Hyperlipidemia Hyperlipoproteinemia Hyperlipoproteinemia (cholesterol, Triglyceride, LDL-C, VLDL) Lead to atherosclerosis and Coronary artery disease (CAD) Lead to atherosclerosis and Coronary artery disease (CAD)

Hyperlipidemia Endothelial injury Thrombosis Atherosclerosis Smooth muscle cell proliferation Macrophage inflammatory/immunologic mechanism

Atherosclerosis Atherosclerosis is a disease which characterized by intimal thickening and lipid deposition. Atherosclerosis is a disease which characterized by intimal thickening and lipid deposition. Definition

Atherosclerosis

Hypolipidemic drugs  Bile Acid Sequestering resins  HMG CoA Reductase Inhibitors  Fibric Acid Derivatives  Nicotinic Acid (Niacin)  Probucol

CE= cholesteryl ester

Colestyramine, colestipol Mechanism of action Binds to bile acid in intestine and prevents its transformation into cholesterol

C l i n i c a l u s e s: ** hypercholesterolemia when a statin is contraindicated ** uses unrelated to atherosclerosis, including: pruritus in patients with partial biliary obstruction (bile acids that deposit into the skin is responsible for the pruritus)

A d v e r s e e f f e c t s : GIT symptoms - nauzea, abdominal bloating,نفخ constipation or diarrhea, because resins not absorbed. resins are unappetizing. This can be minimized by suspending them in fruit juice interfere with the absorption of fat-soluble vitamins and drugs (chlorothiazide, digoxin, warfarin) These drugs should be given at last 1 hour before or 4-6 hours after resin

Effect on Lipids LDL  20-30% HDL  2-8% TG  10% (Esp.TG>250mg/dl )

2. HMG CoA Reductase Inhibitors (Statin) lovastatin atorvastatin pravastatin simvastatin Fluvastatin Rosuvastatin

Mechanism of Statin Specific competitive inhibitor to HMG CoA Reductase Enzyme which is the rate limiting step in cholesterol biosynthesis Specific competitive inhibitor to HMG CoA Reductase Enzyme which is the rate limiting step in cholesterol biosynthesis

The synergism effect of statin and resin

Effect on Lipids LDL  25-55% HDL  5-10% TG  10-20% (triglycerides < 250 mg/dl)  35-45% (triglycerides > 250 mg/dl)

A d v e r s e e f f e c t s - mild gastrointestinal disturbances - increased plasma activities in liver enzymes - severe myositis (rhabdomyolysis) and angio-oedema (rare) and angio-oedema (rare)

Clinical Use Hyperlipidemia In atherosclerosis

3. Fibric acid derivatives (fibrates) 3. Fibric acid derivatives (fibrates) Clofibrate gemfibrozil fenofibrate bezafibrate ciprofibrate

Mechanism of action - - increase the activity of lipoprotein lipase, - - increase the activity of lipoprotein lipase, hence increasing hydrolysis of triglyceride in chylomicrons and VLDL particles. hence increasing hydrolysis of triglyceride in chylomicrons and VLDL particles. - reduce hepatic VLDL production and increase hepatic LDL uptake. - Produce a modest decrease in LDL (~ 10%) and increase in HDL (~ 10%). - But, a marked decrease in TGs (~ 30%).

Effect on Lipids TG TG  25-40%  25-40% HDL HDL  5-15% LDL LDL  15-20%

Toxicity GI nausea., vomiting, gall stone nausea., vomiting, gall stone Skeletal Muscle Myopathy, weakness (Esp. with Statins) Myopathy, weakness (Esp. with Statins)Liver Increase aminotransferase Increase aminotransferase Hematologic change Anemia, leukopenia Anemia, leukopenia

Uses: 1st-line defense for: *mixed dyslipidemia (i.e. raised serum TG and CHO) * patients with low HDL and high risk of atheromatous disease (often type 2 diabetic patients) * patients with severe treatment- resistant dyslipidemia (combination with other lipid-lowering drugs). * Indicated in patients with VERY HIGH [TG]s who are at risk for pancreatitis

nicotinic acid (vitamin B3) Water soluble vitamin Nicotinic acid acts by decreasing esterification of hepatic TG, and increasing the activity of lipoprotein lipase. Nicotinic acid acts by decreasing esterification of hepatic TG, and increasing the activity of lipoprotein lipase. It decreases hepatic TG production and VLDL Secretion (by ~ 30-50%) It decreases hepatic TG production and VLDL Secretion (by ~ 30-50%) modest reduction in LDL and increase in HDL. Nicotinic acid was the 1st lipid- lowering drug to decrease mortality in patients with CAD. modest reduction in LDL and increase in HDL. Nicotinic acid was the 1st lipid- lowering drug to decrease mortality in patients with CAD. A d v e r s e e f f e c t s: A d v e r s e e f f e c t s: flushing, palpitations, GIT disturbances. flushing, palpitations, GIT disturbances. Currently, nicotinic acid is rarely used. Currently, nicotinic acid is rarely used.

Other Other LIPID-LOWERING DRUGS Fish oil (rich in highly unsaturated fatty acids) the omega-3 marine TG - reduce plasma TG but increase CHO (CHO is more strongly associated wih coronary artery disease) -the effects on cardiac morbidity or mortality is unproven ( although there is epidemiological evidence that eating fish regularly does reduce ischemic heart disease)

Ezetimibe: Inhibitors of Intestinal CHO Absorption: Reduces CHO absorption and decreases LDL with little change in HDL May be synergistic with statins: so good for combination therapy.

A potent lipophilic antioxidant A potent lipophilic antioxidant Probucol

A t h e r o g e n e s i s involves several stages: - endothelial dysfunction with altered PGI 2 and NO synthesis -endothelial cells monocyte attachment - bind LDL - oxidatively modified LDL is taken up by macrophages - having taken up oxidised LDL, these macrophages (now foam cells) migrate subendothelially - atheromatous plaque formation - rupture of the plaque

HDL Prevent Foam Cell Formation LDL LDL Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines Intima HDL Promote Cholesterol Efflux Foam Cell