PDE5 Inhibitors
Sildenafil, Tadalafil, Vardenafil, Avanafil
Evidence grade 5 of 5, Settled. Read how the Atlas grades evidence.
The written rationale for this grade is still being prepared.
- FDA
- FDA Approved (Sildenafil 1998)
Reference only. Not medical advice.
What can go wrong
Absolute contraindication with nitrates (nitroglycerin, isosorbide), the combination can cause potentially fatal hypotension. Caution with alpha-blockers and in recent cardiac events. Common effects: headache, flushing, dyspepsia, nasal congestion; sildenafil and vardenafil can cause transient blue-tinged vision (PDE6 cross-reactivity); rare reports of NAION (non-arteritic anterior ischemic optic neuropathy) and priapism. Counterfeit online product is a documented safety hazard.
This is something to take to a clinician. The Atlas can tell you what is known about pde5 inhibitors in general. It cannot tell you what is happening in your body, and the difference matters most for exactly the symptoms that bring people to this page.
A class of oral drugs that inhibit phosphodiesterase type 5, preventing breakdown of cGMP and sustaining the smooth-muscle relaxation that lets blood fill the corpora cavernosa. Backed by multiple Cochrane reviews and 100+ RCTs; first-line per AUA, EAU, and ISSM. Sildenafil was originally developed as a cardiovascular drug for angina before its erectile effect was observed in trials.
The first-line treatment for erectile dysfunction worldwide.
What people take it for
What it is taken for. Approval, where it exists, covers only some of these.
- Erectile dysfunction
- First-line oral therapy for organic, psychogenic, and mixed ED
- Pulmonary arterial hypertension
- Sildenafil (Revatio) and tadalafil (Adcirca) approved separately at different dosing
- Benign prostatic hyperplasia
- Tadalafil 5mg daily approved for LUTS/BPH
How it works
PDE5 inhibitors block phosphodiesterase type 5, the enzyme that degrades cyclic GMP in penile smooth muscle. With cGMP preserved, the nitric-oxide arousal signal is amplified and sustained, allowing the corpora cavernosa to fill in response to sexual stimulation. They do not initiate an erection independently, arousal and intact nitric oxide signaling are still required.
- Sildenafil half-life
- ~4 hrs
- Tadalafil half-life
- ~17.5 hrs
- Vardenafil half-life
- ~4-5 hrs
- Avanafil half-life
- ~5 hrs
How it is taken
Sildenafil 25-100mg as needed, taken 30-60 min before activity, food-sensitive (high-fat meals delay absorption). Tadalafil 10-20mg as needed or 2.5-5mg daily for spontaneity. Vardenafil 5-20mg as needed. Avanafil 50-200mg with the fastest onset.
What people get wrong
Often saidBigger dose means a bigger erection
ActuallyBeyond the effective dose there is no added benefit, only more side effects. PDE5 inhibitors enable an erection in response to arousal; they do not create one on their own.
Often saidThey are an aphrodisiac that boosts desire
ActuallyThey act on blood flow, not libido. A man with low desire from low testosterone or depression will not be helped by the drug alone.
Who profits, and who pushes back
Andrea Tosi and reviewers of compounded combinations
Combining PDE5 inhibitors with each other or stacking them into compounded multi-ingredient products has not been studied for safety or efficacy, and FDA-approved labeling explicitly advises against co-administering two ED drugs; the apparent value of such combos rests on marketing rather than controlled evidence.
Irwin Goldstein
PDE5 inhibitors treat the symptom but not the underlying endothelial and vascular disease; framing a pill as a cure can let clinicians and patients skip the cardiovascular workup that erectile dysfunction should trigger.
Cochrane and systematic reviewers
Head-to-head superiority among the four agents is weak; most apparent differences reflect pharmacokinetics and patient preference rather than robust efficacy gaps, and much comparative trial data is industry-funded with short follow-up.
How we got here
Sildenafil began as a candidate angina/hypertension drug (UK-92480) at Pfizer's Sandwich, UK laboratory. In phase I cardiovascular trials it underperformed for angina, but male volunteers reported increased erections; Pfizer pivoted development toward ED. The FDA approved Viagra on March 27, 1998, creating an entirely new pharmaceutical category and a cultural phenomenon. Tadalafil and vardenafil followed in 2003, avanafil in 2012, and generic sildenafil in 2017.
- 1989Sildenafil synthesized as a cardiovascular candidate
- 1998FDA approves Viagra for ED
- 2003Cialis and Levitra approved
- 2012Avanafil (Stendra) approved
- 2017Generic sildenafil arrives, prices collapse
Set against the alternatives
Sildenafil acts in 30-60 min but is food-sensitive; tadalafil lasts up to 36 hours and enables a daily low-dose option ('the weekend pill'); vardenafil is similar to sildenafil with slightly higher potency; avanafil has the fastest onset (~15 min) and a more selective profile with fewer visual effects.
| Agent | Onset | Duration | Status |
|---|---|---|---|
| Sildenafil | 30-60 min | 4-6 hrs | Generic since 2017 |
| Tadalafil | 30-45 min | up to 36 hrs | Generic |
| Vardenafil | 30-60 min | 4-6 hrs | Generic |
| Avanafil | ~15 min | ~6 hrs | Branded (Stendra) |
What we do not know
- Why do an estimated 30-35 percent of men show inadequate response to PDE5 inhibitors, and can responders be predicted before prescribing?
- Do PDE5 inhibitors confer cardiovascular or mortality benefits beyond erectile function, as some observational cohorts suggest, or is that confounding?
- What explains the reported association signals between PDE5 use and lower Alzheimer risk, and will randomized trials confirm any neuroprotective effect?
- Can daily low-dose tadalafil reverse, rather than merely mask, endothelial dysfunction in the penile vasculature over time?
- Is there a real difference in long-term satisfaction between on-demand and daily dosing strategies across the class?
What could change
Sublingual and orodispersible formsFaster-onset films and chewables aiming to undercut the 30-60 min wait, though many marketed versions are compounded and not individually FDA-approvedRepurposing researchActive investigation of PDE5 inhibitors in Alzheimer prevention, pulmonary hypertension, Raynaud, and cardioprotectionCombination and adjunct strategiesStudies pairing PDE5 inhibitors with low-intensity shockwave therapy or with L-arginine pathways to rescue non-respondersNext-generation PDE5 chemistryEffort toward agents with cleaner selectivity to reduce visual, nasal, and headache side effects
At a glance
- Onset (sildenafil)
- 30-60 min
- Onset (avanafil)
- ~15 min, fastest
- Tadalafil duration
- up to 36 hrs
- Generic sildenafil since
- 2017
- Approvals
- 1998, 2003, 2003, 2012
What this entry does not yet cover
What follows is unfinished work on our side, not a finding about PDE5 Inhibitors. A short entry is not a safe entry.
- Cost and market. We have not documented what it sells for or who sells it.
- Supply chain. We have not mapped where it is made.
- Who uses it. We have not documented the user groups.
- Children and teenagers. We have not checked what is known about younger people.
- Where we land. We have not taken a position on this yet.
Sources
The studies below are named and described, but not linked. You cannot open them from here and check our reading against them, which means this page is our summary of the literature rather than a document you can verify. Weigh it accordingly until the links exist.
The studies that matter
Cochrane review of sildenafil2002
Significant improvement in successful intercourse vs placebo across dozens of RCTs
Goldstein et al. (pivotal sildenafil trial)1998
Dose-dependent improvement in erectile function; published NEJM, basis of approval
Tadalafil once-daily program2006-2008
Established efficacy and tolerability of low-dose daily dosing