Sildenafil, widely recognised as Viagra, is a phosphodiesterase type 5 (PDE5) inhibitor licensed in the UK for erectile dysfunction and pulmonary arterial hypertension. Understanding how sildenafil is metabolised is essential for safe prescribing, particularly in patients with hepatic or renal impairment, older adults, and those taking interacting medications. The drug undergoes extensive hepatic metabolism primarily via the cytochrome P450 enzyme CYP3A4, producing an active metabolite that contributes to its therapeutic effect. This article explores the metabolic pathways of sildenafil, factors affecting its breakdown, clinically significant drug interactions, and practical implications for patient safety and treatment optimisation.

What Is Sildenafil and How Does It Work?

Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor licensed in the UK for the treatment of erectile dysfunction and pulmonary arterial hypertension. It was originally developed by Pfizer and is available under the brand name Viagra for erectile dysfunction, as well as Revatio for pulmonary hypertension (typically dosed at 20 mg three times daily). The Medicines and Healthcare products Regulatory Agency (MHRA) has approved sildenafil for use in adults, and it is also available in generic formulations.

The mechanism of action centres on the inhibition of PDE5, an enzyme found predominantly in the smooth muscle of the corpus cavernosum and pulmonary vasculature. During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells, which activates guanylate cyclase. This enzyme increases levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation and increased blood flow. PDE5 normally breaks down cGMP, thereby terminating the vasodilatory response. By inhibiting PDE5, sildenafil prolongs the action of cGMP, enhancing erectile function when sexual stimulation occurs.

Key pharmacological properties include:

• Rapid oral absorption with peak plasma concentrations reached within 30–120 minutes

• Bioavailability of approximately 40% due to first-pass hepatic metabolism

• Duration of action typically 4–5 hours

• Selectivity for PDE5 over other phosphodiesterase isoenzymes, though partial inhibition of PDE6 explains the visual disturbances sometimes reported

It is important to note that sildenafil does not cause spontaneous erections; sexual stimulation is required for the drug to be effective. The medication works by facilitating the natural erectile response rather than artificially inducing it.

Which Enzymes Break Down Sildenafil?

Sildenafil undergoes extensive hepatic metabolism, primarily via the cytochrome P450 (CYP) enzyme system. The principal enzyme responsible for sildenafil metabolism is CYP3A4, which is the major pathway for its biotransformation. A secondary pathway involves CYP2C9, which serves as a minor route for metabolic clearance. Understanding these metabolic pathways is clinically significant because they determine drug exposure, efficacy, and potential for interactions.

The primary metabolite of sildenafil is N-desmethyl sildenafil (UK-103,320), which retains approximately 50% of the parent compound's pharmacological activity against PDE5. This active metabolite has a similar selectivity profile and contributes to the overall therapeutic effect. The metabolite undergoes further metabolism and is eventually eliminated, predominantly via faecal excretion (approximately 80%) with a smaller proportion excreted renally (approximately 13%).

The metabolic process involves:

• Oxidative N-demethylation by CYP3A4 to form the active metabolite

• Further oxidation and conjugation reactions

• Conversion to inactive metabolites that are eliminated

• Minimal renal excretion of unchanged sildenafil (less than 2%)

The terminal half-life of sildenafil is approximately 3–5 hours in healthy adults, though this can be prolonged in patients with hepatic impairment or severe renal dysfunction. The reliance on hepatic metabolism means that conditions or medications affecting CYP3A4 activity can significantly alter sildenafil plasma concentrations, potentially increasing the risk of adverse effects or reducing therapeutic efficacy. Genetic polymorphisms in CYP enzymes may contribute to inter-individual variability in drug response, though the clinical significance of this varies between patients.

Factors That Affect Sildenafil Metabolism

Several physiological and pathological factors can influence how sildenafil is metabolised, potentially requiring dose adjustments or additional monitoring. Age is an important consideration: older adults (over 65 years) typically demonstrate reduced hepatic metabolism and clearance, resulting in approximately 40% higher plasma concentrations compared to younger individuals. The Summary of Product Characteristics (SmPC) suggests considering a 25 mg starting dose in patients aged 65 years and over.

Hepatic impairment significantly affects sildenafil metabolism because the liver is the primary site of drug biotransformation. Patients with hepatic impairment show increased sildenafil exposure, and a reduced starting dose of 25 mg should be considered. In severe hepatic impairment (Child-Pugh class C), sildenafil should be used with caution and at reduced doses due to potentially increased plasma concentrations and risk of adverse effects.

Renal function also influences sildenafil clearance, though to a lesser extent than hepatic function. Severe renal impairment (creatinine clearance <30 mL/min) is associated with reduced clearance of both sildenafil and its active metabolite, potentially doubling plasma concentrations. A starting dose of 25 mg is advisable in this population.

Additional factors affecting metabolism include:

• Food intake: High-fat meals can delay absorption and reduce peak plasma concentrations by approximately 29%, though total bioavailability remains unchanged

• Concomitant medications: CYP3A4 inhibitors or inducers significantly affect sildenafil metabolism (discussed in detail in the next section)

• Genetic factors: Individual variations in metabolic enzymes may influence drug response

Patients should be advised to take sildenafil consistently with regard to food intake to maintain predictable therapeutic effects.

