PDE5 inhibitors

High-yield Verified · Oct 2026

Prototype: sildenafil

PDE5 inhibitors are a class of medications used for sildenafil.

Medical view → mechanisms, drug comparisons and Step 1 pharmacology

They amplify a signal the body must start — no sexual stimulation, no effect. The danger is in what else dilates when cGMP stays high.

How it works in the body

The system involved, what goes wrong, and how the drug and body interact.

01 How an erection is amplified

During sexual stimulation, nitric oxide (NO) is released in the corpus cavernosum. NO activates guanylate cyclase, raising cGMP, which relaxes cavernosal smooth muscle and lets blood flow in. PDE5 breaks down cGMP; inhibiting it keeps cGMP high, so the erection is enhanced.

The drugs have no direct relaxant effect and no effect in the absence of sexual stimulation — they only amplify a signal that stimulation starts. Their names share the stem -afil.

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Sexual stimulation starts the signal; PDE5 inhibitors keep cGMP from being broken down.

02 The four drugs

Sildenafil (Viagra) and vardenafil have terminal half-lives of about 4 to 5 hours; avanafil about 5 hours. Tadalafil (Cialis) lasts much longer — a mean terminal half-life of 17.5 hours — and is labeled for benign prostatic hyperplasia as well as erectile dysfunction, alone or together. All are cleared mainly by CYP3A4.

Sildenafil is also marketed as Revatio, and tadalafil as Adcirca, for pulmonary arterial hypertension (see the Pulmonary hypertension agents page). The labels warn not to combine them with another PDE5 inhibitor.

03 Nitrates, riociguat and α-blockers

Nitrates raise cGMP formation while PDE5 inhibitors block its breakdown, so together they cause severe, potentially life-threatening hypotension. Every PDE5 inhibitor is contraindicated with organic nitrates in any form, regular or intermittent (see the Nitrates page). If a nitrate becomes medically necessary in a life-threatening situation, the labels require at least 48 hours after tadalafil and at least 12 hours after avanafil, with close supervision; for sildenafil and vardenafil a safe interval has not been determined. Guanylate cyclase stimulators such as riociguat are also contraindicated, for the same reason.

PDE5 inhibitors and α-blockers are both vasodilators, so their effects on blood pressure add. Patients should be stable on the α-blocker before a PDE5 inhibitor is started, at the lowest dose (see the α-adrenergic antagonists page). Tadalafil is not recommended with α-blockers for BPH. Substantial alcohol and other antihypertensives also add to the drop in blood pressure.

04 Rare but serious effects

An erection lasting more than 4 hours needs immediate medical help: untreated priapism can damage penile tissue and cause permanent loss of potency. Sudden loss of vision in one or both eyes may signal non-arteritic anterior ischemic optic neuropathy (NAION), and sudden hearing loss has been reported; in either case the drug is stopped and medical attention sought.

Sexual activity itself carries cardiac risk, so these drugs are generally not used in men for whom sexual activity is inadvisable because of their cardiovascular status. Vardenafil prolongs the QT interval and is avoided in congenital QT prolongation and with class IA or III antiarrhythmics.

Drug names

Generic Brand

sildenafil Viagra

tadalafil Cialis

vardenafil —

avanafil —

Indications

Sildenafil (Viagra) — treatment of erectile dysfunction
Tadalafil (Cialis) — treatment of erectile dysfunction; the signs and symptoms of benign prostatic hyperplasia; and ED with the signs and symptoms of BPH
Vardenafil — treatment of erectile dysfunction
Avanafil — treatment of erectile dysfunction in adult males

Mechanism of action

During sexual stimulation, nitric oxide released in the corpus cavernosum activates guanylate cyclase, increasing cGMP, which relaxes cavernosal smooth muscle and allows blood inflow. PDE5 degrades cGMP; selective PDE5 inhibition keeps cGMP elevated and enhances the erection. The drugs have no direct relaxant effect and no effect without sexual stimulation. Weaker inhibition of PDE6 in the retina is thought to underlie color-vision changes.

In plain terms

Arousal sends a chemical signal that relaxes the penis’s blood vessels so it fills with blood. An enzyme normally switches that signal off. These drugs block the off switch — so the signal works better, but only once arousal has started it.

Therapeutic effects — what you'll see working

Success is an erection firm enough for intercourse in response to sexual stimulation — or, with tadalafil for BPH, fewer urinary symptoms — without hypotension.

Improved erectile response BPH symptom relief (tadalafil)

Improved erectile response: With sexual stimulation, inhibition of PDE5 raises cGMP in the corpus cavernosum, causing smooth muscle relaxation and blood inflow.
BPH symptom relief (tadalafil): Tadalafil treats the signs and symptoms of BPH; PDE5 inhibition raises cGMP in the prostate and bladder smooth muscle, though how this relieves symptoms has not been established.

