5. Anti-hyperlipidemic Agents
 Arteriosclerosis
is excessive
endogeneous products from blood.
formation
and
deposition
of
 In 1984 a 1% drop in serum cholesterol was found to reduce the risk
to coronary heart disease (CHD) by nearly 2%.
1
Lipoproteins
• Particles found in plasma that transport
lipids including cholesterol
• Lipoprotein classes
– chylomicrons: take lipids from small intestine
through lymph cells
– very low density lipoproteins (VLDL)
– intermediate density lipoproteins (IDL)
– low density lipoproteins (LDL)
– high density lipoproteins (HDL)
2
Lipoprotein Particles
Classification of lipoprotein particles
3
Composition
Density
Size
Chylomicrons
TG (90%) >>, CE
Low
Large
VLDL
TG (60%) > CE
IDL
CE > TG
LDL
CE (50%) >> TG
HDL
CE (25%) > TG
High
Small
Role of Lipids (Lipoproteins) in Metabolism
Triglycerides
Major energy source for cells
Cholesterol
Cell growth, cell division, membrane
repair, steroid hormone production
Lipids
Transport of fat soluble vitamins
4
Factors promoting elevated blood lipids
• age
– men >45 years of age; women > 55 years of age
• family history of CHD
• smoking
• hypertension >140/90 mm Hg
• low HDL cholesterol
• obesity >30% overweight
• diabetes mellitus
• inactivity/ lack of exercise
5
Strategy for Controlling Hyperlipidemia
Biosynthesis
Diet
FIBRATES
STATINS
HMG CoA reductase
Ezetimibe
Serum Cholesterol
LDL-R
Cellular Cholesterol
Conversion to
hormones within
cells or storage
as granules
Bile Acids
Re-absorption
Intestine
Feces
6
BILE ACID
SEQUESTRANTS
Lipoprotein
catabolism
– The drugs currently in use can be classified according to their
main mode of action into:
5.1. Drugs affecting lipoprotein production through inhibition of
different stages of lipid synthesis and lipoprotein formation.
5.2. Drugs that induce substances that interfere with intestinal
absorption and reabsorption of lipids during enterohepatic
circulation.
5.3. Compounds that directly enhance the rate of metabolic
degradation.
7
5.1. Drugs affecting lipoprotein production
5.1.1. Nicotinic acid and derivatives
CO2H
Nicotinic Acid (Niacin)
It reduces serum cholesterol and TG levels
N
The exact mechanism is unknown. It is known that niacin decreases
lipolysis in adipose tissue, decreases TG esterification in the liver
and increase LPL (lipoprotein lipase) activity. Niacin is rapidly
absorbed.
8
Acipimox
N
H3C
N
CO2H
2-Carboxy-5-methylpyrazine-4-oxide
O
It has greater antilipolytic activity than nicotinic acid (Niacin).
5.1.2. Aryloxyisobutyric acid and 3ry butylphenol derivatives (Fibrates)
– The drugs of this class have similar chemical, pharmacological,
and
clinical
properties
which
act
primarily
as
antihypertriglyceridemic agents, the decrease in cholesterol levels
is only moderate. The fibrates are almost never used alone.
They are mostly used in combination with bile acid sequestering
agents.
9
Clofibrate
O
O
OR
H3C
CH3
Cl
R = H: Clofibric acid, 2-(4-chlorophenoxy)-2-methylpropionic acid.
R = C2H5: Clofibrate, ethyl 2-(4-chlorophenoxy)-2-methylpropionate
Clofibrate is metabolized to chlorophenoxyisobutyric acid (CPIB) which is the
active form of the drug.
Synthesis
O
O
Cl
OH +
+
CHCl3
NaOH
Cl
10
O
H3C
O
ONa
CH3
O
C2H5I
Cl
H3C
OEt
CH3
Gemfibrozil
H3C
H3C
CH3
O
CO2H
CH3
5-(2,5-Dimethylphenoxy)-2,2-dimethylpentanoic acid
It was introduced in 1981 and remains the second most useful
antihyperlipidemic agent. It primarily decreases serum triglycerides.
Simfibrate
O
O
O
O
O
H3C
O
CH3
Cl
It is an identical twin ester prodrug of Clofibrate.
11
H3C
CH3
Cl
Etofibrate
O
O
O
N
O
H3C
CH3
O
Cl
It is a non-identical twin ester prodrug, combines the structural elements of
nicotinic acid and Clofibrate, therefore, it is used in all types of hyperlipidemias.
