Hypolipidemic drugs

Hypolipidemic drugs

1. Moderator : Dr. Ali Ahmad Presentor : Dr.Roohana Hasan JR-1 HYPOLIPIDEMIC DRUGS

2. Introduction Hyperlipidemia is a condition excess of fatty substances called lipids, largely cholesterol and triglycerides, in the blood. It results from abnormalities in lipid metabolism or plasma lipid transport or a disorder in the synthesis and degradation of plasma lipoproteins.

3. Serum Lipid Level (mg/ dL ) and Risk of CAD and IHD based on NCEP Guidelines 2001

4. Lifestyle Diabetes Mellitus Kidney disease Pregnancy Hypothyroidism Genetic Alcohol Drugs- Thiazides , Cyclosporin , Glucocorticoids , Beta Blockers. Causes of Hyperlipidemia

5. Current cigarette smoking   Defined as smoking within the preceding 30 days Age   Male >45 years of age or female >55 years of age Family history of premature CHD   A first-degree relative (male <55 years of age or female <65 years of age when the first CHD clinical event occurs)

6. Hypertension   Blood pressure 140/90 or use of antihypertensive medication, irrespective of blood pressure Low HDL-C   <40 mg/ dL (consider <50 mg/ dL as "low" for women) Obesity   Body mass index >25 kg/m 2 and waist circumference >40 inches (men) or >35 inches (women) Type 2 diabetes mellitus

7. Hyperlipoproteinaemias Primary: due to: (a) A single gene defect: is familial and called ‘monogenic’ or genetic (b) Multiple genetic, dietary and physical activity related causes: ‘polygenic’ or multifactorial .

8. Types of primary hyperlipoproteinaemias

9. Secondary : associated with Diabetes, Myxoedema , Nephrotic syndrome, Chronic alcoholism, Drugs (corticosteroids, oral contraceptives, β blockers) etc.

10. Lipids- Hterogenous group of compounds related to fatty acids, which are insoluble in fatty acids and are source of energy. Lipoproteins- Spherical particles of water soluble proteins, that transport neutral lipids through body fluids.

11. Lipid metabolism

12. • Life style modification. Regular exercise. • Obesity reduction. • Stop smoking & alcoholism. • Diet. • Restrict intake of saturated fat. Fish intake-oily sea fish. Eg -Tuna & Mackarel . • Plenty of fruits & vegetebles . • TREAT THE UNDERLYING CAUSE. Treatment strategies

13. Clinical guidelines recommend the drug therapy to be started along with lifestyle changes in patients with IHD or in patients with having LDL greater than 130mg/dl.

14. Lowering LDL cholesterol Reducing total serum cholesterol and triglycerides Increasing HDL cholesterol The goals of treatment are:

15. Primary prevention involves management of risk factors to prevent a first-ever CHD event . Secondary prevention patients are those who have had a prior CHD event and whose risk factors are treated most aggressively. Recently , the concept of primordial prevention has been applied to CHD prevention

16. The primordial prevention guidelines include 150 minutes/week of moderate-intensity exercise (walking 20-30 minutes/day. Dietary recommendations include reducing total calories from fat to <30% and saturated fat to <7% to avoid trans fat; consuming <300 mg of cholesterol/day, a variety of oily fish twice a week or more often, and oils/foods rich in      - linolenic acid (canola, flaxseed, and soybean oils; flaxseed; and walnuts); restricting sugary beverages to <36 oz/week for a person consuming 2000 Kcal daily

17. hyp0lipidemic Drugs Several different classes of drugs are used to treat hyperlipidemia . These classes differ not only in their mechanism of action but also in the type of lipid reduction and the magnitude of the reduction.

