What Are Bile Acid Sequestrants?

Bile acid chelating agents are basic anion exchange resins, which are difficult to dissolve in water and are not easily destroyed by digestive enzymes. Is a class of safe and effective drugs for lowering plasma TC and LDL-C. Commonly used drugs are chlestyramine (cholestyramine) and colestipo. These drugs have the pharmacological effect of blocking the reabsorption of bile acids, promoting their excretion, and increasing the excretion rate of bile acids. Clinically, it is mainly used for TC and LDL-C elevation, and TG levels are normal and statins cannot be used for familial hypercholesterolemia. This medicine can also be used for itching of the skin during jaundice and for the treatment of digitalis poisoning.

Drug Name: Bile acid chelator
Whether prescription drugs: prescription
Main indications: Jaundice, digitalis poisoning

Adverse reactions: Gastrointestinal reaction
Main medication contraindications: Cannot be taken with weak acid drugs for a long time
Drug type: chemical
Main medicine: Cholestyramine, colestipol

Mechanism and characteristics of bile acid chelator

Effect of Bile Acid Chelators on Bile Acid Enterohepatic Circulation

Bile acid couplers (including anion exchange resins with alkyl quaternary ammonium salts, benzyl quaternary ammonium salts, and oxazole sulfonium salt active groups) are a class of anion exchange compounds that bind irreversibly to bile acids in the intestine, so Obstructs the enterohepatic circulation of bile acids, promotes the excretion of bile acids from feces, thereby accelerating the conversion of cholesterol to bile acids, and reducing cholesterol levels in the liver and plasma. Long-term administration reduces total cholesterol levels by 10% to 30% and decreases LDL by 10% to 35%. Because bile acid chelator drugs are not absorbed by the body and do not enter the systemic circulation, they are safe and reliable to use.

Regulation of bile acid sequestrants on bile acid synthesis genes

These drugs increase CYP7A1 activity and promote bile acid synthesis. Experimental studies have shown that bile acid refluxing into the liver can activate farnesyl derivative X receptor (FXR), thereby regulating the activity of CYP7A1 and bile acid synthesis in the liver. Bile acid chelator drugs reduce bile acid backflow into the liver, inactivate the receptor (FXR) in the liver, and then release the inhibition of CYP7A1 transcription, promote bile acid synthesis in the liver, and thus maintain bile acid pool balance in the body. Therefore, due to the increase in bile acid synthesis, cholesterol in the body is consumed, and the serum cholesterol level is reduced to achieve the purpose of lowering blood lipids.

LDL Bile acid chelator increases LDL receptor expression

The synthesis of bile acids in the liver consumes cholesterol, so more cholesterol needs to be obtained from peripheral tissues, so that the LDL receptor activity on the surface of liver cells is enhanced, the number is increased, and more peripheral low-density lipoproteins are transported to the liver to supplement the lack of cholesterol in the liver . Studies conducted in patients with LDL-C levels between 130 and 220 mg / dl (average 158 mg / d1) showed that LDL-C was reduced by an average of 15% to 18% and total cholesterol was reduced by 7% after 24 weeks of treatment 10% ^[1] .

Bile acid sequestrants reduce intestinal cholesterol absorption

During the process of intestinal absorption of exogenous cholesterol, the bile acids need to be emulsified, and the bile acids chelated by the resin are discharged from the intestines with feces, which affects the digestion and absorption of cholesterol from the intestines. ^[2]

Pharmacological effects of bile acid chelator

Ch bile acid production is catalyzed by 7-hydroxylase, which bile acid can inhibit this enzyme's activity in a feedback manner. This class of drugs blocks the reabsorption of bile acids, promotes their excretion, and can increase the excretion rate of bile acids by up to 10 times. Due to the large loss of bile acids, the conversion of Ch in liver to bile via 7-hydroxylase is accelerated, and a large amount of Ch-containing LDL in plasma enters liver cells via receptors, which causes the levels of TC and LDL-C in plasma to decrease. This class of drugs does not affect HDL-C in plasma and has a small effect on VLDL, but may be accompanied by Ganzhou TG synthesis, which increases plasma TG levels.

Clinical application and efficacy of bile acid chelator

This class of drugs is suitable for any hypercholesterolemia other than homozygous familial, such as heterozygous familial hyperlipidemia (FH), in which colesevelam hydrochloride is recommended for the treatment of FH by the National Lipid Association ^3] . In addition, resins are the only safe lipid-lowering drugs for pregnant patients with hyperlipidemia. These drugs can be used alone or in combination with statins. Cholestyramine, one of the bile acid chelator drugs, was one of the three major lipid-lowering drugs (gefibezi and lovastatin) commonly used abroad. Cholestyramine is superior to fenofibrate in the treatment of hyperlipidemia In combination with statins, cholesterol, LDL-ch, ApoB decreased and HDL levels increased even more ^[4] . Recently, some scholars have observed the clinical efficacy of rosuvastatin and cholestyramine in the treatment of dyslipidemia, and the results show that the effects of both are exact, but more reports tend to better the combination of these drugs and statins Efficacy. According to more reports analysis and market research of blood lipid-lowering prescriptions in hospitals, the order of lipid-lowering drugs application from 2008 to 2012 is probably statins, fibrates, proprietary Chinese medicines, marine fish oil preparations, and others. Among them, statins The proportion of steroids has increased to 70% or more each year. In recent years, bile acid chelators have been rarely used in clinical applications. The literature reports that they have severe gastrointestinal adverse reactions and have almost withdrawn from the market. However, such reports lack convincing practical data. ^[2]

Adverse reactions and treatment of bile acid chelator

More, gastrointestinal reactions are common, such as nausea, bloating, constipation, etc. Plasma TG levels have increased. Due to the irreversible combination of this class of drugs and bile acids, it affects the absorption of fats in food, and can cause fat scabs at high doses. Cholestylam is used in the form of chlorides, so prolonged use can cause perchlorate. Long-term use can affect the absorption of fat-soluble vitamins (A, D, E, K), folic acid, and other weakly acidic drugs, such as butepine, phenobarbital, vitamin C, etc., as it should be avoided in combination with the above drugs. ^[5]

(1) The most common adverse reaction is constipation, and regular use of stool softeners can be considered. In addition, the lack of bile acids can interfere with fat absorption and cause steatosis.

(2) Excessive doses, such as 5 to 24 g / d of cholestyramine and 5 to 30 g / d of colestipol, taken 2 to 3 times before meals; and has an ammonia odor, which makes patients Unbearable, especially for non-critically ill patients, often reluctant to take medication.

(3) Obvious gastrointestinal adverse reactions, such as indigestion, constipation, nausea, abdominal pain, hemorrhoids, anal fissures, and exacerbation of hernias, cause difficulties in long-term medication.

(4) Because the drug is a combination resin, long-term application can reduce the absorption of multivitamins A, D, and K, resulting in insufficient fat-soluble vitamins. In addition, it can also affect the absorption of magnesium, calcium, iron, and zinc. Therefore, pay attention to supplement the corresponding elements when applying.

(5) Affect the absorption of some acidic drugs, such as thiazines, coumarins and digitalis, so it is recommended to use it with other drugs at least 4 to 6 hours apart.

These adverse reactions are milder than other medications, and they are mostly present in high-dose medications and elderly patients. In the past, only specific data on bloating after discontinuation of the drug proved that data on other adverse reactions were scarce. Because it is not widely used at present. Therefore, large-scale clinical research is lacking. ^[2]