2. Learning Objectives How does hyperlipemia differ from hyperlipoproteinemia? What are the atherogenic lipoproteins? Describe the major characteristics of: (a) chylomicrons, (b) very low density lipoproteins or VLDL, (c) low-density lipoproteins or LDL, and (d) high-density lipoproteins or HDL. What are the primary hypertriglyceridemias and how do they differ from each other? What are the most common causes of secondary hyperlipoproteinemia? What dietary measures should be initiated before using drugs for treatment of hyperlipoproteinemia?

3. 1. Niacin (nicotinic acid) What is niacin and how it is excreted? How does it lower plasma VLDL and LDL and in what forms of hyperlipidemia is it most effective? What are its common toxic effects? 2. Fenofibrate What is fenofibrate and how does it affect the various plasma lipoproteins? How is it metabolized and excreted? What is its mechanism of action and in what forms of hyperlipidemia is it most effective? What are its common toxic effects? 3. Gemfibrozil What is gemfibrozil and how does it differ from fenofibrate? How does it affect the various plasma lipoproteins? How is it metabolized and excreted? What is its mechanism of action and in what forms of hyperlipidemia is it most effective? What are its common toxic effects?

4. 4. Bile acid-binding resins (colesevelam, colestipol and cholestyramine) What are colesevelam, colestipol and cholestyramine and how do they affect the various plasma lipoproteins? What is their mechanism of action and in what forms of hyperlipidemia are they most effective? What are their common toxic effects? 5. Lovastatin, atorvastatin, fluvastatin, simvastatin, pravastatin, and rosuvastatin What are the HMG-CoA Reductase Inhibitors and how do they affect the various plasma lipoproteins? What is their mechanism of action and in what forms of hyperlipidemia are they most effective? What are their common toxic effects? 6. Ezetimibe How does it work? What are its adverse effects?

5. BLOOD LIPIDS BLOOD LIPIDS  Main blood lipids, cholesterol and triglyceride have to be packaged into lipoprotein balls for transport in blood or they would just float to the top like fat in chicken soup.  Lipids are transported as macromolecular particles called lipoproteins; hyperlipidemia is a metabolic disorder with increased levels of lipoproteins while hyperlipemia refers to an increased plasma triglyceride level.  Hypolipidemic drugs are increasingly important because hyperlipidemia is a major risk factor for atherosclerosis and atherosclerosis is now a leading cause of death in all Western countries.  Lipids are transported into arterial walls by lipoproteins which include: Low-density (LDL) Low-density (LDL) Intermediate-density (IDL) Very low-density (VLDL) High-density (HDL) High-density (HDL) Lipoprotein (a) (Lp(a))

6. Lipoprotein Structure  Lipoproteins are microscopic spherical particles, 7-100 nm in diameter; each particle includes: Lipid membrane containing free cholesterol and phospholipids arranged in a monolayer Hydrophobic core containing: Cholesteryl esters (cholesterol molecule linked to a fatty acid) Triglycerides (glycerol molecule linked to three fatty acids)  Apolipoproteins (high-molecular weight protein molecules) are integrated into the lipid membrane in two forms: B100 in VLDL, IDL, LDL, and Lp(a) lipoproteins B48 in chylomicrons and their remnants lipoprotein particle

7. Lipoprotein classes and functions [1] Chylomicrons and chylomicron remnants – for dietary lipid absorption and delivery to muscle and fat tissue [2] VLDL, IDL, and LDL – for lipid production and transport HDL [3] HDL –transfers cholesterol and apolipoproteins among different lipoprotein subclasses and to the liver

8.  Lipoprotein names originate from layer location after centrifugation  Heaviest layer at the bottom and lightest at the top  Heavier or lower layers contain more protein and less fat  Lighter or upper layers contain more fat

