From the Guidelines
Sildenafil works in males primarily by inhibiting phosphodiesterase type 5 (PDE5), an enzyme that breaks down cyclic guanosine monophosphate (cGMP) in the penis, as supported by high-quality evidence from various studies, including those published in the Annals of Internal Medicine 1.
Mechanism of Action
When a man is sexually stimulated, nitric oxide is released in the erectile tissue, which activates the enzyme guanylate cyclase. This enzyme increases levels of cGMP, causing smooth muscle relaxation in the corpus cavernosum, allowing increased blood flow into the penis. By blocking PDE5, sildenafil prevents the breakdown of cGMP, maintaining higher concentrations of this molecule and prolonging the relaxation of smooth muscle.
Key Points
- Sildenafil is typically taken orally at doses of 25-100mg approximately 30-60 minutes before sexual activity, with effects lasting 4-5 hours, as indicated by improvement in erectile function related to higher dose for sildenafil (50 mg vs. 25 mg but not 100 mg vs. 50 mg) 1.
- The medication should not be taken with nitrates due to potentially dangerous drops in blood pressure.
- Common side effects may include headache, flushing, indigestion, and nasal congestion.
- Sildenafil only works in the presence of sexual stimulation and doesn't increase sexual desire.
- High-quality evidence indicated that all 5 agents (sildenafil, vardenafil, tadalafil, mirodenafil, and udenafil) improved erections (range, 73% to 88%) compared with placebo (range, 26% to 32%) 1.
Clinical Considerations
- Sildenafil was more effective than non–PDE-5 inhibitor treatments, such as sublingual apomorphine, psychotherapy, continuous positive airway pressure, phentolamine, and alfuzosin, in improving erectile function 1.
- Sildenafil combined with other ED therapies resulted in greater improvements in erectile function and frequency of penile penetration or maintenance of erection than did sildenafil alone 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. In addition to pulmonary vascular smooth muscle and the corpus cavernosum, PDE-5 is also found in other tissues including vascular and visceral smooth muscle and in platelets.
The mechanism of action of Sildenafil in males with erectile dysfunction is through the inhibition of PDE-5 in the corpus cavernosum, leading to an increase in cGMP and resulting in relaxation of smooth muscle and vasodilation 2.
- The selectivity of sildenafil for PDE-5 is important for its efficacy and safety profile.
- The inhibition of PDE-5 in the corpus cavernosum is the basis for the treatment of erectile dysfunction.
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, 6
- 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, 5, 6
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 has a half-life of approximately 4 hours 5
Clinical Efficacy and Safety
- Sildenafil has been shown to be effective in improving erectile function in men with erectile dysfunction (ED) 3, 4, 5, 6, 7
- Common adverse events include headache, flushing, dyspepsia, nasal congestion, urinary tract infection, abnormal vision, diarrhea, dizziness, and rash 3
- Sildenafil is contraindicated in men who are taking organic nitrates, due to the potential for a precipitous decrease in blood pressure 3, 6