Sildenafil Tablets for Erectile Dysfunction
By William T. Elliott, MD, and James Chan, PharmD, PhD
To unprecedented fanfare, pfizer has introduced sildenafil (Viagra), its new oral drug for erectile dysfunction in men-the first oral drug ever approved for this indication. Sildenafil was approved by the FDA on March 27, 1998, an event that was carried by nearly every newspaper in the country, most suggesting that the drug is a major breakthrough for the estimated 20 million or more American men who suffer from erectile dysfunction.
Sildenafil is a competitive and selective inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5 (PDE5).1,2 This isoenzyme is responsible for the degradation of cyclic guanosine monophosphate in the corpus cavernosum.
Sildenafil is indicated for the treatment of erectile dysfunction.
Sildenafil is the first orally effective drug approved by the FDA for erectile dysfunction. Previously approved treatments involve intracavernosal injection or transurethral insertion of alprostadil, which tend to be unappealing to many patients. Unlike alprostadil, sildenafil does not directly cause an erection. It has no direct effect on smooth muscle relaxation in the corpus cavernosum but, instead, requires sexual stimulation. Erection is therefore more physiological and "natural."
Common side effects of sildenafil compared to placebo include headache (16% vs 4%), flushing (10% vs 1%), and dyspepsia (7% vs 2%). Abnormal vision (e.g., color tinge to vision, increased sensitivity to light, or blurred vision) has been reported with a frequency of 3%. The inhibition of PDE type 6 in the retina may be responsible for the abnormalities in color vision.2 Dyspepsia and abnormal vision were more common at the 100 mg dose (17% and 11%, respectively). In addition, 100 mg of sildenafil has been reported to reduce blood pressure by 10 mmHg. Sildenafil is contraindicated in patients taking nitrates, as it has been shown to potentiate the hypotensive effects of nitrates.2 Sildenafil should be used with caution in patients with anatomical deformation of the penis (e.g., Peyronie's disease, cavernosal fibrosis), or in patients predisposed to priapism (e.g., sickle cell anemia, multiple myeloma, leukemia).2
Sildenafil is supplied in 25 mg, 50 mg, and 100 mg tablets. The recommended dose is 50 mg taken approximately one hour before sexual activity, although it may be taken anywhere from one-half hour to four hours prior. The dose may be increased to a maximum recommended dose of 100 mg or decreased to 25 mg. Taking one dose more than once daily is not recommended.2 Elderly patients (> 65 years), patients with severe hepatic or renal impairment, and patients taking potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, intraconazole) should consider a starting dose of 25 mg to reduce the potential for side effects.2 Enzyme inducers such as rifampin are expected to decrease the plasma levels of sildenafil. A high-fat meal will delay the absorption of sildenafil, with a mean delay in the time to peak plasma concentration of about one hour.2
Penile erection involves the relaxation of the smooth muscle in the corpus cavernosum. Sexual stimulation releases nitric oxide, which activates the enzyme guanylate cyclase. This enzyme produces cyclic guanosine monophospate (cGMP), which results in smooth muscle relaxation. Phosphodiesterase degrades cGMP, which terminates its relaxant effect. By inhibiting this enzyme, sildenafil increases the level of cGMP, thus enhancing the relaxation effect of the smooth muscles in the corpus cavernosum.
Sildenafil has been administered to about 3000 patients; however, very few of the data have been published. There have been 21 placebo-controlled trials, and duration of double-blind trials varies from two to six months.2,3 Clinical efficacy of the drug was assessed primarily by a self-administered questionnaire. The questionnaire addressed the ability to achieve and maintain an erection for intercourse. In addition, patients also kept a diary of their sexual history.2,3
In patients with erectile dysfunction attributed to organic, psychogenic, or mixed etiologies, patients on 25 mg, 50 mg, and 100 mg reported improvements in their erection of 61-62%, 73-74%, and 78-82%, respectively compared to 24%-28% for placebo.2,3 Generally, sildenafil patients reported about 48-66% successful intercourse per attempt compared to 12-20% on placebo.2 Patients with greater baseline impairment of erectile dysfunction and men with diabetes or radical prostate surgery did not respond as well.2
Male erectile dysfunction is a common and underreported disorder. The estimated prevalence in men between the ages of 50 and 70 years is 52%.4 Current treatment includes vacuum devices, penile implants, intracavernosal injections (e.g., alprostadil), and urethral suppository (e.g., MUSE). Sildenafil is the first FDA-approved oral product for this problem. Long-term effects of sildenafil are not known, and it does not affect the underlying cause of erectile dysfunction. Physicians should, whenever possible, seek out the underlying cause of the problem when considering sildenafil.
The drug, while promising, raises some concerns, especially regarding inappropriate use. The drug does not affect libido and is not an aphrodisiac. Still, demand for the drug is expected to be high as men seek to improve their sexual prowess-even men with normal sexual function. Before any significant promotion by Pfizer, the lay public has been exposed to the drug by way of the printed and electronic news media. With such high public awareness, sildenafil will certainly be one of the most successful drug releases, assuming a good safety record. The wholesale cost of sildenafil is $7 per tablet for all strengths. Many insurers may not cover this drug because of its potential cost due to high patient demand.