1 - Anti-Hyperlipidimic Agents 4

Taiz University
Pharmacy department , third level
Anti-Hyperlipidimic Agents
Dr: Eyad Al-sabaei
2022. 12. 11
1
Introduction
Atherosclerosis is a condition characterized by damage to the

arteries.
During this condition, the concentration of lipids, specifically
cholesterol, in plasma is increased which may put the patient at
an increased risk for ischemic heart diseases, myocardial
infarction, and cerebral vascular accidents.
 Lipids lack water solubility and are transported in plasma in the
form of lipoproteins.
Hyperlipidemia, also referred to a s hyperlipoproteinemia, is a

condition characterized by an increase in the lipid concentration in
plasma. Hypocholesterolemia or anti-hyperlipidemic or lipid
lowering agents are the pharmacological agents decreasing the
concentration of lipids in p
2
Classification Anti- hyperlipidemic Agents
The anti- hyperlipidemic agents are classified as follows:
 1) HMG-CoA Reductase Inhibitors (Statins): Lovastatin,
Simvastatin, Pravastatin, and Atorvastatin.
 2) Bile Acid Sequestrants (Resins): Cholestyramine and Colestipol.
 3) Fibric Acid Derivatives (Fibrates): Clofibrate, Gemfibrozil,

Bezafibrate, and Fenofibrate.
 4) Triglyceride Synthesis and Lipolysis Inhibitors: Nicotinic acid.
 5) Others: Probucol and Omega-3 fatty acids.
3
Mechanism of Action
Anti-hyperlipidemic agents act by the following mechanism of
action:
 1) HMG-CoA Reductase Inhibitors (Statins): HMG-CoA reductase
(3 -hydroxy-3methylglutaryl-coenzyme A reductase) is the enzyme
responsible for the conversion of HMG -CoA to mevalonate.
Statins act by inhibiting HMG-CoA reductase. Biosynthesis of
cholesterol requires mevalonate as a building block. HMG -CoA
binds to HMG -CoA reductase. Statins act as a competitive
inhibitor of HMG -CoA resulting in a decrease in the production of
mevalonate. When administered, statins are inactive and is
hydrolyzed to the active β-hydroxy acid form within the body.
 Bile Acid Sequestrants (Resins): These are basically large
polymeric compounds serving as ion exchange resins. They
exchange anions like chloride ions for bile acids. These
compounds sequester the bile acids by binding to them, thus,
preventing their enterohepatic circulation. As the bile acid
sequestrants are larger in size, they are not absorbed well from
the gut into the bloodstream. And hence, are excreted out from
the body in the form of faeces (once they pass through the GIT),
along with any bile acids bound to them. 4
 Fibric Acid Derivatives (Fibrates): The mechanism of action of
fibrates is not clear. They act by reducing the synthesis of hepatic
triglycerides and increasing their peripheral clearance.
 Triglyceride Synthesis and Lipolysi s Inhibitors: The release of

free fatty acids from adipose tissue is partially inhibited by
nicotinic acid. It also increases the lipoprotein activity which may
in turn increase the elimination rate of triglycerides from plasma.
As a result, the total LDLs (bad cholesterol) and triglycerides are
reduced, and thus HDLs (good cholesterol) is increased.
5
SAR of HMG CoA-Reductase Inhibitors
Mevastatin and lovastatin are the lead compounds in development

of additional HMGRIs.
The ethylene bridge present between the lactone and bicyclic rings
is essential for HMGRIs’ activity. It was observed that the
replacement of bicyclic ring with other lipophilic rings is possible.
The overall activity of the compounds is affected by the size and
shape of these rings.
Simvastatin and pravastatin can be obtained by making minor
modification ns to the bicyclic ring and side chain ester of
lovastatin.
 The hydrophilicity of pravastatin (a ring-opened dihydroxyacid with
a 6 -hydroxyl group) is more than that of lovastatin and simvastatin.
6
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This hydrophilic nature has led to the following advantages:
1) Minimum penetration into the lipophilic membranes of
peripheral cells,
2) Better selectivity for hepatic tissues, and
3) Reduced side effects of lovastatin and simvastatin.
By replacing the bicyclic ring with various substituted, aromatic

ring systems, compounds (like Fluvastatin), atorvastatin, and
cerivastatin can be developed. However, the potency of these
compounds is less than that of mevastatin.
 In a research it was concluded that the activity of HMGRIs can
be optimized by a variety of aromatic substitutions and
heterocyclic ring systems.
The activity of mevastatin can be retained by up to 30% and a

number of active compounds can be produced by substituting
with pyrrole (a key intermediate in substitutions and addition of
spacer groups).
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SAR of Fibrates
Chemically, fibrates are analogues of phenoxyisobutyric acid. All the
compounds of this class are analogues of the following structure:
The isobutyric acid group in the structure is essential for activity.

