Continuing Education:  Cardiac Drugs – Lecture V
Lipid Lowering Agents
Larry Birnbaum, PhD, FASEP, EPC
Associate Professor
Department of Exercise Physiology
The College of St. Scholastica
Duluth, MN  55811

For several years, drugs that lower blood cholesterol levels have been used prophylactically to reduce the risk of developing CAD.  They are also used to treat CAD with the intent of halting the progression of the disease [1].  There are different groups of cholesterol lowering drugs.  These groups include HMG CoA reductase inhibitors (commonly known as statins), fibric acid derivatives, resins, and a miscellaneous group. 

The HMG-CoA reductase inhibitors are considered a first-line therapy for the treatment of high cholesterol [2].  These drugs inhibit HMG-CoA reductase, which mediates the first committed step in cholesterol biosynthesis, and induce an increase in high-affinity LDL receptors.  They decrease LDL cholesterol levels by increasing the fractional catabolic rate of LDL and the liver's extraction of LDL precursors.  They also produce a modest decrease in triglycerides and a modest increase in HDL cholesterol.  Adverse effects include mild GI disturbances, liver damage, hypersensitivity syndromes including a lupus-like disorder, shortened sleep period (not pravastatin), and myopathy [3].  Patients should be monitored for damage to muscle.  If the drug is continued after myopathy has been detected by elevation of creatine kinase (CK), severe myositis, rhabdomyolysis and acute renal failure can occur.  HMG-CoA reductase inhibitors are contraindicated in pregnancy, children, serious illness, trauma, or major surgery.  Drug interactions may occur with cyclosporine, gemfibrozil, niacin, and erythromycin.  Myopathy is much more likely to occur is the patient is taking these drugs [3].  They work synergistically with resins.  Examples include lovastatin (Mevacor), pravastatin (Pravochol), simvastatin (Zocor), atorvastatin (Lipitor), rosuvastatin (Crestor).

Fibric acid derivatives, also known as fibrates, are believed to increase activity of lipoprotein lipase in adipose tissue and in so doing increase catabolism of VLDL [3].  Others claim their mechanism of action is not known, but they reduce production of cholesterol, increase the breakdown of triglycerides, and promote elimination of certain types of cholesterol from the body. This action leads to reduced triglyceride levels, VLDL levels, and LDL levels.  Gemfibrozil produces a moderate increase in HDL.  Since studies showed no effect on decreasing the risk of death, they are used mostly in combination with other cholesterol-lowering agents [4].  Fibrates are mainly used to lower high triglyceride levels.  They are not as effective as "statins" in lowering total cholesterol and LDL cholesterol.  Both gemfibrozil and clofibrate may cause GI distress and an increased incidence of gallstones.  Gemfibrozil has been associated with musculoskeletal pain and hypokalemia.  These drugs should not be administered to patients with hepatic or renal dysfunction, and caution should be exercised in pregnant women, obese patients, American Indians, and patients with biliary tract disease.  It is important to note that clofibrate is seldom used because of its association with a small increase in risk of gastrointestinal and hepatobiliary neoplasia [3].  Gemfibrozil (Lobid) and fenofibrate capsules (Antara, Lofibra) or tablets (Tricor,Triglide) are members of this group.  Clofibrate (Atromid-S) is no longer available [4]. 

Resins bind to bile acids in the intestine, which inhibits their reabsorption and increases their excretion by up to tenfold.  Recall that bile acids are required for intestinal absorption of fats.  Therapeutically, they increase the number of LDL receptors on hepatocytes [5], thereby increasing LDL clearance from the plasma producing lower plasma levels.  In some patients, they weakly stimulate VLDL synthesis resulting in small increases in VLDL, HDL, and triglyceride.  Constipation is the most common undesired effect, although flatulence, bloating, heartburn, and steatorrhea also occur.  If fat malabsorption occurs, deficiencies of the fat-soluble vitamins (A, D, E, and K) may ensue.  A deficiency of vitamin K can result in hypoprothrombinemia.  Supersaturation of cholesterol in bile may lead to increased incidence of gallstones and cholecystectomy.  The resins are prevalently used to lower LDL cholesterol.  They should not be used in patients with high triglyceride levels.  They may impair the absorption of several drugs, especially lipid-soluble drugs.  Examples of bile acid-binding resins include cholestyramine (Cholybar, Questran), colesevelam (Welchol), colestipol (Colestid).

The miscellaneous category of cholesterol lowering drugs include nicotinic acid (Niacin), probucol (Lorelco), ezetimibe (Zetia), and Vytorin (a combination of ezetimibe and simvastatin).  Nicotinic acid inhibits VLDL secretion and decreases production of LDL.  Probucol increases LDL catabolism.  It may inhibit early stages of cholesterol biosynthesis and slightly inhibit dietary cholesterol absorption.  It may inhibit the oxidation and tissue deposition of LDL cholesterol.  Ezetimibe blocks the absorption of cholesterol.  Nicotinic acid reduces VLDL levels, LDL levels; and has variable effects on HDL levels.  Probucol lowers serum cholesterol.  Ezetimibe reduces total cholesterol, LDL-C, apo B, and triglycerides, and increases HDL-C.  Potential unpleasant side effects with nicotinic acid include flushing, itching, rashes, pruritus, dry skin, increased pigmentation, GI distress, increased urinary frequency, dysuria, hyperuricemia which may precipitate gout.  Hepatic and pancreatic disturbances may occur with high doses.  Probucol may produce dizziness or fainting, fast or irregular heartbeat, or GI disturbances.  Musculoskeletal, GI, or respiratory system disturbances may occur with ezetimibe.  Nicotinic acid should not be used in patients with severe peptic disease.  As will other cholesterol lowering drugs, liver function should be monitored, and if hepatotoxicity occurs, the drug should be discontinued. 

References

1.  http://www.webmd.com/content/pages/9/1675_57815

2.  http://www.drugdigest.org/DD/Comparison/NewComparison/0,10621,37-15,00.html

3.  http://heartdisease.about.com/cs/cardiacdrugs/index.htm

4.  http://www.drugdigest.org/DD/Comparison/NewComparison/0,10621,35-15,00.html

5.  Lehne, R. A. (1998). Pharmacology for Nursing Care, 3rd Ed. Philadephia: W. B. Saunders Co.