Bile acid sequestrant

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The bile acid sequestrants are a group of resins used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by combining with bile constituents and preventing their reabsorption from the gut. In general, they are classified as hypolipidemic agents, 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. [1]

Contents

Mechanism

Bile acid sequestrants are polymeric compounds that serve as ion-exchange resins. Bile acid sequestrants exchange anions such as chloride 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. [2]

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. [3]

Medical uses

Hyperlipidemia

As bile acids are biosynthesized from cholesterol, disruption of bile acid reabsorption will decrease cholesterol levels, in particular, low-density lipoprotein (commonly known as "bad cholesterol") in blood. Consequently, these drugs have been used for the treatment of hypercholesterolemia and dyslipidemia. [4] [5] [6]

Use of these agents as hypolipidemic agents has decreased markedly since the introduction of the statins, 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 fibrates (another major group of cholesterol-lowering drugs), which are thought to increase the risk of rhabdomyolysis 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). This condition of bile acid malabsorption occurs after surgery to the ileum, in Crohn's disease, with a number of other gastrointestinal causes, or is commonly a primary, idiopathic condition. The SeHCAT test can be used for diagnosis. Bile salt diarrhea can also be a side-effect of gallbladder removal. [1]

Bile acid sequestrants are the principal therapy for bile acid-induced diarrhea. [7] [1] 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 them hard to tolerate, as although the diarrhea may improve, bloating and abdominal pain can worsen. [8] [9]

Use in other conditions

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. [10]

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.

Cholestyramine has been used in the treatment of Clostridioides difficile 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 gastrointestinal tract, such as constipation, diarrhea, bloating, and flatulence. 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. [8]

Vitamins

They can also bind fat-soluble vitamins, such as vitamin A, vitamin D, vitamin E, and vitamin K. This effect could result in a vitamin deficiency, and so checking blood levels and possible supplementation has been suggested. [8]

Examples

Three drugs are members of this class; all are synthetic polymeric resins: [1]

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

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 cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Malabsorption</span> Medical condition

Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal (GI) tract. Impairment can be of single or multiple nutrients depending on the abnormality. This may lead to malnutrition and a variety of anaemias.

<span class="mw-page-title-main">Ezetimibe</span> Medication used to treat high cholesterol

Ezetimibe is a medication used to treat high blood cholesterol and certain other lipid abnormalities. Generally it is used together with dietary changes and a statin. Alone, it is less preferred than a statin. It is taken by mouth. It is also available in the fixed combinations ezetimibe/simvastatin, ezetimibe/atorvastatin, ezetimibe/rosuvastatin, and ezetimibe/bempedoic acid.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

<span class="mw-page-title-main">Colestyramine</span> Pharmaceutical drug

Colestyramine (INN) or cholestyramine (USAN) 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 it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them strongly in the resin matrix. The functional group of the anion exchange resin is a quaternary ammonium group attached to an inert styrene-divinylbenzene copolymer.

<span class="mw-page-title-main">Blood in stool</span> Medical condition

Blood in stool or rectal bleeding looks different depending on how early it enters the digestive tract—and thus how much digestive action it has been exposed to—and how much there is. The term can refer either to melena, with a black appearance, typically originating from upper gastrointestinal bleeding; or to hematochezia, with a red color, typically originating from lower gastrointestinal bleeding. Evaluation of the blood found in stool depends on its characteristics, in terms of color, quantity and other features, which can point to its source, however, more serious conditions can present with a mixed picture, or with the form of bleeding that is found in another section of the tract. The term "blood in stool" is usually only used to describe visible blood, and not fecal occult blood, which is found only after physical examination and chemical laboratory testing.

<span class="mw-page-title-main">Bile acid</span> Steroid acid found predominantly in the bile of mammals and other vertebrates

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.

<span class="mw-page-title-main">Fenofibrate</span> Drug of the fibrate class, mainly used to reduce cholesterol levels

Fenofibrate, is an oral medication of the fibrate class used to treat abnormal blood lipid levels. It is less commonly used compared than statins because it treats a different type of cholesterol abnormality to statins. While statins have strong evidence for reducing heart disease and death, there is evidence to suggest that fenofibrate also reduces the risk of heart disease and death. However, this seems only to apply to specific populations of people with elevated triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Its use is recommended together with dietary changes.

<span class="mw-page-title-main">Sitosterolemia</span> Medical condition

Sitosterolemia is a rare autosomal recessively inherited lipid metabolic disorder. It is characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Healthy persons absorb only about 5% of dietary plant sterols, but sitosterolemia patients absorb 15% to 60% of ingested sitosterol without excreting much into the bile. The phytosterol campesterol is more readily absorbed than sitosterol.

Postcholecystectomy syndrome (PCS) describes the presence of abdominal symptoms after a cholecystectomy.

