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Recommended Reading: Management of Hyperlipidemic States Formative Assessment Practice question Clinical: E-Medicine Articles Hypertriglyceridemia
CV Pharmacology-
Prepared and presented by: Marc Imhotep Cray, M.D. Professor Pharmacology
Definition
Hyperlipidemia, hyperlipoproteinemia or dyslipidemia is the presence of raised or abnormal levels of lipids and/or lipoproteins in the blood Lipids are insoluble in aqueous solution Lipids (fatty molecules) are transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence on metabolism
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Definition(2)
Lipid and lipoprotein abnormalities are extremely common in the general population, and are regarded as a highly modifiable risk factor for cardiovascular disease due to the influence of cholesterol, one of the most clinically relevant lipid substances, on atherosclerosis In addition, some forms may predispose to acute pancreatitis
Link out: http://themedicalbiochemistrypage.org/cholesterol.html 3
Intestinal Uptake of Lipids Composition of Lipoprotein Complexes Lipid Profile Values Classification of Apoproteins Chylomicrons Very Low Density Lipoproteins, LDLs Intermediate Density Lipoproteins, IDLs Low Density Lipoproteins, LDLs High Density Lipoproteins, HDLs LDL Receptors Clinical Significance of Lipoprotein Metabolism
Cholesterol Biosynthesis
http://themedicalbiochemistryp age.org/cholesterol.html
Classification of Hyperlipidemia
Fredrickson classification of Hyperlipidemias
Hyperlipopr oteinemia
Source: http://en.wikipedia.org/wiki/Hyperlipidemia#Classification
Pathobiology of Atherosclerosis
When excess cholesterol deposits on cells and on the inside walls of blood vessels it forms an atherosclerotic plaque The first step of atherosclerosis is injury to the endothelium which results in atherosclerotic lesion formation When the plaque ruptures, blood clots form which lead to decreased blood flow, resulting in cardiovascular events
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Complications of Hyperlipidemia
Macrovascular complications:
Unstable Angina (chest pain) Myocardial Infarction (heart attack) Ischemic Cerebrovascular Disease (stroke) Coronary Artery Disease (heart disease)
Microvascular complications:
Retinopathy (vision loss) Nephropathy (kidney disease) Neuropathy (loss of sensation in the feet and legs)
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High fat intake Obesity Type 2 diabetes mellitus Advanced age Hypothyroidism Obstructive liver disease Genetics Drug induced: glucocorticoids, thiazide diuretics, beta blockers, protease inhibitors, sirolimus, cyclosporine, progestins, alcohol
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The fasting lipid profile (TC, LDL-C, HDL-C, TG) is analyzed The following individuals are recommended for screening:
All adults 20 years and older should be screened at least once every 5 years Individuals with family history of premature cardiovascular disease should be screened more frequently
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Presence of cardiovascular risk factors or cardiovascular disease Family history of premature cardiovascular disease, hyperlipidemia, or diabetes mellitus Diabetes mellitus or glucose intolerance Central obesity
An individual with a combination of lipid profile with history and physical exam, will be treated according to the ATP III guideline
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High blood pressure Presence or absence of risk factors Presence or absence of kidney or liver disease, peripheral vascular disease, abdominal aortic aneurysm, cerebral vascular disease
See: Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program Slide Shows
Total -C
100-129 mg/dL --------------------------Near or above optimal 130-159 mg/dL---------------------------Borderline high 160-189 mg/dL --------------------------High > or = 190 mg/dL -----------------------Very high <200 mg/dL------------------------------ Desirable 200-239 mg/dL---------------------------Borderline high > or= 240 mg/dL-------------------------High <150 mg/dL------------------------------Optimal 150-199 mg/dL --------------------------Borderline high 200-499 mg/dL --------------------------High > or = 500 mg/dL -----------------------Very high <40 mg/dL -------------------------------Low >60 or = 60 mg/dL --------------------- High
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TG-C:
HDL cholesterol:
Treatment Goals
