Sildenafil
Brand names: Viagra (erectile dysfunction), Revatio (pulmonary arterial hypertension) · Generic available · PDE5 inhibitor
What is Sildenafil?
Sildenafil (brand names Viagra and Revatio) is a prescription medication and one of the most widely known drugs in the world. It was originally developed by Pfizer as a cardiovascular drug — researchers noticed its vasodilating effects on blood vessels — and it subsequently became the first oral treatment for erectile dysfunction approved by the FDA in 1998. A decade later, it was also approved under the brand name Revatio for the treatment of pulmonary arterial hypertension, a serious disease involving dangerous blood pressure elevations in the lung circulation.
Sildenafil is now available as a generic medication, making it considerably more affordable than the original branded products. It belongs to the class of drugs called phosphodiesterase type 5 (PDE5) inhibitors, which also includes tadalafil (Cialis) and vardenafil (Levitra). While these drugs share the same mechanism, they differ in their onset of action, duration of effect, and specificity for PDE5 versus other phosphodiesterase enzymes.
What is Sildenafil Used For?
Sildenafil is prescribed for two distinct medical indications that share a common underlying pharmacological mechanism — vasodilation through cGMP preservation:
- Erectile dysfunction (ED) — sold as Viagra: ED is defined as the consistent or recurrent inability to attain and maintain an erection sufficient for satisfactory sexual performance. Sildenafil does not cause erections spontaneously; sexual stimulation is required. It works by enhancing the natural erectile response to arousal.
- Pulmonary arterial hypertension (PAH) — sold as Revatio: PAH is a progressive disease where blood pressure in the pulmonary arteries is pathologically elevated, forcing the right ventricle of the heart to work excessively hard and eventually leading to right heart failure. Sildenafil dilates the pulmonary vasculature, reducing the resistance the heart must pump against, and has been shown to improve exercise capacity in PAH patients.
- Off-label uses: Sildenafil has been studied for Raynaud's phenomenon, high-altitude pulmonary edema, female sexual dysfunction, and as an agent to improve outcomes in certain cardiac conditions — though none of these represent FDA-approved indications.
How Does Sildenafil Work?
The physiological basis of a normal erection involves a cascade of events: sexual stimulation causes nerve endings and vascular endothelial cells in the penis to release nitric oxide (NO). Nitric oxide activates an enzyme called guanylate cyclase, which converts GTP into cyclic GMP (cGMP). cGMP activates protein kinases that cause the smooth muscle cells in the corpus cavernosum — the spongy erectile tissue of the penis — to relax. This smooth muscle relaxation allows the penile arteries to dilate and blood to rush in, compressing the penile veins and trapping blood to create an erection. Normally, the enzyme phosphodiesterase type 5 (PDE5) terminates this response by breaking down cGMP.
Sildenafil is a potent and selective inhibitor of PDE5. By blocking cGMP degradation, it prolongs and enhances the vasodilatory response to sexual stimulation — without altering the initial nitric oxide release. This is why sildenafil requires sexual stimulation to work: it amplifies an existing physiological signal rather than creating one independently. In the pulmonary circulation, PDE5 is highly expressed, and sildenafil's inhibition of PDE5 in pulmonary arteries causes sustained vasodilation, reducing pulmonary vascular resistance. Sildenafil also partially inhibits PDE6, which is expressed in retinal photoreceptors — this accounts for the visual side effects (color tinge, blurred vision) some users experience.
Side Effects
Common Side Effects
- Headache — the most frequent side effect, reported by approximately 15% of users, caused by cerebral vasodilation
- Facial flushing and warmth (dilation of facial blood vessels)
- Nasal congestion (vasodilation in nasal mucosa)
- Dyspepsia (indigestion, heartburn)
- Visual disturbances — blue or blue-green color tinge to vision, increased light sensitivity, or blurred vision (due to PDE6 inhibition in the retina; usually mild and transient)
- Back pain and muscle aches (more commonly seen with tadalafil but can occur)
- Dizziness
Serious Side Effects
- Severe hypotension with nitrates — ABSOLUTE CONTRAINDICATION: Combining sildenafil with any nitrate medication (nitroglycerin tablets, patches, or sprays; isosorbide mononitrate; isosorbide dinitrate; amyl nitrite/"poppers") can cause an abrupt, severe, and potentially fatal drop in blood pressure. Both drug classes dilate blood vessels through related but additive mechanisms, and the combined effect can cause blood pressure to collapse catastrophically. There is NO safe combination. Patients who take nitrates for chest pain (angina) must not use sildenafil. This is an absolute contraindication — not a relative one.
- Non-arteritic anterior ischemic optic neuropathy (NAION): A rare but serious cause of sudden, painless vision loss in one eye, likely related to reduced blood flow to the optic nerve. Risk appears higher in patients who already have certain optic nerve anatomical features ("disc at risk") or who have cardiovascular risk factors. Report any sudden vision changes immediately and stop the drug pending evaluation.
- Sudden hearing loss: A small number of cases of sudden, one-sided sensorineural hearing loss have been reported. Stop the medication and seek immediate medical evaluation if sudden hearing loss or tinnitus (ringing in ears) occurs.
- Priapism: A prolonged, painful erection lasting more than 4 hours, unrelated to sexual stimulation. This is a urological emergency requiring immediate medical treatment. Delay in treatment can result in permanent erectile dysfunction due to ischemic tissue damage.
- Cardiac events: While sexual activity itself places demands on the cardiovascular system, sildenafil should be used with caution in patients with significant cardiovascular disease. Patients who experience chest pain, dizziness, or nausea during sexual activity should stop and seek medical evaluation.