<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein cholesterol, in the blood and early cardiovascular diseases. The most common mutations diminish the number of functional LDL receptors in the liver or produce abnormal LDL receptors that never go to the cell surface to function properly. Since the underlying body biochemistry is slightly different in individuals with FH, their high cholesterol levels are less responsive to the kinds of cholesterol control methods which are usually more effective in people without FH. Nevertheless, treatment is usually effective.

Radiation enteropathy is a syndrome that may develop following abdominal or pelvic radiation therapy for cancer. Many affected people are cancer survivors who had treatment for cervical cancer or prostate cancer; it has also been termed pelvic radiation disease with radiation proctitis being one of the principal features.

<span class="mw-page-title-main">Colesevelam</span> Pharmaceutical drug

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 Cholestagel. In Canada, it is marketed by Valeant as Lodalis.

<span class="mw-page-title-main">Colestipol</span> Chemical compound

Colestipol is a bile acid sequestrant used to lower blood cholesterol, specifically low-density lipoprotein (LDL). It is also used to reduce stool volume and frequency, and in the treatment of chronic diarrhea.

<span class="mw-page-title-main">Colestilan</span> Chemical compound

Colestilan is a medication that acts as a phosphate binder and bile acid sequestrant. It is an ion-exchange resin, is an orally administered bile acid sequestrant that is being developed by Mitsubishi Tanabe Pharma Corporation for the treatment of hypercholesterolaemia and hyperphosphataemia. It has been launched in Japan for hypercholesterolaemia. For the treatment of hyperphosphataemia, it is launched in Austria, Germany, the Czech Republic, Portugal and the United Kingdom, is registered in the EU. Phase III development in paediatric patients with hyperphosphataemia associated with chronic kidney disease was underway in the UK and Germany. However, the company discontinued the development. In addition, the phase II development in type-2 diabetes mellitus and phase I development in hyperphosphataemia, in Japan, was also discontinued by the company.

<span class="mw-page-title-main">SeHCAT</span> Chemical compound

SeHCAT is a drug used in a clinical test to diagnose 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 diarrhea or bile salt malabsorption. It can result from malabsorption secondary to gastrointestinal disease, or be a primary disorder, associated with excessive bile acid production. Treatment with bile acid sequestrants is often effective. It is recognised as a disability in the United Kingdom under the Equality Act 2010

<span class="mw-page-title-main">Obeticholic acid</span> Chemical compound

Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept Pharmaceuticals Inc. hold the worldwide rights to develop OCA outside Japan and China, where it is licensed to Dainippon Sumitomo Pharma.

References

  1. 1 2 3 4 Wilcox C, Turner J, Green J (May 2014). "Systematic review: the management of chronic diarrhoea due to bile acid malabsorption". Aliment. Pharmacol. Ther. 39 (9): 923–39. doi: 10.1111/apt.12684 . PMID   24602022. S2CID   12016216.
  2. ↑ Which Medicines Lower 'Bad' (LDL) Cholesterol?
  3. ↑ FDA Heart Health Online – Bile Acid Sequestrants
  4. ↑ Hashim SA, Vanitallie TB (April 1965). "Cholestyramine resin therapy for hypercholesteremia: clinical and metabolic studies". JAMA. 192: 289–93. doi:10.1001/jama.1965.03080170017004. PMID   14271976.
  5. ↑ Heel RC, Brogden RN, Pakes GE, Speight TM, Avery GS (March 1980). "Colestipol: a review of its pharmacological properties and therapeutic efficacy in patients with hypercholesterolaemia". Drugs. 19 (3): 161–80. doi:10.2165/00003495-198019030-00001. PMID   6988203. S2CID   27745975.
  6. ↑ Wong NN (2001). "Colesevelam: a new bile acid sequestrant". Heart Disease (Hagerstown, Md.). 3 (1): 63–70. doi:10.1097/00132580-200101000-00009. PMID   11975771.
  7. ↑ Hofmann AF, Poley JR (August 1969). "Cholestyramine treatment of diarrhea associated with ileal resection". N. Engl. J. Med. 281 (8): 397–402. doi:10.1056/NEJM196908212810801. PMID   4894463.
  8. 1 2 3 Walters, JR; Pattni, SS (2010). "Managing bile acid diarrhoea". Therapeutic Advances in Gastroenterology. 3 (6): 349–57. doi:10.1177/1756283X10377126. PMC   3002596 . PMID   21180614.
  9. ↑ Beigel F, Teich N, Howaldt S, et al. (June 2014). "Colesevelam for the treatment of bile acid malabsorption-associated diarrhea in patients with Crohn's disease: A randomized, double-blind, placebo-controlled study". J Crohns Colitis. 8 (11): 1471–9. doi: 10.1016/j.crohns.2014.05.009 . PMID   24953836.
  10. ↑ Datta DV, Sherlock S (January 1963). "Treatment of pruritus of obstructive jaundice with cholestyramine". Br Med J. 1 (5325): 216–9. doi:10.1136/bmj.1.5325.216. PMC   2123703 . PMID   14025214.
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