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