1. Biosynthesis and Metabolism of Cholesterol
CH3-C-SCoA OOC-CH2-C-CH2-C-SCoA O OH
CH3
acetyl coenzyme A hydroxy-3-methyl-glutaryl-CoA
HMG CoA
reductase
cholesterol
-OOC-CH2-C-CH2-CH2-OH OH
CH3
mevalonate
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2. Biosynthesis and Metabolism of Cholesterol
liver
various tissues
Bile Acids
(cholic acid, desoxy
cholic acid, etc.)
Hormones
(testosterone, progesterone
cortisol, estradiol, etc.)
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3. Anti-Hypercholesterolemic Agents
Overall Organization of the Topic
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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4. 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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5. Lipoprotein Particles
Structure
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6. 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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7. 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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8. 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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9. Anti-hyperlipidemic Drugs - Statins
Inhibit the rate limiting step in cholesterol biosynthesis (HMG CoA reductase)
Lower total cholesterol and LDL
Competitive inhibitors with affinity higher than the substrate (HMG CoA)
Most used in Type IIa and IIb hyperlipidemias R
trans-trans-trans
cis-trans-trans
cis-trans-cis
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10. Anti-hyperlipidemic Drugs - Statins
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11. Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding
For example,
Mevastatin
Lovastatin
Simvastatin
Fluvastatin
Atorvastatin
Cerivastatin
HMG CoA substrate
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12. Anti-hyperlipidemic Drugs - Statins
Pharmacokinetic properties of statins – case of cerivastatin
Bioavailabilty
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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13. 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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MEDC 603 Steroids

14. 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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15. 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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16. 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
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