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LIPID AND CHOLESTEROL
LOWERING
----------------------------AGENTS
RAVINDRA MISHRA
M.Pharm 2nd
Sem.
SCHOOL OF PHARMACEUTICAL SCIENCES
R.G.P.V
1
CONTENTS
 Defination
 Introduction
 Type of hyperlipoproteinaemias
 Hypolipidaemic drugs
 Uses
 Biological evaluation of hypolipidemic
drugs
2
DEFINATION
The term hyperlipidemia or more
precisely hyperlipoproteinemia refer
to conditions in which the
concentrations of cholestrol and/or
triglyceride- rich lipoproteins are
elevated above normal levels. The
term hyperlipemia is restricted to
conditions that involve increased
levels of triglycerides in plasma 3
INTRODUCTION
 These are the drugs which lower the level of lipids and
lipoproteins in blood.
 These drugs have the potential to prevent
cardiovascular diseases by retarding the accelerated
atherosclerosis in hyperlipidaemic individuals.
 Atheromatous disease is the commonest causes of
death (e.g. myocardial infarction) and disability (e.g.
stroke) in industrial countries. 4
 Atheroma is a focal disease of the intima of large and medium-
sized arteries
 Atherogenesis involves several stages:
I. Endothelial dysfunction with altered PGI2 and NO synthesis
II. Monocyte attachment
III. Endothelial cells bind LDL
IV. Oxidatively modified LDL is taken up by macrophages
V. Having taken up oxidised LDL, these macrophages (now foam
cells) migrate subendothelially
VI. Atheromatous plaque formation.
5
TYPES OF HYPERLIPIDEMIA
 Hyperlipidemia or hyperlipoproteinemia may be
1.primary-----
They are generally genetically determined and are divided
into two major group
1.Those that are caused by an inherited single gene defect,
called monogenic hyperlipoproteinemia.
2.those caused by a combination of multiple genetic factors
That act a long with the enviormental causes,such as dietary
and physical activity, these are called multifactorial or
polygenic hyperlipoproteinemias.
6
THE SECONDRY
HYPERLIPOPROTEINEMIAS
They are associated with a more
generalized metabolic disturbance
such as diabetes mellitus,
hyperthyrodism or chronic
alcoholism, some drug eg: thiazide,
beta blockers , (propanalol,atenalol)
estrogens, retinoids may cause
hyperlipidemia.
7
CHARACTERISTICS AND FUNCTIONS
OF PLASMA PROTEIN
Lipoprotein
Class
Diameter Lipid content Source of
lipid
function
Chy. 100-500 TG>>CHE Diet Dietary TG
transport
Chy rem. 30-50 CHE>>TG Diet,Chy Dietary CH
transport
VLDL 40-80 TG>>CHE Liver Endogenous TG
transport
IDL 30-35 CHE>=TG VLDL Transport CHE
&TG to liver,
source of LDL
LDL 20-25 CHE IDL Transport CH to
tissues and liver
HDL 5-10 Phospholipids,
CHE
Tissues ,Cell
memb.
Removal of
cholesterol from
tissues.
8
TYPES OF PRIMARY
HYPERLIPOPROTEINAEMIAS
Type Disorder Cause Occurrence Elevated plasma
lipoproteins
l Familial lipoprotein
lipase deficiency
G Very rare Chy
lla Familial
hypercholestrolaemia
G Less common LDL
llb Polygenic
hypercholestrolaemia
MF commonest LDL
lll Familial
dysbetalipoprotienae
mia
G rare IDL,Chy rem.
