Chapter 50

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 50

Prophylaxis of Coronary Heart Disease: Drugs That Help Normalize Cholesterol

and Triglyceride Levels

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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.


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)


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


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


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


Atherogenesis More than just deposit of lipids Now considered primarily a chronic

inflammatory process Infiltration of macrophages, T lymphocytes,

and other inflammatory mediators


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)


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


Treatment of High-LDL Cholesterol Therapeutic lifestyle changes (TLCs)

Smoking cessation The TLC diet Exercise


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.


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


Treatment Goals for Metabolic Syndrome

Reduce the risk for atherosclerotic disease Reduce the risk for type 2 diabetes Increase physical activity


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


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



Mechanism of cholesterol reduction Clinical trials Therapeutic uses

Hypercholesterolemia Primary and secondary prevention of CV events Post-MI therapy Diabetes Potential uses



Adverse effects Common

• Headache• Rash• GI disturbances

Rare • Myopathy/rhabdomyolysis• Hepatotoxicity


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


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


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


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


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


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


Ezetimibe Adverse effects

Myopathy Rhabdomyolysis Hepatitis Pancreatitis Thrombocytopenia

Drug interactions Statins Fibrates Bile-acid sequestrants Cyclosporine


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)


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


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)


Other Products Used to Alter Plasma Lipid Levels

Fenofibrate Fenofibric acid Drug combinations

Niacin/lovastatin Simvastatin/niacin, simvastatin/ezetimibe Pravastatin/aspirin Atorvastatin/amlodipine


Other Products Used to Alter Plasma Lipid Levels

Lovaza Fish oil Plant stanol and sterol esters Estrogen Cholestin

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