Sildenafil, widely recognised under the brand name Viagra, is a phosphodiesterase type 5 (PDE5) inhibitor used to treat erectile dysfunction and pulmonary arterial hypertension. Understanding how sildenafil increases blood flow is key to appreciating its therapeutic effects and safety profile. The drug works by blocking the enzyme PDE5, which normally breaks down cyclic guanosine monophosphate (cGMP), a chemical messenger that relaxes smooth muscle in blood vessel walls. By prolonging cGMP activity, sildenafil enhances vasodilation and blood flow in targeted tissues, particularly the penile corpus cavernosum and pulmonary arteries. Sexual stimulation is required for sildenafil to work in erectile dysfunction, as it does not cause an erection independently.

What Is Sildenafil and How Does It Work?

Sildenafil is a medication belonging to a class of drugs known as phosphodiesterase type 5 (PDE5) inhibitors. Originally developed in the 1990s by Pfizer for cardiovascular conditions, it was subsequently licensed for the treatment of erectile dysfunction (ED) and later for pulmonary arterial hypertension (PAH). In the UK, sildenafil is available under the brand name Viagra for ED and Revatio for PAH, with generic formulations widely prescribed. Viagra Connect 50 mg is available as a pharmacy medicine without prescription following pharmacist assessment, while other formulations remain prescription-only.

The drug works by selectively inhibiting the enzyme phosphodiesterase type 5, which is found predominantly in the smooth muscle cells lining blood vessels in certain tissues, including the corpus cavernosum of the penis and the pulmonary vasculature. Under normal physiological conditions, sexual stimulation triggers the release of nitric oxide (NO) in penile tissue, which activates an enzyme called guanylate cyclase. This enzyme increases levels of cyclic guanosine monophosphate (cGMP), a chemical messenger that causes smooth muscle relaxation and vasodilation, thereby facilitating increased blood flow.

PDE5 naturally breaks down cGMP, limiting the duration and extent of vasodilation. By inhibiting PDE5, sildenafil prolongs the action of cGMP, enhancing and sustaining the blood flow response. It is important to note that sildenafil does not cause an erection on its own ; sexual stimulation is required to initiate the nitric oxide–cGMP pathway. The medication typically begins to work within 30 to 60 minutes of oral administration, with effects lasting approximately four to six hours. High-fat meals may delay absorption and onset of action. For ED, the typical starting dose is 50 mg taken approximately 1 hour before sexual activity, with possible adjustment between 25-100 mg based on response. It should not be taken more than once daily and is not indicated for those under 18 years of age.

The Mechanism: How Sildenafil Increases Blood Flow

The mechanism by which sildenafil increases blood flow is rooted in its pharmacological action on the nitric oxide–cGMP signalling pathway. When nitric oxide is released in response to sexual arousal or other physiological triggers, it binds to guanylate cyclase receptors in vascular smooth muscle cells. This binding stimulates the production of cGMP, a secondary messenger that activates protein kinases, leading to reduced intracellular calcium levels. The decrease in calcium causes smooth muscle relaxation, which in turn dilates blood vessels and increases blood flow to the target tissue.

Phosphodiesterase type 5 is the enzyme responsible for hydrolysing cGMP into its inactive form, 5'-GMP. In doing so, PDE5 acts as a natural brake on vasodilation, ensuring that blood flow returns to baseline once the initial stimulus has ceased. Sildenafil competitively inhibits PDE5, preventing the breakdown of cGMP and thereby prolonging smooth muscle relaxation and vasodilation. This effect is particularly pronounced in tissues where PDE5 is highly expressed, such as the penile corpus cavernosum and pulmonary arteries.

The selectivity of sildenafil for PDE5 over other phosphodiesterase isoforms is crucial to its therapeutic profile. While the drug has some affinity for PDE6 (found in the retina) and PDE11 (present in skeletal muscle), its primary action remains on PDE5. This selectivity minimises off-target effects, though it does not eliminate them entirely. The enhanced blood flow resulting from PDE5 inhibition is dose-dependent, with typical doses for erectile dysfunction ranging from 25 mg to 100 mg, and for pulmonary arterial hypertension, 20 mg three times daily as per MHRA-approved indications in the Revatio Summary of Product Characteristics.

Effects of Sildenafil on Blood Vessels and Circulation

Sildenafil exerts its effects primarily on the vascular smooth muscle, leading to vasodilation in specific vascular beds. In the context of erectile dysfunction, the drug facilitates increased blood flow to the penile arteries and corpus cavernosum, enabling the engorgement necessary for an erection. This localised effect is contingent upon the presence of nitric oxide, which is released during sexual stimulation, ensuring that the drug's action is appropriately targeted.

Beyond the penile vasculature, sildenafil also affects the pulmonary circulation. In patients with pulmonary arterial hypertension, elevated pressures in the pulmonary arteries result from vasoconstriction and vascular remodelling. By inhibiting PDE5 in the pulmonary vasculature, sildenafil promotes vasodilation, reduces pulmonary vascular resistance, and improves right ventricular function. Sildenafil is licensed in the UK for pulmonary arterial hypertension and is provided through NHS England specialist pulmonary hypertension services. The European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines include PDE5 inhibitors in their treatment recommendations for PAH.

