Sildenafil

Mechanism of action

Sildenafil selectively inhibits phosphodiesterase type 5 (PDE5), an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP) in smooth muscle cells. In the corpus cavernosum of the penis, sexual stimulation triggers nitric oxide (NO) release from endothelial cells and nonadrenergic-noncholinergic neurons. NO activates guanylate cyclase, which increases intracellular cGMP levels. cGMP causes smooth muscle relaxation, vasodilation, and increased blood flow.

By inhibiting PDE5, sildenafil prevents cGMP breakdown, prolonging and enhancing the vasodilatory effects of NO. This mechanism requires endogenous NO release, which is why sexual stimulation is necessary for sildenafil to produce an erection. The drug does not directly cause smooth muscle relaxation or vasodilation in the absence of NO.

In pulmonary arterial hypertension, PDE5 is highly expressed in pulmonary vascular smooth muscle. Sildenafil-induced PDE5 inhibition leads to pulmonary vasodilation and reduced pulmonary artery pressure. The selectivity for PDE5 over other phosphodiesterase isoforms minimizes effects on cardiac contractility and vascular tone in other vascular beds, though some cross-reactivity with PDE6 (retina) and PDE11 accounts for certain adverse effects.

Indications

Erectile dysfunction (ED): Sildenafil is FDA-approved for the treatment of erectile dysfunction in adult men. It is effective regardless of baseline severity and etiology, including psychogenic, organic, or mixed causes. The drug is taken on an as-needed basis prior to sexual activity.

Pulmonary arterial hypertension (PAH): Sildenafil (marketed as Revatio for this indication) is approved for PAH to improve exercise capacity and delay clinical worsening. It is used in WHO Group 1 pulmonary hypertension. The dosing regimen for PAH differs from that used for erectile dysfunction, with regular scheduled dosing rather than on-demand use.

Off-label uses: Sildenafil has been used off-label for Raynaud phenomenon, high-altitude pulmonary edema prevention, and certain cases of female sexual dysfunction, though evidence for these indications is less robust. It is sometimes used in neonatal persistent pulmonary hypertension, though this remains controversial.

Pharmacokinetics

Absorption: Sildenafil is rapidly absorbed after oral administration, with peak plasma concentrations reached in 30 to 120 minutes (median 60 minutes) on an empty stomach. High-fat meals delay absorption and reduce peak concentration by approximately 29%, though total bioavailability is unchanged. Absolute bioavailability is approximately 40% due to first-pass metabolism.

Distribution: Sildenafil is highly protein-bound (approximately 96%) and has a volume of distribution of 105 L. It distributes into tissues, including the corpus cavernosum, where it exerts its therapeutic effect.

Metabolism: Sildenafil is primarily metabolized in the liver by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, CYP2C9. The major circulating metabolite (N-desmethyl sildenafil) is pharmacologically active and accounts for approximately 20% of sildenafil's pharmacologic effect. This metabolite has a similar PDE5 selectivity profile.

Elimination: The terminal half-life of sildenafil is approximately 3-5 hours. Both sildenafil and its metabolite are eliminated primarily via feces (approximately 80%) and, to a lesser extent, urine (approximately 13%). Clearance is reduced in elderly patients and those with hepatic or severe renal impairment, necessitating dose adjustment.

Adverse effects

Common adverse effects:

• Headache (most common, up to 16% of patients)
• Flushing due to systemic vasodilation
• Dyspepsia and gastroesophageal reflux
• Nasal congestion
• Dizziness

Visual disturbances: Sildenafil has mild cross-reactivity with PDE6, which is present in retinal photoreceptors. This can cause transient visual changes including blue-green color tinge (cyanopsia), increased light sensitivity, and blurred vision. These effects are typically mild and resolve within hours.

Cardiovascular effects: Sildenafil causes mild, transient decreases in blood pressure (mean reductions of 8-10 mmHg systolic and 5-6 mmHg diastolic). In healthy individuals, this is usually well-tolerated. However, when combined with nitrates, profound and potentially fatal hypotension can occur due to additive vasodilatory effects. Myocardial infarction and sudden cardiac death have been reported, though causality is unclear given the underlying cardiovascular risk factors in many users.

Priapism: Prolonged erections lasting more than 4 hours (priapism) are rare but serious. Priapism requires emergency treatment to prevent permanent erectile tissue damage. Risk is higher in patients with sickle cell disease, multiple myeloma, or leukemia.

Non-arteritic anterior ischemic optic neuropathy (NAION): Rare cases of sudden vision loss due to NAION have been reported. The causal relationship remains uncertain, as patients using PDE5 inhibitors often have vascular risk factors independently associated with NAION.

