ABSTRACT: The number of medical therapies for patients with erectile dysfunction (ED) has increased in recent years because of our expanded understanding of the physiologic and neurologic causes of ED. Oral agents range from testosterone to antidepressants to phosphodiesterase inhibitors. Nitroglycerin and minoxidil have shown some effectiveness as topical agents. Alprostadil, which can be applied intraurethrally, is also effective as intracavernosal injection therapy. Prostaglandin E1 and papaverine are effective as intracavernosal injection agents. Some studies have shown that combined use of intracavernosal injection and oral therapy produces satisfactory erections.
Key words: erectile dysfunction, intracavernosal injection, phosphodiesterase-5 inhibitors, prostaglandin E1
Erectile dysfunction (ED) affects men across all age groups and probably is underreported for many reasons, not the least of which is embarrassment. Physicians might not investigate a case of ED for similar reasons.
The Massachusetts Male Aging Study (MMAS) was the first cross-sectional, community-based, random-sample, multidisciplinary, epidemiologic survey of ED and its physiologic and psychosocial correlates in men in the United States.1 From the prevalence rates reported in the MMAS, between the ages of 40 and 70 years, the probability of complete ED increased from 5.1% to 15%, moderate dysfunction increased from 17% to 34%, and mild dysfunction remained constant at about 17%.2
Autonomic and somatic nerves innervate the penis. Sympathetic and parasympathetic fibers in the cavernous nerves regulate blood flow into the corpus cavernosum during erection and detumescence. Impulses from parasympathetic nerves and nonadrenergic, noncholinergic nerves initiate erection. This neural stimulus leads to release of nitric oxide from the nonadrenergic, noncholinergic nerves and, possibly, the endothelial cells. Nitric oxide enters the smooth muscle cells, stimulating guanylate cyclase to convert cyclic guanosine triphosphate (cGTP) to cyclic guanosine monophosphate (cGMP), which, in turn, activates protein kinase G and stimulates phosphorylation of proteins that regulate corporal and vascular smooth muscle tone.
These series of events, which lead to cavernosal smooth muscle relaxation, permit rapid blood flow into the penis and the development of an erection. As pressure within the corporal body increases, small emissary veins traversing the tunica albuginea are occluded, trapping blood in the corpus cavernosum. The erection is maintained until ejaculation, which usually leads to detumescence.
Multiple factors contribute to the occurrence of ED. The International Society of Impotence Research3 and the American Urological Association (AUA) Guidelines for Treatment of Erectile Dysfunction4 have recommended classifications for ED into vasculogenic (arterial, cavernosal, or mixed), psychogenic (situational or generalized), endocrinologic, drug-induced, and neurogenic. Certain conditions, such as cardiovascular disease, diabetes, hypertension, and tobacco abuse, are related to the occurrence of ED. These risk factors for ED are also known to coexist.
The specific issues of causes and classifications of ED will not be discussed in this article. A review article by Melman and Gingell5 may serve as reference for the reader.
Improvements in our understanding of the physiology and neurology of erectile function have led to the current array of pharmacologic therapies for ED, which we review here. We also discuss treatments that are being studied.
Currently available oral agents for ED are listed in the Table.
Testosterone as a therapeutic agent for ED is important in the treatment of the hypogonadal patient. Suspect low testosterone levels in patients with low libido; depression; decreased intellectual abilities, lean body mass, low bone mineral density, and skin turgor; changes in body hair distribution; changes in sleep patterns; and increased visceral fat. As an oral agent, it is available as testosterone undecenoate. When taken orally, testosterone is metabolized during "first-pass" circulation through the liver. Because of liver metabolism, ingestion requires dosages that exceed 200 mg/d to maintain normal serum levels. Large doses of testosterone are toxic to the liver and may cause hepatitis, cholestatic jaundice, hepatomas, hemorrhagic liver cysts, and hepatocarcinoma.
