The bile acid sequestrants are a group of resins used to bind certain components of

bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...

in the

gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organ (biology), organs of the digestive syste ...

. They disrupt the

enterohepatic circulation Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...

bile acid Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts. Primary b ...

s by combining with bile constituents and preventing their reabsorption from the gut. In general, they are classified as

hypolipidemic agent Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholestero ...

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 Bile acid malabsorption (BAM), known also as bile acid diarrhea, is a cause of several gut-related problems, the main one being chronic diarrhea. It has also been called bile acid-induced diarrhea, cholerheic or choleretic enteropathy, bile salt di ...

Mechanism

Bile acid sequestrants are

polymer A polymer (; Greek '' poly-'', "many" + ''-mer'', "part") is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...

ic compounds that serve as

ion-exchange resin An ion-exchange resin or ion-exchange polymer is a resin or polymer that acts as a medium for ion exchange. It is an insoluble matrix (or support structure) normally in the form of small (0.25–1.43 mm radius) microbeads, usually white or ye ...

s. Bile acid sequestrants exchange

anion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

s such as

chloride The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride salts ...

ions for bile acids. By doing so, they bind bile acids and sequester them from the enterohepatic circulation. The liver then produces more bile acids to replace those that have been lost. Because the body uses cholesterol to make bile acids, this reduces the level of LDL cholesterol circulating in the blood. Bile acid sequestrants are large polymeric structures, and they are not significantly 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.

Medical uses

Hyperlipidemia

As bile acids are biosynthesized from

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

, disruption of bile acid reabsorption will decrease cholesterol levels, in particular,

low-density lipoprotein Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

(commonly known as "bad cholesterol") in blood. Consequently, these drugs have been used for the treatment of

hypercholesterolemia Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...

and

dyslipidemia Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...

. Use of these agents as

s has decreased markedly since the introduction of the

statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low ...

s, which are more efficacious than bile acid sequestrants at lowering

LDL Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

. They are occasionally used as an adjunct to the statins as an alternative to the

fibrate In pharmacology, the fibrates are a class of amphipathic carboxylic acids and esters. They are derivatives of fibric acid (phenoxyisobutyric acid). They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), ...

s (another major group of cholesterol-lowering drugs), which are thought to increase the risk of

rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...

when used with statins. The bile-acid-binding resins can raise triglycerides modestly (about 5%) and cannot be used if the triglycerides are elevated.

Bile acid malabsorption

Chronic 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 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 ma ...

). This condition of

occurs after surgery to the

, in

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...

, with a number of other gastrointestinal causes, or is commonly a primary, idiopathic condition. The

SeHCAT SeHCAT (23-seleno-25-homotaurocholic acid, selenium homocholic acid taurine, or tauroselcholic acid) is a drug used in a clinical test to diagnose bile acid malabsorption. Development SeHCAT is a taurine-conjugated bile acid analog which was syn ...

test can be used for diagnosis. Bile salt diarrhea can also be a side-effect of

gallbladder In vertebrates, the gallbladder, also known as the cholecyst, is a small hollow organ where bile is stored and concentrated before it is released into the small intestine. In humans, the pear-shaped gallbladder lies beneath the liver, although ...

removal. Bile acid sequestrants are the principal therapy for bile acid-induced diarrhea.

Cholestyramine Colestyramine ( INN) or cholestyramine ( USAN) (trade names Questran, Questran Light, Cholybar, Olestyr) is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, wh ...

colestipol Colestipol (trade names Colestid, Cholestabyl) is a bile acid sequestrant used to lower blood cholesterol, specifically low-density lipoprotein (LDL).Drugs.comColestipol Hydrochloride/ref> It is also used to reduce stool volume and frequency, and ...

and

colesevelam Colesevelam is a bile acid sequestrant administered orally. It was developed by GelTex Pharmaceuticals and later acquired by Genzyme. It is marketed in the U.S. by Daiichi Sankyo under the brand name Welchol and elsewhere by Genzyme as Cholestage ...

have all been used. Doses may not need to be as high as those previously used for hyperlipidemia. Many patients find them hard to tolerate, as although the diarrhea may improve, bloating and abdominal pain can worsen.

Use in other conditions

In chronic

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

diseases such as

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

, bile acids may deposit in the skin, causing

pruritus Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...

(itching). Hence, bile acid sequestrants may be used for the prevention of

in patients with chronic liver disease. Bile acid sequestrants may also be used to treat

hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism ...

as an adjunct therapy. By inhibiting the enterohepatic circulation, more L-thyroxine will be lost through defecation, thus lowering body

thyroxine File:Thyroid_system.svg, upright=1.5, The thyroid system of the thyroid hormones T3 and T4 rect 376 268 820 433 Thyroid-stimulating hormone rect 411 200 849 266 Thyrotropin-releasing hormone rect 297 168 502 200 Hypothalamus rect 66 216 386 25 ...

levels. Cholestyramine has been used in the treatment of ''

Clostridioides difficile ''Clostridioides difficile'' ( syn. ''Clostridium difficile'') is a bacterium that is well known for causing serious diarrheal infections, and may also cause colon cancer. Also known as ''C. difficile'', or ''C. diff'' (), is Gram-positive spe ...

'' infections, in order to absorb toxins A and B.

Side effects

As bile acid sequestrants are designed to stay in the gut; in general, they do not have systemic side effects. However, they may cause problems in the

, such as

constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...

diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

bloating Abdominal bloating (or simply bloating) is a short-term disease that affects the gastrointestinal tract. Bloating is generally characterized by an excess buildup of gas, air or fluids in the stomach. A person may have feelings of tightness, press ...

, and

flatulence Flatulence, in humans, is the expulsion of gas from the intestines via the anus, commonly referred to as farting. "Flatus" is the medical word for gas generated in the stomach or bowels. A proportion of intestinal gas may be swallowed environm ...

. Some patients complain of the bad taste. Because bile acid sequestrants are not well-absorbed from the gut, they are generally regarded as safe in pregnant women. However, by interfering with vitamin absorption (see below), they could cause vitamin deficiencies that may affect the fetus. So, vitamin supplementation may be considered, with appropriate intervals between dosing of the vitamins and bile acid sequestrants.

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.

Vitamins

They can also bind

fat-soluble vitamin A vitamin is an organic molecule (or a set of molecules closely related chemically, i.e. vitamers) that is an essential micronutrient that an organism needs in small quantities for the proper functioning of its metabolism. Essential nutri ...

s, such as

vitamin A Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably bet ...

vitamin D Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...

vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vitami ...

, and

vitamin K Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulation ...

. This effect could result in a vitamin deficiency, and so checking blood levels and possible supplementation has been suggested.

Examples

Three drugs are members of this class; all are synthetic

ic resins: *

(generic and various propriety names) *

Colestipol Colestipol (trade names Colestid, Cholestabyl) is a bile acid sequestrant used to lower blood cholesterol, specifically low-density lipoprotein (LDL).Drugs.comColestipol Hydrochloride/ref> It is also used to reduce stool volume and frequency, and ...

(Colestid, Colestipid) *

Colesevelam Colesevelam is a bile acid sequestrant administered orally. It was developed by GelTex Pharmaceuticals and later acquired by Genzyme. It is marketed in the U.S. by Daiichi Sankyo under the brand name Welchol and elsewhere by Genzyme as Cholestage ...

(Cholestagel in Europe, Welchol in the US, Lodalis in Canada)

References

{{Lipid modifying agents Hepatology Bile acid sequestrants