Narrated Cholesterol

Chapter 49: 

Chapter 49 Prophylaxis of Coronary Heart Disease: Drugs That Help Normalize Cholesterol and Triglyceride Levels

Prophylaxis of Coronary Heart Disease (CHD): 

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 alter plasma lipid levels

Cholesterol: 

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)

Slide 4: 

Fig. 49-1. Basic structure of plasma lipoproteins.

Plasma 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: 

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 to the space underlying the arterial epithelium.

Slide 7: 

Fig. 49-2. Progression of atherosclerosis. A, Damaged endothelium. B, Diagram of fatty streak and lipid core formation. C, Diagram of fibrous plaque. Raised plaques are visible: some are yellow and some are white. D, Diagram of a complicated lesion, showing a thrombus (in red) and collagen (in blue).

Atherogenesis: 

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: 

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)

Children and Adolescents: 

Children and Adolescents Elevated cholesterol in pediatric patients is a growing concern.

CHD Risk Assessment: 

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

Slide 14: 

Fig. 49-3. Tables for calculating Framingham Risk Prediction Scores. To determine an individual ’ s 10-year risk of developing clinical coronary disease, simply circle the appropriate points for each of the five risk factors considered (age, total cholesterol, smoking status, HDL cholesterol, and systolic blood pressure) and then add up the points. The point total indicates the 10-year risk. For example, a total of 13 points indicates a 10-year risk of 12% for men. (Framingham scores can also be determined using a web-based calculator, such as the one provided by the NCEP at p2010.nhlbihin.net/atpiii/calculator.asp. )

Treatment of High LDL Cholesterol: 

Treatment of High LDL Cholesterol Therapeutic lifestyle changes (TLCs) The TLC diet Weight control Exercise Smoking cessation

Drug Therapy: Not the First-Line Therapy: 

Drug Therapy: Not the 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)

Treatment Goals for Metabolic Syndrome: 

Treatment Goals for Metabolic Syndrome Reduce the risk for atherosclerotic disease Reduce the risk for type 2 diabetes Lose weight Increase physical activity

Drugs and Other Products to Alter Plasma Lipid Levels: 

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): 

HMG-CoA Reductase Inhibitors (Statins) Atorvastatin (Lipitor), simvastatin (Zocor) 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 CV events Increased bone formation

HMG-CoA Reductase Inhibitors (Statins): 

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

HMG-CoA Reductase Inhibitor (Statins): 

HMG-CoA Reductase Inhibitor (Statins) Adverse effects Common Headache Rash GI disturbances Rare Myopathy/rhabdomyolysis Hepatotoxicity Peripheral neuropathy May be some connection Parkinson ’ s disease

HMG-CoA Reductase Inhibitor (Statins): 

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): 

Nicotinic Acid (Niacin) Reduces LDL and TG levels Increases HDL levels more effectively than any other drug Decreases production of VLDLs Mechanism of action Effect on plasma lipoproteins Therapeutic use Lowering TG levels Mixed elevation of LDLs and TGs HDL cholesterol (Niaspan)

Nicotinic Acid (Niacin): 

Nicotinic Acid (Niacin) Adverse effects Skin (flushing, itching) Intense flushing initially; can pretreat with aspirin Also decreased with SR version of niacin Gastrointestinal Hepatotoxicity Most likely with Slo-Niacin; less likely with Niaspan Hyperglycemia Gouty arthritis Can raise blood levels of homocysteine May increase risk for CHD

Bile Acid-Binding Sequestrants: 

Bile Acid-Binding Sequestrants Previously were first-line drugs Now primarily used as adjuncts to statins Cholestyramine (Questran) Colestipol (Colestid) Colesevelam (Welchol) 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

Ezetimibe (Zetia): 

Ezetimibe (Zetia) Mechanism of action and impact on plasma lipids Inhibits cholesterol absorption Therapeutic use Reducing total cholesterol, LDL cholesterol, and apolipoprotein B Approved for monotherapy and combined use with statins (slightly increases risk for liver damage)

Ezetimibe (Zetia): 

Ezetimibe (Zetia) Adverse effects Myopathy Rhabdomyolysis Hepatitis Pancreatitis Thrombocytopenia Drug interactions Statins Fibrates Bile-acid sequestrants Cyclosporine

Fibric Acid Derivatives (Fibrates): 

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 for 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 (Lopid): 

Gemfibrozil (Lopid) 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 (Lopid): 

Gemfibrozil (Lopid) Therapeutic uses Reduces high levels of plasma triglycerides (VLDLs) Treatment reserved for patients who have not responded to weight loss and 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: 

Other Products Used to Alter Plasma Lipid Levels Fenofibrate (Tricor, Antara, Lofibra, Triglide) Fenofibric acid (TriLipix) Drug combinations Niacin/lovastatin Simvastatin/niacin, simvastatin/ezetimibe Pravastatin/aspirin Atorvastatin/amlodipine

Other Products Used to Alter Plasma Lipid Levels: 

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