Antihyperlipidemic Agents. Hyperlipidemia Hyperlipidemia is the most prevalent indicator for...

Hyperlipidemia

Hyperlipidemia is the most prevalent indicator for susceptibility to atherosclerotic heart disease.

it is a term used to describe elevated plasma levels of lipids that are usually in the form of lipoproteins.

Lipoproteins Metabolism Dietary

Fat Intestines Chylomicrones Lipoprotein Remnants

FFA Receptor

Liver

Liver

VLDL LipoproteinLipase

Lipase

FFA

IDL LDL

LDL receptorLiver

LDL receptorExtrahepatic tissue

HDL

LCAT

Exogenous Pathway

Endogenous Pathway

Exogenous and endogenous Pathways of lipoprotein metabolism

Lipid-lowering drugs can be classified into:

Sequestering agents (Bile acids sequestrants) Inhibitor of de novo cholesterol biosynthesis. (HMG-

CoA Reductase inhibitors) Alteration of cholesterol metabolism Inhibition of lipoprotein synthesis. Miscellaneous.

Cholestyramine Resin (Questran)

It is a styrene copolymer with divinylbenzene with quaternary ammonium functional groups.

HC

H2C

HC

H2C

CH2N(CH3)3CH2H2C

n

Cl

Colestipol HCl (Colestid)

It is a high-molecular-weight, insoluble, granular copolymer.

It reduces cholesterol levels without affecting triglycerides.

N N

NH2

N

R

OHR

HOCl

Colesevelam (Welchol)

It does not possess Cl- ion (as in Cholestyramine and colestipol) and is not an anion-exchange resin.

H2N HN HN HN

H2N HN HN HN

(CH2)6 (CH2)9CH3

(CH2)6 (CH2)9CH3

N(CH3)3

N(CH3)3

n

OH

H3C C

O

SCoA

Acetyl CoA

3

C

SCoA

CH2COOH

O

HO

H3C

HMG-CoA

HMG-CoAReductase

C

OH

CH2COOHHO

H3C

Mevalonic acid

HOCholesterol

Lovastatin (Mevacor)

It is a potent inhibitor of HMG-CoA reductase.

For inhibitory effect on HMG-CoA reductase, the lactone ring must be hydrolyzed to the open-ring heptanoic acid

CH3

O

CH3

O

HO

O

O

H3C

Simevastatin (Zocor)

It is an analogue of Lovastatin.

CH3

O

O

HO

O

O

H3C

H3C CH3

Dextrothyroxine sodium (Choloxin)

O-(4-Hydroxy-3,5-diiodsophenyl)-3,5-diiodo-D-tyrosine monosodium hydrate.

HO

I

I

O

I

I

H2C C

NH2

H

COONa H2O

Clofibrate (Atromid-S)

Ethyl 2-(p-chlorophenoxy)-2-methylpropionate

Cl O C COOC2H5

CH3

CH3

Clofibrate is prepared by Williamson synthesis.

OH

Cl

+H3C

H3CC O

NaOH- H2O

O

Cl

C

CH3

O

CH3

Na

CHCl3

O

Cl

C

CH3

C

CH3

Cl

ClCl

+3NaOH

-3NaCl

O

Cl

C

CH3

COONa

CH3

O

Cl

C

CH3

COOC2H5

CH3 C2H5OHH2SO4

Gemfibrozil (Lopid)

5-(2,5-Dimethylphenoxy)-2,2-dimethyl pentanoic acid

It is structurally similar to clofibrate. Its mechanism of action and use are similar

to those of clofibrate.

CH3

H3C

O (CH2)3 C COOH

CH3

CH3

Finofibrate (Tricor)

2-[4-(4-Chlorobenzoyl)phenoxy]-2-methylpropanoic acid 1-methylethyl ester.

It has structural features represented in clofibrate.

CCl O OC CHCH3

CH3

C

OCH3

CH3

O

Structure-activity relationship of fibrates

Aromatic ring O Spacer group C

CH3

CH3

C

O

OH

Probucol (Lorelco)

4,4-[(1-Methylethyliden)-bis thio-[2,6-bis(1,1-dimethyethyl)] phenol.

Probucol has high lipophilic characters with strong antioxidant properties.

HO

(H3C)3C

(H3C)3C

S C S

CH3

CH3

OH

C(CH3)3

C(CH3)3

Nicotinic acid, Niacin

3-Pyridine carboxylic acid.

It has the ability to inhibit lipolysis (i.e. prevent the release of free fatty acids and glycerol from fatty tissues).

N

OHC

O

Pentaerthritol tetranicotinate

Pentaerthritol tetranicotinate is an example of molecular association in which a tetra-replicate of nicotinic acid was developed (Molecular replication).

COO

OO

N

N N

N

OO

O O

β-Sitosterol

Sitosterol is a plant sterol, whose structure is identical with that of cholesterol, except for the substituted ethyl group on C-24 of its side chain.

The drug inhibits the absorption of dietary cholesterol from the gastrointestinal tact.

H3C

H3C

HO

H2C

CH2

CH3H3C

H2CCH3

CH3