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
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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

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

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

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
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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
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 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

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 High risk: CHD or CHD 3 4 equivalents (10-year risk of CHD >20%) Moderately high risk: 2+ risk 5 factors (10-year risk of CHD 10-20%) Moderate risk: 2+ risk factors (10-year risk of CHD <10%) LDL-C goal <100 mg/dL (optional: <70 mg/dL) Initiate TLC2 100 mg/dL Consider Drug Therapy2 100 mg/dL (optional goal: <100 mg/dL)

<130 mg/dL (optional: <100 mg/dL)

130 mg/dL

130 mg/dL (optional: 100-129 mg/dL)

<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

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Sites and mechanism of drugs for hyperlipidemia

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HMG-CoA reductase inhibitors

Therapy

Low-Density Lipoprotein (LDL) Cholesterol Concentration

High-Density Lipoprotein (HDL) Cholesterol Concentration

Total Triglyceride Concentration

Other 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, 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
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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

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

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