9. CHYLOMICRONS AND FAT ABSORPTION 20% of the body’s cholesterol comes from food:  From which cholesteryl esters and triglycerides are hydrolyzed to form cholesterol and fatty acids   Cholesterol and fatty acids are solubilized by bile salts and phospholipids secreted into the small intestine   Solubilized cholesterol and fatty acids are absorbed by enterocytes in the duodenum and proximal jejunum   Long-chain fatty acids in enterocytes form chylomicrons   Chylomicrons secreted into lymph, thoracic duct, and veins   Triglycerides from circulating chylomicrons are hydrolyzed by lipoprotein lipase in adipose and muscle tissues   Chylomicron remnants are formed and removed by binding apoE to hepatic LDL receptors

10. ENDOGENOUS LIPOPROTEINS  Endogenous lipoproteins synthesized in the liver transport fatty acids and cholesterol to peripheral tissues  Hepatic synthesis accounts for 80% of the body’s cholesterol  Hepatic synthesis is affected by dietary fat intake because increased fat intake delivers more fatty acids to the liver  After a fatty meal, Hepatocytes initiate triglycerides & cholesterol synthesis  Triglycerides and cholesterol fused with apolipoprotein B 100 to form mature VLDL that is secreted into blood  Lipoprotein lipase in muscle/adipose tissues removes triglyceride core of VLDL to form remnants IDL and LDL  LDL is removed by liver (LDL receptors) and macrophages

11. ENDOGENOUS LIPOPROTEINS (“bad cholesterol”)  LDL (“bad cholesterol”) makes up 65-75% of total plasma cholesterol  Elevated LDL is a major risk factor for atherosclerosis LDL that is not taken up by hepatic LDL receptors migrates into vascular intima to be taken up by scavenger receptors on phagocytic cells Oxidized LDL accumulates in foam cells (“good cholesterol”)  HDL (“good cholesterol”) synthesized by liver and intestine draws free cholesterol from cholesterol-rich cells  To be esterified by lecithin:cholesterol acyl transferase (LCAT)  Forming larger hydrophobic core of cholesteryl esters in HDL  HDL transfers cholesteryl esters to VLDL, IDL, LDL and chylomicrons  HDL decreases the amount of cholesterol available for tissue deposition by removing it from macrophages and promoting its return to the liver inversely  Plasma HDL level is inversely related to risk of cardiovascular disease

13. Metabolism of Lipoproteins of Hepatic Origin

14. LIPOPROTEIN DISORDERS  Primary Hypertriglyceridemias and  Primary Hypercholesterolemias Increase the risk of CAD  Secondary Hyperlipoproteinemias should be ruled out before primary disorders can be diagnosed

15. Treatment Guidelines Table 35–1 National Cholesterol Education Program: Adult Treatment Guidelines (2001). Desirable Borderline to High High Total cholesterol < 200 200–239 > 240 LDL cholesterol < 130 130–159> 160 HDL cholesterol > 60 Men> 40 Women> 50 Triglycerides< 120120–199> 200

16. HYPOLIPIDEMIC DRUGS atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin I. HMG-CoA Reductase Inhibitors (“Statins”): atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin III. Fibric Acid Derivatives: gemfibrozil (3) and fenofibrate Nicotinic Acid II. Niacin (2) (Nicotinic Acid, vitamin B3) IV. Bile Acid-Binding Resins: colestipol (5), cholestyramine (4), colesevelam V. Intestinal Sterol Absorption Inhibitor: ezetimibe (6) VI. Intestinal pancreatic lipase Inhibitor: Orlistat (7) Memorize ‘lovastatin’(1) identify others with common endings as ‘statin’

17. HMG-CoA  Structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase which is the intermediate formed during mevalonate synthesis inhibiting HMG-CoA reductase  All statins act by inhibiting HMG-CoA reductase to: Reducecholesterol [1] Reduce hepatic formation of cholesterol Increase high-affinity LDL [2] Increase high-affinity LDL receptors in liver cells to lower plasma LDL  Also decrease plasma triglycerides and increase HDL cholesterol  Lovastatin and simvastatin are prodrugs  Lovastatin and simvastatin are prodrugs while atorvastatin, fluvastatin, pravastatin, and rosuvastatin are active congeners  GI absorption is almost complete for fluvastatin and varies from 40-75% for the others; all have high first-pass hepatic extraction and mostly excreted in bile HMG-CoA Reductase Inhibitors (“Statins”) NBME

