A physician and PharmD evaluate sildenafil
June 1, 1998
A physician and PharmD evaluate sildenafil
By William T. Elliott, MD 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 approved for this indication. Sildenafil was approved by the U.S. Food and Drug Administration 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 30 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.
Indications
Sildenafil is indicated for the treatment of erectile dysfunction.
Potential advantages
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."
Potential disadvantages
Common side effects of sildenafil vs. 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 mm/Hg. Sildenafil is contraindicated in patients taking nitrates, as it has been shown to potentiate the hypotensive effects of nitrates.2 Use caution in patients with anatomical deformation of the penis (e.g., Peyronie's disease, cavernosal fibrosis) or in those predisposed to priapism (e.g., sickle-cell anemia, multiple myeloma, leukemia).2
Dosing information
Sildenafil is supplied in 25 mg, 50 mg, and 100 mg tablets. The recommended dose is 50 mg taken about one hour before sexual activity, although it may be taken anywhere from 1¼2 hour to four hours prior. The dose may be increased to a maximum recommended 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 those 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 absorption of sildenafil, with a mean delay in the time to peak plasma concentration of about one hour.2
Comments
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. Phos ph o diesterase 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, few 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 was assessed mainly by a self-administered questionnaire, which addressed the ability to achieve and maintain an erection for intercourse. 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% to 62%, 73% to 74%, and 78% to 82%, respectively, vs. 24% to 28% for placebo.2,3 Generally, sildenafil patients reported about 48% to 66% successful intercourse per attempt vs. 12% to 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
Clinical implications
Male erectile dysfunction is common and underreported. The estimated prevalence in men ages 50 to 70 is 52%.4 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 are unknown, 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 concerns, especially regarding inappropriate use. It does not affect libido. Still, demand 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 through the news media. With such high public awareness, sildenafil certainly will be one of the most successful drug releases, assuming a good safety record.
(Editor's note: Elliott chairs the regional pharmacy and therapeutics committee, Kaiser of Northern Califor nia, and is an assistant professor of medicine at the University of California at San Francisco. Chan heads drug information at Kaiser of Northern California.)
References
1. Boolell M, et al. Int J Impot Res 1996; 8:47-52.
2. Viagra Product Information. Pfizer Labs. March 1998.
3. Lue TF. J Urol 1997; 157:181 (abstract).
4. Pelfman HA, et al. J Urol 1994; 151:54-61.
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