S tier · elite
Sildenafil's approval for erectile dysfunction rests on large, replicated, double-blind randomised trials with unambiguous separation from placebo on both patient-reported and event-level endpoints, and a well-characterised safety profile refined over more than two decades of postmarketing surveillance.
sildenafil
Sildenafil is a selective phosphodiesterase type 5 inhibitor approved for the treatment of erectile dysfunction, with a separate approval under a different brand for pulmonary arterial hypertension. Efficacy for erectile dysfunction was established in sequential double-blind randomised trials and has been replicated extensively.
the explanation
Sildenafil is the original Viagra. It helps blood flow into the penis in response to sexual stimulation, and large blinded trials showed clearly better results than placebo.
regulatory status
FDA-approved
Approved for the treatment of erectile dysfunction (Viagra) and, under a separate brand and label, for pulmonary arterial hypertension (Revatio). Widely approved internationally; available on prescription and, in some jurisdictions, under pharmacist supervision.
how it works · proposed mechanism
Sildenafil is a competitive inhibitor of phosphodiesterase type 5, the cGMP-degrading enzyme in vascular smooth muscle.
Nitric oxide-cGMP amplification
Sexual stimulation releases nitric oxide in the corpus cavernosum, which activates guanylate cyclase to produce cyclic GMP. Sildenafil blocks the PDE5 enzyme that degrades cGMP, raising and prolonging the signal.
Requires sexual stimulation
Because sildenafil amplifies an existing nitric oxide signal rather than generating one, it has little effect without sexual stimulation. This is a defining feature distinguishing it from intracavernosal vasodilators.
Systemic vasodilation and nitrate risk
PDE5 is also expressed in systemic and pulmonary vasculature, producing mild blood pressure reduction. Combined with a nitric oxide donor the effect is synergistic and can cause profound hypotension, which is why nitrates are an absolute contraindication.
what’s reported
evidence shape
5 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
Sildenafil's S grade is earned entirely on erectile dysfunction in men with a diagnosed condition, and it says nothing about recreational performance enhancement in men without ED, where controlled evidence of benefit is not the basis of the approval. It is also a prescription medicine with an absolute nitrate contraindication and documented ocular and otological signals, so treating an S grade as a green light for casual unsupervised use inverts what the evidence actually shows.
key published findings
- Human trial (double-blind, randomised): Goldstein and colleagues studied 532 men in a 24-week dose-response trial and 329 additional men in a 12-week dose-escalation trial; 69% of intercourse attempts were successful on sildenafil versus 22% on placebo.
- Human trial (same study): mean successful attempts per month were 5.9 with sildenafil versus 1.5 with placebo, and the mean score for achieving erections was 100% higher after treatment than at baseline (4.0 vs 2.0) at the highest strength studied.
- Human trial (same study, safety): headache, flushing and dyspepsia were the common adverse effects, occurring in 6% to 18% of participants.
- Human observational (cohort with nested case-control): Etminan and colleagues, analysing the PharMetrics Plus database 2006-2020, reported an adjusted incidence rate ratio for ischaemic optic neuropathy of 2.02 (95% CI 1.14-3.58), with an incidence of 3.2 cases per 10,000 person-years.
- Human observational (case-crossover): Flahavan and colleagues prospectively enrolled 279 men with confirmed NAION at 41 US ophthalmology sites and reported a 12-month rate ratio of 3.52 (95% CI 1.59-7.79) for PDE5 inhibitor exposure, though the 30-day estimate of 2.27 (95% CI 0.99-5.20) crossed unity.
limitations of the evidence
- The pivotal efficacy trials enrolled men with diagnosed erectile dysfunction, so results do not establish benefit in men without the condition.
- NAION evidence is observational; erectile dysfunction and NAION share vascular risk factors, so confounding by indication cannot be fully excluded despite adjustment.
- Endpoints are patient-reported diary and questionnaire measures, which are validated but subject to unblinding through the drug's noticeable side effects.
documented safety signals
- ABSOLUTE CONTRAINDICATION: co-administration with organic nitrates or nitric oxide donors in any form, due to potentially profound and dangerous hypotension.
- ABSOLUTE CONTRAINDICATION: co-administration with guanylate cyclase stimulators such as riociguat.
- Non-arteritic anterior ischaemic optic neuropathy (NAION) has been reported; the label instructs stopping the drug and seeking medical attention for sudden loss of vision in one or both eyes. Permanent visual loss can result.
- Sudden decrease or loss of hearing, sometimes with tinnitus and dizziness, has been reported; the label instructs prompt discontinuation and medical attention.
- Priapism: erections persisting longer than 4 hours require immediate medical assistance, as untreated priapism can cause permanent erectile tissue damage.
- Additive hypotension with alpha-blockers and other antihypertensives, and with alcohol.
- Caution in patients for whom sexual activity is inadvisable due to underlying cardiovascular status, and in those with recent stroke, myocardial infarction or unstable angina.
- Exposure is substantially increased by strong CYP3A4 inhibitors, and reduced by inducers, creating interaction-driven variability.
- Caution in anatomical penile deformity and in conditions predisposing to priapism such as sickle cell disease, multiple myeloma and leukaemia.
- Counterfeit sildenafil is among the most commonly falsified medicines worldwide, with unregulated products documented to contain wrong or undeclared active content.
identity
| full name | Sildenafil citrate |
| category | Sexual Health |
| modality | small molecule |
| formula | C22H30N6O4S |
| molar mass | 474.6 g/mol |
| cas | 139755-83-2 |
| half-life | ~4 h (terminal, sildenafil and active metabolite) |
laboratory handling
| storage | Marketed tablets are stored at controlled room temperature in the original container per the approved label. |
| solubility | Sildenafil citrate is described in the label as soluble in water; the free base is markedly less water-soluble, which is why the citrate salt is used in marketed tablets. |
| co-studied with | Documented interaction hazards rather than a regimen: absolute contraindication with nitrates and with guanylate cyclase stimulators; additive blood pressure lowering with alpha-blockers, other antihypertensives and alcohol; and substantially raised exposure with strong CYP3A4 inhibitors. Concomitant use with other PDE5 inhibitors or with unapproved 'herbal' products adulterated with PDE5 inhibitors is a recognised source of unintended overdose. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
5 citedDailyMed / US FDA · 2024 · official
New England Journal of Medicine · 1998 · randomized
New England Journal of Medicine · 1998 · randomized
JAMA Ophthalmology · 2022 · observational
others in Sexual Health