1. Reduce total cholesterol and LDL (bad) cholesterol 2. Prevent the formation of atherosclerotic plaques and stop the progression of established plaques 3. Prevent heart disease 4. Prevent morbidity and mortality
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Non-Pharmacological Treatment
Lipid lowering therapy should be started with lifestyle modification for at least 12 weeks 1. Increase physical activity 2. Weight reduction
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Diet modification:
Total fat 25-35% of total calories Saturated fat <7% of total calories Polyunsaturated fat up to 10% total calories Monounsaturated fat up to 20% total calories Carbohydrates 50-60% total calories Fiber 20-30 g/ day total calories Protein 15% total calories Cholesterol <200 mg/day Total calories Achieve and maintain desirable body weight
See: Treatment of Diabetic Dyslipidemia / Medscape WebMD Med Student Section 15
Pharmacological Treatment
If non-pharmacological treatment is not successful, a lipid-lowering drug should be started, especially in high risk populations 1st step:
3rd step:
2nd step:
Initiate LDL-lowering drug therapy Start with statins, bile acid sequestrants, or nicotinic acid Evaluate after 6 weeks If goal was not reached, intensive lipidlowering treatment should be started Increase dose of statins Bile acid sequestrants or nicotinic acid should be added Evaluate after 6 weeks
4th step:
If goal is not reached, intensive lipid lowering should be continued or individual should be referred to a lipid specialist If goal was reached, other lipid risk factors should be treated Monitor response and compliance
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Pharmacological Treatment
Statins (HMG CoA Reductase Inhibitors) Atorvastatin (Lipitor ) Simvastatin (Zocor) Lovastatin (Mevacor): extended release Pravastatin (Pravachol) Fluvastatin (Lescol): Lescol XL: 80 mg tablets Rosuvastatin (Crestor): tablets
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Granules: 5-30 g by mouth daily given once or 2-4 times a day with meal Tablets: 2-16 g by mouth daily
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Nicotinic Acid
Mechanism of action:
Nicotinic acid decreases the clearance of ApoA1 to increase HDL; it inhibits the synthesis of VLDL Decreases LDL cholesterol by 5-25 % Increases HDL cholesterol by 15-35% Decreases TG by 20-50% Nicotinic acid is the most potent drug that increases HDL cholesterol
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Effectiveness:
Nicotinic Acid(2)
Side effects: Flushing (taking aspirin or ibuprofen can reduce symptoms) Increases blood glucose due to impaired insulin sensitivity Gout Liver toxicity associates with sustained release form (Niaspan) Upper stomach distress and muscle weaknes Avoid use in: Chronic liver disease Severe gout Use with caution in: Type 2 diabetes (high dose) Gout Peptic ulcer disease
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Fibric Acids
Mechanism of action: Fibric acid up-regulates fatty acid transport protein and fatty acid oxidation; thus it reduces the formation of VLDL, increases formation of HDL, and enhances the breakdown of TG Agents: Gemfibrozil (Lopid) Fenofibrate (Tricor)
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Fibric Acids(2)
Effectiveness: Reduces LDL cholesterol by 20-50% with normal TG Increases LDL cholesterol with high TG Reduces TG by 20-50% Increases HDL cholesterol by 10-20% Fibric acids are very effective in lowering TG and preventing pancreatitis Fibric acids reduce VLDL, but fibric acids might increase LDL and total cholesterol
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Fibric Acids(3)
Side effects:
Dyspepsia, gallstones, muscle ache, rash Unexplained non-coronary heart disease deaths seen in a World Health Organization (WHO) study Weakness, tiredness, elevations in muscle enzyme Severe renal disease Severe hepatic disease Fibric acids bind to albumin and increase the effect of anticoagulants
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Drug interaction:
Ezetimibe (Zetia)
Mechanism of action: Inhibits absorption of cholesterol in the small intestine; thus it decreases the delivery of cholesterol to the liver and increases the clearance of cholesterol from the blood Side effects: chest pain, dizziness, diarrhea, abdominal pain Drug interaction: Bile acid sequestrants decrease ezetimibe concentrations Ezetimibe should be spaced 2 hours before or 4 hours after bile acid sequestrants administration Fibric acids increase ezetimibe concentrations
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