Mechanism of Action of Sildenafil for Erectile Dysfunction
Sildenafil works by selectively inhibiting phosphodiesterase type 5 (PDE5), which increases cyclic guanosine monophosphate (cGMP) levels in the corpus cavernosum, potentiating smooth muscle relaxation and enhancing blood flow to the penis during sexual stimulation. 1, 2
Physiological Pathway
- During sexual stimulation, nitric oxide (NO) is released from nerve endings in the penis 3
- NO activates guanylate cyclase, which increases production of cGMP in the corpus cavernosum 2, 4
- cGMP is responsible for relaxation of smooth muscle in the corpus cavernosum, allowing increased blood flow and erection 4
- PDE5 is the predominant enzyme that breaks down cGMP in the penis 2
- Sildenafil selectively inhibits PDE5, preventing the breakdown of cGMP 1, 5
- The resulting increased cGMP levels enhance smooth muscle relaxation and blood flow, facilitating erection 2, 6
Key Characteristics
- Sildenafil does not directly cause erections but enhances the natural erectile response to sexual stimulation 3, 2
- It has no effect in the absence of sexual stimulation 2
- Sildenafil is rapidly absorbed after oral administration, with peak plasma concentrations within 30-120 minutes 5, 2
- The elimination half-life is 3-5 hours 5
- Sildenafil is metabolized primarily by hepatic enzymes CYP3A4 (major route) and CYP2C9 (minor route) 2
Clinical Efficacy
- High-quality evidence shows that sildenafil significantly improves erections (73-88% improvement) compared to placebo (26-32%) 7, 8
- The weighted mean percentage of successful sexual intercourse attempts is 69% for sildenafil versus 35.5% for placebo 7
- Efficacy is dose-dependent, with improvement related to higher doses (50 mg vs. 25 mg), though less additional benefit when increasing from 50 mg to 100 mg 8, 5
- Sildenafil is effective for erectile dysfunction of various etiologies, including diabetes, depression, cardiovascular disease, and prostate cancer 7, 8
Important Considerations
- Sildenafil is contraindicated with nitrate medications due to the risk of severe hypotension 5, 2
- Common adverse effects include headache, flushing, dyspepsia, nasal congestion, and visual disturbances 8, 5, 6
- Lower starting doses (25mg) may be appropriate for elderly patients and those with hepatic or renal impairment 5
- Patients should be instructed that sexual stimulation is necessary for the medication to work 7
- Multiple trials may be required to establish efficacy for an individual patient 7
- In men with testosterone deficiency, combining testosterone therapy with sildenafil may be more effective than sildenafil alone 7
Sildenafil represents a significant advancement in erectile dysfunction treatment as it provides an effective oral therapy that works by enhancing the natural physiological process of erection rather than artificially inducing it 3, 6.