What Are PDE5 Inhibitors And How Do They Work?

By GetOPT Review Team · Reviewed by Jeremie Walker, MD, MBA · September 14, 2026

PDE5 Inhibitors: What They Are and How They Work

Everything You Need to Know About PDE5 Inhibitors for ED

What Are PDE5 Inhibitors?

Phosphodiesterase type 5 (PDE5) inhibitors are often the first treatment option for people with erectile dysfunction (ED), the inability to get or maintain an erection firm enough to have sex. Researchers accidentally discovered PDE5 as a side effect of potential use for hypertension and angina.

Since 1998, PDE5 inhibitors have been the first-line treatment for ED. The common types are:

Sildenafil (Viagra)
Tadalafil (Cialis)
Vardenafil (Levitra or Staxyn)

Aside from ED treatment, research also suggests that PDE5 inhibitors may help treat diabetes, heart disease, cancer, and potentially cognitive disorders.

How Do PDE5 Inhibitors Work for ED?

Young loving couple in bedroom

To better understand how PDE5 inhibitors work for ED, we must first walk through the complex process of penile erection.

Erection occurs when men become sexually aroused. Nerve impulses from the brain stimulate the muscles to relax, allowing blood to flow to the penile tissue (corpora cavernosa).

The parasympathetic nervous system becomes activated during sexual arousal. This brain activity prompts Nitric Oxide (NO) release and increased production of a molecule called cyclic GMP (cGMP).

cGMP relaxes the muscles and increases blood flow by approximately 20% to 40%, expanding microvessels of the corpora cavernosa.

However, a predominant enzyme in the penis called PDE5 breaks down the cGMP and inhibits an erection. Physiologically, this results in ED because of the lack of blood flow in the penis.

PDE5 inhibitors help with ED by decreasing the activity of PDE5 enzymes to raise the level of cGMP, the primary mechanism of penile erection–eventually leading to relaxed muscles and full erections.

Are Type 5 Inhibitors Safe?

All type 5 inhibitors are generally well tolerated even in patients with a history of cardiovascular disease. Research suggests that these inhibitors may be helpful in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease.

Also, PDE5 therapy significantly improves scores on the International Index of Erectile Function, a multidimensional instrument for evaluating male sexual function compared to the placebo group.

What are PDE5 Inhibitors’ Side Effects?

While generally safe, some common side-effects may depend on the type of PDE5 inhibitor. These side effects may include:

Headache
Muscle pain
Facial flushing
Nasal congestion
Dyspepsia
Interactions with other medications (such as erythromycin and HIV protease inhibitors)
Low blood pressure (hypotension) if taken simultaneously.

ED and cardiovascular disease may coexist and share many of the same risk factors. Talk to your doctor if you have existing comorbidities such as hypertension before deciding to take any PDE5 inhibitors.

Contraindications and Drug Interactions

The interaction that matters most in this drug class is with nitrates. The prescribing information for both sildenafil and tadalafil states that use with nitrates in any form is contraindicated, because a PDE5 inhibitor potentiates the blood-pressure-lowering effect of a nitrate. That covers nitroglycerin tablets and sprays, isosorbide, and recreational nitrites. If you carry nitroglycerin for chest pain, say so before a PDE5 inhibitor is prescribed.

Alpha-blockers are the second interaction worth knowing about, and many men over 40 take one for prostate symptoms or blood pressure. Both labels direct that a patient should already be stable on alpha-blocker therapy before a PDE5 inhibitor is started, and that it be started at the lowest recommended dose. That is a sequencing decision your prescriber makes, which is why the full list of what you take carries more weight here than it might appear.

Bring that complete list to the appointment: prescriptions, anything over the counter, and supplements. Your physician weighs it against your blood pressure and your cardiac history before deciding whether a PDE5 inhibitor suits you, and which one. If you want that reviewed alongside the labs that explain why erections changed in the first place, an Opt Health membership includes a lab panel, a physician's review, and follow-up testing.

Which Foods Contain PDE5 Inhibitors?

Osage orange | What Are PDE5 Inhibitors And How Do They Work? | Which Foods Contain PDE5 Inhibitors?

Some herbs naturally contain PDE5 inhibitors. These include:

Horny goat weed (Epimedium)
Black ginger (Kaempferia parviflora)
Tribulus Terrestris
Osage orange (Maclura Pomifera)

However, more research is needed to evaluate the efficacy of these herbs for ED.

Summary

PDE5 inhibitors help with ED and in the treatment of several conditions, for instance, diabetes, hypertension, and cancer. Research is also looking for its potential benefits in cognitive health.

PDE5 is generally well tolerated, although some people may experience side effects. It is advisable to talk to your doctor before taking PDE5 supplements or herbs if you have an existing illness or are on medication.

If you are concerned about erectile dysfunction, feel free to consult us. Opt Health is a telemedicine platform that helps reconnect men with life, sexual vitality, and wellness. At Opt Health, doctors can diagnose you with ED online, then prescribe ED medications. Get personalized support and insight from top-tier physicians, available for you 24/7. Contact us today or leave a comment below.

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This article is part of our guide to erectile dysfunction. See how Opt Health treats ED at the root cause.