2. DRUGS for DYSLIPIDEMIAS MED PHARM 2/22/2010

3. DYSLIPIDEMIAS A MODIFIABLE RISK FACTOR for CV DISEASE LIFESTYLE MODIFICATION WORKS BETTER THAN DRUGS AND IS CHEAPER 1 MG/ML INCREASE LDL-C INCREASES RISK OF CV DISEASE 2-3% 1 MG/ML HDL DECREASE INCREASES CHD RISK BY 3-4%

4. Heistad D. N Engl J Med 2003;349:2285-2287 An Unstable Arterial Plaque and the Mechanisms of Plaque Rupture

5. FATES OF CHOLESTEROL Membrane structure Precursor of steroid hormones and vitamin D Esterification for storage Esterification for elimination Precursor to bile salts

6. Nabel E. N Engl J Med 2003;349:60-72 The Basic Components of Cholesterol Synthesis and Excretion

7. Figure 1. General structure of a lipoprotein.

8. General Features of Lipoproteins  Apolipoproteins: specific lipid-binding proteins that attach to the surface intracellular recognition for exocytosis of nascent particle after synthesis activation of lipid-processing enzymes in the bloodstream, binding to cell surface receptors for endocytosis and clearance.  Main lipid components triacylglycerols cholesterol esters phospholipids  Major lipoproteins of the endogenous system: very low density lipoproteins (VLDL) intermediate density lipoproteins (IDL) low density lipoproteins (LDL) high density lipoproteins (HDL)  Electrophoretic mobility (charge): HDLs =  lipoproteins LDLs =  -lipoproteins VLDLs = pre-  lipoproteins (intermediate between  and  mobility).

9. 0% 20% 40% 60% 80% 100% Chylo- microns VLDLLDLHDL Lipoprotein Type Composition C P T C P T T P C C P T Figure 2. The major classes of lipoproteins and their relative content of triacylglycerol (T), cholesterol (C) and protein (P).

10. Summary of Lipoprotein classes: Lipo- protein SourceApo Proteins in Mature Protein:Lipid/ Major (minor) Lipid Transported Function VLDLliverB100, CII, E 1:9 triacylglycerol (CE) Synthesized: FFA  adipose/muscle CE  LDL IDLBloodB100, E1:3 cholesterol ester CE  liver via apo E receptor LDLbloodB1001:3 cholesterol ester CE to liver (70%) and peripheral cells (30%) Causal agent in CHD H DL liverA1, CII, E ("ACE") 1:1 cholesterol ester supplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport

11. MITOCHONDRION Fatty acids Acetyl CoA  -oxidation oxaloacetate Citrate Mevalonate CHOLESTEROL smooth endoplasmic reticulum HMG CoA reductase Acetoacetyl CoA HMG CoA cytoplasm HMG-CoA synthase Thiolase Figure 2. Formation of mevalonate from HMG-CoA is the rate limiting and regulated step in the biosynthesis of cholesterol Lyase (requires ATP) OAA  malate  pyruvate+NADPH malic enzyme (2) Acetyl CoA Statins +Acetyl CoA

12. Mevalonate Active Isoprenoids (C 5 ) Squalene (C 30 ) 3ATP CO 2 Several Condensation Steps 3ADP NADPH NADP + Stage 2 Squalene (C 30 ) Cyclization Squalene epoxidase/ cyclase Lanosterol (C 30 ) (4-ring structure) O2O2 NADPH NADP + Stage 3 Stage 4 Lanosterol (C 30 ) (19 steps) O2O2 NADPH NADP + 3 CH 3 Cholesterol (C 27 ) Acetyl CoA (C 2 ) HMG-CoA Reductase Mevalonate (C 6 ) NADPH NADP + Stage 1 Figure 3. The four stages of cholesterol biosynthesis rate-determining step cholesterol activates proteolytic degradation amount controlled by induction/repression hormonally controlled via phosphorylation

13. THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA STATINS Competitive inhibitors of HMG-CoA reductase Act at low concentration (10 -9 ) Block HMG-CoA binding site limiting substrate access to catalytic site Decreased cholesterol synthesis: in liver = decreased VLDL output and hence LDL production in all tissues = LDL receptor induction  increased LDL uptake Increase HDL by boosting apo A1 production Side effects: liver damage (monitor plasma AST/ALT) myopathy that can lead to fatal rhabdomyolysis (monitor plasma CK) negative interactions with other lipi d-lowering drugs (fibrates inhibit statin metabolism)

14. THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA BILE ACID SEQUESTERING RESINS (cholestyramine/colestipol) Cholesterol is excreted by conversion to bile acids in liver cells Bile acids are recycled from ileum via enterohepatic circulation to feedback repress 7  - hydroxylase Sequestering resins bind bile salts (made from bile acids) to reduce recycling Chain of events: reduced recycling lowers liver bile salt concentration  lowers feedback repression  increases hydroxylase activity  increases cholesterol conversion to bile acids  lowers cholesterol concentration  more LDL receptors  increased hepatic uptake of LDL  lowers plasma cholesterol Side effects: increases blood triglycerides abdominal fullness  lowers food intake

15. THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA NICOTINIC ACID Water soluble vitamin (niacin; B3) Increases circulating HDL May lower circulating LDL Combined with statin may slow progression of heart disease Proposed mechanism – decreased release by adipsoe tissue of fatty acids to lower availability for making TAGs and cholesterol for VLDL Side effects: headache, dizziness long term use linked to liver damage (monitor ALT/AST) flushing (most common)

16. THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA FIBRATES Improve HDL Little effect on LDL Lower circulating triglyceride concentrations Prescribed in combination with statins Mechanism unknown Inhibit the metabolism of statins – Increases risk of statin myopathy

17. THERAPIES FOR TREATING HYPERCHOLESTEROLEMIA EZETIMIBE (ZETIA) Lowers intestinal absorption of dietary cholesterol Binds to the Niemann-Pick C1-Like1 (NPC1L1) protein on epithelial cells NPC1L1 mediates cholesterol uptake from intestinal lumen Side effects: diarrhea, headache, and less commonly myalgia and liver effects that should be monitored.

18. STATINS Actions independent of lipid lowering Endothelial function Coagulation Vascular inflammation Smooth muscle Plaque stability