Introduction. Classification . Drugs used in Anti Hyperlipidaemics Agents Mechanism of action . SAR. Structure Adverse Drug Reactions . Uses.

1. 3RD UNIT
ANTI-HYPERLIPIDEMIC
AGENTS
Prepared by
G. Nikitha, M.Pharmacy
Assistant Professor
Department of Pharmaceutical Chemistry
Sree Dattha Institute Of Pharmacy
Hyderabad
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Subject: Medicinal Chemistry-II
Year: B.Pharmacy 3rd Year
Semister: 1st Semister

2. CONTENTS
 Introduction.
 Classification .
 Drugs used in Anti Hyperlipidaemics Agents
 Mechanism of action .
 SAR.
 Structure
 Adverse Drug Reactions .
 Uses.
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3. INTRODUCTION
 Lipids are naturally fat like components of cells in the body.
 Although body synthesis the required amount of lipids additional
amount is derived from food and can be harmful.
 These plasma lipids are water insoluble and hence need to
transported through carriers known as lipoproteins.
 An increase in lipid particularly cholesterol a condition involving
damage of heart.
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4. Lipoproteins are of 4 types:
 High density lipoprotein (HDL)
 Low density lipoprotein (LDL)
 Intermediate density lipoprotein (IDL)
 Very low density lipoprotein (VLDL)
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5. CLASSIFICATION
1. HMG-COA reductase inhibitors:
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Simvatain
Metastatin
Lovastatin

6. 6
Pravastatin Atorvastatin
Rosuvastatin

7. 2. Fabric acid derivative:
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Clofibrate Gemfibrozil

8. 8
benzafibrate
Fenofinrate
Ciprofribrate

9. 3. Bile acid Sequestrantes
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Cholestyramine
Colestipol

10. 4. Inhibition of LDL oxidation
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Probucol
5. Lypolysis/ Triglyceride synthesis inhibitor
Nicotinic acid

11. 6. Miscellaneous drugs
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Ezetimibe
Dextrothyroxine
β-sitosterol

12. 7. New Drugs
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Patavastain

13. HMG-COA REDUCTASE INHIBITORS
13

14. 1. HMG-COA reductase inhibitors:
This class of drug is known to be the most efficient and best
tolerated among all other antihyerlipidaemic drugs.
Mechanism of action:
Cholesterol is synthesizes in the liver by the conversion of 3-
hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonic
acid by the enzyme HMG-CoA reductase. Statins act by inhibiting
this rate limiting enzyme, thereby resulting in reduced hepatic
cholesterol synthesis. This in turn results in compensatory increase
in synthesis of high affinity LDL receptors on the surface of liver
cells and consequent increase in the uptake and catabolism of
plasma IDL and LDL. Thus a significant decrease in plasma LDL
cholesterol levels is achieved. 14

15. SAR of HMG-COA reductase inhibitors :
 Mevastatin and Lovastatin are the lead compounds in the
development of HMGRIs.
 Lactone ring, bicyclic rings Ethylene Bridge are very important for
the activity.
 Provastatin is the ring opened dihydroxyacid with a 6 hydroxyl
group is more hydrophilic. So it has the low penetration to the
peripheral tissues and less side effects.
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16. Common for all statins
 The 3,5 dihydroxycarboxylate is essential for inhibitory activity.
Compounds containing a lactone are prodrugs requiring in vivo
hydrolysis.
 The absolute stereochemistry of the 3-and 5-hydroxyl groups must
be same as the Mevastatin and Lovastatin.
 A double bound between C6 and C7 can either increase or decrease
activity. The ethyl group provides optimal activity for compounds
containing ring A and some heterocyclic rings (pyrrole ring of
atorvastatin). The ethenyl group is optimal for compounds with other
rings such as indole and pyrimidine rings seen in fluvastatin and
cerivastatin.
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17.  Ring A sub class- the decline ring is essential for anchoring the
compound to the enzyme active site. Replacement with the
cyclohexane ring resulted in 10,000 fold decrease in activity.
 Stereochemistry of the ester chain is important for activity, the
conversion of this ester to an ether resulted in a decrease in activity.
 Methyl substitution at R2 position increases activity (simvastatin is
more potent than Lovastatin).
 β hydroxyl group substitution at R1 position enhances
hydrophilicity and provides some cellular specificity. 17

