Hyperlipoproteinemia

1. 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.

2. Lipoprotein Structure

3. Drugs for Hyperlipoproteinemia Drugs which lower the lipoproteins have a potential to prevent the CVA and CAD by retarding atherosclerosis.

4. 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“

5. Hyperlipoproteinemia

6. Lipoprotein metabolism

7. DRUGS FOR HYPERLIPOPROTEINEMIA RESINS STATINS NIACIN FIBRATES

8. 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

9. . +ve -ve

10. 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.

11. Bile acid Sequestrants : Adverse effects : • Constipation • Deficiency of fat soluble vitamins

12. 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.

13. HMG CoA reductase Inhibitors:

14. 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

15. HMG CoA reductase Inhibitors : • Lovastatinand Simvastatin • Fluvastatin – Less myopathy • Atorvastatin (Lipitor)– antioxidant effect

16. 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

17. HMG CoA reductase Inhibitors: • Adverse effects : Headache Sleep disturbances Hepatotoxicity Myopathy (muscle tenderness)

18. Fibric acid derivatives : • Fenofibrate • Gemfibrozil • These are PPAR α (peroxisome proliferator-activated receptors), which increases lipoprotein lipase synthesis

19. Fenofibrate • Mechanism • Activation of these receptors alters the transcription of a number of genes involved in triglyceride metabolism including lipoprotein lipase and apolipoprotein CIII.

20. 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

21. 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

22. Fibric acid derivatives : Adverse effects : • Gall stones with clofibrate • Myopathy • Nausea • Skin Rash

23. Nicotinic acid : Broad spectrum • It reduces VLDL and TG production • It increase HDL • Effective drug in reducing LDL.

24. Nicotinic acid : Adverse effects : • Cutaneous dilator – flushing, itching • Liver dysfunction • Hyperglycemia • Potentiates gout (decrease uric A. secretion), diabetes and peptic ulcers

25. 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

26. Drugs for Hyperlipoproteinemia