PDE5 inhibitors
High-yield Verified · Oct 2026Nitric oxide turns cGMP on; PDE5 turns it off. Block the off switch and every source of cGMP — including a nitrate — is amplified.
Nursing view → administration, monitoring and patient teaching
Drugs
Mechanism
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.
NO, guanylate cyclase and cGMP
During sexual stimulation, nitric oxide is released from nerve terminals and endothelial cells in the corpus cavernosum. NO activates guanylate cyclase, which raises cGMP. cGMP activates cGMP-dependent protein kinase, which lowers intracellular calcium, increases potassium efflux and deactivates myosin light chain kinase — the smooth muscle relaxes, the sinusoids fill with blood, and the subtunical veins are compressed against the tunica albuginea.
PDE5 degrades cGMP. Inhibiting it keeps cGMP elevated, but only when NO is being released: sildenafil has no direct relaxant effect on isolated corpus cavernosum and no effect in the absence of sexual stimulation. Sildenafil is a structural mimic of cGMP that competes for the enzyme’s catalytic site. The same cGMP rise in the pulmonary arteries is why sildenafil and tadalafil also treat pulmonary arterial hypertension (Pulmonary hypertension agents page).
Why nitrates and riociguat are contraindicated
Nitrates increase cGMP formation while PDE5 inhibitors block its degradation, so together they produce severe, life-threatening hypotension; the labels contraindicate organic nitrates or NO donors in any form, regular or intermittent (Nitrates page). Guanylate cyclase stimulators such as riociguat feed the same pathway and are contraindicated too.
The labeled waiting periods differ by drug. Sildenafil and vardenafil have terminal half-lives of about 4 to 5 hours, and avanafil about 5 hours; tadalafil’s mean terminal half-life is 17.5 hours. If a nitrate becomes essential in a life-threatening situation, the labels require at least 48 hours after tadalafil and at least 12 hours after avanafil, with close hemodynamic monitoring; for sildenafil and vardenafil a safe interval has not been determined.
α-blockers, CYP3A4 and the QT interval
PDE5 inhibitors and α-adrenergic blockers are both vasodilators, so their blood-pressure effects add and can cause symptomatic hypotension. Patients should be stable on the α-blocker first, and the PDE5 inhibitor started at the lowest dose (α-adrenergic antagonists page). For BPH, tadalafil is not recommended with an α-blocker at all.
All four are cleared mainly by CYP3A4. Ritonavir increased sildenafil exposure 11-fold; potent inhibitors (ritonavir, ketoconazole, itraconazole) and erythromycin raise exposure, and avanafil is not used with strong inhibitors at all. Rifampin, an inducer, reduced tadalafil exposure by 88%. Vardenafil also prolongs the QT interval, so it is avoided in congenital QT prolongation and with class IA or III antiarrhythmics.
Selectivity and the side effects
Sildenafil is only about 10-fold more selective for PDE5 than for PDE6, a retinal enzyme in phototransduction; this lower selectivity is thought to underlie its color-vision changes — transient blue/green discrimination impairment. It is about 4,000-fold more selective for PDE5 than for PDE3, which controls cardiac contractility. Tadalafil inhibits PDE11, found in prostate, testes and skeletal muscle, within the therapeutic range, but the clinical consequence of PDE11 inhibition has not been defined.
Vasodilation explains the common effects — headache, flushing, nasal congestion. Back pain and myalgia are also on the common lists for sildenafil and tadalafil; with tadalafil they generally occur 12 to 24 hours after a dose. The rare serious effects are labeled class-wide: priapism (an erection over 4 hours needs immediate care), sudden vision loss that may be NAION, and sudden hearing loss.
Tadalafil and BPH
Tadalafil is labeled for the signs and symptoms of benign prostatic hyperplasia, alone or with ED. PDE5 inhibition raises cGMP in prostate and bladder smooth muscle and their vascular supply, though the mechanism of symptom relief has not been established. Because of its long half-life, tadalafil for once daily use gives continuous plasma levels — a point the label asks prescribers to weigh when assessing interactions with nitrates, α-blockers, antihypertensives and potent CYP3A4 inhibitors.
Comparing the drugs
PDE5 inhibitors compared
| Drug | Labeled uses | Terminal half-life | Nitrate interval if essential | Distinctive label point |
|---|---|---|---|---|
| Sildenafil (Viagra) | ED (Revatio: PAH) | About 4 hours | Not determined | Only ~10-fold selective vs PDE6, thought to underlie color-vision changes |
| Tadalafil (Cialis) | ED; BPH; ED with BPH (Adcirca: PAH) | 17.5 hours | At least 48 hours | Pain in limb among common effects; not with α-blockers for BPH |
| Vardenafil | ED | About 4–5 hours | Not determined | QT prolongation |
| Avanafil | ED in adult males | About 5 hours | At least 12 hours | Not used with strong CYP3A4 inhibitors |
Pharmacokinetics
- Sildenafil
- Rapidly absorbed (bioavailability about 41%); a high-fat meal slows absorption. Cleared by CYP3A4 (major) and CYP2C9 (minor) to an active N-desmethyl metabolite with half the PDE5 potency; both have terminal half-lives of about 4 hours. Age over 65, hepatic impairment and severe renal impairment raise its levels.
- Tadalafil
- Metabolized by CYP3A4 to an inactive catechol metabolite; mean terminal half-life 17.5 hours. Steady state is reached within 5 days of once-daily dosing.
- Vardenafil and avanafil
- Vardenafil’s terminal half-life is about 4 to 5 hours; ritonavir prolongs it to 26 hours. Avanafil’s terminal half-life is about 5 hours, and both can be taken with or without food.