18.  Ring B sub class- either zero or one (five or six member
heterocyclic).
 The para-flurophenyl cannot be coplanar with the central aromatic
ring. (Structural restraints to cause coplanarity have resulted in a loss
of activity).
 R substitution with aryl groups of hydrocarbon chains enhances
lipophilicity and inhibitory activity.
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19. Pharmacokinetics:
All strains of oral administration get absorbed to the extent of 40-
90% except fluvastatin which is completely absorbed. Lovastatin
and simvastatin are prodrugs which get hydrolysed to active
metabolites in the GIT while atorvastatin, fluvastine, rosuvastatin are
fluorinated compounds which are activate drugs. All statins undergo
first pass metabolism and excreted mainly through bile.
Adverse Drug Reactions:
 Nausea, headache, rashes, and bowel upset
 Sleep disturbances
 Memory loss, impotence, gynaecomatia, peripheral neuropathy
 Liver damage
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20. Therapeutic Uses:
 Statins are useful in both primary and secondary
hypercholesterolaemia. They cause reduction in the progression of
atherosclerotic lesions and occurrence of myocardial infarction.
 Statins are the first line drugs for primary hyperlipidaemics which
increased LDL and total cholesterol level.
 They are used to reduce the incidence of myocardial infarction in
patients
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21. Lovastatin
Structure:
IUPAC: 8-{2-[-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-
hexahydronaphthalen-1-yl -2-methylbutanoate
Properties:
white or almost white crystalline powder, insoluble in water, soluble
in acetone and sparingly soluble in ethanol, practically insoluble
in hexane.
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Molecular formula: C24H36O5

22. Pharmacokinetics:
Oral route of administration, Lovastatin is given as a lactone prodrug
and thus, in order to produce its mechanism of action, it is required
to be converted to the active beta-hydroxy form. This drug activation
process does not seem to be related to CYP isoenzyme activity. but
rather to be controlled by the activity of serum paraoxonase,
Following an oral dose of 14C-labeled lovastatin to man, 10% of the
dose was excreted in urine and 83% in feces. The latter represents
absorbed drug excreted in bile, together with unabsorbed drug.
Adverse Drug Reactions:
 pain in your stomach area, constipation
 Nausea, headache
 Heartburn, memory loss/forgetfulness
 weakness/lack of energy, muscle pain
 Confusion, inability to fall asleep 22

23. Therapeutic Uses:
 Lovastatin is used to decrease the amount of cholesterol and other
fatty substances in your blood.
 If cholesterol builds up in your arteries, it may block the flow of
blood to your heart, brain, or other parts of your body. This raises
your risk of serious problems, such as a heart attack or stroke.
Lowering your cholesterol level lowers these risks
Dose:
10-80 mg/ day
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24. FABRIC ACID DERIVATIVE
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25. 2. Fabric acid derivative
This groups of drugs are derivatives of fibric acid like isobutyric acid
and include gemfibrozil, benzafibrate, fenofibrate.
Mechanism of action:
 These are known to simulate the nuclear transcription receptor called
peroxisome proliferator activated receptor-α (PPAR-α) which
controls the expressions of genes mediating triglyceride metabolism.
 They enhance the activity of lipoprotein lipase (LPL) which is
responsible for the hydrolysis of VLDL triglycerides. Hence
incorporation of fatty acids into VLDL in the liver is decreased and
there by synthesis and secretion of VLDL is inhibited.
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26. SAR of Fabric acid derivative:
 Isobutyric acid group is essential for activity.
 Compounds containing an ester, such as clofibrate and fenofibrate
are prodrugs and require in vivo hydrolysis.
 Substitution at para position of the aromatic ring with a chloro group
or a chlorine containing isopropyl ring produce compound with
significantly longer half life.
 Most of drugs contain a phenoxyisobutyric acid, the addition of an
m-propyl spacer as seen in gemfibrozil results in an active drug.
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27. Pharmacokinetics:
They are completely absorbed from the gastrointestinal tract. They
mostly exist in protein bound form and are mainly excreted in an
unchanged through urine.
Adverse Drug Reactions:
 Allergic reactions, nausea, diarrhea are common side effects.
 Weight gain
 Increase in serum amino transferases or alkaline phosphatase levels
and reversible myopathy have also reported.
 Chronic therapy may increases the risk of gall stone formation.
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28. Therapeutic Uses:
 Fibrates are the first line drugs used in the treatment of
hypertriglyceridaemic especially those associated with low HDL-C
level.
 They are effective in decreasing genetic hypertriglyceridaemic and
dysbetalipoproteinaemia.
 They are also effective in treating familial combined
hypertriglyceridaemia and hyperlipidaemics associated with type-2
diabetes.
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29. Clofibrate
Structure:
IUPAC: ethyl 2-(4-chlorophenoxy)-2-methylpropanoate
Properties:
Colorless to pale yellow liquid, faint characteristic odor, faint
characteristic taste, insoluble in water, soluble in alcohol,
chloroform, miscible with acetone and ether.
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Molecular Formula: C12H15ClO3

