1. 1 Drugs for Hyperlipidemia Lipids are necessary for human life Cholesterol –Essential component of cell membrane –Precursor to the sterol and steroid compounds Triglycerides (TG) –Composed of 3 fatty acids and glycerol –Main storage form of fuel, generate high-energy compound such as ATP, that provides energy for muscle contraction and metabolic reactions 59-291 Section 3, Lecture 7

2. 2 Hyperlipidemia Hyperlipoproteinemia Increases concentrations of lipids and lipoproteins Hypercholesterolemia; high concentration of cholesterol –Atherosclerosis and coronary artery disease Hypertriglyceridemia; high concentration of triglyceride –Pancreatitis –Development of atherosclerosis and heart disease

3. 3 Coronary Heart Disease (CHD) The main cause of premature death in industrialized countries Modifiable risk factors –Hypertension –Cigarette smoking –Low high density lipoprotein (HDL) <40 mg/dl Unmodifiable risk factors –Male gender –Family history of premature CHD; CHD in first-degree male relative <55, female <65 –Advance age; Men>45, Women >55

4. 4 Progression of CHD Damage to endothelium and invasion of macrophages Smooth muscle migration Cholesterol accumulates around macrophage and muscle cells Collagen and elastic fibers form a matrix around the cholesterol, macrophages and muscle cells

5. 5 Lipoproteins and Lipid transport Lipids are insoluble in plasma and must be transported Lipoproteins are distinguished according to their buoyant density, lipid and protein composition, role in lipid transport and association with apoproteins Chylomicrons Very Low-Density Lipoproteins (VLDL) Low- Density Lipoproteins (LDL) High Density Lipoproteins (HDL)

6. 6 Chylomicrons- transport dietary lipids from the gut to the adipose tissue and liver Chylomicron remnants- produced from Chylomicrons by lipoprotein lipases in endothelial cells and transport cholesterol to the liver VLDL-made in the liver and secreted in to plasma deliver triglycerides to adipose tissue in the process get converted to IDL and LDL LDL- (bad cholesterol) delivers cholesterol to peripheral tissues via receptors and is phagocytosed by macrophages thus delivering cholesterol to the plaques (atheromas) phagocytosed HDL- (good cholesterol) produced in gut and liver cells, HDL transports cholesterol from atheromas to the liver (reverse cholesterol transport)

7. 7 Causes and Types of Hyperlipoproteinemia Genetics and environmental factors Increase the formation or reduce the clearance of LP from circulation Factors –Biochemical defects in LP metabolism –Excessive dietary intake of lipids –Endocrine abnormality –Use of drugs that perturb LP formation or catabolism

8. 8 Primary Hyperlipoproteinemia Caused by a monogenic defect (a specific defect at a single gene) LDL cholesterol levels are severely high –Deficiency of LDL receptors –Defect in the structure of apoprotien B LDL receptors do not recognize LDL, LDL remains in circulation VLDL and TG levels are severely high –Lipoprotein lipase deficiency Prevents delivery of TG to adipose tissue

9. 9 Polygenic-environmental hyperlipidemia –Milder forms of hyperlipidemia –Influence of several genes –Excessive of dietary intake –More common than primary form –Responsible for most cases of accelerated atherosclerosis Secondary hyperlipidemia –Alcoholism –Diabetes melitus –Uremia –Drugs;  blockers, oral contraceptives, thiazide diuretics –Diseases: hypothyroidism, nephrotic syndrome, obstructive liver disease

10. 10 Guidelines for Management of Hypercholesterolemia; The Adult Treatment Panel III (ATPIII) Therapeutic lifestyle changes (TLC) and drug therapy for persons in different risk categories Risk CategoryLDL-C goalInitiate TLC 2 Consider Drug Therapy 2 High risk: CHD or CHD equivalents 3 (10-year risk 4 of CHD >20%) <100 mg/dL (optional: <70 mg/dL) ≥100 mg/dL≥100 mg/dL (optional goal: <100 mg/dL) Moderately high risk: 2+ risk factors 5 (10-year risk of CHD 10-20%) <130 mg/dL (optional: <100 mg/dL) ≥130 mg/dL≥130 mg/dL (optional: 100-129 mg/dL) Moderate risk: 2+ risk factors (10-year risk of CHD <10%) <130 mg/dL≥130 mg/dL≥160 mg/dL Lower risk: 0-1 risk factor<160 mg/dL≥160 mg/dL≥190 mg/dL (optional: 160-190 mg/dL) Risk factors: cigarette smoking, hypertension, low HDL-C, family history of premature CHD, and age

11. 11 Drugs for hypercholesterolemia –3-hydroxy-3- methyglutaryl Co A (HMG-CoA) reductase inhibitor –Bile acid-binding resin –Ezetimibe Drugs for reducing elevated TG and to raise HDL-C levels –Fibric acid derivatives –niacin

12. 12 Sites and mechanism of drugs for hyperlipidemia

13. 13 Therapy Low-Density Lipoprotein (LDL) Cholesterol Concentration High-Density Lipoprotein (HDL) Cholesterol Concentration Total Triglyceride ConcentrationOther Effects HMG-CoA reductase inhibitors ↓20-50%↑10%↓10-40% Increase in hepatic LDL receptors. Adverse effects: abdominal cramps, constipation, diarrhea, heartburn Hepatitis, elevate serum levels of hepatic enzymes, Myopathy (Myalgia, Myositis, Rhabdomyolysis) HMG-CoA reductase inhibitors

14. 14 Bile Acid-Binding Resins Moderately effective with excellent safety record Large MW polymers containing Cl - Resin binds to bile acids and the acid-resin complex is excreted –prevents enterohepatic cycling of bile acids –obligates the liver to synthesize replacement bile acids from cholesterol The liver increases the number of LDL receptors to obtain more cholesterol The levels of LDL-C in the serum are reduced as more cholesterol is delivered to the liver Little effect on levels of HDL-C and TG Excellent choice for people that cannot tolerate other types of drugs

15. 15 Adverse effects GI side effects, constipation and fecal impaction, which can be prevented by increased water consumption, anal irritation and skin rash Bind to digoxin, varfarin, thyroxin; take resins 2 h before or after taking other medicines

16. 16 Practice Questions List 4 risk factors associated with CHD Cigarette smoking Low HDL-C Hypertension Family history of premature CHD Age