antilipemic agents

1. Antilipemic Agents Heather L. Kappeler, Pharm.D.

3. Introduction Cholesterol Advantages Is deposited in the stratum corneum of the skin to help ? evaporation of water and create impermeability to water soluble compounds (helps keep moisture in skin) 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.

4. Introduction Cholesterol Origin Endogenous synthesis of cholesterol increases at night An increase in dietary cholesterol produces only a small ? in blood levels of cholesterol because ingestion inhibits endogenous synthesis Dietary saturated fats ? blood cholesterol levels because they are converted to cholesterol in the body.

5. 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

6. 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)

7. 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

8. 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 �Beta Shift� � clinical phenomenon of ? levels of LDL in plasma after hypertriglyceridemia High levels increases risk of pancreatitis

9. 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

10. 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

11. 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

12. 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.�

13. 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

14. Introduction Coronary artery disease (CAD) Risk factors of CAD HTN, smoking, diabetes, age over 50, low HDL, family HX, and (obesity, sedentary lifestyle) Individuals without CAD Want total cholesterol < 200 mg/dl, HDL > 35 mg/dl, and LDL < 130 mg/dl Individuals with CAD Want LDL < 100 mg/dl

15. Treatment of hyperlipidemia Treatment (tx) Non-Pharmacological Therapy � 1st line tx 1. Diet modification Decrease intake of total fat and especially saturated fat Increase fiber intake Increase Omega-3-fatty acids (found in fish) ? homocysteine ? fruits and vegetables (antioxidants) ? simple sugars (sucrose) Moderate alcohol consumption (EtOH can ? TG)

16. Treatment of hyperlipidemia Treatment Non-Pharmacological Therapy � 1st line tx 2. Exercise (will ? HDL levels) 3. Reduce risk factors if possible Drug Therapy Niacin (Nicotinic acid, niaspan�, slo-niacin, vitamin B3) Decreases VLDL and LDL and significantly ? HDL MOA 1. Inhibits VLDL secretion into the blood thereby preventing production of LDL 2. Increases clearance of VLDL via lipoprotein lipase pathway

17. Antilipemic agents Treatment Drug Therapy Niacin MOA 3. Inhibits FFA release from adipose tissues by inhibiting the intracellular lipase system 4. Reduces circulating fibrinogen (contributes to clot formation) and ? tissue plasminogen activator (clot dissolver) 5. HDL catabolic rate is decreased 6. Reduces the plasma level of Lp(a) lipoprotein, which can increase risk of CAD

18. Antilipemic agents Treatment Drug Therapy Niacin Indications DOC for ? levels of TG (VLDL) in pts at risk for pancreatitis Mixed elevation of LDL and VLDL (alone or in combination with reductase inh.) Elevation of TG (VLDL) and low levels of HDL (Niaspan� - approved for elevating HDL levels) Start with low dose and gradually increase Given 1-3g/day in divided doses or once daily with extended release. Give at night with food.

19. Antilipemic agents Treatment Drug Therapy Niacin - Adverse effects Flushing Harmless cutaneous vasodilation Uncomfortable sensation of warmth Occurs after drug is started or ? dose Lasts for the first several weeks Can give 325mg aspirin 30 minutes before each dose (prevents prostaglandin synthesis). Can also take ibuprofen QD in place of ASA

20. Antilipemic agents Treatment Drug Therapy Niacin - Adverse effects Pruritis, rashes, dry skin acanthosis nigricans (eruption of velvet warty benign growths and hyperpigmentation) Associated with insulin resistance Will have to d/c drug if occurs Nausea and abdominal discomfort Reduce dosage and may need to use inhibitors of gastric acid secretion or antacids (not containing aluminum) Avoid in pts with severe peptic disease

21. Antilipemic agents Treatment Drug Therapy Niacin - Adverse effects Hepatotoxicity Severe is rare, and reversible Occurs mostly with older sustained release forms Monitor liver fx regularly Liver injury is less likely with Niaspan� (given once daily) the new extended release formulation Carbohydrate tolerance may be moderately impaired (hyperglycemia) Reversible Can still be given to diabetics receiving insulin

22. Antilipemic agents Treatment Drug Therapy Niacin - Adverse effects Hyperuricemia Occurs in about 1/5 of pts Occasionally precipitates gout Hypotension Especially seen in pts on antihypertensive meds Can ? homocysteine levels which ? risk of CAD (give folic acid to ? homocysteine levels)

23. Antilipemic agents Treatment Drug Therapy Fibrates (gemfibrozil [Lopid�], fenofibrate [Tricor�], clofibrate [Atromid-S�], bezafibrate) Little or no effect on LDL ? VLDL (TG) moderate ? of HDL MOA Ligand for the nuclear transcription regulator, peroxisome proliferator-activated receptor-a (PPAR- a) MOA mostly unknown

24. Antilipemic agents Treatment Drug Therapy Fibrates MOA ? activity of lipoprotein lipase for lipolysis of triglyceride (? clearance) ? lipolysis in adipose tissue, ? FFA release ? secretion of VLDL by liver ? uptake of FFA by liver ? HDL levels moderately

25. Antilipemic agents Treatment Drug Therapy Fibrates Indication: Hypertriglyceridemia Gemfibrozil � 600mg QD-BID (half life 1.5hrs) Fenofibrate � 1-3 67mg tablets QD (half life 20hrs) Taken with food - ? absorption Max reduction of VLDL is achieved within 3-4 weeks of treatment Adverse Effects Rashes GI disturbances (nausea, abdominal pain, diarrhea)

