Bile Acid Sequestrants
Verified · Oct 2026The resins never enter the blood. They act by draining the bile-acid pool, so the liver must spend its own cholesterol — and fetch more from LDL — to refill it.
Nursing view → administration, monitoring and patient teaching
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Drugs
Mechanism
Non-absorbed resins (polymers) that bind bile acids in the intestine into an insoluble complex excreted in the feces, interrupting the enterohepatic circulation. The liver upregulates cholesterol 7-α-hydroxylase to convert more cholesterol into bile acids, increasing hepatic LDL receptors and LDL clearance, so serum LDL-C falls despite increased hepatic cholesterol synthesis. How colesevelam improves glycemic control is unknown.
The enterohepatic circulation and the liver’s response
Cholesterol is probably the sole precursor of bile acids. Bile acids are secreted into the intestine, emulsify dietary fat, and are largely reabsorbed and returned to the liver through the portal circulation; very little reaches the serum.
The sequestrants bind bile acids into an insoluble complex that passes in the feces. As the pool shrinks, cholesterol 7-α-hydroxylase — the rate-limiting step of bile-acid synthesis — is disinhibited, so more hepatic cholesterol is converted to bile acids. To meet that demand the liver both increases HMG-CoA reductase (more synthesis) and increases LDL receptors, raising LDL clearance. Plasma cholesterol falls even though synthesis rises, because the newly made cholesterol is shunted into bile acids; serum triglycerides may rise or stay unchanged.
An anion-exchange resin: why it binds drugs and causes acidosis
Cholestyramine and colestipol are basic anion-exchange resins in the chloride form. Their chloride can be replaced by other anions with greater affinity for the resin — bile acids, but also many drugs — so cholestyramine delays or reduces the absorption of acidic drugs such as warfarin and thiazides and even basic ones such as propranolol, along with thyroxine, digitalis, tetracycline and penicillin G. Drugs that undergo enterohepatic circulation can also be affected.
The chloride released in exchange explains the hyperchloremic acidosis that prolonged use can cause, especially in younger and smaller patients, and with renal insufficiency, volume depletion or spironolactone. Binding bile acids also impairs fat digestion and absorption, so the fat-soluble vitamins A, D, E and K are lost; vitamin K deficiency produces hypoprothrombinemia and bleeding.
Colesevelam: a different polymer, a different profile
Colesevelam is a hydrophilic, non-absorbed polymer that is not hydrolyzed by digestive enzymes; it lowers LDL-C by the same bile-acid mechanism but is also labeled to improve glycemic control in type 2 diabetes, by an unknown mechanism. It can raise triglycerides — more so in diabetes trials, and most with sulfonylureas or insulin — which is why triglycerides above 500 mg/dL and prior hypertriglyceridemia-induced pancreatitis are contraindications.
Because it is not absorbed and does not interfere with CYP450 enzymes, its interactions are about binding in the gut: it lowers exposure of drugs such as levothyroxine, phenytoin, cyclosporine, warfarin, oral contraceptives, olmesartan and sulfonylureas, which are given 4 hours earlier. Unusually, it increases exposure to extended-release metformin.
Comparing the drugs
The three sequestrants
| Drug | Form | Labeled uses beyond hypercholesterolemia | Contraindications | Spacing of other drugs |
|---|---|---|---|---|
| Cholestyramine | Powder, mixed with fluid (chloride-form resin) | Pruritus from partial biliary obstruction | Complete biliary obstruction; hypersensitivity | ≥ 1 h before or 4–6 h after |
| Colestipol | Tablets or granules (chloride-form resin) | None | Hypersensitivity | ≥ 1 h before or 4 h after |
| Colesevelam | Tablets (oral suspension for children) | Type 2 diabetes glycemic control; HeFH aged 10 to 17 | TG > 500 mg/dL; hypertriglyceridemia-induced pancreatitis; bowel obstruction | ≥ 4 h before |
In the LRC-CPPT, cholestyramine reduced the combined rate of coronary heart disease death plus nonfatal MI by 19% relative to placebo over 7 years.
