Transcript Drugs for Hyperlipidemia

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
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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
Collagen and
elastic fibers
form a matrix
around the
cholesterol,
macrophages
and muscle
cells
Cholesterol
accumulates
around
macrophage 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 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)
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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
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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
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–
–
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Alcoholism
Diabetes melitus
Uremia
Drugs; b 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
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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
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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
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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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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
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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
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List 4 risk factors associated with CHD
Cigarette smoking
Low HDL-C
Hypertension
Family history of premature CHD
Age
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