Drugs for Hepatic Encephalopathy

Drugs for hepatic encephalopathy lower gut-derived ammonia and other toxins and correct precipitating factors. The main drugs are non-absorbable disaccharides and rifaximin, with limited roles for other agents.

Mechanism. Lactulose acidifies the colon, converts ammonia to non-absorbable ammonium and speeds transit. Rifaximin is a poorly absorbed antibiotic that reduces ammonia-producing gut bacteria. L-ornithine L-aspartate supports ammonia clearance by liver and muscle.

• Lactulose in overt episodes: 30 to 45 mL (20 to 30 g) every 1 to 2 hours until two soft stools, then titrate to 2 to 3 soft stools daily. Enema 300 mL in 700 mL of water for patients who cannot swallow.
• Rifaximin 550 mg twice daily, added to lactulose after a second episode.
• L-ornithine L-aspartate 20 to 40 g daily intravenously, or oral granules.
• Oral branched chain amino acids for protein intolerance.
• Neomycin and metronidazole are poor choices because of kidney, hearing and nerve toxicity.

Differences. Lactulose is first-line. Rifaximin is well tolerated but costly and not widely available in East Africa.

• Overt episode: find and treat the precipitant first: infection (spontaneous bacterial peritonitis, urine, chest), gastrointestinal bleeding, constipation, dehydration from diuretics or diarrhoea, hypokalaemia, hyponatraemia, kidney injury, sedatives, hypoglycaemia, portal vein thrombosis or a new liver tumour. Give lactulose.
• Grades III and IV (West Haven): protect the airway, with intubation when the Glasgow Coma Scale is 8 or less; nurse in a high dependency or intensive care unit.
• Secondary prophylaxis: lactulose after the first episode; add rifaximin after a second episode while on lactulose.
• Nutrition: protein 1.2 to 1.5 g/kg daily with a late evening snack; do not restrict protein.
• Minimal encephalopathy: treat when it affects driving or work.

Contraindications. Galactosaemia (lactulose); intestinal obstruction.

Adverse effects. Lactulose: bloating, diarrhoea, dehydration, hypernatraemia and hypokalaemia from overuse, which can worsen encephalopathy. Rifaximin: nausea, peripheral oedema, headache, Clostridioides difficile infection (rare).

Interactions. Ciclosporin and other P glycoprotein inhibitors raise rifaximin exposure. Sedatives, opioids and benzodiazepines precipitate encephalopathy.

Special groups.

• Pregnancy: lactulose acceptable; avoid rifaximin.
• Breastfeeding: lactulose acceptable; rifaximin has limited data.
• Children: lactulose weight-based.
• Older adults: monitor fluids and sodium.
• Kidney impairment: avoid neomycin.
• Severe liver impairment: rifaximin exposure rises; use with care.

Monitoring. West Haven grade, stool count, sodium, potassium, creatinine and glucose.

Referral and escalation. Grade III or IV, no response within 48 hours, or recurrent episodes despite lactulose and rifaximin need specialist review, assessment for large portosystemic shunts and consideration for transplant.