Key Facts

Prescribing in hepatic impairment is more complex than renal impairment because there is no single test equivalent to eGFR to quantify hepatic drug-handling capacity. Clinical assessment, Child-Pugh score, and cautious prescribing are essential.

Pharmacokinetic Changes

• Absorption: portal-systemic shunting → drugs bypass first-pass metabolism → increased oral bioavailability (e.g. morphine bioavailability increases from ~30% to ~80%)
• Distribution: reduced albumin → increased free drug fraction; ascites → increased Vd for water-soluble drugs
• Metabolism: Phase I (CYP450) reduced first; Phase II (glucuronidation, etc.) relatively preserved until advanced disease
• Excretion: biliary excretion may be impaired (cholestasis); renal function often impaired too (hepatorenal syndrome)

Pharmacodynamic Changes

• Increased CNS sensitivity: to benzodiazepines, opioids — risk of precipitating hepatic encephalopathy
• Coagulopathy: reduced synthesis of clotting factors → increased sensitivity to warfarin and other anticoagulants
• Hypoalbuminaemia: altered drug binding → increased effect of protein-bound drugs
• Portal hypertension: may increase susceptibility to GI bleeding with NSAIDs/anticoagulants

Pathophysiology

• Progressive hepatocyte loss → reduced CYP450 content and enzyme activity
• Portal-systemic shunting → drugs bypass hepatic extraction → increased systemic exposure
• Reduced hepatic blood flow (cirrhosis) → reduced clearance of high-extraction drugs (morphine, propranolol, GTN, lidocaine)
• Cholestasis → reduced biliary excretion of drugs eliminated via bile

Signs of Drug Accumulation

• Hepatic encephalopathy: confusion, asterixis, drowsiness — precipitated by sedatives, opioids, diuretics (hyponatraemia, hypokalaemia)
• Excessive anticoagulation: bleeding — warfarin, DOACs
• Opioid toxicity: respiratory depression, sedation — reduced first-pass metabolism
• Hypoglycaemia: reduced hepatic gluconeogenesis + reduced insulin clearance
• Fluid retention: reduced albumin + NSAID-induced sodium retention → worsened ascites

Drug-Induced Liver Injury (DILI)

• Paracetamol: dose-dependent hepatotoxicity — reduce max dose to 2 g/day in chronic liver disease
• Methotrexate: cumulative hepatotoxicity → fibrosis → cirrhosis
• Sodium valproate: idiosyncratic hepatotoxicity — avoid in liver disease
• Isoniazid: hepatotoxicity in ~10–20%; monitor LFTs
• Statins: usually safe; monitor LFTs; avoid if decompensated

Red Flags

• New confusion/encephalopathy after starting sedative/opioid
• Jaundice deepening after starting new drug → DILI
• GI bleeding in cirrhotic patient on NSAID or anticoagulant
• Acute liver failure: coagulopathy + encephalopathy — stop all hepatotoxic drugs

Hepatic Function Assessment

• Child-Pugh score: uses albumin, bilirubin, INR, ascites, encephalopathy → Class A (5–6), B (7–9), C (10–15)
• MELD score: uses bilirubin, INR, creatinine → predicts mortality; used for transplant listing
• LFTs: ALT/AST (hepatocellular damage), ALP/GGT (cholestasis), bilirubin, albumin — monitor before and during treatment
• INR: reflects synthetic function — elevated INR indicates significant impairment

Drug Monitoring

• TDM: for narrow TI drugs — phenytoin (correct for albumin), digoxin, theophylline
• Phenytoin correction: corrected level = measured / (0.2 × albumin in g/L + 0.1) — low albumin increases free fraction
• INR monitoring: essential for warfarin; also baseline indicator of synthetic function

Bloods

• FBC: thrombocytopenia (portal hypertension), anaemia
• U&Es: hepatorenal syndrome, electrolyte disturbance
• Glucose: hypoglycaemia risk
• Ammonia: if encephalopathy suspected (not always reliable)

Special Tests

• Liver biopsy: if drug-induced liver injury suspected and diagnosis uncertain
• FibroScan: non-invasive liver fibrosis assessment

General Principles

• Consult BNF hepatic impairment guidance for each drug
• Use Child-Pugh score to guide dose adjustments — many drugs contraindicated in Child-Pugh C
• Start low, go slow: lower starting doses, longer dosing intervals, careful titration
• Avoid hepatotoxic drugs where possible
• Monitor LFTs: before starting potentially hepatotoxic drugs and during treatment
• Prefer drugs with renal elimination: where clinically appropriate

Key Drug Adjustments

• Paracetamol: max 2 g/day in chronic liver disease (some guidelines suggest 3 g); avoid in acute liver failure
• Opioids: reduce dose significantly; avoid morphine/codeine (reduced first-pass → increased bioavailability); prefer fentanyl patches or reduced-dose oxycodone
• Benzodiazepines: avoid long-acting (diazepam); if essential, use short-acting at reduced dose (lorazepam — glucuronidation, less affected)
• Warfarin: increased sensitivity — lower doses, frequent INR monitoring
• NSAIDs: avoid — fluid retention, GI bleeding, renal impairment
• Metformin: generally avoid in significant liver disease (lactic acidosis risk, especially with concomitant renal impairment)
• Statins: avoid in decompensated liver disease; may use cautiously in compensated cirrhosis (monitor LFTs)
• Lactulose, rifaximin: used FOR hepatic encephalopathy — not affected by liver disease

Specific Situations

• Cirrhosis + pain: paracetamol (reduced dose) is safest; avoid NSAIDs; opioids with extreme caution
• Cirrhosis + infection: antibiotics generally safe but check hepatotoxicity (flucloxacillin → cholestatic DILI)
• Cirrhosis + ascites: spironolactone + furosemide (standard); NSAIDs contraindicated

Referral Criteria

• Hepatology: drug dosing in severe liver disease (Child-Pugh C), suspected DILI
• Clinical pharmacology: complex prescribing in hepatic impairment
• Palliative care: pain management in liver disease

• Careful prescribing in hepatic impairment prevents drug-related harm
• DILI: most drug-induced hepatotoxicity is reversible on drug withdrawal; ~10% of acute liver failure is drug-induced
• Paracetamol: leading cause of acute liver failure in UK — dose reduction in liver disease is essential
• Hepatic encephalopathy precipitated by drugs: usually reversible with drug withdrawal and lactulose/rifaximin
• Advanced cirrhosis (Child-Pugh C): many drugs contraindicated; specialist input essential

Child-Pugh Classification

Drug Safety in Liver Disease