Drug Interactions
Sildenafil has several critically important drug interactions, most notably the absolute contraindication with nitrates. It is also metabolized primarily by the liver enzyme CYP3A4, making it susceptible to interactions with drugs that inhibit or induce this enzyme.
| Drug / Drug Class | Interaction Type | Effect & What to Do |
|---|---|---|
| Nitrates (nitroglycerin, isosorbide mononitrate/dinitrate, amyl nitrite) | Pharmacodynamic — ABSOLUTE CONTRAINDICATION | Additive vasodilation from two synergistic mechanisms causes potentially fatal hypotension. Do not use sildenafil in any patient taking any form of nitrate medication. This includes recreational "poppers" (amyl or butyl nitrite). If a patient who uses sildenafil needs emergency nitrate therapy for acute chest pain, inform the treating medical team immediately so they can manage the interaction. |
| Alpha-blockers (doxazosin, tamsulosin, terazosin) | Pharmacodynamic (additive hypotension) | Alpha-blockers are used for high blood pressure and benign prostatic hyperplasia. Combining them with sildenafil significantly increases the risk of orthostatic hypotension (blood pressure drop on standing) and fainting. If both are needed, careful monitoring and appropriate timing is required; tamsulosin (at standard doses) may be somewhat safer in combination than non-selective alpha-blockers. |
| CYP3A4 inhibitors (ritonavir, ketoconazole, itraconazole, clarithromycin, erythromycin, grapefruit juice) | Pharmacokinetic (markedly increased sildenafil levels) | These drugs dramatically reduce the liver's ability to metabolize sildenafil, raising blood levels many-fold. The HIV drug ritonavir raises sildenafil levels by approximately 11-fold, massively increasing the risk of adverse effects. Dose reduction or avoidance may be required; discuss with the prescriber or pharmacist before combining. |
| CYP3A4 inducers (rifampin, carbamazepine, phenytoin, St. John's Wort) | Pharmacokinetic (reduced sildenafil levels) | These drugs speed up sildenafil metabolism, potentially reducing its effectiveness. Patients may experience a diminished response. |
| Other antihypertensives and cardiovascular drugs | Pharmacodynamic (additive blood pressure lowering) | Sildenafil has mild blood pressure-lowering effects at therapeutic doses. Combining it with antihypertensive medications, especially multiple agents or those with strong vasodilatory effects, can produce meaningful additive hypotension. Blood pressure should be considered before prescribing. |
Who Should Not Take Sildenafil?
- Anyone currently taking any form of nitrate medication — this is an absolute contraindication due to the risk of fatal hypotension
- Anyone who has used recreational nitrite inhalants ("poppers") within the last 24 hours
- People with severe cardiovascular disease, recent (within 6 months) heart attack, stroke, or life-threatening arrhythmia
- People with hypotension (resting blood pressure below 90/50 mmHg) or uncontrolled hypertension
- People with severe hepatic (liver) impairment — sildenafil elimination is substantially impaired
- People with known retinal disorders such as retinitis pigmentosa, which involves abnormal PDE in retinal cells
- People with anatomical penile abnormalities predisposing to priapism (Peyronie's disease, blood cell disorders causing clots)
- Sildenafil is not intended for use in women for ED indications; the PAH indication (Revatio) is approved in both sexes
- Children (for ED indication); use of Revatio in pediatric PAH requires specialist guidance
Frequently Asked Questions
Why can't sildenafil be taken with nitrates?
Both sildenafil and nitrate drugs work by increasing the availability of cyclic GMP (cGMP) in blood vessel smooth muscle cells — just through different steps in the same biochemical pathway. Nitrates are converted to nitric oxide, which drives cGMP production. Sildenafil prevents cGMP breakdown. The two effects combine and amplify each other, causing a severe and potentially uncontrollable drop in blood pressure that can lead to fainting, heart attack, stroke, or death. This is not a manageable interaction — it is an absolute contraindication. There is no safe timeframe for combining them; sildenafil's effects can persist for 24 hours or more after the last dose.
Does sildenafil work for everyone with erectile dysfunction?
No — sildenafil is effective for many men with erectile dysfunction, but not all. Response rates in clinical trials are generally around 60–70% for the general ED population, though they vary significantly depending on the underlying cause of ED. Men whose ED is primarily caused by psychological factors, minor vascular insufficiency, or medication side effects tend to respond well. Those with severe vascular disease, nerve damage (neuropathy from diabetes, for example), hormonal deficiencies, or ED following certain prostate surgeries may have a lower response rate. Sildenafil also requires sexual arousal to be effective — it does not produce erections in the absence of stimulation.
What is the difference between Viagra and Revatio?
Viagra and Revatio contain the same active ingredient — sildenafil citrate — but they are prescribed at different strengths and for different conditions. Viagra is marketed for erectile dysfunction; Revatio is marketed for pulmonary arterial hypertension (PAH), a lung disease. The Revatio dose is lower than the standard Viagra dose. In terms of pharmacology, they are identical — what differs is the approved indication, typical dose, and labeling. Generic sildenafil is available in both dose ranges.
Does food or alcohol affect sildenafil?
Taking sildenafil with a high-fat meal can slow and reduce its absorption, delaying the time to effect. For the ED indication, it is often recommended to take sildenafil on an empty stomach or with a light meal to ensure it works as expected within a predictable timeframe. Alcohol can worsen sildenafil-related side effects, particularly hypotension and dizziness, and can also independently worsen erectile function by impairing arousal and vascular response. Grapefruit and grapefruit juice can significantly raise sildenafil blood levels by inhibiting CYP3A4 in the gut wall and should be avoided.
Related Drugs
Other PDE5 inhibitors in the same drug class: