Does sildenafil affect the liver? Sildenafil, widely recognised as Viagra, is a phosphodiesterase type 5 (PDE5) inhibitor used for erectile dysfunction and pulmonary arterial hypertension. Whilst generally well-tolerated, understanding its hepatic effects is crucial, particularly for patients with liver conditions. Current evidence indicates minimal direct liver toxicity in healthy individuals, though dose adjustments are necessary for those with hepatic impairment. This article examines sildenafil's impact on liver function, safe prescribing practices, and monitoring considerations aligned with UK guidance from the MHRA, BNF, and EMA.

Does Sildenafil Affect the Liver?

Sildenafil, commonly known by the brand name Viagra, is a phosphodiesterase type 5 (PDE5) inhibitor primarily prescribed for erectile dysfunction and pulmonary arterial hypertension. Whilst sildenafil is generally well-tolerated, questions about its effects on liver function are clinically relevant, particularly for patients with pre-existing hepatic impairment.

Current evidence suggests that sildenafil has minimal direct hepatotoxic effects in individuals with normal liver function. The Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) have not identified significant liver damage as a common adverse effect in clinical trials or post-marketing surveillance. However, abnormal liver function tests have been reported rarely in product information, and isolated case reports have documented instances of elevated liver enzymes (transaminases) in patients taking sildenafil.

For patients with mild to moderate hepatic impairment (Child-Pugh class A or B), sildenafil can be used with dose adjustments, as reduced liver function affects drug metabolism and clearance. The standard starting dose is typically reduced to 25 mg in these individuals. For severe hepatic impairment (Child-Pugh class C), limited data are available, and sildenafil should be used with caution, starting at the lowest dose (25 mg).

Key considerations include:

• Sildenafil does not commonly cause liver damage in healthy individuals

• Pre-existing liver disease requires dose modification

• Regular monitoring may be appropriate for patients with hepatic conditions

• There is no evidence that sildenafil causes chronic liver disease, though very rare cases of hepatotoxicity have been reported

Patients with known liver conditions should always inform their prescriber before starting sildenafil, ensuring appropriate dosing and monitoring protocols are established.

Signs of Liver Problems to Watch For

Whilst hepatotoxicity associated with sildenafil is uncommon, patients and healthcare professionals should remain vigilant for signs that may indicate liver dysfunction. Early recognition of potential hepatic complications enables timely intervention and prevents progression to more serious conditions.

Common warning signs of liver problems include:

• Jaundice – yellowing of the skin or whites of the eyes, indicating elevated bilirubin levels

• Dark urine – tea-coloured or brown urine suggesting bilirubin excretion

• Pale stools – clay-coloured or pale faeces indicating reduced bile flow

• Persistent fatigue – unusual tiredness not explained by other factors

• Abdominal discomfort – particularly pain or tenderness in the upper right quadrant

• Unexplained nausea or vomiting – especially if persistent or worsening

• Loss of appetite – significant reduction in food intake over several days

• Easy bruising or bleeding – suggesting impaired hepatic synthesis of clotting factors

Patients experiencing jaundice should seek urgent same-day medical assessment. Emergency care (999/A&E) is warranted for confusion, severe abdominal pain, vomiting blood, black stools, or marked bleeding/bruising. For other symptoms whilst taking sildenafil, patients should contact their GP promptly for clinical assessment. These symptoms are non-specific and may indicate various conditions unrelated to medication use.

Healthcare professionals should consider baseline liver function tests (LFTs) before initiating sildenafil in patients with risk factors for hepatic disease, including chronic alcohol use, viral hepatitis, non-alcoholic fatty liver disease, or concurrent hepatotoxic medications. If liver dysfunction is suspected during treatment, patients should stop taking sildenafil and seek prompt medical advice. Assessment should include serum transaminases (ALT, AST), alkaline phosphatase, bilirubin, and coagulation studies. Referral to hepatology services may be appropriate for persistent or severe abnormalities.

Patients and healthcare professionals are encouraged to report suspected adverse reactions to sildenafil via the MHRA Yellow Card scheme.

