ANTIHYPERLIPIDEMIC AGENTS ppt

Tribhuwan University
Universal College of Medical Sciences
ANTIHYPERLIPIDEMIC AGENTS
PRESENTED BY:
SHESHBHAN CHAUDHARY
7th BATCH B.PHARMACY
UCMS, BHAIRAHAWA

Introduction
 Hyperlipidemia is a condition in which the levels of lipid or
fat i.e ( usually triglycerides and cholesterol) is elevated in
the blood .
 thus, to overcome such hyperlipidemia condition ,
antihyperlipidemic agents is used.
 Antihyperlipidemia agents are the diverse group of
pharmaceuticals that are used in the treatment of high
levels of fats (lipids), such as cholesterol, in the blood .
July 15, 2023
Medicinal chemistry II
2

 Hyperlipidemia describes the elevated plasma level of lipids
(usually cholesterol)that are usually in the form of
lipoproteins
 They are also called lipid-lowering drugs or hypoglycemic
drugs .
 Atherosclerosis, MI, stroke, Angina pectoris etc are risk
factors of hyperlipidemia
July 15, 2023 Medicinal chemistry II 3
Contd..

Types of hyperlipidemia
 Mainly divided into following two types
a) Primary hyperlipidemia:
It is caused due to genetic defect in single gene
b) Secondary hyperlipidemia:
They are associated with a more generalized
metabolic disorder like DM, hyperthyroidism, chronic
alcoholism, etc

 The plasma lipoproteins are chylomicrons ,
VLDL,IDL, LDL ,and HDL.
Normal plasma lipid levels (mg/dL)
Total cholesterol < 200
LDL cholesterol < 100
HDL cholesterol
. Men <40
. Women <50
Triglycerides <150

Causes of hyperlipidemia
 Important causes of hyperlipidemia are;
 Lifestyle(high fat diet ,lack of exercise )
Diabetes mellitus
 kidney diseases
 Hypothyroidism
 Genetic
 Alcohol
Drugs like- thiazides , cyclosporin, Glucocorticoids , Beta
blockers.

Biosynthesis of cholesterol
 The biosynthesis of cholesterol can be learned under 5
stages,
a) Synthesis of HMG coA
b) Formation of mevalonate (6C)
c) Production of isoprenoid units (5C)
d) Synthesis of squalene (30C)
e) Conversion of squalene to cholesterol(27C)
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Degradation of cholesterol

Classification
(HMG CoA) reductase inhibitor(statins): lovastatin ,
simvastatin , pravastatin
 Phenoxy isobutyricacid derivatives (fibrates) : clofibrate,
fenofibrate, Gemfibrozil
 Pyridine derivatives(niacin): Nicotinic acid
 Bile acid sequestrans(resins) : cholestyramine , colestipol
Cholesterol absorption inhibitor (Ezetimbe)
 Miscellaneous antihyperlipidemic agent : Gugulipid,
omega-3 fatty acid ,Thyroxine sodium
 LDL oxidation inhibitor: Probucol

A) HMG CoA REDUCTASE INHIBITORS

FIBRIC ACID DERIVATIVES

C) Pyridine derivatives
July 15, 2023
21

D) Bile acid subsequant

E) Cholesterol absorption inhibitor

F) Miscellaneous

G) LDL Oxidation Inhibitor

A) Statins
 They are the most effective agents for lowering of lipid
level in blood i.e first lines of drugs.
 They lower total cholesterol and LDL particles.
 They are competitive inhibitors of HMG-CoA reductase
enzymes which is the rate-limiting enzyme that is
responsible for cholesterol synthesis.
HMG-CoA has a conformation similar to the lactone moiety
of statins, results in binding at the same site without any
productive effect.

Contd..

B) Fibrates : Clofibrate
 Clofibrate is a stable , colourless to pale yellow liquid
with a faint odour and a characterstics taste.
It is soluble in organic solvent and insoluble in water.
drug of choice in the treatment of type III
hyperlipoproteinemias and lesser extent, in types IIb and
IV hyperlipoproteinemias. The drug is not effective in
types I and IIa.
July 15, 2023 medicinal chemistry II 29

Synthesis
 It is prepared by williamson synthesis, in which condensation of p-
chlorophenol with ethyl alpha- bromoisobutyrate or interaction of
mixture of acetone, p- chlorophenol and chloroform in the presence
of excess KOH or NaOH, the acid is formed further on esterification to
give clofibrate.

Mechanism of action
It stimulate Peroxisome Proliferator Activated receptors
[PPARs] which lead to
• Activate fatty acid oxidation and inhibit triglyceride
synthesis .
• Reduce expression of apo C III and enhance action of
lipoprotein lipase enzyme , significantly reduce VLDL level.
• Increase LDL receptor in the lever that result increase LDL
uptake and degradation.
On animal studies ,fibrates causes lowering of plasma
cholesterol by inhibiting cholesterol synthesis in liver and
by increasing biliary excretion of cholesterol into the feces

Metabolism
The prodrug fenoﬁbrate undergoes rapid hydrolysis to
produce fenoﬁbric acid. This active metabolite can then be
further metabolized by oxidative or conjugate pathways

SAR Of Fibrate

Contd..
 Isobutyric acid and phenoxy moiety is essential for activity.
 Compounds containing ester such as clofibrate and
fenofibrate is a prodrugs and requires in vivo hydrolysis.

