Bile Acid Sequestrants

Bile acid sequestrants are non-absorbed resins that bind bile acids in the intestine and prevent their reabsorption. The liver uses cholesterol to make new bile acids, raising LDL receptor expression and lowering LDL cholesterol by 15% to 25%. They are second or third line lipid drugs, and are useful in pregnancy, children, bile acid diarrhoea and cholestatic itch.

Members. Cholestyramine, colestipol and colesevelam.

Mechanism. The resins bind negatively charged bile acids by ion exchange and are excreted in faeces. Colesevelam is a more selective, better tolerated polymer. Hepatic cholesterol synthesis and VLDL production increase, so triglycerides can rise.

Pharmacokinetics. None is absorbed, so there is no systemic toxicity, no renal or hepatic dose adjustment, and effect appears within days. Other drugs may bind to the resin in the gut.

• Cholestyramine: powder sachets; gritty and often unpalatable; most evidence.
• Colestipol: granules or tablets.
• Colesevelam: tablets or powder; fewer gastrointestinal effects and fewer drug interactions; lowers HbA1c by about 0.5% in type 2 diabetes.

• Hypercholesterolaemia (add-on): cholestyramine 4 g once or twice daily, increased to 8 to 16 g daily in 2 divided doses (maximum 24 g daily). Colestipol 5 g once or twice daily increasing to 30 g daily. Colesevelam 3.75 g daily as 6 tablets once daily or 3 tablets twice daily (625 mg each), or powder.
• Pregnancy and breastfeeding: the lipid drug of choice because it is not absorbed.
• Bile acid diarrhoea (after ileal resection, cholecystectomy, Crohn disease): cholestyramine 4 g once or twice daily, increased as tolerated.
• Cholestatic pruritus (primary biliary cholangitis, partial biliary obstruction): cholestyramine 4 g once or twice daily, given at least 4 hours apart from other drugs.
• Leflunomide washout: cholestyramine 8 g three times daily for 11 days.
• Selection: use when statins and ezetimibe are not tolerated or sufficient, in pregnancy, and for children with familial hypercholesterolaemia. Start low and increase slowly to improve tolerance.

Contraindications. Complete biliary obstruction, bowel obstruction, and hypersensitivity. Triglycerides over 4.5 mmol/L (400 mg/dL) are a contraindication or caution, because of worsening hypertriglyceridaemia and pancreatitis.

Adverse effects. Constipation (frequent), bloating, flatulence, nausea, bad taste, haemorrhoids and, rarely, bowel obstruction. Long-term use can lower absorption of fat-soluble vitamins (A, D, E, K) and folate, with hypoprothrombinaemia and bleeding if vitamin K is deficient. Hyperchloraemic acidosis has been reported in children.

Interactions. Binding lowers absorption of warfarin, digoxin, levothyroxine, thiazide diuretics, beta blockers, statins, ezetimibe, mycophenolate, ursodeoxycholic acid, and antiepileptic drugs such as phenytoin. Other medicines are taken at least 1 hour before or 4 to 6 hours after cholestyramine and colestipol. Colesevelam has fewer interactions, with ciclosporin and levothyroxine still taken 4 hours apart.

Monitoring. Lipid profile at 4 to 6 weeks, triglycerides, INR with warfarin, fat-soluble vitamins in prolonged use, and bowel habit.

Referral and escalation. Severe abdominal pain, vomiting or absent bowel movements needs urgent assessment for obstruction.

Special groups. Pregnancy: acceptable, with vitamin supplements. Children: cholestyramine used in familial hypercholesterolaemia under specialist care. Older adults: constipation risk, so start low. Kidney disease: no dose change.