Clofibrate and fenofibrate (compounds containing an ester) are pro
drugs and require in vivo hydrolysis. Compounds with longer half-
lives are yielded by substituting a chloro group or chlorine -
containing isopropyl ring at the para position of the aromatic ring.
Mostly a phenoxyisobutyric acid is present in t he compounds, the
addition of a m-propyl spacer (as in gemfibrozil) results in an active
drug. 9
Individual Drugs
 1. Clofibrate: is a fibric acid derivative used for treating
hyperlipoproteinemia type III and severe hypertriglyceridemia.
Mechanism of Action: Clofibrate acts by increasing the activity of

Lipoprotein Lipase (LL) outside the liver, and thus increases the
lipolysis of lipoprotein triglycerides. Degradation of chylomicrons
occurs. Conversion of VLDLs into LDLs and that of LDLs into HDLs
takes place. At the same time, lipid secretion into the bile (hence
into the intestine) increases to some extent. Synthesis of
apolipoprotein B (a carrier molecule for VLDL) is also inhibited and
its clearance is increased by clofibrate.
Uses: It is used for primary dysbetalipoproteinemia (ty pe III
hyperlipidemia) which does not sufficiently respond to diet. This
helps in controlling high cholesterol and high triglyceride levels.
10
Lovastatin: is a hydroxymethylglutaryl coenzyme A (HMG -CoA)
reductase inhibitor. It is obtained by Aspergillus terreus . It is a
natural product derived from polyketide, and contains an
oxidation susceptible hetero-annular diene ring system.
Mechanism of Action: Lovastatin is a competitive inhibitor of

HMG -CoA reductase enzyme and has Ki value of 1.4 nM. This
inhibition restricts the biosynthesis of mevalonic acid (precursor
in the production pathway of terpenes and steroids). Lovastatin
acts on the liver, which is the major site of cholesterol
biosynthesis, lipoprotein production, and LDL catabolism.
However, cholesterol synthesis is also necessary for
extrahepatic tissues, hence, long-term treatment with lovastatin
can result in adverse reactions due to extrahepatic action.
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Uses
 1) It is used as an alternative in individuals having dyslipidemia at
risk of atherosclerotic vascular disease.
 2) It is used for reducing the risk of myocardial infarction, unstable

angina, and coronary revascularisation methods in patients having
risk related to increased total cholesterol, increased LDL
cholesterol, and below average HDL cholesterol.
 3) It is used to delay the progression of coronary atherosclerosis in

patients having coronary heart disease.
 4) It is used as an adjunct to diet for decreasing total cholesterol,

LDL cholesterol and apo-lipoprotein B level in adolescents (10-17
years).
12
Cholestyramine (or colestyramine) is a bile acid sequestrant,
which is a polymeric compound that acts as an ion exchange resin .
Cholestyramine resin is hydrophilic, however water-insoluble.
Mechanism of Action: Cholestyramine binds to and prevents the

reabsorption of bile in GIT . Since cholestyramine resin is a
strong anion exchange resin, it can exchange its chloride anions
with anionic bile acids in the GIT and bind them strongly in the
resin matrix. The functional group of the anion exchange resin is a
quaternary ammonium group attached to an inert styrene-
divinylbenzene copolymer.
Uses:
 1) It is used as an adjunct to diet for decreasing the elevated serum
cholesterol levels in patients having primary hypercholesterolemia
(raised LDL cholesterol) and not responding to diet.
 2) It is also used for treating pruritus related to partial biliary
obstruction. 13
Colestipol: is a highly cross-linked and insoluble basic anion
exchange resin. It is used as an anti-cholesteremic. It is also
used to decrease the triglyceride levels.
Mechanism of Action: binds bile acids in the intestine forming a

complex that is excreted in the feces. This nonsystemic action
results in a partial removal of the bile acids from the
enterohepatic circulation, preventing their reabsorption
Uses: It is used as an adjunct to diet for decreasing the
elevated serum total and LDL-C in patients having primary
hypercholesterolemia ( raised LDL cholesterol ) and not
responding to diet.
14
Thankyou
15

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Taiz University

Pharmacy department , third level

Dr: Eyad Al-sabaei

Atherosclerosis is a condition characterized by damage to the

Hyperlipidemia, also referred to a s hyperlipoproteinemia, is a

 2) Bile Acid Sequestrants (Resins): Cholestyramine and Colestipol.

 3) Fibric Acid Derivatives (Fibrates): Cloﬁbrate, Gemﬁbrozil,

 4) Triglyceride Synthesis and Lipolysis Inhibitors: Nicotinic acid.

 5) Others: Probucol and Omega-3 fatty acids.

 Triglyceride Synthesis and Lipolysi s Inhibitors: The release of

Mevastatin and lovastatin are the lead compounds in development

By replacing the bicyclic ring with various substituted, aromatic

The activity of mevastatin can be retained by up to 30% and a

The isobutyric acid group in the structure is essential for activity.

Mechanism of Action: Cloﬁbrate acts by increasing the activity of

Mechanism of Action: Lovastatin is a competitive inhibitor of

 2) It is used for reducing the risk of myocardial infarction, unstable

 3) It is used to delay the progression of coronary atherosclerosis in

 4) It is used as an adjunct to diet for decreasing total cholesterol,

Mechanism of Action: Cholestyramine binds to and prevents the

Mechanism of Action: binds bile acids in the intestine forming a

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