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Drug therapy of hyperlipoproteinemia Statins Examples Lovastatin Simvastatin Pravastatin Fenofibrate Gemfibrozil -Increase the activity of lipoprotein lipase which is responsible for clearance of triglyceride + increases the secretion of VLDL in liver leading to decrease in VLDL and triglyceride (3550 %), mild increase in HDL. -The effect is mediated by activation of peroxisome proliferator activated receptors (PPARs) Cholestyramine Colestipol -Act by binding to bile acids in the intestine, so they increase their fecal secretion and this lead to: 1-Decrease the intestinal absorption of cholesterol. 2-Increase conversion of cholesterol to bile acids 1 and 2 decrease serum cholesterol and cause compensatory stimulation of HMGCoA reductase Niacin Ezetimibe -It is a new agent that inhibits absorption of dietary and biliary cholesterol. -It acts by binding to specific protein on the epithelium of the brush border of the small intestine which is a critical mediator for cholesterol absorption and this protein is Niemann Pick C1-Like 1 -Reduces cholesterol absorption only and decreases delivery of cholesterol to the liver leading to stimulation of its synthesis, so it needs its combination with statins. -Reduces cholesterol absorption by 54 % and cholesterol serum by 15-20 % as a monotherapy -Its effect on coronary diseases and long term safety are not yet evaluated -It is well tolerated but may cause myalgia, diarrhea, headache and allergic reactions. Fibric acid derivatives Bile acid binding resins Niacin (nicotinic acid) Ezetimibe Mechanism action of -Decrease the production of VLDL with secondary decrease in LDL and increase in HDL -The most effective agent in increasing HDL (30-40 %) -Used in doses much higher than used as vitamin 1-Inhibition of HMGCoA reductase enzyme which is the rate limiting enzyme in cholesterol synthesis -So they decrease LDL, increase HDL and decrease triglyceride 2-Recently, they have pleitropic or non-lipid lowering effects that reduce the coronary diseases due to antioxidant, antiinflammatory properties and enhancement of nitric oxide bioavailability Therapeutic uses -Treatment of hypercholesterolemia with high level of LDL. -Agents of choice as it is the most effective, best tolerated and less side effects. -Treatment of hypertriglyceridemia as they decrease incidence of fatal and nonfatal myocardial infarction by 34 % 1-Treatment of hypercholesterolemia (better in combination with lovastatin ), used orally, not absorbed due to large size, present in powder form 2-Treatment of digoxin toxicity 1-GIT upsets (nausea, constipation, indigestion, abdominal discomfort) 2-Decrease the absorption of fat soluble vitamin as vitamin K due to lack of bile salts. 3-Binds to drugs in GIT decreasing absorption of digoxin, warfarin, thyroxin, aspirin, iron -Treatment of hyperlipoproteinemia in combination with other drugs. Side effects 1-Dose-dependent hepatic toxicity. 2-Myopathy (more if used with fibrate or nicotinic acid) so need monitoring of liver and muscle enzymes 1-Myositis (tenderness, weakness, stiffness, and cramps) 2-Increase the incidence of gall stone formation. 3-GIT disturbances 4-Rash, urticaria, headache, impotence and anemia 1-Cutaneous flushing, itching due to release of PG more in first 7-14 days, decreased by: a) Pretreatment with aspirin 30 min. before each dose. b) Begin by small dose. 2-Hepatotoxicity. 3-Induce insulin resistance and may cause severe hyperglycemia in diabetics 4-Elevate serum uric acid 5-Atrial arrhythmia in elder.