18. Classification of Hypolipidemic Drugs First Line Therapy 1. HMG- CoA reductase inhibitors ( Statins ): Lovastatin , Simvastatin , Pravastatin , Atorvastatin , Rosuvastatin , Pitavastatin 2. Bile acid sequestrants (Resins): Cholestyramine , Colestipol 3. Inhibitors of Intestinal Absorption of Cholesterol: Stanol Esters, Ezetimibe . 4. CETP Inhibitors: Torcetrapib , Anacetrapib

19. Second Line Therapy Lipoprotein lipase activators ( PPARα activators, Fibrates ): Clofibrate , Gemfibrozil , Bezafibrate , Fenofibrate Lipolysis and triglyceride synthesis inhibitor: Nicotinic acid (Niacin) Miscellaneous Agents: Gugulipid and Fish oil Derivatives .

20. HMG- CoA REDUCTASE INHIBITORS ( Statins ) The statins are the most effective and best-tolerated agents for treating dyslipidemia . These drugs are competitive inhibitors of HMG- CoA reductase , which catalyzes an early, rate-limiting step in cholesterol biosynthesis.

21. History Statins were isolated from a mold, Penicillium citrinum , and identified as inhibitors of cholesterol biosynthesis in 1976 by Endo and colleagues. The first statin studied in humans was compactin , renamed mevastatin , which demonstrated the therapeutic potential of this class of drugs.

22. Alberts and colleagues at Merck developed the first statin approved for use in humans, lovastatin (formerly known as mevinolin ), which was isolated from Aspergillus terreus . Pravastatin and simvastatin are chemically modified derivatives of lovastatin . Atorvastatin , fluvastatin , rosuvastatin , and pitavastatin are structurally distinct synthetic compounds.

23. They competitively inhibit conversion of 3-Hydroxy-3-methyl glutaryl coenzyme A (HMG- CoA ) to mevalonate (rate limiting step in CH synthesis) by the enzyme HMG- CoA reductase .

24. Cholesterol Synthesis

25. LDL is also reduced by enhancing the removal of precursors of of LDL. Eg ; VLDL and IDL. Reducing hepatic VLDL production also leads to reduction in the level of LDL. This also reduced the level of TG.

26. Therapeutic doses reduce CH synthesis by 20–50%. This results in compensatory increase in LDL receptor expression on liver cells → increased receptor mediated uptake and catabolism of IDL and LDL. Over long-term, feedback induction of HMG- CoA reductase tends to increase CH synthesis, but a steady-state is finally attained with a dose-dependent lowering of LDL-CH levels.

27. Actions Effect on Lipid Levels Effect of TG: Significant reduction in TG Level (35-45%) if the TG > 250mg/dl. If TG <250 mg/dl – maximum reduction is <25% LDL is also reduced.

28. Effect on LDL-C Depending upon the statin its dose the degree of reduction in the level of LDL ranges from 20-55% Statins Dose Range Fluvastatin 20-80mg 20 35 Pravastatin 10-40mg 20 35 Lovastatin 10-80mg 20 40 Cervistatin 0.2-0.8mg 20 40 Simvastatin 10-80mg 26 50 Atorvastatin 10-80mg 31 55 Rosuvastatin 5-40mg 36 55 Percentage Reduction in LDL-C in Min Dose Max Dose

29. Effect on HDL-C Increased irrespective of the dose and statins used but if the HDL-C <35mg/dl- the effect may be variable. Simvastatin produces greater increase in HDL-C and apoA-1 level than Atorvastatin and Rosuvastatin . Level of Lp (a) is not affected by the Statins .

30. Direct Cardioprotective Effects Statins have direct cardioprotective effects independant of lipid lowering effects

31. Effect on Endothelium Hypercholestroleamia depresses the acetylcholine induced vasodilatation in coronary arteries. Statins increase the synthesis of endothelial NO by stabilization of endothelial synthase mRNA. Endothelial dysfunction is also reversed by statins .

