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
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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 energyfor muscle contraction and metabolic reactions
59-291 Section 3, Lecture 7
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HyperlipidemiaHyperlipoproteinemia
• Increases concentrations of lipids andlipoproteins
• Hypercholesterolemia; high concentrationof cholesterol– Atherosclerosis and coronary artery disease
• Hypertriglyceridemia; high concentration oftriglyceride– 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 toendothelium andinvasion ofmacrophages
Collagen andelastic fibersform a matrixaround thecholesterol,macrophagesand musclecells
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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 proteincomposition, role in lipid transport andassociation with apoproteins
• Chylomicrons• Very Low-Density Lipoproteins (VLDL)• Low- Density Lipoproteins (LDL)• High Density Lipoproteins (HDL)
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Chylomicrons- transportdietary lipids from the gut tothe adipose tissue and liverChylomicron remnants-produced from Chylomicronsby lipoprotein lipases inendothelial cells andtransport cholesterol to theliverVLDL-made in the liver andsecreted in to plasma delivertriglycerides to adiposetissue in the process getconverted to IDL and LDLLDL- (bad cholesterol)delivers cholesterol toperipheral tissues viareceptors and isphagocytosed bymacrophages thus deliveringcholesterol to the plaques(atheromas)HDL- (good cholesterol)produced in gut and livercells, HDL transportscholesterol from atheromasto the liver (reversecholesterol transport)
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Causes and Types ofHyperlipoproteinemia
• 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 remainsin 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
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 fecalimpaction, which can be prevented byincreased water consumption, analirritation and skin rash
• Bind to digoxin, varfarin, thyroxin; takeresins 2 h before or after taking othermedicines
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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