Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 CHAPTER 29 Hypolipidemic Drugs

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 2 Danger – Heart attack Coronary heart disease causes ½ of all deaths in USA Caused by: –Elevated low density lipoproteins (↑ LDL) –Elevated triglycerides (  TG) –Decreased high density lipoproteins (↓ HDL) Reduction of the LDL level is the primary goal of cholesterol-lowering therapy

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 3

4 Clinical Indication Adjunct therapy to reduce elevated cholesterol especially in patients with elevated low density lipoproteins (LDL) who do not respond to dietary adjustment Prevent the progression of coronary atherosclerosis in coronary heart disease Prevent the risk of death from acute coronary episodes

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 5 Lipoproteins Are produced in liver and intestines to transport lipids (fats) such as cholesterol triglycerides Vary in density from Very low density (VLDL) Low density (LDL) involved in atherosclerosis High density (HDL) cardioprotective

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 6 Risk Factors Associated with Coronary Heart Disease Age Men > 45 yrs Women > 55 yrs History of Smoking Hypertension Antihypertension medications Premature menopause Obesity Hormone imbalance Diabetes mellitus Low HDL, high LDL levels

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 7 Hypolipdemic Drugs Bile acid sequestrants (binders) cholestyramine, colestipol HMG-CoA Reductase Inhibitors block cholesterol synthesis atrovastatin, cervastatin, lovastatin, pravastatin, simastatin Alter lipid and lipoprotein metabolism clofibrate, dextrothyroxine, gemfibrozil, niacin

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 8 Bile acid sequesterants Bind bile acids and cholesterol in bowel and deplete body pool - liver removes more LDL from blood to synthesize more bile salts – Hence lowers blood level of LDL Cholestyramine (Questran) Colestipole (Colestid)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 9 HMG-CoA reductase inhibitors This enzyme is the rate-limiting step in hepatic synthesis of cholesterol –Note: serum cholesterol – 1/3 dietary, 2/3 synthesized by liver Lowers VLDL,LDL & triglyceride Raises HDL Lovastatin (Mevacor) Atrovastatin (Lipitor)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 10

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 11 Adverse Effects of HMG-CoA Reductase Inhibitors Elevated serum liver enzymes (AST, ALT) Muscle aches Muscle weakness Elevate serum creatine phosphokinase (CPK) Headache Dizziness Diarrhea Abdominal cramping, flatulence Alteration of taste

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 12 Fibric Acids Increases the uptake of fat by fat cells from VLDL and chylomicrons by activating lipoprotein lipase – lowers cholesterol & TG Gemfibrozil (Lopid) Fenofibrate (Tricor)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 13 Nicotinic Acid Inhibits lipolysis and release of fatty acids in fat cells – lowers synthesis of triglycerides by liver – lowers VLDL & LDL Niacin (Niacor)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 14 Cholesterol Absorption Inhibitors Acts at mucosal surface of the small bowel to block absorption of dietary cholesterol Ezetimibe (Zetia) Problems: –Most cholesterol is not dietary –Foul smelling stools –Blocks fat soluble vitamins (A,D,E,K)

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 15 HMG-CoA Reductase Inhibitors Patients who have –Acute liver disease –Hypersensitivity –Persistent elevation in serum liver enzymes Pregnancy Patients using gemfibrozil because severe cardiomyopathy may develop Dextrothyroxine Patients with angina, myocardial infarction, arrhythmias, congestive heart failure Pregnancy Contraindications

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 16 HMG-CoA Reductase Inhibitors Competition for liver enzymes, increase levels Alcohol, antifungal drugs, digoxin, warfarin Decrease HMG-CoA Inhibitor levels Nicotinic acid, propranolol Dextrothyroxine Increase bleeding with anticoagulants Block antidiabetic drugs, increase serum glucose Bile Acid Sequestrants Bind fat soluble vitamins, drugs to reduce absorption Vitamins A, D, K Anticoagulants, aspirin, furosemide, glipizide, methyldopa Drug Interactions

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 17