Testosterone has also been used in its parenteral form, which obviates liver metabolism but produces supraphysiologic levels during the first 72 hours after injection, with gradual decrease over the next 2 to 3 weeks. Subcutaneous implants with extended-release testosterone have been shown to provide sustained levels for 3 to 6 months.6 These implants are not commonly used. A mucoadhesive buccal system has been used for treatment of hypogonadal men; testosterone has been successfully replaced to physiologic levels with minimal adverse events.7 Testosterone can also be delivered transdermally (see Topical Agents).8,9
Yohimbine is an alkaloid derived from the bark of the central African yohimbine tree, as well as the South American quebracho-blanco tree. It is an a2-adrenergic antagonist that promotes sexual function by blocking presynaptic receptors and increasing adrenergic receptor activity. It also alters serotonin and dopamine transmission. Yohimbine is effective in castrated rats but has only moderate effects in men.10 In a study by Morales and colleagues,11 men receiving 6 mg of yohimbine 3 times per day for 10 weeks did not have a significant response compared with the placebo group. In patients with behavioral or psychogenic ED, however, response rates have been reported to be as high as 62%.12 Side effects of this drug include GI disturbances, headache, palpitations, agitation, anxiety, and elevated blood pressure.
Trazodone is an antidepressant that has been reported to have a positive effect on erectile function, although this is controversial.13,14 It has a-adrenergic blocking ability and central inhibition of serotonin uptake. It seems to be most effective for patients with sexually stimulated erections and nocturnal tumescence.13 Trazodone is a sedative agent that can cause drowsiness, nausea, emesis, changes in blood pressure, and priapism. It is currently not recommended for use in patients with ED by the ED Guideline Update Panel of the AUA, based on their review of the literature and panel consensus.4
Sildenafil is a selective phosphodiesterase-5 (PDE5) inhibitor and was the first drug of this class to be approved by the FDA. Phosphodiesterase breaks down cGMP, the intracellular second messenger of erection. Sildenafil enhances the effects of nitric oxide by inhibiting the catabolism of cGMP by PDE5.
More than 20 trials (including randomized, placebo-controlled, double-blind studies) have been conducted to determine the clinical efficacy of sildenafil in patients ranging in age from 19 to 87 years, with a mean age of 55. Overall responses to sildenafil were dose-related, with no added benefit and more side effects from doses higher than 100 mg. This drug improves erections for intercourse in patients with diabetes (56%), hypertension (70%), spinal cord injury (80%), and radical prostatectomy (42.5%).15-17 As reported by Zippe and associates,18 70% of men after bilateral nerve-sparing prostatectomy had improvement with sildenafil. This drug can be effective as early as 30 minutes but more commonly after 1 hour of oral intake. Alcohol consumption and high-fat meals affect absorption. Drugs that alter the cytochrome P-450 system, such as cimetidine, ketoconazole, and erythromycin, increase plasma levels of sildenafil.
Side effects of sildenafil include headache, flushing, dyspepsia, nasal congestion, altered vision, diarrhea, dizziness, and arthralgia. Use of sildenafil is absolutely contraindicated in patients who are receiving nitrate therapy for heart disease.
Recent reports have established the occurrence of nonarteritic ischemic optic neuropathy in patients taking sildenafil. However, the risk is not significantly higher than that in the general population, and it appears that most patients had significant arteriosclerotic risk factors or disease.19 Screen and counsel patients accordingly.
Vardenafil, also a PDE5 inhibitor, has a mechanism of action similar to that of sildenafil. Prolongation of the QT interval has been reported.17,20,21
Tadalafil is the third FDA-approved PDE5 inhibitor. It has the longest duration of action--up to 36 hours.17,22 It provides the potential benefit of better sexual spontaneity. On the other hand, prolonged exposure to active drug may be associated with prolonged or delayed adverse events. This drug has been associated with muscle pain in about 10% of patients.
