Lipid Lowering Drugs PDF
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Newcastle University
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This document provides an overview of lipid-lowering drugs and their mechanisms of action for treating cardiovascular disease. It discusses various types of lipid-lowering drugs, such as HMG-CoA reductase inhibitors, fibrates, and cholesterol absorption inhibitors.
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Lipid Lowerin g Drugs It is used to treat cardiovascular disease Offer atorvastatin 20 mg for the primary prevention of cardiovascular disease to people who have 10% or greater 10-year What is the risk of developing cardiovascular disease...
Lipid Lowerin g Drugs It is used to treat cardiovascular disease Offer atorvastatin 20 mg for the primary prevention of cardiovascular disease to people who have 10% or greater 10-year What is the risk of developing cardiovascular disease For people 85 years or older consider primary atorvastatin 20 mg as statins may be of prevention benefit in reducing the risk of non-fatal myocardial infarction of statins in Primary dyslipidaemia: Combination of dietary and genetic factors Familial cardiovascul Hypercholesterolaemia (FH) high risk of CHD ar disease Secondary dyslipidaemia: Consequence of other conditions such as: diabetes mellitus, alcoholism and renal disease How can we treat dyslipidaemia pharmacologically and non- pharmacologically ? Non- pharmacologically: Cardioprotective diet, Pharmacologically: weight loss, physical Anti-hyperlipidaemic activity, reduce drugs alcohol consumption and smoking cessation What are the different lipid lowering drugs? HMG-CoA reductase inhibitors Fibrates Cholesterol absorption inhibitors Ezetimibe & Bile-acid binding resins Omega fatty acids Nicotinic acid What are HMG-CoA reductase inhibitors? Simvastatin, Pravastatin, Lovastatin, Atorvastatin, Rosuvastatin and Fluvastatin There mechanism of action is that they block HMG-CoA Reductase, which is a rate limiting step in cholesterol synthesis and blocks conversion of HMG CoA to mevalonic acid Short-acting, specific and reversible inhibitors: Simvastatin & Lovastatin Long-lasting inhibitors: Atorvastatin As it blocks cholesterol synthesis, it upregulates LDL receptor synthesis and increases LDL clearance by the liver. They as short-acting, orally administered at night (cholesterol synthesis happens at night), well absorbed, Liver metabolism by CYP-P450’S except rosuvastatin (CYP3A4 site of drug-drug interactions?), glucuronidation occurs and Simvastatin and Lovastatin is given in its inactive form. Clinical use: Prevent FH LDL reduced by 30% and raised HDL by 20%, Secondary prevention of MI & stroke Adverse effects: well tolerated but may have muscle pain, GI What are the beneficial effects of HMG CoA reductase inhibitors? Endothelial function improves Improved vascularisation of ischaemic tissue Atherosclerotic plaque stabilisation Reduces vascular inflammatory response Reduces platelet activation Enhances fibrinolysis Antithrombotic Fibrates Gemofibrozil, Fenofibrate, Bezafibrate Mechanism of action: Agonist at the peroxisome-activated receptor (PPAR-a) nuclear receptor that regulates lipid metabolism Increases synthesis of lipoprotein lipase in adipose tissue, stimulates fatty acid oxidation in the liver, Increases expression of apoA-I and apoA5 & increases hepatic LDL uptake Causes a marker reduction of circulating VLDL and TG, modest reduction in LDL (10%), Increased LDL uptake by liver Clinical use: Hypertriglyceridemia, Mixed hyperlipidaemia (raised TG plus cholesterol), TG levels reduced by 20-30%, cholesterol reduced by 10-15% associated and rise in HDL It is well absorbed from the GI tract, high degree of binding to albumin, Metabolised by CYP450’s (CYP3A4), and creates potential drug-drug interactions and is primarily excreted via the kidneys Adverse effects: Rash, GI disturbance common, Rhabdomyolysis (unusual) causing renal failure, Clofibrate may cause gall stones Rhabdomyolysis: It is breakdown of skeletal muscle due to direct and indirect muscle injury, if not treated urgently may cause kidney damage. Cholesterol absorption inhibitors Ezetimibe Inhibits intestinal absorption of cholesterol by interfering with Niemann-Pick C1 Like 1 (NPC1L1) transport protein, decreasing LDL & VLDL It is administered orally, absorbed into the intestinal epithelial cells (site of action), extensively metabolised (>80%) into the active metabolite, enterohepatic recycling slows elimination and half-life is around 22 hrs Clinical use: Treatment of hyperlipidaemia in combination with statins Adverse effects: Mild diarrhoea, abdominal pain & headache Severe: rash & angioedema It can be secreted by breast milk (contraindicated in breast milk) It binds to bile acid in the gut, prevents reabsorption, diverting hepatic cholesterol to BA synthesis, upregulates Colestipol LDL receptors increasing LDL removal from the blood and Administered by the mouth and stays in Cholestyram the GI tract ine Clinical use: Primary Hypercholesterolemia when statin is Cholestrol contraindicated, Pruritus associated with Absorption billary obstruction & Bile acid diarrhoea Inhibitors Adverse effects: Constipation, bloating, Malabsorption of vitamin K, folic acid, ascorbic acid and disrupts absorption of digitalis, thiazides, warfarin and iron In the liver it reduces VLDL synthesis reduction in VLDL & LDL In adipose tissue it reduces hormone-sensitive lipase activity reduces TG Reduces catabolic rate for HDL: increases HDL Increases clearance of VLDL by activating lipoprotein lipase Nicotinic It is readily absorbed in the GIT following oral administration, metabolised in the liver and excreted acid via kidneys Clinical use: Hypercholesterolemia and (Niacin) Hypertriglyceridemia with low levels of HDL Adverse effects: Cutaneous flushing (common), associated with pruritus & palpitation, Reduced with pre-treatment of aspirin or other NSAIDs, Dose- dependent nausea & abdominal discomfort, Moderate elevation of liver enzymes to severe hepatotoxicity & Hyperuricemia (high acidic urine) in 20% of the patient Pruritus: itchiness