18. Mechanism of Action on Cholesterol inhibition of HMG CoA reductase  Act by competitive inhibition of HMG CoA reductase which catalyzes cholesterol synthesis   Decreased cholesterol in hepatocytes causes cleavage of sterol regulatory element binding protein (SREBP), a cytoplasmic transcription factor  up-regulation of the LDL- receptor  SREBP diffuses into the nucleus to bind to sterol response elements (SRE) and cause up-regulation of the LDL- receptor  increases plasma LDL clearance  Increased LDL-R expression results in increases plasma LDL clearance and reduces circulating LDL levels NBME

19. Claimed Pleiotropic Statin Effects  Reversal of endothelial dysfunction – improved vasodilatory response to NO  Decreased inflammation – decrease in inflammatory plasma proteins  Decreased coagulation – decreases in prothrombin activation and in endothelial cell tissue factor production  Improved plaque stability – thicker fibrous cap on plaques (prevents uptake of cholesterol by endothelial macrophages) NBME

20. Therapeutic Uses of Statins  Useful for lowering plasma LDL  Useful for lowering plasma LDL given alone or in combination with resins, niacin, or ezetimibe  Now first-line therapy for elevated LDL levels  Significantly reduce mortality from myocardial infarction and in CVD patients at high risk night  Best given at night when most of cholesterol synthesis occurs  Absorption enhanced when taken with food  Usual daily doses vary from 10-80 mg pregnant or lactating women  Statin safety has not been established in pregnant or lactating women NBME

21. Statin Toxicity: Hepatic serum aminotransaminase  Indicated by elevations in serum aminotransaminase  Manifested as malaise, anorexia, and precipitous fall in LDL liver disease or alcoholism  More pronounced in patients with liver disease or alcoholism  Atorvastatin, lovastatin, and simvastatin cytochrome P450 3A4  Atorvastatin, lovastatin, and simvastatin are catabolized mainly by cytochrome P450 3A4 increased macrolide antibiotics, cyclosporine, ketoconazole, fibrates, etc; or grapefruit juice [1] Concentrations increased by drugs that inhibit P450 3A4 (macrolide antibiotics, cyclosporine, ketoconazole, fibrates, etc; or grapefruit juice 1 liter daily) reduced barbiturates, phenytoin, rifampin, “glitazones”, etc [2] Concentrations reduced by drugs that increase expression of P450 3A4 (barbiturates, phenytoin, rifampin, “glitazones”, etc)  Fluvastatin and rosuvastatin ncreased ketoconazole, metronidazole, sulfinpyrazone, amiodarone, and cimetidine  Fluvastatin and rosuvastatin are catabolized mainly by CYP2C9; plasma concentrations may be increased by drugs that inhibit CYP2C9 like ketoconazole, metronidazole, sulfinpyrazone, amiodarone, and cimetidine  Pravastatin  Pravastatin is not metabolized by P450 and is preferred whenever concurrent treatment with other drugs is required NBME

22. STATIN TOXICITY: skeletal muscles creatine kinase  Increased creatine kinase activity indicates skeletal muscle toxicity occurring as rhabdomyolysis (generalized skeletal muscle pain, tenderness, or weakness)  Measure serum aminotransferase and creatine kinase before treatment and every 6-12 months thereafter NBME

23. Niacin (Nicotinic Acid, vitamin B3)  Water-soluble vitamin converted to the amide, incorporated into niacinamide adenine dinucleotide (NAD) and excreted in urine  Large doses (1.5-3 g/day) required lipase activity  Decreases lipase activity in adipose tissues  Reduce free fatty acid flux to the liver  Decrease hepatic synthesis of triglycerides and VLDL  Lower plasma LDL and triglycerides Lower plasma LDL and triglycerides elevate plasma HDL  Also increases apoAI to elevate plasma HDL  Currently the most effective drug for elevating HDL NBME

