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IVMS-CV Pharmacology-Hyperlipidemia Agents


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IVMS-CV Pharmacology-Hyperlipidemia Agents

  1. 1. CV Pharmacology- Drugs Used in Treating Hyperlipidemia Prepared and presented by: Marc Imhotep Cray, M.D. BMS / CK-CS Teacher Recommended Reading: Management of Hyperlipidemic States Formative Assessment Practice question Clinical: E-Medicine Articles Hypertriglyceridemia
  2. 2. 2 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
  3. 3. 3 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 Learn more: Hyperlipidemia A 4-ml sample of hyperlipidemic blood with lipids separated into the top fraction ( perlipidemia#Classification)
  4. 4. 4 From:
  5. 5. 5 Links to Cholesterol Metabolism and Lipoprotein  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
  6. 6. 6 Fredrickson classification of hyperlipidemias ( Hyperlipo- proteinemia Synonyms Defect Increased lipoprotein Main symptoms Treatment Serum appearance Estimated prevalence Type I Buerger-Gruetz syndrome or familial hyperchylomicr onemia Decreased lipoprotein lipase (LPL) Chylomicrons Acute pancreatitis, lipemia retinalis, eruptive skin xanthomas, hepatosplenom egaly Diet control Creamy top layer One in 1,000,000[ Familial apoprotein CII deficiency Altered ApoC2 LPL inhibitor in blood Type II Familial hypercholester olemia LDL receptor deficiency LDL Xanthelasma, arcus senilis, tendon xanthomas Bile acid sequestrants, statins, niacin Clear One in 500 for heterozygotes Familial combined hyperlipidemia Decreased LDL receptor and increased ApoB LDL and VLDL Statins, niacin, fibrate Clear 1 in 100 Type III Familial dysbetalipoprot einemia Defect in Apo E synthesis IDL Tuboeruptive xanthomas and palmar xanthomas Fibrate, statins Turbid One in 10,000 Type IV Familial hypertriglycerid emia Increased VLDL production and decreased elimination VLDL Can cause pancreatitis at high triglyceride levels Fibrate, niacin, statins Turbid One in 100 Type V Increased VLDL production and decreased LPL VLDL and chylomicrons Niacin, fibrate Creamy top layer and turbid bottom
  7. 7. 7 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
  8. 8. 8 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)
  9. 9. 9
  10. 10. 10 Risk Factors for Hyperlipidemia  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
  11. 11. 11 How to Diagnose Patients with Hyperlipidemia  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
  12. 12. 12 How to Diagnose Patients with Hyperlipidemia (2)  History and physical examination:  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  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  An individual with a combination of lipid profile with history and physical exam, will be treated according to the ATP III guideline See: Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program Slide Shows
  13. 13. 13 Lipoprotein Level Classification  LDL-C < 100 mg/dL-----------------------------Optimal  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  Total -C  <200 mg/dL------------------------------ Desirable  200-239 mg/dL---------------------------Borderline high  > or= 240 mg/dL-------------------------High  TG-C:  <150 mg/dL------------------------------Optimal  150-199 mg/dL --------------------------Borderline high  200-499 mg/dL --------------------------High  > or = 500 mg/dL -----------------------Very high  HDL cholesterol:  <40 mg/dL -------------------------------Low  >60 or = 60 mg/dL --------------------- High
  14. 14. 14 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
  15. 15. 15 Non-Pharmacological Treatment Lipid lowering therapy should be started with lifestyle modification for at least 12 weeks 1. Increase physical activity 2. Weight reduction 3. 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
  16. 16. 16 Pharmacological Treatment  If non-pharmacological treatment is not successful, a lipid- lowering drug should be started, especially in high risk populations  1st step:  Initiate LDL-lowering drug therapy  Start with statins, bile acid sequestrants, or nicotinic acid  Evaluate after 6 weeks  2nd step:  If goal was not reached, intensive lipid-lowering treatment should be started  Increase dose of statins  Bile acid sequestrants or nicotinic acid should be added  Evaluate after 6 weeks  3rd 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  4th step:  Monitor response and compliance
