PDE5 Inhibitors: Types, How They Work, & More

PDE5 inhibitors are medications that improve blood flow to certain tissues, including tissues in the penis to treat erectile dysfunction (ED). They work by slowing or stopping the action of phosphodiesterase-5, an enzyme found in the smooth muscle cells of blood vessels.

PDE5 inhibitors were originally made to treat cardiovascular health issues. But today, they’re most commonly used for ED.

Below, we’ll explain what PDE5 inhibitors are, how they work, and how you might be able to use them to treat erectile dysfunction. We’ll also discuss several important topics related to PDE5 inhibitors, from side effects and interactions to frequently asked questions.

PDE5 inhibitors, or phosphodiesterase type 5 inhibitors, are medications that block the actions of cGMP-specific phosphodiesterase type 5 — an enzyme that controls blood vessels in the penis and other parts of the body. This makes blood flow freely to the corpus cavernosum (the vascular tubes where blood engorges the penis) to allow for an erection.

Common PDE5 inhibitors available today include:

• Viagra® (which contains the active ingredient sildenafil)

• Cialis® (and its generic tadalafil)

• Levitra® (and generic vardenafil)

• Stendra® (avanafil)

Initially, PDE5 inhibitors were developed as treatments for cardiovascular conditions like angina (chest pain) and hypertension (high blood pressure). 

In early-’90s clinical trials, patients who received the first PDE5 inhibitor — a substance named UK-92,480 — reported several side effects, including penile erections.

The researchers testing UK-92,480 (which is now known as sildenafil, or Viagra) didn’t find the erection side effects of PDE5 inhibition significant at first. But over time, the focus of the trials shifted from cardiovascular conditions to erectile dysfunction.

These days, PDE5 inhibitors are used by tens of millions of men in the United States (and many more worldwide) to treat ED.

Besides erectile dysfunction, some PDE5 inhibitors are prescribed for premature ejaculation (PE) — another common form of male sexual dysfunction.

The first PDE5 inhibitors hit the market in the late 1990s. Today, several are available in the U.S. and internationally as prescription medications for ED, pulmonary hypertension, and benign prostatic hyperplasia.

Ahead, the four most common PDE5 inhibitors, how they work, dosages, and who they might be best for.

1. Sildenafil (Viagra®, Revatio®)

Sildenafil citrate, which is sold as a generic medication (just called sildenafil) and under the brand name Viagra, is arguably the most well-known PDE5 inhibitor on the market. It was first approved by the FDA (U.S. Food and Drug Administration) in 1998 as a treatment for ED and is used by millions of men worldwide.

Sildenafil (or brand-name Revatio) is also FDA-approved to treat pulmonary arterial hypertension.

Sildenafil was the original PDE5 inhibitor — the first medication of its type to become available to the public. It’s gone through rigorous clinical studies, systematic reviews, and meta-analyses in the last few decades. This medication appeals to many because of its low cost, wide availability, and long track record.

Sildenafil is a short-acting PDE5 inhibitor that provides relief from ED symptoms for roughly four hours. It can be taken with or without food, usually about an hour before sexual activity.

The recommended dose of sildenafil is 50 milligrams (mg), used as needed. This may be reduced to 25 milligrams or increased to 100 milligrams based on the severity of your ED and your response to sildenafil.

We offer generic sildenafil and Viagra online, following a consultation with a licensed healthcare provider who can determine if a prescription is appropriate.

2. Tadalafil (Cialis®, Adcirca®)

Tadalafil, available as a generic drug and as Cialis, is a long-lasting PDE type 5 inhibitor that was approved by the FDA in 2003. It’s sometimes called the “weekend pill” because it can offer relief from erectile dysfunction for up to 36 hours per dose.

This long duration of action makes tadalafil a good choice for guys who prefer a one-and-done tablet they can take as needed.

You can also get daily Cialis. This version of tadalafil offers an “always-on” effect — you take it once a day without having to time it with planned sexual activity.

The recommended dose of tadalafil for as-needed use is 10 milligrams, which might be adjusted to 20 milligrams or decreased to 5 milligrams, depending on how it’s working and how well you’re tolerating the drug.

Daily-use tadalafil comes in lower concentrations. It’s typically taken at a starting dose of 2.5 milligrams and may be bumped up to 5 milligrams over time.

Generic tadalafil and brand-name Adcirca are also prescribed to treat pulmonary hypertension.

We offer generic tadalafil and Cialis for ED, following an online consultation with a licensed healthcare provider who can assess your needs.

3. Avanafil (Stendra®)

Avanafil (sold as Stendra) is a newer, second-generation PDE5 inhibitor. It works in the same way as other PDE5 drugs but has a more selective mechanism of action that makes it less likely to cause certain side effects.

Avanafil was approved by the FDA in 2012, making it the newest PDE5 inhibitor available on the market. Currently, it’s only sold as Stendra, with no generic medications available.

