Antihyperlipidemic Drugs Anticholesterolemic Drugs

A 60-year-old man with hypertension and type II diabetes comes in for a follow-up visit. Along with making appropriate diet and lifestyle changes, he is taking an ACE inhibitor-thiazide diuretic combination for his hypertension and metformin for his diabetes. His blood pressure and diabetes are under acceptable control..

Routine blood work revealed normal electrolytes, renal function, and liver enzymes. He is noted to have elevated total cholesterol and low-density lipoprotein (LDL) levels, which have remained high in spite of his lifestyle changes. In an effort to reduce his risk of developing coronary artery disease, you start him on a 3-hydroxy-3 methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.

What is the mechanism of action of HMG-CoA reductase inhibitors?

Competitive inhibition of the rate-limiting enzyme in cholesterol biosynthesis results in compensatory increase in plasma cholesterol uptake in the liver mediated by an increase in the number of LDL receptors.

 What effect do they have on total and LDL cholesterol levels?

Effect on total cholesterol: Up to 30 percent reduction. Effect on LDL cholesterol: Up to 50 percent reduction.

 What are the common adverse effects of HMGCoA reductase inhibitors?

Common adverse events: Elevated liver enzymes myalgia and myositis, irritability, sleep disturbance, anxiety.and hepatotoxicity,

Drugs that decrease plasma lipids are among the most commonly prescribed today. Some of these affect primarily cholesterol (e.g., the statins) and are useful in the treatment of hypercholesterolemia while other agents affect primarily triglycerides (e.g., gemfibrozil). The LDL cholesterol treatment goal is determined by assessing the risk of cardiovascular disease of individual patients.

Agents Used for Hypercholesterolemia

Statins
widest use. The statins are structural analogs of the substrate HMG-CoA that inhibit the activity of the enzyme HMG-CoA reductase at nanomolar concentrations. This enzyme is required for the synthesis of isoprenoids and cholesterol. By inhibiting de novo biosynthesis of cholesterol, cellular uptake of cholesterol from plasma via the LDL receptor is increased, reducing plasma cholesterol levels.

Statins
Because statins have additional actions to inhibit the production of the triglyceride-rich VLDL, this makes them useful in the management of patients with hypertriglyceridemia; atorvastatin and rosuvastatin are particularly effective in this regard.

Statins
There is evidence that statins also have antiinflammatory activity, and this may contribute to their reduction in cardiovascular events. Statins may also reduce the rate of bone resorption and thereby lessen osteoporosis. This effect is thought to be caused by the inhibition of isoprenoid biosynthesis in osteoclast precursors, which inhibits their differentiation into mature osteoclasts.

Statins
Six statins are approved in the United States: lovastatin, rosuvastatin, fluvastatin, atorvastatin, pravastatin, and simvastatin. They differ in efficacy: Rosuvastatin has been reported to reduce LDL cholesterol by more than 60 percent; atorvastatin, approximately 50 percent; and pravastatin and fluvastatin, approximately 35 percent. All of the statins are active orally. Lovastatin and simvastatin areprodrugs that are converted to their active metabolite by the liver.

Statins
The two major adverse effects associated with statin use are hepatotoxicity and myopathy.

Bile-Acid-Binding Resins
The bile acid sequestrants are also useful in reducing plasma cholesterol. Cholestyramine, colestipol, and colesevelam are ionexchange resins that nonspecifically bind bile acids within the intestine and thereby reduce their enterohepatic circulation. This increases de novo hepatic bile acid synthesis and the cholesterol for this synthesis comes, in part, from the plasma via the LDL receptor. Bile acid sequestrants typically reduce plasma cholesterol by 1520 percent with no effect on triglycerides.

Inhibitors of Cholesterol Absorption

Ezetimibe is a new class of cholesterol-lowering drug that acts within the intestine to reduce cholesterol absorption. Ezetimibe appears to block one or more of these cholesterol transporters, thereby reducing cholesterol absorption.

Nicotinic Acid
Niacin, at doses well beyond those used as a vitamin, has effects on all plasma lipids. It reduces LDL cholesterol by 2030 percent and reduces triglycerides by 3545 percent. It is the best agent available for increasing HDL. Niacin inhibits VLDL production in the liver by inhibiting both the synthesis and esterification of fatty acids.

Nicotinic Acid
LDL levels are reduced as a consequence of the decline in VLDL synthesis. Niacin inhibits lipolysis in adipose tissue which reduces the supply of fatty acids to the liver, further decreasing VLDL synthesis. The limiting adverse effect of niacin is cutaneous flushing and itching, and dyspepsia is common at the doses (1 g/day) necessary to affect lipids.

Nicotinic Acid
More medically serious adverse effects include hepatotoxicity and hyperglycemia. Niacin induces an insulinresistant state causing hyperglycemia. For this reason niacin should not be used in diabetic patients. Agents Used for HypertriglyceridemiaFibrates

Agents Used for HypertriglyceridemiaFibrates

The fibrates include clofibrate, fenofibrate, ciprofibrate, bezafibrate, and gemfibrozil. These agents predominantly cause a decline plasma triglycerides and a small decrease in LDL cholesterol. HDL levels are increased.