  17. 17. 17 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
  18. 18. 18 Statins (HMG CoA Reductase Inhibitors)(2) Effectiveness of statins:  Reduce LDL cholesterol by 18-55% Decrease TG by 7-30%  Raise HDL cholesterol by 5-15%  Statins are the most effective in lowering LDL cholesterol  Statins are the most effective in patient who has low HDL and high LDL
  19. 19. 19 Statins (HMG CoA Reductase Inhibitors)(3) Mechanism of action:  Statins inhibit HMG-CoA reductase (enzyme involved in cholesterol synthesis) thus decreasing mevalonic acid production and stimulating LDL breakdown Click and learn more
  20. 20. 20 Statins (HMG CoA Reductase Inhibitors)(4) Side effects:  Muscle aches  Increased liver enzymes Muscle break down leading to renal failure  Fatigue, mild stomach disturbances, headache, or rash
  21. 21. 21 Statins (HMG CoA Reductase Inhibitors)(5) Avoid use in:  Active or chronic liver disease and pregnancy Use with caution with:  Concomitant use of cyclosporine, macrolide antibiotics, antifungal agents.  For example: Itraconazole, ketoconazole, erythromycin, clarithromycin, cyclosporine, nefazodone, HIV antiretrovirals  When statins are used with fibric acids and niacin, appropriate caution should be taken because of increasing incidence of muscle breakdown
  22. 22. 22 Statins (HMG CoA Reductase Inhibitors)(6) Drug- food interaction:  Grapefruit juice increases concentration of statins  Pravastatin, rosuvastatin & fluvastatin concentrations are not affected by grapefruit juice Monitoring:  Muscle soreness, tenderness, or pain  Liver function tests : baseline, 4-6 weeks after starting therapy, and then annually  Muscle enzyme levels when individual has muscle pain
  23. 23. 23 Bile Acid Sequestrants Mechanism of action:  Bile acid sequestrants bind to bile acids in the intestine, thus inhibits uptake of intestinal bile salts into the blood and increases the fecal loss of bile salt- bound LDL
  24. 24. 24 Bile Acid Sequestrants(2) 1) Cholestyramine (Questran®): Usual dose: 4 g by mouth 1-2 times a day with meal to a maximum of 24 g per day 2) Colesevelam (Welchol®) Usual dose: 3 tablets by mouth twice daily with meals or 6 tablets once daily with a meal 3) Colestipol (Colestid®)  Usual dose:  Granules: 5-30 g by mouth daily given once or 2-4 times a day with meal  Tablets: 2-16 g by mouth daily
  25. 25. 25 Bile Acid Sequestrants(3) Effectiveness:  Reduces LDL cholesterol by 15-30%  Increases HDL cholesterol by 3-5%  Increases TG Drug interaction:  Decreased absorption of fat soluble Vitamins: A, D, E, K, C and folic acid  Decreased absorption of other drugs: tetracycline, thiazide diuretics, aspirin, phenobarbital, pravastatin, digoxin
  26. 26. 26 Bile Acid Sequestrants(4) Side effects:  Stomach upset, constipation accompanied by heart burn, nausea, and bloating Avoid use in:  A disease called dysbetalipoproteinemia  Triglycerides >400 mg/dL Use caution if:  Triglycerides >200 mg/dL  Colesevalam is much better tolerated than cholestyramine or colestipol  Statins and other drugs should be taken 1-2 hours before and 4-5 hours after bile acid sequestrants
  27. 27. 27 Nicotinic Acid Mechanism of action:  Nicotinic acid decreases the clearance of ApoA1 to increase HDL; it inhibits the synthesis of VLDL Effectiveness:  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
  28. 28. 28 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
  29. 29. 29 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®)
  30. 30. 30 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
  31. 31. 31 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 Avoid use in:  Severe renal disease  Severe hepatic disease Drug interaction:  Fibric acids bind to albumin and increase the effect of anticoagulants
  32. 32. 32 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
  33. 33. 33 Recommended Reading: Management of Hyperlipidemic States Formative Assessment Practice question Clinical: E-Medicine Articles Hypertriglyceridemia For Further Study