One advantage of avanafil is that it works quickly, so it can be taken shortly before sexual stimulation. While most ED medications need an hour to start working, research shows that avanafil can provide relief from erectile dysfunction in as little as 15 minutes.

This makes avanafil a good medication to consider if you want something you can take just before sex, without having to worry too much about timing.

Though avanafil does have some potential adverse effects, it’s less likely to cause the vision issues that can occur with other phosphodiesterase 5 inhibitors.

We offer Stendra online through our telehealth platform, following a consultation with a healthcare provider who’ll determine if a prescription is appropriate.

4. Vardenafil (Levitra®, Staxyn™)

Vardenafil was approved by the FDA in 2003. It’s sold under the brand names Levitra and Staxyn as a treatment for erectile dysfunction. It’s also available as a generic medication. 

Vardenafil works similarly to sildenafil. It provides relief from ED for slightly longer, though, with the effects of a typical dose lasting four to eight hours.

One key advantage of vardenafil is that it generally isn’t affected by food, meaning you can take it after a meal without any reduction or delay in its effectiveness. Like other PDE5 inhibitors, vardenafil is only available with a prescription.

At a simple level, PDE5 inhibitors work by blocking the action of the enzyme phosphodiesterase type 5.

The PDE5 enzyme breaks down a cyclic nucleotide called (hormone-signaling protein) cyclic guanosine monophosphate, or cGMP. cGMP is responsible for smooth muscle relaxation and regulating blood flow to parts of the body, including the erectile tissue of the penis.

Stopping this releases nitric oxide, which causes the blood vessels that supply your penis to widen. As blood flows to your penis, the corpora cavernosa starts to expand, creating a larger, firmer erection.

You can think of PDE5 as a metaphorical red light for this process. When the enzyme degrades cGMP, it prevents the smooth muscle inside your blood vessels from relaxing and restricts the supply of blood to your penis.

When the effects of PDE5 are inhibited, cGMP levels increase and the penile arteries can dilate to a larger size, making it easier to get and sustain an erection. 

Though PDE5 inhibitors are best known for their effects on blood flow to the penis, they can also affect other areas of the body in which the PDE5 enzyme is active. This includes the pulmonary vasculature (blood vessels inside the lungs) and the lower urinary tract.

Currently, PDE5 inhibitors are approved by the FDA to treat erectile dysfunction, pulmonary hypertension, and benign prostatic hyperplasia. Here’s what to know.

Erectile Dysfunction (ED)

PDE5 inhibitors are best known for their effects on erectile dysfunction. Popular prescription ED pills — like Viagra, Cialis, Levitra, and Stendra — work by curbing the effects of PDE5 to improve blood flow to the penis.

These medications all come in tablet form, making them easy to take shortly before you plan to have sex.

At this point, PDE5 inhibitors are generally viewed as the gold standard in the treatment of erectile dysfunction. Not only are they highly effective, but they typically work quickly, can be taken as needed, and usually only cause mild, short-lived side effects.

Pulmonary Hypertension (PH)

Some PDE5 inhibitors are used to help manage cardiovascular diseases, specifically pulmonary hypertension, a form of high blood pressure affecting the arteries in the lungs.

As treatments for pulmonary hypertension, PDE5 inhibitors work by opening the blood vessels that carry blood from your heart to your lungs, allowing for easier blood flow.

Not all PDE5 inhibitors are used for this condition. Currently, sildenafil (sold as Revatio when used for PH) and tadalafil (sold as Adcirca) are prescribed for pulmonary hypertension.

Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia (enlarged prostate) is a very common condition among older men. In the U.S., 70 percent of all men in their 60s and 80 percent aged 70 and older are affected by some degree of benign prostatic hyperplasia.

Right now, Cialis (tadalafil) is the only PDE5 inhibitor approved by the FDA to treat the signs and symptoms of benign prostatic hyperplasia.

PDE5 inhibitors are generally safe, effective medications when used as directed. However, like other medications, they can potentially cause side effects and interact with other medications.

PDE5 Inhibitor Side Effects

Most side effects caused by PDE5 inhibitors are mild and temporary. But there are several severe side effects that can occur when these prescription drugs are misused, taken with other medications, or used by people with certain underlying health conditions. 

Common adverse effects of PDE5 inhibitors include:

• Headaches

• Facial flushing

• Dyspepsia (indigestion)

• Nasal congestion

• Cold-like symptoms

• Visual abnormalities

• Back pain or muscle pain

Severe side effects from PDE5 inhibitors are rare, but they can happen. These include: 

• Priapism. This is a prolonged, painful erection that can last several hours and damage the penile tissue. It’s a very rare side effect that requires urgent medical attention.

• Hearing issues. A very small number of men who use PDE5 inhibitors report an issue called sudden sensorineural hearing loss (SSHL). This is an uncommon side effect that, like priapism, requires immediate medical attention.

• Vision abnormalities. Some PDE5 inhibitors may cause vision impairment issues, such as sudden vision loss in one or both eyes. Like priapism and hearing problems, it’s a potentially severe side effect that calls for immediate medical attention.

