Presentation on theme: "Department of Pharmacology, LSUHSC,"— Presentation transcript:
1 Department of Pharmacology, LSUHSC, Lipid Lowering AgentsHamid Boulares, Ph.D.Department of Pharmacology, LSUHSC,Tel:
2 LIPID TRANSPORT - Overview AtherosclerosisChylomicrons: large lipoprotein particles that transport dietary lipids from the intestines to other locations in the body. They are one of the 5 major groups of lipoproteins (chylomicrons, VLDL, IDL, LDL, HDL) which enable fats and cholesterol to move within the water based solution of the blood stream.Chylomicron remnant: Once triglyceride stores are distributed, the chylomicron returns APOC2 (but keeps APOE) back to the HDL and thus becomes a chylomicron remnant. APOB48 and APOE are important to identify the chylomicron remnant in the liver for endocytosis and breakdown.IDL: intermediate DensityVLDL: Very low DensityHDL: High DensityLCAT: Lecithin-Acetyl-CoAC-acyltransferase
3 Lipoproteins and Their Structure Lipoproteins and their structure. Lipoproteins provide an essential function by packaging and allowing systemic transport of molecules essential for life.Surface: monolayer of polar lipids, unesterified cholesterol and apolipoproteinsApolipoproteins: Add stability to structure; act as ligands for cell surface receptors or co-factors for enzymatic reactionsCore: Cholesteryl esters (cholesterol esterified to fatty acid), TG
4 Characteristics of Lipoproteins ApoEVLDL : endogenous triglycerides; catabolized by lipoprotein lipase (LPL), short half-lifeIDL: cholesteryl esters, converted to LDL by hepatic lipaseLDL: apoB-mediated uptake by LDL receptor, long half-lifeHDL: phospholipids cholesteryl esters, removed by hepatic scavenger receptor Bsecreted to bile, steroid synthesis, VLDL synthesis.
5 Plasma Lipoproteins: Classes & Functions Very Low Density Lipoprotein (VLDL)Synthesized in liverTransport endogenous triglycerides to peripheral tissue90% lipid, 10% proteinMetabolized by LPLApo B-100Receptor bindingApo C-IILPL activatorApo ERemnant receptor binding5
6 Plasma Lipoproteins: Classes & Functions Intermediate Density Lipoprotein (IDL)Synthesized from VLDL during VLDL degradationTriglyceride transport and precursor to LDLApo B-100Receptor bindingApo C-IILPL activatorApo E6
7 Plasma Lipoproteins: Classes & Functions Low Density Lipoprotein (LDL)Synthesized from IDLCholesterol transport78% lipid, 58% cholesterol & CEApo B-100Receptor binding7
8 FYILDL receptorCharacterized by Michael Brown and Joseph Goldstein (Nobel prize winners in 1985)Receptor also called B/E receptor because of its ability to recognize particles containing both Apo B and EActivity occurs mainly in the liverReceptor recognizes apo E more readily than apo B-1008
9 Dyslipidemia and atherosclerosis Many clinical trials demonstrate that increase of LDL levels induce formation of atherosclerosis plaques.3.0For any level of LDL-C, HDL-C is inversely related to CHD risk2.0Risk of CHD1.025450.0HDL-C(mg/dL)6510016022085LDL-C(mg/dL)Gordon T et al. Am J Med 1977;62:Slide source:
11 Secondary Hyperlipidemia Hypertriglyceridemia (VLDL)Diabetes, oral contraceptives (estrogen), hypothyroidism, hypopituitarism, high sugar diet and high alcohol intake (increased production and decreased clearance of VLDL).Hypercholesterolemia (LDL)High cholesterol (fat) diet, hypopitutarism and hypothyroidism (decreased LDL receptors).
12 Classification of Lipoprotein Analysis Results (mg/dl) Total Cholesterol:<200 desirableborderline high>240 highHDL Cholesterol:<40 low>60 highLDL Cholesterol:<100 optimalnear/above optimalborderline highhigh>190 very highTriglycerides:<150 normalhighhigh>500 very high
13 Modes to reduce lipid levels: 1. Therapeutic lifestyle changes.- improved diet: reduce the intake of saturated fat to < 7% of calories.- reduce the cholesterol intake to < 200 mg/day.- weight reduction- increased physical activity2. Medication.
