PDE5 Inhibitors: Common ED Drugs & How They Work

If you’ve searched online for information about treating erectile dysfunction (ED), you’ve likely heard of medications called PDE5 inhibitors.

PDE5 inhibitors are medications that improve blood flow to certain tissues, including the tissue of the penis. They work by inhibiting the action of phosphodiesterase-5, an enzyme that can be found in the smooth muscle cells of blood vessels.

Although PDE5 inhibitors were originally designed to treat cardiovascular health issues, they’re most commonly used today to treat erectile dysfunction.

Common PDE5 inhibitors available today include Viagra® (which contains the active ingredient sildenafil), Cialis® (tadalafil), Levitra® (vardenafil) and Stendra® (avanafil).

Below, we’ve explained what PDE5 inhibitors are, how they work and how you might be able to use them to treat erectile dysfunction.

We’ve also discussed several important topics related to PDE5 inhibitors, from side effects and interactions to frequently asked questions and more.

PDE5 inhibitors, or phosphodiesterase type 5 inhibitors, are medications that block the actions of cGMP-specific phosphodiesterase type 5 -- an enzyme that’s responsible for controlling the size of the blood vessels that supply the penis and other parts of the body.

Originally, PDE5 inhibitors were developed as treatments for cardiovascular conditions such as angina and hypertension (high blood pressure). 

During clinical trials carried out in the early 1990s, patients who received the first PDE5 inhibitor -- a substance named UK-92,480 -- reported several side effects, including penile erections.

Initially, the researchers testing UK-92,480 (which is now known as sildenafil, or Viagra), viewed this as of minor significance. However, over time, the focus of the trials changed from conditions such as angina and hypertension to the use of PDE5 inhibitors to treat erectile dysfunction.

These days, PDE5 inhibitors such as sildenafil and others are used by tens of millions of men in the United States and many more worldwide to treat erectile dysfunction.

In addition to treating ED, some PDE5 inhibitors are also used to treat premature ejaculation -- another common form of male sexual dysfunction.

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

The PDE5 enzyme breaks down a cyclic nucleotide called cyclic guanosine monophosphate, or cGMP, which is responsible for relaxing smooth muscle tissue and regulating blood flow to parts of the body, including the erectile tissue of the penis.

To understand how PDE5 inhibitors work as treatments for ED, it’s important to quickly go over the basics of how your body gets and sustains an erection.

When you’re sexually stimulated, your nervous system releases neurotransmitters, or chemical messengers, into the corpora cavernosa -- the soft, sponge-like erectile tissue that forms most of your penis.

These neurotransmitters trigger the release of nitric oxide, which causes the blood vessels that supply your penis to become wider. As blood flows to your penis, the corpora cavernosa starts to expand, creating a larger, firmer erection.

In order to maintain blood pressure inside your penis and sustain the erection, a type of fibrous tissue called the tunica albuginea traps blood inside the corpora cavernosa during sex.

A variety of factors can affect this process, including health issues such as high blood pressure, cardiovascular disease and damage to the nerves in and around your penis.

You can think of PDE5 as a type of metaphorical red light for this process. When PDE5 is able to degrade cyclic guanosine monophosphate, 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.

While 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.

Other areas of the body affected by PDE5 inhibitors include the pulmonary vasculature (blood vessels inside the lungs) and the lower urinary tract. 

Like other medications, the effects of most PDE5 inhibitors aren’t immediate. Depending on the specific medication you take, you’ll typically need to wait for 15 to 60 minutes before you’ll find it easier to get an erection.

One important point to note is that PDE5 inhibitors won’t cause you to become sexually aroused on their own, or to get erections randomly. 

Instead, they’ll make it easier for you to get and maintain an erection only when you already feel sexually aroused or stimulated. 

PDE5 inhibitors are used to treat several conditions that affect areas of the body in which blood flow is controlled by the PDE5 enzyme. Currently, PDE5 inhibitors are approved by the FDA to treat the following conditions:

Erectile Dysfunction (ED)

PDE5 inhibitors are best known for their effects on erectile dysfunction. Popular prescription ED pills such as Viagra (sildenafil), Cialis (tadalafil), Levitra (vardenafil) and Stendra (avanafil) work by inhibiting 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. 

