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IVMS-CV Pharmacology-Hyperlipidemia Agents
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IVMS-CV Pharmacology-Hyperlipidemia Agents IVMS-CV Pharmacology-Hyperlipidemia Agents Presentation Transcript

  • CV Pharmacology-Drugs Used in Treating Hyperlipidemia Recommended Reading: Management of Hyperlipidemic States Formative Assessment Practice question Clinical: E-Medicine Articles Hypertriglyceridemia 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 2
  • Definition(2) see notes and link out for more on cholesterol 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 View slide
  • Schematic and Notes Below From: http://www.emedicine.com/MED/topic2921.htm#Multimediamedia3 4 View slide
  • Links to Cholesterol Metabolism and Lipoprotein on themedicalbiochemistrypage.org 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 Cholesterol Biosynthesis LDL Receptors http://themedicalbiochemistryp Clinical Significance of Lipoprotein age.org/cholesterol.html Metabolism 5
  • Classification of Hyperlipidemia Fredrickson classification of HyperlipidemiasHyperlipoproteinemia Source: http://en.wikipedia.org/wiki/Hyperlipidemia#Classification 6
  • 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 7
  • 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) 8
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  • 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 10
  • 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 11
  • How to Diagnose Patients with Hyperlipidemia (2) History and physical  High blood pressure examination:  Presence or absence of risk  Presence of cardiovascular factors risk factors or cardiovascular  Presence or absence of disease kidney or liver disease,  Family history of premature peripheral vascular disease, cardiovascular disease, abdominal aortic aneurysm, hyperlipidemia, or diabetes cerebral vascular disease mellitus  An individual with a  Diabetes mellitus or glucose combination of lipid profile intolerance with history and physical  Central obesity exam, will be treated according to the ATP III guideline See: Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program Slide Shows 12
  • 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 13
  • Treatment Goals1. Reduce total cholesterol and LDL (bad) cholesterol2. Prevent the formation of atherosclerotic plaques and stop the progression of established plaques3. Prevent heart disease4. Prevent morbidity and mortality 14
  • Non-Pharmacological TreatmentLipid lowering therapy should be started with lifestyle modification 3. Diet modification: for at least 12 weeks  Total fat 25-35% of total calories1. Increase physical activity  Saturated fat <7% of total calories2. Weight reduction  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  3rd step: not successful, a lipid-lowering drug  If goal is not reached, intensive should be started, especially in high risk lipid lowering should be populations continued or individual should 1st step: be referred to a lipid specialist  If goal was reached, other lipid  Initiate LDL-lowering drug therapy risk factors should be treated Start with statins, bile acid sequestrants, 4th step:  or nicotinic acid   Evaluate after 6 weeks  Monitor response and compliance 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 16
  • Pharmacological TreatmentStatins (HMG CoA Reductase Inhibitors) Atorvastatin (Lipitor® ) Simvastatin (Zocor®) Lovastatin (Mevacor®): extended release Pravastatin (Pravachol®) Fluvastatin (Lescol®): Lescol XL: 80 mg tablets Rosuvastatin (Crestor®): tablets 17
  • Statins (HMG CoA ReductaseInhibitors)(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 18
  • 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 breakdownClick and learn more 19
  • Statins (HMG CoA ReductaseInhibitors)(4)Side effects: Muscle aches Increased liver enzymes Muscle break down leading to renal failure Fatigue, mild stomach disturbances, headache, or rash 20
  • Statins (HMG CoA Reductase Inhibitors)(5)Avoid use in: Active or chronic liver disease and pregnancyUse 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 21
  • Statins (HMG CoA Reductase Inhibitors)(6)Drug- food interaction: Grapefruit juice increases concentration of statins Pravastatin, rosuvastatin & fluvastatin concentrations are not affected by grapefruit juiceMonitoring: 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 22
  • Bile Acid SequestrantsMechanism 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 23
  • 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 day2) Colesevelam (Welchol®) Usual dose: 3 tablets by mouth twice daily with meals or 6 tablets once daily with a meal3) 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 24
  • Bile Acid Sequestrants(3)Effectiveness: Reduces LDL cholesterol by 15-30% Increases HDL cholesterol by 3-5% Increases TGDrug 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 25
  • Bile Acid Sequestrants(4)Side effects: Stomach upset, constipation accompanied by heart burn, nausea, and bloatingAvoid use in: A disease called dysbetalipoproteinemia Triglycerides >400 mg/dLUse 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 26
  • Nicotinic AcidMechanism of action:  Nicotinic acid decreases the clearance of ApoA1 to increase HDL; it inhibits the synthesis of VLDLEffectiveness:  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 27
  • 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 weaknesAvoid use in:  Chronic liver disease  Severe goutUse with caution in:  Type 2 diabetes (high dose)  Gout  Peptic ulcer disease 28
  • Fibric AcidsMechanism 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 TGAgents:Gemfibrozil (Lopid®)Fenofibrate (Tricor®) 29
  • 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 30
  • 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 enzymeAvoid use in:  Severe renal disease  Severe hepatic diseaseDrug interaction:  Fibric acids bind to albumin and increase the effect of anticoagulants 31
  • 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 bloodSide effects: chest pain, dizziness, diarrhea, abdominal painDrug 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 32
  • For Further Study Recommended Reading: Management of Hyperlipidemic States Formative Assessment Practice question Clinical: E-Medicine Articles Hypertriglyceridemia 33