How do PDE5 inhibitors differ in onset and duration of action and which is best for on‑demand use?
Executive summary
PDE5 inhibitors differ primarily in pharmacokinetics—how quickly they reach effective blood levels (onset) and how long they remain active (duration)—and those differences drive which drug is optimal for “on‑demand” sexual activity; avanafil and vardenafil generally offer the quickest onset, tadalafil the longest duration, and sildenafil sits between them as the historically dominant option with well‑characterized effects [1] [2] [3]. Choosing the best agent for on‑demand use therefore depends on whether rapid onset, a long sexual window, tolerability, food interactions, or cardiovascular profile is the priority [4] [5] [6].
1. How pharmacokinetics set these drugs apart
PDE5 inhibitors share the same mechanism—blocking PDE5 to raise cGMP and enable erection—but differ in Tmax (time to peak concentration) and half‑life, which translate into clinically meaningful differences in onset and duration; avanafil shows a shorter Tmax (reported 15–45 minutes), sildenafil and vardenafil typically have median Tmax around 60 minutes, and tadalafil’s Tmax can be longer (around 2 hours) while its half‑life is far longer than the others (leading to a prolonged effect) [1] [7] [4].
2. Who acts fastest: the onset comparison
Clinical and pharmacokinetic reviews identify avanafil as having the fastest onset in many studies—onset as early as 15 minutes and median Tmax 30–45 minutes—while orodispersible vardenafil formulations also achieve rapid peak levels; sildenafil and vardenafil commonly reach effective levels within 30–60 minutes, with patients traditionally advised to wait up to an hour for maximal effect [1] [2] [3] [7].
3. Who lasts longest: the duration comparison
Tadalafil stands apart with the longest duration of action—typically 24–36 hours and reports of efficacy up to 72 hours—making it the agent of choice when a prolonged window or daily dosing is desired, whereas the other agents have shorter effective windows (multiple reviews estimate avanafil >6 hours, sildenafil at least ~12 hours, and vardenafil ~10 hours depending on study and dose) [3] [4] [8].
4. Practical considerations beyond raw speed and length
Efficacy is broadly similar across approved agents, but side‑effect profiles and interactions matter: sildenafil is more often associated with visual disturbances, vardenafil carries a QT‑prolongation warning in some contexts, and tadalafil has been linked to myalgia or back pain; avanafil is highlighted in the literature for fewer visual effects and favorable selectivity for PDE5 over PDE6 and PDE1, which may reduce off‑target adverse events [2] [3] [7]. Food, especially fatty meals, can slow or reduce absorption of sildenafil and vardenafil but not tadalafil, which can be an important practical point when timing on‑demand use [5] [6].
5. Which is best for on‑demand use
For strict on‑demand needs—minimizing the wait between dosing and sexual activity—avanafil and rapid‑acting vardenafil (including orodispersible formulations) are often favored, with avanafil cited for possibly the fastest real‑world onset and a cleaner visual side‑effect profile in comparative reviews [3] [2] [8]. Sildenafil remains a reasonable on‑demand choice because of extensive evidence, but requires more planning about timing and meals [3] [5]. Tadalafil is better conceptualized as an option for broad spontaneity (a long window or daily low‑dose use) rather than the fastest on‑demand trigger [3] [4].
6. Caveats, alternatives and patient‑centered choice
Head‑to‑head randomized trials, particularly comparing newer agents like avanafil against the classics, are limited, and reported onset/duration vary with dose, formulation, food state, and individual factors (age, liver function, comorbidities), so recommendations must be individualized; clinicians balance speed, duration, side effects, drug interactions (notably nitrates and some antibiotics/antivirals), cost, and patient preference when selecting an on‑demand PDE5 inhibitor [1] [9] [6]. The literature supports avanafil or rapid vardenafil for quickest on‑demand onset, tadalafil for the longest window, and sildenafil as a well‑studied middle ground—each choice driven by what “on‑demand” means for the patient (immediate onset vs. long spontaneity vs. familiarity and evidence base) [2] [3] [4].