lV Hypertriglyceridaemia MF,G common VLDL
V Familial combined
hyperlipidaemia
G Less common VLDL, LDL 9
CLASSIFICATION OF HYPOLIPIDEMIC
DRUGS
1. HMGCoA reductase inhibitors
2. Bile acid sequestrants
3. Fibric acid derivatives
4. Nicotinic acid
5. Others (Ezetimibe,Gugulipid)
10
(According to Rang, Dale 1999
CHO
Bile duct
GIT
bile acids
ENDOGENOUS
PATHWAY for lipids
EXOGENOUS
PATHWAY for lipids
bile acids
CHO
Peripheral tissues
fat
+ CHO
+ fatty
acids
HEPATOCYTE
ACoA
MVA
LDL
receptors
VLDL
TG CHO
lipase
CHO
CHO
CHO
LDL
HDL
CHO
Uptake of
CHO
Fatty
acids
Fatty
acids
CHO from
cells
Chylomikr
TG CHO
GIT
Chylomikr
remn
CHO TG
STATINS
STATINS
FIBRATES
FIBRATES
FIBRATES
RESINS
11
MOA HYPERLIPIDIMIC
12
HMGCOA REDUCTASE INHIBITORS
13
MOA OF HMG COA REDUCTASE
INHIBITORS
HMG CoA reductase inhibitors lower plasma cholesterol
by three related mechanisms-
 Inhibition of cholesterol biosynthesis
 Enhancement of receptor-mediated LDL uptake
 Reduction of VLDL precursors
Inhibition of HMG CoA reductase enzyme causes an
initial decrease in hepatic cholesterol.
Compensatory mechanism result in an enhanced expression
of HMG CoA reductase and LDL receptors. The net
result of all these effects is a decrease in cholesterol
synthesis ,receptor mediated LDL uptake, and overall
lowering of plasma LDL level.
14
SAR OF HMGCOA REDUCTASE
INHIBITORS
 Mevastatin and lovastatin are the lead compounds in the
development of HMGRIs.
 Lactone ring, bicylic rings and ethylene bridge are very important
for activity.
 Pravastatin is the ring opened dihydroxyacid with a 6 hydroxyl
group is more hydrophilic than lovastatin.so it has the low
penetration to the peripheral tissues and less side effects.
H3C
CH3
O
HO
O
O
O
CH3
LOVASTATIN
OH
H3C
CH3
HO
O
O
O
PRAVASTATIN
CH3
OH
15
OH
COOH
HO
H
1
2
3
4
5
67
Ring system
R1
CH3
C7
H
O
O
H3C
CH3R2
Ring A
Y
X
W
F
n
C7
Ring B
 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 bond b/w 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.
Common for all Statins
16
 Ring A subclass-the decalin ring is essential for anchoring the compound
to the enzyme active site. Replacement with a cyclohexane ring resulted in
10,000 fold decrease in activity.
 Stereochemistry of the ester side chain is important for activity, the
conversion of this ester to an ether resulted in a decrease in activity.
 Methyl subtitution at the R2 position increases activity (simvastatin is more
potent than lovastatin).
 β hydroxyl group substitution at the R1 position enhances hydrophilicity
and may provide some cellular specificity.
N
NH
OH
COONa
H
HO
O
F
Atorvastatin
OH
COONa
H
HO
N
F
Fluvastatin
OH
COONa
H
HO
N
H3CO
F
Cerivastatin
17
 Statins are the first choice drug for primary hyperlipidaemias with raised LDL and
CH levels.
 They are the first choice drugs for dyslipidaemia in diabetics.
Ring B subclass
Substituents W,X,Y can be either carbon or nitrogen. (n) is equal to
either zero or one (five or six member heterocyclic).
The para- fluorophenyl 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.
Adverse effects
Headache, nausea ,bowel upset, rashes
Rise in serum transaminase.
Myopathy- This is more common when nicotinc acid, gemfibrozil,or
CYP3A4 inhibitors given concurrent.
Uses
18
FIBRIC ACID
DERIVATIVES
19
MECHANISM OF ACTION
 Clofibrate and gemfibrozil both drug cause a
decrease in plasma tri-acylglycerol levels by
stimulating lipoprotein lipase activity, thereby
hydrolysing triacyl glycerols in chylomicrons and
VLDL, and thus hastening the removal of these
particles from the plasma. In contrast, Hdl levels
rise moderately. Animal studies show that the
fibrates can cause a lowering of plasma
cholesterol by inhibiting cholesterol syenthesis in
liver and by increasing biliary excretion of
cholesterol into the feces. The fibrates also
appear to lower plasma fibrinogen levels. 20
SAR OF FIBRATES
1) Isobutyric acid group is essential for activity.
2) Compounds containing an ester, such as clofibrate and fenofibrate are
prodrugs and require in vivo hydrolysis.
3) Substitution at the para position of the aromatic ring with a chloro group
or a chlorine containing isopropyl ring produce compound with
significantly longer half life.
4) Most of drugs contain a phenoxyisobutyric acid, the addition of an m-
propyl spacer as seen in gemfibrozil results in an active drug.
