Lipid-Lowering Agents Edward JN Ishac, Ph.D. Smith Building, Room 742 eishac@vcu.edu 828-2127 Department of Pharmacology and Toxicology Medical College of Virginia Campus of Virginia Commonwealth University Richmond, Virginia, USA Agents used in the treatment of HT, CHF, Leading Causes of Death in the U.S Arrhythmia and Angina Drug Class Hyper- CHF Arrhyth Angina Contraindications/Cautions/Notes tension mia 1,000,000 aaa aaa Beta-Blockers aaa aaa Caution: CHF (unstable CHF, a a bronchospasm, significant bradycardia); or in diabetes, asthma 750,000 (use β 1-selective), depression Ca++-Channel CHF, Gingival hyperplasia, reflex aaa aaa aaa a a a blockers tachycardia, constipation 500,000 ACEI / ARBs aaa aaa Low GFR, renal stenosis, glossitis, a a tetrogenic, cough (ACEI), taste, ↑ renal mechanics 250,000 Diuretics Low GFR, hypokalemia → CG; aaa aaa a a glucose intolerance → diabetes 0 aa a Cardiac glycosides Many Rx interactions, low TI, [K+] , H C R A D I A important, low K+ →↑ toxicity n e a e c i l f a z a n s c l u h b r c p i Vasodilators aaa aa Flushing, dizziness, headache, d e e t e e i r e t n i D r m a e reflex tachycardia, combo Rx n z i t s s a e o t s e r r ' Na+-Channel blockers aaa Effects enhanced in depolarized a y s s a D D tissue, damaged tissue. Phase 0 e i i s s e e Nitrates aa Tolerance, flushing, dizziness, aaa a a s s a headache, reflex tachycardia e e Data NIH 2000 Relative Risk for CHD vs Total Cholesterol Abbreviations and Definitions (Lipids) TG [Triglyceride] VLDL, IDL, CM FFA [Free Fatty Acids] TG, primary energy source C [Cholesterol] VLDL, IDL, LDL, HDL, CM CE [Cholesterol ester] VLDL, IDL, LDL, HDL, CM 1
Relative size, density and TG/Chol Abbreviations and Definitions (Lipoproteins) ratio of different lipoproteins VLDL [very-low-density lipoprotein] [TG / CE] Apo B-100 [ATH] Triglyceride IDL [intermediate-density lipoprotein] [TG / CE] Apo B-100 [ATH] Cholesterol LDL [low-density lipoprotein] [TG / CE] Apo B-100 [very ATH] Chylomicron VLDL HDL [high-density lipoprotein] [C / CE] Apo A, C, E [non-ATH] IDL 95% TG LDL 80% TG 5% Chol 50% TG 20% Chol HDL CM [chylomicrons] [TG / CE] Apo B-48 [non-ATH] 50% Chol 10% TG 90% Chol 5% TG 95% Chol Abbreviations and Definitions (Enzymes) Abbreviations and Definitions (Apoproteins) Lipoprotein [TG] Lipase TG ⇒ FFA [VLDL, CM] LPL C II apoprotein C II [lipoprotein lipase activator] [HDL] HMG-CoA Reductase – Rate limiting step C synthesis A-1 apoprotein A-1 [LCAT cofactor] [HDL] E apoprotein E [required for LP binding to receptors] [HDL] CETP Cholesterol ester transfer protein (HDL) CE [HDL] exchanged for TG in lipoproteins B-48 apoprotein B-48 [structural apo for CMs] LCAT Lecithin:Cholesterol Acyltransferase (HDL) B-100 apoprotein B-100 [structural apo for VLDL, IDL, LDL] takes up lipoprotein C and ⇒ CE for CETP Atherosclerosis Pathogenesis of Atherosclerosis Significance: Major cause of death in U. S. Pathogenesis: Injury to blood vessel and infiltration of LDL and platelets. Formation of foam cells when LDL (oxidized) is internalized. Blood vessel is narrowed by plaque and blood clot reduces blood flow to brain (stroke) and heart (heart attack). Cell Injury Cell Proliferation Plaque Formation 2
Coronary Occlusion Atherosclerosis Timeline Atherosclerosis Timeline Foam Foam Atheroma Atheroma Fatty Fatty Intermediate Intermediate Fibrous Fibrous Complicated Complicated Cells Cells Streak Streak Lesion Lesion Plaque Plaque Lesion/Rupture Lesion/Rupture Endothelial Dysfunction Endothelial Dysfunction From First From Third From Fourth Decade Decade Decade Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104). Surgical Treatment Atherosclerosis (Coronary bypass, angioplasty, stents) Risk Factors: Hypertension age obesity Diabetes high fat diet smoking Stress low HDL lack of exercise Family history High levels of VLDL, IDL and LDL. Treatment : appropriate diet and drugs lowers mortality and morbidity 20 to 40%. Lipoprotein Metabolism I LDL Structure Apo CII & E on HDL Transfer To CM & VLDL ⇑ CMs TG, apo CII, E ⇑ CMRs AI & B48 Intestine → CMs —[LPL] → CMRs → Liver [non-ATH] 3