Pharmacokinetics
- Absorption
- Essentially none: under 0.17% of a radiolabeled colestipol dose and about 0.05% of a colesevelam dose appear in urine. The resins are hydrophilic but insoluble in water and are not hydrolyzed by digestive enzymes.
- Distribution and metabolism
- Confined to the gastrointestinal tract; colesevelam is not metabolized systemically and does not interfere with cytochrome P450 enzymes.
- Onset and offset
- Maximum lipid response to colesevelam within 2 weeks; with colestipol the cholesterol fall is usually evident by one month and returns to baseline within one month of stopping.
- Glycemic time course (colesevelam)
- HbA1c reduction first seen after 4–6 weeks, maximal after 12–18 weeks.
- Drug interactions
- Mainly by binding in the gut, not by enzyme effects — hence management by separating doses (≥ 1 hour before or 4–6 hours after cholestyramine; 1 hour before or 4 hours after colestipol; at least 4 hours before colesevelam). Stopping cholestyramine can raise the level of a drug such as digitalis that was titrated while it was being bound.
Uses & drug choice
- Primary hypercholesterolemia (elevated LDL-C) — with diet, alone or with a statin
- Colesevelam for heterozygous familial hypercholesterolemia in boys and postmenarchal girls aged 10 to 17
- Colesevelam to improve glycemic control in adults with type 2 diabetes
- Cholestyramine for pruritus from partial biliary obstruction
Adverse effects
- Constipation, bloating, dyspepsia
- The resin is not absorbed, so its adverse effects are mainly gastrointestinal; constipation is more likely at high doses and in patients over 60.
- Bowel and esophageal obstruction
- Constipating effects can progress to impaction or obstruction (especially with motility disorders or prior GI surgery), and the large tablets can lodge in the esophagus.
- Hypertriglyceridemia and pancreatitis (colesevelam)
- Like other bile acid sequestrants, colesevelam can increase serum triglycerides — more in type 2 diabetes and with sulfonylureas or insulin — and very high triglycerides can cause acute pancreatitis.
- Vitamin deficiency and bleeding
- Binding bile acids impairs fat digestion and absorption, so vitamins A, D, E and K (and folate) fall; vitamin K deficiency causes hypoprothrombinemia.
- Hyperchloremic acidosis
- Cholestyramine and colestipol are chloride-form anion-exchange resins; prolonged use may produce hyperchloremic acidosis, especially in younger and smaller patients.
Toxicity & antidote
A patient who took 150% of the maximum recommended cholestyramine dose for several weeks had no ill effects. The chief potential harm of overdose is gastrointestinal obstruction; its location, degree and the presence of normal gut motility determine treatment.
Interactions
Contraindications
- Cholestyramine: complete biliary obstruction (no bile reaching the intestine) — Labeled contraindication: in complete biliary obstruction, bile is not secreted into the intestine.
- Colesevelam: serum triglycerides > 500 mg/dL, or a history of hypertriglyceridemia-induced pancreatitis — Colesevelam can raise triglycerides, and hypertriglyceridemia can cause acute pancreatitis.
- Colesevelam: history of bowel obstruction — Postmarketing bowel obstruction has occurred with colesevelam.
- Cholestyramine, colestipol: hypersensitivity to any component — Listed as a contraindication on both labels.
- Gastroparesis, other GI motility disorders, major GI surgery, or pre-existing constipation use caution — Constipating effects can lead to impaction or bowel obstruction (colesevelam is not recommended in motility disorders or after major GI surgery).
- Difficulty swallowing (colesevelam and colestipol tablets) use caution — The large tablets can cause dysphagia or esophageal obstruction; colesevelam oral suspension is the alternative.
- Phenylketonuria (Prevalite) use caution — Prevalite contains phenylalanine.
High-yield
- Raise triglycerides — colesevelam contraindicated above 500 mg/dL
- A-D-E-K lost — fat-soluble vitamins; vitamin K deficiency → bleeding
- Interactions — bind other drugs; space the doses
- Distended — constipation, impaction, obstruction
Practice questions
Q1A 52-year-old man starts cholestyramine for primary hypercholesterolemia. After 3 months his LDL-C has fallen 20%. A study of his hepatic metabolism would most likely show increased activity of which enzyme as the primary adaptive response?
