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
 Biosynthesis of Cholesterol

O CH3 O
CH3-C-SCoA -
OOC-CH2-C-CH2-C-SCoA
OH
acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA

HMG CoA
reductase

CH3
CH3 CH3

CH3
CH3 -
OOC-CH2-C-CH2-CH2-OH
CH3 OH
HO mevalonate
cholesterol
 Metabolism of Cholesterol

O
H 3C CH3 H 3C
CH 3 R12 CH R
CH 3 3

CH3 CH 3

Liver
HO HO R7
H
cholesterol
cholic acids; R7 and R12 = H or OH; R = OH
glycocholic acid R7 = R12 = OH; R = NHCH 2COOH
taurocholic acid R7 = R12 = OH; R = NHCH 2CH2SO3H

O CH 3 O CH 3
CH3 CH3

CH 3
Liver, tissues
CH3

HO O
pregnenolone progesterone
 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%.
 Lipoprotein Particles

Structure
 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 CE > TG High Small
 Transport of Lipoprotein Particles
Bile Acids LDL
Dietary fat Cholesterol
LDL-R

INTESTINE LIVER EXTRA-HEPATIC

TISSUE

VLDL IDL LDL

Chylomicrons HDL

LCAT
Lipoprotein lipase Lipoprotein lipase

Free fatty acids adipose Free fatty acids adipose

tissue tissue
 Hyperlipidemia
Types of hyperlipidemias
I IIa IIb III IV V
Lipids
Cholesterol N- N- N- N-
Triglycerides N N-
Lipoproteins
Chylomicrons N N N N
VLDL N- N- N-
LDL N-
HDL N N N N-
N = normal, = increase; = decrease; = slight increase; = slight decrease
 Strategy for Controlling Hyperlipidemia

STATINS
Diet Biosynthesis

HMG CoA reductase

Ezetimibe
LDL-R
Serum Cholesterol Cellular Cholesterol

Conversion to
Bile Acids hormones within
cells or storage
Re-absorption as granules
Intestine
Lipoprotein
BILE ACID catabolism
SEQUESTRANTS FIBRATES
Feces
Anti-hyperlipidemic Drugs - Statins

HO O HO
R R COONa
R O R OH
O O
R'
O CH2CH2 O CH2CH2
CH3 CH3 CH3 CH3

R'' HO

R' R'' Pravastatin

Mevastatin H H
Lovastatin H CH3
Simvastatin CH3 CH3
 Anti-hyperlipidemic Drugs - Statins

_
HO HO HO
COO Ca + COONa COONa
OH OH OH

F F F
CH3
CH 3 CH3
N
H CH3 N
CH 3
O N CH3
O H3C

NH H3C CH3

Atorvastatin Cerivastatin Fluvastatin

_ _ +
HO + HO
COO Ca COO Ca
OH OH

F F
CH 3

CH 3
N N N

N
O S CH 3
H 3C O

Rosuvastatin Pitavastatin
 Anti-hyperlipidemic Drugs - Statins

Rationale – competitive binding

HO O HO HO
COONa COOH
O OH SCoA

For example, For example, HMG CoA substrate

Mevastatin Fluvastatin
Lovastatin Atorvastatin
Simvastatin Cerivastatin
 Anti-hyperlipidemic Drugs - Statins

Pharmacokinetic properties of statins – case of cerivastatin

Bioavail. Dosage Protein Metabolites

(mg) Binding
Atorvastatin ~14% 10 – 80 >98% Active
Cerivastatin ~60% 0.2 – 0.3 >99% Active
Fluvastatin ~24% 10 – 80 98% Active
Lovastatin ~5% 10 – 80 >95%
Pravastatin ~17% 10 – 40 ~50%
Simvastatin ~5% 10 - 80 ~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.
 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
 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- (peroxisome proliferator-activated receptor 
• Most used in Type III, IV and V hyperlipidemias
 Anti-hyperlipidemic Drugs - Fibrates

CH 3 CH 3 CH3

O CH 2CH2CH 2 C COOH Cl O C COOCH 2CH3

CH 3 CH 3
H3C
Gemfibrozil Clofibrate
{No longer recommended because of an
H increase in overall mortality and adverse events}
CH3
N
O O C COOH CH 3
O
CH 3 O C COOCH(CH 3)2

CH 3
Cl
Bezafibrate Cl Fenofibrate
CH 3

O C COOH

Cl Cl CH 3

Ciprofibrate

{rhabdomyolysis … highest
PPAR- affinity  clinical trials
stopped in the US}
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
Anti-hyperlipidemic Drugs – Bile Acid Sequestrants
H H
C C C N CH2CH2 N
H2
CH2
CHOH
Cl
- CH2
+ N CH2CH2 N
CH2CH2 CH2N(CH3)3

n n
Cholestyramine Resin Colestipol hydrochloride

H2N HN HN HN

(CH2)6NMe3+ (CH2)9CH3
HO
(CH2)6NMe3+ (CH2)9CH3

H2N HN HN HN

Colesevelam
 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

COOH

CONH2
N
CH3
N N
 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

OH
OH

N
F O