Prescription ·Strong evidence ·Reviewed May 2026
Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor originally developed for angina and subsequently approved for erectile dysfunction (ED) and pulmonary arterial hypertension (PAH). As Viagra, it is the most recognized ED medication worldwide. As Revatio, it is used at lower doses for PAH to improve exercise capacity. Its on-demand dosing makes it the standard first-line oral therapy for ED.
The bottom line
Evidence rating strong. Most-documented uses: effective first-line oral treatment for erectile dysfunction, improves exercise capacity in pulmonary arterial hypertension, rapid onset allows on-demand use. 10 sources indexed (2023–2025), with 3 interaction records on file.
Core mechanism
Selectively inhibits phosphodiesterase type 5 (PDE5), the enzyme that degrades cyclic GMP (cGMP) in penile corpus cavernosum smooth muscle. During sexual stimulation, nitric oxide is released, activating guanylate cyclase to produce cGMP, which relaxes smooth muscle and increases blood flow. By preventing cGMP breakdown, sildenafil potentiates the erectile response. In PAH, the same mechanism relaxes pulmonary vascular smooth muscle, reducing pulmonary artery pressure.
High-fat meals delay absorption by approximately 1 hour and reduce peak concentration by 29%; for fastest onset, take on an empty stomach. Bioavailability ~41%.
L-arginine is a nitric oxide precursor, and sildenafil enhances NO/cGMP signaling by inhibiting PDE5. Combined use can cause additive vasodilation and significant hypotension.
Recommendation: Use caution when combining. Start L-arginine at low doses. Monitor for headache, dizziness, flushing, and low blood pressure. Do NOT combine with nitrates.
St. John's Wort induces CYP3A4, the primary enzyme metabolizing sildenafil. This can reduce sildenafil effectiveness.
Recommendation: Avoid SJW with sildenafil as it may reduce its effectiveness.
L-Citrulline can increase L-arginine availability and nitric-oxide-dependent signaling, which is upstream of sildenafil's PDE5 effect. In a small randomized crossover pilot study, L-citrulline-containing supplementation improved erectile function in men continuing on-demand PDE5 inhibitor therapy. This can be a useful therapeutic synergy, but additive vasodilation may cause flushing, headache, or dizziness.
Recommendation: If you add L-citrulline to sildenafil, start with a low dose and assess tolerability on a day when you can sit or lie down if lightheaded. Avoid nitrates and avoid heavy alcohol use with the combination.
Numbered references. Citations throughout the page link here.
Chua WY, Lim LKE, Wang JJD et al.. Sildenafil and risk of Alzheimer disease: a systematic review and meta-analysis. Aging. 2025
Poudel S, Gautam S, Adhikari P et al.. Physiological Effects of Sildenafil Versus Placebo at High Altitude: A Systematic Review. High altitude medicine & biology. 2024
Hirata K, Nakahari A, Takeoka M et al.. Prophylactic sildenafil to prevent bronchopulmonary dysplasia: A systematic review and meta-analysis. Pediatrics international : official journal of the Japan Pediatric Society. 2024
Awad AK, Gad ER, Abdelgalil MS et al.. Sildenafil for congenital heart diseases induced pulmonary hypertension, a meta-analysis of randomized controlled trials. BMC pediatrics. 2023
Chen Z, Huang Y, Cao D et al.. Function of sildenafil on diseases other than urogenital system: An umbrella review. Frontiers in pharmacology. 2023
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