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Screening Hepatoprotective Drugs Seminar
1. Seminar presentation on:
Screening Of Hepatoprotective
Drugs
PRESENTED BY: SIRAJUDDIN MOLLA
1ST SEM, M.PHARM
DEPARTMENT OF PHARMACOLOGY
SPER, JAMIA HAMDARD
2. Introduction and function of liver
Hepatotoxicity and drug causing DILI
Hepatoprotective agent
Methods of Screening of hepatoprotectives
CONTENT
3. Liver is large, meaty organ that located in the right
upper quadrant of the abdomen below the
diaphragm
It is the only organ found in vertebrates which
detoxifies various metabolites, synthesizes proteins
and produces biochemical's necessary for digestion.
INTRODUCTION:
It has a surprising role in the maintenance,
performance and regulating homeostasis of the
body.
It is involved with almost all the biochemical pathways
to growth, fight against disease, nutrient supply,
energy provision and reproduction.
4. 500 VITAL FUNCTIONS
• Immunity against infection
• Factory for proteins and cholesterol
• Excretes wastes via bile
• Regulates blood clotting
• Clears blood of drugs, Chemicals, alcohol
• Converts excess glucose to starch for storage
• Excretes bile for fat digestion
What does the liver do?
5. • The major cause in India is ethanol and it is suspected
that more than half of the cases of Hepatotoxicity is
caused by alcohol.
• Chemicals like carbon tetrachloride (CCl4), phosphorous
aflatoxins, chlorinated hydrocarbon etc.
• Drugs i.e. DILI (drugs induced liver injury)
• Autoimmune disorders
• Infections like viral hepatitis
LIVER TOXICITY
6. Drug Metabolites.
(the good, the bad and the
Drugs and the Liver
Liver Disease
Drugs LIVER
Drug-Drug Interactions
Drug Elimination
7. DRUGS CAUSING DILI
Anti tuberculosis drugs All drugs causes hepatotoxicity except
ethambutol
Anti-convulsant drugs Carbamazepine, valproic acid
NSAIDS Paracetamol, diclofenac, indomethacin, oxicam
group
Anti-microbials Dapsone, ketoconazole, Sulfonamides,
antiretrovirals
Anaesthetics Enflurane, Isoflurane
8. • Aspartate Serum Transferase(AST)
• Alanine Amino Transferase (ALT)
• Alkaline Phosphatase(ALP)
• Lactate dehydrogenase(LDH)
• Total Bilirubin transferase (GGT) levels(TB)
• Total protein (TP)
• Triglycerides (TG)
• Gammaglutamyl transferase (GGT) levels
Markers of Hepatotoxicity
Liver function tests check the levels of certain enzymes and proteins
in the blood. Levels that are higher or lower than normal can
indicate liver problems. Some common liver function tests include
9. N acetylcysteine
Penicillamine
Anti oxidants
• Melatonin
• Vitamins
• Glutathion
• Beta-carotene
cardiotropin 1
Herbal medications e.g. silymarine
S-adenosyl methionine (SAM)
LIST OF HEPATOPROTECTIVE
AGENTS
10. 1. Hepatitis in Long Evans Cinnamon rats
2. Temporary hepatic ischemia
3. Carbontetrachloride induced liver fibrosis in rats
4. Bile duct ligation induced liver fibrosis in rats
5. Galactosamine induced liver necrosis
6. Thiocetamide induced necrosis of liver
7. Paracetamol induced liver damage in rats
8. Rifampicin + Isoniazid induced hepatotoxicity in
METHODS FOR SCREENING
OF HEPATOPROTECTIVES
IN VITRO METHOD
1. Primary hepatocyte cell culture
2. Stellate cell culture
3. Kupffer cell culture.
4. Liver cirrhosis and necrosis
5. Inhibition of proline
hydroxylation
IN VIVO METHODS:
12. Fresh hepatocyte preparations and primary cultured hepatocytes are
used
The basic method :
• Isolation of hepatocytes by perfusion of liver with collagenase
or utilization primary cultured hepatocytes.
• Determination of the viability of the hepatocytes.
• Incubation of the cell culture with hepatotoxin and with or
without the test drugs.
• Determination of the activity of transaminases released into
the medium by the hepatocytes.
PRIMARY HEPATOCYTE CELL
CULTURE
• Hepatotoxins: ccl4, paracetamol, d- galactosamine, tert- Butyl
hydroperoxide and ethanol.
13. • In chronic injury there is hepatic stellate cell(HSC)
activation.
• There is secretion of matrix by activated stellate
cells results in liver fibrosis and ultimately cirrhosis.
• Stellate cells are isolate from rat liver by
collagenase / pronase digestion
• The test drugs are incubated with the activeted
stellate cell culture by hepatotoxins
STELLATE CELL CULTURE
• Parameters studied: morphology of the cells, alfa-
SMA expression, cell count with thymidine incorporation
and inhibition in synthesis of collagen type I and III.
15. Paracetamol is one of the most commonly and widely used
analgesic anti-pyretic drug used in higher dose lead to
hepatic damage.
It gets metabolised to an active metabolite N-acetyl-p-
benzoquinone imine by the cytochrome P-450
enzyme system which results in an oxidative stress
liver glutathione and glycogen depletion.
PARACETAMOL INDUCED
LIVER DAMAGE IN RATS:
16. The animal are sacrificed after 24h and the blood/serum is
used for biochemical analysis and the liver for
histopathological studies
Procedure:
Wistar rats of either sex weight(150-200g) are used.
Paracetamol 2g/kg body weight is administered orally as a
single dose
The animal are given the test drug foe 6 days prior to
paracetamol administration and on the seventh day along
with paracetamol
17. Purpose and Rationale:
The long evans cinnamon rat is useful model to study
genetically transmitted hepatitis and chronic liver disease
Due to excessive copper accumulation in the liver of long
evans cinnamon rats, making this animal a model for Wilson's
disease in human.
Chelation therapy or feeding copper deficient diet decreases
symptoms in Long Evans Cinnamon rat and Wilson's disease.
Hepatitis in long evans
cinnamon rat:
18. The occurance of jaundice is esasily observable as the time
when the ears and tails tuen yellow and the urine becomes
bright ending in death of aminal within about a week.
PROCEDURE
Long evans cinnamon rats of age of 5 weeks are housed in
temprature and humidity controlled room.
Group of 6-10 rats are given different diets on a 15% purified
egg protein diet and supplemented with vitamins or drugs are
supplied via minipumps intraperitoneally implanted under
ether anesthesia.
19. Essentials of medical pharmacology by KD Tripathi
Rang and Dale's pharmacology
Drug discovery and evaluation by H. Gerhard
Vogel
Slideshare
REFERENCES