Cholestyramine: Mechanism and Dosing for Hyperlipidemia
Cholestyramine is a bile acid sequestrant that lowers LDL-cholesterol by 10-28% depending on dose, with the standard adult dose being 8-16 grams daily divided into two doses, though it can be titrated up to 24 grams daily if needed. 1
What is Cholestyramine?
Cholestyramine is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine and prevents their reabsorption. 1 As the bile acid pool decreases, the hepatic enzyme cholesterol 7-α-hydroxylase is upregulated, which increases conversion of cholesterol to bile acids. 1 This creates increased demand for cholesterol in liver cells, resulting in upregulation of HMG-CoA reductase and increased numbers of hepatic LDL receptors. 1 These compensatory effects increase clearance of LDL-cholesterol from the blood, resulting in decreased serum LDL-C levels. 1
FDA-Approved Indications
Cholestyramine is FDA-approved as an adjunct to diet to decrease LDL-cholesterol in adults with primary hyperlipidemia. 1
Standard Dosing Regimen
Starting Dose
- Begin with 4 grams (one packet or scoop) once or twice daily 2
- The American College of Cardiology guidelines recommend starting at 8 grams daily divided into 2 doses 1
Maintenance Dose
- 8-16 grams daily divided into 2 doses 1, 2
- Increases should be gradual with lipid assessment at intervals of at least 4 weeks 2
Maximum Dose
Expected LDL-Cholesterol Reduction
The dose-response relationship is well-established:
- 8 grams daily: 16-22% LDL-C reduction 3
- 10.4% reduction versus placebo in monotherapy trials 1
- 16 grams daily: 23-27% LDL-C reduction 3
- 24 grams daily: 27-28% LDL-C reduction 3
Administration Requirements
Cholestyramine must never be taken in dry powder form. 2 Mix each packet or scoopful with at least 2-3 ounces of water or other non-carbonated beverage and stir to uniform consistency. 2 It may also be mixed with highly fluid soups or pulpy fruits with high moisture content such as applesauce or crushed pineapple. 2
The suggested time of administration is at mealtime, though this may be modified to avoid interference with absorption of other medications. 2
Critical Drug Interactions and Timing
All other medications must be taken at least 1 hour before or 4 hours after cholestyramine to avoid impaired absorption. 1, 3 This is particularly critical for:
- Thyroid hormone replacement therapy 1, 3
- Warfarin (monitor INR frequently during initiation) 1
- Oral contraceptives 1
- Cyclosporine 1
- Phenytoin 1
- Sulfonylureas 1
Adverse Effects and Monitoring
The most common adverse effects are gastrointestinal: constipation, dyspepsia, and nausea. 1
Important monitoring considerations:
- Triglyceride levels may increase or remain unchanged; monitor for hypertriglyceridemia 1
- Fat-soluble vitamin deficiencies can occur; oral vitamins should be given at least 4 hours before cholestyramine 1, 3
- Vitamin K deficiency with long-term use 3
- TSH may increase in patients on thyroid hormone replacement 3
Post-marketing reports include bowel obstruction, esophageal obstruction, and fecal impaction. 1, 3
Cardiovascular Outcomes Evidence
The LRC-CPPT trial demonstrated that cholestyramine reduced the risk of definite CHD death and/or definite nonfatal MI by 19% (p<0.05) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia treated for an average of 7.4 years. 1 This represents the only cardiovascular outcomes trial data available for bile acid sequestrants, as colesevelam and colestipol have not been studied for cardiovascular morbidity and mortality. 1
Combination Therapy
Cholestyramine's lipid-lowering effects are enhanced when combined with statins, with additive effects on LDL-cholesterol. 2 When added to low- to moderate-intensity statins, bile acid sequestrants provide an additional 10-16% reduction in LDL-C. 1
Clinical Pitfalls
- Poor palatability and gastrointestinal side effects lead to poor compliance, particularly in long-term use 1
- Contraindicated in patients with triglycerides >500 mg/dL, history of hypertriglyceridemia-induced pancreatitis, or bowel obstruction 1
- Avoid in patients with gastroparesis or other GI motility disorders 1
- Can cause hyperchloremic metabolic acidosis, particularly in volume-depleted patients or those with renal failure 4