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Drugs in dyslipidaemias Dr Sanjeewani Fonseka Department of Pharmacolgy.

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Presentation on theme: "Drugs in dyslipidaemias Dr Sanjeewani Fonseka Department of Pharmacolgy."— Presentation transcript:

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

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

12 Well absorbed Metabolized in liver Extensive pre- systemic metabolism

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

14 Statins Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin statin cont;

15 Clinical use Primary prevention Secondary prevention

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

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

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

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 (PPAR α ) 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 Clinical use Mixed dyslipidaemia Low HDL Fibrates cont

24 Well absorbed Elimination renal Fibrates cont

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

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

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

35 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 Niacin cont;

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 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

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