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Nicotinic Acid (Niacin)

Nicotinic Acid (Niacin)

fi-Sitosterol. Sitosterol is a plant sterol, whose structure is identical with that of cholesterol, except for the substituted ethyl group on C-24 of its side chain. Although the mechanism of its hypolipidemic effect is not clearly understood, it is suspected that the drug inhibits the absorption of dietary cholesterol from the gastrointestinal tract. Sitosterols are absorbed poorly from the mucosal lining and appear to compete with cholesterol for absorption sites in the intestine.

responsible for cholesterol absorption. Although it may be used alone, it is marketed as a combination product with simvastatin under the trade name Vytorin.72

Probucol, USP. Probucol, 4,4'-[(1-methylethylidene) bis(thio)]bis[2,6-bis(1,1-dimethylethyl)phenol], DH-581 (Lorelco), is a chemical agent that was developed for the plastics and rubber industry in the 1960s. The probucol molecule has two tertiary butylphenol groups linked by a dithiopropy-lidene bridge, giving it a high lipophilic character with strong antioxidant properties. In humans, it causes reduction of both liver and serum cholesterol levels, but it does not alter plasma triglycerides. It reduces LDL and (to a lesser extent) HDL levels by a unique mechanism that is still not clearly delineated. The reduction of HDL may be caused by the ability of probucol to inhibit the synthesis of apoprotein A-1, a major protein component of HDL.71 It is effective at reducing levels of LDL and is used in hyperlipoproteinemias characterized by elevated LDL levels.

Ezetimibe. Ezetimibe, (3r,4s)-1-(4-fluorophenyl)-3-((3s)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydrox-yphenyl)-2-azetidinone (Zetia), is an antihyperlipidemic agent that has usefulness in lowering cholesterol levels. It acts by decreasing cholesterol absorption in the intestine by blocking the absorption of the sterol at the Brush boarder. Specifically, the ^-lactam binds to the Niemann-Pick C1-Like 1 (NPC1L1) protein on the gastrointestinal tract that is f


HMG-CoA Reductase Inhibitors

Drugs in this class of hypolipidemic agents inhibit the enzyme HMG-CoA reductase, responsible for the conversion of HMG-CoA to mevalonate in the synthetic pathway for the synthesis of cholesterol (Fig. 19.19). HMG-CoA reduc-tase is the rate-limiting catalyst for the irreversible conversion of HMG-CoA to mevalonic acid in the synthesis of cholesterol. The activity of HMG-CoA reductase is also under feedback regulation. When cholesterol is available in sufficient amounts for body needs, the enzyme activity of HMG-CoA reductase is suppressed.

Elevated plasma cholesterol levels have been correlated with an increase in cardiovascular disease. Of the plasma lipoproteins, the LDL fraction contains the most cholesterol. The source of cholesterol in humans is either the diet or the de novo synthesis with the reduction of HMG-CoA by HMG-CoA reductase as the rate-limiting step. Ingested cholesterol as the free alcohol or ester is taken up after intestinal absorption and transported to the liver and other body organs through the exogenous pathway (Fig. 19.19). The LDL delivers cholesterol to peripheral cells. This process occurs after binding of LDL to specific LDL receptors located on the surface of cell membranes. After binding and endocyto-sis of the receptor and LDL, lysosomal degradation of this complex in the cell makes cholesterol available for use in cellular membrane synthesis. It is generally accepted that total plasma cholesterol is lowered most effectively by reducing LDL levels. Therefore, the population of LDL receptors is an important component of clearing the plasma of cholesterol. HMG-CoA reductase inhibitors contribute to this by directly blocking the active site of the enzyme. This action has a twofold effect on cholesterol plasma levels; it causes a decrease in de novo cholesterol synthesis and an increase in hepatic LDL receptors. These HMG-CoA reduc-

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