Adverse effects

The common effects are vasodilation — headache, flushing, nasal congestion — plus dyspepsia, back pain and myalgia. The serious ones are hypotension with interacting drugs, priapism, and sudden vision or hearing loss.

Hypotension with nitrates, riociguat, α-blockers or alcohol Report immediately

PDE5 inhibitors potentiate the hypotensive effects of nitrates and guanylate cyclase stimulators, and add to α-blockers, other antihypertensives and substantial alcohol.

Nitrates and riociguat are contraindicated. With α-blockers, the patient is stable on the α-blocker first and the PDE5 inhibitor starts at the lowest dose; symptomatic hypotension — dizziness, lightheadedness, fainting — can occur.

Prolonged erection and priapism Report immediately

Erections lasting more than 4 hours and priapism (painful erections over 6 hours) have been reported.

If priapism is not treated immediately, penile tissue damage and permanent loss of potency can result. Use with caution in anatomical deformation of the penis or conditions that predispose to priapism, such as sickle cell anemia, multiple myeloma or leukemia.

Sudden vision loss (NAION) Report immediately

Sudden loss of vision in one or both eyes may be a sign of non-arteritic anterior ischemic optic neuropathy, reported rarely with all PDE5 inhibitors.

Patients stop the drug and seek medical attention. Men who have had NAION are at increased risk of recurrence, and a “crowded” optic disc also raises the risk.

Sudden hearing loss Report immediately

Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported in temporal association with PDE5 inhibitors.

Patients stop the drug and seek prompt medical attention.

Cardiovascular risk of sexual activity Hold & notify

Treatments for erectile dysfunction should generally not be used in men for whom sexual activity is inadvisable because of their cardiovascular status.

Their systemic vasodilation calls for caution with left ventricular outflow obstruction (such as aortic stenosis) and severely impaired autonomic control of blood pressure. Patients who develop angina, dizziness or nausea at the start of sexual activity stop and discuss it with their physician.

QT prolongation (vardenafil) Hold & notify

Vardenafil increases the QTc interval; patients with congenital QT prolongation or taking class IA or III antiarrhythmics should avoid it.

Headache, flushing, dyspepsia, nasal congestion, back pain Expected

These are among the most common adverse reactions on the sildenafil and tadalafil labels, along with myalgia; sildenafil’s list adds abnormal vision, and tadalafil’s pain in limb.

Tadalafil’s back pain or myalgia generally occurs 12 to 24 hours after a dose and typically resolves within 48 hours. Transient blue/green color discrimination changes are consistent with PDE6 inhibition in the retina.

Interactions

PDE5 inhibitors + organic nitrates (including nitroglycerin) or nitric oxide donors drug

Severe hypotension — contraindicated.

PDE5 inhibitors + riociguat or other guanylate cyclase stimulators drug

Potentiated hypotension — contraindicated.

PDE5 inhibitors + α-blockers or other antihypertensives drug

Additive blood-pressure lowering — be stable on the α-blocker first and start the PDE5 inhibitor at the lowest dose.

PDE5 inhibitors + strong CYP3A4 inhibitors (ritonavir, ketoconazole, itraconazole, clarithromycin) or erythromycin drug

Higher drug exposure — sildenafil, tadalafil and vardenafil need dose limits; avanafil is not used with strong inhibitors.

Tadalafil + CYP3A4 inducers (rifampin) drug

Markedly reduced tadalafil exposure.

Vardenafil + class IA or III antiarrhythmics drug

Additive QT prolongation — avoid.

Tadalafil + substantial alcohol (5 units or more) food

Greater potential for orthostatic signs and symptoms — both are vasodilators.

Tadalafil + grapefruit juice food

Likely to increase tadalafil exposure (CYP3A4 inhibition).

Contraindications

Apart from hypersensitivity, the contraindications are the drugs that would add to the same cGMP pathway: nitrates and guanylate cyclase stimulators. Everything else is a caution about blood pressure, the heart, the eye, or a predisposition to priapism.

Any PDE5 inhibitor — organic nitrates or nitric oxide donors in any form, regular or intermittent

Labeled contraindication — PDE5 inhibitors potentiate the hypotensive effect of nitrates.

Any PDE5 inhibitor — guanylate cyclase stimulators such as riociguat

Labeled contraindication — PDE5 inhibitors may potentiate their hypotensive effects.

Sildenafil, tadalafil or avanafil — hypersensitivity to the drug or a component

Labeled contraindication; tadalafil reactions have included Stevens-Johnson syndrome and exfoliative dermatitis.

Men for whom sexual activity is inadvisable because of cardiovascular status use caution

Sexual activity carries cardiac risk in preexisting cardiovascular disease.

α-blocker therapy (and, for tadalafil in BPH, α-blockers at all) use caution

Additive vasodilation can cause symptomatic hypotension; tadalafil with α-blockers is not recommended for BPH.

