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Lipid-Lowering Drugs. What are lipoproteins? Lipoproteins are protein-lipid complexes.

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Presentation on theme: "Lipid-Lowering Drugs. What are lipoproteins? Lipoproteins are protein-lipid complexes."— Presentation transcript:

1 Lipid-Lowering Drugs

2 What are lipoproteins? Lipoproteins are protein-lipid complexes.

3 The Players – Lipids Triacylglycerol Phospholipids Cholesterol Cholesteryl esters

4 The Players - Apolipoproteins Apo AI (liver, small intestine) –Structural; activator of lecithin:cholesterol acyltransferase (LCAT) Apo AII (liver) –Structural; inhibitor of hepatic lipase; component of ligand for HDL binding Apo A-IV (small intestine) –Activator of LCAT; modulator of lipoprotein lipase (LPL) Apo A-V (liver) –Direct functional role is unknown; regulates TG levels.

5 Apolipoproteins Apo B-100 (liver) –Structural; synthesis of VLDL; ligand for LDL-receptor Apo B-48 (small intestine) –Structural; synthesis of chylomicrons; derived from apo B- 100 mRNA following specific mRNA editing Apo E (liver, macrophages, brain) –Ligand for apoE receptor; mobilization of cellular cholesterol

6 Apolipoproteins Apo C-I (liver) –Activator of LCAT, inhibitor of hepatic TGRL uptake Apo C-II (liver) –Activator of LPL, inhibitor of hepatic TGRL uptake Apo C-III (liver) –Inhibitor of LPL, inhibitor of hepatic TGRL uptake

7 Amphipathic Helices Lipoprotein Surface

8 Lipoprotein Classes Doi H et al. Circulation 2000;102: ; Colome C et al. Atherosclerosis 2000; 149: ; Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15: HDLLDL Chylomicrons, VLDL, and their catabolic remnants > 30 nm 20–22 nm 9–15 nm D<1.006 g/ml D= g/ml D= g/ml Lipids Online

9 Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport

10 Lipoprotein Metabolism Exogenous/chylomicron pathway (dietary fat) Endogenous pathway (lipids synthesized by the liver) HDL metabolism (apolipoprotein transfer, cholesteryl ester transfer, reverse cholesterol transport

11 Surface Monolayer Phospholipids (12%) Free Cholesterol (14%) Protein (4%) Hydrophobic Core Triglyceride (65%) Cholesteryl Esters (8%) TG Rich: VLDL Cholesterol and Atherosclerosis, Grundy)

12 VLDL Metabolism Cholesterol and Atherosclerosis, Grundy) Apo C’s and apoE and cholesteryl ester are acquired from HDL in circulation

13 Fatty Acid Transport Cholesterol and Atherosclerosis, Grundy) ApoC-II activates lipoprotein lipase which catalyses the hydrolysis of TG

14 VLDL Conversion to LDL Cholesterol and Atherosclerosis, Grundy) Further action on IDL by hepatic lipase loses additional apolipoproteins (apoE) becomes and is converted to LDL

15 Surface Monolayer Phospholipids (25%) Free Cholesterol (15%) Protein (22%) Hydrophobic Core Triglyceride (5%) Cholesteryl Esters (35%) CE Rich: LDL Cholesterol and Atherosclerosis, Grundy)

16 LDL Metabolism Cholesterol and Atherosclerosis, Grundy) Hepatic Lipase Cholesteryl ester transfer protein LDL is removed by apoB100 receptors which are mainly expressed in the liver

17 LDL Uptake by Tissues Cholesterol and Atherosclerosis, Grundy) Defects in the LDL receptor leads to familial hypercholesterolemia XX

18 Surface Monolayer Phospholipids (25%) Free Cholesterol (7%) Protein (45%) Hydrophobic Core Triglyceride (5%) Cholesteryl Esters (18%) CE Rich: HDL Cholesterol and Atherosclerosis, Grundy)

