Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor licensed in the UK for treating erectile dysfunction in adult men and pulmonary arterial hypertension. As the first PDE5 inhibitor developed, sildenafil—widely known as Viagra—works by selectively blocking the PDE5 enzyme, which enhances blood flow to the penis during sexual stimulation. It is available on NHS prescription and as an over-the-counter pharmacy medicine (Viagra Connect 50 mg). Understanding how sildenafil functions as a PDE5 inhibitor helps patients and clinicians make informed treatment decisions whilst recognising important safety considerations.

What Is Sildenafil and How Does It Work?

Yes, sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor. It is licensed in the UK for the treatment of erectile dysfunction (ED) in adult men and pulmonary arterial hypertension (PAH). Sildenafil was the first PDE5 inhibitor to be developed and is widely recognised by its brand name Viagra, though generic formulations are now extensively available.

In the UK, sildenafil for ED is available as a prescription medicine and as Viagra Connect 50 mg, which is a pharmacy medicine available without prescription. For PAH, sildenafil is marketed as Revatio and is licensed for adults and children aged 1 year and older under specialist supervision.

Sildenafil works by selectively inhibiting the enzyme phosphodiesterase type 5, which is found predominantly in the smooth muscle cells of the corpus cavernosum of the penis and in the pulmonary vasculature. Under normal physiological conditions, sexual stimulation triggers the release of nitric oxide (NO) in penile tissue. Nitric oxide activates the enzyme guanylate cyclase, which increases levels of cyclic guanosine monophosphate (cGMP). This second messenger causes smooth muscle relaxation, allowing increased blood flow into the penis and facilitating an erection.

PDE5 naturally breaks down cGMP, thereby limiting the duration and intensity of the erectile response. By inhibiting PDE5, sildenafil prevents the degradation of cGMP, prolonging smooth muscle relaxation and enhancing erectile function. It is important to note that sildenafil does not cause an erection without sexual stimulation—it merely facilitates the natural erectile response when arousal occurs.

For ED, sildenafil typically takes effect within 30-60 minutes and lasts for up to 4 hours. High-fat meals may delay its onset of action. In pulmonary arterial hypertension, the same mechanism applies to the pulmonary vasculature, where increased cGMP levels lead to vasodilation and reduced pulmonary artery pressure. Sildenafil is used to improve exercise capacity in patients with PAH.

Understanding PDE5 Inhibitors: Mechanism of Action

Phosphodiesterase type 5 inhibitors represent a class of medications that share a common pharmacological mechanism: the selective inhibition of the PDE5 enzyme. This enzyme is part of a larger family of phosphodiesterases responsible for breaking down cyclic nucleotides, which are crucial intracellular signalling molecules. PDE5 is highly selective for cGMP and is predominantly expressed in vascular smooth muscle, particularly in the corpus cavernosum and pulmonary arteries.

The therapeutic action of PDE5 inhibitors depends on the nitric oxide–cGMP pathway. When nitric oxide is released in response to sexual stimulation or other physiological triggers, it binds to guanylate cyclase receptors, increasing intracellular cGMP. Elevated cGMP activates protein kinase G, which phosphorylates various target proteins, leading to smooth muscle relaxation, vasodilation, and increased blood flow. PDE5 inhibitors prolong this effect by preventing cGMP breakdown, thereby amplifying and sustaining the physiological response.

Selectivity is key to the safety profile of PDE5 inhibitors. While there are multiple phosphodiesterase isoforms (PDE1 through PDE11), sildenafil and related drugs are designed to preferentially inhibit PDE5. Sildenafil does have some activity against PDE6 (found in the retina), which may account for visual disturbances such as blue-tinged vision or increased light sensitivity. Other PDE5 inhibitors, such as tadalafil and vardenafil, have slightly different selectivity profiles, influencing their side effect patterns and duration of action.

