From the Guidelines
Sildenafil works in males by inhibiting phosphodiesterase type 5 (PDE5), an enzyme that breaks down cyclic guanosine monophosphate (cGMP) in the penis, as shown in high-quality evidence from RCTs 1. 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 erection. The improvement in erectile function was related to higher dose for sildenafil, as indicated in the study 1. Some key points to consider when prescribing sildenafil include:
- The typical dose is 50mg taken approximately one hour before sexual activity, with a range of 25-100mg depending on response and tolerability.
- The medication works only in the presence of sexual stimulation and its effects typically last 4-5 hours.
- Sildenafil should not be taken with nitrates due to the risk of dangerous drops in blood pressure.
- Common side effects include headache, flushing, dyspepsia, nasal congestion, and visual disturbances. It's also important to note that high-quality evidence from RCTs showed that PDE-5 inhibitors, including sildenafil, improved successful sexual intercourse and erections in men with erectile dysfunction, regardless of the underlying medical condition 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 phosphodiesterase type 5 (PDE5) with a mean IC50 of 0.0039 microM 3.
- The mechanism of action of sildenafil involves the inhibition of PDE5, which leads to an increase in the intracellular levels of cyclic guanosine monophosphate (cGMP) 4, 5.
- cGMP is a second messenger of nitric oxide (NO) and plays a crucial role in the relaxation of corporal smooth muscle and penile erection 4, 5.
- The neuronal release of NO binds to the heme-containing region of guanylate cyclase, increasing levels of cGMP, which leads to a cascade of reactions resulting in corporal smooth muscle relaxation and penile erection 4.
Role of PDE5 in Penile Erection
- PDE5 is the main PDE activity in human corpora cavernosa, with PDE2 and 3 also identified 3.
- The inhibition of PDE5 by sildenafil enhances the erectile response to visual sexual stimulation, highlighting the important role of PDE5 in human penile erection 3.
- Sildenafil has been shown to enhance the NO-dependent relaxation of the isolated human corpus cavernosum and the intracavernosal pressure in the anesthetized dog without affecting systemic blood pressure and heart rate 5.