[Aromatic ring]-O-[Spacer group] C
CH3
CH3
C
OH
O
C
CH3
CH3
C
O
OCH2CH3OCl
Clofibrate
C
CH3
CH3
C
O
OO
Fenofibrate
C
O
CH
CH3
CH3
21
C
CH3
CH3
C
O
OH(CH2)3O
CH3
H3C Gemfibrozil
 Skin rashes, body ache, impotence.
 Gemfibrozil + statins increase risk of myopathy.
 Incidence of gallstone is seen with clofibrate.
 Contraindicated during pregnancy.
Adverse effects
22
BILE ACID SEQUESTRANTS
 These two are chemically as anion exchange resins. So they
selectively bind and exchange the negatively charged atoms or
molecules with one other.
 The chloride ion of cholestyramine can be displaced by exchanged
with other anions(bile acids) which have a greater affinity for the
positively charged functional groups on the resin.
H
C
H2
C
H
C
H2
C
CH2N(CH3)3
+
Cl
_
C
H
H2
C
n
Colestyramine resin
N NR
NH2
HO
R
N
OH
R+
Cl-
Colestipol
23
MOA OF BILE ACID SEQUESTRANTS
 These drugs lower plasma LDL levels by indirectly increasing
the rate at which LDL is cleared from the blood stream.
 Under normal conditions approx 97% of bile acids are
reabsorbed into entero-hepatic circulation.
 These drugs are not orally absorbed but act locally on GIT to
interrupt this process.
 Results the decrease conc. of bile acids to the liver.
 Removes the feedback inhibition of 7ἀ hydroxylase and
increases the hepatic conversion of cholesterol to bile acids.
 Compensatory effects: Decrease in liver cholesterol, increased
expression of LDL and induction of HMGCoA red.
24
SAR OF BILE ACID SEQUESTRANTS
 Cholestyramine is a copolymer consisting primarily of polystyrene
with small amt. of divinyl benzene as a crosslinking agent.
 In addition it contain some fixed quarternary ammonium groups.
 These positively charged grps. functions as binding sites for anions.
 Colestipol is a copolymer of tetraethylenepentamine and
epichlorhydrin . It contain basic secondary and tertiary amines.
 Total nitrogen content of cholestipol 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 cholestipol.
25
NICOTINIC ACID
MOA of nicotinic acid---- it main action appears to be due to
an inhibition of hepatic syenthesis and release of
VLDL,which lead to a reduction in VLDL,IDL and ldl
levels in addition, nicotinic acid causes a decrease in the
release of free fatty acid from adipocytes ther by
decreasing hepatic production of try gleceride syenthesis.
Because of an additional effect-activation of lipoprotein
lipase, there is a decrease in plasma triglyceride which is
assosiated with an increase HDL c level
N
C
O
OH
Nicotinic acid
26
ADVERSE EFFECTS
 Flushing ,heat ,itching due to cutaneous vasodilation action
 Dyspepsia
 Dryness and hyper pigmentation of skin
 Liver dysfunction and jaundice
.
27
BIOLOGICAL EVALUATION
The biological study of Antihyperlipidaemic agents involves
following stages:
1.Induction of Hyperlipidemia
Hyperlipidaemia is induced in Wistar albino rats by single
intraperitoneal injection of freshly prepared solution of Triton-X-100
(100 mg/kg) in physiological saline solution after overnight fasting for
18 hrs.
The animals are then divided into four groups of five rats each.
 The first group is given standard pellet diet, water and orally
administered with 5% CMC.
 The second group is given a single dose of triton administered at a dose
of 100mg/kg. After 72 hours of triton injection, this group received a daily
dose of 5% CMC for 7 days. 28
The third group is administered a daily dose of test drug 0.5g/day
suspended in 5%CMC, for 7 days, after inducing hyperlipidemia.
The Fourth group is administered with the standard Fenofibrate
65mg/kg, i.p. for 7 days
2.Collection of blood
On the 8thday, blood is collected by retro orbital sinus puncture,
under mild ether anaesthesia. The collected samples are centrifuged
for 10 minutes. Then serum samples are collected and used for
various biochemical experiments. The animals are then sacrificed
and the liver collected .
