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PDE5 Inhibitors (Procedures)

Phosphodiesterase type 5 (PDE5) inhibitors are the standard oral treatment for erectile dysfunction, and the AUA guideline advises informing every man with ED of this option unless it is contraindicated.[1] By inhibiting PDE5, they prevent the degradation of cyclic GMP, enhance nitric oxide–mediated smooth muscle relaxation in the corpus cavernosum and facilitate erection in response to sexual stimulation. Available agents include sildenafil, tadalafil, vardenafil, and avanafil, with differences in onset, duration, and food or alcohol interactions.

For detailed drug information, see the PDE5 inhibitor pharmacology hub.

Indications​

IndicationPractical role
Erectile dysfunctionStandard oral pharmacotherapy when sexual stimulation is possible and nitrates are not required[1]
LUTS / BPHTadalafil 5 mg daily only; the 2026 AUA BPH guideline advises offering it with or without ED [2][5]
Penile rehabilitation after radical prostatectomyA network meta-analysis found regular sildenafil 100 mg associated with higher erectile-function recovery than placebo after nerve-sparing surgery, while on-demand PDE5i were not shown better than placebo; the AUA guideline advises that early PDE5i use may not improve spontaneous erections[1][3]
Peyronie's disease with EDTreats concomitant ED; disease-modifying antifibrotic benefit remains exploratory
Recurrent ischemic priapismDaily PDE5i has been described as a preventive option in case series with conflicting results[4]

Poor responders include men with severe diabetes, pelvic radiation injury, major neurogenic injury, severe veno-occlusive dysfunction, untreated hypogonadism, or incorrect use. Escalation should move deliberately to intracavernosal injections, intraurethral alprostadil, vacuum erection device, or penile prosthesis.

Mechanism & Agents​

AgentUsual use patternPractical differentiator
SildenafilOn-demandA high-fat meal delays onset and lowers peak levels[6]
TadalafilOn-demand or dailyLongest duration (label: effect up to 36 hours); the PDE5i with a US label for BPH[7]
VardenafilOn-demandLabel advises avoiding it with congenital QT prolongation and class IA or III antiarrhythmics[8]
AvanafilOn-demandThe 100- or 200-mg dose may be taken as early as about 15 minutes before sexual activity; the 50-mg dose is taken about 30 minutes before.[9]

PDE5 inhibitors do not create an erection without sexual stimulation. They preserve NO-driven cGMP signaling. If the upstream neural stimulus is absent or severely impaired, response falls, and therapies that act directly on the corpora, such as ICI, are used.

Key Steps​

  1. Confirm that sexual activity is safe. Screen for organic nitrates or nitrites and guanylate-cyclase stimulators such as riociguat. Before selecting an agent and starting dose, review alpha-blockers, other hypotensive drugs, CYP3A4 inhibitors, and renal and hepatic function; the STENDRA label directs against avanafil use with strong CYP3A4 inhibitors.[6][7][8][9]
  2. Clarify the goal: on-demand intercourse support, daily LUTS/ED therapy, or post-prostatectomy rehabilitation.
  3. Start with a sensible agent and dose, then titrate to effect rather than declaring early failure.
  4. Teach correct use: timing, food effect, need for stimulation, and the expected number of attempts before judging efficacy. Counsel patients to seek emergency care for an erection lasting more than four hours and to stop the drug and seek prompt assessment for sudden visual or hearing loss.[6][9]
  5. Screen for reversible contributors: hypogonadism, medication effects, poorly controlled diabetes, untreated sleep apnea, depression, pelvic pain, and relationship barriers.
  6. If response is inadequate, switch agents or escalate to MUSE, ICI, VED or implant according to the patient's goals and manual comfort. MUSE is discontinued in the United States (see intraurethral alprostadil).

Inadequate response. Confirm adequate dose, timing, food instructions, and sexual stimulation over more than one attempt before judging response. Trying another agent is an option, not a prerequisite to injections, devices, or prosthesis.[1] For rehabilitation after radical prostatectomy, scheduled dosing has a different purpose than on-demand intercourse support, so the regimen should match the indication.

Outcomes & Evidence​

The AUA ED guideline recommends that every man be informed of PDE5 inhibitors unless contraindicated , and that the dose be titrated for efficacy .[1] The 2018 AUA review reported mean IIEF-EF gains of about 8–9 points with sildenafil, tadalafil, vardenafil and avanafil versus about 2 with placebo.[1] A 2026 dose-specific network meta-analysis of on-demand therapy (83 trials; 6,029 participants) ranked sildenafil highest for achieving IIEF-EF >26, but its between-agent comparisons were indirect.[11] Men taking nitrates regularly should not use PDE5 inhibitors.[1] Tadalafil 5 mg daily improves LUTS/BPH symptom scores at 12 weeks in product-label trials and is the only PDE5 inhibitor with a US BPH indication.[5][7] In a Cochrane review, PDE5 inhibitors improved IPSS by a mean 1.89 points more than placebo (95% CI 1.50–2.27 points; 4,293 participants; low-certainty evidence over six to 12 weeks).[2]

For penile rehabilitation, the evidence is mixed. A network meta-analysis of 22 studies (2,711 patients) found that regular sildenafil 100 mg was associated with higher erectile function recovery than placebo (OR 4.00, 95% CrI 1.40–13.4; moderate certainty), while on-demand PDE5i were not shown to be better than placebo.[3] The AUA guideline advises telling men who want to preserve erectile function after radical prostatectomy or radiotherapy that early PDE5i use may not improve spontaneous, unassisted erections .[1] The regimen should therefore match the goal: assisted erections in the early recovery period, or attempted recovery of unassisted function.

