1. Anti-Hypercholesterolemic Agents
Biosynthesis and Metabolism of Cholesterol
What is arteriosclerosis?
- Link between arteriosclerosis and cholesterol
Lipoproteins particles
- Structure and classification of lipoprotein particles
Hyperlipidemias
- Types and overall strategy to control hyperlipidemias
Anti-hyperlipidemic Agents
- Classes
Statins
Fibrates
Bile Acid Sequestrants
Nicotinic Acid
Ezetimibe
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MEDC 603 Steroids

2. Arteriosclerosis
Arteriosclerosis is excessive formation and deposition of endogeneous products from blood.
In 1984 a 1% drop in serum cholesterol was found to reduce the risk to coronary heart disease (CHD) by nearly 2%.
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3. Lipoprotein Particles
Structure
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4. Transport of Lipoprotein Particles
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5. Lipoprotein Particles
Classification of lipoprotein particles
Composition
Density
Size
Chylomicrons
TG >> C, CE
Low
Large
VLDL
TG > CE
IDL
CE > TG
LDL
CE >> TG
HDL
High
Small
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6. Hyperlipidemia Types of hyperlipidemias I IIa IIb III IV V Lipids
Cholesterol N-
Triglycerides N
Lipoproteins
Chylomicrons
VLDL
LDL
HDL
N = normal, = increase; = decrease; = slight increase; = slight decrease
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7. Strategy for Controlling Hyperlipidemia
STATINS
Diet
Biosynthesis
HMG CoA reductase
Ezetimibe
Cellular Cholesterol
LDL-R
Serum Cholesterol
Bile Acids
Intestine
Re-absorption
Lipoprotein
catabolism
Conversion to
hormones within
cells or storage
as granules
Feces
BILE ACID
SEQUESTRANTS
FIBRATES
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8. Anti-hyperlipidemic Drugs - Statins
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9. Anti-hyperlipidemic Drugs - Statins
Atorvastatin Cerivastatin Fluvastatin
Rosuvastatin Pitavastatin
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10. Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding
For example,
Mevastatin
Lovastatin
Simvastatin
Fluvastatin
Atorvastatin
Cerivastatin
HMG CoA substrate
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MEDC 603 Steroids

11. Anti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins – case of cerivastatin
Bioavail.
Dosage (mg)
Protein Binding
Metabolites
Atorvastatin
~14%
10 – 80
>98%
Active
Cerivastatin
~60%
0.2 – 0.3
>99%
Fluvastatin
~24%
98%
Lovastatin
~5%
>95%
Pravastatin
~17%
10 – 40
~50%
Simvastatin
~95%
Typically all statins possess side effects. The most dominant side effect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis of rhabdomyose) or weakening of skeletal muscles.
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12. Anti-hyperlipidemic Drugs - Fibrates
Older generation drugs; introduced in 1981
Second most useful anti-hyperlipidemic drugs
Primarily decrease serum triglycerides
Increase lipoprotein catabolism; increase TG usage by the body
Most used in Type III, IV and V hyperlipidemias
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13. Anti-hyperlipidemic Drugs – Bile Acid Sequestrants
Anion exchange resins
Water insoluble and inert to digestive enzymes
Not absorbed through the GI tract
Positively charged nitrogens sequester bile acid re-absorption
Lower serum LDL levels
Most useful in type IIa and IIb hyperlipidemias
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14. Anti-hyperlipidemic Drugs – Nicotinic Acid
Administered in large doses (0.5 to 6 grams daily)
Reduces triglycerides and total cholesterol
Increases biliary secretion of cholesterol, but not bile acids
Useful in Type IIa, IIb, III, IV and V hyperlipidemias
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15. Anti-hyperlipidemic Drugs – Ezetimibe
Approved in October 2002
Reduces serum LDL, TC, and TG and increases HDL
Prevents the absorption of cholesterol from diet
Useful in Type IIa, IIb, III, IV and V hyperlipidemias
9/18/2018
MEDC 603 Steroids