15 Anion-Exchange Resins Lipid Lowering Drugs:Anion-Exchange ResinsCholestyramine and Colestipol and ColesevelamSequester bile acids (BA) in the gut hence blocking enterohepatic cycling of BAUsually used in combination with a statinMajor side effects – bitter taste, nausea constipationImportant interactions – bind polar drugs such as warfarin, digoxin, thyroxine and statins: give 1 hr before resin15
16 STATINS STATINS Mechanism of Action Increased LDLUptakeHMG CoA reductaseSTATINSMechanism of Action
17 Lipid Lowering Drugs: STATINS Fungal metabolites: Lovostatin (MEVACOR), Simvastatin (ZOCOR), Provastatin (PRAVACHOL)Synthetic derivatives Fluvastatin (LESCOL), Atorvastatin (LIPITOR) and Rosuvastatin (CRESTOR)They have short half-lives (~2 hours except atorvastatin at 14h) but effective with once daily administrationAll have slightly higher efficacy if given at nightAll except pravastatin are metabolised through CYP enzymes in the liver which is the source of important drug-drug interactions (e.g. with warfarin)Major side effects: Hepatitis and myositis (inflammation of the muscles)
18 Fatal Rhabdomyolysis with Statins The major adverse effect of clinical significance associated with statin use is myopathyRhabdomyolysis; Breakdown of muscle proteins (myoglobin, creatine kinase) that leads to renal toxicity. Symptoms include muscle pain and weakness and dark urine due to muscle catabolismReason for Cerivastatin (Baycol) withdrawal from the market (~20-fold greater risk compared to other statins)Risk increased by combination with:Fibrates especially for gemfibrozil/cerivastatinNicotinic acidProtease Inhibitors (HAART therapy)-Highly Active AntiRetroviral Therapy
19 Pleiotropic effects of statins on the vasculature Clinical Science Clin. Sci. (2003) 105,
20 Lipid Lowering Agents: Nicotinic Acid (Niacin) hepatic VLDL synthesis by inhibiting adipose tissue lipolysis VLDL clearance by LPL activityIs the licensed agent with largest impact on HDL (30-50% )Lowers lipoproteins VLDL, IDL, LDL (by ~ 30%)Usually employed in combination with fibrate, resin or statinMajor side effectsFlushing – prostaglandin mediatedSkin drying & GI intoleranceExacerbates gout ( uric acid secretion), diabetes (promotes insulin resistance) and peptic ulcers20
21 Lipid Lowering Drugs: Fibrates Gemfibrozil and FenofibrateAct as PPAR ligands- multiple changes ApoA HDL LPL FA uptake and oxidation in muscle cells FA oxidation in hepatocytes and TG synthesisNet Effects VLDL (TG), LDL and HDLAbsorbed efficiently (>90%) when given with a meal but not on an empty stomachMain side effectsGI intolerance1-2% in the incidence of gallstones due to cholesterol synthesisImportant interactions increased risk of myopathy in dose requirements (~30%) for warfarin- fibrates displace warfarin from albumin
22 Lipid Lowering Drugs: EZETIMIBE Novel inhibitor of intestinal cholesterol transporter - inhibits intestinal cholesterol uptake and transport by ~ 50%Metabolite has 400x the potency of parent compound and prolongs action by enterohepatic cyclingNo important adverse effects OR significant drug interactionsUnlike resins does not raise TG -synergism with statins(e.g. ezetimibe/simvastatin, marketed as Vytorin and Inegy)NPCIL1: Niemann-Pick Cl-like channel 1 protein22
23 Progression of Drug Therapy in Primary Prevention If LDL goal not achieved, intensify drug therapy or refer to a lipid specialistIf LDL goal not achieved, intensify LDL-lowering therapyMonitor response and adherence to therapyInitiate LDL-lowering drug therapy6 wks6 wksQ 4-6 moStart statin or bile acid resin or nicotinic acidConsider higher dose of statin or add a bile acid sequestrant or nicotinic acidIf LDL goal achieved, treat other lipid risk factors23