AntihyperlipidemicAgents_Fall2007

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AntiAnti--Hypercholesterolemic AgentsHypercholesterolemic 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 CholesterolBiosynthesis of Cholesterol

CH3-C-SCoA -OOC-CH2-C-CH2-C-SCoAO O

OH

CH3

acetyl coenzyme A 3-hydroxy-3-methyl-glutaryl-CoA

HMG CoAreductase

CH

3

CH3

CH3

CH3

CH3

OH

cholesterol

-OOC-CH2-C-CH2-CH2-OH

OH

CH3

mevalonate



Metabolism of CholesterolMetabolism of Cholesterol

CH3

CH3

CH3

OH

CH3

CH3

CH3

CH3

CH3

OH R7H

R12 R

O

CH3

CH3

CH3

OH

O

CH3

CH3

CH3

O

O

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

taurocholic acid R7 = R12 = OH; R = NHCH 2 CH 2 SO3H

pregnenolone

Liver

Liver, tissues

progesterone



ArteriosclerosisArteriosclerosis

Arteriosclerosis is excessive formation and deposition ofendogeneous 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 ParticlesLipoprotein Particles

Structure



Lipoprotein ParticlesLipoprotein 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





HyperlipidemiaHyperlipidemia

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 HyperlipidemiaStrategy for Controlling Hyperlipidemia

Serum Cholesterol Cellular CholesterolLDL-R

Conversion to

hormones within

cells or storage

as granules

HMG CoA reductase

STATINS

Diet Biosynthesis

Bile Acids

Intestine

Feces

Re-absorption

BILE ACIDSEQUESTRANTS

Lipoproteincatabolism

FIBRATES

Ezetimibe



AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs -- StatinsStatins

CH3

CH2CH

2O

O

CH3

R'

R''

O

OOH

R' R''

Mevastatin H H

Lovastatin H CH3

Si vastatin CH3 CH

3

R

R

CH3

CH2CH

2O

O

OH

CH3

OH

OH

COONa

Pr avastatin

R

R




N

OH

OH

COONa

CH

CH

CH CH

OCH

F

NH

NH

F

OH

OH

COO Ca

CH¡

CH¡

O

_+

N

OH

OH

COONa

CH

CH

F

Atorvastatin Cerivastatin Fl vastatin

N N

OH

OH

CH3

CH3

NS CH

3

F

O

O

CH3

COO Ca

_+

N

OH

OH

COO Ca

F

_ +

R os vastatin Pitavastatin




Rationale ² competitive binding

O

OOH OH

OH

COONa OH

SCoA

COOH

O

For example,

Mevastatin

Lovastatin

Simvastatin

For example,

Fluvastatin

Atorvastatin

Cerivastatin

HMG CoA substrate




Pharmacokinetic properties of statins ² case of cerivastatin

Bioavail. Dosage

(mg)

Protein

Binding

Metabolites

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 sideeffect, cited in the withdrawal of cerivastatin, is rhabdomyolysis (lysis

of rhabdomyose) or weakening of skeletal muscles.




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



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-E (peroxisome proliferator-activated receptor E

Most used in Type III, IV and V hyperlipidemias

AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs -- FibratesFibrates



AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs -- FibratesFibrates

O

CH¢

CH¢

CH£

CH£

CH£

COOH

CH¢

CH¢

OCl COOCH£

CH¢

CH¢

CH¢

O

N

H

O

Cl

COOH

CH¢

CH¢

OO

Cl

COOCH(CH¢

)£

CH¢

CH¢

O

Cl Cl

COOH

CH¢

CH¢

emfi zil Cl fi ate

C C

C

Bezafi ate

C

Fenofi ate

C

Ci ofi ate

{No longer recommended because of an

increase in overall mortality and adverse events}

{rhabdomyolysis « highest

PPAR-E affinity clinical trials

stopped in the US}



AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs ² ² Bile Acid SequestrantsBile Acid Sequestrants

Anion exchange resins

Water insoluble and inert to digestive enzymes

Not absorbed through the GI tract

Positively char ged nitrogens sequester bile acid re-absorption

Lower serum LDL levels

Most useful in type IIa and IIb hyperlipidemias



AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs ² ² Bile Acid SequestrantsBile Acid Sequestrants

N CH2CH

2 N

CH2

CHOH

CH2

N CH2CH

2N

CH

CH

2

CH

CH2N(CH

3)3CH2CH2

Cl-

+

Cholestyramine Resin Colestipol hydrochloride

NH

(CH¤

) ¥ CH ¦

NH

(CH¤

)6NMe3+

NHNH¤

NH

(CH¤ )¥

CH3

NH

(CH¤ )6NMe

3+

NH

OH

NH¤

Colese elam



AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs ² ² Nicotinic AcidNicotinic Acid

N

COOH

Administered in lar ge doses (0.5 to 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

N

NCH

3N

CONH2



N

O

F

F

OHOH

AntiAnti--hyperlipidemic Drugshyperlipidemic Drugs ² ² EzetimibeEzetimibe

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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