Factors Increasing HDL Levels Lipoprotein Metabolism II Exercise Moderate Alcohol Intake ⇑ VLDL Weight Reduction (overweight) ⇑ IDL Stop Smoking ⇑ LDL Lipid-lowering drugs ⇑ HDL (Resins, Statins, Fibrates, Ezitimibe & Niacin) Increased HDL levels are antiatherogenic HDL enhances the clearance of LPs and Cholesterol Liver → VLDL -[LPL] → IDL -[LCAT/CETP] → LDL → Tissues Primary Hyperlipidemia (fasting blood sample) Secondary Hyperlipidemia Hypertriglyceridemia (VLDL) Hypertriglyceridemia (TG 400-2,000 mg%) [PA= pro-atherosclerosis] 1. Increased CMs (low LPL), non-atherogenic Diabetes, oral contraceptives (estrogen), 2. Increased CMs and VLDLs (low LPL & increased VLDL production) [PA] hypothyroidism, hypopituitarism, high sugar diet 3. Increased VLDL (increased VLDL production and decreased LPL) [PA] and high alcohol intake (increased production and 4. Increased IDL & CM remnants (decreased clearance, low apo E) [PA] decreased clearance of VLDL). Hypercholesterolemia (C 250-800 mg%) 1. Increased VLDL and LDL (increased VLDL production) [PA] Hypercholesterolemia (LDL) 2. Increased LDL (increased LDL production and decreased LDL clearance) [ ↓ LDL receptors in genetic disorders, 50% heterozygote and 100% High cholesterol (fat) diet, hypopitutarism and homozygote ) [PA]. hypothyroidism (decreased LDL receptors). Resins - MOA MAO of Resins and Statins Resins: Colestipol, Cholestyramine and Colesevelam 1. Bind bile salts and block enterohepatic cycle of bile acids. 2. Lower cellular cholesterol content by increasing bile acid synthesis. 3. Increase LDL receptors in liver. 4. Rise in receptor-mediated endocytosis of LDL lowers plasma LDL levels. 5. Increase in cholesterol biosynthesis (bad). 6. Increase in plasma VLDL levels (bad) [do not use in patients with elevated VLDL] Cholestyramine 7. Modest increase in HDL levels (10%) [good] Normal + Statins Colestipol Colesevelam 4
Beneficial Effects of Resins Adverse Effects of Resins Gritty bad taste, patients don’t like Increase cellular cholesterol biosynthesis Lower LDL levels about 15 to 25% Increase plasma VLDL levels ( do not use in patients Increase HDL levels about 10% with ⇑ VLDL). Relatively safe drugs (no systemic absorption) GI: nausea, constipation, bloating (less with Good combo agents with statins Colesevelam [Welchol]) Decreases morbidity and mortality of CAD Decreases absorption of other agents - fat soluble vitamins A, D, E & K - aspirin, thiazides, digoxin, phenobarbital Statins - MOA MAO of Resins and Statins Statins : Fluvastatin, Rosuvastatin, Pravastatin, Lovastatin, Simvastatin and Atorvastatin. 1. Competitive inhibitors of HMG-CoA reductase which regulates cholesterol formation. 2. Decreased cellular cholesterol level increases LDL receptors. 3. Rise in receptor-mediated endocytosis of LDL lowers plasma LDL levels. [15-50%] 4. Modest increase in HDL levels (10%) 5. Statins + Resins are good combination for lowering elevated LDL levels. Cholestyramine Normal + Statins 6. Atorvastatin and simvastatin also lower VLDL. Colestipol Colesevelam Adverse Effects of Statins Beneficial Effects of Statins May produce headaches, rashes and myopathy (muscle damage) Lower plasma LDL levels, best agents (15 to 50%) May cause rhabdomyolysis (muscle wasting) and Increase plasma HDL levels (10%) liver injury (higher doses). Monitor liver function - alanine aminotransferase (ALT) Atorvasatin & Simvastatin also lower plasma VLDL - aspartate aminotransferase (AST) ComboRx with Resins to lower plasma LDL Rhabdomyolysis potentiated with Gemfibrozil (avoid). Reduce morbidity and mortality of CAD Caution: elderly, women (CI: pregnancy), children, hypothyroid, renal and liver dysfunction and drug interactions (reduced metabolism). 5
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