Bile acid sequestrants, cholesterol-lowering

As discussed above, obesity is associated with dyslipidemia, a condition where high levels of low-density lipoprotein cholesterol (LDL-C) is common. Elevated LDL-C is strongly associated with an elevated risk of coronary artery disease and for this reason a number of lipid-lowering therapies that target LDL-C have been developed. These include bile-acid sequestrants (BAS), statins (HMG-CoA reductase inhibitors), cholesterol absorption inhibitors, and fibrates. ... 

Prior to 1987, the lipid-lowering armamentarium was limited essentially to dietary changes (reductions in saturated fats and cholesterol), the bile acid sequestrants (cholestyramine and colestipol), nicotinic acid (niacin), the fibrates, and probucol. Unfortunately, all of these treatments have limited efficacy or tolerability or both. Substantial reductions in LDL cholesterol (up to 47%) accompanied by increases in HDL cholesterol of up to 32% could be achieved by the combination of a lipid-lowering diet, a bile acid sequestrant, and the subsequent addition of nicotinic acid (Illingworth et al., 1981). However, this therapy is not easy to administer or tolerate and was therefore often unsuc-... 

Receptor numbers have been increased by the administration of cholestyramine or colestipol, bile acid sequestrants that diminish the bile acid pool, force the liver to convert more cholesterol into bile acids (Dll), lower the intracellular cholesterol in hepatic cells, and thus increase the number of hepatic B-100,E receptors (K25, S27). 

The primary goal of therapy is the control of the hypercholesterolemia and prevention of atherosclerotic cardiovascular disease. Patients with heterozygous FH can usually be successfully treated with medications to lower the LDL cholesterol to acceptable levels (Table 14-2). They are generally responsive to treatment with statins, alone or in combination with other drugs, such as bile acid sequestrants (such as cholestyramine) or cholesterol absorption inhibitors (such as ezetimibe) that act additively to upregulate the expression of the functioning LDL receptor as described in the Biochemical Perspectives section. In a few cases, a more aggressive treatment with LDL apheresis (discussed in this section) may have to be considered in order to reach acceptable LDL cholesterol levels. 

Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. Bile acid sequestrants bind bile acids in the gut, preventing their re-absorption. In so doing, more endogenous cholesterol is directed to the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are excreted in the faeces. 

A combination of bile acid sequestrants with nicotinic acid or probucol or an HMG-CoA reductase inhibitor can be used to produce synergistic effects in lowering plasma lipoprotein levels, particularly LDL. The efficacy of drug treatment was shown in a recent study in which lovas-tatin and colestipol were used to reduce cholesterol levels in men with CHD. The rate of progression of coronary lesions was decreased and that of regression increased. These changes also were associated with reduced cardiovascular abnormalities. 

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. 

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... 

Statins Ezitimibe Omega-3 triglycerides Bile acid sequestrants Fibrates Nicotinic acid derivatives Inhibit HMG-CoA reductase Inhibits absorption of cholesterol from the intestine Inhibit VLDL synthesis in the liver Bind bile acids in the intestine Lower levels of circulating VLDLs and LDLs by unknown mechanism Reduce the release of VLDLs from the liver... 

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. 

Cholestyramine and colestipol are bile acid sequestrants that enhance cholesterol loss into the feces, thereby stimulating new bile salt synthesis, which lowers liver cholesterol levels and consequently plasma LDL levels. Their adverse effects are also listed. 

Bile Acid Sequestrants Polymeric Drugs as Cholesterol-Lowering Agents... 

They are used to soften and purify water, to purify fruit juices, in the separation of metals from each other (for example, separating plutonium and uranium in nuclear reactors), in the manufacture and purification of sugars and in the manufacture of pharmaceutical products. The ion exchange polymers colestyramine, colestipol and colesevelam are also known as bile acid sequestrants and are used to lower serum cholesterol concentrations. They are not absorbed from the intestine, where they bind bile acids, reducing their reabsorption after biliary excretion. The pool of bile acids becomes depleted, resulting in upregulation of cholesterol 7-a-hydroxylase, which increases conversion of cholesterol to bile acids. 

Bile Acid Sequestrants Polymeric Cholesterol-Lowering Drugs... 

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.]... 

MECHANISM OF ACTION The bUe-acid sequestrants are highly positively charged and bind negatively charged bile acids. The resins are not absorbed, and the bound bile acids are excreted in the stool. Since >95% of bile acids are normally reabsorbed, interruption of this process depletes the pool of bile acids and increases hepatic bile-acid synthesis. As a result, hepatic cholesterol content declines, stimulating the production of LDL receptors. The increase in hepatic LDL receptors increases LDL clearance and lowers LDL-C levels, but this effect is partially offset by the enhanced cholesterol synthesis caused by upregulation of HMG-CoA reductase. Inhibition of reductase activity by a statin substantially increases the effectiveness of the resins. 

Since her admission to the hospital for an acute myocardial infarction, Ann ] Jeina has been taking the bile salt sequestrant cholestyramine and the HMG-CoA rednctase inhibitor pravastatin to lower her blood cholesterol levels (see Chapter 34). She also takes 160 mg acetylsalicylic acid (ASA aspirin) each day. At her most recent visit to her cardiologist, she asked whether she shonld... 

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