19 HDL Metabolism Nascent HDL (lipid-poor apoA-I) is produced by the liver and intestine

20 Hepatic Cholesterol Metabolism

21 Hepatic Cholesterol Synthesis Cholesterol and Atherosaclerosis, Grundy) Rate Limiting Only pathway for cholesterol degradation Energetically expensive; prefer to conserve what is already made/acquired – LDL receptor pathway

22 LDL Cellular Metabolism Cholesterol and Atherosaclerosis, Grundy) LDL are taken up by the LDL Receptor into clathrin-coated pits

23 Endothelial Dysfunction Increased endothelial permeability to lipoproteins and plasma constituents mediated by NO, PDGF, AG-II, endothelin. Up-regulation of leukocyte adhesion molecules (L-selectin, integrins, etc). Up-regulation of endothelial adhesion molecules (E-selectin, P- selectin, ICAM-1, VCAM-1). Migration of leukocytes into artery wall mediated by oxLDL, MCP-1, IL-8, PDGF, M-CSF. Ross, NEJM; 1999

24 Formation of Fatty Streak SMC migration stimulated by PDGF, FGF-2, TGF-B T-Cell activation mediated by TNF-a, IL-2, GM-CSF. Foam-cell formation mediated by oxLDL, TNF-a, IL-1,and M- CSF. Platelet adherence and aggregation stimulated by integrins, P-selectin, fibrin, TXA2, and TF. Ross, NEJM; 1999

25 Formation of Advanced, Complicated Lesion Fibrous cap forms in response to injury to wall off lesion from lumen. Fibrous cap covers a mixture of leukocytes, lipid and debris which may form a necrotic core. Lesions expand at shoulders by means of continued leukocyte adhesion and entry. Necrotic core results from apoptosis and necrosis, increased proteolytic activity and lipid accumulation. Ross, NEJM; 1999

26 Development of Unstable Fibrous Plaque Rupture or ulceration of fibrous cap rapidly leads to thrombosis. Occurs primarily at sites of thinning of the fibrous cap. Thinning is a result of continuing influx of and activation of macrophages which release metalloproteinases and other proteolytic enzymes. These enzymes degrade the matrix which can lead to hemorrhage and thrombus formation Ross, NEJM; 1999

27 Role of LDL in Atherosclerosis Steinberg D et al. N Engl J Med 1989;320: Endothelium Vessel Lumen LDL LDL Readily Enter the Artery Wall Where They May be Modified LDL Intima Modified LDL Modified LDL are Proinflammatory Hydrolysis of Phosphatidylcholine to Lysophosphatidylcholine Other Chemical Modifications Oxidation of Lipids and ApoB Aggregation Lipids Online

28 Role of LDL in Atherosclerosis Endothelium Vessel Lumen Monocyte Macrophage MCP-1MCP-1 Adhesion Molecules Foam Cell Intima Modified Remnants Cytokines Cell Proliferation Matrix Degradation Doi H et al. Circulation 2000;102: Growth Factors Metalloproteinases Remnant Lipoproteins Remnants Lipids Online

29 HDL Prevent Foam Cell Formation LDL LDL Miyazaki A et al. Biochim Biophys Acta 1992;1126: Endothelium Vessel Lumen Monocyte Modified LDL Macrophage MCP-1 Adhesion Molecules Cytokines Intima HDL Promote Cholesterol Efflux Foam Cell Lipids Online

30 Atherosclerosis and lipoprotein metabolism Atheromatous disease is ubiquitous and underlies the commonest causes of death (e.g. myocardial infarction) and disability (e.g. stroke) in industrial countries Hypertension and dyslipidemia are ones of the most important risk factors, amenable to drug therapy ATHEROMA is a focal disease of the intima of large and medium-sized arteries 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 - monocyte attachment - endothelial cells 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