Drug Interactions and Sildenafil Metabolism

Drug interactions involving sildenafil are clinically important and can be broadly categorised into those affecting its metabolism and those where sildenafil affects other medications. The most significant interactions involve CYP3A4 inhibitors and inducers, which can substantially alter sildenafil plasma concentrations.

Strong CYP3A4 inhibitors markedly increase sildenafil exposure and include:

• Ritonavir: Can increase sildenafil concentrations up to 11-fold; co-administration should be avoided where possible. If unavoidable, do not exceed 25 mg sildenafil in 48 hours

• Other protease inhibitors: Increase sildenafil exposure; dose reduction to 25 mg is recommended

• Azole antifungals (ketoconazole, itraconazole): Increase sildenafil exposure approximately 4-fold; dose reduction to 25 mg is recommended

• Macrolide antibiotics (erythromycin, clarithromycin): Moderate increases in sildenafil levels; consider dose reduction

• Grapefruit juice: Contains furanocoumarins that inhibit intestinal CYP3A4; patients should avoid large quantities

Conversely, CYP3A4 inducers reduce sildenafil efficacy by accelerating its metabolism:

• Rifampicin: Significantly reduces sildenafil concentrations

• Anticonvulsants (carbamazepine, phenytoin): May decrease sildenafil effectiveness

• Bosentan: Induces CYP3A4 and reduces sildenafil exposure, particularly relevant in pulmonary arterial hypertension

• St John's wort: Herbal preparation that induces CYP3A4; should be avoided

The most critical interaction involves nitrates and nitric oxide donors (glyceryl trinitrate, isosorbide mononitrate, nicorandil). This combination is absolutely contraindicated because both drug classes enhance cGMP-mediated vasodilation, potentially causing severe, life-threatening hypotension. Nitrates should not be used within at least 24 hours after sildenafil administration.

Sildenafil is also contraindicated with riociguat (a soluble guanylate cyclase stimulator) due to the risk of profound hypotension.

Alpha-blockers (doxazosin, tamsulosin) used for benign prostatic hyperplasia can cause additive hypotensive effects. If co-prescription is necessary, patients should be stabilised on alpha-blocker therapy first, and sildenafil should be initiated at 25 mg with careful blood pressure monitoring. Non-selective alpha-blockers pose a higher risk of interaction.

Patients must inform all healthcare professionals about sildenafil use, particularly in emergency situations where nitrate administration might be considered for chest pain.

Clinical Implications for Patients Taking Sildenafil

Understanding sildenafil metabolism has important practical implications for safe and effective prescribing. Dose individualisation is essential, particularly in vulnerable populations. The standard starting dose for erectile dysfunction is 50 mg taken approximately one hour before sexual activity, with adjustments to 25 mg or 100 mg based on efficacy and tolerability. However, patients with hepatic impairment, severe renal dysfunction, those aged 65 years and over, or those taking CYP3A4 inhibitors should commence treatment at 25 mg.

Common adverse effects related to PDE5 inhibition include:

• Headache (occurring in approximately 16% of patients)

• Flushing and facial warmth

• Dyspepsia and gastro-oesophageal reflux

• Nasal congestion

• Visual disturbances (blue-tinged vision, increased light sensitivity)

• Dizziness related to vasodilation

These effects are generally mild to moderate, dose-dependent, and transient. Patients should be counselled that adverse effects often diminish with continued use. Patients should report suspected adverse reactions via the MHRA Yellow Card scheme.

Patient safety advice should emphasise:

• Never combine with nitrates: This includes sublingual glyceryl trinitrate spray, which may be used for angina

• Seek immediate medical attention for priapism (erection lasting >4 hours), sudden vision loss, or sudden hearing loss

• Avoid excessive alcohol: Can potentiate hypotensive effects and impair erectile function

• Disclose all medications: Including over-the-counter preparations and herbal supplements

When to contact a GP or seek urgent care:

• Chest pain during sexual activity (do not use nitrates; call 999 and inform healthcare professionals about recent sildenafil use)

• Priapism requiring emergency treatment to prevent permanent damage

• Sudden loss of vision in one or both eyes (possible non-arteritic anterior ischaemic optic neuropathy)

• Severe hypotension, syncope, or cardiovascular symptoms

• Inadequate response after appropriate dose titration (may indicate underlying vascular disease requiring investigation)

Sildenafil should be used with caution in patients with recent myocardial infarction or stroke (within 6 months), unstable angina, severe hypotension, and is not recommended in patients with retinitis pigmentosa. NICE Clinical Knowledge Summaries recommend that patients with erectile dysfunction should undergo cardiovascular risk assessment before initiating treatment, as erectile dysfunction may be an early marker of cardiovascular disease. Regular medication review ensures ongoing appropriateness and provides opportunities to address any concerns about efficacy or tolerability.

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