Prior NAION, a “crowded” optic disc, or retinitis pigmentosa use caution

Higher risk of NAION; retinitis pigmentosa, in which some patients have genetic disorders of retinal phosphodiesterases, has not been studied.

Penile deformity, or sickle cell anemia, multiple myeloma or leukemia use caution

Predisposition to priapism.

Avanafil — strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin and others) use caution

The label says not to use avanafil with them; they greatly increase its exposure.

Vardenafil — congenital QT prolongation or class IA or III antiarrhythmics use caution

Vardenafil prolongs the QT interval and should be avoided.

When to hold

Assess before giving — these findings mean hold the dose and act.

Chest pain needing nitroglycerin in a patient who has taken a PDE5 inhibitor

Tell the provider which PDE5 inhibitor and when — nitrates are contraindicated; if one is essential after tadalafil or avanafil, it is given only after the labeled interval with close hemodynamic monitoring; after sildenafil or vardenafil, a safe interval has not been determined.

Erection lasting more than 4 hours

Seek immediate medical care — untreated priapism can permanently damage penile tissue.

Sudden loss of vision in one or both eyes, or sudden hearing loss

Stop the drug and seek medical attention — possible NAION or sudden sensorineural hearing loss.

Dizziness, lightheadedness or fainting after a dose, especially with an α-blocker

Hold and notify — symptomatic hypotension.

Labs & levels

Test Therapeutic / normal Toxic / critical

Blood pressure When starting with an α-blocker or antihypertensives, and after adding CYP3A4 inhibitors — —

Vision and hearing Ask about sudden changes during therapy — —

Nursing considerations

The RN-specific layer — each action paired with the reason it matters.

Before starting

Ask about nitrates in any form — including as-needed nitroglycerin — and riociguat.

Why: Both are contraindicated: the combination can cause severe hypotension.

Review α-blockers, antihypertensives and CYP3A4 inhibitors (such as ritonavir or ketoconazole) on the medication list.

Why: They add to blood-pressure lowering or raise drug levels; with an α-blocker the patient should already be stable on it.

Ask about heart disease and whether sexual activity is safe for the patient.

Why: These drugs are generally not used when sexual activity is inadvisable because of cardiovascular status.

Teaching

Explain that the drug works only with sexual stimulation.

Why: PDE5 inhibitors have no effect in its absence.

Teach the patient to seek immediate care for an erection lasting more than 4 hours.

Why: Untreated priapism can permanently damage penile tissue.

Teach the patient to stop the drug and seek care for sudden vision loss in one or both eyes or sudden hearing loss.

Why: These may signal NAION or sudden hearing loss.

Teach the patient to tell emergency staff that a PDE5 inhibitor was taken if chest pain develops, and to avoid combining it with other PDE5 inhibitors (including those taken for pulmonary hypertension) or heavy alcohol.

Why: Nitrates may be withheld or delayed after a PDE5 inhibitor, and combinations further lower blood pressure.

Remind the patient that the drug offers no protection against sexually transmitted infections.

Why: The labels advise counseling on protective measures.

Common questions

What are PDE5 inhibitors used for?

Sildenafil (Viagra) for treatment of erectile dysfunction. Tadalafil (Cialis) for treatment of erectile dysfunction. Vardenafil for treatment of erectile dysfunction. Avanafil for treatment of erectile dysfunction in adult males.

How do PDE5 inhibitors work?

What are the serious side effects of PDE5 inhibitors?

Watch for PDE5 inhibitors potentiate the hypotensive effects of nitrates and guanylate cyclase stimulators, and add to α-blockers, other antihypertensives and substantial alcohol; erections lasting more than 4 hours and priapism (painful erections over 6 hours) have been reported; sudden loss of vision in one or both eyes may be a sign of non-arteritic anterior ischemic optic neuropathy, reported rarely with all PDE5 inhibitors.

When should a nurse hold PDE5 inhibitors, and what safety checks apply?

Chest pain needing nitroglycerin in a patient who has taken a PDE5 inhibitor: tell the provider which PDE5 inhibitor and when — nitrates are contraindicated; if one is essential after tadalafil or avanafil, it is given only after the labeled interval with close hemodynamic monitoring; after sildenafil or vardenafil, a safe interval has not been determined. Erection lasting more than 4 hours: seek immediate medical care — untreated priapism can permanently damage penile tissue. Sudden loss of vision in one or both eyes, or sudden hearing loss: stop the drug and seek medical attention — possible NAION or sudden sensorineural hearing loss. Dizziness, lightheadedness or fainting after a dose, especially with an α-blocker: hold and notify — symptomatic hypotension.

What labs should be monitored with PDE5 inhibitors?

Monitor blood pressure, and vision and hearing.

Sources

Reviewed by Hae Suk Lee, RN

Educational summary for nursing students. Always verify against current prescribing information and your institution's protocols before administering. Not medical advice.