31 Atherosclerosis and lipoprotein metabolism LIPIDSCHOLESTEROL (CHO)TRIGLYCERIDES (TG), LIPIDS, including CHOLESTEROL (CHO) and TRIGLYCERIDES (TG), are transported in the plasma as lipoproteins, of which there are four classes: chylomicrons - chylomicrons transport TG and CHO from the GIT to the tissues, where they are split by lipase, releasing free fatty acids.There are taken up in muscle and adipose tissue. Chylomicron remnants are taken up in the liver very low density lipoproteins - very low density lipoproteins (VLDL), which transport CHO and newly synthetised TG to the tissues, where TGs are removed as before, leaving: low density lipoproteins - low density lipoproteins (LDL) with a large component of CHO, some of which is taken up by the tissues and some by the liver, by endocytosis via specific LDL receptors high density lipoproteins - high density lipoproteins (HDL).which absorb CHO derived from cell breakdown in tissues and transfer it to VLDL and LDL

32 Atherosclerosis and lipoprotein metabolism There are two different pathways for exogenous and endogenous lipids: CHO + TG CHYLOMICRONS TRIGL FREE FATTY ACIDS THE EXOGENOUS PATHWAY : CHO + TG absorbed from the GIT are transported in the lymph and than in the plasma as CHYLOMICRONS to capillaries in muscle and adipose tissues. Here the core TRIGL are hydrolysed by lipoprotein lipase, and the tissues take up the resulting FREE FATTY ACIDS CHO CHO is liberated within the liver cells and may be stored, oxidised to bile aids or secreted in the bile unaltered VLDL Alternatively it may enter the endogenous pathway of lipid transpor in VLDL

33 Atherosclerosis and lipoprotein metabolism CHO may be stored oxidised to bile acids secreted in the bile unaltered ENDOGENOUS PATHWAY EXOGENOUS PATHWAY

34 Atherosclerosis and lipoprotein metabolism THE ENDOGENOUS PATHWAY CHO TGVLDL TG CHO and newly synthetised TG are transported from the liver as VLDL to muscle and adipose tissue, there TG are hydrolysed and the resulting FATTY ACIDS FATTY ACIDS enter the tissues The lipoprotein particlesLDL The lipoprotein particles become smaller and ultimetaly become LDL, CHO which provides the source of CHO for incorporation into cell membranes, for synthesis of steroids, and bile acids Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins CHOHDL VLDLLDL CHO can return to plasma from the tissues in HDL particles and the resulting cholesteryl esters are subsequently transferred to VLDL or LDL One species of LDL – lipoprotein - is associated with atherosclerosis (localised in atherosclerotic lesions). LDL can also activate platelets, constituting a further thrombogenic effect

35 Dyslipidemia total CHO concentration The normal range of plasma total CHO concentration < 6.5 mmol/L. There are smooth gradations of increased risk with LDL CHO concHDL CHO conc elevated LDL CHO conc, and with reduced HDL CHO conc. Dyslipidemia can be primary or secondary. The primary forms are genetically determined Secondary forms are a consequence of other conditions such as diabetes mellitus, alcoholism, nephrotic sy, chronic renal failure, administration of drug…

36 Lipid-lowering drugs Several drugs are used to decrease plasma LDL-CHO Drug therapy to lower plasma lipids is only one approach to treatment and is used in addition to dietary management and correction of other modifiable cardiovascular risk factors

37 Statins LIPID-LOWERING DRUGS: Statins HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors. The reductase catalyses the conversion of HMG-CoA to mevalonic acid; blocks the synthesis of CHO in the liver: Simvastatin + pravastatin + atorvastatin decrease hepatic CHO synthesis: lowers total and LDL increase in synthesis of CHO receptors + increased clearance of LDL + increased clearance of LDL Stimulates the exprssion of more enzyme  restores CHO synthesis to normal. Several studies demonstrated positive effects on morbidity and mortality. Reltatively few side-effects... However, adverse effects: myopathy (incr in pts given combined therapy with nicotinic acid or fibrates. Should not be given during pregnancy.

