1. Lipid-lowering drugs

2. 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

3. Atherosclerosis and lipoprotein metabolism LIPIDS, including CHOLESTEROL (CHO) and TRIGLYCERIDES (TG), are transported in the plasma as lipoproteins, of which there are four classes: - chylomicrons transport TG and CHO from the GIT to the tissues, where - 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 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 (VLDL), which transport CHO and newly synthetised TG to the tissues, where TGs are removed as before, leaving: - 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 (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 - 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 LDL receptors - high density lipoproteins (HDL).which absorb CHO derived from cell breakdown in tissues and transfer it to VLDL and LDL - high density lipoproteins (HDL).which absorb CHO derived from cell breakdown in tissues and transfer it to VLDL and LDL

4. Atherosclerosis and lipoprotein metabolism There are two different pathways for exogenous and endogenous lipids: 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 is liberated within the liver cells and may be stored, oxidised to bile aids or secreted in the bile unaltered CHO is liberated within the liver cells and may be stored, oxidised to bile aids or secreted in the bile unaltered Alternatively it may enter the endogenous pathway of lipid transpor in VLDL Alternatively it may enter the endogenous pathway of lipid transpor in VLDL

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

6. (According to Rang, Dale 1999) CHOBile duct v.portae GIT bile acids ENDOGENOUS PATHWAY for lipids EXOGENOUS PATHWAY for lipids chylomicr TGCHO chylomicr remn bile acids CHO Fig.1a Peripheral tissues ENDOGENOUS PARTHWAY Fat + CHO + fatty acids HEPATOCYTE CHO TG Fatty acids

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

8. (According to Rang, Dale 1999) CHO Bile duct v.portae GIT bile acids ENDOGENOUS PATHWAY for lipids EXOGENOUS PATHWAY for lipids bile acids CHO Fig.1b Peripheral tissues HEPATOCYTE ACoA MVA LDL receptors VLDL TG CHO lipase CHO LDL HDL CHO Uptake of CHO Fatty acids CHO from cells CHO

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

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

11. Statins Resins Others Fibrates LIPID-LOWERING DRUGS

12. (According to Rang, Dale 1999) CHO Bile duct v.portae GIT bile acids ENDOGENOUS PATHWAY for lipids EXOGENOUS PATHWAY for lipids bile acids CHO Fig.1c Peripheral tissues fat + CHO + fatty acids HEPATOCYTE ACoA MVA LDL receptors VLDL TG CHO lipase CHO LDL HDL CHO Uptake of CHO Fatty acids Fatty acids CHO from cells Chylomikr TGCHO GIT Chylomikr remn CHO TG STATINS FIBRATES RESINS

13. LIPID-LOWERING DRUGS LIPID-LOWERING DRUGS Statins Statins HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors. The reductase catalyses the conversion of HMG-CoA to mevalonic acid Simvastatin + pravastatin + atorvastatin decrease hepatic CHO synthesis decrease hepatic CHO synthesis increase in synthesis of CHO receptors + increased clearance of LDL + increased clearance of LDL Several studies demonstrated positive effects on morbidity and mortality

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

15. 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 Simvastatin is an inactive pro-drug

16. 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 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 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 Atorvastatin lowers serum CHO in patients with homozygous familiar hypercholesterolemia

17. 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) and angio-oedema (rare)

18. LIPID-LOWERING DRUGS LIPID-LOWERING DRUGS Fibrates Fibrates - stimulate the beta-oxidative degradation of fatty acids - liberate free fatty acids for storage in fat or for metabolism in striated muscle - 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

19. LIPID-LOWERING DRUGS LIPID-LOWERING DRUGS Fibrates 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

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

21. LIPID-LOWERING DRUGS LIPID-LOWERING DRUGS Fibrates Fibrates C l i n i c a l u s e s 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)

22. LIPID-LOWERING DRUGS Bile acid binding resins Bile acid binding 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)

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

24. LIPID-LOWERING DRUGS LIPID-LOWERING DRUGS Bile acid binding resins Bile acid binding resins A d v e r s e e f f e c t s : GIT symptoms - nauzea, abdominal bloating, GIT symptoms - nauzea, abdominal bloating, constipation or diarrhea constipation or diarrhea resins are unappetising. This can be minimized by resins are unappetising. This can be minimized by suspending them in fruit juice suspending them in fruit juice interfere with the absorption of fat-soluble vitamins interfere with the absorption of fat-soluble vitamins and drugs (chlorothiazide, digoxin, warfarin) and drugs (chlorothiazide, digoxin, warfarin) These drugs should be given at last 1 hour before or 4-6 hours after a resin

25. LIPID-LOWERING DRUGS Others Others Nicotinic acid inhibits hepatic TG production and VLDL secretion modest reduction in LDL and increase in HDL A d v e r s e e f f e c t s: flushing, palpitations, GIT disturbances

26. LIPID-LOWERING DRUGS Others 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)

27. Lipid-lowering drugs