Your SlideShare is downloading. ×
Hyperlipidemia
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Introducing the official SlideShare app

Stunning, full-screen experience for iPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Hyperlipidemia

1,572
views

Published on


0 Comments
2 Likes
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total Views
1,572
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
78
Comments
0
Likes
2
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. Lipid Lowering Drugs Dr. Hiwa K. Saaed, Ph.D.
  • 2. Drugs used to lower lipid levels  HMG-CoA reductase inhibitors (HMGs or statins)  Fibric acid derivatives  Niacin (nicotinic acid)  Bile acid sequestrants  Cholesterol absorption inhibitors
  • 3. Atherosclerosis and lipoprotein metabolism Major plasma lipids Cholesterol ‘Chol’ (free & esterified), Phospholipids (pl), Triacylglycerols (TG), and Free fatty acids (FFA) LIPIDS, (Chol) and (TG), are transported in the plasma as lipoproteins, of which there are four classes: - chylomicrons  transport TG and Chol from the GIT to the tissues,  Where they are split by lipase, releasing FFAs  FFAs are taken up in muscle and adipose tissue.  Chylomicron remnants are taken up in the liver
  • 4. - very low density lipoproteins (VLDL), which transport Chol and newly synthetised TG to the tissues, where TGs are removed as before, leaving LDL: - low density lipoproteins (LDL) with a large component of Chol, some of which is taken up by the tissues and some by the liver, by endocytosis via specific LDL receptors - high density lipoproteins (HDL), which absorb Chol derived from cell breakdown in tissues and transfer it to VLDL and LDL Atherosclerosis and lipoprotein metabolism
  • 5. Atherosclerosis and lipoprotein metabolism There are two different pathways for exogenous and endogenous lipids: THE EXOGENOUS PATHWAY: Chol + TG absorbed from the GIT are transported in the lymph and than in the plasma as CHYLOMICRONS to capillaries in muscle and adipose tissues. Here the core TG are hydrolysed by lipoprotein lipase, and the tissues take up the resulting FREE FATTY ACIDS (FFA)  Chol is liberated within the liver cells and may be stored, oxidised to bile aids or secreted in the bile unaltered  Alternatively it may enter the endogenous pathway of lipid transport in VLDL
  • 6. Atherosclerosis and lipoprotein metabolism cholesterol may be stored oxidised to bile acids secreted in the bile unaltered ENDOGENOUS PATHWAY EXOGENOUS PATHWAY
  • 7. Atherosclerosis and lipoprotein metabolism THE ENDOGENOUS PATHWAY Chol and newly synthetised TG are transported from the liver as VLDL to muscle and adipose tissue, there TG are hydrolysed and the resulting FATTY ACIDS enter the tissues The lipoprotein particles become smaller and ultimetaly become LDL ,which provides the source of Chol for incorporation into cell membranes, for synthesis of steroids, and bile acids
  • 8.  Cells take up LDL by endocytosis via LDL receptors that recognise LDL apolipoproteins  Chol can return to plasma from the tissues in HDL particles and the resulting cholesteryl esters are subsequently transferred to VLDL or LDL  One species of LDL – lipoprotein - is associated with atherosclerosis (localised in atherosclerotic lesions). LDL can also activate platelets, constituting a further thrombogenic effect Atherosclerosis and lipoprotein metabolism
  • 9. LIPID + PROTEIN (LIPOPROTEIN)  Lipids are insoluble in plasma, combine with specific proteins (apolipoproteins): Soluble lipoproteins are classified: 1. Chylomicrons (CM): v rich in TG, v low APOL 2. Very low density lipoproteins (VLDL): same as CM 3. Low density lipoproteins (LDL): v rich in cholesterol- atherosclerosis-CHD-CVA 4. High density lipoproteins (HDL): good cholesterol 5. Intermediate density lipoproteins (IDL)
  • 10. Types of Lipoproteins Lipid Protein Content Lipoprotein Classification Content Most chylomicron Least  very-low density lipoprotein (VLDL)   Intermediate-density lipoprotein (IDL)  Least High-density lipoprotein (HDL) Most
  • 11. Clinical squelae of the hyperlipoproteinemia The 2 major clinical squelae of the hyperlipoproteinemia are:  Acute pancreatitis: occurs in pts w marked hyperlipidemia  Atherosclerosis: certain plasma lipoptns play an essential role in atherogenesis “LDL, IDL, HDL” those that contain lipoptn (apo) B100 The characteristic cellular components in atherosclerotic plaques are foam cells which are transformed macrophages & smooth muscle cells that has become filled with cholesterol esters “endocytosis”.
