Mechanism of Action of Welchol (Colesevelam) and Ursodiol in Treating Diarrhea
Welchol (Colesevelam) Mechanism of Action
Colesevelam is a non-absorbable bile acid sequestrant that binds bile acids in the intestinal lumen, forming insoluble complexes that are excreted in feces, thereby preventing their reabsorption and reducing the secretory effects of excess bile acids in the colon. 1
Specific Pharmacological Properties
Colesevelam is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and remains unabsorbed in the gastrointestinal tract, with distribution limited entirely to the gut lumen. 1
The drug has 4-6 times stronger binding affinity to bile acids compared to cholestyramine, maximizing interaction with bile salts while reducing potential drug-drug interactions. 2
Colesevelam is not metabolized systemically and does not interfere with cytochrome P450 enzymes, with only 0.05% of administered radioactivity excreted in urine. 1
Clinical Mechanism in Bile Acid Diarrhea
By binding excess bile acids in the colon, colesevelam prevents their secretory and osmotic effects that cause diarrhea, with therapeutic response typically achieved within 2 weeks of treatment. 1, 3
In a 2023 randomized controlled trial, colesevelam achieved 64% remission rate versus 16% with placebo in patients with bile acid diarrhea diagnosed by C4 concentration >46 ng/mL, demonstrating clear superiority. 3
Colesevelam treatment increases fecal concentrations of all bile acid species while decreasing serum concentrations of secondary bile acids, confirming its mechanism of promoting fecal bile acid excretion. 4
Tolerability Advantages
Colesevelam is better tolerated than cholestyramine for bile salt malabsorption treatment, with lower rates of gastrointestinal side effects and better palatability. 2
Common adverse events with colesevelam are transient and include abdominal pain (23% of patients), bloating (41%), and nausea (18%), with no serious adverse events reported in clinical trials. 3
Ursodiol (Ursodeoxycholic Acid) Mechanism of Action
Ursodiol does NOT have a direct mechanism of action for treating diarrhea caused by bile acid malabsorption and should not be used for this indication.
Actual Pharmacological Actions
Ursodiol suppresses hepatic synthesis and secretion of cholesterol and inhibits intestinal absorption of cholesterol, but does not reduce bile acid production or secretion. 5
The drug's therapeutic actions are in the liver, bile, and gut lumen where it solubilizes cholesterol in bile, changing bile from cholesterol-precipitating to cholesterol-solubilizing. 5
Ursodiol undergoes 90% absorption in the small bowel, enters portal circulation with large first-pass hepatic extraction, and is conjugated with glycine or taurine before secretion into bile. 5
Why Ursodiol is Inappropriate for Bile Acid Diarrhea
Ursodiol does not bind bile acids, does not reduce bile acid secretion into the intestine, and does not prevent the secretory effects of bile acids in the colon that cause diarrhea. 5
The drug's mechanism involves increasing bile acid concentration in bile (reaching 60% of total bile acid pool with high doses), which would theoretically worsen rather than improve bile acid diarrhea. 5
No guidelines recommend ursodiol for treatment of bile acid diarrhea or bile acid malabsorption, as its pharmacological profile is fundamentally incompatible with this therapeutic goal. 2
Critical Clinical Distinction
The key mechanistic difference is that colesevelam removes excess bile acids from the enterohepatic circulation by binding them in the gut lumen, while ursodiol increases bile acid concentration in bile and has no effect on reducing colonic bile acid exposure. 1, 5
Appropriate Treatment Algorithm
For bile acid diarrhea, bile acid sequestrants (cholestyramine, colesevelam, or colestipol) are the appropriate first-line therapy, with colesevelam preferred due to superior tolerability. 2, 6
Colesevelam should be started at 1,875 mg (three 625 mg tablets) twice daily with meals, with therapeutic response expected within 2 weeks. 1, 3
Ursodiol has no role in treating bile acid diarrhea and should be reserved for its approved indications: gallstone dissolution and primary biliary cholangitis. 5