Cholestyramine plasma cholesterol decrease

Cholestyramine, a chelating agent, binds chlordecone present in the gastrointestinal tract and limits its enterohepatic recirculation (Boylan et al. 1978 Cohn et al. 1978). This interaction leads to increased excretion of the chlordecone and decreased toxicity. Thus, persons being treated with cholestyramine to lower plasma cholesterol may experience increased excretion of chlordecone and decreased toxicity. The use of cholestyramine as a therapeutic agent in cases of chlordecone poisoning is discussed more fully in Section 2.8.2, Reducing Body Burden. 

Several other agents have beneficial effects on plasma lipid profiles occurring through various cellular mechanisms.89 Cholestyramine (Questran), for example, attaches to bile acids within the gastrointestinal lumen and increases the fecal excretion of these acids. This action leads to decreased plasma cholesterol concentrations because cholesterol breakdown is accelerated to replace the bile acids that are lost in the feces. 

The reabsorption of bile is impeded by oral administration of positively charged polymers, such as cholestyramine, that bind negatively charged bile salts and are not themselves absorbed. Cholesterol synthesis can be effectively blocked by a class of compounds called statins (e.g., lovastatin, which is also called mevacor Figure 26.22). These compounds are potent competitive inhibitors (AT j < 1 nM) of HMG-CoA reductase, the essential control point in the biosynthetic pathway. Plasma cholesterol levels decrease by 50% in many patients given both lovastatin and inhibitors of bile-salt reabsorption. Lovastatin and other inhibitors of HMG-CoA reductase are widely used to lower the plasma cholesterol level in people who have atherosclerosis, which is the leading cause of death in industrialized societies. 

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. 

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. 

Bile-acid-binding resin results in an interruption of the eiiterohepatic circulation of bile salts and in their iitcreased excretion in the feces. This drug therapy can pnsduce a 20-25" decrease in plasma LDL-cholesterol. A side effect of cholestyramine is constipation, but this problem can be relieved by a high fiber diet. 

D. Cholestyramine binds bile acids strongly so that they cannot be reabsorbed in the intestinal tract, thus increasing the flow of cholesterol to bile acid synthesis and decreasing cholesterol levels in the plasma. However, by binding bile acids, cholestyramine also decreases the absorption of fat-soluble vitamins and fatty acids, which must be taken up in micelles formed with bile acids. Although absorption of vitamin A and linolenic acid may be compromised, the patient needs to be concerned about vitamin K, which is required for blood clot formation. 

Answer D. Cholestyramine and colestipol are resins that sequester bile acids in the gut, preventing their reabsorption. This leads to release of their feedback inhibition of 7-alpha hydroxylase and the diversion of cholesterol toward new synthesis of bile acids. Increase in high-affinity LDL receptors on hepatocyte membranes decreases plasma LDL. These drugs have a small but significant effect to increase plasma HDL rather than decrease it, but their ability to increase TGs precludes their clinical use in the management of hypertriglyceridemias. 

Mevinolin 13.6,7,8,8a-hexahydro-p,6-dihydroxy-2,6-dimethyl-8-(2-methyl-l-oxobutoxy)-l-naphtha-lene-heptanoic acid 6-lactone (Fig.), a fungal metabolite from the culture medium of Aspergillus terreus The parent hydroxyadd (mevolinic acid) is a potent competitive i bitor K 0.6 nM) of 3-hydroxy-3-me-thyl utaryl-CoA reductase (EC 1.1.134). Chal administration of M. produces a 30% decrease of plasma LDL cholesterol and a moderate increase in the number of LDL receptors in human heterozygotes for familial hypercholesterolemia (see Lipoproteins). When M. is administered with Cholestyramine (see). 

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