  • 12. Coronary Heart Disease (CHD)  CHD is the cause of about half of all deaths in the United States.  The incidence of CHD is correlated with: 1. elevated levels of LDL cholesterol and TGs 2. low levels of HDL cholesterol. The risk of CHD in patients with cholesterol levels of 300 mg/dL is 3 to 4 times greater than that in patients with levels less than 300 mg/dL Other risk factors: smoking, HTN, obesity and DM
  • 13. HMG-CoA REDUCTASE INHIBITORS ("statins")  block cholesterol synthesis at the rate-limiting step; Inhibit HMG-CoA reductase, which is used by the liver to produce cholesterol  increase uptake of LDL from circulation by inducing LDL receptor expression  most effective drugs at reducing circulating LDL  most significant side effects are myopathies, changes in liver enzymes and drug-drug interactions
  • 14. Hepatic Cholesterol Synthesis Rate Limiting Only pathway for cholesterol degradation Energetically expensive; prefer to conserve what is already made/acquired – LDL receptor pathway
  • 15. Inhibition of HMG CoA reductase by the statin drugs.
  • 16. Summary of 3-hydroxy-3-methylglutaryl coenzyme (HMG CoA) reductase inhibitors.
  • 17. Adverse effects of statins  Mild, transient GI disturbances  Rash  Headache  Myopathy (muscle pain)  Elevations in liver enzymes
  • 18. LIPID-LOWERING DRUGS- StatinsPromising pharmacodynamic actions: improved endothelial function reduced vascular inflammation and platelet aggregability antithrombotic action stabilisation of atherosclerotic plaques increased neovascularisation of ischaemic tissue enhanced fibrinolysis immune suppression osteoclast apoptosis and increased synthetic activity in osteoblasts
  • 19. Activation of lipoprotein lipase by fibrates: Clofibrate, gemfibrozil, (Lopid), fenofibrate • Ligand for peroxisome proliferator activated receptors (PPARs) increase expression of Lipase  activating lipase, hence increasing hydrolysis of TG in chylomicrons and VLDL particles.  reduce hepatic VLDL production  increase hepatic LDL uptake.  Also suppress release of FFA from the adipose tissue,  inhibit synthesis of TGs in the liver,  and increase the secretion of cholesterol in the bile Produce a modest decrease in LDL (~ 10%) and increase in HDL (~ 10%).But, a marked decrease in TGs (~ 30%).
  • 20. Fibrates-Side Effects  Abdominal discomfort  Diarrhea  Nausea  Blurred vision  Increased risk of gallstones, because?  Prolonged prothrombin time  Liver studies may show increased function
  • 21. CHOLESTEROL ABSORPTION INHIBITOR (EZETIMIBE)  selectively inhibits the cholesterol transporter in the intestine - reduces absorption by ~50%  induces LDL receptor expression a synergistic with statins  potentiates side effects of statins (including myopathies)
  • 22. Bile acid binding resins (Anion-exchange resins) cholestyramine, colestipol, colesevelam sequester bile acids in the GIT prevent their reabsorption and enterohepatic recirculation The result is: decreased absorption of exogenous CHO and increased metabolism of endogenous CHO into bile acid acids increased expression of LDL receptors on liver cells increased removal of LDL from the blood reduced concentration of LDL CHO in plasm (while an unwanted increase in TG)
  • 23.  Bile acids are necessary for absorption of cholesterol  decreases absorption of fat-soluble vitamins and other drugs Therapeutic Uses  Type II hyperlipoproteinemia  Relief of pruritus associated with partial biliary obstruction (cholestyramine) Side Effects: Constipation, Heartburn, nausea, belching, bloating
  • 24. NIACIN (NICOTINIC ACID)/VIT B3  Vitamin B3  Lipid-lowering properties require much higher doses than when used as a vitamin  vitamin dose ~15-35 mg/day;  antihyperlipidemic activity 1-2 g, 3x day  Effective, inexpensive, often used in combination with other lipid-lowering agents
  • 25. Niacin- mechanism of action:  stimulation of a nicotinic acid receptor (discovered in 2003) that is found on adipocytes decreases the release of FFAs from adipocytes  a decreased synthesis of TG and VLDL in the liver à decrease in circulating VLDL and LDL levels  nicotinic acid is the most potent drug for increasing HDL levels
  • 26. Niacin inhibits lipolysis in adipose tissue, resulting in decreased hepatic VLDL synthesis and production of LDLs in the plasma.
  • 27. adverse effects of Niacin  Flushing (due to histamine release)  Pruritus an intense cutaneous flush and pruritus, which decreases after several days but is severe enough to decrease compliance  GI distress
  • 28. Niacin  To minimize side effects of niacin, start on low initial dose and gradually increase it, and take with meals.  Small doses of aspirin or NSAIDs may be taken 30 minutes before niacin to minimize cutaneous flushing.
  • 29. Thank you