26. Antilipemic agents Treatment Drug Therapy Fibrates - Adverse Effects Gallstones (upper abdominal discomfort, intolerance of fried food, bloating) Gemfibrozil ? biliary cholesterol saturation Use with caution in pts with biliary tract ds, women, obese pts, and Native Americans Myopathy (muscle injury) Tenderness, weakness, or unusual muscle pain Will increase risk of statin-induced myopathy when used together (rhabdomyolysis has occurred rarely)

27. Antilipemic agents Treatment Drug Therapy Fibrates - Adverse Effects Hepatoxicity Arrythmias Hypokalemia Displaces warfarin from plasma albumin since drug is highly protein bound. Need to ? warfarin dose

28. Antilipemic agents Treatment Drug Therapy Bile Acid-Binding Resins (colestipol [Colestid�] and cholestyramine [Questran�]) Will ? LDL, may ? VLDL (would require niacin combo if ? TG prior to tx) MOA Bile acids, the metabolites of cholesterol, are normally reabsorbed in the jejunum and ileum. When resins are given, they bind to bile acids in the intestinal lumen, prevent their reabsorption and increase their excretion.

29. Antilipemic agents Treatment Drug Therapy Bile Acid-Binding Resins MOA ? excretion creates a demand for ? synthesis of bile acid. Liver cells must have an ? cholesterol supply (provided by LDL) to synthesize bile acid. Liver cells will ? their LDL receptors, ?ing uptake of LDL from plasma. Indication Used alone to ? LDL (by 15-20%) Normally used as adjuncts to the statins to ? LDL (by 50%)

30. Antilipemic agents Treatment Drug Therapy Bile Acid-Binding Resins Indication Can be used to relieve pruitis in pts who have cholestasis Can be used for severe digitalis toxicity Dispensed in powder form (must be mixed with fluid). Cholestyramine 4-12g BID. Colestipol 5-30g/day in divided doses and also in 1g tablets (2-16g/day) taken w/ fluid Adverse Effects Max reductions of LDL occur in one month Must be taken with meals

31. Antilipemic agents Treatment Drug Therapy Bile Acid-Binding Resins Adverse Effects Constipation Bloating, indigestion, nausea Large doses may impair absorption of fats or fat soluble vitamins (A, D, E, and K) Drug Interactions Resins bind digoxin, warfarin, thiazide diuretics, tetracycline, thyroxine, iron salts, pravastatin, fluvastatin, folic acid, phenylbutazone, aspirin, ascorbic acid (these agents should be given 1 hour before the resin or 4 hours after)

32. Antilipemic agents Treatment Drug Therapy HMG COA Reductase Inhibitors (�statins�) (lovastatin [Mevacor�], fluvastatin [Lescol�], pravastatin [Pravachol�], simvastatin [Zocor�], atorvastatin [Lipitor �], cerivastatin [Baycol �]) Most Effective for ? LDL Will ? HDL and ? VLDL Fewest adverse effects and tolerated best

33. Antilipemic agents Treatment Drug Therapy (�statins�) MOA Inhibits hepatic HMG CoA reductase Inhibition of cholesterol synthesis causes hepatocytes to synthesize more LDL receptors Hepatocytes are able to remove more LDLs from the blood Decrease production of apolipoprotein B-100, thereby ? production of VLDL ? plaque cholesterol content

34. Antilipemic agents Treatment Drug Therapy (�statins�) MOA ? inflammation at the plaque site Improve abnormal endothelial function Enhance the ability of blood vessels to dilate ? risk of thrombosis (inhibits platelet aggregation and blocks thrombin synthesis) Statins have high first pass extraction by liver (only a small fraction of each dose reaches the general circulation) Prodrugs � lovastatin and simvastatin

35. Antilipemic agents Treatment Drug Therapy (�statins�) � Indications Used alone to ? LDL Used with bile acid � binding resins to ? LDL Used with niacin to ? LDL, ? VLDL, and ? HDL Enhanced if taken with food (except for pravastatin � taken without food) Give in the evening Half life is 1-3 hours (except atorvastatin � 14 hours)

36. Antilipemic agents Treatment Drug Therapy (�statins�) � Indications Atorvastatin is most efficacious agent for use in severe hypercholesterolemia High potency (>40-50% LDL lowering) � atorvastatin, simvastatin, cerivastatin Low potency (20-40% LDL lowering) � lovastatin, fluvastatin, pravastatin ? LDL within 2 weeks; max reduction in 4-6 weeks

37. Antilipemic agents Treatment Drug Therapy (�statins�) � Indications New Drug: Altocor� Extended release lovastatin Slightly more effective than regular lovastatin Take without food

38. Antilipemic agents Treatment Drug Therapy (�statins�) � Adverse Effects Since LDL cholesterol levels will return to pretreatment values if drugs are withdrawn, treatment must continue lifelong Statins are pregnancy category X HA, rash, GI disturbances (dyspepsia, cramps, flatulence, constipation, abdominal pain)

39. Antilipemic agents Treatment Drug Therapy (�statins�) � Adverse Effects Hepatotoxicity D/C med if aminotransferase activity is elevated more than 3X the upper normal limit Check LFTS at baseline, 6 wks, 12 wks, then every 6 months Myopathy (0.5% of pts) Risk highest with lovastatin and especially in combination with Fibrates Cyp3A4 drug interactions with all statins excepts for pravastatin and fluvastatin

40. Antilipemic agents Treatment Drug Therapy New Drug Class Ezetimibe (Zetia�) Cholesterol lowering agent Will challenge the statins Approved for monotherapy or in combo with statins (especially Zocor�) Currently in phase III trials