32. Effect on Plaque Stability Inhibits the infilteration of monocytes in arterial wall. Inhibits the secretion of metalloproteinases secreted by macrophages. The metalloproteinases degrade matrix and weaken the fibrous cap of atherosclerotic plaque . Statins also appear to modulate the cellularity of the artery wall by inhibiting proliferation of smooth muscle cells and enhancing apoptosis. Reduced proliferation of smooth muscle cells and enhanced apoptosis- retard initial hyperplasia and restenosis .

33. Effect on Inflammation C- Reactive Protein – marker for high risk CAD. Statins Reduces the baseline CRP.

34. Effect on Lipoprotein Oxidation Oxidative changes in LDL occurs and important in the uptake of lipoprotein cholesterol by macrophages, cytotoxicity with lesions. Statins inhibits the oxidative changes and thus subsequent effect.

35. Effect on Coagulation Statins decrease platelet aggregation and also reduce the level of fibrinogen. Increased level of fibrinogen may be involved in increased incidence of CAD

36. Atorvastatin This newer and most popular statin is more potent and appears to have the highest LDL-CH lowering efficacy at maximal daily dose of 80 mg. At this dose a greater reduction in TGs is noted if the same was raised at baseline. Atorvastatin has a much longer plasma t½ of 18– 24 hr than other statins , and has additional antioxidant property.

37. Rosuvastatin This is another newer, commonly used and potent statin (10 mg rosuvastatin ~ 20 mg atorvastatin ), with a plasma t½ of 18–24 hours. Greater LDL-CH reduction can be obtained in severe hypercholesterolaemia ; partly due to its longer persistence in the plasma. In patients with raised TG levels, rosuvastatin raises HDL-CH by 15–20% (greater rise than other statins ).

38. Potency of Statins Potency Order for reduction in LDL-C: Rosuva > Atorva > Simva > Lova > Prava > Fluva Potency Order for reduction in TG: Atorva > Prava > Rosuva > Simva > Lova > Fluva Potency Order for increase in HDL-C: Prava > Simva > Rosuva = Fluva = Lova > Atorva

39. HMG- CoA reductase activity is maximum at midnight, so all statins are administered at bed time to obtain maximum effectiveness. However, this is not necessary for atorvastatin and rosuvastatin , which have long plasma t½. All statins , except rosuvastatin are metabolized primarily by CYP3A4.

40. Adverse effects Gastrointestinal complaints Headache Rashes Sleep disturbances Hepatotoxicity - Rise in serum transaminase Myopathy - Rise in CPK levels Peripheral Neuropathy Cataract Lupus Like Syndrome

41. Interactions Enzyme inducers ( Phenytoin , Rifampicin , Greisofulvin , Phenobarbitone ) Reduces the plasma concentration of statins metabolized by CYP3A4 ( Lovastatin , Simvastatin , Atorvastatin ) Simulataneous consumption of grape or its juice Increases the plasma levels of statins .

42. Contraindications Liver Disease-Inc serum Tranaminase Pregnant Women Lactating Women Trauma Major surgeries

43. Therapeutic Uses Primary hyperlipidaemias with raised LDL and total CH levels, with or without raised TG levels (Type IIa , IIb , V), Secondary hypercholesterolaemia - (diabetes, nephrotic syndrome)

44. Bile Acid Sequestrants Mechanism of Action Bile acid sequestrants are  polymeric  compounds that serve as  ion-exchange resins . Bile acid sequestrants exchange  anions  such as  chloride  ions for bile acids. By doing so, they bind bile acids and sequester them from the enterohepatic circulation. The liver then produces more bile acids to replace those that have been lost. Because the body uses cholesterol to make bile acids, this reduces the amount of LDL cholesterol circulating in the blood.

45. Pharmacokinetics Bile acid sequestrants are large polymeric structures, and they are not significantly absorbed from the gut into the bloodstream. Thus, bile acid sequestrants , along with any bile acids bound to the drug, are excreted via the feces after passage through the gastrointestinal tract.