5.1.3. Probucol
H3C
CH3
H3C
CH3
CH3
CH3
HO
OH
H3C
H3C
H3C
S
CH3
CH3
CH3
S
H3C
CH3
It was developed for the plastics and rubber industry in 1960. The molecule has 2
identical groups of 3ry butylphenol groups linked by a dithiopropylidene bridge,
giving it a high lipophilic character with strong antioxidant properties. In humans
it reduces LDL and causes reduction of both liver and serum cholesterol.
12
5.1.4. HMG-CoA Reductase Inhibitors (Statins)
O
CH3
-OOC-CH -C-CH -C-SCoA
2
2
CH3-C-SCoA
Acetyl CoA
acetyl coenzyme A
O
d
HMG CoA
Reductase
HMG CoA
OH
3-hydroxy-3-methyl-glutaryl-CoA
d
Mevalonic Acid
d
Cholesterol
CH3
CH3
CH3
CH3
HMG CoA
reductase
CH3
CH3
-OOC-CH -C-CH -CH -OH
2
2
2
OH
mevalonate
HO
cholesterol
Statins are most effective cholesterol lowering drugs. Statins lower
total cholesterol and LDL particles, they are competitive inhibitors.
The HMG-CoA has a conformation similar to the lactone moiety of
statins resulting in binding at the same site without any productive
effect.
13
O
HO
O
HO
COONa
OH
HO
COOH
SCoA
O
For example,
Mevastatin
Lovastatin
Simvastatin
For example,
Fluvastatin
Atorvastatin
Cerivastatin
HMG CoA substrate
competitive binding due to Similarity in conformation of the active
moiety.
14
Statins
Inhibit the rate limiting step in cholesterol biosynthesis (HMG
CoA reductase)
• Lower total cholesterol and LDL
• Competitive inhibitors with affinity higher than the substrate
(HMG CoA)
•
HO
R'
O
R
O
O
O
CH3
R
R
O
O
CH2CH2
CH3
R'
Mevastatin H
Lovastatin H
Simvastatin CH3
R''
H
CH3
CH3
COONa
OH
CH2CH2
CH3
HO
R''
15
HO
R
Pravastatin
CH3
Statins
HO
F
H2C
N
_
COO Ca+
OH
HO
F
CH2
CH3
CH3
CH3
O
NH
CH3
H3C
O
16
COONa
OH
F
CH3
N
N
H3C
CH3
CH3
Cerivastatin
Atorvastatin
HO
COONa
OH
Fluvastatin
All statins are highly protein bound (95-98%) except for pravastatin (50%)
 Most
statins have a short half-life of about 1-3 hr except for
atorvastatin which has a t1/2 of about 14 h.
17
Bioavailabilty
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%
5.2. Drugs affecting intestinal absorption and reabsorption
5.2.1. Ion-Exchange Resins and Sitosterol
Enterohepatic
Circulation of Bile
Liver
Bile acid binding resins prevent
the reabsorption of bile acids,
causing them to be eliminated
via the large bowel. This forces
the liver to remove cholesterol
from the circulation (via an
upregulation of LDL-C
receptors) in order to make
more bile, causing a decreases
systemic cholesterol levels.
Gall
Bladder
Small
Intestine
18
Bile acids are created in the
liver using cholesterol and are
secreted into the small intestine
to aid in digestion. They are
reabsorbed in the distal end
and are taken back to the liver
in the portal circulation.
Side effects:
Constipation
Dyspepsia
Gas bloating
Colestipol and cholestyramine are anion exchange resins that are
approved in 1970s for the reduction of elevated serum cholesterol
in patients with hypercholesterolemia.
One of greatest advantage of these polymeric agents is that they
can be safely used for pregnant women.
19
H3C
b-Sitosterol
CH3
CH3
It has a structure very similar to that
of cholesterol, it inhibits cholesterol
absorption competitively.
CH3
CH3
CH3
HO
Ezetimibe
OH
OH
N
F
O
F
It is a once-daily orally active cholesterol
absorption inhibitor, launched in 2002 as a
hypolipidemic agent. It acts in the
intestinal wall to inhibit cholesterol
absorption through a novel mechanism
with an as yet undiscovered target
It has no significant effect on the activity of the major drugmetabolizing enzymes.
20
5.3. Thyroxine Analogs
Thyroid hormones increase the catabolic rate of cholesterol and the elimination
of LDL from the plasma, but LDL synthesis remains unchanged.
Dextrothyroxine (D-Thyroxine).
I
I
NH2
HO
I
I
21
CO2H
6. Anticoagulants
Compounds that do not allow blood to clot are called
anticoagulants.
Drugs that dissolve pre-formed clot including streptokinase are not
referred to as anticoagulants.
Hemostasis is a combination of events that occur due to physical
and chemical forces. The initial steps lead to a reduction in the
blood flow due to the formation of a cellular plug. The later steps
utilize chemical energy to form a blood clot, medically known as
thrombus.
