HMG-CoA-Reductase inhibitors

B. Cholesterol metabolism in liver cell and cholesterol-lowering drugs liver meets its increased cholesterol demand by enhancing the expression of HMG CoA reductase and LDL receptors (negative feedback).

At the required dosage, the resins cause diverse gastrointestinal disturbances. In addition, they interfere with the absorption of fats and fat-soluble vitamins (A, D, E, K). They also adsorb and decrease the absorption of such drugs as digitoxin, vitamin K antagonists, and diuretics. Their gritty texture and bulk make ingestion an unpleasant experience.

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lac-tones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A). Atorvasta-tin has the longest duration of action. Normally viewed as presystemic elimination, efficient hepatic extraction serves to confine the action of the statins to the liver. Despite the inhibition of HMG CoA reductase, hepatic cholesterol content does not fall, because hepato-cytes compensate any drop in cholesterol levels by increasing the synthesis of LDL receptor protein (along with the reductase). Because the newly formed re-ductase is inhibited, too, the hepatocyte must meet its cholesterol demand by uptake of LDL from the blood (B). Accordingly, the concentration of circulating LDL decreases, while its hepatic clearance from plasma increases. There is also a decreased likelihood of LDL being oxidized into its proatheroslerotic degradation product. The combination of a statin with an ion-exchange resin intensifies the decrease in LDL levels. A

rare, but dangerous, side effect of the statins is damage to skeletal musculature. This risk is increased by combined use of fibric acid agents (see below).

Nicotinic acid and its derivatives (pyridylcarbinol, xanthinol nicotinate, acipimox) activate endothelial lipopro-tein lipase and thereby lower triglyceride levels. At the start of therapy, a prostaglandin-mediated vasodilation occurs (flushing and hypotension) that can be prevented by low doses of acetyl-salicylic acid.

Clofibrate and derivatives (bezafi-brate, etofibrate, gemfibrozil) lower plasma lipids by an unknown mechanism. They may damage the liver and skeletal muscle (myalgia, myopathy, rhabdo-myolysis).

Probucol lowers HDL more than LDL; nonetheless, it appears effective in reducing atherogenesis, possibly by reducing LDL oxidation.

<a3-Polyunsaturated fatty acids (ei-cosapentaenoate, docosahexaenoate) are abundant in fish oils. Dietary supplementation results in lowered levels of triglycerides, decreased synthesis of VLDL and apolipoprotein B, and improved clearance of remnant particles, although total and LDL cholesterol are not decreased or are even increased. High dietary intake may correlate with a reduced incidence of coronary heart disease.

Low systemic availability

3-Hydroxy-3-methyl- Mevalonate

3-Hydroxy-3-methyl- Mevalonate

Ldl Accumulation
A. Accumulation and effect of HMG-CoA reductase inhibitors in liver
Ldl Effects

B. Regulation by cellular cholesterol concentration of HMG-CoA reductase and LDL-receptors

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