The document discusses various classes of antilipidemic drugs and their mechanisms of action. It describes: 1) HMG-CoA reductase inhibitors like lovastatin, simvastatin, and pravastatin which work by inhibiting the HMG-CoA reductase enzyme, a key step in cholesterol synthesis. This lowers cholesterol production and increases LDL receptors. 2) Fibric acid derivatives like clofibrate and gemfibrozil which lower triglyceride levels more than cholesterol by inhibiting triglyceride synthesis. 3) Nicotinic acid which reduces free fatty acid release from fat tissues, lowering triglyceride production in the liver and cholesterol levels. 4)

1. Antilipidemic drugs

2. Learning outcomes
◼ Describe the chemistry of antilipidemic drugs.
◼ Describe the differentiation between the
different classes from chemical structures
and chemical names.
◼ Describe their structure-activity relationship.
◼ Describe the mechanism of action.

3. Lipoprotein class
◼ Lipoproteins are macromolecules consisting of lipid
substances like cholesterol and triglycerides
◼ Noncovalently bound with proteins (lipoproteins) and
carbohydrates(glycolipids).
◼ These combinations solubilize the lipids and prevent
them to form insoluble aggregates in the plasma.
◼ They have special shape and consist of a non polar
core surrounded by a monolayer of phospholipids
whose polar groups are oriented toward the lipid
phase of the plasma.
◼ A small number of cholesterol molecules and proteins
termed as apolipoproteins.
◼ These apolipoproteins appear to be able to solubilize
lipids for transport in an aqueous surrounding such as
plasma.

5. Hyperlipoproteinimias
◼ HMG CoA reductase inhibitors:
❑ Drugs inhibit the enzyme HMG-CoA (Hydroxy
Methyl glutaryl coenzyme A) which is
responsible for the conversion of HMG-CoA to
mevalonate in the synthetic pathway of
cholesterol.

6. Drug therapy
◼ Clofibrate, chemically known as ethyl-2-(p-
chlorophenoxy)-2-methyl propionate
• It is stable, colorless to pale
yellow liquid with faint odor and
characteristic taste.
•Soluble in organic solvents and
insoluble in water.
•It is an acid and esterifies to
clofibrate.
•Both acid and ester are active.
•Ester preferred for medicinal use

7. Clofibrate
◼ It is hydrolyzed rapidly to 2-p-chlorophenoxy-2-methyl
propionic acid by esterase in vivo.
◼ This acid is used as a hypolipidemic agent.
◼ It is absorbed more slowly and to a smaller extent than
ester.
◼ The aluminum salt of an acid gives even lower blood
levels than p-chlorophenoxy-2-methyl propionic acid.

8. Clofibrate
◼ It is a lipid lowering agent used for controlling the high cholesterol
and triacylglyceride level in the blood.
◼ It lowers triglyceride levels in the serum much more than
cholesterol levels and decrease the levels of FFAs and
phospholipids.
◼ It inhibits the incorporation of acetate into the synthesis of
cholesterol, between the acetate and mevalonate step, by
inhibiting glyceryl-3-phosphate acyl transferase.
◼ It regulates cholesterol synthesis by inhibiting 3-hydroxy-3-methyl
glutarate coenzyme A catalyzed by HMG-CoA reductase.

9. HMG CoA
reductase

10. Gemfibrozil
◼ 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid.
◼ It is similar in action to clofibrate.

11. Gemfibrozil
◼ It reduces plasma levels of VLDL triglycerides and
stimulates clearance of VLDL from plasma.
◼ It has little effect on cholesterol plasma levels but does
not cause an increase of HDL.
◼ It absorbs quickly form the gut and excreted unchanged
in the urine.
◼ The drug has plasma half-life of 1.5 hours, but reduction
of plasma VLDL concentration takes between 2-5 days
to become evident.

12. Fenofibrate
◼ 2-[4-(4-chlorobenzoyl)phenoxy]-2-methyl propionic acid-1-
methylethyl ester.
◼ It has structural features represented in clofibrate.
◼ The primary difference involves the second aromatic ring.
◼ This imparts a greater lipophilic character than exists in clofibrate,
resulting more potent hypocholesteromic and triglyceride lowering
agent.
◼ This structural modification results in a lower dose requirement than
with clofibrate or gemfibrozil.
Clofibrate Fenofibrate

13. Dextrothyroxine Sodium
◼ O-(4-hydroxy-3,5-diiodophenyl)3,5-diiodo-D-tyrosine
monosodium salt hydrate.
◼ It occurs as a light yellow powder.
◼ It is stable in dry air, but discolors on the exposure to
light.
◼ It should be stored in light resistant containers.
◼ Slightly soluble in water, slightly soluble in alcohol
and insoluble in acetone, chloroform and ether.

14. Mechanism of action
◼ It appears to be stimulation of oxidative catabolism of
cholesterol in the liver through stimulation of 7-α-
cholesterol hydroxylase, the rate limiting enzyme in
the conversion of cholesterol to bile acids.
◼ The bile acids are conjugated with glycine or taurine
and excreted by the biliary route in the feces.
◼ It increases the number of LDL receptors, enhancing
removal of LDL from plasma.

15. Cholestyramine resin
◼ It is a chloride form of a strongly basic anion exchange
resin. It is a styrene copolymer with divinyl benzene with
quaternary ammonium functional groups.
◼ It is a useful agent in lowering plasma lipids.
◼ It remains in GI tract, where it readily exchanges
chloride ions for bile acids in the small intestine, to
be excreted as bile salts in the feces.