3.Liver lipid extraction
The liver is homogenized in cold 0.15M KCl and extracted with
CHCl3 CH3OH (2% v/v). This lipid extract is used for the
estimation of lipid parameters.
29
4. Biochemical analysis-
The serum and liver extract were assayed for total cholesterol,
triglycerides, phospholipids, high-density lipoprotein (HDL),
low-density lipoprotein (LDL), and very low-density lipoprotein
(VLDL) using standard protocol methods.
30
THANK YOU !!!
31

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Ppt hyperlipidimic

  • 1. LIPID AND CHOLESTEROL LOWERING ----------------------------AGENTS RAVINDRA MISHRA M.Pharm 2nd Sem. SCHOOL OF PHARMACEUTICAL SCIENCES R.G.P.V 1
  • 2. CONTENTS  Defination  Introduction  Type of hyperlipoproteinaemias  Hypolipidaemic drugs  Uses  Biological evaluation of hypolipidemic drugs 2
  • 3. DEFINATION The term hyperlipidemia or more precisely hyperlipoproteinemia refer to conditions in which the concentrations of cholestrol and/or triglyceride- rich lipoproteins are elevated above normal levels. The term hyperlipemia is restricted to conditions that involve increased levels of triglycerides in plasma 3
  • 4. INTRODUCTION  These are the drugs which lower the level of lipids and lipoproteins in blood.  These drugs have the potential to prevent cardiovascular diseases by retarding the accelerated atherosclerosis in hyperlipidaemic individuals.  Atheromatous disease is the commonest causes of death (e.g. myocardial infarction) and disability (e.g. stroke) in industrial countries. 4
  • 5.  Atheroma is a focal disease of the intima of large and medium- sized arteries  Atherogenesis involves several stages: I. Endothelial dysfunction with altered PGI2 and NO synthesis II. Monocyte attachment III. Endothelial cells bind LDL IV. Oxidatively modified LDL is taken up by macrophages V. Having taken up oxidised LDL, these macrophages (now foam cells) migrate subendothelially VI. Atheromatous plaque formation. 5
  • 6. TYPES OF HYPERLIPIDEMIA  Hyperlipidemia or hyperlipoproteinemia may be 1.primary----- They are generally genetically determined and are divided into two major group 1.Those that are caused by an inherited single gene defect, called monogenic hyperlipoproteinemia. 2.those caused by a combination of multiple genetic factors That act a long with the enviormental causes,such as dietary and physical activity, these are called multifactorial or polygenic hyperlipoproteinemias. 6
  • 7. THE SECONDRY HYPERLIPOPROTEINEMIAS They are associated with a more generalized metabolic disturbance such as diabetes mellitus, hyperthyrodism or chronic alcoholism, some drug eg: thiazide, beta blockers , (propanalol,atenalol) estrogens, retinoids may cause hyperlipidemia. 7
  • 8. CHARACTERISTICS AND FUNCTIONS OF PLASMA PROTEIN Lipoprotein Class Diameter Lipid content Source of lipid function Chy. 100-500 TG>>CHE Diet Dietary TG transport Chy rem. 30-50 CHE>>TG Diet,Chy Dietary CH transport VLDL 40-80 TG>>CHE Liver Endogenous TG transport IDL 30-35 CHE>=TG VLDL Transport CHE &TG to liver, source of LDL LDL 20-25 CHE IDL Transport CH to tissues and liver HDL 5-10 Phospholipids, CHE Tissues ,Cell memb. Removal of cholesterol from tissues. 8
  • 9. TYPES OF PRIMARY HYPERLIPOPROTEINAEMIAS Type Disorder Cause Occurrence Elevated plasma lipoproteins l Familial lipoprotein lipase deficiency G Very rare Chy lla Familial hypercholestrolaemia G Less common LDL llb Polygenic hypercholestrolaemia MF commonest LDL lll Familial dysbetalipoprotienae mia G rare IDL,Chy rem. lV Hypertriglyceridaemia MF,G common VLDL V Familial combined hyperlipidaemia G Less common VLDL, LDL 9
  • 10. CLASSIFICATION OF HYPOLIPIDEMIC DRUGS 1. HMGCoA reductase inhibitors 2. Bile acid sequestrants 3. Fibric acid derivatives 4. Nicotinic acid 5. Others (Ezetimibe,Gugulipid) 10
  • 11. (According to Rang, Dale 1999 CHO Bile duct GIT bile acids ENDOGENOUS PATHWAY for lipids EXOGENOUS PATHWAY for lipids bile acids CHO Peripheral tissues fat + CHO + fatty acids HEPATOCYTE ACoA MVA LDL receptors VLDL TG CHO lipase CHO CHO CHO LDL HDL CHO Uptake of CHO Fatty acids Fatty acids CHO from cells Chylomikr TG CHO GIT Chylomikr remn CHO TG STATINS STATINS FIBRATES FIBRATES FIBRATES RESINS 11
