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# Phosphodiesterase-5 inhibitors

Drugs that keep cGMP high in smooth muscle, so blood vessels relax. Used for erectile dysfunction and pulmonary arterial hypertension.

Updated Nov 1, 2026

## What they are

Oral inhibitors of phosphodiesterase type 5 (PDE5), the enzyme that breaks down cyclic GMP in vascular and erectile smooth muscle. Sildenafil and tadalafil treat erectile dysfunction and pulmonary arterial hypertension (PAH); tadalafil also treats the urinary symptoms of benign prostatic hyperplasia. They do not cause an erection by themselves: they amplify the nitric oxide signal released during sexual stimulation.

## Mechanism of action

Nitric oxide activates soluble guanylyl cyclase, which makes cyclic GMP (cGMP); cGMP activates protein kinase G and relaxes smooth muscle. PDE5 ends the signal by hydrolysing cGMP. Blocking PDE5 keeps cGMP high wherever nitric oxide is being made: in the corpus cavernosum (erection), in the pulmonary arteries (lower pulmonary vascular resistance) and in the systemic vessels (a small fall in blood pressure). Because the effect depends on nitric oxide, anything that adds nitric oxide or cGMP (nitrates, riociguat) multiplies it.

Target: Phosphodiesterase type 5 (PDE5A), the cGMP-degrading enzyme of smooth muscle

## Key points

- Never with nitrates in any form (nitroglycerin, isosorbide, amyl nitrite): the combination can cause severe, refractory hypotension.
- Also contraindicated with riociguat, which stimulates the same nitric oxide–cGMP pathway.
- Typical effects come from vasodilation: headache, flushing, nasal congestion and dyspepsia; tadalafil also causes back pain and myalgia.
- Sildenafil also weakly inhibits PDE6 of the retina, which explains transient blue-green colour vision changes.
- Red flags: an erection lasting more than four hours (priapism), sudden loss of vision (NAION) or sudden hearing loss.

## Drugs in this class

- [**Sildenafil** A PDE5 inhibitor that relaxes smooth muscle: it treats erectile dysfunction and, in other strengths, pulmonary… Phosphodiesterase type 5 (cGMP-specific phosphodiesterase)](https://durgical.com/en/pharmacology/sildenafil/)
- [**Tadalafil** A long-acting PDE5 inhibitor for erectile dysfunction, the urinary symptoms of an enlarged prostate and pulmonary… Phosphodiesterase type 5 (cGMP-specific phosphodiesterase)](https://durgical.com/en/pharmacology/tadalafil/)
- [**Vardenafil** An oral PDE5 inhibitor for erectile dysfunction; works only with sexual stimulation and must never be combined with… Phosphodiesterase type 5 (cGMP-specific phosphodiesterase)](https://durgical.com/en/pharmacology/vardenafil/)

## Others in the class

- Vardenafil
- Avanafil

## Test yourself

Think of the answer, then tap the question to see it.

## Which second messenger do PDE5 inhibitors keep high?

Cyclic GMP (cGMP), made by guanylyl cyclase when nitric oxide is released; PDE5 normally breaks it down.

## Why are PDE5 inhibitors contraindicated with nitrates?

Nitrates donate nitric oxide and raise cGMP; blocking its breakdown at the same time can cause severe, life-threatening hypotension.

## Which other pulmonary hypertension drug must not be combined with a PDE5 inhibitor?

Riociguat, a soluble guanylyl cyclase stimulator: the combination potentiates hypotension.

## Do PDE5 inhibitors produce an erection without sexual stimulation?

No. They amplify the nitric oxide released during sexual stimulation; without it there is little cGMP to protect.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: [DailyMed - SILDENAFIL CITRATE tablet](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8127ff38-2761-49ec-8ce7-7f971f521cfb) (DailyMed (U.S. National Library of Medicine), 2026); [DailyMed - TADALAFIL tablet, film coated](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ad14d63-42e7-493f-b56c-e02a4fd139f7) (DailyMed (U.S. National Library of Medicine), 2026).

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