38 LIPID-LOWERING DRUGS Statins Promising pharmacodynamic actions: improved endothelial function reduced vascular inflammation and platelet aggregability antithrombotic action stabilisation of atherosclerotic plaques increased neovascularisation of ischaemic tissue enhanced fibrinolysis immune suppression osteoclast apoptosis and increased synthetic activity in osteoblasts

39 Statins LIPID-LOWERING DRUG Statins Pharmacokinetics -well absorbed when given orally -extracted by the liver (target tissue), undergo extensive presystemic biotransformation Simvastatin is an inactive pro-drug

40 Statins LIPID-LOWERING DRUG Statins C l i n i c a l u s e s Secondary prevention of myocardial infarction and stroke in patients who have symptomatic atherosclerotic disease (angina, transient ischemic attacks) following acute myocardial infarction or stroke Primary prevention of arterial disease in patients who are at high risk because of elevated serum CHO concentration, especially it there are other risk factors for atherosclerosis Atorvastatin lowers serum CHO in patients with homozygous familiar hypercholesterolemia

41 Statins LIPID-LOWERING DRUG Statins 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)

42 Fibrates LIPID-LOWERING DRUGS: Fibrates - stimulate the β-oxidative degradation of fatty acids - liberate free fatty acids for storage in fat or for metabolism in striated muscle - Are ligands for nuclear txn receptor, peroxisome proliferator- activated recptor-α (PARP-α) - increase the activity of lipoprotein lipase, 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%).

43 LIPID-LOWERING DRUGS Fibrates O t h e r e f f e c t s : improve glucose tolerance inhibit vascular smooth muscle inflammation fenofibrate clofibrate gemfibrozil ciprofibrate

44 LIPID-LOWERING DRUGS Fibrates A d v e r s e e f f e c t s: in patients with renal impairment myositis (rhabdomyolysis) myoglobulinuria, acute renal failure Fibrates should be avoided in such patients and also in alcoholics) mild GIT symptoms

45 LIPID-LOWERING DRUGS Fibrates 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

46 LIPID-LOWERING DRUGS Bile acid binding resins (Anion-exchange resins) sequester bile acids in the GIT prevent their reabsorption and enterohepatic recirculation The r e s u l t is: decreased absorption of exogenous CHO and increased metabolism of endogenous CHO into bile acid acids increased expression of LDL receptors on liver cells increased removal of LDL from the blood reduced concentration of LDL CHO in plasma (while an unwanted increase in TG)

47 Anion-exchange Resins Increase the excretion of bile acids, causing more CHO to be converted to BAs. The decr in hepatocyte [CHO]  compenatory incr in HMG CoA reductase activity and the number of LDLRs. Because these resins don’t work in patients with homozygous familial hypercholesterolemia, increased expression of hepatic LDLRs is the main mechanism by which resins lower plasma CHO.

48 LIPID-LOWERING DRUGS Bile acid binding resins Colestyramin colestipol anion exchange resins C l i n i c a l u s e s: heterozygous familiar hypercholesterolemia an addition to a statin if response has been inadequate hypercholesterolemia when a statin is contraindicated uses unrelated to atherosclerosis, including: pruritus in patients with partial biliary obstruction bile acid diarrhea (diabetic neuropathy)

49 LIPID-LOWERING DRUGS Bile acid binding resins A d v e r s e e f f e c t s : GIT symptoms - nauzea, abdominal bloating, constipation or diarrhea, bec 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 a resin

50 LIPID-LOWERING DRUGS Others Nicotinic acid inhibits 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 decr overall mortality in patients with CAD. But its use is limited by the desirable A d v e r s e e f f e c t s: flushing, palpitations, GIT disturbances. Currently, nicotinic acid is rarely used.

51 LIPID-LOWERING DRUGS Others 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)

52 LIPID-LOWERING DRUGS Others Inhibitors of Intestinal CHO Absorption: Ezetimibe: Reduces CHO and phytosterol absorption and decreases LDL CHP by ~18%, but with little change in HDL CHO. May be synergistic with statins: so good for combination therapy.

53 Drug Combinations Severe hyperlipidemia often requires multiple LLDs to get the job done. As usual, combinations should involve drugs with different mechanisms of action (e.g., statins with fibrates). Even though some combinations (foregoing) may increase risk of, say, myopathy, the benefits of lowering LDL CHO outweigh the small incr in adverse effects. Recent trial with gemfibrozil (fibrate) decr myocardial infarction, stroke, and overall mortality in men with CAD assoc with low HDL (this drug inc HDL CHO w/o decr LDL CHO).

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