There are no comparative studies of PDE5 inhibitors to date. All 3 drugs have equivalent efficacy in the management of general ED, ED associated with diabetes, and postprostatectomy ED. Sildenafil has added efficacy in ED associated with spinal cord injury and antidepressant medications. Some patients who have failed to respond to intracavernosal injections may be "salvaged" by PDE5 inhibitors with good response.23
Apomorphine is a sublingual agent that has been tested in doses of 2, 4, and 6 mg. It is unrelated to morphine and is not an opiate. Apomorphine, a dopaminergic agonist, has proerectile properties; its action stimulates the paraventricular nucleus, which is considered the sexual drive center in mammals. In rats, apomorphine has shown a positive effect on sexual arousal, producing yawning and erection. In humans, sexual stimulation is necessary.
Time to onset of action after sublingual dosing is 12 minutes. Eating does not affect plasma levels. On self-assessment questionnaires, response rates from 32% to 59% have been reported. Side effects include nausea, dizziness, sweating, somnolence, yawning, and emesis. No interaction with nitrates has been reported. This drug has been marketed in Europe.
Phentolamine, an a1-adrenergic antagonist, is used mostly as part of intracavernosal therapy, although it has been used as an oral agent. Norepinephrine is the principal neurotransmitter of detumescence. Phentolamine blocks postjunctional adrenergic receptors. In its oral form, it has shown mild efficacy over placebo. In self-assessment using the International Index of Erectile Function, improvement in erections was noted by 37% (40-mg dose) and 45% (80-mg dose).24 Adverse effects include headache, facial flushing, and nasal congestion. This drug has been withheld from commercial release because of growth of brown fatty tumors in rats.
Nitroglycerin, a smooth muscle relaxant, tested as a transdermal paste or cream by Heaton and Morales,25 demonstrated a better response than did placebo. Minoxidil was also studied as a topical agent and was compared with placebo and nitroglycerin.26 A 1994 study showed increased effectiveness of minoxidil over nitroglycerin and placebo by demonstrating increased penile blood flow, diameter, and rigidity. The application sites were the penile shaft or glans penis.26 Broderick15 noted that with topical agents, the "primary impediment to drug absorption is the relatively thick, bilayered tunica albuginea." It appears that transglandular absorption would be more effective; however, studies are limited.26
Transdermal testosterone is a commonly used delivery system. It provides steady-state levels of androgen replacement and is safe, simple to apply, and effective in restoring physiologic levels of testosterone.8,9
Prostaglandin E1 (PGE1) has been the primary medication used in intraurethral therapy for ED. Alprostadil, a synthetic PGE1, is intraurethrally delivered as a pellet, which is inserted into the distal urethra by the Medicated Urethral System for Erection (MUSE) applicator. PGE1 stimulates adenyl cyclase to increase levels of cyclic adenosine monophosphate (cAMP), thereby lowering intracellular calcium levels and ultimately causing relaxation of smooth muscle.27 This preparation is rapidly absorbed through the urethra.
According to Padma-Nathan and coworkers,28,29 500 µg of alprostadil applied by MUSE is equivalent to 10 µg of alprostadil applied by cavernosal injection, but the MUSE treatment produces less penile rigidity. In 1997, these investigators reported a 43% successful intercourse rate with MUSE application.28 MUSE has been associated with penile pain, vaginal discomfort in partners (10%), and hypotension and syncope (up to about 6%); therefore, in-office initial administration is strongly recommended.
Intracavernosal injection therapy (ICI) has been reported since the late 1970s. In 1983, Brindley30 demonstrated the effectiveness of ICI with phenoxybenzamine. Subsequently, multiple groups have used multiple drugs--either single agents or combinations--as ICI regimens.
PGE1 and alprostadil cause smooth muscle relaxation and vasodilation through elevation of intracellular cAMP. After injection, most of the medication is metabolized locally, without significant systemic levels achieved. A review by Linet and Neff31 reported that doses of 10 to 20 µg of alprostadil achieved good erections in 70% to 80% of patients. In 1996, multicenter and worldwide reports by the Alprostadil Study Group32 reported an efficacy rate of 86%. Side effects include pain at the injection site or during erection (16%), priapism (1%), prolonged erection of 4 to 6 hours (5%), hematoma (1.5% to 8%), and fibrosis (2%). PGE1 is commercially available as a lyophilized powder or as a liquid. The liquid or reconstituted form requires refrigeration.
Papaverine inhibits phosphodiesterase, leading to increased cAMP and cGMP levels. It also blocks calcium influx channels, thus leading to smooth muscle and penile vasculature relaxation. As a single agent, it is has been reported to produce erections in up to 55% of patients.33 It is inexpensive and does not need refrigeration. With papaverine use, there is an incidence of priapism (up to 35%) and of fibrosis (up to 33%).34 Other side effects include dizziness, cold sweats, and hypotension.
Phentolamine is a competitive a-adrenergic blocking agent that causes increased penile blood flow but does not achieve intracavernosal pressure that is elevated enough to produce erections. It may increase norepinephrine levels by presynaptic blockade of prejunctional a-receptors, thus having an antagonistic effect on erection. It is not effective for ED as a single agent.
Forskolin was mentioned in a 2001 review as another agent under investigation.35 This agent, as described by Mulhall and colleagues,36 was added to a trimixture of papaverine, phentolamine, and PGE1 as a mode of "salvage" for treatment failures. In this study, 60% of patients reported improvement in rigidity and/or duration of erection. Forskolin is not FDA-approved. Similarly, atropine has been added to the trimixture with a reported efficacy rate of 95%.37 This is currently an off-label use as well.
Other agents that have been under investigation for use in therapy for ED include vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptides, linsidomine, and sodium nitroprusside.14 VIP has been studied in Asia and in Europe.38 To date, its use remains experimental. Calcitonin-related peptides were studied in the 1990s,39 but no recent studies have been published. Recent studies on linsidomine and sodium nitroprusside are based on animal models; thus, their efficacy in humans remains uncertain.40,41
Combination injection therapy was first reported in 1985 and involved phentolamine (0.5 mg) plus papaverine (30 mg).42 Efficacy was reported as 72% in 250 patients. Further studies with different dosages have been reported in the literature, with similar or improved efficacy as high as 87%.43 The combination of papaverine and phentolamine has been effective in psychogenic, neurogenic, and vasculogenic ED, although patients in the last group require larger doses. For this combination, rates of priapism are 1% to 23%, and of fibrosis, 1% to 16%.
The addition of PGE1 to the mixture of papaverine and phentolamine had a reported efficacy of 92% in 116 patients.44 This trimixture is attractive because of its lower cost, reduced incidence of pain compared with alprostadil alone, and high efficacy. In general, this mixture is reserved for men in whom PGE1 monotherapy has failed or who have significant penile pain with high doses of PGE1.
COMBINATION ORAL/INJECTION THERAPIES
In a study of 44 patients, Mazo and associates45 compared monotherapy using alprostadil or sildenafil with therapy combining the 2 drugs. They reported that the combination produced a high erection response: 100%, 85.7%, and 55.5% in patients with arterial, neurogenic, and veno-occlusive ED, respectively. A retrospective drug combination study in 34 postprostatectomy patients by Mydlo and coworkers46 reported a 68% efficacy rate and suggested using ICI intermittently based on patient response to sildenafil. These studies have been published in the European urologic literature, but this experience has not been reported in the United States to date.
Nehra and colleagues47 studied a group of 28 patients who had undergone radical prostatectomy to determine the effects of combined therapy with application of alprostadil by MUSE and sildenafil. At 30 months, the study demonstrated an efficacy rate of 100% in producing erections successful for penetration with use of sildenafil, 100 mg, and MUSE/alprostadil, 1000 µg. Also at 30 months, 8 patients decreased the sildenafil dose to 50 mg.
One study in conscious rabbits suggested that combined use of apomorphine and sildenafil improves erection response.48 Although there are crossover, randomized, placebo-controlled, open-label, and double-blind trials that compare apomorphine with sildenafil, and although off-label combination use has been discussed, in our present review of the literature, we did not encounter any combination trials that demonstrate efficacy in humans.49
In patients who are hypogonadal (testosterone level less than 400 ng/dL), combination therapy with testosterone gel 1% and sildenafil has proved effective.50 *
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