other reasons given for resuming injection therapy included superior rigidity, sustained erection after ejaculation, adverse events associated with sildenafil, and the cost of sildenafil (McMahon et al, 2000).
However, the most common underlying cause of dissatisfaction and discontinuation cited by sildenafil users was a perceived lack or loss of efficacy. Fagelman and coworkers monitored 164 patients at 3-4 months and 6-12 months after sildenafil was prescribed (Fagelmen et al, 2001). At the first follow-up visit, 38% of patients had not renewed their prescription for sildenafil. Among these patients, 83% cited a lack of sildenafil efficacy and 8% cited drug-associated adverse events as the reasons for discontinuing the drug. Other causes of treatment discontinuation included cost and decreased libido. Among the patients who renewed their prescription for sildenafil (62%) after the first follow-up visit and were available at the second follow-up visit (n = 82), 22% had not renewed the prescription by the second visit, with 78% citing a lack of efficacy as the reason for discontinuing the drug. In another study, Madduri (2001) interviewed 55 patients 18-21 months after they started taking sildenafil. Forty-seven percent of these patients discontinued sildenafil mainly because of dissatisfaction with the drug's performance (46%). Other reasons given included cost (27%), media scare (19%), and adverse events (8%).
Inadequate dosing and failure by the physician to give thorough instructions (or of the patient to follow them) may be responsible for the lack of efficacy experienced by some men who would otherwise respond to sildenafil treatment (Madduri, 2001). For instance, some patients who are regarded as sildenafil failures may have attempted intercourse too early after dosing or after a meal, whereas others may not have received sufficient sexual stimulation prior to attempting intercourse (El-Galley et al, 2001). It is likely that some of these patients could respond to sildenafil after receiving appropriate dose titration and instruction (Goldstein et al, 1998; Hatzichristou, personal communication).
Worsening of an existing medical condition or the development of a new illness may also interfere with the successful treatment of ED. Shabsigh and associates (1998) showed that patients with ED and depression have less libido and are much more likely to discontinue treatment than are patients with ED and no depression. In addition, low sexual interest due to an undiagnosed or newly occurring androgen deficiency could result in poor treatment outcome, as most therapies have no effect on libido.
Properly assessing the patient and his partner; referring the patient, his partner, or both to a psychologist if necessary; educating the couple with regard to expectations, sexual stimulation, and dosing instructions will undoubtedly increase the chances for successful therapy. In addition, patient follow-up is essential to assess whether the treatment is working, address any changes that may have occurred in the patient's physical condition or personal life, and adjust therapy accordingly (Hatzichristou, 2002). A well-informed patient with realistic expectations, a treatment tailored to suit his needs and preferences, and the proper support from his partner and physician will have the best chance for success.
Conclusions
Oral drugs have become the first-line therapeutic option for many men with
ED. Sildenafil in particular has had a profound effect on ED awareness among
medical professionals and the general public and has changed the way men with
ED are treated. Sublingual apomorphine, although it is not as effective or
widely used as sildenafil, has proven to be an adequate alternative. However,
despite the high level of efficacy and ease of use provided by oral therapy
today, there remains a significant proportion of patients who find that
currently available drugs do not meet their expectations; as a result, the
rate of non-adherence to treatment is high. Although caution must be exercised
in interpreting the results, as they can be influenced by the methods used for
evaluation, available information does suggest that a significant reason for
patient dissatisfaction with or discontinuance of sildenafil is lack of
efficacy or loss of efficacy over time. Many factors may be responsible for
inadequate efficacy, including inappropriate dosage, lack of proper
instruction regarding sexual stimulation or food or alcohol intake, increase
in ED severity over time, and loss of libido, as well as partner-related
issues. Unrealistic expectations may also have a negative influence on the
response to treatment. Only a small proportion of patients discontinue
sildenafil because of intolerable adverse events.
The successful treatment of men with ED is a complex process and involves more than just the physiological response to treatment (Hansen-Divers et al, 1998). For example, some men opted for therapy with drugs other than sildenafil because of sildenafil's delayed response. "Real-life" effectiveness of a treatment for ED includes spontaneity, restoration of a sex life that does not require a lot of scheduling, erections that feel more natural and less mechanical, and partner satisfaction.
New oral agents, such as the future generation of PDE5 inhibitors, may help obviate some of the current barriers to ED treatment. Tadalafil and vardenafil are the two newest drugs of this kind. These agents have demonstrated a high level of efficacy and good safety in clinical trials when taken by men with ED of various etiologies and levels of severity (Padma-Nathan et al, 2001; Porst et al, 2001). Tadalafil and vardenafil are currently in marketing review by the Food and Drug Administration for the treatment of men with ED. This further refinement of PDE5 inhibitors is likely to offer not just selectivity and safety advantages, but substantial pharmacodynamic advantages as well. For instance, an extended period of responsiveness may permit an increase in the spontaneity of sexual experiences in couples with ED. In addition, the absence of food-drug interactions may allow more patients to respond successfully.
Because the ultimate goal of therapy is to prevent or modify the disease and to provide a cure, and because no available treatment today meets these criteria, new research in this direction is needed. Although the perfect therapy for ED does not exist, with the numerous treatments available today and in development, the future is promising. The challenge will be to identify and understand issues that are important to both the patient and his partner in order to provide them with an option that will safely treat the symptoms of ED, but also restore their normal sexual relationship. Because the patient population is heterologous in goals, preferences, age, and ED etiologies, a large choice of drugs and a tailored treatment will result in better treatment outcome.
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