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What are PDE5 Inhibitors, and How Do They Work?

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Medically approved by Dr Earim Chaudry
Chief Medical Officer
iconLast updated 4th May 2021
In 30 seconds…

What are PDE5 inhibitors? A group of drugs including Sildenafil, Tadalafil, and Vardenafil – among others – PDE5 inhibitors are the most effective medical treatment for erectile dysfunction (ED) on the market.

To give them their full name, they are phosphodiesterase 5 inhibitors, and they work to treat ED by targeting that enzyme, PDE5, which is responsible for smooth muscle contraction in the penis. Intervene here and blood flow to the penis can be improved – thus increasing the chance that you will achieve and sustain an erection.

Be aware, though, that medicines have side effects – albeit rare and generally low in severity. PDE5 inhibitors are no exception. If you have low blood pressure or some form.

Erectile Dysfunction and PDE5 Inhibitors

Of all the treatment options for erectile dysfunction, PDE5 inhibitors are the most recognisable, safe, and effective. Millions of men in the UK alone rely on them to ensure they can achieve and sustain an erection long enough for sex.

But what actually are PDE5 inhibitors? They are a group of similar medicines – and the chances are you will know some of them. The mighty Sildenafil – also known by a popular brand that uses it, Viagra, is the most famous. Tadalafil (or Cialis) is a popular option too. Yet, Vardenafil, Avanafil, Udenafil, and others work along similar lines.

In this article, we’re going to show you what it is that PDE5 inhibitors do – and why so many men use them for the treatment of erectile dysfunction (ED). Simply enough, they are safe, easy to use, and effective in 80% of men. You wouldn’t want anything else from your treatment.

What are PDE5 Inhibitors?

So, what are PDE5 inhibitors? Let’s start from the beginning. And that means that, before we turn to the PDE5 inhibitors, we need to talk about PDE5 itself.

PDE5 inhibitors target this PDE5, an enzyme more fully known as phosphodiesterase type-5. Sitting in the smooth muscles that line your blood vessels, the enzyme is responsible for the contraction of these muscles. This means it plays a pivotal role in controlling your blood flow. And that’s a crucial part of the process of achieving an erection.

While PDE5 is famously in the blood vessels supplying the penis, it is also elsewhere in the body. For example, it is in the lungs and it helps control blood flow to your pulmonary arteries, too. This is why PDE5 inhibitors are also used for the treatment of pulmonary hypertension and angina – along with benign prostatic hyperplasia and lower urinary tract symptoms too.

What Do PDE5 Inhibitors Do During an Erection?

In the simplest terms, PDE5 inhibitors encourage blood flow. Through the inhibition of that crucial enzyme, they enable your blood vessels to relax and widen. In the case of ED, this means that more blood gets to where you need it – increasing the chances of your getting and keeping an erection.

How do these drugs do this? We’ll need to get a little technical. Usually, when you are aroused, nitric oxide is released in your penis – and this chemical kickstarts the process that produces cyclic guanosine monophosphate (cGMP). This is crucial, because this cyclic GMP relaxes your smooth muscles and controls how much blood enters and exits the penis.

However, PDE5 tends to destroy cGMP. And that’s how PDE5 inhibitors intervene. With PDE5 inhibited, cGMP can hang around for longer, encouraging better blood flow. And this, as we know, means better erections.

What are the Important PDE5 Inhibitors for Treating ED?

So, we know the science behind PDE5 inhibitors. Now, we need to look at the drugs themselves. While there is a list that is ever-growing – including still unapproved newcomers like Mirodenafil, Lodenafil, and Udenafil – the most common medications in the group are more familiar. These are Sildenafil and Tadalafil.


Sildenafil – or Sildenafil Citrate – is known due to the brand, Viagra, which uses it as its active ingredient. This is the original PDE5 inhibitor designed by Pfizer. However, different names don’t mean a different substance – and it is the Sildenafil itself that does the heavy lifting.

You can expect Sildenafil to be at its most effective around an hour after you have taken it – and its effects should last for about 4-6 hours. This should give you all the time you need to enjoy it.

Importantly, it is licenced in the UK for the treatment of ED – while many of the less familiar PDE5 inhibitors are not. This is because many clinical trials have shown Sildenafil to work in about 80% of cases. One systematic review in European Urology of 150 different trials found that Sildenafil is the most effective PDE5 inhibitor there is.


Tadalafil (Cialis) is the main alternative to Sildenafil. Usually, it is used when men don’t see results from Sildenafil. However, it does have its own specific features, which may make it preferable.

For example, while Tadalafil is effective about 30-45 minutes after ingestion, it lasts much longer than Sildenafil. We’re talking 36 hours. No, this doesn’t mean that you will have an erection for all that time. It means that, if the feeling takes you, you’ll be supported to achieve an erection in the whole length of that time. You do still need to be aroused.

It has a very similar effectivity rate to Sildenafil. You just get that extra flexibility.

What About the Other PDE5 Inhibitors?

Vardenafil (or Levitra) and Avanafil (Stendra) are the other most common PDE5is. However, they do not perform as well as the bigger names in trials. The meta-analysis in European Urology cited above, for example, found Sildenafil better for efficacy, and Tadalafil preferable for tolerability.

However, these alternatives offer possible options if the more familiar treatments do not effectively restore erectile function in your specific case.

What are the Side Effects of PDE5 Inhibitors?

When you are considering which medicines to take, it is important to consider two things: contraindications and possible drug interactions.

We know how PDE5 inhibitors work – and this should give us some idea about possible adverse effects. Firstly, these include those related to your blood pressure. As a result of vasodilation – the widening of your blood vessels – blood pressure drops. This means that dizziness, fatigue, and drowsiness are all possible side effects. Flushing, headaches, and indigestion can happen too.

However, it is not only about your blood pressure. Sildenafil, for example, has been known to cause changes to your vision. This is because an effect of Sildenafil can be to interact with PDE6, which is found in the retina. Tadalafil, meanwhile, is known to cause back pain too. These side effects are mild and temporary however. 

And Drug Interactions?

Due to the way that PDE5 inhibitors work, the Food and Drug Administration (FDA) has advised against its combination with nitrates. Both cause blood vessels to relax, meaning that seriously low blood pressure (hypotension) is a possibility. In some cases, this can be fatal.

There are also warnings when it comes to alpha-blockers, which should be avoided with Tadalafil. However, they can be used alongside Sildenafil if you take them 6 hours apart. For calcium channel blockers and diuretics, the same applies – they should only be taken more than 6 hours after taking a PDE5 inhibitor (or vice versa). Speak to a Manual clinician if you have any questions about this. 

If you are taking medications for cardiovascular disease, it is advised that you seek advice from a healthcare provider before taking PDE5is.

Key Takeaways

What are PDE5 inhibitors? The most effective treatment for erectile dysfunction, these drugs target the enzyme responsible for smooth muscle contraction in the penis. As a result, they promote increased blood flow to where you need it – and increase the chances of your achieving and sustaining an erection.

Tadalafil and Sildenafil are your best bets. They are most effective and they are approved by health bodies in the UK and USA. This is not yet true of many of the others.

While we've ensured that everything you read on the Health Centre is medically reviewed and approved, information presented here is not intended to be a substitute for professional medical advice, diagnosis, or treatment. It should never be relied upon for specific medical advice. If you have any questions or concerns, please talk to your doctor.

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