Systemic vascular effects are generally modest at therapeutic doses. According to the Viagra SmPC, sildenafil can cause a mild reduction in systemic blood pressure, typically in the range of 8–10 mmHg systolic and 5–6 mmHg diastolic. This effect is usually well tolerated in healthy individuals but can be clinically significant in patients taking nitrates or those with pre-existing hypotension. Caution is advised when co-administering sildenafil with alpha-blockers due to the risk of symptomatic hypotension; patients should be haemodynamically stable on alpha-blocker therapy before starting sildenafil, and a lower starting dose (25 mg) should be considered. The drug does not significantly affect heart rate or cardiac output in most patients.

Common vascular-related adverse effects include headache (due to cerebral vasodilation), flushing, and nasal congestion. Visual disturbances, such as a blue tinge to vision or increased light sensitivity, occur in a small proportion of patients and are attributed to mild PDE6 inhibition in the retina. These effects are generally transient and resolve as the drug is metabolised and eliminated from the body.

Clinical Uses of Sildenafil Beyond Erectile Dysfunction

While sildenafil is best known for its role in treating erectile dysfunction, its vasodilatory properties have led to its use in several other clinical contexts. The most established alternative indication is pulmonary arterial hypertension (PAH), a progressive condition characterised by elevated blood pressure in the pulmonary arteries. Sildenafil, marketed as Revatio for this indication, is licensed in the UK for the treatment of PAH to improve exercise capacity and delay clinical worsening. The typical dose is 20 mg three times daily, which is lower than that used for erectile dysfunction.

There are several off-label uses for sildenafil that are not routinely recommended in UK practice and should only be considered under specialist guidance. Some studies have explored sildenafil's role in high-altitude pulmonary oedema (HAPE), where the drug's ability to reduce pulmonary artery pressure may help prevent or mitigate symptoms in susceptible individuals ascending to high altitudes. However, UK travel health guidance prioritises acclimatisation and acetazolamide for prevention, with descent being the primary treatment for established HAPE. Sildenafil is not routinely advised for this purpose.

Sildenafil has also been investigated in Raynaud's phenomenon, a condition characterised by episodic vasospasm in the fingers and toes. According to NICE Clinical Knowledge Summaries, while small studies have shown that PDE5 inhibitors may reduce the frequency and severity of attacks, evidence remains limited and the drug is not routinely recommended for this purpose. Similarly, there is ongoing research into the use of sildenafil in heart failure with preserved ejection fraction (HFpEF), though the RELAX trial showed no clear benefit, and it is not recommended for this indication.

Patients considering sildenafil for off-label uses should consult their GP or specialist, as the evidence base varies considerably and potential risks must be weighed against uncertain benefits. The MHRA-approved indications remain erectile dysfunction and pulmonary arterial hypertension, and prescribing outside these contexts should be undertaken with caution and appropriate clinical justification.

Safety Considerations When Taking Sildenafil

Sildenafil is generally well tolerated, but certain safety considerations must be observed to minimise the risk of adverse effects and drug interactions. The most important contraindications include concurrent use of nitrates (such as glyceryl trinitrate for angina), nitric oxide donors (including 'poppers' or amyl nitrite), nicorandil, and riociguat (a guanylate cyclase stimulator). The combination with nitrates can cause severe, potentially life-threatening hypotension, as both enhance nitric oxide–cGMP signalling, leading to profound vasodilation and cardiovascular collapse.

Sildenafil should be used with caution in patients with cardiovascular disease, particularly those with recent myocardial infarction, stroke, or life-threatening arrhythmias within the past six months. The MHRA advises that sexual activity itself carries cardiovascular risk, and patients should be assessed for their fitness to engage in such activity before sildenafil is prescribed. Those with uncontrolled hypertension or hypotension (systolic BP <90 mmHg) should also be carefully evaluated.

Caution is needed when co-administering sildenafil with alpha-blockers due to the risk of symptomatic hypotension. Patients should be stable on alpha-blocker therapy before starting sildenafil, and a lower starting dose (25 mg) should be considered. A reduced starting dose (25 mg) should also be considered for older adults and those with renal or hepatic impairment. Sildenafil should not be taken more than once daily for erectile dysfunction. High-fat meals may delay absorption, and grapefruit juice should be avoided as it can increase drug exposure.

Common adverse effects include headache, flushing, dyspepsia, nasal congestion, and visual disturbances. These are usually mild and transient. Rare but serious adverse effects include priapism (a prolonged, painful erection lasting more than four hours), sudden hearing loss, and non-arteritic anterior ischaemic optic neuropathy (NAION), a form of vision loss. Patients experiencing priapism, sudden vision or hearing loss should stop taking sildenafil and seek immediate medical attention. If chest pain occurs after taking sildenafil, patients should call 999 and inform healthcare providers about sildenafil use, as nitrates should be avoided.

Drug interactions are an important consideration. Sildenafil is metabolised primarily by the cytochrome P450 enzyme CYP3A4, and co-administration with strong CYP3A4 inhibitors can significantly increase sildenafil levels. With ritonavir, sildenafil should be avoided; if unavoidable, do not exceed 25 mg in 48 hours. Other potent CYP3A4 inhibitors (such as ketoconazole or erythromycin) may require dose adjustment. Conversely, CYP3A4 inducers (such as rifampicin) may reduce efficacy. Patients should always inform their GP or pharmacist of any new medications to ensure safe and effective use of sildenafil. Suspected adverse reactions should be reported via the MHRA Yellow Card Scheme.

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