Erectile dysfunction (ED) is defined by the National Institutes of Health Consensus Panel on Impotence as the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance.(1)It is the second most common disorder of male sexual dysfunction, with nearly 30 million men affected in the United States.(2)The causes of ED broadly are psychogenic and organic (physical), but many patients have a multifactorial etiology. Organic causes of ED can include vascular, endocrine, and neurologic problems.(3)
Although ED may have deleterious effects on quality of life, it remained largely an underdiagnosed disorder until recently because many men were reluctant and sometimes embarrassed to address this sensitive issue with their physician.(3)Furthermore, the treatment of ED was limited to injectable products or marginally effective oral therapy. With the availability of effective oral therapy and greater public awareness, more patients are seeking medical help and are asking for effective medication therapy. The purpose of this article will be to review the major drugs used to treat ED.
Physiology of Erection
A good understanding of erectile physiology is necessary in order to understand how medications used to treat ED work. An erection is a vascular process controlled by the central nervous system. Sympathetic nervous system activation induces erectile tissue contraction, which reduces blood flow through the corpora cavernosa, increases blood flow outside the penis, and results in a flaccid penis. Inhibition of sympathetic tone occurs with sexual stimulation, resulting in smooth muscle relaxation and vasodi-latation in the penile tissue. Smooth muscle relaxation increases blood flow through the corpora cavernosa, leading to penile rigidity and erection.
Nitric oxide (NO) is an important neurotransmitter involved in erection. NO release in response to sexual stimuli by endothelial and neural cells catalyzes the production of cyclic guano-sine monophosphate (cGMP), which promotes penile smooth muscle dilatation. Other neurotransmitters thought to be involved in the erectile mechanism include prostaglandins, vasoactive intestinal peptide, serotonin, and dopamine. Many drugs used to treat ED work by modulation of these neurotransmitters.
The 2 principal drugs used to treat ED are sildenafil and alprostadil; however, treatment can include the use of yohimbine, trazodone, papaverine, phentolamine, androgens, or bromo-criptine. A summary of agents used to treat ED is shown in Table 1. The choice of drug therapy for ED depends on the etiology.
Sildenafil citrate, the only phospho-diesterase inhibitor currently approved by the FDA for the treatment of ED, is commonly prescribed. Sildenafil was the 46th most dispensed drug in 2001.(4)Sildenafil acts by inhibiting the cGMP-specific phos-phodiesterase type 5 (PDE5) enzyme in the corpora cavernosa, which prevents the breakdown of cGMP to an inactive compound. The resulting increased availability of cGMP enhances the erectile response, because cGMP is able to relax the penile smooth muscle and vasodilate the penile arteries. Sildenafil does not directly induce erection of the penis but augments the response to sexual stimulation.
Results vary, depending on the cause of the ED, but studies have shown good efficacy rates for silde-nafil. A meta-analysis of 27 trials including a total of 6659 patients was 18 recently published.(5)Overall, sildenafil was more efficacious than placebo in improving erectile function. The primary efficacy parameter, successful sexual intercourse attempts, was 57% for men given sildenafil and 21% for men given placebo. Sildenafil also was found to be well tolerated.
The usual dosage range for sildenafil is 25 to 100 mg daily. The maximum recommended dose is 100 mg/day. Sildenafil should be taken as needed 30 to 60 minutes before sexual intercourse, no more than once daily. Patients should be informed that silde-nafil has no effect in the absence of sexual stimulation, and it should not be taken with a fatty meal because this may decrease the onset of action. Dose adjustment is necessary for men who are over 65 years old, men with hepatic impairment, men with renal impairment (creatinine clearance <30 mL/min), and men who are concurrently taking potent cytochrome P-450 34A inhibitors. The adjusted starting dose is 25 mg daily in these populations. If taken with a protease inhibitor, the recommended maximum dose of sildenafil is 25 mg every other day, since protease inhibitors increase the half-life of sildenafil.
The most serious adverse effect of sildenafil is hypotension, especially if the drug is given with organic nitrates. When nitrates are combined with sildenafil, a life-threatening drop in blood pressure may result. Sildenafil is absolutely contraindicated in those taking nitrates and should be used with caution in those with cardiovascular diseases. Table 2 summarizes The American College of Cardiology/ American Heart Association expert consensus statement on the safe use of sildenafil in patients with cardiovascular disease.(6)Other adverse effects of sildenafil include headache, dizziness, flushing, abnormal vision, dyspepsia, and nasal congestion.
A new phosphodiesterase inhibitor, vardenafil, has gained preliminary approval from the FDA and will soon be available in the United States. Vardenafil 5 to 20 mg daily has been effective in treating ED in clinical studies, and dose adjustment for renal impairment is not necessary.(7)The tolerability and the side-effect profile of vardenafil are similar to those of silde-nafil. Other phosphodiesterase inhibitors, such as talafadil, are in late stages of clinical development.