30. Pharmacokinetics:
Oral route of administration, Hepatic and gastrointestinal: rapid de-
esterification occurs in the gastrointestinal tract and/or on first-pass
metabolism to produce the active form, clofibric acid (chlorophenoxy
isobutyric acid [CPIB]), eliminated through urine.
Adverse Drug Reactions:
 Head ache, Nausea , Vomiting
 Fever
 Blood in urine
 Sweating of feet
 Increase of appetite, Stomach pain, gastric problems
 Weight gain
 Chest pain
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31. Therapeutic Uses:
 Used in the treatment of III, IV, V hyperlipidaemics
 They are also effective in treating familial combined
hypertriglyceridaemia and hyperlipidaemics associated with type-2
diabetes.
Dose:
5 to 2 grams a day. This is divided into two to four doses.
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32. BILE ACID SEQUESTRANTES
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33. 3. Bile acid Sequestrantes
Mechanism of actions:
They are insoluble non-absorbable basic anion exchange resins
which bind with bile acids and form insoluble complexes in the
intestine which gets excreted in faces.
Adverse Drug Reactions:
 Head ache, Vomiting
 Constipation, Heart burn are common
Therapeutic Uses:
 Cholestyramine is used as an anti-hyperlipidaemic in children and
pregnant women.
 It is also used in treating pruritus associated with biliary cirrhosis
and cholestatic jaundice. 33

34. SAR of Bile acid Sequestrantes:
 Cholestyramine is a copolymer consisting primarily of polystyrene
with small amount of divinyl benzene as a cross linking agent.
 In addition it contains some fixed quaternary ammonium groups.
 These positively charged groups function as binding sites for anions.
 Colestipol is a copolymer of tetraethylenepentamine and
epichlorhydrin. It contains basic secondary and tertiary amines.
 Total nitrogen content of Colestipol is greater than Cholestyramine
the functional ion exchange capacity of the resin depends upon
intestinal pH and may be less than Cholestyramine.
 The adsorption capacity of Cholestyramine for bile salts is more
than the Colestipol.
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35. Cholestyramine
Structure:
IUPAC: [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium
Properties:
White or almost white fine powder, hygroscopic insoluble in water,
methylene chloride, ethanol.
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Molecular Formula: C21H30ClN

36. Pharmacokinetics:
Oral route of administration, metabolized through bile acids.
Cholestyramine resin adsorbs and combines with the bile acids in
the intestine to form an insoluble complex which is excreted in the
feces.
Adverse Drug Reactions:
 Constipation.
 Upset stomach or stomach pain.
 Diarrhea or loose stools.
 Nausea.
 Vomiting.
 Belching.
 Loss of appetite.
 Skin irritation.
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37. Therapeutic Uses:
Cholestyramine is used to reduce high cholesterol levels. It's given to
people with high cholesterol who haven't been able to lower their
cholesterol enough with diet changes. This drug is also used to treat
itching due to partial bile obstruction.
Dose:
4 to 16g/day
37

38. Colestipol
Structure:
IUPAC: N'-[2-[2-(2-aminoethylamino)ethylamino]ethyl]ethane-1,2-
diamine;hydrochloride
Properties:
Yellow to orange beads, hygroscopic in nature, it does not dissolve
in water, dilute aqueous solution of acids and alkali, insoluble in
ethanol, dichloromethane. 38
Molecular Formula:C8H24ClN5

39. Pharmacokinetics:
 Oral route of administration, Colestipol hydrochloride binds bile
acids in the intestine forming a complex that is then ultimately
excreted in the feces. In humans, less than 0.17% of a single 14C-
labeled colestipol hydrochloride dose is excreted in the urine when
given following 60 days of chronic dosing of 20 grams of colestipol
hydrochloride per day.
 The increased fecal loss of bile acids due to colestipol hydrochloride
administration leads to increased oxidation of cholesterol to bile
acids, it is not absorbed into the systemic circulation nor is it
hydrolyzed by any digestive enzymes. Its action is ultimately limited
to the lumen of the gastrointestinal tract, where it is eventually
passed into the feces
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40. Adverse Drug Reactions:
 Constipation, Diarrhea
 stomach/abdominal pain, gas,
 Nausea and vomiting may occur.
 Weakness
 Confusion
 Rashes
Therapeutic Uses:
 It is used along with a proper diet to lower cholesterol in
the blood. Lowering cholesterol helps decrease the risk for strokes
and heart attacks.
Dose:
5-30 mg day
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41. Reference books
 Text book of Medicinal chemistry volume-1-3rd edition by
V.Alagarasamy.
 Text book of Medicinal chemistry volume-2-3rd edition by
V.Alagarasamy.
 Medicinal chemistry by Rama Rao Nadendla.
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42. THANK YOU
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