  • 14. MOA OF HMG COA REDUCTASE INHIBITORS HMG CoA reductase inhibitors lower plasma cholesterol by three related mechanisms-  Inhibition of cholesterol biosynthesis  Enhancement of receptor-mediated LDL uptake  Reduction of VLDL precursors Inhibition of HMG CoA reductase enzyme causes an initial decrease in hepatic cholesterol. Compensatory mechanism result in an enhanced expression of HMG CoA reductase and LDL receptors. The net result of all these effects is a decrease in cholesterol synthesis ,receptor mediated LDL uptake, and overall lowering of plasma LDL level. 14
  • 15. SAR OF HMGCOA REDUCTASE INHIBITORS  Mevastatin and lovastatin are the lead compounds in the development of HMGRIs.  Lactone ring, bicylic rings and ethylene bridge are very important for activity.  Pravastatin is the ring opened dihydroxyacid with a 6 hydroxyl group is more hydrophilic than lovastatin.so it has the low penetration to the peripheral tissues and less side effects. H3C CH3 O HO O O O CH3 LOVASTATIN OH H3C CH3 HO O O O PRAVASTATIN CH3 OH 15
  • 16. OH COOH HO H 1 2 3 4 5 67 Ring system R1 CH3 C7 H O O H3C CH3R2 Ring A Y X W F n C7 Ring B  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 bond b/w 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. Common for all Statins 16
  • 17.  Ring A subclass-the decalin ring is essential for anchoring the compound to the enzyme active site. Replacement with a cyclohexane ring resulted in 10,000 fold decrease in activity.  Stereochemistry of the ester side chain is important for activity, the conversion of this ester to an ether resulted in a decrease in activity.  Methyl subtitution at the R2 position increases activity (simvastatin is more potent than lovastatin).  β hydroxyl group substitution at the R1 position enhances hydrophilicity and may provide some cellular specificity. N NH OH COONa H HO O F Atorvastatin OH COONa H HO N F Fluvastatin OH COONa H HO N H3CO F Cerivastatin 17
  • 18.  Statins are the first choice drug for primary hyperlipidaemias with raised LDL and CH levels.  They are the first choice drugs for dyslipidaemia in diabetics. Ring B subclass Substituents W,X,Y can be either carbon or nitrogen. (n) is equal to either zero or one (five or six member heterocyclic). The para- fluorophenyl 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. Adverse effects Headache, nausea ,bowel upset, rashes Rise in serum transaminase. Myopathy- This is more common when nicotinc acid, gemfibrozil,or CYP3A4 inhibitors given concurrent. Uses 18
  • 20. MECHANISM OF ACTION  Clofibrate and gemfibrozil both drug cause a decrease in plasma tri-acylglycerol levels by stimulating lipoprotein lipase activity, thereby hydrolysing triacyl glycerols in chylomicrons and VLDL, and thus hastening the removal of these particles from the plasma. In contrast, Hdl levels rise moderately. Animal studies show that the fibrates can cause a lowering of plasma cholesterol by inhibiting cholesterol syenthesis in liver and by increasing biliary excretion of cholesterol into the feces. The fibrates also appear to lower plasma fibrinogen levels. 20
  • 21. SAR OF FIBRATES 1) Isobutyric acid group is essential for activity. 2) Compounds containing an ester, such as clofibrate and fenofibrate are prodrugs and require in vivo hydrolysis. 3) Substitution at the para position of the aromatic ring with a chloro group or a chlorine containing isopropyl ring produce compound with significantly longer half life. 4) Most of drugs contain a phenoxyisobutyric acid, the addition of an m- propyl spacer as seen in gemfibrozil results in an active drug. [Aromatic ring]-O-[Spacer group] C CH3 CH3 C OH O C CH3 CH3 C O OCH2CH3OCl Clofibrate C CH3 CH3 C O OO Fenofibrate C O CH CH3 CH3 21
  • 22. C CH3 CH3 C O OH(CH2)3O CH3 H3C Gemfibrozil  Skin rashes, body ache, impotence.  Gemfibrozil + statins increase risk of myopathy.  Incidence of gallstone is seen with clofibrate.  Contraindicated during pregnancy. Adverse effects 22
