From the Guidelines
Sildenafil works by inhibiting phosphodiesterase type 5 (PDE5), an enzyme that breaks down cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of blood vessels, thereby enhancing the natural physiological process of erection. This mechanism is supported by various studies, including a clinical practice guideline from the American College of Physicians 1. When sexual stimulation occurs, nitric oxide is released, which activates guanylate cyclase to produce cGMP. The cGMP then relaxes smooth muscle and increases blood flow to the corpus cavernosum of the penis, facilitating erection. By blocking PDE5, sildenafil prevents the breakdown of cGMP, allowing it to accumulate and prolong the vasodilatory effects.
Some key points to consider about sildenafil's mechanism of action include:
- The drug's efficacy is dose-dependent, with higher doses (50 mg vs. 25 mg) showing greater effectiveness, although this effect plateaus at higher doses (100 mg vs. 50 mg) 1.
- Sildenafil is more effective than non-PDE5 inhibitor treatments, such as sublingual apomorphine and psychotherapy, in improving erectile function 1.
- The combination of sildenafil with other ED therapies, such as psychotherapy and alfuzosin, can result in greater improvements in erectile function than sildenafil alone 1.
- The effects of sildenafil last about 4-5 hours, though it requires sexual stimulation to work, highlighting the importance of proper dosing and timing.
Overall, the inhibition of PDE5 by sildenafil is a well-established mechanism of action that has been shown to be effective in treating erectile dysfunction, and its use has been supported by various clinical guidelines and studies 1.
From the FDA Drug Label
Sildenafil is an inhibitor of cGMP specific phosphodiesterase type-5 (PDE-5) in the smooth muscle of the pulmonary vasculature, where PDE-5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation
- The mechanism of action of Sildenafil (Viagra) is through the inhibition of PDE-5, which leads to an increase in cGMP and subsequent relaxation of smooth muscle cells.
- This action results in vasodilation of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic circulation 2.
From the Research
Mechanism of Action of Sildenafil
- Sildenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5) 3, 4, 5, 6, 7
- It enhances the relaxant effect of nitric oxide (NO) on the corpus cavernosum by inhibiting PDE5, which is responsible for degradation of cGMP in this tissue 3, 4, 6, 7
- When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil increases concentrations of cGMP in the corpus cavernosum, causing smooth muscle relaxation and blood flow into the penis, resulting in an erection 3, 4, 6
- Sildenafil has no direct relaxant effect on human corpus cavernosum but enhances the relaxant effect of NO on the corpus cavernosum 3, 4
Pharmacokinetics and Pharmacodynamics
- Sildenafil is rapidly absorbed after oral administration, with absolute bioavailability of 40% 3
- Maximum plasma concentrations are reached within 30 to 120 minutes after oral dosing in the fasting state 3
- Sildenafil is cleared predominantly by the hepatic microsomal isoenzymes CYP3A4 (major route) and CYP2C9 (minor route) 3
- The drug is a potent inhibitor of PDE5 from human corpus cavernosum, with high selectivity for PDE5 relative to other PDE isozymes 4, 5
Clinical Implications
- Sildenafil is effective in the treatment of erectile dysfunction, with statistically significant improvement in erectile function compared with placebo 3
- The use of sildenafil is contraindicated in men who are taking organic nitrates, because of the potential for a precipitous decrease in blood pressure 3, 6
- Sildenafil may potentiate the hypotensive effects of nitric oxide donor agents on the vasculature 5, 6