Erectile dysfunction can range in severity. Some men with ED may find it difficult or impossible to get an erection at any time, while others may be able to get an erection, but find it difficult to sustain an erection that’s firm or consistent enough for penetrative sex.

Currently, 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, last for anywhere from a few hours to longer than a day, and generally only cause mild, transient side effects.

Pulmonary Hypertension (PH)

Some PDE5 inhibitors are used to treat pulmonary hypertension, a form of high blood pressure that affects the arteries in the lungs. 

Pulmonary hypertension can affect blood flow throughout your body and cause symptoms such as shortness of breath, chest pain, tiredness and a fast heart rate. Over time, it can cause the heart to weaken and contribute to heart failure.

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 prescribed to treat pulmonary hypertension. Currently, sildenafil (sold as Revatio® when prescribed for PH) and tadalafil (sold as Adcirca®) are prescribed to manage the symptoms of pulmonary hypertension.

Benign Prostatic Hyperplasia (BPH)

Benign prostatic hyperplasia, or prostate enlargement, is a very common condition that tends to occur in older men. In fact, data shows that 70 percent of all US men in their 60s and 80 percent of men in their 70s or older are affected by some degree of benign prostatic hyperplasia.

Symptoms of BPH include a frequent, urgent need to urinate, dribbling after urination, a need to urinate during the night and pain after ejaculation or during urination. Over the long term, BPH can contribute to urinary tract infections (UTIs) and damage to the renal system.

Right now, Cialis (tadalafil) is the only PDE5 inhibitor that’s approved by the FDA as a treatment for the signs and symptoms of benign prostatic hyperplasia.

The first PDE5 inhibitors became available in the late 1990s. Today, several PDE5 inhibitors are available in the United States and internationally as prescription medications for ED, pulmonary hypertension and benign prostatic hyperplasia.

We’ve listed the four most common PDE5 inhibitors below and explained how each medication works. 

Sildenafil (Viagra, Revatio)

Sildenafil, which is sold as a generic medication and under the brand name Viagra, is arguably the most well-known PDE5 inhibitor on the market. It was first approved by the FDA in 1998 as a treatment for ED and is used by millions of men worldwide.

The FDA has currently approved sildenafil as a treatment for erectile dysfunction and pulmonary arterial hypertension. 

Sildenafil was the original PDE5 inhibitor -- the first medication of its type to become available to the public. Key advantages of sildenafil include its low cost, availability and its long track record, with decades of use and a huge number of clinical studies behind it. 

Sildenafil is a short-acting PDE5 inhibitor that provides relief from ED symptoms for a period of approximately four hours. For optimal results, it should be used with or without food about one hour before sexual activity.

The recommended dose of sildenafil is 50mg, used as needed. This may be reduced to 25mg or increased to 100mg 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 will determine if a prescription is appropriate.

Tadalafil (Cialis, Adcirca)

Tadalafil, which is available as a generic drug and as Cialis, is a long-lasting PDE5 inhibitor that was approved by the FDA in 2003. It’s referred to as the “weekend pill” due to the fact that it can provide relief from erectile dysfunction for up to 36 hours per dose.

This long duration of action makes tadalafil a good choice for people that prefer to avoid taking multiple tablets to treat ED over the course of several days. 

Tadalafil is also available in daily-use form. This version of tadalafil offers an “always-on” effect, meaning it can be taken without regard to timing of sexual activity.

The recommended dose of tadalafil for use as needed is 10mg, which may be adjusted to 20mg or decreased to 5mg based on efficacy and tolerability. Daily-use tadalafil is typically taken at a starting dose of 2.5mg, which may be increased to 5mg per day over time.

We offer generic tadalafil and Cialis online, following a consultation with a licensed healthcare provider who will determine if a prescription is appropriate.

Avanafil (Stendra)

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

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

This makes avanafil a good medication to consider if you want something that you can take just before sex, without having to plan your medication use ahead of time. 

Although avanafil does have some adverse effects, it’s less likely to cause the vision issues that can occur with other PDE5 inhibitors.