Understanding this mechanism is essential for both prescribers and patients, as it clarifies why PDE5 inhibitors require sexual stimulation to be effective and why they are contraindicated with nitrate medications and soluble guanylate cyclase stimulators (such as riociguat). These combinations can cause dangerous hypotension by excessively increasing cGMP levels.

Clinical Uses of Sildenafil in the UK

In the UK, sildenafil is licensed for two primary indications: erectile dysfunction in men and pulmonary arterial hypertension in both men and women. For erectile dysfunction, sildenafil is available in doses of 25 mg, 50 mg, and 100 mg, typically taken approximately one hour before sexual activity. The standard starting dose is 50 mg, which may be adjusted based on efficacy and tolerability. Sildenafil should not be taken more than once in a 24-hour period.

Generic sildenafil 50 mg is generally available on NHS prescription, subject to local formulary policies. Other strengths and branded versions may have different prescribing restrictions. Viagra Connect 50 mg is available from pharmacies without prescription following assessment by a pharmacist.

For pulmonary arterial hypertension, sildenafil (Revatio) is prescribed at a different dosing regimen (typically 20 mg three times daily) and is available on the NHS under specialist supervision. Treatment is usually initiated and monitored by physicians with expertise in PAH management, often in tertiary centres.

Patient safety is paramount. Sildenafil is contraindicated in patients:

• Taking nitrates (such as glyceryl trinitrate) for angina

• Taking riociguat for pulmonary hypertension

• With severe cardiovascular disease where sexual activity is inadvisable

• With recent stroke, unstable angina, or myocardial infarction

Sildenafil should be used with caution in patients taking alpha-blockers (risk of symptomatic hypotension), those with anatomical penile abnormalities, or conditions predisposing to priapism. Dose adjustments may be needed in hepatic/renal impairment and when taking potent CYP3A4 inhibitors.

Patients should seek urgent medical attention if they experience priapism (erection lasting longer than 4 hours), sudden vision or hearing loss, or severe chest pain. If chest pain occurs after taking sildenafil, nitrates should not be used for at least 24 hours. Suspected side effects should be reported via the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk).

Other PDE5 Inhibitors Available on the UK Market

In addition to sildenafil, several other PDE5 inhibitors are licensed and available in the UK, each with distinct pharmacokinetic properties that may suit different patient needs. The main alternatives include tadalafil, vardenafil, and avanafil.

Tadalafil (brand name Cialis) is notable for its longer duration of action, with effects lasting up to 36 hours. This allows for greater spontaneity, as it does not need to be timed as precisely around sexual activity. Tadalafil is available in on-demand doses (10 mg and 20 mg) and a daily low-dose formulation (2.5 mg or 5 mg) for men who anticipate frequent sexual activity. For PAH, tadalafil is marketed as Adcirca and is prescribed under specialist supervision. Tadalafil is also licensed for benign prostatic hyperplasia with lower urinary tract symptoms.

Vardenafil (brand name Levitra) has a similar onset and duration of action to sildenafil but may have a slightly different side effect profile. It is available in 5 mg, 10 mg, and 20 mg doses. Some patients who do not respond adequately to one PDE5 inhibitor may benefit from trying an alternative, though individual responses vary.

Avanafil (brand name Spedra) is a newer PDE5 inhibitor that can work as quickly as 15-30 minutes after taking it, according to its product information. It is available in 50 mg, 100 mg, and 200 mg doses and may be preferred by men seeking a faster-acting option.

Availability on the NHS varies by local formulary policies. All PDE5 inhibitors are also available via private prescription. The choice between agents depends on individual patient factors, including frequency of sexual activity, comorbidities, concomitant medications, and patient preference.

All PDE5 inhibitors share the same contraindications with nitrates and riociguat, and similar cautions apply regarding cardiovascular risk, alpha-blockers, and CYP3A4 inhibitors/inducers (though the extent of interactions varies between agents). Healthcare professionals should discuss the benefits and risks of each option to support informed decision-making.

Frequently Asked Questions