1. Agents used in Hyperlipidemia

2. Objectives: To review the proposed role of lipoprotein in the formation of atherosclerotic plaques. To study various types of hyperlipidemia. To describe various strategies for the treatment of hyperlipidemia. To describe the four main classes of drugs used to treat hyperlipidemia, to understand their mechanisms of action, effects upon serum lipid concentrations and side effects.

3. Risk factors in artherosclerosis Hyperlipidemia Hypertension Cigaratte smoking Diabetes mellitus OTHER FACTORS: genetic background, diet, obesity, lack of exercise, stress, etc.

4. Introduction Cholesterol Needed for the synthesis of bile salts which are needed for digestion and absorption of fats. –Origin Is synthesized in the liver. Acetyl CoA is converted to mevalonic acid and ultimately to cholesterol by hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase.

5. Lipoproteins particles found in plasma that transport lipids including cholesterol lipoprotein classes chylomicrons: take lipids from small intestine through lymph cells very low density lipoproteins (VLDL) intermediate density lipoproteins (IDL) low density lipoproteins (LDL) high density lipoproteins (HDL)

6. Lipoprotein structure

7. LDL molecule

8. Introduction Lipoproteins –Serve as carriers for transporting lipids (cholesterol and triglycerides) in the blood. –Apolipoproteins Embedded in the lipoprotein shell Three functions –1. Serve as recognition sites for cell-surface receptors; allowing cells to bind and ingest the lipoprotein. –2. Activate enzymes that will metabolize the lipoprotein –3. ↑ structural stability of the lipoprotein

9. Introduction Lipoproteins –Apolipoproteins All lipoproteins that deliver lipids to peripheral tissues (nonhepatic tissues) contain apolipoprotein B-100 (Ex: VLDL, LDL) All lipoproteins that transport lipids from peripheral tissues back to the liver contain apolipoprotein A-I (Ex: HDL)

10. Introduction Lipoproteins –Lipoproteins of importance VLDL (very low density lipoprotein) –Contain triglycerides (TGs) and some cholesterol –Account for nearly all TGs in the blood –Contain B-100 –Deliver triglycerides from the liver to adipose tissues and muscles. TGs are hydrolyzed and removed by lipoprotein lipase. Results in free fatty acids for storage in adipose tissue or oxidation in cardiac tissue or skeletal muscle

11. Introduction Lipoproteins –Lipoproteins of importance VLDL (very low density lipoprotein) –Remnants of hydrolysis are IDL (intermediate density lipoproteins), which can be transported to liver or converted to LDL –High levels increases risk of pancreatitis

12. Introduction Lipoproteins –Lipoproteins of importance LDL (low density lipoprotein) –“ Bad cholesterol ” –Contain cholesterol –Account for 60-70% of cholesterol in the blood –Contains B-100 –Delivers cholesterol to peripheral tissues

13. Introduction Lipoproteins –Lipoproteins of importance LDL (low density lipoprotein) –Formed from IDL, the remnants of VLDL –Makes the greatest contribution to coronary atherosclerosis »Oxidized LDL contributes to atherosclerotic plaque –Removed from plasma via endocytosis by liver converting it to bile acids excreted in GI

14. Introduction Lipoproteins –Lipoproteins of importance HDL (high density lipoprotein) –“ Good cholesterol ” –Contain cholesterol –Account for 20-30% of cholesterol in the blood –Some contain Apo I and Apo II –Apo I is cardioprotective –Transports cholesterol from the peripheral tissues back to the liver – promotes cholesterol removal –Antiatherogenic

15. Introduction Mechanism of action for atherosclerotic plaque formation –LDL cholesterol moves into the subendothelial space of the artery –LDLs undergo oxidation –Once oxidized, the LDLs attract monocytes from the circulation inhibiting their motility –Monocytes are converted to macrophages which take up LDL cholesterol –The more cholesterol macrophages engulf, the larger they become. They are then referred to as “ foam cells. ”

16. Introduction Mechanism of action for atherosclerotic plaque formation –A fatty streak is produced in the arterial wall by accumulation of foam cells –Accumulation of foam cells can cause rupture of the endothelium causing platelet adhesion resulting in formation of microthrombi –Repeated rupture and healing process eventually results in plaque formation –As the plaque grows, it impedes blood flow resulting in anginal pain and ultimately an MI

17. Consequences of atherosclerotic plague (fibrous) Calcification Plaque rupture Hemorrhage into plaque Fragmentation Weakening of vessel wall  Rigidity of vessel wall Thrombosis Narrowing of lumen Emboli Aneurysm

18. Lipoprotein Metabolism and Artherosclerosis EXOGENOUS ENDOGENOUS DIETARY FAT INTESTINE CHYLOMICRONS LIVER Chylomicron remnants Cholesterol, Bile acids FFA Adipose tissue, Muscle VLDL IDL FFA LDL EXTRHEPATIC CELLS HDL Atherosclerotic plague LCAT LL

19. Genetic Types of Hyperlipidemias Type I  chylomicrons   serum triglycerides. Deficiency of lipoprotein lipase. It is not associated with an increased risk of coronary heart diseases. Treatment: Low fat diet. No drug therapy is effective for type I hyperlipidemia.

