Cholesterol action mechanisms

Probucol. Probucol is an antioxidant that is effective in lowering LDL cholesterol. Whereas probucol was known to lower cholesterol after relatively simple clinical trials (160), its mechanism of action as an antioxidant in the treatment of atherosclerosis is quite novel. Probucol has been shown to have the abiUty to produce regression of atherosclerotic lesions in animal models (161). Probucol therefore represents a novel class of pharmaceutical agent for the treatment of atherosclerosis. This effect occurs mechanistically, in part, by preventing oxidation of LDL, a necessary step in foam cell formation. This antioxidant activity has been shown in laboratory experiments and its activity in lowering LDL cholesterol in human studies is well documented (162). 

Mechanism of action of statins cholesterol synthesis pathway... 

HMG-CoA-Reductase Inhibitors. Figure 1 Mechanism of action of statins - cholesterol synthesis pathway. The conversion of acetyl CoA to cholesterol in the liver. The step of cholesterol biosynthesis inhibited by HMG-CoA reductase inhibitors (statins) is shown. 

Angiotensin II binds to specific adrenal cortex glomerulosa cell receptors. The hormone-receptor interaction does not activate adenylyl cyclase, and cAMP does not appear to mediate the action of this hormone. The actions of angiotensin II, which are to stimulate the conversion of cholesterol to pregnenolone and of corticosterone to 18-hydroxycorticosterone and aldosterone, may involve changes in the concentration of intracellular calcium and of phospholipid metabolites by mechanisms similar to those described in Chapter 43. 

Niacin reduces plasma LDL cholesterol, lipoprotein (a), triglycerides and raises HDL cholesterol in all types of hyperlipoproteinemia [26]. Although available on the market for more than 40 years, the mechanisms of action of niacin are poorly understood. Putative mechanisms are the activation of adipose tissue LPL, diminished HTGL activity, a reduced hepatic production and release of VLDL, and composi-... 

A 40-year-old male with markedly elevated cholesterol, diagnosed as having heterozygous familial hypercholesterolemia, is treated with cholestyramine. What is the mechanism of action of cholestyramine ... 

Leng-Peschlow, E. (1993). Effect of fibre on key enzymes of cholesterol synthesis and degradation In "Workshop on the Mechanisms of Action of Dietary Fibre on Lipid and Cholesterol Metabolism." Published by the Commission of the European Communities, Luxembourg, pp. 99-101. 

Turley, S. D., and Dietschy, J. M. (1995). Mechanisms of LDL-cholesterol lowering action of psyllium hydrophillic mucilloid in the hamster. Biochim. Biophys. Acta 1255,177-184. 

Most of us are familiar with the effects of cholesterol. Exhibit 1.3 provides an explanation of how cholesterol is formed and the mechanism of action for Lipitor and Zocor in lowering the sterol. 

Treatment Various drugs are available that have different mechanisms of action and effects on LDL (cholesterol) and VLDL (triglycerides) (A). Their use is indicated in the therapy of primary hyperlipoproteinemias. In secondary hyperlipoproteinemias, the immediate goal should be to lower lipoprotein levels by dietary restriction, treatment of the primary disease, or both. 

Pharmacology Nicotinic acid (but not nicotinamide) in gram doses produces an average 10% to 20% reduction in total and LDL cholesterol, a 30% to 70% reduction in triglycerides, and an average 20% to 35% increase in HDL cholesterol. Nicotinic acid also decreases serum levels of apolipoprotein B-100, the major component of VLDL and LDL fractions. The mechanism by which nicotinic acid exerts these effects is not entirely understood but may involve several actions, including a decrease in esterification of hepatic triglycerides. 

Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds. Ezetimibe does not inhibit cholesterol synthesis in the liver or increase bile acid excretion. 

In summary, based on the observation of divergent in vitro and in vivo SAR, a new class of cholesterol-lowering compounds was discovered. Subsequent biological characterization of the first generation lead compound SCH-48461, limited the site of action to be at or near the intestinal villi, with the most probable mechanism being the inhibition of luminal absorption. An SAR optimization based solely on an in vivo assay and without biochemical characterization of the molecular target led to the design of ezetimibe (1). 

The lowered concentration of bile acids returning to the liver by the enterohepatic circulation results in derepression of 7-a-hydroxylase, the rate-limiting enzyme for conversion of cholesterol to bile acids. This results in increased use of cholesterol to replace the excreted bile acids and lowering of hepatic cholesterol (mechanism VI in Fig. 23.2). Thus, similar to the statins, the ultimate actions of the bile acid-sequestering resins are up-regulation of transcription of the LDL receptor gene, increased hepatic receptor activity, and lowering of plasma LDL cholesterol (mechanism VII in Fig. 23.2). 

Mechanism of Action An antihyperlipidemic that inhibits hydroxymethylglutaryl-CoA (HMG CoA) reductase, the enzyme that catalyzes the early step in cholesterol synthesis. Therapeutic Effect Decreases LDL and VLDL cholesterol, and plasma triglyceride levels increases HDL cholesterol concentration. 

Mechanism of Action An antihyperlipoproteinemic that binds with bile acids in the intestine, forming an insoluble complex. Binding results in partial removal of bile acid from enterohepatic circulation. Therapeutic Effect Removes LDL cholesterol from plasma. 

Mechanism of Action A lipid-bile acid sequestrant and nonsystemic polymer that binds with bile acids in the intestines, preventing their reabsorption and removing them from the body Therapeutic Effect Decreases LDL cholesterol. Pharmacokinetics Not absorbed. Primarily eliminated in feces. 

Mechanism of Action A glucocorticoid that stimulates initial reaction in synthesis of adrenal steroids from cholesteroL Therapeutic Effect Increases endogenous corti-coid synthesis. 

Mechanism of Action An antihyperlipidemic that inhibits cholesterol absorption in the small intestine, leadingtoadecreasein the delivery of intestinal cholesterol to the liver. Therapeutic Effect Reduces total serum cholesterol, LDL cholesterol, and triglyceride levels and increases HDL cholesterol concentration. 

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