Chapter 50

1. Chapter 50 Prophylaxis of Coronary Heart Disease: Drugs That Help Normalize Cholesterol and Triglyceride Levels

2. Prophylaxis of Coronary Heart Disease (CHD) • Cholesterol • Plasma lipoproteins • Role of LDL cholesterol in atherosclerosis • Detection, evaluation, and treatment of high cholesterol: recommendations from ATP III • Drugs and other products used to improve plasma lipid levels ATP = Adult Treatment Panel; LDL = low-density lipoprotein.

3. Cholesterol • Component of all cell membranes and membranes of intracellular organelles • Required for synthesis of certain hormones and bile salts • Deposited in stratum corneum of the skin • Comes from dietary sources • Manufactured by cells, primarily in the liver • Increased dietary cholesterol produces only a small increase in cholesterol in the blood (inhibits endogenous cholesterol production)

4. Plasma Lipoproteins • Structure and function of lipoproteins • Function • Basic structure • Apolipoproteins • Recognition sites for cell-surface receptors • Activate enzymes that metabolize lipoproteins • Increase the structural stability of lipoproteins

5. Plasma Lipoproteins • Classes of lipoproteins • Six major classes of plasma lipoproteins • Three relevant to coronary atherosclerosis • Very-low-density lipoproteins (VLDLs) • Triglycerides • Low-density lipoproteins (LDLs) • Cholesterol primary core lipid • Greatest contributor to coronary heart disease (CHD) • High-density lipoproteins (HDLs) • Cholesterol

6. Role of LDL Cholesterol in Atherosclerosis • LDLs initiate and fuel development of atherosclerosis • Process begins with transport of LDLs from the arterial lumen into endothelial cells, then into the space underlying the arterial epithelium

7. Atherogenesis • More than just deposit of lipids • Now considered primarily a chronic inflammatory process • Infiltration of macrophages, T lymphocytes, and other inflammatory mediators

8. Detection, Evaluation, and Treatment of High Cholesterol • Cholesterol screening • Every 5 years for adults over the age of 20 years • Total cholesterol • HDL cholesterol • Less than 40 mg/dL:low to undesirable • LDL cholesterol • Less than 100 mg/dL:desirable • Triglycerides (TGs)

9. CHD Risk Assessment • Factors in risk assessment • Identifying CHD risk factors • Calculating 10-year CHD risk • Identifying CHD risk equivalents • Diabetes • Atherosclerotic disease other than CHD • Framingham risk score greater than 20% • Identifying an individual’s CHD risk category • Each type of dyslipidemia a patient has contributes independently to CHD risk

10. Treatment of High-LDL Cholesterol • Therapeutic lifestyle changes (TLCs) • Smoking cessation • The TLC diet • Exercise

11. Drug Therapy: Not First-Line Therapy • Drugs should be used only if TLCs fail • HMG-CoA reductase inhibitors • Bile-acid sequestrants • Nicotinic acid (niacin) • Fibrates (reduce levels of TGs, not LDLs) HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A.

12. Secondary Treatment Targets • Metabolic syndrome • High blood glucose • High triglycerides • High apolipoprotein B • Low high-density lipoprotein (HDL) • Small LDL particles • Prothrombotic state • Proinflammatory state • Hypertension • High triglycerides • Levels above 150 mg/dL

13. Treatment Goals for Metabolic Syndrome • Reduce the risk for atherosclerotic disease • Reduce the risk for type 2 diabetes • Increase physical activity

14. Drugs and Other Products to Alter Plasma Lipid Levels • High LDL: contributes most to cardiovascular disease • Also consider • High total cholesterol • Low HDL cholesterol • High triglycerides • Drugs can improve lipid profiles, but not all improve clinical outcomes

15. HMG-CoA Reductase Inhibitors (Statins) • Most effective drugs for lowering LDL • Reduction of LDL cholesterol • Elevation of HDL cholesterol • Reduction of triglyceride levels • Nonlipid beneficial cardiovascular actions • Promote plaque stability • Reduce the risk for cardiovascular (CV) events • Increased bone formation