22
The Physical Process
23
Types of Anticoagulants
6.1. Endogenous Inhibitors of Clotting
6.2. Exogenous Inhibitors of Clotting
The control of clotting is a major medical concern. Several
inhibitors have been developed with different mechanisms of
anticoagulant action. These include:
6.2.1. Heparins
Heparin is a mucopolysaccharide with a molecular weight ranging
from 6,000 to 40,000 Da. The average molecular wt. of most
commercial heparin preparations is in the range of 12,000 - 15,000.
24
25
The polymeric chain is composed of repeating disaccharide unit of
D-glucosamine and uronic acid linked by 1¯¯>4 interglycosidic bond.
O3SO
O3SO
O3SO
COO
CH2
O
O
OH
OH
SO3
OH
O
O
O
COO
OH
OSO3
O
HN
O
O
OH
O
CH2
CH2
OSO3
HN
O
O
HN
SO3
SO3
Few hydroxyl groups on each of these monosaccharide residues
may be sulfated giving rise to a polymer with that is highly
negatively charged.
26
SAR
1. The key structural unit of heparin is a unique
pentasaccharide sequence. This sequence consists of
three D-glucosamine and two uronic acid residues.
2. The central D-glucosamine residue contains a unique 3O-sulfate moiety that is rare outside of this sequence.
3. Four sulfate groups on the D-glucosamines are found to
be critical for retaining high anticoagulant activity.
Elimination of any one of them results in a dramatic
reduction in the anticoagulant activity.
4. Removal of the unique 3-O-sulate group results in complete
loss of the anticoagulant activity. Removal of sulfate groups
other than the critical ones seems to not affect the
anticoagulant
activity.
27
Only a third of the chains in commercial heparin
preparations have this unique pentasaccharide sequence.
Thus, more than 2/3rd of heparin chains are probably
not active as anticoagulants. LMW heparin preparations
may have considerably varying proportion of chains with
the active site.

Metabolism
Partially metabolized in the liver by heparinase to
uroheparin, which has only slight antithrombin activity,
20-50% is excreted unchanged.
28
Low-Molecular-Weight Heparins (LMWH)
They are preparations that have lower average
molecular weight than heparin. The average molecular
weight of these LMWH typically ranges from 2,000 to
8,000 Da.
They are made by enzymatic or chemical controlled
hydrolysis of unfractionated heparin. These molecules
have very similar chemical structure as unfractionated
heparin except for some changes that may have been
introduced due to the enzymatic or chemical treatment.
The overall advantage in the use of these LMWH
appears to be in the decreased need for monitoring
patients in comparison to heparin.
29
Properties of Heparin
Because of its highly acidic sulfate groups, heparin (or LMW
heparins) exists as a polyanion at physiologic pH.
–
–The heparin polysaccharide chain is degraded in the gastric
acid and must therefore be administered intravenously or
subcutaneously.
– LMW heparin, because of its smaller
bioavailable when given subcutaneously.
size,
is
more
– Heparin is typically not given intramuscularly because of the
danger of hematoma formation.
– Peak activity of heparin is reached within minutes of
administration and is found to last 2-6 h (iv) or 8-12 h (sc).
– Heparin is relatively non-toxic and can be safely used in
pregnancy because it does not cross the placental barrier.
30
Heparin overdose or hypersensitivity may result in
excessive bleeding.
–
– If hemorrhage occurs the anticoagulant effect of
heparin can be reversed in minutes by administration of
protamine sulfate, a low molecular weight protein that
has multiple positively charged groups.
31
Fondaparinux sodium
It is introduced in 2002 in the US for prophylaxis of
deep vein thrombosis which may lead to pulmonary
embolism following major orthopaedic surgery.
–
It is the first of a new class of antithrombic agents
distinct from LMWH and heparin. This entirely
synthetic molecule is a copy of pentasaccharide
sequence.
–
32
6.2.2. Coumarins
Coumarin and its derivatives are principal oral anticoagulants.
Coumarin is water insoluble, however 4-hydroxy substitution
confers weakly acidic properties to the molecule that makes it
water soluble under slightly alkaline conditions.
The followings are the structures of coumarin and its derivatives (Coumarin,
4Hydroxycoumarin, Warfarin and Dicoumarol) :
33
Warfarin is marketed as the sodium salt as racemate , however,
The S(-) isomer is about 5 - 8 times more potent than the R(+)
isomer.
34
Warfarin is a competitive antagonist of Vitamin K
35
Warfarin inhibits the vitamin K cycle
Warfarin
Epoxide
Reductase
CYP2C9
Inactivation
Pharmacokinetic
 -Carboxylase
36
Vitamin K-dependent clotting factors
(FII, FVII, FIX, FX, Protein C/S/Z)
Synthesis of Warfarin
O
O
O
OH
OH
(CH3CO)2O
OH
Strong base
Nonaq.
