A Comparison of Five PDE5 Inhibitors: Sildenafil, Tadalafil, Avanafil, Aildenafil, and Simenafil
Disclaimer: This article is for informational purposes only and does not constitute medical advice. PDE5 inhibitors are prescription medications. Consult a qualified healthcare professional before using any of these drugs, especially if you have cardiovascular disease, take nitrates, or have liver or kidney problems.
PDE5 inhibitors are first-line oral treatments for erectile dysfunction (ED). They work by inhibiting phosphodiesterase type 5, which increases cGMP, relaxes smooth muscle, and improves blood flow to the penis. They require sexual stimulation to be effective. The five drugs discussed here differ in onset, duration, selectivity, food interactions, and side-effect profiles.
| Drug | Onset | Duration | Half-life (t₁/₂) | Typical starting dose | Food effect | Key features |
|---|---|---|---|---|---|---|
| Sildenafil | 30–60 min | 4–6 h | 3–5 h | 50 mg | Marked: Tmax delayed ~60 min, Cmax ↓29% | Classic PDE5 inhibitor; extensive clinical data; possible visual effects |
| Tadalafil | 30–120 min | Up to 36 h | 17.5 h | 10 mg as needed or 5 mg daily | Minimal | Longest duration; daily dosing option; back and muscle pain |
| Avanafil | 15–30 min | ~6 h | ~5–6 h | 50–200 mg (typical 100 mg) | Minimal; Cmax ↓39% with high-fat meal | Fastest onset; high PDE5 selectivity; fewer visual effects |
| Aildenafil | 30–60 min | ~2–4 h | ~4 h | 60 mg | Limited data | Chinese-developed; short-acting; rapid clearance |
| Simenafil | <30 min | ~12–18 h | 8–11 h | 2.5–5 mg (reported) | Minimal; unaffected by moderate alcohol | Chinese 1.1 new drug; very low effective dose; high selectivity |
Note: Aildenafil and Simenafil are not widely approved outside China. Data are based mainly on Chinese clinical trials and labeling. Avanafil half-life is often reported as ~5–6 hours, though some sources describe a longer terminal half-life.
1. Onset of Action: Avanafil and Simenafil Are Fastest
Avanafil is one of the fastest-acting PDE5 inhibitors. It can begin working in about 15 minutes, with a median Tmax of 30–45 minutes. Simenafil, a newer Chinese PDE5 inhibitor, is also reported to act within 30 minutes.
Sildenafil and Aildenafil generally require 30–60 minutes. Sildenafil’s median Tmax is about 60 minutes. Aildenafil reaches peak plasma concentration in about 60–90 minutes, although some reports suggest it may begin working within 30–60 minutes.
Tadalafil has a slower onset, with a median Tmax of about 2 hours, but it lasts much longer.
2. Duration of Action: Tadalafil and Simenafil Lead
Tadalafil has the longest effective window, lasting up to 30–36 hours. Its half-life is about 17.5 hours, which allows for once-daily low-dose use (5 mg).
Simenafil has a half-life of 8–11 hours and a reported duration of 12–18 hours. This places it between tadalafil and the shorter-acting agents, offering a longer window while still being relatively controllable.
Sildenafil (4–6 hours), Avanafil (~6 hours), and Aildenafil (2–4 hours) are short-acting and best suited for more planned sexual activity.
3. Selectivity and Side Effects: Avanafil and Simenafil Are More Selective
Common side effects of PDE5 inhibitors include headache, flushing, nasal congestion, and dyspepsia. These are largely due to smooth muscle relaxation.
Avanafil has greater selectivity for PDE5 over PDE6 than sildenafil, so it is less likely to cause visual disturbances such as blue-tinted vision. Headache and flushing may also be less frequent.
Simenafil is described as a highly selective PDE5 inhibitor. Phase III clinical data suggest a lower incidence of adverse reactions than older agents, with fewer reports of visual blurring and muscle aches.
Sildenafil, especially at higher doses (100 mg), can cause transient visual changes due to cross-inhibition of PDE6.
Tadalafil is associated with a characteristic risk of back pain and muscle pain, reported in about 5.5% and 1.3% of clinical trial participants, respectively.
Aildenafil trial data show an adverse reaction rate of about 20.12% at 60 mg. The most common events were flushing (6.71%), dizziness (4.96%), and headache (3.79%), mostly mild to moderate.
4. Food and Alcohol Interactions
Sildenafil is the most affected by food. A high-fat meal can delay Tmax by about 60 minutes and reduce Cmax by 29%.
Tadalafil, Avanafil, and Aildenafil are less affected. For avanafil, a high-fat meal reduces Cmax by about 39%, but Tmax is only delayed to about 1.25 hours.
Simenafil is notable for being unaffected by moderate alcohol consumption, which may be convenient in social settings.
5. Special Populations
Simenafil appears to have a broader applicable population: elderly patients and those with mild-to-moderate liver impairment or mild-to-severe kidney impairment may be able to use it.
Aildenafil has a short half-life of about 4 hours, so accumulation is less likely. This may be an advantage for older patients with reduced liver or kidney function, who might start at a lower dose such as 30 mg.
Sildenafil requires dose reduction in moderate hepatic impairment. Tadalafil should be used cautiously in severe renal impairment.
6. Absolute Contraindications for All PDE5 Inhibitors
All PDE5 inhibitors are absolutely contraindicated with nitrates (e.g., nitroglycerin), because the combination can cause life-threatening hypotension. They are also contraindicated with guanylate cyclase stimulators such as riociguat. Caution is needed with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, erythromycin), which can increase plasma levels and adverse effects.
Conclusion
- Fastest onset: Avanafil (15–30 minutes) or Simenafil (<30 minutes).
- Longest duration: Tadalafil (up to 36 hours), ideal for a more spontaneous or flexible schedule.
- Best side-effect profile in terms of selectivity: Avanafil and Simenafil, with fewer visual and muscle-related effects.
- Social drinking: Simenafil is reported to remain effective with moderate alcohol.
- Older patients with mild liver or kidney impairment: Simenafil has broader data; Aildenafil’s short half-life also reduces accumulation risk.