Bile acid sequestrants (BAS) are a class of medication used to manage cholesterol levels. These drugs function within the digestive tract rather than being absorbed into the body’s circulation. They are large, polymeric compounds that act as ion-exchange resins to bind certain substances within the gut. This non-systemic approach means their therapeutic effect is initiated locally and depends on their interaction with the digestive process.
How Bile Acid Sequestrants Interrupt Digestion
The body recycles most of its bile acids through the enterohepatic circulation. Bile acids are synthesized in the liver using cholesterol and released into the small intestine to aid in the digestion and absorption of dietary fats. Normally, over ninety-five percent of these bile acids are reabsorbed from the lower small intestine and returned to the liver via the portal vein for reuse.
Bile acid sequestrants intervene in this cycle by acting as positively charged resins that attract and bind to the negatively charged bile acids. This binding creates a large, insoluble complex within the gut lumen that cannot be reabsorbed through the intestinal wall. The bound bile acids are sequestered and excreted from the body through the feces, increasing the fecal loss of bile acids.
This interruption reduces the amount of bile acids returning to the liver. To compensate, the liver must increase its production of new bile acids. This synthesis is achieved by upregulating cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in converting cholesterol into bile acids. By forcing the liver to convert its internal stores of cholesterol, the sequestrants initiate a cascade that impacts lipid metabolism.
Role in Lowering Cholesterol Levels
The liver’s increased demand for cholesterol to synthesize new bile acids is the mechanism for lowering cholesterol. The drop in cholesterol content within the liver cells (hepatocytes) is sensed by the regulatory protein SREBP-2. This protein triggers an increase in the number of low-density lipoprotein (LDL) receptors present on the surface of the liver cells.
The newly expressed LDL receptors actively pull more LDL cholesterol from the circulating bloodstream. This receptor-mediated clearance reduces the total amount of “bad” cholesterol circulating in the plasma. Examples of these medications include Cholestyramine (Prevalite), Colestipol (Colestid), and Colesevelam (Welchol).
As a single therapy, bile acid sequestrants lower LDL cholesterol levels by approximately fifteen to thirty percent. While less potent than statin medications, BAS are frequently prescribed for patients who cannot tolerate statins due to side effects. They are often combined with statins to achieve a more aggressive reduction, sometimes approaching fifty percent reduction in LDL cholesterol levels.
Other Conditions Treated by Sequestrants
Beyond lipid management, bile acid sequestrants treat conditions related to excess bile acids. One significant application is the treatment of chronic diarrhea caused by bile acid malabsorption. This condition occurs when bile acids are not properly reabsorbed in the small intestine and spill into the colon, where they cause irritation and water secretion.
The sequestrants bind the excess bile acids in the colon, preventing them from stimulating this secretory effect and resolving the chronic, watery diarrhea. This is often a welcome relief for patients who have undergone certain gastrointestinal surgeries, such as gallbladder removal. The drugs are also used to alleviate pruritus, or itching, associated with various liver diseases.
In liver conditions involving partial biliary obstruction, bile acids can build up and deposit in the skin, causing intense itching. By binding bile acids in the gut and promoting their excretion, the sequestrants reduce overall circulating bile acid levels in the blood. Colesevelam, a newer sequestrant, also has an approved indication for improving glycemic control in patients with Type 2 diabetes.
Practical Considerations for Use
Because bile acid sequestrants are not absorbed into the body, they rarely cause systemic side effects. Their most common adverse effects are localized to the gut, including constipation, which is reported in up to fifty percent of patients. Other frequent gastrointestinal complaints include abdominal discomfort, bloating, nausea, and excessive gas.
The administration of BAS varies. Cholestyramine and Colestipol often come as a gritty powder that must be mixed with liquid, which some patients find unpalatable. Colesevelam is available in tablet form, which is generally better tolerated and may reduce some of the gastrointestinal side effects. Patients are often encouraged to start with a low dose and slowly increase it to minimize the initial occurrence of constipation.
A significant consideration when taking these medications is their potential for non-specific drug interactions. The resins can bind to other orally administered medications in the digestive tract, such as thyroid hormones, certain antibiotics, and warfarin, preventing their proper absorption. Patients are advised to take other medications at least one hour before or four to six hours after taking the sequestrant to ensure the other drugs are fully absorbed. Furthermore, long-term use can reduce the absorption of fat-soluble vitamins (A, D, E, and K), potentially requiring supplementation.