Initial studies with sildenafil (Viagra) included men with both psychogenic and organic causes of erectile dysfunction. Pooled data from a controlled trial of 416 men found that improved erectile function was reported by 28 percent of the men treated with placebo, compared to 61, 72, and 78 percent of those treated with 25, 50, and 100 mg of sildenafil. Virtually identical frequencies of response (24 versus 63, 74, and 82 percent at the three doses of sildenafil) were noted in a review of 1000 men treated worldwide.

Similarly, in a dose-escalation study of 25 to 100 mg of sildenafil in 532 men with either organic (70 percent), psychogenic (11 percent), or mixed erectile dysfunction (18 percent), 69 percent of all attempts at sexual intercourse were successful in the men who took sildenafil compared to 22 percent of those who took placebo. The mean number of successful attempts at intercourse each month was 5.9 with sildenafil versus 1.5 with placebo. Headache, flushing, and dyspepsia were the most common adverse effects, occurring in 6 to 18 percent of the men.

All do not respond to the drug as well, however. Only 56 percent of diabetic men have improved erections with sildenafil.

Among men who have had a prostatectomy it is effective only in those who had a nerve-sparing operation.

In a study of healthy male volunteers without erectile dysfunction, sildenafil 100 mg caused no changes in seminal parameters or erectile function when compared to placebo. Because sildenafil treatment is associated with a marked reduction in the post-ejaculatory time refractory time, men are capable of having a second erection in a shorter time frame than was possible without this therapy.

Dose
Sildenafil is absorbed well during fasting, and the plasma concentrations are maximal within 30 to 120 minutes (mean, 60). It is eliminated predominantly by hepatic metabolism, and the terminal half-life is about four hours. The recommended starting dose is 50 mg taken one hour before sexual activity. The maximal recommended frequency is once per day. On the basis of effectiveness and side effects, the dose may be increased to 100 mg or decreased to 25 mg.

Adverse Effects and Drug Interactions
An inhibitor of the PDE normally responsible for the breakdown of corporal cGMP, the second messenger in penile erection, oral sildenafil citrate exerts no erectogenic effect in the absence of sexual stimulation.

The agent is highly selective for PDE5, and its inhibitory effect on PDE5 is more robust than on other PDE isoforms, by approximately 2 to 3 orders of magnitude vs PDE1 and more than 3 orders of magnitude vs PDE2, PDE3, and PDE4. The fact that sildenafil's inhibitory effect for PDE5 is approximately several thousand times higher compared with that for the PDE3 isoform may be clinically relevant because the latter is involved in cardiac contractility.

On the other hand, the inhibitory effects of oral sildenafil are only about 1 order of magnitude greater for PDE5 compared with PDE6, an enzyme found in the retina. Consequently, some patients taking sildenafil report dose-related visual disturbances, including blue-green color discrimination, particularly at peak levels of sildenafil in plasma. Despite the effects of sildenafil on PDE6-mediated phototransduction, the agent was not associated with significant decrements in visual acuity or changes in either ocular pressure or pupillometric parameters when administered at supratherapeutic doses in preapproval clinical trials.[33] Other, more frequent adverse events observed with sildenafil in pivotal preapproval clinical trials included headache, with a placebo-adjusted frequency of 12%; flushing, 9%; and dyspepsia, 5%.

In addition to being present in relatively high concentrations within the human corpus cavernosum smooth muscle, PDE5 can also be isolated from other connective tissues, such as vascular and visceral smooth muscle, skeletal muscle, and platelets. The intrinsic antiaggregant, antithrombotic, and vasodilator effects of NO may, therefore, be augmented in the presence of sildenafil.

Side effects associated with sildenafil are related to its vasodilatory properties and are similar to those induced by nitrates. These include headache, lightheadedness, dizziness, flushing, distorted vision, and, in some cases, syncope. It may also have retinal side effects due to inhibition of phosphodiesterase type 6.

Cardiovascular Effects.
Men at highest risk for syncope are those who take other vasodilators such as nitrates. Concurrent use of sildenafil and nitrates in any form, regularly or intermittently, is contraindicated. If a man who has taken sildenafil has an acute ischemic syndrome, nitrates should not be prescribed within 24 hours (longer in patients with renal or hepatic dysfunction). Support for this negative interaction comes from one randomized, placebo-controlled study of patients with stable coronary artery disease who were treated with isosorbide mononitrate for five to seven days before a dose of sildenafil and a second study in which sublingual nitroglycerin was given one hour before sildenafil. Coadministration of sildenafil with either nitrate produced a significantly greater reduction in blood pressure compared to the nitrate alone.

More serious complications, such as myocardial infarction or sudden death, can occur. By November 1998, the United States Food and Drug Administration had received reports of 130 men who died within hours to days after taking sildenafil. In the majority, myocardial infarction was confirmed; another 27 deaths were attributed to cardiac arrest. In 48 men, the cause of death could not be ascertained. One death was ascribed to homicide and another to drowning. Seventy percent of the men who died had known cardiovascular disease and several were using nitrate medication concurrently with sildenafil.

One potential cause for sudden death during sildenafil treatment is a direct electrophysiologic effect of the drug. Similar to the class III antiarrhythmic agents, sildenafil can prolong myocardial repolarization and has reverse-use dependency. This effect is seen at higher plasma concentrations of the drug, which may be found in conditions of impaired drug elimination (hepatic or renal insufficiency), during coadministration of another CYP3A substrate/inhibitor, or after drug overdose.

Sexual activity was thought to be a likely contributor to myocardial infarction in only 0.9 percent of 858 men in one study. Thus, the absolute increase in risk caused by sexual activity is low (one chance in a million for a healthy man). According to data from the National Center for Health Statistics and the Framingham Heart Study, the rate of death from myocardial infarction or stroke for men in the age range in which erectile dysfunction is common is approximately 170 per million men per week. Therefore, it appears that sildenafil therapy is safe for most men. Nevertheless, given that most of the men who died had underlying cardiovascular disease, cardiovascular status should be carefully assessed before treatment.

In response to the concern of physicians, the American Heart Association has published a guideline for sildenafil therapy.

The vasodilatory properties of sildenafil may also have an adverse effect in some patients with a hypertrophic cardiomyopathy; the decrease in preload and afterload can increase the outflow obstruction, culminating in an unstable hemodynamic state.

However, sildenafil is generally well-tolerated in men with coronary artery disease not using nitrates. This was illustrated in a study of 14 men with stable symptoms, but greater than 70 percent stenosis of at least one coronary artery, who underwent hemodynamic evaluation after a single dose of sildenafil (100 mg) at least 24 hours after the discontinuation of nitrates. Blood velocity and flow reserve were assessed using a Doppler guidewire and intracoronary adenosine administration. Although there were small decreases (<10 percent) in systemic and pulmonary arterial pressures, there was no effect on intracardiac pressures, heart rate, cardiac output, peak coronary flow velocity, coronary-artery diameter, or coronary vascular resistance. Coronary flow reserve increased by 13 percent in both stenotic and control arteries. These data support the consensus position of the American College of Cardiology and the American Heart Association that sildenafil is safe for men with stable coronary artery disease who are not taking nitrates.