20. Genetic Types of Hyperlipidemias Type IIA  LDL + normal VLDL   serum cholesterol + normal TG Caused by  numbers LDL receptors (genetic predisposition).  risk of ischemic heart disease. Treatment: Low cholesterol and low saturated fat in the diet + drug therapy.

21. Genetic Types of Hyperlipidemias Type IIB  LDL +  VLDL   serum TG +  cholesterol. Caused by liver overproduction of VLDL. Treatment: Dietary restriction of cholesterol and saturated fat and alcohol + drug therapy.

22. Genetic Types of Hyperlipidemias Type III  serum IDL   serum TG +  cholesterol. Caused by mutation of apolipoprotein E gene  overproduction or underutilization of IDL.  risk of coronary and peripheral vascular disease. Treatment: Weight reduction (if necessary), dietary restriction of cholesterol and alcohol + drug therapy.

23. Genetic Types of Hyperlipidemias Type IV  VLDL + normal LDL   serum TG+ normal Cholesterol. Caused by overproduction or decreased removal of serum VLDL. Patients are frequently obese, diabetic, and hyperuricemic. Pregnant women and alcoholics. Treatment: Weight reduction (if necessary) is of primary importance. Dietary and alcohol restriction + drug therapy.

24. Genetic Types of Hyperlipidemias Type V  VLDL +  chylomicrons   cholesterol +  triglycerides. Caused by either increased production or decreased clearance of VLDL and chylomicrons (mixed type I and type IV). Occurs most commonly in adults who are obese and/or diabetic. Weight reduction (if necessary) is important. Diet should include protein, low fat and controlled carbohydrate, and no alcohol + drug therapy.

25. General Approach to the Management of Hyperlipidemia Secondary causes of hyperlipidemia (alcoholism, diabetes, uremia, the use of drugs such as  -blockers, oral contraceptives, thiazides) should be excluded before treatment is considered. Dietary modifications: low cholesterol, saturated fat and calories (hypercholesteremia), omega-3 fatty acids (hypertriglyceridemia). Drug therapy: only when patients do not respond to dietary modifications.

26. Guidelines for Drug Therapy Hypercholesterolemia: HMG-CoA reductase inhibitors, bile acid-binding resins. Hypercholesterolemia + hypertriglyceridemia: Fibric acid derivatives, niacin. Specialized purposes: probucol

27. Sites & Mechanisms of Drugs for Hyperlipidemia Bile acids Acetyl-CoA Cholesterol Proteins & TGs VLDL  IDL  LDL Bile acids Bile acid Binding resins LDL receptor Gemfibrozil & niacin HMG-CoA Reductase inhibitors Fatty acids  TGs LL Gut Liver Blood Adipose tissue Stimulated by gemfibrozil and niacin

28. A. HMG-CoA Reductase Inhibitors DrugOral Absorpt Routes of Eliminat. Eliminat. t1/2 (hrs) Other propert. Atorvastatin 12% Metabolism 14Active Fluvastatin 25% Metabolism <1Active Pravastatin 17% Metabolism 1.8Active Lovastatin 5% Metabolism 3.5Prodrug Simvastatin <5% Metabolism 3Prodrug

29. Inhibition of HMG-CoA Reductase C OH C CH 2 CoA CH 3 CH 2 C O O O HMG-CoA HMG-CoA reductase 2 NADPH + 2H + 2 NADP +  HMG-CoA reductase inhibitors C CH 2 OH OH CH 2 CH 3 C O O CH 2 Mevalonic Acid Cholesterol CoA

30. Mechanism of action (HMG-CoA reductase inhibitors Mechanism of action (HMG-CoA reductase inhibitors ) Inhibition of HMG-CoA reductase. Increase in LDL receptors.

31. Therapeutic uses (HMG-CoA reductase inhibitors) Lowering plasma cholesterol levels in all types of hyperlipidemias (  cardiac disease-related mortality rate by 42%). Homozygotes familial hypercholesterolemia usually lack LDL receptors, hence benefit less from treatment with these drugs. Often given in combination with other antihyperlipidemic drugs. Effective in addition to other measurements such as diet and exercise.

32. Adverse effects (HMG-CoA reductase inhibitors) Liver: Biochemical abnormalities in liver function. Serum transaminase levels should be measured periodically. Muscle: Myopathy and rhabdomyolsis. Serum creatine kinase （ CK ） levels should be determined. Increased coumarin levels. Contraindicated in pregnancy and nursing mothers. Should not be used in children.

33. B. Bile acid binding resins (cholestyramine, colestipol) Pharmacokinetics and chemistry: They are large molecular weight polymers containing a chloride ion that can be exchanged for bile acids in the gut. They are not absorbed from the gut and are excreted in the feces. Especially valuable for patients who can not tolerate other antihyperlipidemic drugs. Suitable for young patients, may need to take the drug therapy for a long time.