46. Therapeutic Uses Heterozygous familial hypercholestrolemia / Type 3 Hyperlipoprotenemia Pruritis Digitalis Toxicity Coronary Artery Disease

47. Adverse Effects Gastrointestinal side effects- Dyspepsia Bloating Constipation Gritty sensation Hypoprothrombenemia – reduced absorption of Vitamin K- Patients taking Anticoagulant. Malabsorption of Folic Acid Hyperchloreamic Acidosis Hypertriglyceridemia Dry flaking Skin

48. Interactions Cholestyramine and colestipol bind and interfere with the absorption of many drugs They reduce the absorption of vitamins Thiazides Furosemide Propranolol L- thyroxine Digoxin Warfarin , Statins ( Pravastatin and Fluvastatin ). Vitamin K Folic Acid Ascorbic Acid Severe Hypertriglyceridemia - Increase TG levels Contraindications

49. Lipoprotein Lipase Activators ( Fibrates ) Halogenated Fibrates First Generation : Clofibrate Second Generation : Fenofibrate , Bezafibrate , Ciprofibrate Non Halogenated Fibrates Gemfibrozil

50. Mechanism of Action Fibrates reduce TG- activate a nuclear receptor- PPAR alpha Stimulates beta oxidation of Fatty Acids Increase LPL synthesis Reduce production of Apo C3 Inhibits Lipolysis and receptor mediated clearance. VLDL clearance is enhanced

51. Fibrate -mediated increases in HDL-C are due to PPAR stimulation of apoA -I and apoA -II expression, which increases HDL levels. PPARα may also mediate enhanced LDL receptor expression in liver seen particularly with second generation fibrates like bezafibrate , fenofibrate . Fibrates decrease hepatic TG synthesis as well.

52. Pharmacokinetics All of the fibrate drugs are absorbed rapidly and efficiently (>90%) when given with a meal but less efficiently when taken on an empty stomach. The ester bond is hydrolyzed rapidly. Peak plasma concentrations -within 1-4 hours. The t 1/2 ranges from 1.1 hours ( gemfibrozil ) to 20 hours ( fenofibrate ). The fibrate drugs are excreted predominantly as glucuronide conjugates; 60-90% of an oral dose is excreted in the urine.

53. Adverse Effects Gastrointestinal side effects Myopathy Rash Urticaria Hair loss Fatigue Headache Impotence Anemia Increse in serum transaminases and ALP

54. Therapeutic Uses Type 3 Hypercholestrolemia Severe Hypertriglyceridemia Familial combined hyperlipidemia

55. Interactions Coagulants Gemfibrozil + Cervistatin - Rhabdomyolysis , Acute Renal Failure Contraindications Pregnancy Renal Dysfunction Hepatic Dysfunction

56. Niacin –Pyridoxine-3-carboxylic acid Water soluble vitamin B complex group One of the oldest drug used in the treatment of dyslipidemia LIPOLYSIS AND TRIGLYCERIDE SYNTHESIS INHIBITOR (Niacin)

57. Mechanism of Action In adipose tissue, niacin inhibits the lipolysis of triglycerides by hormone-sensitive lipase- reduces transport of free fatty acids to the liver and decreases hepatic triglyceride synthesis. Acting on GPR109A, niacin stimulates the G i –adenylyl cyclase pathway in adipocytes , inhibiting cyclic AMP production and decreasing hormone-sensitive lipase activity, triglyceride lipolysis , and release of free fatty acids. Niacin also may inhibit a rate-limiting enzyme of triglyceride synthesis, diacylglycerol acyltransferase-2.

58. In the liver, niacin reduces triglyceride synthesis by inhibiting both the synthesis and esterification of fatty acids, effects that increase apoB degradation. Reduction of triglyceride synthesis reduces hepatic VLDL production-reduced LDL levels. Niacin also enhances LPL activity-promotes clearance of chylomicrons and VLDL triglycerides.

