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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

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HyperlipidemiaHyperlipoproteinemia

• 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

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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

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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

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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)

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Chylomicrons- transport dietary lipids from the gut to the adipose tissue and liverChylomicron remnants- produced from Chylomicrons by lipoprotein lipases in endothelial cells and transport cholesterol to the liverVLDL-made in the liver and secreted in to plasma deliver triglycerides to adipose tissue in the process get converted to IDL and LDLLDL- (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)

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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; blockers, oral contraceptives, thiazide

diuretics– Diseases: hypothyroidism, nephrotic syndrome,

obstructive liver disease

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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 equivalents3 (10-year risk4 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 factors5 (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

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• 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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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, heartburnHepatitis, elevate serum levels of hepatic enzymes, Myopathy (Myalgia, Myositis, Rhabdomyolysis)

HMG-CoA reductase inhibitors

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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