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Chapter 11: Drugs Used in Treating Hyperlipidemia

Table of Contents
Introduction Definitions Hyperlipidemias--Clinical consequences Athersclerosis Acute pancreatitis Lipoprotein Classification Plasma proteins in atherogenesis Athersclerotic Plaques Components Factors promoting Development Properties High-density lipoproteins (HDL) and atherogenesis Cigarette smoking & CHD Hyperlipoproteinemia Pathophysiology Lipoprotein Metabolism: Normal Catabolism and Synthesis Chylomicrons VLDL LDL Lp(a) Lipoprotein HDL Lipoprotein disorders Overview Primary Hypertriglyceridemia Triglyceride elevation: mechanism Associated conditions Familial hypertriglyceridemia (severe) Familial hypertriglyceridemia (moderate) Familial combined hyperlipoproteinemia Familial lipoprotein lipase deficiency clinical presentation Familial Apoprotein CII Deficiency Familial dysbetalipoproteinemia clinical presentation treatment Primary Hypercholesterolemia Familial hypercholesterolemia Clinical manifestations (heterzygous) Clinical manifestations (homozygous) Mechanism Clinical management Familial Ligand-Defective Apolipoprotein B Mechanism Clinical consequence Treatment Familial Combined Hyperlipoproteinemia Lp(a) Hyperlipoproteinemia HDL Deficiency Genetic Factors Familial hypoalphalipoproteinemia Secondary Hyperlipoproteinemia Hypertriglyceridemia Hypercholesterolemia	Treatment Dietary for patients with elevated serum LDL for patients with elevated triglycerides Pharmacological Management of Hyperlipidemia Overview Niacin Overview Chemistry/Pharmacokinetics Mechanism of Action Clinical Use Toxicity Gemfibrozil Overview Pharmacokinetics Mechanism of Action Clinical Use Toxicity Bile acid Binding Resins Overview Chemistry/Pharmacokinetics Mechanism of Action Clinical Uses Toxicity HMG-CoA reductase Inhibitors Overview Chemistry/Pharmacokinetics Mechanism of Action Clinical Use Toxicity Drug Combinations Overview Gemfibrozil & Bile Acid-Binding Resin Reductase inhibitor & Binding Acid-Binding Resin Niacin & Bile Acid-Binding Resin Niacin & Reductase Inhibitor Combination of Resin, Niacin, & Reductase Inhibitor

Introduction
- Definitions:
  - Human plasma lipids -- transported as protein complexes, lipoproteins
  - Abnormally high levels of any lipoproteins species called:
    - hyperlipoproteinemias
    - hyperlipidemias
    - hyperlipemia (refers to elevated triglyceride levels only)
- Hyperlipidemias: Major clinical consequences
  - Atherosclerosis
    - > 50% of coronary heart disease (CHD) in United States is due to abnormal lipoprotein and plasma lipid levels/metabolism
    - Usually elevated lipoprotein inpatients with CHD results from (in the context of some degree of genetic predisposition):
      - excess body weight
      - sedentary lifestyle
      - diets high in saturated and total fat
  - Acute pancreatitis (associate with hyperlipidemia)
- Lipoprotein: Classification: based on densities -- 5 classes:
  1. chylomicrons
  2. very low-density lipoproteins VLDL
  3. intermediate density lipoproteins IDL
  4. low-density lipoproteins LDL
  5. high-density lipoproteins HDL
Plasma proteins in atherogenesis:
- Apolipoprotein (Apo)
- Two forms of Apo B:-- apolipoprotein responsible for cholesterol transported to artery wall

Atherosclerotic Plaques:

"The two morphologic components are:

The fibrous cap which is sub-endothelial and contains lipid laden macrophages (foam cells), lymphocytes, and smooth muscle cells.

The underlying atheroma "soft center", consisting of masses of lipid, cell debris and foam cells."

Ó 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

Component: foam cells --macrophages & smooth muscle cells, filled with cholesteryl esters
Factors promoting atherosclerosis development:
- Lipoprotein glycation (associated poorly controlled diabetes) promotes foam cell development
- Arterial hypertension
  - Blood pressure control may be useful in prevention stroke/and coronary artery disease
Atheromatous plaque properties:
- growth over time (increased foam cell number; collagen & fibrin accumulation)
- Lesion calcification may occur
- Symptoms due to coronary artery disease may occur abruptly-- sequence:
  1. endothelial cell rupture over active plaques
  2. then platelet activation followed by:
  3. thrombus formation (occlusive thrombosis)

"The red-brown thrombus is seen occluding the coronary artery.
Thrombosis occurs with injury to the endothelium, for example, when an atherosclerotic plaque ruptures.
This can occur at any time, even before the plaque has significantly occluded the coronary.
Thrombosis, of course, will cause 100% occlusion, and can occur within a matter of seconds.
Thrombosis is definitely linked to the onset of angina, as is often demonstrated in the cardiac catheterization lab."
Ó 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

High-density lipoproteins (HDL) and atherogenesis
- Antiantherogenic characteristics:
  - remove cholesterol from artery wall
  - reduce atherogenic lipoprotein oxidation
- Low HDL levels: independent CHD risk factor
- Atherogenic lipoprotein impairment of coronary arteriole dilation (mediated by nitric oxide)
Cigarette smoking and Coronary Heart Disease:
- risk factor for CHD
- Associated with:
  - decreased HDL levels
  - less effective cholesterol retrieval
  - endothelial cytotoxicity
  - enhanced atherogenic lipoproteins oxidation
  - increased thrombogenesis

Primary Reference: Malloy, M. J, and Kane, J. P., Agents Used in Hyperlipidemia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 563-577.
Primary Reference: Ginsberg, H. N and Goldberg, I. J. Disorders of Intermediary Metabolism: Disorders of Lipoprotein Metabolism, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2138-2149.