Introduction to bile acid sequestrants for lowering blood lipid levels

Bile acid sequestrants for lowering blood lipid levels:

This class of drugs works by blocking the absorption of bile acids or cholesterol from the intestines, causing them to be excreted in the feces and reducing the levels of free cholesterol in liver cells. They accelerate the breakdown and metabolism of low-density lipoprotein (LDL) cholesterol through the liver’s own regulatory mechanisms, thereby reducing cholesterol and LDL levels. They are only suitable for isolated hypercholesterolemia.

Due to the high cost and large dosage of these drugs, as well as the potential for foreign body and gastrointestinal reactions, they can easily cause constipation. Long-term use can interfere with the absorption of fat-soluble vitamins A, D, E, and K, making them less acceptable to patients. Therefore, they are rarely used nowadays.

(1) Cholestyramine (Bile acid sequestrants):

• [effect] it is used to treat primary hypercholesterolemia, and can also remove irritating cholic acid, so as to relieve skin itching caused by primary biliary cirrhosis and biliary obstruction. It can reduce low-density lipoprotein and cholesterol.
• [usage and dosage] 1~6 times a day, 4~5g each time, the total amount is no more than 24 times a day.
• [adverse reactions] common adverse reactions include vomiting, nausea, gastrointestinal bleeding. Large doses can cause steatorrhea and osteoporosis. It can also have bad taste and constipation. Constipation can be alleviated by eating more fiber. Those with bad taste can be corrected with seasoning. Rare adverse reactions include lipodysentery, diarrhea, severe abdominal pain and intestinal obstruction.
• [precautions] for those who take colexemide for a long time, vitamin A, vitamin D, vitamin K, calcium and folic acid can be appropriately supplemented. Especially pregnant and lactating women. Because colexemide will interfere with the absorption of digoxin, warfarin, probucol, fibrates and statins, it should be taken 1-4 hours before taking colexemide or 4 hours after taking colexemide.

(2) Colestipol (Bile acid sequestrants):

• [Action] This drug can reduce serum cholesterol and LDL-C levels, promote regression or slow the progression of atherosclerotic plaques, but has no significant effect on triglycerides.
• [Dosage] Take 1 to 2 times daily, 10 to 20 grams each time, mix with water or beverage before consumption to reduce esophageal irritation. It is generally recommended to take before meals or at bedtime.
• [Adverse Reactions] Adverse reactions include nausea, vomiting, constipation, dizziness, abdominal discomfort, and allergic reactions.
• [Precautions] Since this drug affects the absorption of cefaclor, thiazide diuretics, lincomycin, phenobarbital, and warfarin, it should be taken 1 hour before or 4 hours after taking the medication to ensure good absorption.

(3) Probucol (Bile acid sequestrants):

• [Action] This drug can lower cholesterol and LDL-C levels, which is beneficial for the prevention and treatment of atherosclerosis. It can also lead to regression of Achilles tendon xanthomas and skin xanthomas in patients.
• [Dosage] Take twice daily, 0.2 to 0.5 grams each time. Take with breakfast and dinner.
• [Adverse Reactions] Common adverse reactions include abdominal pain, diarrhea, and nausea. Rare adverse reactions include elevated levels of serum transaminases, alkaline phosphatase, creatine kinase, as well as transient increases in bilirubin, uric acid, blood urea nitrogen, and blood glucose.
• [Precautions] Prolonged use of this drug can cause prolongation of the Q-T interval on the electrocardiogram (EKG), so it should be avoided in patients with low blood potassium, arrhythmias, and prolonged Q-T interval.

Development of Bile acid sequestrants

Bile acid sequestrants, also known as bile acid resins, are a class of pharmaceutical drugs used primarily for the treatment of hypercholesterolemia (high cholesterol levels) and dyslipidemia. Their development has been a significant part of the evolution of lipid-lowering therapies. Here is a brief overview of the key milestones in the development of bile acid sequestrants:

1. Early Discoveries: The concept of using bile acids to manage cholesterol levels dates back to the 1950s. Researchers discovered that bile acids, which are synthesized from cholesterol in the liver, play a crucial role in the absorption of dietary fats and cholesterol in the intestine. This led to the idea that binding bile acids in the intestine could reduce their reabsorption and, consequently, lower cholesterol levels.
2. First Generation Sequestrants: The first bile acid sequestrant, cholestyramine, was developed in the 1960s. Cholestyramine is a polymeric quaternary ammonium cation exchange resin. It works by binding bile acids in the intestine, preventing their reabsorption and promoting their excretion. This forces the liver to use more cholesterol to synthesize new bile acids, thereby lowering overall cholesterol levels. Cholestyramine was approved by the FDA in 1973 for the treatment of hypercholesterolemia.
3. Improvements and New Formulations: Following the success of cholestyramine, other sequestrants were developed to address some of the limitations of the first-generation drugs. Colestipol, another cation exchange resin, was introduced in the 1970s. It has a similar mechanism of action to cholestyramine but is available in a different formulation that may be better tolerated by some patients.
4. Second Generation Sequestrants: In the 1990s, a new generation of bile acid sequestrants was developed, aiming to improve patient compliance and reduce side effects. Colesevelam is an example of a second-generation sequestrant. It has a different chemical structure that results in fewer gastrointestinal side effects compared to earlier resins. Colesevelam was approved by the FDA in 2000.
5. Combination Therapies and Research: More recent developments in the field have focused on combining bile acid sequestrants with other lipid-lowering agents to enhance efficacy. Additionally, research continues to explore the potential of these drugs in other therapeutic areas, such as type 2 diabetes and inflammatory bowel disease, where they may have additional benefits beyond cholesterol management.
6. Current Use and Future Directions: Bile acid sequestrants remain an important option in the treatment of hypercholesterolemia, particularly for patients who cannot tolerate or do not respond well to other lipid-lowering therapies. Ongoing research is exploring new formulations and combinations to further improve their effectiveness and tolerability.

In summary, the development of bile acid sequestrants has evolved from initial discoveries in the 1950s to the introduction of first- and second-generation drugs, with ongoing efforts to refine these therapies and expand their clinical applications. These drugs have played a significant role in the management of cholesterol disorders and continue to be a valuable tool in the therapeutic arsenal against cardiovascular disease.