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• Primary prevention


  Statin treatment: Offer atorvastatin 20 mg for the primary prevention of cardiovascular disease to people who have a 10% or greater 10-year risk of developing cardiovascular disease
• Primary prevention for people 85 years or older


  Consider atorvastatin 20 mg as statins may be of benefit in reducing the risk of non-fatal myocardial infarction
• Dyslipidaemia


  Primary: combination of dietary and genetic factors, familial hypercholesterolaemia (FH) high risk of CHD

  Secondary: consequence of other conditions, e.g. diabetes mellitus, alcoholism, renal disease
• Non-Pharmacological treatment of Dyslipidaemia

  • Cardioprotective diet
  • Weight loss
  • Physical activity
  • Reduce alcohol consumption
  • Smoking cessation
• Pharmacological treatment of Dyslipidaemia

  • Anti-hyperlipidaemic drugs
• Lipid Lowering Drugs


  • HMG-CoA reductase inhibitors
  • Fibrates
  • Cholesterol absorption inhibitors

  Ezetimibe

  Bile-acid binding resins

  Omega Fatty Acids

  Nicotinic acid
• Statins: HMG CoA Reductase Inhibitors

  Simvastatin, Pravastatin, Lovastatin, Atorvastatin, Rosuvastatin, Fluvastatin
• Statins: HMG CoA Reductase Inhibitors

  • Short-acting, Oral, night, Well absorbed, Liver Cytochrome P450 metabolism - not rosuvastatin, CYP3A4 - site of drug interactions, glucuronidation, Simvastatin and lovastatin given in inactive form
• Statins: HMG CoA Reductase Inhibitors


  Blocks HMG CoA Reductase enzyme: rate limiting step in cholesterol synthesis, blocks convertion HMG CoA to mevalonic acid

  Short acting, Specific, reversible inhibitors: simvastatin, lovastatin

  Longer lasting inhibitors: atrovastatin

  Blocks Cholesterol synthesis: upregulates LDL receptor synthesis, increases LDL clearance by liver
• Clinical use of Statins: HMG CoA Reductase Inhibitors


  Primary Hyperlipidaemia (e.g. FH): Reduce LDL by 30%, Raise HDL by 20%

  Secondary Hypercholesterolemia: DM, Secondary prevention of MI & stroke
• Adverse Effects of Statins: HMG CoA Reductase Inhibitors

  Well tolerated but may have muscle pain, GI disturbance, insomnia, rash, Rarely myositis and angio-oedema
• Scandinavian Simvastatin Survival Study (4S's) - reduced relative risk, Serum LDL reduced by 35%, Death reduced by 30%, Death by CHD reduced by 42%
• Effects of Statins: HMG CoA Reductase Inhibitors

  • Endothelial function improves, Improved vascularisation of ischaemic tissue, Atherosclerotic plaque stabilisation, Reduces vascular inflammatory response, Reduced platelet activation, Enhanced fibrinolysis, Antithrombotic
• Fibrates


  Gemfibrozil, Fenofibrate, Bezafibrate
• Mechanism of Action of Fibrates


  Agonist at peroxisome proliferator-activated receptor (PPAR-alpha) nuclear receptor that regulates lipid metabolism, Increase synthesis of lipoprotein lipase by adipose tissue, Stimulates fatty acid oxidation in the liver, Increases expression of apoA-I and apoA5, Increases hepatic LDL uptake
• Effects of Fibrates


  Marked reduction circulating VLDL and TG, Modest reduction in LDL (10%), Increase LDL uptake by liver
• Clinical use of Fibrates

  Hypertriglyceridemia, Mixed hyperlipidaemia (raised TG plus cholesterol), TG levels reduced by 20-30%, cholesterol reduced by 10-15% associated rise in HDL
• Pharmacokinetics of Fibrates


  • Well-absorbed from the gastrointestinal tract, High degree of binding to albumin, Metabolised by the cytochrome P450 (CYP3A4) - potential drug interactions, Primarily excreted via the kidneys
• Adverse effects of Fibrates


  Rash, GI disturbance common, Rhabdomyolysis (unusual) causing renal failure, Clofibrate may cause gall stones
• Cholesterol Absorption Inhibitors: Ezetimibe


  Mechanism of Action: Inhibits intestinal absorption of cholesterol by interfering with Neimann-Pick C1-Like 1 (NPC1L1) transport protein, Decreases LDL and VLDL
• Pharmacokinetics of Ezetimibe


  • Administered orally, Absorbed into intestinal epithelial cells (site of action), Extensively metabolized (>80%) into active metabolite, Enterohepatic recycling slows elimination, t1/2 ~ 22 hours
• Clinical use of Ezetimibe

  Treatment of hyperlipidaemia in combination with statins
• Adverse Effects of Ezetimibe


  Mild: Diarrhoea, abdominal pain, headache, Rash and angioedema, Secreted into breast milk, contraindicated in breastfeeding
• Cholesterol Absorption Inhibitors: Colestipol, Cholestyramine


  Mechanism of Action: Binds bile acid (BA) in gut, prevents reabsorption, diverting hepatic cholesterol to BA synthesis, upregulates LDL receptors increasing LDL removal from the blood
• Pharmacokinetics of Colestipol, Cholestyramine

  Administered by mouth (stays in the GIT)
• Clinical use of Colestipol, Cholestyramine

  Primary hypercholesterolemia when statin is contraindicated, Pruritus associated with biliary obstruction, Bile acid diarrhoea
• Adverse effects of Colestipol, Cholestyramine

  Constipation, bloating, Malabsorption of vitamin K, folic acid, ascorbic acid, Disrupts absorption of digitalis, thiazides, warfarin, iron
• Mechanism of Action of Nicotinic Acid (Niacin)


  Liver: Reduces VLDL synthesis, Reduces VLDL and LDL

  Adipose tissue: Reduces hormone-sensitive lipase activity, Reduces TG

  Reduces catabolic rate for HDL: increases HDL

  Increase clearance of VLDL by activating lipoprotein lipase
• Pharmacokinetics of Nicotinic Acid (Niacin)

  Readily absorbed in GIT following oral administration, Metabolised in the liver, Excreted via kidneys
• Clinical use of Nicotinic Acid (Niacin)


  Hypercholesterolemia, Hypertriglyceridemia with low levels of HDL
• Adverse effects of Nicotinic Acid (Niacin)

  Cutaneous flushing (common), Associated with pruritus & palpitation, Reduced with pre-treatment of aspirin or other NSAIDs, Dose-dependent nausea and abdominal discomfort, Moderate elevation of liver enzymes to severe hepatotoxicity, Hyperuricemia in 20% of the patient