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

2. Biosynthesis 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

3. Metabolism of Cholesterol

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%.

5. Lipoprotein Particles
Structure

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

7. Transport of Lipoprotein Particles

8. 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

9. 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

10. Anti-hyperlipidemic Drugs - Statins

11. Anti-hyperlipidemic Drugs - Statins
Atorvastatin Cerivastatin Fluvastatin
Rosuvastatin Pitavastatin

12. Anti-hyperlipidemic Drugs - Statins
Rationale – competitive binding
For example,
Mevastatin
Lovastatin
Simvastatin
Fluvastatin
Atorvastatin
Cerivastatin
HMG CoA substrate

13. 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.

14. Anti-hyperlipidemic Drugs - Statins
Metabolic properties of statins
Rapid first pass metabolism significantly reduces bioavailability
Metabolism is complex
Extensive conversion between the lactone and open-chain forms
Glucuronidated forms as well
Other than these three, many other lesser metabolites
Inhibitors of cytochrome P450 increase bioavailability of statins ….. Greater incidences of myopathy ….. E.g., cyclosporin, gemfibrozil, erythromycin, itraconazole, etc.
Rhabdomyolysis …. A rare complication of statin treatment …. Characterized by breakdown of muscles ….. Release of myoglobin into blood, which travels to kidneys and stops working of its tubules …. Also muscle breakdown increase K+, which induces cardiac arrythmias and death

15. 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
activate PPAR-a (peroxisome proliferator-activated receptor a)
Most used in Type III, IV and V hyperlipidemias

16. Anti-hyperlipidemic Drugs - Fibrates
{No longer recommended because of an increase in overall mortality and adverse events}
{rhabdomyolysis … highest PPAR-a affinity  clinical trials stopped in the US}

17. 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

18. Anti-hyperlipidemic Drugs – Bile Acid Sequestrants

19. 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

20. 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