Antihyperlipedemics

• Treatment goals

  Reduction of LDL-C is the primary goal of cholesterol-lowering therapy
• Lifestyle changes


  • Diet
  • Exercise
  • Weight reduction
• Lifestyle changes can lead to modest decreases in LDL-C and increases in HDL-C
• Most patients are unable to achieve significant LDL-C reductions with lifestyle modifications alone, and drug therapy may be required
• Primary treatment option for hypercholesterolemia

  • HMG CoA reductase inhibitors (statins)

  
• HMG CoA reductase inhibitors (statins)


  Competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol synthesis

  
• Examples of statins


  • Simvastatin
  • Rosuvastatin
  • Atorvastatin
• Effects of HMG CoA reductase inhibitors

  • Decrease triglyceride levels
  • May increase HDL cholesterol levels

  
• These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias
• All statins are metabolized in the liver, with some metabolites retaining activity
• Excretion of statins takes place principally through bile and feces, but some urinary elimination also occurs
• Elevated liver enzymes may occur with statin therapy; liver function should be evaluated prior to treatment
• Niacin (nicotinic acid)


  Can reduce LDL-C by 10% to 20% and is the most effective agent for increasing HDL-C
• Niacin also lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3 grams/day
• Niacin can be used in combination with statins
• Mechanism of action of Niacin

  Inhibits lipolysis
• Niacin is administered orally
• Conversion of Niacin


  Converted in the body to nicotinamide, which is incorporated into the cofactor nicotinamide adenine dinucleotide (NAD+)
• Niacin, its nicotinamide derivative, and other metabolites are excreted in the urine
• Administration of aspirin prior to taking niacin decreases the flush, which is prostaglandin mediated
• Slow titration of the dosage reduces initial adverse effects
• Niacin inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia and gout
• Fibrates


  • Fenofibrate
  • Gemfibrozil
• Effects of fibrates


  Lower serum triglycerides<|>Increase HDL levels

  
• Mechanism of action of fibrates

  Modulation of the activity of peroxisome proliferator-activated receptor alpha (PPAR)

  
• Fibrates are used in the treatment of hypertriglyceridemia
• Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII

  
• Bile acid–binding resins


  • Cholestyramine
  • Colestipol
  • Colesevelam

  
• Bile acid sequestrants


  Have significant LDL cholesterol–lowering effects, although the benefits are less than those observed with statins
• Bile acid sequestrants are anion-exchange resins that bind negatively charged bile acids and bile salts in the small intestine
• The resin/bile acid complex is excreted in the feces, thus lowering the bile acid concentration
• This causes hepatocytes to increase conversion of cholesterol to bile acids

  
• Intracellular cholesterol concentrations decrease, activating an increased hepatic uptake of cholesterol-containing LDL particles, leading to a fall in plasma LDL-C

  
• Pharmacokinetics of bile acid sequestrants

  • Insoluble in water
  • Large molecular weights
  • Not absorbed or metabolically altered by the intestine
  • Totally excreted in feces
• Other drugs should be taken at least 1 to 2 hours before, or 4 to 6 hours after, the bile acid–binding resins
• Cholesterol absorption inhibitor


  Ezetimibe selectively inhibits absorption of dietary and biliary cholesterol in the small intestine

  
• Ezetimibe leads to a decrease in the delivery of intestinal cholesterol to the liver
• This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood

  
• Ezetimibe lowers LDL cholesterol by approximately 17%
• Ezetimibe is often used as an adjunct to statin therapy or in statin-intolerant patients due to its modest LDL lowering