DRUGS for DYSLIPIDEMIAS MED PHARM 2/22/2010

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%

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

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

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

Figure 1. General structure of a lipoprotein.

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).

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).

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

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

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

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)

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

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)

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

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.

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