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Hypolipidemic drugs

Hypolipidemic drugs. A. Introduction . Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG). Dietary TGs are packaged by the liver into a lipoprotein known as very low density lipoprotein (VLDL). .

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Hypolipidemic drugs

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  1. Hypolipidemic drugs

  2. A. Introduction • Over 93% of the fat that is consumed in the diet is in the form of triglycerides (TG).

  3. Dietary TGs are packaged by the liver into a lipoprotein known as very low density lipoprotein (VLDL).

  4. This lipoprotein delivers the TG to adipose tissue to be stored.

  5. Excess dietary carbohydrates are converted into triglycerides and also stored in adipose tissue.

  6. Dietary intake supplies only about 20 – 25% of the cholesterol needed everyday to build cell membranes,

  7. synthesize bile acids/salts,

  8. synthesize hormones of the adrenal glands (aldosterone, cortisol)

  9. and synthesize the sex hormones.

  10. The other 75 – 80% of our daily need for cholesterol is synthesized in the liver.

  11. The primary function of low density lipoprotein (LDL) is the transport of this cholesterol synthesized in the liver.

  12. As it travels through the circulation LDL reacts with LDL receptors on various nonhepatic cells.

  13. Once binding occurs, endocytosis brings the LDL complex inside the cell.

  14. A high dietary intake of saturated fat, as well as a genetic predisposition to synthesize LDL in the liver, results in elevated levels of LDL in the bloodstream.

  15. Dietary saturated fat in particular is one of the primary dietary determinants of hypercholesterolemia, as demonstrated by numerous studies (Keys et al, 1966; Wilson et al (The Framingham Study), 1980; Steinburg, 2004 and 2005).

  16. These studies illustrate the importance of substituting unsaturated fat for saturated fat in the diet.

  17. Saturated fats raise LDL cholesterol by decreasing the synthesis of LDL receptors.

  18. The genetic predisposition involves dysfunction of LDL receptors. An absence of LDL receptors is found in many individuals, so receptor deficiency may be both dietary and genetic.

  19. In some cases there is an LDL receptor, but a mutation alters the binding site in such a way that LDL is no longer able to bind to the cell.

  20. A third type of defect involves LDL binding to the receptor, but cannot be brought into the cell.

  21. The overall results are about the same, no matter which defect you consider, cholesterol is not removed from the circulation

  22. LDL cholesterol that does not react with a LDL receptor continues to circulate.

  23. It is able to penetrate injured endothelial cells that line artery walls.

  24. These cells are damaged by infections, smoking, diabetes, and high blood pressure.

  25. Injured endothelial cells become inflamed, resulting in the release of numerous inflammatory cytokines (TNF, interleukins, oxygen radicals).

  26. Macrophages adhere to injured endothelium via vascular cell adhesion molecules (VCAM) and release enzymes that create oxidative stress and oxidize LDL.

  27. The oxidation of LDL is an important step in atherogenesis as it activates further immune and inflammatory responses (i.e. entry of monocytes across endothelium).

  28. These monocytes differentiate into macrophages, which then engulf the LDL, becoming foam cells

  29. These LDL laden foam cells accumulate in significant amounts, forming lesions called fatty streaks.

  30. Once formed, fatty streaks produce more toxic oxygen radicals and cause immunologic and inflammatory changes (production of more cytokines) resulting in progressive damage to the vessel wall.

  31. It has been demonstrated by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) studies that coronary artery disease begins decades before clinical complications manifest, with 15 year olds often exhibiting early lesions.

  32. Generally, coronary artery disease doesn’t manifest clinically until thirty or more years later with the appearance of angina, coronary thrombosis and/or sudden death.

  33. B. Risk factors for CAD • Risk factors can be categorized as: • conventional nonmodifiable • conventional modifiable • nontraditional

  34. 1. Conventional nonmodifiable risk factors for CAD include • a. advanced age

  35. b. male gender or women after menopause

  36. c. family history of heart disease

  37. 2. Conventional modifiable risk factors for CAD include: • a. hyperlipidemia

  38. b. hypertension

  39. c. cigarette smoking

  40. d. Type 2 diabetes and insulin resistance

  41. e. obesity, particularly central obesity

  42. f. sedentary life style

  43. g. atherogenic diet

  44. In individuals with known CAD, 80-90% will have the risk factors of smoking, diabetes, dyslipidemia or hypertension, and many people will have several of these risks

  45. 3. Nontraditional risk factors for CAD include • a. increased serum markers for inflammation and thrombosis

  46. Of the numerous markers of inflammation that have been linked to an increase in CAD risk, C- reactive protein (CRP) has been explored in the greatest depth.

  47. CRP is a protein mostly synthesized in the liver, whose plasma concentration increases shortly after infarction as part of the systemic inflammatory response.

  48. CRP is an indirect measure of atherosclerotic plaque and is an important indicator of CAD risk.

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