PDE5 inhibitors: what are they, types, how they work

If you’ve ever done an internet search on erectile dysfunction (ED) treatment options, you’ve likely run into multiple names of medicines like Viagra, Cialis, Levitra, and Stendra, not to mention their generic equivalents. These are all phosphodiesterase 5 inhibitors or "PDE5 inhibitors", but getting a handle on which one is right for you can be challenging. 

Read on to learn more about PDE5 inhibitors, including why they’re popular choices for treating ED.

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Phosphodiesterase type 5 inhibitors, also known as PDE5 inhibitors, are prescription medications that can effectively treat several conditions, like pulmonary arterial hypertension and benign prostatic hyperplasia (BPH). However, they are most recognizable for their treatment of erectile dysfunction (ED). 

Briefly, ED is sexual dysfunction characterized by trouble getting or keeping erections long enough for satisfying sex. Some people with ED may even notice a loss of morning erections.

ED is a common experience, affecting over half of American men between 40–70 years of age (Sooriyamoorthy, 2021). If your healthcare provider recommends a prescription medication to improve your erectile function, it is typically one of the PDE5 inhibitors. 

While erections may seem simple, they involve a surprisingly complicated process.

Before an erection can happen, a messenger called cyclic guanosine monophosphate (or cGMP for short) tells the blood vessels in the penis to relax (also called vasodilation), which allows for more blood flow. The blood fills the erectile tissue and you get an erection. 

An erection ends due to the enzyme phosphodiesterase-5 (PDE5), which breaks down cGMP, ending the signal to maintain the erection. This part is where these ED drugs do their thing. Inhibition of the PDE5 enzyme stops the breakdown of cGMP, thereby allowing your penile blood vessels to stay dilated and your erection to last longer (Padda, 2021). 

But it’s important to remember that PDE5 inhibitors are not magic pills. They cannot make an erection appear from thin air. You need sexual stimulation and arousal to start the erection process. PDE5 inhibitors then help nature maintain the desired course. 

As mentioned, these drugs treat several different conditions. However, we will focus on the ones used to treat erectile dysfunction. 

Examples of PDE5 inhibitors (and their generic counterparts) include:

• Viagra (sildenafil)

• Cialis (tadalafil)

• Levitra (vardenafil)

• Stendra (avanafil)

The generic versions work just as well as the brand-name ones and, in most cases, are less expensive. Check with your healthcare professional and insurance provider if you are unsure how much PDE5 inhibitors will cost you. 

Viagra is the brand name for sildenafil citrate and is the first PDE5 inhibitor FDA-approved to treat ED. Sildenafil and Viagra come in 25 mg, 50 mg, and 100 mg oral tablets. The maximum daily dose for Viagra is 100 mg per day.

How long it lasts

Viagra usually takes around an hour to work, but you can take it anywhere from 30 minutes to four hours before sexual activity. It typically lasts in your body for up to 4–5 hours, but your age, health, and diet all affect the exact amount of time it will work. You can take Viagra with food, but it may take longer to start working if you eat a high-fat meal (DailyMed-a, 2022; Zucchi, 2019). 

Common side effects

The most common side effects of Viagra include (Padda, 2021):

• Headaches

• Facial flushing

• Indigestion/heartburn 

• Back pain

• Stuffy nose

• Nausea 

Cialis (generic name tadalafil) is another common prescription medication used to treat erectile dysfunction. Cialis and tadalafil come in 2.5 mg, 5 mg, 10 mg, and 20 mg tablets. The maximum daily dose for Cialis is 20 mg per day. 

How long it lasts

Like Viagra, the effects of Cialis usually start around 30–60 minutes after taking it. One benefit of Cialis is that it may last up to 36 hours. Because of this, you can use Cialis in two different ways: You can take Cialis as-needed in anticipation of sex (like Viagra) or take it at the same time every day. 

Only 2.5 mg and 5 mg are used as daily doses to treat ED. Taking the medication daily integrates it into your routine and eliminates the need to plan for sex. You can take it with or without food (DailyMed-a, 2022; Zucchi, 2019).

Common side effects

The most common side effects of Cialis include (DailyMed-b, 2022):

• Headaches

• Indigestion/heartburn

• Back pain

• Muscle aches

• Nasal congestion

• Flushing

• Pain in arms or legs

Levitra (generic version vardenafil) is also used to treat erectile dysfunction. Levitra and vardenafil come in four doses (2.5 mg, 5 mg, 10 mg, and 20 mg). The maximum daily dose for Levitra is 20 mg per day. 

How long it lasts

Levitra lasts about 4–5 hours, and most people take it 30–60 min before sex. Like Viagra, other factors like your age and overall health may affect how long it lasts. You can take Levitra with or without food. However, a high-fat meal can delay its effect (DailyMed-a, 2021; Zucchi, 2019). 

Common side effects

The most common side effects of Levitra are similar to Viagra and include (DailyMed-a, 2021):

• Headache

• Runny nose

• Flushing

• Heartburn (dyspepsia)

• Flu-like symptoms

• Nausea

• Dizziness/lightheadedness

• Back pain

Levitra may also increase the likelihood of QT prolongation (a change seen on an EKG), which can sometimes be followed by irregular heartbeats. 

Stendra (generic name avanafil) is the newest PDE5 inhibitor approved for ED treatment. It is not available in a generic form, only as a brand-name drug. Stendra comes in 50 mg, 100 mg, and 200 mg tablets. The maximum daily dose is 200 mg daily.

