How Do PDE5 Inhibitors Work? A Complete Guide to ED Medications

PDE5 inhibitors are prescription medications that treat erectile dysfunction by blocking the PDE5 enzyme, allowing increased blood flow to the penis during sexual stimulation.

These medications are the most commonly prescribed treatment for erectile dysfunction (ED) and include well-known brand names like Viagra®, Cialis®, Levitra®, and Stendra®. While they all work through the same biological pathway, they differ in how quickly they take effect, how long they last, and how they’re used.

This guide explains how PDE5 inhibitors work, how each medication compares, and how newer combination therapies are expanding ED treatment options.

What Are PDE5 Inhibitors?

PDE5 inhibitors are a class of medications designed to improve erectile function by supporting the body’s natural response to sexual arousal. They do not cause spontaneous erections — sexual stimulation is still required — but they make it easier to achieve and maintain an erection once arousal occurs.

They are primarily prescribed for erectile dysfunction.

👉 Learn more about common erectile dysfunction symptoms and causes

How PDE5 Inhibitors Work in the Body

An erection begins in the brain and nervous system. During sexual arousal, the body releases nitric oxide (NO) into the erectile tissue of the penis. Nitric oxide increases levels of cyclic guanosine monophosphate (cGMP), which relaxes smooth muscle and allows blood vessels to widen.

This increased blood flow fills the erectile chambers, producing an erection.

The enzyme phosphodiesterase type 5 (PDE5) naturally breaks down cGMP. In men with ED, this breakdown can happen too quickly.

PDE5 inhibitors work by blocking the PDE5 enzyme, allowing cGMP to remain active longer. This improves blood flow and helps sustain an erection — but only in the presence of sexual stimulation.

The Main PDE5 Inhibitors for Erectile Dysfunction

There are four primary PDE5 inhibitors approved for ED treatment in the U.S. Each works similarly but differs in onset time and duration.

Sildenafil (Generic for Viagra®)

Sildenafil is a short-acting PDE5 inhibitor and was the first medication approved for ED.

• How it works: Improves blood flow during sexual stimulation

• Time to work: 30–60 minutes

• How long it lasts: About 4 hours

• Notes: High-fat meals can delay onset

This aligns with FDA labeling and standard clinical guidance.

Tadalafil (Generic for Cialis®)

Tadalafil is a long-acting PDE5 inhibitor known for flexibility and spontaneity.

• How it works: Sustains increased blood flow over a longer period

• Time to work: 30–60 minutes

• How long it lasts: Up to 36 hours

• Notes: Available as daily low-dose or as-needed

The 36-hour duration is FDA-supported and widely cited.

Vardenafil (Generic for Levitra® / Staxyn™)

Vardenafil is similar to sildenafil but slightly more selective.

• How it works: Enhances blood flow by inhibiting PDE5

• Time to work: 30–60 minutes

• How long it lasts: About 4–5 hours

• Notes: Food may have less impact than sildenafil

Avanafil (Stendra®)

Avanafil is designed for faster onset.

• How it works: Selectively targets PDE5

• Time to work: As little as 15 minutes

• How long it lasts: Up to 6 hours

• Notes: Often less affected by food

Both onset and duration align with FDA labeling and prescribing references.

PDE5 Inhibitor Comparison at a Glance

Sildenafil (Generic for Viagra®)

• Time to work: 30–60 minutes

• Duration: ~4 hours

• Best for: Short-acting, as-needed use

Tadalafil (Generic for Cialis®)

• Time to work: 30–60 minutes

• Duration: Up to 36 hours

• Best for: Longest duration and spontaneity

Vardenafil (Generic for Levitra® / Staxyn™)

• Time to work: 30–60 minutes

• Duration: 4–5 hours

• Best for: Predictable short-term use

Avanafil (Stendra®)

• Time to work: As little as 15 minutes

• Duration: Up to 6 hours

• Best for: Fastest onset

Common Side Effects of PDE5 Inhibitors

Most side effects are mild and temporary. Common ones include:

• Headache

• Facial flushing

• Nasal congestion

• Indigestion

• Back or muscle pain (more common with tadalafil)

Do not use PDE5 inhibitors if you take nitrates (commonly prescribed for chest pain), and consult a healthcare provider about other medications and heart conditions before use.

Which PDE5 Inhibitor Is Best?

There is no single “best” ED medication. The right choice depends on:

• Desired onset speed

• How long you want effects to last

• Daily vs as-needed use

• Overall health and medications

A licensed healthcare provider can help determine the most appropriate option.

How Rugiet Ready Works: Combining PDE5 Inhibitors With Apomorphine

Rugiet Ready combines sildenafil (the active ingredient in Viagra®) and tadalafil (the active ingredient in Cialis®) with apomorphine to address both the physical and neurological components of erectile function.

Sildenafil and tadalafil are PDE5 inhibitors that work by improving blood flow to the penis during sexual stimulation. Apomorphine is a dopamine agonist that works in the brain to enhance sexual arousal and initiate the erectile response.

Together, these medications support a more complete and reliable erection by acting on multiple stages of the sexual response.

How the Medications Work Together

• Sildenafil (Viagra®) provides faster, short-acting blood flow support

• Tadalafil (Cialis®) offers longer-lasting blood flow support, remaining active for up to 36 hours

• Apomorphine boosts arousal signaling in the brain by activating dopamine receptors involved in sexual desire

By combining two PDE5 inhibitors with complementary durations and pairing them with a centrally acting dopamine agonist, Rugiet Ready supports both immediate responsiveness and extended effectiveness.

Why Apomorphine Matters

Apomorphine is a dopamine agonist, meaning it stimulates dopamine receptors in the brain that are involved in sexual motivation and arousal. Erections begin in the brain, and dopamine plays a critical role in initiating the signals that lead to an erection.

While PDE5 inhibitors improve blood flow, they do not directly increase arousal. Apomorphine helps bridge that gap by enhancing the brain’s sexual response, which can be especially helpful for men who experience delayed arousal, performance anxiety, or inconsistent results with PDE5 inhibitors alone.

Sublingual Troche for Faster Onset

Rugiet Ready is delivered as a sublingual troche that dissolves under the tongue rather than being swallowed.

This form of delivery allows the medication to be absorbed directly into the bloodstream, which can:

• Lead to effects in 15 minutes or less

• Reduce delays caused by digestion

• Provide more predictable onset timing

How Long Does Rugiet Ready Last?

Because Rugiet Ready includes tadalafil, a long-acting PDE5 inhibitor, it can remain effective for up to 36 hours, offering a wider window for spontaneity compared to short-acting ED medications alone.

As with all prescription erectile dysfunction treatments, Rugiet Ready should be used under the guidance of a licensed healthcare provider.

Final Takeaway

PDE5 inhibitors remain the foundation of erectile dysfunction treatment by improving blood flow during sexual stimulation. From short-acting options like sildenafil to long-lasting medications like tadalafil — and combination therapies like Rugiet Ready — modern ED treatment offers more flexibility and personalization than ever before.