24. Niacin  Therapeutic Uses Drug of choice for patients with elevated LDL and lowered HDL Normalizes LDL when combined with resin or statin for Treatment of heterozygous familial hypercholesterolemia and other hypercholesterolemias Also effective in: Familial combined hyper­lipoproteinemia, Familial dysbetalipoproteinemia  Toxicity cutaneous vasodilation aspirin Most common toxic effect is cutaneous vasodilation with warm sensation (reduced by taking with aspirin) Pruritus, rashes, dry skin, nausea, and abdominal discomfort May elevate aminotransferases but true hepatotoxicity is rare Glucose tolerance Glucose tolerance may be impaired hyperuricemia May cause hyperuricemia and gout NBME

25. Fibric Acid Derivatives  Fenofibrate and gemfibrozil PPAR-   Fenofibrate and gemfibrozil act as ligands for the nuclear transcription factor PPAR-  (peroxisome proliferator- activated receptor-alpha) in hepatocytes triglycerides  Activation of hepatic PPAR-  decreases plasma triglycerides, VLDL, and LDL, and increases plasma HDL  Used for treatment of hypertriglyceridemia and dysbetalipoproteinemia  Toxic effects rare but may include skin rashes, GI symptoms, myopathy, arrhythmias, hypokalemia, and increases in aminotransferases or alkaline phosphokinase, Decreases in white blood count or hematocrit warfarin Potentiate anticoagulants; warfarin Rarely rhabdomyolysis incidence of gallstones Increased incidence of gallstones NBME

26. Gall stone during Gemfibrozil therapy Skin necrosis caused by therapeutic dose of Warfarin concomitantly give with Gemfibrozil

27. Bile Acid-Binding Resins  Colestipol, cholestyramine, colesevelam bind bile acids  Colestipol, cholestyramine, colesevelam are large cationic exchange resins, insoluble in water, that bind bile acids to prevent their intestinal absorption and increase excretion  Upregulate 7  -hydroxylase the hepatic enzyme that catalyzes synthesis of bile acids from cholesterol  Increased bile acid synthesis reduces the amount of hepatic cholesterol  Reduction in hepatic cholesterol increases LDL receptors  Enhances removal of LDL from the circulation  Lowers plasma LDL and elevates plasma HDL NBME

28. Bile Acid-Binding Resins  Therapeutic Uses: Treatment of primary hypercholesterolemia May be used for treating digoxin toxicity because they bind digoxin  Toxicity No significant systemic effects because they are not absorbed Have an unpleasant sandy or gritty quality Heartburn and diarrhea reported occasionally Bloating and constipation Bloating and constipation occur due to decreased fat absorption hypoprothrombinemia Cause hypoprothrombinemia due to vitamin K malabsorption Steatorrhea in patients with bowel disease or cholestasis Gallstone formation enhanced in obese patients digoxin, thiazides, tetracycline, fluvastatin, thyroxine, or aspirin (small,lipid soluble drugs) May impair absorption of certain drugs like digoxin, thiazides, tetracycline, fluvastatin, thyroxine, or aspirin (small,lipid soluble drugs) NBME

29. INTESTINAL STEROL ABSORPTION INHIBITOR: Ezetimibe absorption of cholesterol  Inhibits intestinal absorption of cholesterol and phytosterols  Reduces plasma LDL & minimal increase in HDL  Effective even when there is no dietary cholesterol because it inhibits absorption of cholesterol excreted in bile  Therapeutic Uses For treatment of primary hypercholesterolemia Single daily dose of 10 mg reduces LDL by 18%  Toxicity Low incidence of reversible hepatic impairment NBME

30. FDA Communication The U.S. Food and Drug Administration (FDA) has communicated that to date no advantage has been found by using the ezetimibe/simvastatin combination, even though it lowered LDL cholesterol more effectively compared to simvastatin alone, there was no difference seen in mean change in carotid intima-media thickness; adverse events were similar between both groups.

