CV Pharmacology-Drugs Used in Treating HyperlipidemiaPrepared and Presented by: Marc Imhotep Cray, M.D.Professor PharmacologyRecommended Reading:Management of Hyperlipidemic StatesFormative AssessmentPractice questionClinical:E-Medicine ArticlesHypertriglyceridemia9/29/20092DefinitionHyperlipidemia, hyperlipoproteinemiaor dyslipidemiais the presence of raised or abnormal levels of lipidsand/or lipoproteinsin the bloodLipids are insoluble in aqueous solutionLipids (fatty molecules) are transported in a proteincapsule, and the density of the lipids and type of protein determines the fate of the particle and its influence on metabolism9/29/20093Definition(2) see notes and link out for more on cholesterolLipid and lipoprotein abnormalities are extremely commonin the general population, and are regarded as a highly modifiable risk factor for cardiovascular diseasedue to the influence of cholesterol, one of the most clinically relevant lipid substances, on atherosclerosisIn addition, some forms may predispose to acute pancreatitisLink out:http://themedicalbiochemistrypage.org/cholesterol.html9/29/20094Schematic and Notes Below From:http://www.emedicine.com/MED/topic2921.htm#Multimediamedia39/29/20095Links to Cholesterol Metabolism and Lipoprotein on themedicalbiochemistrypage.orgIntestinal Uptake of LipidsComposition of Lipoprotein ComplexesLipid Profile ValuesClassification of ApoproteinsChylomicronsVery Low Density Lipoproteins, LDLsIntermediate Density Lipoproteins, IDLsLow Density Lipoproteins, LDLsHigh Density Lipoproteins, HDLsLDL ReceptorsClinical Significance of Lipoprotein MetabolismCholesterol Biosynthesishttp://themedicalbiochemistrypage.org/cholesterol.html9/29/20096Classification of HyperlipidemiaFredrickson classification of HyperlipidemiasHyperlipoproteinemiaSynonymsProblemsLabs descriptionTreatmentType IBuerger-Gruetz syndrome, Primary hyperlipoproteinaemia, or Familial hyperchylomicronemiaDecreased lipoprotein lipase(LPL) or altered ApoC2Elevated ChylomicronsDiet ControlType IIaPolygenic hypercholesterolaemiaor Familial hypercholesterolemiaLDL receptordeficiencyElevated LDLonlyBile Acid Sequestrants, Statins, NiacinType IIbCombined hyperlipidemiaDecreased LDL receptorand Increased ApoBElevated LDLand VLDLand TriglyceridesStatins, Niacin, FibrateType IIIFamilial DysbetalipoproteinemiaDefect in ApoEsynthesisIncreased IDLDrug of choice: FibrateType IVFamilial HyperlipemiaIncreased VLDLproduction and Decreased eliminationIncreased VLDLDrug of choice: Fibrate, NiacinType VEndogenous HypertriglyceridemiaIncreased VLDLproduction and Decreased LPLIncreased VLDLand ChylomicronsNiacin, FibrateSource: http://en.wikipedia.org/wiki/Hyperlipidemia#Classification9/29/20097Pathobiology of AtherosclerosisWhen excess cholesterol depositson cells and on the inside walls of blood vessels it forms an atherosclerotic plaqueThe 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 9/29/20098Complications of HyperlipidemiaMacrovascular 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) 9/29/200999/29/200910Risk Factors for HyperlipidemiaHigh 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, alcohol9/29/200911How to Diagnose Patients with Hyperlipidemia The fasting lipid profile (TC, LDL-C, HDL-C, TG)is analyzedThe following individuals are recommended for screening: All adults 20 years and oldershould be screenedat least once every 5 yearsIndividuals with family history of premature cardiovascular diseaseshould be screened more frequently9/29/200912How 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 guidelineSee: Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program Slide Shows 9/29/200913Lipoprotein 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 9/29/200914Treatment 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 9/29/200915Non-Pharmacological Treatment Lipid lowering therapy should be started with lifestyle modification for at least 12 weeks1.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 weightSee: Treatment of Diabetic Dyslipidemia /Medscape WebMD Med Student Section9/29/200916Pharmacological Treatment If non-pharmacological treatmentis 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 9/29/200917Pharmacological Treatment Statins (HMG CoA Reductase Inhibitors)Atorvastatin (Lipitor® )Simvastatin (Zocor®)Lovastatin (Mevacor®): extended releasePravastatin (Pravachol®)Fluvastatin (Lescol®): Lescol XL: 80 mg tablets Rosuvastatin (Crestor®): tablets 9/29/200918Statins (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 9/29/200919Statins (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 more9/29/200920Statins (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 9/29/200921Statins (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 breakdown9/29/200922Statins (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 9/29/200923Bile 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 9/29/200924Bile 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 9/29/200925Bile 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 acidDecreased absorption of other drugs:tetracycline, thiazide diuretics, aspirin, phenobarbital, pravastatin, digoxin 9/29/200926Bile 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 9/29/200927Nicotinic Acid Mechanism 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 acidis the most potentdrug that increases HDL cholesterol 9/29/200928Nicotinic Acid(2)Side effects:Flushing (taking aspirin or ibuprofen can reduce symptoms) Increases blood glucose due to impaired insulin sensitivity Gout Liver toxicityassociates with sustained release form (Niaspan) Upper stomach distress and muscle weaknes Avoid use in: Chronic liver diseaseSevere gout Use with caution in: Type 2 diabetes (high dose) Gout Peptic ulcer disease 9/29/200929Fibric 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 TGAgents:Gemfibrozil (Lopid®) Fenofibrate (Tricor®)9/29/200930Fibric 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 9/29/200931Fibric 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 anticoagulants9/29/200932Ezetimibe (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 9/29/200933Recommended Reading:Management of Hyperlipidemic StatesFormative AssessmentPractice questionClinical:E-Medicine ArticlesHypertriglyceridemiaFor Further Study