Since most PDE5 inhibitors target the same enzyme, medications like sildenafil, tadalafil, and vardenafil generally have similar side effects. We’ve discussed these effects more in our guides to sildenafil, tadalafil, and vardenafil side effects. 

As noted, avanafil is a newer medication that’s more selective for PDE5. This makes it less likely to cause some side effects than older PDE5 inhibitors. However, Stendra side effects can still happen, so only use it as prescribed and look out for discomfort and other abnormal issues.

PDE5 Inhibitor Drug Interactions

PDE5 inhibitors can interact with other medications, including certain prescription drugs for high blood pressure, heart disease, myocardial infarction, and bacterial, fungal, and viral infections.

To prevent drug interactions, make sure to tell your healthcare provider about any and all medications you currently use or have recently used before taking a PDE5 inhibitor.

Find answers to frequently asked questions about PDE5 inhibitor drugs below.

Can PDE5 Inhibitors Interact With Other Medications?

PDE5 inhibitors are safe to use with most other medications. However, there are several potential drug interactions you should be aware of before taking sildenafil, tadalafil, vardenafil, or avanafil to treat ED, pulmonary hypertension, or benign prostatic hyperplasia.

In some cases, PDE5 inhibitor drug interaction can be dangerous and even life-threatening. The biggest risk comes from taking these drugs alongside other medications affecting cardiovascular function.

PDE5 inhibitors can also interact with nitrates, meds often prescribed for hypertension, angina, and heart failure. Some illicit drugs and supplements (like “poppers”) that contain alkyl nitrites can also interact with PDE5 inhibitors.

When used with nitrates like nitroglycerin, PDE5 inhibitors can cause a sudden, serious decline in blood pressure that may result in dizziness or fainting. It could even lead to life-threatening cardiovascular events like heart attack or stroke. 

Other medications — including alpha blockers, antibiotics, antifungal medications, and drugs used to treat HIV — can also potentially interact with PDE5 inhibitors.

And it’s not safe to use more than one PDE5 inhibitor at a time for erectile function or any other purpose.

Are PDE5 Inhibitors Available Over the Counter?

PDE5 inhibitors aren’t available over the counter. To prevent dangerous drug interactions and contraindications, pharmacology experts at the FDA have made these drugs prescription-only in the United States, including sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra), and avanafil (Stendra).

To buy and use these medications, you’ll need a valid prescription from a healthcare provider. You can do this by:

• Talking to your primary care provider

• Meeting with a urologist (a doctor specializing in ED and conditions affecting the urinary tract and male reproductive system)

• Accessing ED medication through our online platform

Online telehealth platforms like Hims make it pretty simple to access this type of prescription medication — and you get your meds shipped directly to you.

Do PDE5 Inhibitors Lower Blood Pressure?

Because of their vasodilation effects, PDE5 inhibitors like sildenafil can cause a small reduction in blood pressure. This effect is very mild, with a typical reduction of 8.4/5.5 mmHg (millimeters of mercury) following a normal dosage of sildenafil for erectile dysfunction.

Although PDE5 inhibitors can produce a minor drop in arterial blood pressure, they’re not used to treat hypertension and shouldn’t be used as high blood pressure medications. And people with hypotension (low blood pressure) shouldn’t use them, either.

What’s the Best PDE5 Inhibitor for ED?

There’s no “best” PDE5 inhibitor med for everyone. According to research, the three most commonly prescribed PDE5 inhibitors — sildenafil, tadalafil, and vardenafil — are equally effective at treating erectile dysfunction. 

In some cases, one PDE5 inhibitor may be better suited to your needs than others. In general:

• Short-acting PDE5 inhibitors, such as sildenafil and vardenafil, are the best options to treat erectile dysfunction for short periods, such as one night at a time.

• Long-lasting PDE5 inhibitors, like tadalafil, are worth considering if you want to take one pill for multiple days of effects or are interested in a long-term, daily-use medication.

• Newer PDE5 inhibitors, such as avanafil, are likely the best option for those prone to side effects from other ED medications. It can also be good if you want a medication that works quickly and can be taken almost immediately before sex. 

If you’re currently prescribed a PDE5 inhibitor for ED and think a different medication could be a better choice for your needs, talk to your healthcare provider. It’s normal to use multiple PDE5 inhibitors before landing on one that works best. 

Interested in trying a PDE5 inhibitor or exploring other ways to treat ED? Here’s what to keep in mind:

• Erectile dysfunction is a common problem for men of all ages. In fact, an estimated 30 million men are affected by ED in the United States alone.

• The good news is that most cases of erectile dysfunction can be treated.

• Often, a combination of healthy habits and PDE5 inhibitors, including the medications listed above, give you the best chance at successfully treating ED.

We offer several ED medications online, including generic sildenafil, Viagra, generic tadalafil, Cialis, and Stendra.

You can also learn more about the causes of ED and treatment options in our guide to erectile dysfunction.