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Transcript
Drugs in dyslipidaemias Dr Sanjeewani Fonseka Department of Pharmacolgy Atheroma • Focal disease of intima • Deposition of C in arterial wall Atheromatous disease • myocardial infarction • Cerebo vascular accidents chy remnant chy TAG Exo Lipids FFA FFA Skeletal, cardiac and adipose Endo tissue (+ cholesterol) Synthesized VLDL LDL by liver Cleared by liver Liver - bile Cell membrane HDL Dyslipidaemias • Hypercholesterolaemia • Hypertriglyceridaemia • Mixed dyslipidaemia Dyslipidaemias Primary Secondary • Genetically • • • • • • • • Cassify according to lipoprotein particle DM Alcohol Nephrotic CRF Hypothyroidism Liver disease Drugs Drugs in dyslipidaemias • • • • • • Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids Drugs in dyslipidaemias • • • • • • Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids Statins • Competitive inhibition of HMG CoA reductase • HMG Co A HMG Co A reductase • Reduced C in the liver • ↑ Expression of LDL receptor • Increased LDL clearance mevalonic acid • Activation of sterol regulatory element binding protein 2 (SREBP2) • ↑ Expression of gene encoding LDL receptor statin cont; Other effects of statins • Improve endothelial function • Decreased coagulation • Decreased inflammation • Improved stability of atherosclerotic plaques statin cont; • Well absorbed • Metabolized in liver • Extensive pre- systemic metabolism statin cont; Statins • ↓ LDL-cholesterol by 25-55% • ↑ HDL-cholesterol by 5% • ↓ triglycerides by 10-35% • Given once daily (nocte) statin cont; Statins • • • • • • Lovastatin Pravastatin Simvastatin Fluvastatin Atorvastatin Rosuvastatin statin cont; Clinical use • Primary prevention • Secondary prevention statin cont; Statins: adverse effects • Hepatotoxicity • Myotoxicity • Dyspepsia, abdominal pain, diarrhoea • Angioedema statin cont; Statins: hepatotoxicity • • • • Asymptomatic ↑ ALT, AST First 6 months Discontinued if ALT / AST > 3 times the upper limit of normal range statin cont; Statins: myotoxicity • Pain / tenderness, weakness • ↑ CK > 10 times upper limit of normal • Reversible • ↑ risk with concurrent fibrate therapy, hypothyroidism, renal insufficiency Drugs in dyslipidaemias • • • • • • Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids Fibrates • Activate peroxisome proliferatoractivated receptor-α (PPARα) • Heterodimer binds to peroxisome proliferator response elements (PPREs) in the promoter regions of specific genes Fibrates cont Fibrates cont: • Gemfibrozil, fenofibrate • ↓ LDL-cholesterol by 5-20% • ↑ HDL-cholesterol by 10-35% • ↓ triglycerides by 20-50% Fibrates cont Clinical use • Mixed dyslipidaemia • Low HDL Fibrates cont • Well absorbed • Elimination renal Fibrates cont Fibrates: adverse effects • • • • • Gastrointestinal discomfort Myopathy ↑ liver transaminases Gallstone formation (Gemfibrozil) Displace warfarin from albumin binding sites Drugs in dyslipidaemias • • • • • • Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids 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 7αhydroxylase in hepatocytes Bile acid binding resins cont; Bile acid binding resins cont • Increased expression of the LDL receptor • Concurrent up-regulation of hepatic cholesterol and triglyceride synthesis Bile acid binding resins cont • Cholestyramine, colestipol • ↓ LDL-cholesterol by 15-30% • ↑ HDL-cholesterol by 3-5% • Triglycerides: no effect or ↑ 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 Drugs in dyslipidaemias • • • • • • Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids Niacin • Also known as nicotinic acid • ↓ LDL-cholesterol by 5 – 25% • ↑ HDL-cholesterol 15 – 35% • ↓ Triglycerides by 20 – 50% 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) 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 Drugs in dyslipidaemias • • • • • • Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids 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 Inhibitors of cholesterol absorption • rapidly absorbed by enterocytes • Eliminated in bile • Undergoes enterohepatic circulation • Clinical benefit uncertain Drugs in dyslipidaemias • • • • • • Statins Fibrates Bile acid binding resins Niacin Inhibitors of cholesterol absorption Omega-3 fatty acids Omega-3 fatty acids • Eicosapentaenoic acid (EPA) • Docosahexaenoic acid (DHA) • Reduce triglycerides • Increase C • Benefit - uncertain Summary • Most important hyperlipidaemia is hypercholesterolaemia • Most effective drug – statin • Drugs reduce risk of MI