16. Mechanism of action
◼ Reduce the amounts of reabsorbed bile acids
◼ It results in increased catabolism of cholesterol
in the liver.
◼ It increases hepatic breakdown of cholesterol
leading to lower cholesterol levels.

17. Colestipol HCl
◼ High molecular weight, insoluble, copolymer of
tetraethylene pentamine and epichlorohydrin.
◼ It works like a anion exchange, resin-
sequestering agent.
◼ It reduces cholesterol levels without affecting
triglycerides.
Tetraethylene pentamine
Chlorohydrin

18. 1 2
3
4
Colestipol HCl

19. Nicotinic acid(1), β-Sitosterol(2)
1
2

20. Chemistry of Niacin
◼ Niacin (nicotinic acid) may be administered as
aluminum nicotinate. This is a complex of
aluminum hydroxy nicotinate and niacin.
◼ The aluminum salt is hydrolysed to aluminum
hydroxide and niacin in the stomach.
◼ Nicotinic acid has been esterified to prolong its
hypolipidemic effect.

21. Chemistry and physicochemical
propeties of niacin
◼ Pentaerythritol tetranicotinate is more
effective than niacin in reducing
cholesterol.
◼ Sorbitol and Myo-inositol hexanicotinate
polyesters are being used in the treatment of
atherosclerosis.

22. Mechanism of action
◼ The hypolipidemic effect of niacin may be
due to:
❑ The ability to inhibit lipolysis to prevent the release
of FFAs and glycerol from fatty tissues.
❑ There is a reduced reserve of FFA in the liver and
reduced lipoprotein biosynthesis, which
reduces the production of VLDL.
❑ The decreased formation of lipoprotein leads to
the pool of unused cholesterol associated with
VLDL and excreted through biliary duct.

23. β-Sitosterol(A) and Cholesterol(B)
◼ β-Sitosterol is a plant sterol.
◼ Its structure is identical as cholesterol except for the
substituted ethyl group at C-24 of its side chain.
◼ Sitosterols are absorbed poorly from the mucosal
lining and appear to compete with cholesterol for
absorption sites in the intestine.

25. HMG-CoA reductase
inhibitors

26. ◼ Drugs inhibit the enzyme HMG-CoA reductase,
responsible for the conversion of HMG CoA to
Mevalonate.
◼ Mevalonate is key intermediate in the synthesis
of cholesterol.
HMG CoA

27. Function and inhibition of HMG CoA
◼ HMG CoA reductase inhibitors contribute by
blocking the action of HMG CoA enzyme.
◼ It causes lowering cholesterol synthesis and
increase in hepatic LDL receptors.

28. ◼ Drugs in this class of hypolipidemic agents inhibit the
enzyme HMG-CoA reductase, essential in synthesis of
cholesterol.
◼ HMG-CoA reductase inhibitors directly block the active site
of the enzyme(HMG CoA) which has a twofold effect on
cholesterol plasma levels:
a) Decrease in de novo cholesterol synthesis.
b) Increase in hepatic LDL receptors.
HMG-CoA REDUCTASE INHIBITOR

30. HMG CoA Reductase Inhibitors
Rate
limiting
control of
cholesterol
synthesis
(secreted
in lipoproteins)
HMG COA
Mevastatin
(compactin)
Lovastatin
(mevinolin)
Simvastatin
(Synvinolin)
Prevastatin
CS 514,
SQ 31000
Fluvastatin
(Fluindostatin,
SRI 62320)
(Lactone form) (Lactone form) (Lactone form)
Statins are pharmacologic targets to
 Reduce hepatic production
 Peripheral catabolism

31. Statins
◼ ML-236B was later called Compactin(6-demethylmevinolin
or mevastatin). A related fungal metabolite called lovastatin
(mevinolin) was also found to be another good inhibitor of
HMG-CoA reductase. Lovastatin was isolated from
Aspergillus terreus.
compactin
lovastatin
•Today, there are two classes of statins:
Natural Statins: Lovastatin(mevacor),
Compactin, Pravastatin (pravachol),
Simvastatin (Zocor).
Synthetic Statins: Atorvastatin (Lipitor),
Fluvastatin (Lescol),Rosuvastatin.
•Statins are competitive inhibitors of
HMG-CoA reductase. They are bulky and
literally get “stuck” in the active site.
This prevents the enzyme from binding
with its substrate, HMG-CoA.
Ester side-chain

32. Drugs as HMG CoA reductase
inhibitors
◼ Three drugs lovastatin, simavastatin and pravastatin.
◼ These three drugs have similar selection to the substrate
and having minor structural differences.
◼ Lovastatin and simavastatin are lactones and
prodrugs activated by hydrolysis in the liver to their
respective β-hydroxyacids.
◼ Pravastatin is administered as sodium salt of β-
hydroxyacids.

33. Lovastatin
Different Structures of Statins

34. Simvastatin (liphophilic statin)

35. Pravastatin : No lactone ring (hydrophilic statin)

36. Fluvastatin

37. Recent Advances
Atorvastatin

38. Cerivastatin

39. Rosuvastatin

40. Pitavastatin

41. Target: HMG-CoA Reductase (HMGR)
The enzyme that catalyzes
the conversion of HMG-
CoA to mevalonate.
This reaction is the rate-
determining step in the
synthetic pathway.
+ HSCoA
H2C
C
CH3
HO
CH2
C
−
O O
C SCoA
O
H2C
C
CH3
HO
CH2
C
−
O O
H2
C OH
2NADP+
2NADPH
HMG-CoA
mevalonate
HMG-CoA
Reductase
3-hydroxy-3-methylglutaryl-coenzyme A (HMG-
CoA)

42. Thank You