59. Niacin raises HDL-C levels by decreasing the fractional clearance of apoA -I in HDL rather than by enhancing HDL synthesis. This effect is due to a reduction in the hepatic clearance of HDL- apoA -I, but not of cholesteryl esters, thereby increasing the apoA -I content of plasma and augmenting reverse cholesterol transport.

60. Adverse Effects Flushing Acanthosis Nigricans Gastrointestinal- Dyspepsia,Vomiting , Diarrhoea Hepatotoxicity - elevated transaminases and alkaline phosphatase Hyperglycemia Ocular -Toxic amblyopia and maculopathy Cardiovascular- Atrial tachyarrhythmias and Atrial fibrillation

61. Interactions Postural hypotension may occur in patients on antihypertensives when they take nicotinic acid. Risk of myopathy due to statins is increased. Contraindications Diabetes Mellitus Peptic Ulcer Pregnancy Gout

62. It is a novel drug that acts by inhibiting intestinal absorption of cholesterol and phytosterols . Ezetimibe ( Cholesterol Absorption Inhibitor)

63. Mechanism of action Lowers plasma cholesterol levels by inhibiting the absorption from intestine This cause a decrease in the cholesterol delivery to the liver which in turn clears more cholesterol from the blood. Selective action (( not interfere with TGs, lipid-soluble vitamins absorption))

64. Monotherapy or in combination with HMGRI for reduction of elevated total cholesterol. Therapeutic uses Important Points Should not be given with Resins Should not be given in pregnancy

65. Adverse effects Abdominal pain, Fatigue, Coughing, Diarrhea, Back pain Arthralgia

66. LDL oxidation inhibitor: Probucol Acts by inhibiting the synthesis of sterols. Inhibits atherogenesis - Antioxidant action Reduces LDL as well as HDL. Used in patients of severe atherosclerosis with hypercholestrolemia . Cardiotoxicity HDL-C is decresed . Adverse Effects

67. Gugulipid Guggul is made from the sap (gum resin) of the Commiphora mukul tree, which is native to India. Reduces the sectretion and enhances the excretion of cholesterol. VLDL,LDL,TG are reduced. HDL is incresed Used is type 2b and Type 4 hyperlipidemia .

68. Adverse Effects Hepatic damage Diarrhoea Dysentry

69. Newer Drugs

70. CETP-INHIBITORS The cholesteryl ester transfer protein (CETP) facilitates exchange of CHEs with TGs between HDL particles and chylomicrons , VLDL, LDL, etc. It plays an important role in the disposal of HDL-associated CH. Inhibitors of this protein, torcetrapib , anacetrapib , etc. markedly raise HDLCH and lower LDL.

71. They were presumed to have antiatherosclerotic action. However, during a large randomized clinical trial, torcetrapib was found to increase cardiovascular events like angina, MI, heart failure and death. The trial and further development of the drug was stopped in 2007. Whether other CETP inhibitors will have therapeutic value is being investigated, but appears doubtful.

72. Combination Drug Therapy

73. Statin + Niacin- Type 2a and 2b Can be used for incresed LDL and decreased HDL levels. Statins + Ezetimibe - Synergistic combination for Primary Hypercholestrolemia and Type2a Statins + Fibrates - High risk patients on Statin therapy having increased TG levels as their main lipid abnormality. Patient treted with this combination must be observed for Myopathy .

74. Bile Acid Binding Resin + Fibrates - Type 2b. Increased risk of Cholelithiasis . Bile Acid Binding Resin + Niacin- Type 2a and 2b. Resin has neutralizing action which reduces gastric irritation caused by niacin. Resin + Statins - Reduces LDl -C in Type 2a Statins should be given one hour before or four hours after the resin to ensure proper absorption. Resin+ Statin +Niacin- Used in severe disorders due to increased levels of LDL- Type 2a and 2b.

75. Summary