Bile acid sequestrant
Encyclopedia
The bile acid sequestrants are a group of medications used to bind certain components of bile
in the gastrointestinal tract
. They disrupt the enterohepatic circulation
of bile acid
s by sequestering them and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic agent
s, although they may be used for purposes other than lowering cholesterol. They are used in the treatment of chronic diarrhea due to bile acid malabsorption.
ic compounds that serve as ion exchange resin
s. Bile acid sequestrants exchange anions such as chloride
ions for bile acids. By doing so, they bind bile acids and sequester them from enterohepatic circulation.
Since bile acid sequesterants are large polymeric structures, they are not well-absorbed from the gut into the bloodstream. Thus, bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract
.
, the disruption of bile acid reabsorption will decrease cholesterol levels, in particular, low-density lipoprotein (commonly known as "bad cholesterol"). Therefore, they may be used for the treatment of hypercholesterolemia
and dyslipidemia
.
In chronic liver
diseases such as cirrhosis
, bile acids may deposit in the skin, causing pruritus (itching). Hence, bile acid sequestrants may be used for the prevention of pruritus in patients with chronic liver disease.
In addition, diarrhea
may be caused by excess bile salts entering the colon rather than being absorbed at the end of the small intestine (the ileum
). The condition of bile acid malabsorption
occurs after surgery to the ileum
, in Crohn's disease
, with a number of other gastro-intestinal causes, or is commonly a primary, idiopathic condition. The SeHCAT
test can be used for diagnosis. Bile salt diarrhea is a side-effect of gallbladder
removal. Bile acid sequestrants may reduce diarrhea in these patients.
Bile acid sequestrants may also be used to treat hyperthyroidism as an adjunct therapy. By inhibiting the enterohepatic circulation, more L-thyroxine will be lost through defecation, thus lowering body thyroxine levels.
s has decreased markedly since the introduction of the statin
s, which are more efficacious than bile acid sequestrants at lowering LDL. They are occasionally used as an adjunct to the statins (as an alternative to the fibrate
s (another major group of cholesterol-lowering drugs), which are thought to increase the risk of rhabdomyolysis
when used with statins).
In addition, because bile acid sequestrants are not well-absorbed from the gut; in general, they are regarded as safe in pregnant women. However, by interfering with vitamin absorption, they may cause vitamin deficiencies that may affect the fetus. Hence, vitamin supplementation may be warranted, with appropriate intervals between dosing of the vitamins and bile acid sequestrants.
Bile acid sequestrants are the principal therapy for the diarrhea found in bile acid malabsorption
. Cholestyramine, colestipol and colesevelam have all been used. Doses may not need to be as high as those previously used for hyperlipidemia. Many patients find then hard to tolerate, as although the diarrhea may improve, bloating and abdominal pain can worsen .
The bile acid sequestrant Cholestyramine
is used in the treatment of Clostridium difficile
infections, in order to absorb toxins A and B.
ic resins:
(GI tract), such as constipation
, diarrhea
, and flatulence
. Some patients complain of the bad taste.
They may also bind fat-soluble vitamin
s, such as vitamin A
, vitamin D
, vitamin E
, and vitamin K
. This effect may result in a vitamin deficiency. Hence, vitamin supplementation may be warranted.
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
in the gastrointestinal tract
Gut (zoology)
In zoology, the gut, also known as the alimentary canal or alimentary tract, is a tube by which bilaterian animals transfer food to the digestion organs. In large bilaterians the gut generally also has an exit, the anus, by which the animal disposes of solid wastes...
. They disrupt the enterohepatic circulation
Enterohepatic circulation
Enterohepatic circulation refers to the circulation of biliary acids from the liver, where they are produced and secreted in the bile, to the small intestine, where it aids in digestion of fats and other substances, back to the liver....
of bile acid
Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals. Bile salts are bile acids compounded with a cation, usually sodium. In humans, the salts of taurocholic acid and glycocholic acid represent approximately eighty percent of all bile salts. The two major bile acids are cholic...
s by sequestering them and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic agent
Hypolipidemic agent
Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...
s, although they may be used for purposes other than lowering cholesterol. They are used in the treatment of chronic diarrhea due to bile acid malabsorption.
Mechanism
Bile acid sequestrants are polymerPolymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
ic compounds that serve as ion exchange resin
Ion exchange resin
An ion-exchange resin or ion-exchange polymer is an insoluble matrix normally in the form of small beads, usually white or yellowish, fabricated from an organic polymer substrate. The material has highly developed structure of pores on the surface of which are sites with easily trapped and...
s. Bile acid sequestrants exchange anions such as chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
ions for bile acids. By doing so, they bind bile acids and sequester them from enterohepatic circulation.
Since bile acid sequesterants are large polymeric structures, they are not well-absorbed from the gut into the bloodstream. Thus, bile acid sequestrants, along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
.
Indication
Since bile acids are biosynthesized from cholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
, the disruption of bile acid reabsorption will decrease cholesterol levels, in particular, low-density lipoprotein (commonly known as "bad cholesterol"). Therefore, they may be used for the treatment of hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
and dyslipidemia
Dyslipidemia
Dyslipidemia or dyslipidaemia is an abnormal amount of lipids in the blood. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood, often due to diet and lifestyle. The prolonged elevation of insulin levels can lead to dyslipidemia...
