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Hyperlipoproteinemia. Lipoprotein is a biochemical assembly that contains both protein and lipid. Lipids are insoluble in plasma and are transported in the plasma in the form of lipoproteins.
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Hyperlipoproteinemia • Lipoprotein is a biochemical assembly that contains both protein and lipid. • Lipids are insoluble in plasma and are transported in the plasma in the form of lipoproteins. • Hyperlipoproteinemia contributes to the pathogenesis of atherosclerosis and is associated with coronary artery disease.
Drugs for Hyperlipoproteinemia Drugs which lower the lipoproteins have a potential to prevent the CVA and CAD by retarding atherosclerosis.
Lipoproteins • Chylomicrons - carry triacylglycerol from the intestines to the liver and adipose tissue. • Very low density lipoproteins(VLDL) - carry triacylglycerol from the liver to adipose tissue. • Low density lipoprotein (LDL) - carry cholesterol from the liver to the tissues. “Bad cholesterol“ • High density lipoprotein (HDL) - collects cholesterol from the tissues, and transport it back to the liver. “Good cholesterol“
DRUGS FOR HYPERLIPOPROTEINEMIA RESINS STATINS NIACIN FIBRATES
Drugs for Hyperlipoproteinemia • Bile acid Sequestrants :(Resins) • Cholestyramine • Colestipol • These are bile acid binding resins • They are neither digested nor absorbed in the gut • These interrupt enterohepatic circulation of bile salts and increase fecal excretion of bile salts and cholesterol • Increase in LDL receptor in the liver
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Bile acid Sequestrants : Compensatory increase in the activity of HMG CoA reductase results in increased cholesterol synthesis and thus increased VLDL secretion – blunting the long term effectiveness of monotherapy • Mild increase in triglycerides can be seen.
Bile acid Sequestrants : Adverse effects : • Constipation • Deficiency of fat soluble vitamins
HMG CoA reductase Inhibitors : • Most efficacious and well tolerated. • They act by competitive inhibition of HMG CoA reductase – the rate limiting step in cholesterol synthesis.
HMG CoA reductase Inhibitors : • Reduced cholesterol synthesis results in a compensatory increase in the hepatic uptake of plasma cholesterol mediated by an increase in the number of LDL receptors. • Hepatic synthesis of VLDL is reduced • There is an increase in HDL levels
HMG CoA reductase Inhibitors : • Lovastatinand Simvastatin • Fluvastatin – Less myopathy • Atorvastatin (Lipitor)– antioxidant effect
Cardio-Protective actions of Statins : • Endothelial function – increase endothelial NO synthesis • Plaque stability – Suppress smooth muscle cell proliferation, inhibit metalloproteinase • Anti-inflammatory action • Increase activity of paraoxonase - anti-oxidative enzyme • Anticoagulation – reduce platelet aggregation
HMG CoA reductase Inhibitors: • Adverse effects : Headache Sleep disturbances Hepatotoxicity Myopathy (muscle tenderness)
Fibric acid derivatives : • Fenofibrate • Gemfibrozil • These are PPAR α (peroxisome proliferator-activated receptors), which increases lipoprotein lipase synthesis
Fenofibrate • Mechanism • Activation of these receptors alters the transcription of a number of genes involved in triglyceride metabolism including lipoprotein lipase and apolipoprotein CIII.
Effects: • This increases the peripheral catabolism of VLDL and chylomicrons. • This results in a reduction in the plasma concentration of VLDL, most notably in triglycerides. • Fibrates reduce hepatic synthesis of cholesterol, which further reduces plasma triglycerides
Fibric acid derivatives : • Gemfibrozil • These act by activating the lipoprotein lipase – key enzyme in the degradation of VLDL --resulting in lowering of TG • Most effective for reducing TG • Reduce VLDL secretion • Increase HDL synthesis • Modest decrease in LDL levels
Fibric acid derivatives : Adverse effects : • Gall stones with clofibrate • Myopathy • Nausea • Skin Rash
Nicotinic acid : Broad spectrum • It reduces VLDL and TG production • It increase HDL • Effective drug in reducing LDL.
Nicotinic acid : Adverse effects : • Cutaneous dilator – flushing, itching • Liver dysfunction • Hyperglycemia • Potentiates gout (decrease uric A. secretion), diabetes and peptic ulcers
Ezetimibe :Cholesterol uptake inhibitor • It decrease cholesterol absorption by localizing at the brush border of the small intestine. • In addition to this direct effect, decreased cholesterol absorption leads to an increase in LDL-cholesterol uptake into cells, thus decreasing levels in the plasma. • Ezetimibe+Simvastatin -- Vytorin