ADINA INSTITUTE OF PHARMACEUTICAL SCIENCES SAGAR ASS.PRF. IMRAN KHAN

3. •

4. •
(i) Low Density Lipoproteins (LDL): Due to further action of lipoprotein
lipase on IDL in the circulation, most of the remaining triglyceride content of IDL is
digested resulting into the loss of apoproteins C and E from their structure. The
density of particle is increased and diameter is brought down to 18 - 28 nm. These
particles are now termed as LDL which consist of cholesterol, phospholipids and
apoprotein B - 100. LDL also contains B - 74 and B - 26. They have longest plasma
half-life of about 1.5 days amongst the lipoproteins.
LDL Particles are finally delivered to hepatic and certain extrahepatic tissues for
further lysosomal degradation to release the cholesterol, which can be utilised in cell
membrane formation.

5. • Classification of antihyperlipidemic agents
(i) HMG-CoA-reductase Inhibitor: e.g. Lovastatin, Simvastatin, Pravastatin
(ii) Fibric acid derivatives: e.g. Clofibrate, Fenofibrate, Ciprofibrate,
Bezafibrate,
• Gemfibrozil
(i) Bile-acid sequestrants: e.g. Cholestyramine, colestipol
(ii) Inhibition of LDL oxidation: e.g. Probucol
(iii) Miscellaneous Agents: e.g. Nicotinic acid, Neomycin, β-Sitosterol,
Acipimox, Metformin, Dextrothyroxine

6. • A new class of fungal derived compounds are potent inhibitors
of the enzyme -Hydro-methyl-glutaryl-CoA reductase (HMG-
CoA reductase) and includes compactin and mevinolin. This
enzyme is the rate determinig step in the endogenous
synthesis of cholesterol. This enzymes are often referred to
collectively as statins' - a new class of lipid lowering agents.
Compactin was first isolated from the cultures of Penicillium
species in 1976 by Endo while mevinolin (or monacolin K) was
isolated from the cultures of Aspergillus and Monascus
species. These drugs bring about specific, reversible and
competitive blockage of HMG-CoA reductase eading to
decreased hepatic cholesterol synthesis. This induces an
increased rate of hepatic uptake and catabolism of circulating
LDL. Thus the levels of total and LDL-cholesterol are
significantly reduced.

7. •

8. • Mevastatin and lovastatin served as lead compounds in the
development of additional HMGRIS. The lactone and bicyclic
rings as well as the ethylene bridge between them responsible
for the activity of HMGRIs. Additionally, it was found that the
bicyclic ring could be replaced with other lipophilic rings and
that the size and shape of these other ring systems
• Minor modifications of the bicyclic ring and side chain ester of
lovastatin produced simvastatin and pravastatin . Pravastatin,
a ring-opened dihydroxyacid with a 6'-hydroxyl group, is much
more hydrophilic than either lovastatin or simvastatin.
Proposed advantages of this enhanced hydrophobicity are
minimal penetration into the lipophilic membranes of
peripheral cells, better selectivity for hepatic tissues, and a
reduction in the incidence of side effects seen with lovastatin
and simvastatin.

9. • Fibrates can be chemically classified as analogs of
phenoxyisobutyric acid. The SAR for this class of drugs is
sparse; however, all compounds are analogy of the
following general structure (190).
• The iso butyric acid group is essential for activity.
Compounds containing an ester, such as clofibrate and
fenofibrate, are pro-drugs and require in vivo hydrolysis.
Stibstitution at the para position of the aromatic ring with
a chloro group or chlorine containing isopropyl ring
produces compounds with significantly longer half-lives.
While most compounds contain a phenoxyisobutyric acid,
the addition of an m-propyl spacer, as seen in
gemfibrozil, results in an active drug.

10. • Bile acids are secreted by the liver into intestine where
they aid in the dissolution and absorption of lipids. Bile
acids are the metabolic end-products of cholesterol which
are released into the intestine. Major fraction (about 98%)
of bile acids released into the gut is reabsorbed through
the enter hepatic circulation and suppresses the
microsomal hydroxylase enzyme involved in the
conversion of cholesterol to the bile acids. Thus due to
enter hepatic reabsorption of the bile acids further of
cholesterol is suppressed

11. •
Clofibrate is an antilipidemic agent similar to
gemfibrozil. It acts to lower elevated serum lipids by
reducing the very low-density lipoprotein fraction
(Sf 20-400) rich in triglycerides. Serum cholesterol
may be decreased, particularly in those patients
whose cholesterol elevation is due to the presence
of IDL as a result of Type III hyperlipoproteinemia.
Several investigators have observed in their studies
that clofibrate may produce a decrease in
cholesterol linoleate but an increase in palmitoleate
and oleate, the latter being considered atherogenic
in experimental animals. The significance of this
finding is unknown at this time. Reduction of
triglycerides in some patients treated with clofibrate
or certain of its chemically and clinically similar
analogs may be associated with an increase in LDL
cholesterol.

12. • Lovastatin, also known as the brand
name product Mevacor, is a lipid-
lowering drug and fungal metabolite
derived synthetically from a
fermentation product of Aspergillus
terreus. Originally named Mevinolin,
lovastatin belongs to the statin class of
medications, which are used to lower
the risk of cardiovascular disease and
manage abnormal lipid levels by
inhibiting the endogenous production
of cholesterol in the liver.More
specifically, statin medications
competitively inhibit the enzyme
hydroxymethylglutaryl-coenzyme A
(HMG-CoA) Reductase,which
catalyzes the conversion of HMG-CoA
to mevalonic acid

13. • Cholestyramine forms a resin that acts as
a bile acid sequestrant to limit the
reabsorption of bile acids in the
gastrointestinal tract. Cholestyramine resin
is a strong anion exchange resin, allowing
it to exchange its chloride anions with
anionic bile acids present in the
gastrointestinal tract and form a strong
resin matrix. Cholestyramine consists of a
functional group, which is a quaternary
ammonium group attached to an inert
styrene-divinylbenzene copolymer, in the
anion exchange resin.

14. •Colestipol is a lipid-lowering
polymer that binds with bile acids in
the intestine forming a complex that
is excreted in the feces . This non-
systemic action results in a
continuous, partial removal of bile
acids from the enter hepatic
circulation preventing their
reabsorption . This increased fecal
loss of bile acids due to cholesterol
hydrochloride administration leads
to increased oxidation of
cholesterol to bile acids This
results in an increase in the number
of hepatic low-density lipoprotein
(LDL) receptors, and consequently
an increased uptake of LDL

15. • ADINA INSTITUTE OF PHARMACEUTICAL SCIENCES SAGAR
• ASSO. PROF. IMRAN KHAN
• imrankhanaips@gmail.com