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.
Contents
- 1 Mechanism
- 2 Medical uses
- 2.1 Hyperlipidemia
- 2.2 Bile acid malabsorption
- 2.3 Use in other conditions
- 3 Side-effects
- 4 Drug interactions
- 5 Examples
- 6 References
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 amount of LDL cholesterol circulating in the blood.[1]
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.[2]
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.[3][4][5]
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.
Bile acid sequestrants are the principal therapy for bile acid-induced diarrhea.[6][7] 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 Clostridium 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 (GI 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, they could cause vitamin deficiencies that may affect the fetus. Hence, 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.
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.
Examples
Three drugs are members of this class; all are synthetic polymeric resins:
- Cholestyramine (Questran and other propriety names)
- Colestipol (Colestid, Colestipid)
- Colesevelam (Cholestagel in Europe, Welchol in the USA)
References
- ^ <http://www.webmd.com/cholesterol-management/bile-acid-sequestrants-for-high-cholesterol>
- ^ FDA Heart Health Online - Bile Acid Sequestrants
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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: 1471–9. doi:10.1016/j.crohns.2014.05.009. PMID 24953836.
- ^ 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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Lipid modifying agents (C10)
|
|
| GI tract |
| Cholesterol absorption inhibitors, NPC1L1 |
|
|
| Bile acid sequestrants/resins (LDL) |
- Cholestyramine
- Colestipol
- Colestilan
- Colextran
- Colesevelam
|
|
|
| Liver |
| Statins (HMG-CoA reductase, LDL) |
- Simvastatin#
- Atorvastatin
- Fluvastatin
- Lovastatin
- Mevastatin
- Pitavastatin
- Pravastatin
- Rosuvastatin
- Cerivastatin‡
|
|
| Niacin and derivatives (HDL and LDL) |
- Niceritrol
- Niacin
- Nicofuranose
- Aluminium nicotinate
- Nicotinyl alcohol
- Acipimox
|
|
| MTTP inhibitors (VLDL) |
- Dirlotapide
- Lomitapide
- Mitratapide
|
|
|
| Blood vessels |
| Fibrates (PPAR) |
- Clofibrate‡
- Bezafibrate
- Aluminium clofibrate
- Gemfibrozil
- Fenofibrate
- Simfibrate
- Ronifibrate
- Ciprofibrate
- Etofibrate
- Clofibride
- Clinofibrate
|
|
| CETP inhibitors (HDL) |
- Anacetrapib†
- Dalcetrapib§
- Evacetrapib†
- Torcetrapib§
|
|
|
| Combinations |
- Niacin/lovastatin
- Niacin/simvastatin
- Ezetimibe/simvastatin
- Ezetimibe/atorvastatin
- Niacin/laropiprant
|
|
| Other |
- Dextrothyroxine‡
- Probucol
- Tiadenol
- Benfluorex
- Meglutol
- Omega-3-triglycerides
- Magnesium pyridoxal 5-phosphate glutamate
- Policosanol
- Lapaquistat§
- Mipomersen
- Alipogene tiparvovec
|
|
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
|
|
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Index of nutrition
|
|
| Description |
- Vitamins
- Cofactors
- Metal metabolism
- Fats
- metabolism
- intermediates
- lipoproteins
- Sugars
- Glycolysis
- Glycogenesis and glycogenolysis
- Fructose and galactose
|
|
| Disease |
- Vitamins
- Carbohydrate
- Lipid
- Metals
- Other
- Symptoms and signs
|
|
| Treatment |
- Drugs
- Vitamins
- Mineral supplements
|
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