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59-291 Section 3, Lecture 7 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 1 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 2 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 3 Progression of CHD Damage to endothelium and invasion of macrophages Smooth muscle migration Collagen and elastic fibers form a matrix around the cholesterol, macrophages and muscle cells Cholesterol accumulates around macrophage and muscle cells 4 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) 5 Chylomicrons- transport dietary lipids from the gut to the adipose tissue and liver Chylomicron remnantsproduced 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) HDL- (good cholesterol) produced in gut and liver cells, HDL transports cholesterol from atheromas to the liver (reverse cholesterol transport) 6 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 7 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 8 • 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; b blockers, oral contraceptives, thiazide diuretics – Diseases: hypothyroidism, nephrotic syndrome, obstructive liver disease 9 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 Category LDL-C goal Initiate TLC2 Consider Drug Therapy2 High risk: CHD or CHD 3 4 equivalents (10-year risk 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 5 factors (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 10 • 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 11 Sites and mechanism of drugs for hyperlipidemia 12 HMG-CoA reductase inhibitors Therapy HMG-CoA reductase inhibitors Low-Density Lipoprotein (LDL) Cholesterol Concentration High-Density Lipoprotein (HDL) Cholesterol Concentration Total Triglyceride Concentration ↓20-50% ↑10% ↓10-40% Other Effects Increase in hepatic LDL receptors. Adverse effects: abdominal cramps, constipation, diarrhea, heartburn Hepatitis, elevate serum levels of hepatic enzymes, Myopathy (Myalgia, Myositis, 13 Rhabdomyolysis) 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 14 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 15 Practice Questions • • • • • • List 4 risk factors associated with CHD Cigarette smoking Low HDL-C Hypertension Family history of premature CHD Age 16