Hearing loss: Sudden decrease or loss of hearing, sometimes with tinnitus, has been reported rarely and may be permanent.

Contraindications and warnings

Absolute contraindications:

• Concurrent nitrate use: This includes nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, and recreational nitrites ("poppers"). The combination can cause severe, potentially fatal hypotension. Sildenafil must not be used within 24 hours of nitrate administration.
• Hypersensitivity to sildenafil or any component of the formulation

Relative contraindications and warnings:

• Severe cardiovascular disease: Caution in patients with recent myocardial infarction (within 90 days), unstable angina, life-threatening arrhythmias, uncontrolled hypertension (>170/100 mmHg), or severe heart failure. Sexual activity itself poses cardiovascular risk in these patients.
• Anatomical penile deformities: Conditions such as Peyronie disease, angulation, or cavernosal fibrosis may increase priapism risk.
• Retinitis pigmentosa: Avoid use due to theoretical concerns about PDE6 inhibition, though definitive evidence of harm is lacking.
• Hepatic impairment: Reduced clearance necessitates dose reduction, particularly in severe impairment (Child-Pugh class C).
• Severe renal impairment: Dose adjustment recommended for creatinine clearance <30 mL/min.
• Alpha-blocker use: Concurrent use can cause additive hypotension; if necessary, alpha-blockers should be stable before initiating sildenafil at a low dose.

Pregnancy and lactation: Sildenafil is pregnancy category B (no evidence of risk in animal studies; no adequate human studies). It is not indicated for use in pregnant women except for PAH under specialist supervision. Excretion in breast milk is unknown.

Drug interactions

Nitrates (absolute contraindication): As noted above, concurrent use causes profound hypotension. A 24-hour washout period is required after sildenafil before nitrate administration is safe. Conversely, sildenafil should not be used within 24 hours after nitrate use.

CYP3A4 inhibitors: Strong inhibitors such as ketoconazole, itraconazole, ritonavir, clarithromycin, and erythromycin significantly increase sildenafil plasma levels by reducing first-pass metabolism. Significant dose reduction is necessary. Ritonavir, a potent CYP3A4 inhibitor used in HIV therapy, can increase sildenafil concentrations 11-fold.

CYP3A4 inducers: Rifampin, phenytoin, carbamazepine, and other inducers may reduce sildenafil efficacy by increasing metabolism, though this is less commonly clinically significant.

Alpha-blockers: Drugs like doxazosin, tamsulosin, and terazosin can cause additive hypotension when used with sildenafil. If combination therapy is necessary, the alpha-blocker should be at a stable dose, and sildenafil should be initiated at the lowest dose with careful blood pressure monitoring.

Antihypertensives: Sildenafil may potentiate the hypotensive effects of other blood pressure medications, including calcium channel blockers, ACE inhibitors, and diuretics. Monitoring is advised.

Other PDE5 inhibitors: Concurrent use of multiple PDE5 inhibitors (e.g., sildenafil with tadalafil or vardenafil) is not recommended due to lack of data and potential for additive adverse effects.

Grapefruit juice: May moderately increase sildenafil levels via CYP3A4 inhibition; clinical significance is minor but advise patients to avoid large quantities.

Clinical pearls

• Sildenafil requires sexual stimulation to work; it does not cause automatic erections. Patients should be counseled that the drug enhances normal erectile response to stimulation.
• The onset of action is typically 30-60 minutes, but this is delayed by high-fat meals. For optimal effect, advise taking on an empty stomach.
• The most common reason for perceived treatment failure is inadequate trial. Patients should attempt the medication on at least 4-6 separate occasions before concluding it is ineffective.
• Always screen for nitrate use (including PRN nitroglycerin) before prescribing sildenafil. Many patients do not spontaneously disclose intermittent nitrate use.
• The different brand names (Viagra for ED, Revatio for PAH) contain the same active ingredient. Patients should not use both formulations concurrently.
• Sildenafil does not protect against sexually transmitted infections or serve as a contraceptive.
• In the emergency setting, if a patient on sildenafil develops chest pain, nitrates should be withheld for at least 24 hours. Alternative anti-anginal therapies (e.g., morphine, benzodiazepines, beta-blockers) should be used.
• For PAH, sildenafil is typically dosed three times daily at lower individual doses than used for ED, reflecting continuous need for pulmonary vasodilation rather than episodic use.
• Blue vision or color discrimination changes, while typically transient, should prompt consideration of dose reduction or discontinuation if bothersome.
• Priapism is a urologic emergency. Patients should be counseled to seek immediate care if an erection lasts longer than 4 hours.

Practice questions

Frequently asked questions

Conditions it is used for

Related drugs

Sources and further reading

DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: G04BE03

Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.