How does Questran (cholestyramine) lower cholesterol?

Mechanism of Action of Questran (Cholestyramine) in Lowering Cholesterol

Questran (cholestyramine) lowers cholesterol by binding bile acids in the intestine, preventing their reabsorption, which forces the liver to convert more cholesterol into bile acids to replace those lost in feces, ultimately reducing serum LDL cholesterol levels. 1

Primary Mechanism of Action

Cholestyramine works through a multi-step process:

1. Bile Acid Binding: Cholestyramine is a non-absorbed, lipid-lowering polymer that binds bile acids in the intestine, forming an insoluble complex 1, 2

2. Interruption of Enterohepatic Circulation: This complex is excreted in feces, preventing bile acid reabsorption and interrupting the enterohepatic circulation 2

3. Hepatic Compensation: As the bile acid pool decreases, the liver responds by:

   • Upregulating cholesterol 7-α-hydroxylase enzyme activity (up to sixfold increase) 3
   • Increasing conversion of cholesterol to bile acids 1
   • Creating increased demand for cholesterol in liver cells 1

4. Dual Compensatory Effects:

   • Increased transcription and activity of HMG-CoA reductase (cholesterol biosynthetic enzyme) 1, 3
   • Increased expression of hepatic LDL receptors 3

5. Net Result: Enhanced clearance of LDL-C from the bloodstream, leading to decreased serum LDL-C levels 1, 2

Clinical Efficacy

• Cholestyramine monotherapy reduces LDL-C by approximately 10-15% 1
• In the LRC-CPPT trial, cholestyramine treatment resulted in:
  • 7.2% greater reduction in total cholesterol compared to diet and placebo
  • 10.4% greater reduction in LDL-C compared to diet and placebo
  • 19% reduction in coronary heart disease death plus non-fatal myocardial infarction 2

Important Clinical Considerations

Dosing

• Starting dose: 2-4 g/day, gradually titrated based on response
• Typical maintenance dose: 8-16 g/day orally divided into 2 doses
• Maximum dose: 24 g/day 1, 4

Adverse Effects

• Gastrointestinal: Constipation (most common), dyspepsia, nausea, bloating, flatulence 1, 4, 5
• Drug Interactions: Medications should be taken at least 1 hour before or 4 hours after cholestyramine to avoid impaired absorption 1, 4
• Other concerns: May increase triglyceride levels in some patients 1

Contraindications

• Triglycerides >500 mg/dL
• History of hypertriglyceridemia-induced pancreatitis
• Complete biliary obstruction
• Bowel obstruction 4

Practical Considerations

• Poor Palatability: Cholestyramine has taste issues that often lead to poor compliance 1, 4
• Newer Alternatives: Second-generation bile acid sequestrants like colesevelam have improved tolerability and additional glucose-lowering effects 4, 6
• Combination Therapy: Often used with statins or other lipid-lowering agents for enhanced effect 4, 5

Monitoring

• Check lipid levels 4-6 weeks after initiating therapy
• Monitor for potential increases in triglyceride levels
• Consider supplementation of fat-soluble vitamins with long-term use 4

By binding bile acids and preventing their reabsorption, cholestyramine creates a cascade of hepatic responses that ultimately lead to increased clearance of LDL cholesterol from the bloodstream, making it an effective, albeit sometimes poorly tolerated, option for managing hypercholesterolemia.