16. HMG-CoA Reductase Inhibitors (Statins) • Mechanism of cholesterol reduction • Clinical trials • Therapeutic uses • Hypercholesterolemia • Primary and secondary prevention of CV events • Post-MI therapy • Diabetes • Potential uses

17. HMG-CoA Reductase Inhibitors (Statins) • Adverse effects • Common • Headache • Rash • GI disturbances • Rare • Myopathy/rhabdomyolysis • Hepatotoxicity

18. HMG-CoA Reductase Inhibitor (Statins) • Drug interactions • Most other lipid-lowering drugs (except bile acid sequestrants) • Drugs that inhibit CYP3A4 • Use in pregnancy • Dosing should be once daily in the evening • Endogenous cholesterol synthesis increases during the night • Statins have greatest impact when given in the evening

19. Nicotinic Acid (Niacin) • Reduces LDL and TG levels • Increases HDL levels more effectively than any other drug • Effect on plasma lipoproteins • Lowering TG levels • Raising HDL cholesterol

20. Nicotinic Acid (Niacin) • Adverse effects • Skin (flushing, itching) • Intense flushing initially; can pretreat with aspirin • Decreased with SR version of niacin • Gastrointestinal • Hepatotoxicity • Hyperglycemia • Gouty arthritis • Can raise blood levels of uric acid

21. Bile-Acid Sequestrants • Previously were first-line drugs • Now primarily used as adjuncts to statins • Cholestyramine • Colestipol • Colesevelam • Newest and better-tolerated drug • Does not decrease uptake of fat-soluble vitamins (as other bile sequestrants do) • Does not significantly reduce the absorption of statins, warfarin, digoxin, and most other drugs studied

22. Bile-Acid Sequestrants • Colesevelam (cont’d) • Reduction in LDL cholesterol • Increased VLDL levels in some patients • Mechanism of action • Increases LDL receptors on hepatocytes • Prevents reabsorption of bile acids • Therapeutic use • Reduces LDL cholesterol (in conjunction with modified diet and exercise) • Adverse effects • Constipation

23. Ezetimibe • Mechanism of action and impact on plasma lipids • Inhibits cholesterol absorption • Therapeutic use • Reduces total cholesterol, LDL cholesterol, and apolipoprotein B • Approved for monotherapy and combined use with statins

24. Ezetimibe • Adverse effects • Myopathy • Rhabdomyolysis • Hepatitis • Pancreatitis • Thrombocytopenia • Drug interactions • Statins • Fibrates • Bile-acid sequestrants • Cyclosporine

25. Fibric Acid Derivatives (Fibrates) • Most effective drugs available for lowering TG levels • Can raise HDL cholesterol • Little or no effect on LDL cholesterol • Can increase the risk for bleeding in patients on warfarin • Can increase the risk for rhabdomyolysis in patients taking statins • Three drugs in the United States • Gemfibrozil (Lopid) • Fenofibrate (Tricor, others) • Fenofibric acid (TriLipix)

26. Gemfibrozil • Effects on plasma lipoproteins • Decreases plasma TG content • Lowers VLDL levels • Can raise HDL cholesterol • Mechanism • Appears to interact with a specific receptor subtype (PPAR alpha) • Drug interactions • Displaces warfarin from plasma albumin • Measure INR frequently

27. Gemfibrozil • Therapeutic uses • Reduces high levels of plasma triglycerides (VLDLs) • Treatment reserved for patients who have not responded to diet modification • Less effective than statins in reducing LDL • Can raise HDL (not approved for this use) • Adverse effects • Rashes • Gastrointestinal disturbances • Gallstones • Myopathy • Liver injury (hepatotoxic)

28. Other Products Used to Alter Plasma Lipid Levels • Fenofibrate • Fenofibric acid • Drug combinations • Niacin/lovastatin • Simvastatin/niacin, simvastatin/ezetimibe • Pravastatin/aspirin • Atorvastatin/amlodipine

29. Other Products Used to Alter Plasma Lipid Levels • Lovaza • Fish oil • Plant stanol and sterol esters • Estrogen • Cholestin