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Atherosclerosis is the abnormal accumulation of lipids and products resulting from an inflammatory response in the walls of arteries, and is the leading cause of death in the Western world. Heart attacks, angina pectoris, peripheral arterial disease, and strokes are common sequelae of atherosclerosis. In some cases, lowering serum lipid concentrations has been shown to prevent the sequelae of atherosclerosis and decrease mortality in patients with a history of cardiovascular disease and hyperlipidemia. The five drug classes discussed in this chapter (Figure 26–1) are used to decrease serum concentrations of lipids in the blood (hyperlipidemia) and to prevent or reverse associated atherosclerosis, or, in the case of hypertriglyceridemia, prevent pancreatitis. Although the drugs are generally safe and effective, adverse effects include drug–drug interactions and rare toxic reactions in skeletal muscle and the liver.

Figure 26–1.

The five classes of lipid-lowering drugs. These classes are based on the mechanisms of action of these drugs.

Lipids, mainly cholesterol and triglycerides, are transported in human plasma by macromolecular complexes termed lipoproteins. Lipoproteins are composed of a lipid core surrounded by apolipoproteins that regulate the uptake and off-loading of lipids and interactions with cell membrane receptors. The lipoproteins that are primarily responsible for delivering cholesterol and triglycerides to peripheral tissues originate in the liver and contain a key apoprotein called B-100. These B-100–containing lipoproteins include very low-density lipoprotein (VLDL),low-density lipoprotein (LDL), and intermediate-density lipoprotein (IDL) (Figure 26–2). The uptake by cells of B-100–containing lipoproteins can occur by receptor-mediated endocytosis or by scavenger receptors. Receptor-mediated uptake is a carefully regulated process that protects cells from being overloaded with lipids. In contrast, uptake by scavenger receptors is an unregulated process that can overwhelm the ability of a cell to sequester potentially toxic lipids safely. Macrophages in arterial walls use scavenger receptors to take up circulating lipoproteins, especially particles with apolipoproteins that have been modified by free radicals. When these macrophages become overloaded with lipids, they are transformed into distressed foam cells that initiate a local inflammatory response. Engorged foam cells, foam cells that have burst, and the products of the inflammatory responses form the core of an atherosclerotic plaque. Whereas plaques can slowly occlude coronary and cerebral vessels, clinical symptoms are more frequently precipitated by rupture of unstable plaques, leading to occlusive thrombi.

Figure 26–2.

Schematic diagram of lipoprotein handling by hepatocytes. The sites of action of several antihyperlipidemic drugs are shown. LDL receptors (R) are increased by treatment with resins and HMG-CoA reductase inhibitors. For identification of abbreviations of the lipoproteins, some drug classes, and additional discussion, see text.

Another lipoprotein, high-density lipoprotein (HDL), exerts several antiatherogenic effects. HDL participates in pathways that retrieve cholesterol from the artery wall and inhibit the oxidation of atherogenic lipoproteins. Low levels of HDL are ...

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