Bile Acid Sequestrants Resins

If FH is diagnosed, her children and other members of her family should be screened for the condition. Treatment is based on diet which, in patients with FH, almost invariably needs to be combined with cholesterol-lowering drugs such as the HMG CoA reductase inhibitors and/or the bile acid sequestrant resins. 

Bile Acid Sequestrants. The bile acid binding resins, colestipol [26658424] and cholestyramine, ate also effective in controlling semm cholesterol levels (150). Cholestyramine, a polymer having mol wt > ICf, is an anion-exchange resin. It is not absorbed in the gastrointestinal tract, is not affected by digestive enzymes, and is taken orally after being suspended in water (151). 

Bile-acid sequestrants are indigestible, positively charged resins that bind negatively charged bile acids in the lumen of the intestine (reviewed in ref. 34). 

If the findings relating to obesity and improved glycaemic control can be confirmed in human studies such drugs would be highly attractive. As discussed above, bile-acid sequestrants have been used for many years to treat dyslipi-demia in relation to reducing cardiovascular disease risk and the safety profile of these compounds is well established. However, due to the large doses of compound that require to be consumed, compliance is an issue for BAS therapies. In the future, this may be resolved with the development of more specific and efficient resins that require lower doses. 

Bile acid sequestrants cholestyramine resin colestipol hydrochloride... 

Bile acid sequestrates are anion-exchange resins, which sequester bile acid in the intestine. Cholestyramine and colestipol are the most commonly used in this category, which by this mechanism prevents bile acid re-absorption and causes decreased absorption of exogenous cholesterol and increased metabolism of endogenous cholesterol into bile acid in the liver by preventing enterohepatic recirculation. This leads to an increased expression of LDL receptors in liver and causes increased removal of LDL from blood and reduces the LDL cholesterol in the plasma. 

Anion-exchange resins (bile acid sequestrants)... 

Cholestyramine [ban] (colestyramine (inn.jan) cholestyramine resin (usan) MK 325 AP 143 Questran " and many other names) is a polymeric ion-exchange resin, a bile acid sequestrant that is used as an ANTIHYPERIIPIDAEMIC, antipruritic and ANTIDIARRHOEAL. 

Structures of bile acid sequestrants. Cholestyramine and colestipol are hydrophilic yet water-insoluble, nondigestible, and nonabsorbable synthetic resins. They bind bile acids in the intestine to increase their loss in feces and thereby decrease plasma cholesterol levels. 

In addition to the statin drugs which inhibit HMG-CoA reductase a number of other drugs are used to lower cholesterol levels. The first are resins which are also referred to as bile acid sequestrants such as cholestyramine. The resins work by binding to the bile acids followed by excretion of the resin-bile complex. To make up for the loss of the bile acids the body converts cholesterol into bile acids thus reducing the cholesterol levels. 

Bile acid-binding resin therapy Oral administration of a bile acid-binding resin, or sequestrant (D), increases the loss of bile acids from the body by preventing their absorption by intestinal epithelial cells through the IBAT transport protein and reduces bile acids delivered to the blood (0) and then to the liver (0) by the transporter NTCR Step The lower levels of cytoplasmic bile acids reduce the amount of bile acid bound to the nuclear hormone receptor EXP (0) and its suppression (0) of the expression of cholesterol 7a-hydroxylase. The consequent increased levels of expression and activity of cholesterol 7a-hydroxylase (B) reduce the levels of intracellular cholesterol (0). As with the statin treatment, the reduced cellular cholesterol levels (EHB) increase LDLR activity, lower plasma LDL levels, and protect against atherosclerosis. [Part (a) adapted from M. S. Brown and J. L. Goldstein, 1986, Sdence 232 34.]... 