34. Mechanism of Bile Acid Binding Resins Small Intestine Small Intestine Bile acids & salts Insoluble complex Cholesterol  Bile acids Cholesterol  Bile acids A Feces B Liver

35. B. Bile acid binding resins (cholestyramine, colestipol) Mechanisms and pharmacological effects: Bile acids + resins  resin/bile acids complex, excreted in the feces   enterohepatic circulation of bile acids. This action causes hepatocytes to increase conversion cholesterol  bile acids   LDL receptors   serum LDL cholesterol. The final outcome of this events is a decreased total plasma cholesterol concentration.

36. B. Bile acid binding resins (cholestyramine, colestipol) Therapeutic uses: They are the drugs of choice (in combination with diet or niacin) in treating type IIA and IIB hyperlipidemias. In diarrhea caused by excessive bile acid secretion. To relieve pruritus caused by accumulation of bile acids in patients with biliary obstruction.

37. B. Bile acid binding resins (cholestyramine, colestipol) Adverse effects: GI disturbances: constipation, nausea, and flatulence. Impaired absorption of other drugs such as vitamin A, D, E, and K. Absorption of folic acid and ascorbic acid may also be reduced. These drugs should be taken at least 2 hours prior or after taking other medications.

38. C. Fibric acid derivatives (clofibrate, gemfibrozil) Pharmacokinetics: Completely absorbed after oral administration. Gemfibrozil binds extensively to albumin and distributes in body tissues. Gemfibrozil undergoes extensive biotransformation and excreted in urine as glucuronide conjugates.

39. Activation of lipoprotein lipase VLDL Chylomicron remnants IDL Lipoprotein lipase Free fatty acids Clofibrate Gemfibrozil   Capillaries Adipose tissue

40. C. Fibric acid derivatives (clofibrate, gemfibrozil) Mechanisms and pharmacological effects: Activate lipoprotein lipase  promote the delivery of triglycerides to adipose tissue. Interfere with formation of VLDL in the liver. Both effects   serum VLDL and triglycerides +  HDL cholesterol level.

41. C. Fibric acid derivatives (clofibrate, gemfibrozil) Therapeutic uses: For the treatment of hypertriglyceridemia (type IV and V). Useful in patients with mixed hyperlipidemia (type IIB). To increase HDL cholesterol levels in patients with HDL deficiency.

42. C. Fibric acid derivatives (clofibrate, gemfibrozil) Adverse effects and interactions: GI effects: Mild disturbances. Muscle: Myopathy and rhabdomyolysis Should be avoided with the use of HMG- CoA inhibitors.

43. D. Miscellaneous drugs and natural products: Niacin Pharmacokinetics: Niacin is a vitamin (nicotinic acid), well absorbed from the gut and is extensively metabolized.

44. Lipolysis inhibition by Niacin Triglycerol  Fatty acids  Triglycerol  VLDL LDL Niacin ADIPOSE TISSUE LIVER

45. D. Miscellaneous drugs and natural products: Niacin Mechanisms and pharmacological effects: Several grams of the compound is required each day. Strongly inhibits lipolysis in adipose tissue   liver triglyceride synthesis   VLDL level   LDL level. Significantly  HDL level.

46. D. Miscellaneous drugs and natural products: Niacin Therapeutic uses: Most effective single drug in the treatment of mixed hyperlipidemia (type IIB) and hyperlipoproteinemia (type IV), in which both VLDL and LDL are elevated. It is the most potent antihyperlipidemic agent for raising plasma HDL levels.

47. D. Miscellaneous drugs and natural products: Niacin Adverse effects: Intense cutaneous flush (feeling of warmth) and pruritus. Pretreatment with aspirin. Hyperuricemia Impaired glucose tolerance and hepatotoxicity. Gastric disturbances and may activate peptic ulcer.

48. D. Miscellaneous drugs and natural products: Probucol Pharmacokinetics: It is a lipophilic drug with a variable rate of absorption. It carried in the LDL particles and accumulates in the adipose tissues where it may persist for months. Eliminated in the bile.

49. Oxidation of Lipoprotein Microphage LDL oxLDL Foam cell  Probucol Vitamin E Ascorbic a  -Carotene Other anti- oxidants Calcification of plaque

50. D. Miscellaneous drugs and natural products: Probucol Mechanism and pharmacological effects: It inhibits the oxidation of LDL   the development of artherosclerosis. Useful in the treatment of Type IIA and IIB hypercholesterolemia. It’s usefulness is limited to instances in which other antihyperlipidemic agents are ineffective.

51. F. Drug Combinations Drugs may be used in combination to treat hyperlipidemia in patients who do not respond to a single drug therapy, e.g., diet vs. combined therapy. The safest combinations are those consisting of a bile acid-binding resin and either an HMG-CoA reductase inhibitor, niacin, or gemfibrozil.