31. DRUG COMBINATIONS Are useful when: [1] VLDL levels increase during resin therapy of hypercholesterolemia [2] VLDL and LDL are both elevated [3] VLDL or LDL levels are not normalized by a single drug [4] Elevated Lp(a) or HDL deficiency occurs with other hyperlipidemias

32. SUMMARY of HYPOLIPIDEMIC DRUGS DRUG CLASS MechanismLipid Effect I. Statins Inhibit HMG-CoA  LDL, triglycerides;  HDL II. NiacinDecrease adipose lipase activity  LDL, triglycerides;  HDL III. Fibric AcidActivate hepatic PPAR-   triglycerides, LDL;  HDL IV. Bile ResinsPrevent bile acid absorption  LDL V. EzetimibeInhibit intestinal cholesterol absorption  LDL NBME

33. A 40-year-old diabetic woman has a fasting serum levels (mg/dL) of: total cholesterol 300 (desirable 40), and triglycerides 250 (desirable <150). Which of the following would lower cholesterol by binding bile acids in this patient? A) Atorvastatin B) Niacin C) Fenofibrate D) Gemfibrozil E) Colesevelam. Ans = E Colesvelem, cholestyramine, & colestipol are bile acid binding resins

34. Absorption Drug interactions Liver Skeletal muscle PPAR α Gall bladder disease flushing Cholesterolabsorption

35. Now answer following Qs before you practicing MCQs How does hyperlipemia differ from hyperlipoproteinemia? What are the atherogenic lipoproteins? Describe the major characteristics of: (a) chylomicrons, (b) very low density lipoproteins or VLDL, (c) low-density lipoproteins or LDL, and (d) high-density lipoproteins or HDL. What are the primary hypercholesterolemias and how do they differ from each other? What are the most common causes of secondary hyperlipoproteinemia? What dietary measures should be initiated before using drugs for treatment of hyperlipoproteinemia?

36. 1. Niacin (nicotinic acid) What is niacin and how it is excreted? How does it lower plasma VLDL and LDL and in what forms of hyperlipidemia is it most effective? What are its common toxic effects? 2. Fenofibrate What is fenofibrate and how does it affect the various plasma lipoproteins? How is it metabolized and excreted? What is its mechanism of action and in what forms of hyperlipidemia is it most effective? What are its common toxic effects? 3. Gemfibrozil What is gemfibrozil and how does it differ from fenofibrate? How does it affect the various plasma lipoproteins? How is it metabolized and excreted? What is its mechanism of action and in what forms of hyperlipidemia is it most effective? What are its common toxic effects?

37. 4. Bile acid-binding resins (colesevelam, colestipol and cholestyramine) What are colesevelam, colestipol and cholestyramine and how do they affect the various plasma lipoproteins? What is their mechanism of action and in what forms of hyperlipidemia are they most effective? What are their common toxic effects? 5. Lovastatin, atorvastatin, fluvastatin, simvastatin, pravastatin, and rosuvastatin What are the HMG-CoA Reductase Inhibitors and how do they affect the various plasma lipoproteins? What is their mechanism of action and in what forms of hyperlipidemia are they most effective? What are their common toxic effects? 6. Ezetimibe How does it work? What are its adverse effects?

38. Which of the following would reduce serum triglycerides and VLDL levels, reduce hepatic production of apolipoprotein CIII and induce lipoprotein lipase activity via activation of a peroxisome proliferator activator receptor (PPAR α ) in a 56-year-old man with hypertriglyceridemia and hyperliproteinemia? A. Cholestyramine B. Ezetimbe C. Gemfibrozil D. Lovastatin E. Niacin Answer: C Fenofibrate or Gemfibrozil; good for lowering triglycerides

39. A 63-year-old man with congestive heart failure and hypercholesterolemia develops muscle pain and weakness and has a creatine kinase level of 210 U/L (normal = 10 – 70) after he begins pharmacotherapy. Which of the following is most likely responsible for these findings in this patient? A. Atorvastatin B. Digoxin C. Enalapril D. Gemfibrozil E. Niacin Answer: A Stains noted for elevating liver & muscle enzymes