Bile Acid Sequestrants and Drugs for other Biliary Disorders

Synonyms: bile acids.

The majority of gallstones are cholesterol-based. Cholic acids increase the proportion of bile salts in the bile, leading to a lower rate of precipitation of new cholesterol gallstones and dissolution of existing stones.

Indications

• Treatment of cholesterol gallstones^1,2 - laparoscopic cholecystectomy is the treatment of choice for symptomatic gallstone disease but ursodeoxycholic acid is still used for patients unsuitable or reluctant for surgery. It requires unimpaired gall bladder function with small to medium-sized (<5mm, radiolucent stones). Dissolution is too slow for those with severe recurrent biliary symptoms or those with complications. Ursodeoxycholic acid (in a dose of 12mg/kg daily) will reduce stone size by 80% at 6 months and 90% at 12 months.
• Primary biliary cirrhosis (unlicensed) - liver tests, jaundice and ascites improve in majority but marginal therapeutic effect on mortality, liver transplantation, pruritis, fatigue, quality of life and liver histology ^{3 4}.
• Primary sclerosing cholangitis (unlicensed).⁵
• Cystic fibrosis associated liver disease - but Cochrane review concluded insufficient evidence to support its routine use ⁶.

Contraindications²

• Inflammatory bowel disease and other conditions of the small intestine, colon and liver which may interfere with enterohepatic circulation of bile salts (ileal resection and stoma, extra and intra-hepatic cholestasis, severe liver disease).
• Active peptic ulcer disease
• Non-functioning gall bladder
• Radio-opaque gall stones

• Liver impairment - can worsen with bile acid treatment.
• Pregnancy - manufacturer advises against use in pregnancy although there is no evidence of harm and ursodeoxycholic acid is used to treat cholestasis of pregnancy in specialist centres ⁷.

Side-effects²

• Diarrhoea (tolerance usually develops), nausea and vomiting
• Gallstone calcification
• Pruritis

Treatment for gallstones ¹

• Patients should be given dietary advice to avoid excessive cholesterol and calories.^2,2
• Treatment can be for up to 2 years.
• Regular ultrasounds (every 3 months) are required to monitor treatment.
• Regular LFTs are recommended.
• Stop the treatment 2-3 months after the stone has disappeared and repeat the ultrasound at 4-12 weeks to confirm this.
• Long-term prophylaxis may be required after complete dissolution of the stones have been confirmed because they have a recurrence rate of 25% within the first year and 50% by five years.

Interactions²

• Should not be co-prescribed with drugs which increase cholesterol excretion in bile (oestrogen eg oral contraceptives). Ideally non-hormonal method of contraception should be offered.
• Significant interactions also may occur with either ciclosporin or clofibrate.

Synonyms: Anion-exchange resins

Under normal conditions, bile acids produced in the liver enter the gut and undergo recirculation (enterohepatic circulation). Bile acid sequestrants bind bile acids in the gut so that they cannot be recirculated. The increased loss of bile acids can lead to up regulation of LDL-cholesterol clearance and a fall in plasma cholesterol. Cholesterol synthesis may rise negating this fall. Plasma triglycerides, however, rise.

Indications ^8,9

• Pruritis - primary biliary cirrhosis and partial biliary obstruction (used in palliative care).¹⁰
• Diarrhoea ¹¹ associated with Crohn's disease, ileal resection, vagotomy, diabetic neuropathy, radioaction induced diarrhoea.
• Hyperlipidaemias particularly type IIa but note that these drugs will worsen hypertriglyceridaemia.
• Primary prevention of coronary heart disease in men aged 35-59 years with primary hypercholesterolaemia resistant to other measures. Statins are first-line treatments of hypercholesterolaemia and bile acid sequestrants may be used as adjunctive therapy ¹².

Contraindications and cautions^8,9

• Fat-soluble vitamins' absorption will be disrupted. Supplementation of Vitamins A, D and K may be required if treatment is prolonged.
• Hepatic impairment - these drugs are ineffective when biliary obstruction is complete.
• Pregnancy and breast-feeding - whilst the drug is not absorbed, altered vitamin absorption could potentially cause harm.

Side-effects ^8,9

• Constipation (common), diarrhoea, nausea, vomiting and GI discomfort
• Hypertriglyceridaemia
• Increased bleeding tendency (associated with Vit K deficiency)
• Hypochloraemic acidosis (rare, with prolonged use).

Interactions^8,9

Wide potential for interaction because of risk of altered drug absorption: warfarin, thyroid hormones, digoxin, thiazides and valproate's absorption all may be reduced. See individual drug monographs.

Monitoring

If used for the treatment of hypercholesterolaemia, monitor total cholesterol, cholesterol fractions and plasma triglycerides before and during treatment.

Patient advice

• Take other drugs at least 1 hour before or 4-6 hours after colestyramine or colestipol to reduce risk of interference with absorption.