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

We offer Stendra online, following a consultation with a healthcare provider who will determine if a prescription is appropriate.

Vardenafil (Levitra, Staxyn™)

Vardenafil is a PDE5 inhibitor that 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, although it provides relief from ED for slightly longer, with the effects of a typical dose lasting for 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 in its effectiveness. Like other PDE5 inhibitors, vardenafil is only available with a prescription.

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

Most of the side effects caused by PDE5 inhibitors are mild and temporary. However, there are several severe side effects that can occur when PDE5 inhibitors are misused, taken with other medications or used by people with underlying health conditions. 

Common adverse effects of PDE5 inhibitors include:

• Headaches

• Facial flushing

• Dyspepsia (indigestion)

• Nasal congestion

• Cold-like symptoms

• Visual abnormalities

• Back and/or muscle pain

Severe side effects from PDE5 inhibitors are typically uncommon, although they can occur. Rare and serious side effects of PDE5 inhibitors can include: 

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

• Hearing issues. A very small number of men who use PDE5 inhibitors such as sildenafil report developing 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 issues, such as sudden loss of vision in one or both eyes. Like priapism and hearing issues, this is a potentially severe side effect that requires immediate medical attention.

Because 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 a newer medication that’s more selective for PDE5, avanafil is less likely to cause some side effects than older PDE5 inhibitors. However, avanafil can still cause side effects and should only be used as prescribed. 

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

To prevent drug interactions, it’s important to inform your healthcare about all of the medications you currently use or have recently used before taking any type of PDE5 inhibitor.

We’ve provided more information about PDE5 inhibitor drug interactions and safety issues in the section below.

Can PDE5 Inhibitors Interact With Other Medications?

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

In some cases, interactions involving PDE5 inhibitors and other medications can be dangerous and even life-threatening. 

PDE5 inhibitors can interact with nitrates -- a class of prescription medications that are used to treat hypertension, angina and symptoms of heart failure. Some illicit drugs, such as “poppers” that contain alkyl nitrites, can also interact with PDE5 inhibitors.

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

Other medications, such as alpha blockers, antibiotics, antifungal medications and medications used to treat HIV, can also potentially interact with PDE5 inhibitors. It is not safe to use more than one PDE5 inhibitor at a time.

To keep yourself safe, make sure to inform your healthcare provider about any medications you currently use or have recently used before taking any type of PDE5 inhibitor. 

Finally, like other common medications, some PDE5 inhibitors may take longer to start working if taken with fatty food.

Are PDE5 Inhibitors Available Over the Counter?

PDE5 inhibitors such as sildenafil (Viagra), tadalafil (Cialis), vardenafil (Levitra) and avanafil (Stendra) are all prescription medications in the United States. 

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

• Talking to your primary care provider

• Meeting with a urologist (a doctor that specializes in ED and conditions that affect the urinary tract and male reproductive system)

• Accessing ED medication using our online platform

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 in following a normal dosage of sildenafil for erectile dysfunction.

Although PDE5 inhibitors can produce a small drop in arterial blood pressure, they are not used to treat hypertension and should not be used as high blood pressure medications. 

What’s the Best PDE5 Inhibitor?

There’s no “best” PDE5 inhibitor for everyone. Research generally suggests that 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 for treating erectile dysfunction for short periods, such as one night at a time.

• Long-lasting PDE5 inhibitors, such as tadalafil, are worth considering if you want to use a single medication to provide relief from ED for several days, or if you want a daily use medication that you can take on a long-term basis.

• Newer PDE5 inhibitors, such as avanafil, are likely the best option for you if you’re prone to side effects from other ED medications, or if you need 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 that a different medication could be a better choice for you, it’s best to talk to your healthcare provider. It’s normal to use several PDE5 inhibitors before selecting the medication that works best for you. 

Erectile dysfunction is a common problem that can affect 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 with a combination of healthy habits and PDE5 inhibitors, including the medications listed above. 

We offer several ED medications online, including sildenafil and Viagra, tadalafil and Cialis and Stendra. You can also learn more about the causes of ED and treatment options in our guide to erectile dysfunction.