Uses & drug choice
- 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
Adverse effects
- Severe hypotension with nitrates or riociguat
- More cGMP made (NO donors, GC stimulation) plus less broken down (PDE5 inhibition).
- Symptomatic hypotension with α-blockers
- Two vasodilators with additive blood-pressure lowering.
- Headache, flushing, nasal congestion
- Systemic vasodilation.
- Blue/green color-vision changes
- Thought to reflect weaker selectivity over retinal PDE6, which is involved in phototransduction.
- Priapism
- A labeled class effect that can permanently damage penile tissue if untreated; conditions that predispose include sickle cell anemia, multiple myeloma, leukemia and penile deformity.
- Higher exposure and toxicity with ritonavir or azoles
- CYP3A4 inhibition reduces clearance.
Interactions
Contraindications
- 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.
High-yield
Practice questions
Q1A 63-year-old man with stable angina uses isosorbide mononitrate daily and sublingual nitroglycerin as needed. He asks why he cannot take sildenafil for erectile dysfunction.
What best explains the contraindication?
- A.Nitrates increase cGMP formation while sildenafil blocks its breakdown, causing severe hypotension
- B.Sildenafil blocks guanylate cyclase, so the nitrates stop working
- C.Sildenafil constricts the coronary arteries and worsens angina
- D.Sildenafil relaxes vascular smooth muscle directly, independent of nitric oxide
Show answer
A. Nitrates increase cGMP formation while sildenafil blocks its breakdown, causing severe hypotension — Nitrates are NO donors that increase cGMP formation; sildenafil inhibits PDE5, the enzyme that degrades cGMP, so the combination produces severe, life-threatening hypotension — organic nitrates in any form are contraindicated. Sildenafil does not block guanylate cyclase; NO activates it. Sildenafil has systemic vasodilatory, not vasoconstricting, properties, and it has no direct relaxant effect on isolated corpus cavernosum — it works only by amplifying NO-driven cGMP.
Q2A 67-year-old man takes doxazosin for hypertension and BPH and has been stable on it for a year. His physician plans to start sildenafil for erectile dysfunction.
Which plan follows the labeling?
- A.Start at the highest dose so fewer doses are needed
- B.Add a second antihypertensive to blunt the reflex response
- C.No precaution is needed because the two drugs act on different receptors
- D.Start sildenafil at the lowest dose, since he is already stable on the α-blocker
Show answer
D. Start sildenafil at the lowest dose, since he is already stable on the α-blocker — PDE5 inhibitors and α-adrenergic blockers are both vasodilators with additive blood-pressure lowering that can cause symptomatic hypotension. Patients should be stable on the α-blocker before a PDE5 inhibitor is started, and the PDE5 inhibitor should be started at the lowest dose. Sildenafil also lowers blood pressure further with other antihypertensives, so adding one increases the risk, and the receptor difference does not prevent the additive effect.
Q3A 58-year-old man arrives with crushing chest pain. He took tadalafil 20 hours earlier. The team is considering nitroglycerin.
What does the tadalafil label say about nitrate use here?
- A.Nitroglycerin can be given now because tadalafil is short-acting
- B.At least 48 hours should elapse after the last dose before a nitrate is considered, with close hemodynamic monitoring
- C.A nitrate can be given 4 hours after any PDE5 inhibitor
- D.Nitrates can never be given to anyone who has ever taken a PDE5 inhibitor
Show answer
B. At least 48 hours should elapse after the last dose before a nitrate is considered, with close hemodynamic monitoring — Tadalafil’s mean terminal half-life is 17.5 hours. If a nitrate is medically necessary in a life-threatening situation, at least 48 hours should elapse after the last tadalafil dose before it is considered, and then only under close medical supervision with hemodynamic monitoring. About 4 hours is sildenafil’s half-life, not a nitrate interval, and even for sildenafil a safe interval has not been determined. The label allows a nitrate after the interval, so it is not permanently ruled out.
Q4A 55-year-old man notices that everything looks tinged blue-green for a few hours after taking sildenafil. His vision is otherwise normal, and the change resolves.
What best explains this effect?
- A.Sudden ischemia of the optic nerve head from PDE5 inhibition
- B.PDE3 inhibition in the heart
- C.PDE11 inhibition in skeletal muscle
- D.PDE6 inhibition in the retina
Show answer
D. PDE6 inhibition in the retina — Sildenafil is only about 10-fold more selective for PDE5 than for PDE6, a retinal phototransduction enzyme, and this lower selectivity is thought to underlie the transient blue/green color-discrimination changes. NAION presents as sudden loss of vision, not a transient color tinge. Sildenafil is about 4,000-fold more selective for PDE5 than for PDE3, the cardiac contractility enzyme. PDE11 inhibition is a tadalafil property whose clinical consequence has not been defined.
Sources
- Viagra (sildenafil) — FDA label: indication, contraindications, warnings, interactions, mechanism, pharmacokinetics — FDA / DailyMed
- Cialis (tadalafil) — FDA label: ED and BPH indications, nitrate interval, α-blockers, alcohol, half-life, PDE11 — FDA / DailyMed
- Vardenafil tablets (Lannett) — FDA label: indication, contraindications, QT prolongation, half-life — FDA / DailyMed
- Avanafil tablets (Camber) — FDA label: indication, nitrate interval, CYP3A4 inhibitors, half-life — FDA / DailyMed
- Sildenafil — mechanism, nitrate interaction, monitoring — StatPearls (NCBI)
- The use of stems in the selection of INN (-afil) — World Health Organization
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.