Alprostadil is a synthetic prostaglandin E1 analogue with alpha-adren-ergic blocking activity. Alprostadil stimulates cyclic adenosine mono-phosphate (cAMP) production in the corpora cavernosa, and increased levels of cAMP relax smooth muscle and dilate the penile arteries, inducing an erection. The intracavernosal form of alprostadil is administered with a short needle injected through the side of the penis, directly into the corpus cavernosa. The intraurethral form of alprostadil is administered with a hand-held delivery device. An alprostadil pellet is inserted through the penile opening into the urethra and is absorbed through the urethral mucosa into the surrounding erectile tissue. Alprostadil is highly effective in treating ED, with success rates of approximately 80% with intracaver-nosal injection(8)and 65% with urethral administration.(9)
To find the optimal dose for a given patient, alprostadil dose titration is performed in the physician?s office, starting with the lowest dose and increased until erection occurs. The usual dosage range for the intracaver-nosal form of alprostadil is 1.25 to 2.5 mcg. The maximum dose is 60 mcg up to 3 times a week, allowing at least 24 hours between each dose. Some adverse effects include penile pain, bruising at the injection site, priapism, hematoma/ecchymosis, hypotension, headache, and dizziness. The usual dosage range for the intraurethral form of alprostadil is 125 to 250 mcg up to a dose of 1000 mcg. It is recommended that this system be administered after urination to facilitate absorption. The maximum dose is 2 administrations in 24 hours. Adverse effects include penile pain, urethral burning, dizziness, hypotension, minor urethral bleeding/spotting, and female partner burning/itching.
Using alprostadil is contraindicated in men with a predisposition to pri-apism, men in whom sexual activity is inadvisable or contraindicated, and men with abnormal penile anatomy/penile implants. Men using the intraurethral form of alprostadil to treat their ED should avoid sexual intercourse with pregnant women because the alprostadil may cause harm to the unborn fetus.
Trazodone, which is an atypical antidepressant with serotonergic and alpha-adrenolytic activity, is thought to help erection by indirectly stimulating corporeal smooth muscle relaxation.(10,11)Reports of prolonged erection and improved sexual function have prompted use of trazodone to treat ED. Although preliminary data showed efficacy, double-blind, placebo-controlled trials have shown marginal efficacy of trazodone in treating organic ED.(12)Trazodone also may be considered for patients with psy-chogenic ED.
Yohimbine, an indole alkaloid obtained from the bark of the yohimbine tree, is a centrally acting alpha(2) adrenergic-receptor antagonist. It acts at the adrenergic receptors in brain centers associated with libido and erection, and it may facilitate stimulated erections.(10)A meta-analysis of 7 randomized, placebo-controlled studies of men with erectile dysfunction showed that yohimbine was better than placebo in treating ED. This benefit was most significant, however, in patients with psychogenic ED, and efficacy was only marginal in patients with organic ED.(13)Yohimbine is generally recommended for those with psy-chogenic ED.(14)
Papaverine is an opium alkaloid that inhibits phosphodiesterase at the postreceptor level and induces smooth muscle relaxation in the sinusoids and dilation of helicine arteries.(10)It increases cAMP and cGMP concentrations in penile erectile tissue, thus facilitating erection. It is effective and low in cost but can cause significant priapism and fibrosis when used alone at higher dosages. Hepatotoxicity also can occur with papaverine. This adverse-effect profile limits routine use of papaverine; however, lower dosages can be utilized if used in combination with other vasoactive injection therapy.
(Phentolamine, a competitive alpha(1) and alpha(2)adrenergic-receptor blocking agent, dilates arteries and abolishes sympathetic inhibition of erections. Although it does not cause erections alone, it can be used in combination with other vasoactive injection therapy.(10)Significant adverse effects with phentolamine include orthostatic hypotension and tachycardia. Oral phentolamine has been reported to be effective in treating ED and is available in several South American countries but not in the United States. Intracavernous therapy with the lower dosages of combination papaverine and phentolamine is effective in treating ED, is better tolerated, and can be considered for patients who fail with traditional agents. Other combinations include intracavernous therapy with papaverine and alprostadil or with phentolamine and alprostadil. The most effective combination is intracavernous therapy with papaver-ine, phentolamine, and alprostadil (also known as trimix). The response rate with trimix may be as high as 90%.(11)
ED affects a vast number of men in the United States, and it is one of the most common untreated medical disorders. Sildenafil is a major discovery in the treatment of ED. Although not completely effective in all patients, efficacy rates are high for sildenafil. Alprostadil is another effective treatment option, but it requires patient acceptance of the route of administration. A suitable medication therapy can be selected at the discretion of both the physician and the patient. Newer agents, such as vardenafil, will soon be available for use, and other therapies are in clinical development.
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One study linked multiple pregnancies to an increased risk of developing atrial fibrillation later in life, and another investigated the association between premature delivery and cardiovascular disease.
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