  • 23. BILE ACID SEQUESTRANTS  These two are chemically as anion exchange resins. So they selectively bind and exchange the negatively charged atoms or molecules with one other.  The chloride ion of cholestyramine can be displaced by exchanged with other anions(bile acids) which have a greater affinity for the positively charged functional groups on the resin. H C H2 C H C H2 C CH2N(CH3)3 + Cl _ C H H2 C n Colestyramine resin N NR NH2 HO R N OH R+ Cl- Colestipol 23
  • 24. MOA OF BILE ACID SEQUESTRANTS  These drugs lower plasma LDL levels by indirectly increasing the rate at which LDL is cleared from the blood stream.  Under normal conditions approx 97% of bile acids are reabsorbed into entero-hepatic circulation.  These drugs are not orally absorbed but act locally on GIT to interrupt this process.  Results the decrease conc. of bile acids to the liver.  Removes the feedback inhibition of 7ἀ hydroxylase and increases the hepatic conversion of cholesterol to bile acids.  Compensatory effects: Decrease in liver cholesterol, increased expression of LDL and induction of HMGCoA red. 24
  • 25. SAR OF BILE ACID SEQUESTRANTS  Cholestyramine is a copolymer consisting primarily of polystyrene with small amt. of divinyl benzene as a crosslinking agent.  In addition it contain some fixed quarternary ammonium groups.  These positively charged grps. functions as binding sites for anions.  Colestipol is a copolymer of tetraethylenepentamine and epichlorhydrin . It contain basic secondary and tertiary amines.  Total nitrogen content of cholestipol 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 cholestipol. 25
  • 26. NICOTINIC ACID MOA of nicotinic acid---- it main action appears to be due to an inhibition of hepatic syenthesis and release of VLDL,which lead to a reduction in VLDL,IDL and ldl levels in addition, nicotinic acid causes a decrease in the release of free fatty acid from adipocytes ther by decreasing hepatic production of try gleceride syenthesis. Because of an additional effect-activation of lipoprotein lipase, there is a decrease in plasma triglyceride which is assosiated with an increase HDL c level N C O OH Nicotinic acid 26
  • 27. ADVERSE EFFECTS  Flushing ,heat ,itching due to cutaneous vasodilation action  Dyspepsia  Dryness and hyper pigmentation of skin  Liver dysfunction and jaundice . 27
  • 28. BIOLOGICAL EVALUATION The biological study of Antihyperlipidaemic agents involves following stages: 1.Induction of Hyperlipidemia Hyperlipidaemia is induced in Wistar albino rats by single intraperitoneal injection of freshly prepared solution of Triton-X-100 (100 mg/kg) in physiological saline solution after overnight fasting for 18 hrs. The animals are then divided into four groups of five rats each.  The first group is given standard pellet diet, water and orally administered with 5% CMC.  The second group is given a single dose of triton administered at a dose of 100mg/kg. After 72 hours of triton injection, this group received a daily dose of 5% CMC for 7 days. 28
  • 29. The third group is administered a daily dose of test drug 0.5g/day suspended in 5%CMC, for 7 days, after inducing hyperlipidemia. The Fourth group is administered with the standard Fenofibrate 65mg/kg, i.p. for 7 days 2.Collection of blood On the 8thday, blood is collected by retro orbital sinus puncture, under mild ether anaesthesia. The collected samples are centrifuged for 10 minutes. Then serum samples are collected and used for various biochemical experiments. The animals are then sacrificed and the liver collected . 3.Liver lipid extraction The liver is homogenized in cold 0.15M KCl and extracted with CHCl3 CH3OH (2% v/v). This lipid extract is used for the estimation of lipid parameters. 29
  • 30. 4. Biochemical analysis- The serum and liver extract were assayed for total cholesterol, triglycerides, phospholipids, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) using standard protocol methods. 30