Safe Use of Sildenafil: Dosage and Monitoring

Ensuring safe sildenafil use requires careful consideration of patient-specific factors, appropriate dosing, and, where necessary, clinical monitoring. The standard approach to sildenafil prescribing follows the MHRA/EMC Summary of Product Characteristics (SmPC) and BNF recommendations, with modifications based on individual circumstances.

Standard dosing for erectile dysfunction:

• Initial dose: 50 mg taken approximately one hour before sexual activity

• Dose range: 25–100 mg based on efficacy and tolerability

• Maximum frequency: once daily

• Lower starting dose (25 mg) recommended for patients over 65 years or with hepatic/renal impairment

For patients with hepatic impairment, the starting dose should be reduced to 25 mg. In severe hepatic impairment, limited data are available, and sildenafil should be used with caution at the lowest dose.

Important contraindications:

• Concomitant use of nitrates in any form (e.g., glyceryl trinitrate, isosorbide mononitrate)

• Concomitant use of guanylate cyclase stimulators such as riociguat

Cautions and interactions:

• Alpha-blockers: Ensure patients are stable on alpha-blocker therapy before starting sildenafil; consider 25 mg starting dose to minimise risk of symptomatic hypotension

• Ritonavir: Co-administration should be avoided; if unavoidable, do not exceed 25 mg sildenafil in a 48-hour period

• Other potent CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, erythromycin): Consider dose reduction to 25 mg

• CYP3A4 inducers (rifampicin, carbamazepine, phenytoin): May reduce sildenafil efficacy

Monitoring recommendations:

• Baseline liver function tests may be considered in patients with known or suspected hepatic disease

• Routine LFT monitoring is not required for patients with normal liver function

• Patients with pre-existing liver conditions should have periodic hepatic assessment as clinically indicated

• Any new symptoms suggestive of hepatotoxicity warrant prompt LFT evaluation

Patients should be counselled to avoid excessive alcohol consumption whilst taking sildenafil, as alcohol can independently affect liver function and exacerbate hepatic impairment. Additionally, grapefruit juice should be avoided due to its CYP3A4 inhibitory effects.

How Sildenafil Is Processed by the Liver

Understanding sildenafil's hepatic metabolism is essential for appreciating its pharmacokinetic profile, potential drug interactions, and implications for patients with liver disease. The liver plays a central role in sildenafil biotransformation, converting the parent compound into metabolites that are subsequently eliminated from the body.

Mechanism of hepatic metabolism: Following oral administration, sildenafil undergoes extensive first-pass metabolism in the liver, with absolute bioavailability of approximately 40%. The primary metabolic pathway involves the cytochrome P450 enzyme system, specifically CYP3A4 (major pathway) and CYP2C9 (minor pathway). CYP3A4, located predominantly in hepatic microsomes and intestinal epithelium, catalyses N-demethylation of sildenafil to form the active metabolite N-desmethyl sildenafil (UK-103,320).

This active metabolite retains approximately 50% of the pharmacological activity of the parent compound and has similar selectivity for PDE5 enzymes. The metabolite contributes to the overall therapeutic effect, though to a lesser extent than sildenafil itself. Both sildenafil and its metabolite undergo further hepatic metabolism to inactive compounds, which are then conjugated and prepared for elimination.

Elimination pathways:

• Approximately 80% of sildenafil and its metabolites are excreted in faeces via biliary elimination

• Around 13% is eliminated renally through urine

• The terminal half-life of sildenafil is approximately 3–5 hours in individuals with normal hepatic function

In patients with hepatic impairment, reduced CYP3A4 activity leads to decreased hepatic clearance, resulting in elevated plasma concentrations and prolonged half-life. Studies have demonstrated that individuals with cirrhosis experience an 84% increase in sildenafil area under the curve (AUC) and a 47% increase in maximum plasma concentration (Cmax) compared to healthy controls. These pharmacokinetic alterations necessitate dose reduction to prevent excessive drug accumulation and adverse effects.

The hepatic metabolism of sildenafil also explains its susceptibility to drug interactions with CYP3A4 inhibitors and inducers, emphasising the importance of comprehensive medication review before prescribing.

Frequently Asked Questions