HYPERLIPIDEMIAS

PathogenesisHyperlipidemias Atherosclerosis Heart AttacksAnginaPeripheral arterial diseaseStrokeAtherosclerosis LDL HDL Hypertrigliseridemia

Treatment Strategies of HyperlipidemiasDietAlcohol Trigliserid and VLDLDrugs- Hepatic hydroxymethylglutaryl Co-enzim A (HMG-CoA) reductase inhibitor- Reduce cholesterol absorption (ezetimibe)- Reduce bile acid absorption from the intestine (Resins)- secretion of lipoprotein- peripheral clearance of lipoproteins (fibrates)

HMG CoA Reductase InhibitorsPrototype : Lovastatin, Simvastatin, Atorvastatin, FluvastatinMechanism and Effects :- Competitively inhibit mevalonate synthesis by HMG CoA reductase (a process essential for cholesterol biosynthesis)- Have direct antisclerotic effects

HMG CoA Reductase InhibitorsClinical Use :- Reduce LDL cholesterol dramatically- Efficacy of Atorvastatin > than the others reductase inhibitorsToxicity :- Mild elevation of serum aminotransferase (not associated with hepatic damage)- creatine kinase (release from skeletal muscle)- Severe muscle pain and rhabdomyosis- risk of hepatotoxicity and myopathy- Teratogenic ( CI: pragnancy )

ResinsProtoype : Cholestyramine, colestipol, colesevelamMechanism and Effects :- Binds bile acids and similar steroid in the intestine- Preventing absorption of dietary cholesterol & reabsorption of bile acids secreted by the liver- Cause reduction in the LDL cholesterol, have little effect on HDL cholesterol and TG

ResinsClinical Use : - Used in patient with hypercholesterolemia- Reduce pruritus in patient with cholestasis and bile salt accumulationToxicity : - Bloating, constipation, unpleasant gritty taste- Impaired absorption of vitamin (vit K, dietary folates) and drugs (digitalis, thiazides, warfarin, pravastatin, fluvastatin)

EzetimibeMechanism and Effects :- Prevents GI uptake of cholesterol and phytosterol- Reduce LDL cholesterol 18%Toxicity :Increase the risk of hepatic toxicity (when combined with HMG CoA reductase inhibitor)

Niacin (Nicotinic Acid)Mechanism And Effects :- Directly reduces the secretion of VLDL from the liver- Inhibits hepatic synthesis of apolipoproteins or cholesterol- Effects : in LDL cholesterol Reduction in serum TG concentr. Level of HDL may IncreaseClinical Use : Niacin has wide clinical utility

Niacin (Nicotinic Acid)

Niacin (Nicotinic Acid)Toxicity :- cutaneus flushing- nausea and abdominal discomfort (dose-dependent)- pruritus- moderate elevations of liver enzymes and severe hepatotoxicity- Hyperuricemia

Fibric Acid DerivativesPrototype : gemfibrozil, fenofibrate, clofibrateMechanism :- Ligands for the peroxisome, proliferator-activated receptor alpha (PPAR-)- Interaction with PPAR-increase activity of lipoprotein lipase and enhanced clearance of TG-rich lipoproteinsEffects : reduce cholesterol biosynthesisreduce TG concentrationsmall decrease in LDL cholesterolsmall increase in HDL levels

Fibric Acid DerivativesToxicity :- nausea- skin rashes- increase risk of cholesterol gallstone*(caution in patient with a hystory of cholelithiasis)- Increase risk of myopathy (when used in combination with HMG CoA reductase inhibitor

Combination TherapyDietary modification (first treatment)Drug Combination :to achieve the maximum lowering possible with minimum toxicityto achieve the desired effect on the various lipoproteins (LDL, VLDL, HDL)