bile acid sequestrants

Mechanism: These resins bind bile acids in the intestinal lumen, interrupting enterohepatic circulation and increasing fecal bile acid loss. The liver compensates by converting more cholesterol into bile acids via upregulation of cholesterol 7α-hydroxylase, depleting intracellular cholesterol. This triggers upregulation of hepatic LDL receptors, increasing LDL uptake from blood and lowering serum LDL-C by 15-30%. Because hepatic cholesterol synthesis increases as a compensatory mechanism, HMG-CoA reductase activity rises, which can slightly raise triglycerides—making these agents relatively contraindicated in patients with hypertriglyceridemia.

Clinical uses: Primary hypercholesterolemia (adjunct to statins, especially in patients who cannot tolerate statins or in combination therapy), pruritus associated with cholestasis (by removing bile acids that accumulate in skin), and bile acid diarrhea (e.g., after ileal resection or in Crohn's disease affecting the terminal ileum, where bile acid malabsorption leads to colonic irritation).

Adverse effects: GI disturbances are common—bloating, constipation, nausea. Because they are resins that bind substances in the gut, they can also impair absorption of fat-soluble vitamins (A, D, E, K) and interfere with absorption of other drugs (e.g., warfarin, thiazides, statins, thyroxine)—so other medications should be taken 1 hour before or 4-6 hours after the resin.

Key associations for boards: Remember that bile acid sequestrants are safe in pregnancy (not systemically absorbed) unlike statins. They are often paired with statins in combination therapy to maximize LDL lowering (statins decrease cholesterol synthesis while resins decrease bile acid reabsorption, synergistically upregulating LDL receptors). Colesevelam is newer, better tolerated, and also FDA approved for glycemic control in type 2 diabetes (modest effect, mechanism unclear, possibly related to bile acid receptor signaling like FXR and glucose metabolism).