.
In chronic liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
diseases such as cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, bile acids may deposit in the skin, causing pruritus (itching). Hence, bile acid sequestrants may be used for the prevention of pruritus in patients with chronic liver disease.
In addition, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
may be caused by excess bile salts entering the colon rather than being absorbed at the end of the small intestine (the ileum
Ileum
The ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
). The condition of bile acid malabsorption
Bile acid malabsorption
Bile acid malabsorption is a cause of chronic diarrhea. It can result from malabsorption secondary to gastro-intestinal disease or be a primary disorder. Treatment with bile acid sequestrants is often effective.-Classification:...
occurs after surgery to the ileum
Ileum
The ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
, in Crohn's disease
Crohn's disease
Crohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
, with a number of other gastro-intestinal causes, or is commonly a primary, idiopathic condition. The SeHCAT
SeHCAT
SeHCAT is the usual name for 23-seleno-25-homo-tauro-cholic acid . It is used in a clinical test to diagnose bile acid malabsorption.-Development:...
test can be used for diagnosis. Bile salt diarrhea is a side-effect of gallbladder
Gallbladder
In vertebrates the gallbladder is a small organ that aids mainly in fat digestion and concentrates bile produced by the liver. In humans the loss of the gallbladder is usually easily tolerated....
removal. Bile acid sequestrants may reduce diarrhea in these patients.
Bile acid sequestrants may also be used to treat hyperthyroidism as an adjunct therapy. By inhibiting the enterohepatic circulation, more L-thyroxine will be lost through defecation, thus lowering body thyroxine levels.
Role in clinical use
Use of these agents as hypolipidemic agentHypolipidemic agent
Hypolipidemic agents, or antihyperlipidemic agents, are a diverse group of pharmaceuticals that are used in the treatment of hyperlipidemias. They are called lipid-lowering drugs or agents.- Classes of hypolipidemic drugs :...
s has decreased markedly since the introduction of the statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
s, which are more efficacious than bile acid sequestrants at lowering LDL. They are occasionally used as an adjunct to the statins (as an alternative to the fibrate
Fibrate
In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents.- Members :...
s (another major group of cholesterol-lowering drugs), which are thought to increase the risk of rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
when used with statins).
In addition, because bile acid sequestrants are not well-absorbed from the gut; in general, they are regarded as safe in pregnant women. However, by interfering with vitamin absorption, they may cause vitamin deficiencies that may affect the fetus. Hence, vitamin supplementation may be warranted, with appropriate intervals between dosing of the vitamins and bile acid sequestrants.
Bile acid sequestrants are the principal therapy for the diarrhea found in bile acid malabsorption
Bile acid malabsorption
Bile acid malabsorption is a cause of chronic diarrhea. It can result from malabsorption secondary to gastro-intestinal disease or be a primary disorder. Treatment with bile acid sequestrants is often effective.-Classification:...
. Cholestyramine, colestipol and colesevelam have all been used. Doses may not need to be as high as those previously used for hyperlipidemia. Many patients find then hard to tolerate, as although the diarrhea may improve, bloating and abdominal pain can worsen .
The bile acid sequestrant Cholestyramine
Cholestyramine
Cholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
is used in the treatment of Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
infections, in order to absorb toxins A and B.
Examples of bile acid sequestrants
Three drugs are members of this class; all are synthetic polymerPolymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
ic resins:
- CholestyramineCholestyramineCholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...
(Questran) - ColesevelamColesevelamColesevelam is a bile acid sequestrant administered orally. It is developed by Genzyme and marketed in the US by Daiichi Sankyo under the brand name WelChol and elsewhere by Genzyme under the tradename Cholestagel.-Clinical use:...
(Cholestagel in Europe, Welchol in the USA) - ColestipolColestipolColestipol is a bile acid sequestrant.It works in the gut trapping bile salts, and preventing them from being reabsorbed.This leads todecreased enterohepatic recirculation of bile salts,increased synthesis of new bile salts by the liver,...
(Colestid)
Side-effects
Since bile acid sequestrants are designed to stay in the gut, they, in general, do not have systemic side-effects. However, they may cause problems in the gastrointestinal tractGastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
(GI tract), such as constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, and flatulence
Flatulence
Flatulence is the expulsion through the rectum of a mixture of gases that are byproducts of the digestion process of mammals and other animals. The medical term for the mixture of gases is flatus, informally known as a fart, or simply gas...
. Some patients complain of the bad taste.
Drug interactions
In addition to bile acids, bile acid sequestrants may also bind drugs in the GI tract, preventing their absorption into the bloodstream. For this reason, it is generally advised that bile acid sequestrants be spaced several hours apart from other drugs.They may also bind fat-soluble vitamin
Vitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
s, such as vitamin A
Vitamin A
Vitamin A is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light and color vision...
, vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
, vitamin E
Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
, and vitamin K
Vitamin K
Vitamin K is a group of structurally similar, fat soluble vitamins that are needed for the posttranslational modification of certain proteins required for blood coagulation and in metabolic pathways in bone and other tissue. They are 2-methyl-1,4-naphthoquinone derivatives...
. This effect may result in a vitamin deficiency. Hence, vitamin supplementation may be warranted.