OH
O
O
CH3
CH2
O
O
O
O
O
O
CH3
O
ONa
37
O
O
SAR :
The minimal requirements for anticoagulant activity are:
1. 4-hydroxy group.
2. A 3-substituent.
ASSAY of Warfarin (EURP 2000)
Spectrophotometric assay of the its alkaline solution (NaOH) at
the maximum at 308 nm.
38
6.2.3. 1,3-Indanediones
The 1,3-indanediones have been known to be anticoagulant since
1940s. A commercially available indandione is anisindione.
The molecule has a weakly ionizable proton on C-2 that is extracted
in alkaline solutions to confer mildly soluble properties.
O
O
H
OH
OCH3 +
39
O
O
OCH3
H2O
The anion so formed in alkaline solutions is reddish orange. Thus patients on anisindione treatment may be
alarmed to see reddish colored urine. This phenomenon
may be easily distinguished from hematuria by
acidification of the urine which should remove the red
color.
6.2.4. Platelet affecting Drugs
6.2.4.1. Inhibition of prostaglandin (PG) synthesis
Substances that inhibit PG synthesis can prevent only one
of the pathways by which platelets are able to mediate
thrombogenesis. They include COX inhibitors
40
Acetylsalicylic acid (Aspirin)
COOH
CH3
O
O
2-Acetoxybenzoic acid
It inhibits the platelet aggregation in a dose ranging from 160-230
mg.
41
6.2.4.2. Substances influencing cAMP
Increase of cAMP prevents the initial shape changes of
the platelets, their adhesion to surface, the aggregation
and release reaction.
Prostacyclin
CO2H
HO
O
OH
It is the most active platelet aggregation inhibitor. It has a
very short duration of action so it is administered in
continuous infusion. It is unstable in aq. soln, its sod. salt
is42more stable in solid form.
6.2.4.3. Inhibition of platelet-specific agonists-receptor
interaction.
The platelets are activated by substances that interact
with specific receptors in the plasma membrane. Thus
inhibition of these substances will limit the activation.
Ticlopidine
Cl
S
N
It is a long acting platelet aggregation inhibitor (24-48
hrs).
43
44
From: Cleveland Clinic Journal of Medicine; 66(10):615
Direct Thrombin Inhibitors
HIRUDIN – Isolated from leech, hirudino medicinalis. A polypeptide consisting of 65
amino acid residues that binds thrombin in the active site as well as another site called
exosite I
O
H2N-D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly
S
H O
N
H
O
COOH
N
CH3
HOOC-Leu-Tyr-Glu-Glu-Pro-Ile-Glu-Glu-Phe-Asp
H3C
Bivalirudin
NH
Argatroban H2N
O
O
RO
O
N
H
N
O
N
N
RO
H
N R'
O
NH
N
N
N R'
N
N
H
CH3
NH2
NH2
Ximelagatran R = -CH2CH3; R’ = -OH
Melagatran R = -H;
R’ = -H
Dabigatran etexilate R = -CH2CH3; R’ = -COO-nC6H13
Dabigatran
R = -H;
R’ = -H
Figure 2. Structures of direct thrombin inhibitors (DTIs). Shaded oval represents the guanidine or
amidine group that mimics the arginine side chain of the P-1 residue recognized by thrombin.
45
6.2.5. Miscellaneous Anticoagulants
Citric Acid
Sodium citrate is an anticoagulant in vitro.
Sodium citrate cannot be used in vivo because of the toxic
manifestations of sequestering Ca+2 ions.
46
Chelation of Ca2+
Clot prevention
Blood Clotting
Clinical Application
Chelate: claw
O
C
R
Metabolic and Chemical Chelators
O–
Ca2+
C
C
O–
O
Structure
representations
COO–
R
Ca2+
COO–
COOH
HO
COO–
COO–
Ca2+
COO–
COO–
oxalate
citrate
Use: ● collect donated blood
● inhibit blood clotting
O
C
O–
O–
Ca2+
C
C
N
H
O–
Ca2+
O–
C
O
C
O
C
N
47
H
O
EDTA is used
• to detoxify workers exposed to toxic
heavy metals, e.g., Pb, Cd …
• to decalcify atherosclerotic plaques
(chelation therapy) that slows, halts,
or reverses progressive hardening of
arteries that can trigger clots (via
platelet plugs and/or fibrin) thereby
lowering risk for stroke and heart
attacks.
Ca2+
Ethylenediaminetetraacetic acid
(EDTA, Versene)