Drugs in dyslipidaemias

1. Drugs in dyslipidaemias Dr Sanjeewani Fonseka Department of Pharmacolgy

2. Atheroma • Focal disease of intima • Deposition of C in arterial wall

3. Atheromatous disease • myocardial infarction • Cerebo vascular accidents

4. chy remnant chy Cleared by liver TAG Exo FFA FFA Lipids Skeletal, cardiac and adipose tissue Endo Liver - bile (+ cholesterol) Synthesized by liver VLDL LDL Cell membrane HDL

5. Dyslipidaemias • Hypercholesterolaemia • Hypertriglyceridaemia • Mixed dyslipidaemia

6. Dyslipidaemias Primary • Genetically • Cassify according to lipoprotein particle Secondary • DM • Alcohol • Nephrotic • CRF • Hypothyroidism • Liver disease • Drugs

7. Drugs in dyslipidaemias • Statins • Fibrates • Bile acid binding resins • Niacin • Inhibitors of cholesterol absorption • Omega-3 fatty acids

8. Drugs in dyslipidaemias • Statins • Fibrates • Bile acid binding resins • Niacin • Inhibitors of cholesterol absorption • Omega-3 fatty acids

9. Statins • Competitive inhibition of HMG CoA reductase • HMG Co A HMG Co A mevalonic acid reductase • Reduced C in the liver • ↑ Expression of LDL receptor • Increased LDL clearance

10. Activation of sterol regulatory element binding protein 2 (SREBP2) ↑ Expression of gene encoding LDL receptor

11. statin cont; Other effects of statins • Improve endothelial function • Decreased coagulation • Decreased inflammation • Improved stability of atherosclerotic plaques

12. statin cont; • Well absorbed • Metabolized in liver • Extensive pre- systemic metabolism

13. statin cont; Statins • ↓ LDL-cholesterol by 25-55% • ↑ HDL-cholesterol by 5% • ↓ triglycerides by 10-35% • Given once daily (nocte)

14. statin cont; Statins • Lovastatin • Pravastatin • Simvastatin • Fluvastatin • Atorvastatin • Rosuvastatin

15. statin cont; Clinical use • Primary prevention • Secondary prevention

16. statin cont; Statins: adverse effects • Hepatotoxicity • Myotoxicity • Dyspepsia, abdominal pain, diarrhoea • Angioedema

17. statin cont; Statins: hepatotoxicity • Asymptomatic • ↑ ALT, AST • First 6 months • Discontinued if ALT / AST > 3 times the upper limit of normal range

18. statin cont; Statins: myotoxicity • Pain / tenderness, weakness • ↑ CK > 10 times upper limit of normal • Reversible • ↑ risk with concurrent fibrate therapy, hypothyroidism, renal insufficiency

19. Drugs in dyslipidaemias • Statins • Fibrates • Bile acid binding resins • Niacin • Inhibitors of cholesterol absorption • Omega-3 fatty acids

20. Fibrates • Activate peroxisome proliferator-activated receptor-α (PPARα) • Heterodimer binds to peroxisome proliferator response elements (PPREs) in the promoter regions of specific genes

21. Fibrates cont

22. Fibrates cont: • Gemfibrozil, fenofibrate • ↓ LDL-cholesterol by 5-20% • ↑ HDL-cholesterol by 10-35% • ↓ triglycerides by 20-50%

23. Fibrates cont Clinical use • Mixed dyslipidaemia • Low HDL

24. Fibrates cont • Well absorbed • Elimination renal

25. Fibrates cont Fibrates: adverse effects • Gastrointestinal discomfort • Myopathy • ↑ liver transaminases • Gallstone formation (Gemfibrozil) • Displace warfarin from albumin binding sites

26. Drugs in dyslipidaemias • Statins • Fibrates • Bile acid binding resins • Niacin • Inhibitors of cholesterol absorption • Omega-3 fatty acids

27. Bile acid binding resins • Cationic polymer resins that bind non-covalently to negatively-charged bile acids in small intestine • Enterohepatic circulation of bile acids interrupted causing up-regulation of 7α-hydroxylase in hepatocytes

28. Bile acid binding resins cont;

29. Bile acid binding resins cont • Increased expression of the LDL receptor • Concurrent up-regulation of hepatic cholesterol and triglyceride synthesis

30. Bile acid binding resins cont • Cholestyramine, colestipol • ↓ LDL-cholesterol by 15-30% • ↑ HDL-cholesterol by 3-5% • Triglycerides: no effect or ↑

31. Bile acid binding resins cont • Not absorbed from GIT • Bloating & dyspepsia • Decreased absorption of digoxin, warfarin, fat-soluble vitamins • Take one hour before or 4 h after colestyramine

32. Drugs in dyslipidaemias • Statins • Fibrates • Bile acid binding resins • Niacin • Inhibitors of cholesterol absorption • Omega-3 fatty acids

33. Niacin • Also known as nicotinic acid • ↓ LDL-cholesterol by 5 – 25% • ↑ HDL-cholesterol 15 – 35% • ↓ Triglycerides by 20 – 50%

34. Niacin cont; • ↓ adipocyte hormone-sensitive lipase activity • ↓ availability of FFA to liver for TG (VLDL) synthesis • ↑ half-life of apoA-I (major apolipoprotein in HDL)

35. Niacin cont; adverse effects • Cutaneous flushing & pruritus • Release of prostaglandins D2 & E2 • Prevented by aspirin • Extended-release formulations associated with less flushing • hyperuricaemia, impaired insulin sensitivity, myopathy

36. Drugs in dyslipidaemias • Statins • Fibrates • Bile acid binding resins • Niacin • Inhibitors of cholesterol absorption • Omega-3 fatty acids

37. Inhibitors of cholesterol absorption • Ezetimibe • Decreases cholesterol transport from micelles into enterocytes by inhibiting brush border protein NPC1L1 • Reduces cholesterol incorporation into VLDL in liver

38. Inhibitors of cholesterol absorption • rapidly absorbed by enterocytes • Eliminated in bile • Undergoes enterohepatic circulation • Clinical benefit uncertain

39. Drugs in dyslipidaemias • Statins • Fibrates • Bile acid binding resins • Niacin • Inhibitors of cholesterol absorption • Omega-3 fatty acids

40. Omega-3 fatty acids • Eicosapentaenoic acid (EPA) • Docosahexaenoic acid (DHA)

41. Reduce triglycerides • Increase C • Benefit - uncertain

42. Summary • Most important hyperlipidaemia is hypercholesterolaemia • Most effective drug – statin • Drugs reduce risk of MI