 Substitution at the para position of the aromatic ring with
a chloro group or a chlorine containing isopropyl ring
produce a compound with significantly longer half life.
 Most of drugs contain a phenoxyisobutyric acid, the
addition of an n- propyl spacer, as seen in
gemfibrozil,results in an active drug.
 Fibric acid pka value is approximately 3.5.The fibrate
anion predominates at pH 7.4.
 Spacer groups augment molecular lipophilocity and
promote gastrointestinal and hepatic membrane
penetration
Contd..

 Side effect
Nausea and vomiting is common
dyspepsia , gall stone , esinophilia , dizziness ,headache
 Contraindication
in pregnancy, with anticongulant drugs the dose is
reduced by one third to one half to obtain desired
prothrombin time limits.
 Interaction
Gemfibrozil + statins increases the risk of myopathy.
Contd..

C) Pyridine derivatives
 Niacin (Nicotinic acid) is a water-
soluble B vitamin(B3) which inhibit the
synthesis of cholesterol and
triglycerides levels and rises HDL levels
 uses in hyperlipidemia ,in niacin
deficiency(pellagra), sometimes in
treatment of coronary artery diseases
(atherosclerosis).
 Administered in large doses (0.5 to 6
grams per day).

D) Bile acid subsequant
 Cholestyramine is a non –absorbed bile acid subsequent that
is used as a therapy of hyperlipidemia and for pruritis of
chronic liver diseases and biliary obstruction.
 It is a chlorine form of a strong basic anion exchange resin.

Contd..
Is a large, highly positively charged anion exchange resin
that binds to negatively charged anion such as bile acids.
It binds to bile acids creates an insoluble compound that
cannot be reabsorbed and is thus excreated in the feces.

E) Cholesterol absorption inhibitor
 Ezetimibe is an antihyperlipidemic agent that has
usefulness in lowering cholesterol levels. It acts by
decreasing cholesterol absorption in the intestine by
blocking the absorption of the sterol at the Brush
boarder.
 Useful in type IIa, IIb, IV, and V hyperlipidemia.
 Approved in october 2002.

F) Miscellaneous: THYROXINE SODIUM
Dextrothyroxine sodium (Choloxin), occurs as a light yellow to
buff powder. It is stable in dry air but discolors on exposure to
light; hence, it should be stored in light-resistant containers. It
is very slightly soluble in water, slightly soluble in alcohol, and
insoluble in acetone, chloroform, and ether.
It is a synthetic thyroid hormone .

SYNTHESIS

Contd..
 The synthesis comprises following steps:
a) Nitrating tyrosine to give 3,5-dinitro-tyrosine,
b) Acetylating 3,5-dinitro-tyrosine to give 3,5-dinitro-N-
acetyl-tyrosine,
c) Esterifying 3,5-dinitro-N-acetyl-tyrosine to give its ester
form,
d) Ester form again react with p- TsCl in the presence of
pyridine to give corresponding tosylate salt which further
react with 4-methoxy phenol to give 3,5-dinitro-4-p-
methoxy phenoxy-N-acetyl-phenyl alanine ethyl ester,

Contd..
e) The compound obtained from step (d) is hydrogenated to
give 3,5-diamino-4-p-methoxy phenoxy-N-acetyl-phenyl
alanine ethyl ester,
f) The compound obtained in step (e) is tetrazotized and
iodized to give 3,5-diiodo-4-p-methoxy phenoxy-N-acetyl-
phenyl alanine ethyl ester,
g) The compound obtained from step (f) is O- demethylated,
N- deacetylated, and deesterified using aqueous HI in acetic
acid to give 3,5-diiodo-4-p-hydroxy phenoxy-phenyl alanine
followed by preparing HCl salt of same and isolate it,

Contd..
h ) The isolated HCl salt form is then iodinating using methyl
amine ,iodine /KI to give dextro-thyroxine further treating
with sodium carbonate to give official compound i.e
dextrothyroxine sodium.

Mechanism of action
 Dextro-thyroxine appears to be stimulation of oxidative
catabolism of cholesterol in the liver through stimulation of
7-alpha-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 into the feces.
 Although thyroxine does not inhibit cholesterol
biosynthesis, it increases the number of LDL receptors,
enhancing removal of LDL from plasma.

Contd..

Contd..
 Side effects:
Hypersensitivity reaction , difficult breathing, swelling of
lips , arrhythmia , angina .
Interaction :
- with TCAs like amitriptyline which lead to nervousness, a
fast heart rate .
- with anticoagulants lead to bleeding.
 Uses:
- To lower the lipid level in blood( usually cholesterol)
- thyroid disorder

REFERENCES
 Wilson and Grisvold’s . textbook of Organic medicinal and
pharmaceutical chemistry (Twelfth edition )
 Tripathi, K.D., 1994. Essentials of medical pharmacology. Indian
Journal of Pharmacology, 26(2), p.16
 David A. Williams phD. Essentials of Foye`s principles of Medicinal
Chemistry-LWW(2016)
 https://www.ncbi.nlm.nih.gov/pmc/articles.
 https://patents.googles.com( synthesis of Levothyroxine
Sodium) .
 Alagarsamy, V. (2013). Textbook of Medicinal Chemistry Vol I-E-
Book, Elsevier Health Science
 Satyanarayana, U. and Chakrapani, U., 2008. Essentials of
biochemistry. Book and Allied, Kolkata, India,.
July 15, 2023
medicinal chemistry II
50

THANK
YOU!!!!!!!!!!
July 15, 2023
medicinal chemistry II
51

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