The most common drugs used to lower hepatic cholesterol by increasing the formation of bile acids do so by interrupting the enterohepatic circulation. These bile acid sequestrants (e.g., cholestyramine) are Insoluble resins that bind tightly to bile acids in the lumen of the intestines, forming complexes that prevent IBAT-medlated absorption by intestinal epithelial cells. The complexes are excreted in the feces. The resulting decrease in the return of bile acids to the liver causes a drop in the hepatic bile acid pool. As... 

The bile-acid sequestrants are highly positively charged and bind negatively charged bile acids. Because of their large size, the resins are not absorbed, and the bound bile acids are excreted in the stool. Because over 95% of bile acids are normally reabsorbed, intermption of this process depletes the pool of bile acids, and hepatic bile-acid synthesis increases. As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors, an... 

Pravastatin (pravachol) therapy is started with a 20- or 40-mg dose that may be increased to 80 mg it should be taken at bedtime. Since pravastatin is a hydroxy acid, it is bound by bile-acid sequestrants, which reduce its absorption. This is rarely a problem since the resins should be taken before meals and pravastatin should be taken at bedtime. Pravastatin is also marketed in combination with buffered aspirin (PRAVIGARD). The small advantage of combining these two drugs should be weighed against disadvantages inherent in fixed-dose combinations. 

The two established bUe-acid sequestrants or resins (cholestyramine and colestipol) are most often used as second agents if statin therapy does not lower LDL-C levels sufficiently. When used with a statin, cholestyramine and colestipol usually are prescribed at submaximal doses. Maximal doses can reduce LDL-C by up to 25% but are associated with unacceptable gastrointestinal (GI) side effects (bloating and constipation) that limit compliance. Colesevelam is a newer bile-acid sequestrant that is prepared as an anhydrous gel and taken as a tablet. It lowers LDL-C by 18% at its maximum dose. The safety and efficacy of colesevelam have not been studied in children or pregnant women. 

Because of their mechanism of action, bile acid sequestrants can potentially bind with and decrease the oral absorption of almost any other drug. Because these anion-exchange resins contain numerous positive charges, they are much more likely to bind to acidic compounds than to basic compounds or nonelectrolytes. This is not an absolute, however, because cholestyramine and colestipol have been reported to decrease the oral absorption of propranolol (a base) and the lipid-soluble vitamins. A, D, E, and K (nonelectrolytes). As a result, the current recommendation is that all other oral medication should be administered at least 1 hour before or 4 hours after cholestyramine and colestipol. Interestingly, this drug interaction has been used in a beneficial manner to treat digitalis overdose and toxicity. 

The bile acid sequestrants, cholestyramine and colestipol, reduce LDL-cholesterol by up to 30% and their use is supported by RCTs [69]. However, they are not well-tolerated chiefly because of gastro intestinal adverse effects. In patients already on multiple drug therapies timing of administration of resins is difficult as they can interfere with the absorption of other drugs. They need to be given at least 1 h before or at least 4 h after other medications. 

C. Ion-Exchange Resins as Therapeutic Bile Acid Sequestrants... 

Bile acid sequestrants are charged resins that are ingested in a liquid suspension. They bind to bile acids in the intestine and prevent their reabsorption. Since bile acids normally feed back on their own synthesis from cholesterol, these agents evoke a compensatory increase in bile acid synthesis. The diversion of liver cholesterol for bile acid production leads to an upregulation of the LDL receptor and thus a reduction in LDL levels. Because bile acid sequestrants increase cholesterol catabolism and statins decrease cholesterol synthesis, the two agents together act synergistically. 

Cholestyramine, colestipol, and colesevelam are the bile acidbinding resins or sequestrants (BAS) currently available in the United States. Resins are highly charged molecules that bind to bile adds (which are produced from cholesterol) in the gut. The resin-bile acid complex is then excreted in the feces. The loss of bile causes a compensatory conversion of hepatic cholesterol to bile, reducing hepatocellular stores of cholesterol resulting in an up-regulation of LDL receptors to replenish hepatocellular stores which then result in a decrease in serum cholesterol. Resins have been shown to reduce CHD events in patients without CHD.26... 

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