How long it lasts

Stendra starts working as quickly as 15 minutes after taking it, so most people take it 15–30 minutes before sex. It lasts about 4–5 hours for most people. You can take it with or without food, but a high-fat meal may delay its effects (DailyMed-b, 2021; Zucchi, 2019).

Common side effects

The most common side effects of Stendra are similar to the other PDE5 inhibitors and include (DailyMed-b, 2021):

• Headache

• Flushing

• Runny nose

• Flu-like symptoms

• Back pain

Unsurprisingly, the risks associated with PDE5 inhibitors are similar across these four popular drugs, and include priapism, low blood pressure, and blurred vision. 

Priapism

A priapism is a medical emergency where you experience a prolonged erection that lasts more than four hours. If the erection is not relieved emergently, priapism can lead to permanent penis damage. Not only do PDE5 inhibitors increase your risk of developing priapism, but they may also be responsible for up to 25% of priapism cases (Silberman, 2021).

Low blood pressure

PDE5 inhibitors help maintain your erection by encouraging the blood vessels in the penis to relax, increasing blood flow. However, when you take these drugs, they can affect the blood vessels throughout your body. Relaxing (or dilating) your blood vessels makes your blood pressure drop. 

While sometimes this is what we want (like when treating hypertension), an unexpected decrease in blood pressure may be an issue for people with naturally low blood pressure (hypotension). Similarly, if you take other medications to lower your blood pressure, adding PDE5 inhibitors may reduce things further. If your blood pressure drops too low, the results can be fatal (Padda, 2021). 

Blurred vision

Non-arteritic ischemic optic neuropathy (NAION) is an eye condition that causes blurry vision, which can sometimes be permanent. It is a rare risk of PDE5 inhibitors. NAION mainly happens in people who already have other risk factors for this condition (e.g., the shape of their optic nerve, etc.). Before starting a PDE5 inhibitor, talk to your eye care professional about whether you are at an increased risk of developing NAION (Raizada, 2021).

Changes in color vision are a rare side effect of sildenafil and Viagra. Some people report a bluish or greenish tinge to their vision. Fortunately, this does not usually last long (Padda, 2021).

Some people in clinical trials of PDE5 inhibitors noted new heart issues. But the data is unclear as to whether this risk was due to the medications or other factors like the physical strain of sexual activity. If you have preexisting risk factors for heart disease (like high blood pressure, high cholesterol, diabetes, etc.) or a history of cardiovascular disease, heart attacks, or strokes, talk to your healthcare provider before starting a PDE5 inhibitor.

There may be other risks associated with PDE5 inhibitors. Seek medical advice from your pharmacist or healthcare professional if you have questions or concerns.

Before starting any erectile dysfunction medication, talk to your healthcare provider. Discuss your medical history and any over-the-counter supplements or prescription medications you are taking. Knowing this information can help reduce your risk of potential adverse effects of PDE5 inhibitors as well as negative drug interactions. 

Nitrates

One of the most serious drug interactions you’ll see with PDE5 inhibitors happens when someone takes them with nitrates. Nitrates (e.g., nitroglycerin) are drugs often used to treat chest pain (angina) from heart disease or other heart conditions. Amyl nitrite, or "poppers," are another example of nitrates. The use of PDE5 inhibitors with nitrates can lead to a severe drop in blood pressure with potentially fatal consequences. These should not be taken together (Padda, 2021). 

Alpha-blockers

Sticking with the same theme of low blood pressure, you should not take PDE5 inhibitors with alpha-blockers. Alpha-blockers are used to treat high blood pressure or certain prostate issues like benign prostatic hyperplasia (BPH). Combining these drugs with PDE5 inhibitors can again lead to a dangerous situation where your blood pressure is too low. Examples of alpha-blockers include tamsulosin (brand name Flomax) and terazosin (brand name Hytrin) (Padda, 2021).

Other interactions

Lastly, drugs that affect how the liver metabolizes PDE5 inhibitors can increase your risk of side effects. The liver uses the CYP3A4 enzyme system to break down PDE5 inhibitors. Drugs that stop or slow this process include itraconazole, ketoconazole, erythromycin, indinavir, and ritonavir. Grapefruit juice can also affect the CYP3A4 system, so avoid drinking large quantities (Padda, 2021).

There may be other potential drug interactions with PDE5 inhibitors. Seek medical advice from your pharmacist or healthcare professional if you have questions or concerns. 

Although all of these medications are PDE5 inhibitors, they all have subtle differences in action. That means a healthcare professional may suggest one over the other for reasons specific to you. 

There are also lifestyle factors to consider. For instance, daily Cialis allows for more spontaneity in someone’s sex life over oral medications that require planning around sexual activity. 

Some of these drugs have a longer duration of action, but you may prefer a short-acting medication if you experience side effects. Cost is another factor that may sway your decision. Sildenafil is usually the least expensive of the treatments, while Stendra tends to cost more because it is not available as a generic medication. Overall, the decision comes down to many individual factors.

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How we reviewed this article

Every article on Health Guide goes through rigorous fact-checking by our team of medical reviewers. Our reviewers are trained medical professionals who ensure each article contains the most up-to-date information, and that medical details have been correctly interpreted by the writer.

Current version

February 17, 2022

Written by

Chimene Richa, MD

Fact checked by

Steve Silvestro, MD

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About the medical reviewer

Steve Silvestro, MD, Ro

Dr. Steve Silvestro is a board-certified pediatrician and Associate Director, Clinical Content & Education at Ro.