Which enzyme is upregulated first by the drug’s action?
- A.Lipoprotein lipase
- B.Acyl-CoA:cholesterol acyltransferase
- C.Cholesterol 7-α-hydroxylase
- D.Hepatic lipase
- E.PCSK9
Show answer
C. Cholesterol 7-α-hydroxylase — Cholestyramine binds bile acids in the gut; as the bile-acid pool shrinks, cholesterol 7-α-hydroxylase — the rate-limiting step of bile-acid synthesis — is disinhibited, increasing conversion of cholesterol to bile acids. The resulting hepatic demand raises HMG-CoA reductase activity and LDL-receptor number, so LDL-C falls.
Q2A 58-year-old woman with type 2 diabetes and LDL-C of 160 mg/dL has fasting triglycerides of 620 mg/dL. She asks whether colesevelam could treat both her glucose and her cholesterol.
Why is colesevelam inappropriate for her?
- A.It can raise triglycerides, and it is contraindicated with triglycerides above 500 mg/dL
- B.It raises HbA1c
- C.It is contraindicated in type 2 diabetes
- D.It inhibits CYP3A4
- E.It is absorbed and causes hepatotoxicity
Show answer
A. It can raise triglycerides, and it is contraindicated with triglycerides above 500 mg/dL — Colesevelam is labeled to lower LDL-C and to improve glycemic control in type 2 diabetes, but like other bile acid sequestrants it can increase triglycerides, and hypertriglyceridemia can cause acute pancreatitis; it is contraindicated with triglycerides above 500 mg/dL. It is not absorbed and does not interfere with CYP450 enzymes.
Q3A 4-year-old with cholestatic liver disease has been taking cholestyramine for pruritus for many months. Labs show a normal anion gap metabolic acidosis with an elevated serum chloride.
What best explains the acid–base disturbance?
- A.Bile-acid malabsorption causing diarrhea and bicarbonate loss alone
- B.Ketoacidosis from fat malabsorption
- C.Vitamin D deficiency
- D.Lactic acidosis from impaired gluconeogenesis
- E.Chloride released from the chloride-form anion-exchange resin
Show answer
E. Chloride released from the chloride-form anion-exchange resin — Cholestyramine is the chloride form of an anion-exchange resin, and prolonged use may produce hyperchloremic acidosis, especially in younger and smaller patients in whom the relative dose is higher. Diarrheal bicarbonate loss does not fit either: no diarrhea is reported, and the resin’s most common adverse reaction is constipation.
Q4A 70-year-old woman on stable levothyroxine starts cholestyramine and takes both medicines together each morning. Six weeks later her TSH has risen and she feels sluggish.
What is the best explanation and fix?
- A.Cholestyramine induces thyroxine metabolism; increase the levothyroxine dose
- B.Cholestyramine causes primary hypothyroidism; stop it
- C.Levothyroxine causes bile-acid malabsorption; switch to colesevelam
- D.The resin binds levothyroxine in the gut; give levothyroxine at least 1 hour before or 4–6 hours after cholestyramine
- E.Cholestyramine increases TSH secretion directly
Show answer
D. The resin binds levothyroxine in the gut; give levothyroxine at least 1 hour before or 4–6 hours after cholestyramine — Cholestyramine can delay or reduce the absorption of thyroid and thyroxine preparations taken at the same time; other drugs are taken at least 1 hour before or 4–6 hours after the resin. The interaction is binding in the gut, not enzyme induction.
Sources
- PREVALITE (cholestyramine) — FDA label: mechanism, contraindications, constipation, vitamins, drug spacing — FDA / DailyMed
- Colesevelam hydrochloride tablets (Glenmark) — FDA label: contraindications, triglycerides, bowel obstruction, interactions — FDA / DailyMed
- COLESTID (colestipol) tablets — FDA label: administration, drug spacing, adverse reactions — FDA / DailyMed
- COLESTID (colestipol) granules — FDA label: mixing and administration — FDA / DailyMed
- Antilipemic Agent Bile Acid Sequestrants — mechanism, adverse effects, drug interactions — StatPearls (NCBI)
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.