PDE-5 inhibitors are a class of oral medications that treat erectile dysfunction by increasing blood flow to the penis. They work by blocking an enzyme called phosphodiesterase type 5, which normally breaks down a chemical messenger responsible for relaxing blood vessels. Four are currently available in the U.S.: sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra). The American Urological Association recommends them as a primary treatment option for erectile dysfunction unless a specific contraindication exists.
How PDE-5 Inhibitors Work
During sexual arousal, nerve endings and blood vessel cells in the penis release nitric oxide. This triggers production of a molecule called cyclic GMP (cGMP), which relaxes smooth muscle in the penile arteries, allowing them to widen and fill with blood. Under normal circumstances, an enzyme called PDE5 breaks down cGMP relatively quickly, ending the process.
PDE-5 inhibitors block that enzyme, so cGMP stays active longer and accumulates to higher levels. The result is stronger, more sustained blood flow. These drugs don’t create an erection on their own. They amplify the body’s natural arousal response, which is why sexual stimulation is still needed for them to work.
Conditions They Treat
Erectile dysfunction is the most common use, but PDE5 enzymes are found throughout the body, including in the lungs, prostate, bladder, and urethra. That distribution has led to several other approved uses.
Tadalafil is approved to treat lower urinary tract symptoms caused by an enlarged prostate. By relaxing smooth muscle in the prostate and urethra, it reduces urinary urgency, weak stream, and frequent nighttime urination to a degree comparable to older prostate medications. European urology guidelines rate this use with the highest level of supporting evidence. For men dealing with both erectile dysfunction and urinary symptoms, tadalafil can address both with a single daily pill.
Sildenafil and tadalafil are also approved under different brand names to treat pulmonary arterial hypertension, a condition where blood pressure in the lung arteries is dangerously high. The same blood vessel relaxation that helps with erections can reduce strain on the right side of the heart by widening pulmonary blood vessels.
Comparing the Four Available Options
All four drugs work through the same mechanism, but they differ meaningfully in how fast they kick in and how long they last.
- Sildenafil (Viagra) starts working in about 30 minutes, with a practical duration of 4 to 6 hours and a maximum window of around 12 hours.
- Vardenafil (Levitra) has the fastest reported onset at roughly 10 minutes, though it’s typically recommended 30 to 60 minutes before intercourse. It lasts 5 to 7 hours, with a maximum of about 12.
- Tadalafil (Cialis) can begin working in as little as 20 minutes and lasts dramatically longer than the others: 24 to 36 hours, with effects reported out to 72 hours. This long window is why it’s sometimes called the “weekend pill” and why it works as a daily low-dose option.
- Avanafil (Stendra) reaches peak levels in 30 to 45 minutes, has a half-life of about 5 hours, and remains effective for over 6 hours. It was designed to be more selective for PDE5 specifically, which may reduce some side effects.
High-fat meals can delay the absorption of sildenafil, vardenafil, and avanafil, so they work best on an empty or light stomach. Tadalafil is less affected by food.
Common Side Effects
Because PDE-5 inhibitors relax blood vessels throughout the body (not just in the penis), the most frequent side effects relate to that wider vascular effect. In clinical trial data reported to the FDA, headache occurs in roughly 9% to 28% of users depending on the drug and dose. Flushing (a warm, red feeling in the face or chest) affects 5% to 17%. Indigestion hits about 3% to 11%. Some users, particularly those taking sildenafil, report temporary visual changes like a blue tint or increased light sensitivity.
These side effects are generally mild and fade as the drug leaves the body. If one PDE-5 inhibitor causes bothersome effects, switching to another often helps, since their selectivity profiles differ slightly.
Serious Risks and Drug Interactions
The most important safety rule with PDE-5 inhibitors is that they must never be combined with nitrate medications, such as nitroglycerin tablets, isosorbide patches, or amyl nitrite (“poppers”). Both nitrates and PDE-5 inhibitors increase the same blood vessel relaxing pathway. Together, they can cause a sudden, dangerous drop in blood pressure. This interaction is absolute, not dose-dependent.
Rare but serious events have been reported, including a form of sudden vision loss called non-arteritic ischemic optic neuropathy (NAION). Evidence linking PDE-5 inhibitors directly to NAION is limited, but the association has prompted FDA label warnings. Sudden hearing loss has also been reported in rare cases.
Priapism, a prolonged erection lasting more than four hours, is frequently mentioned in drug warnings but is extremely uncommon. Pooled data from 67 placebo-controlled trials involving over 14,000 men found an incidence of 0.1% with sildenafil. Researchers reviewing FDA adverse event reports concluded that extensive counseling about priapism risk is likely unnecessary for routine prescribing, though anyone experiencing a prolonged erection should seek prompt treatment to prevent tissue damage.
An Accidental Discovery
The first PDE-5 inhibitor was never intended to treat erectile dysfunction. In 1986, a research team at Pfizer’s laboratories in Sandwich, England, synthesized sildenafil as a potential treatment for angina (chest pain from reduced blood flow to the heart). Early clinical trials showed disappointing results for angina, but male participants consistently reported an unexpected side effect: improved erections. Pfizer pivoted, and sildenafil was approved for erectile dysfunction in 1998, becoming one of the fastest-selling drugs in pharmaceutical history.
Potential Uses Beyond Erectile Dysfunction
Researchers are investigating PDE-5 inhibitors for conditions well outside their original scope. Both sildenafil and tadalafil can cross into the brain, where PDE5 enzymes are present in neurons and white matter cells. A large UK study found an 18% lower risk of Alzheimer’s dementia in men over 40 who used any PDE-5 inhibitor compared to nonusers, with the strongest effect in men over 70 who also had diabetes or high blood pressure. Animal studies have shown improvements in memory deficits and reductions in a key protein linked to Alzheimer’s after 10 weeks of treatment.
Other active research areas include heart failure, high-altitude illness (where the drugs can reduce dangerous spikes in lung artery pressure), kidney protection, nerve damage, and fertility. PDE-5 inhibitors also have mild blood-thinning properties that may contribute to cardiovascular benefits, though none of these uses are currently approved.