Ursodeoxycholic Acid

Ursodeoxycholic acid (ursodiol) is a hydrophilic bile acid that protects bile duct cells and improves bile flow. It is the first-line treatment for primary biliary cholangitis, is used to dissolve small cholesterol gallstones and prevent them during rapid weight loss, and is used for intrahepatic cholestasis of pregnancy and cholestasis in cystic fibrosis.

Classification. Bile acid; hepatobiliary protective agent.

Mechanism. Displaces toxic hydrophobic bile acids from the bile acid pool, stimulates bile secretion from hepatocytes and cholangiocytes, reduces cholesterol saturation of bile and cholesterol absorption, and has anti-apoptotic and immunomodulatory effects.

Pharmacodynamics. Biochemical improvement (alkaline phosphatase, bilirubin) begins within weeks. Gallstone dissolution takes 6 to 24 months.

Pharmacokinetics. About 90% absorbed in the small intestine. Extensive first-pass hepatic uptake and conjugation with glycine and taurine; enterohepatic circulation. Half-life about 3.5 to 5.8 days.

Metabolism. Conjugated in the liver; partly converted by bacteria in the colon to lithocholic acid, which is excreted in faeces.

Adult oral doses unless stated.

Primary biliary cholangitis.

• 13 to 15 mg/kg daily in two to four divided doses with food, or as a single evening dose.

• Continue for life.

• Reassess response at 12 months using alkaline phosphatase and bilirubin.

Dissolution of cholesterol gallstones (small, radiolucent, in a functioning gallbladder).

• 8 to 12 mg/kg daily, in two divided doses or as a single bedtime dose, for 6 to 24 months.

• Continue for 3 months after stones disappear on ultrasound.

• Recurrence is common after stopping.

Prevention of gallstones during rapid weight loss. 600 mg daily at bedtime, during weight loss.

Intrahepatic cholestasis of pregnancy. 10 to 15 mg/kg daily in two or three divided doses, until delivery.

Cholestasis in cystic fibrosis and other cholestatic liver disease. 15 to 20 mg/kg daily in divided doses, specialist directed.

Children.

• Biliary atresia, paediatric cholestasis: 10 to 30 mg/kg daily in two or three divided doses.

• Cystic fibrosis liver disease: 20 mg/kg daily.

Kidney and liver adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: use in compensated disease; in decompensated cirrhosis, use with caution and specialist advice.

Contraindications.

• Acute cholecystitis or cholangitis; biliary obstruction (common bile duct or cystic duct); frequent biliary colic.

• Calcified gallstones, radio-opaque stones; non-functioning gallbladder.

• Hypersensitivity.

Common adverse effects. Diarrhoea (more often at higher doses), nausea, abdominal discomfort, pruritus and hair thinning.

Serious adverse effects.

• Worsening of primary biliary cholangitis with decompensation in the first weeks (rare).

• Biliary colic and cholecystitis as stones move.

• Hepatic decompensation in advanced cirrhosis.

• Hypersensitivity and rash.

• Calcification of stones.

Major interactions.

• Bile acid sequestrants (cholestyramine, colestipol) and aluminium-containing antacids: reduce absorption; separate by at least 2 hours.

• Ciclosporin: increased absorption; monitor levels.

• Ciprofloxacin: reduced absorption.

• Lipid-lowering agents (clofibrate), oestrogens and oral contraceptives: increase biliary cholesterol and reduce effect on stone dissolution.

• Rifampicin: may reduce effect.

Special groups.

• Pregnancy: avoid in the first trimester; used in the second and third trimesters for intrahepatic cholestasis of pregnancy.

• Breastfeeding: low levels in milk; compatible.

• Children: dose by weight under specialist care.

• Older adults: no adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: caution in advanced disease.

• Regional: availability and cost vary in East Africa; response in cholesterol stones is limited, so surgery is often preferred.

Formulations. Tablets 150 mg, 250 mg, 300 mg and 500 mg; capsules 250 mg and 300 mg; oral suspension 250 mg in 5 mL.

Administration.

• Take with food, swallowing tablets and capsules whole with water.

• A single evening dose is acceptable for primary biliary cholangitis and gallstones.

• Separate from antacids and sequestrants by at least 2 hours.

Baseline. Liver function tests (alkaline phosphatase, bilirubin, transaminases), imaging, and pregnancy status.

Monitoring.

• Liver tests every 3 months in the first year, then every 6 months.

• Response at 12 months in primary biliary cholangitis (alkaline phosphatase and bilirubin).

• Ultrasound every 6 months during gallstone dissolution.

• Stools and abdominal pain.

Therapeutic drug monitoring. Not applicable.

Stopping. For primary biliary cholangitis, treatment is lifelong. For gallstone dissolution, stop when stones have gone for 3 months, or if there is no sign of dissolution by 12 months.

Referral and escalation. Refer inadequate responders in primary biliary cholangitis for second-line therapy and liver transplant assessment. Refer for cholecystectomy if biliary colic recurs.