For recurrent ischemic priapism, daily PDE5i is not acute treatment. The AUA/SMSNA guideline states that optimal strategies to prevent recurrence are unknown .[4] It lists PDE5 inhibitors among agents used in case series, reports conflicting efficacy, and notes that regimented PDE5i therapy may reduce the frequency and duration of episodes.[4] A 2025 randomized phase 2 feasibility trial in 64 men aged 18–40 with sickle cell anemia and recurrent priapism reported 3.02 versus 2.5 episodes per participant-month with hydroxyurea plus tadalafil versus hydroxyurea plus placebo (median follow-up 10 months; placebo-to-tadalafil rate ratio 0.8, 95% CI 0.3–1.9).[12] The 2026 EAU guideline recommends starting preventive PDE5 inhibitors only when the penis is flaccid .[13]

Nitrate interaction. Nitrates in any form are contraindicated with all four agents, whether used regularly or intermittently.[6][7][8][9] The tadalafil label states that in a life-threatening situation at least 48 hours should pass after the last dose before nitrates are considered.[7] The sildenafil label states that the interval after which nitrates can be given safely is unknown.[6] In a study of 18 healthy subjects, the vardenafil label reports no additional blood-pressure or heart-rate effects when 0.4 mg sublingual nitroglycerin was given 24 hours after a 20 mg LEVITRA dose; it says a safe interval for nitrate administration has not been determined.[8] Princeton IV advises avoiding nitrates for at least 24 hours after sildenafil, vardenafil or avanafil and 48 hours after tadalafil.[10] Avanafil's US label permits consideration after 12 hours only in a life-threatening situation with close hemodynamic monitoring; this is distinct from routine nitrate co-use.[9]

References​

1. Burnett AL, Nehra A, Breau RH, et al. "Erectile dysfunction: AUA guideline." J Urol. 2018;200(3):633-641. doi:10.1016/j.juro.2018.05.004

2. Pattanaik S, Mavuduru RS, Panda A, et al. "Phosphodiesterase inhibitors for lower urinary tract symptoms consistent with benign prostatic hyperplasia." Cochrane Database Syst Rev. 2018;11:CD010060. doi:10.1002/14651858.CD010060.pub2

3. Sari Motlagh R, Abufaraj M, Yang L, et al. "Penile rehabilitation strategy after nerve-sparing radical prostatectomy: a systematic review and network meta-analysis of randomized trials." J Urol. 2021;205(4):1018-1030. doi:10.1097/JU.0000000000001584

4. Bivalacqua TJ, Allen BK, Brock GB, et al. "The diagnosis and management of recurrent ischemic priapism, priapism in sickle cell patients, and non-ischemic priapism: an AUA/SMSNA guideline." J Urol. 2022;208(1):43-52. doi:10.1097/JU.0000000000002767

5. Goueli R, Badlani GH, Welliver C, et al. "Management of lower urinary tract symptoms attributed to benign prostatic hyperplasia: AUA guideline (2026) Part II: medical management." J Urol. 2026;216(2):152-160. doi:10.1097/JU.0000000000005098

6. VIAGRA (sildenafil citrate) prescribing information. Pfizer/Viatris. DailyMed.

7. CIALIS (tadalafil) prescribing information. Eli Lilly. DailyMed.

8. LEVITRA (vardenafil) prescribing information. DailyMed.

9. STENDRA (avanafil) prescribing information. Metuchen Pharmaceuticals. DailyMed.

10. Kloner RA, Burnett AL, Miner M, et al. "Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health." J Sex Med. 2024;21(2):90-116. doi:10.1093/jsxmed/qdad163

11. Salonia A, Bettocchi C, Burnett A, et al. "A comparative evaluation of on-demand phosphodiesterase-5 inhibitor efficacy in erectile dysfunction treatment: a systematic review and network meta-analysis of double-blind, placebo-controlled, randomized trials." J Sex Med. 2026;23(7):qdag176. doi:10.1093/jsxmed/qdag176

12. Idris IM, Yusuf AA, Ismail II, et al. "A controlled trial for preventing priapism in sickle cell anemia: hydroxyurea plus placebo vs hydroxyurea plus tadalafil." Blood. 2025;145(26):3101-3112. doi:10.1182/blood.2024027898

13. European Association of Urology. "EAU Guidelines on Sexual and Reproductive Health: Priapism." EAU Guidelines. 2026. Guideline