This document discusses molecular mechanisms of drug-induced hepatotoxicity. It begins with an introduction to hepatotoxicity and classification into intrinsic and idiosyncratic types. Mechanisms of liver damage include direct cell stress, mitochondrial impairment, and immune reactions. Specific drugs that commonly cause liver injury are also identified, such as acetaminophen, nonsteroidal anti-inflammatory drugs, and isoniazid. Patterns of injury include hepatocellular, cholestatic and mixed. Genetic and non-genetic risk factors also contribute to drug-induced liver damage. Images are also provided showing examples of liver damage.

1. MOLECULAR MECHANISM OF DRUG
INDUCED HEPATOTOXICITY
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
FACILITATED BY PRESENTED BY
Dr. Shivalinge Gowda Madhavapriya B N
H.O.D 1st M.Pharm.
Dept. of Pharmacology Dept. of Pharmacology

2. CONTENTS
 Introduction
 Classification
 Mechanism of Liver damage
 Patterns of Injury
 Specific drug or toxin which leads to
hepatotoxicity.
 References
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3. INTRODUCTION
 Hepatotoxicity (from hepatic toxicity) implies
chemical-driven liver damage.
 The liver plays a central role in transforming
and clearing chemicals and is susceptible to the
toxicity from these agents. Certain medicinal
agents, when taken in overdoses and
sometimes even when introduced within
therapeutic ranges, may injure the organ. Other
chemical agents, such as those used in
laboratories and industries, natural chemicals
(e.g., microcystins) and herbal remedies can
also induce hepatotoxicity. Chemicals that
cause liver injury are called hepatotoxins
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4. Classification
1. Intrinsic Hepatotoxicity
2. Idiosyncratic Hepatotoxicity
Allergic
Non-Allergic
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5.  Intrinsic hepatotoxicity is regarded as
dose-dependent and predictable above an
approximate threshold dose, whereas
idiosyncratic hepatotoxicity occurs without
obvious dose-dependency and in an
unpredictable fashion. Allergic
idiosyncratic hepatotoxicity is
characterized by the presence of typical
symptoms and signs of adaptive immune
reactions, including fever, skin reactions,
eosinophilia, formation of autoantibodies,
and a short latency time particularly after
re-exposure.
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Signs and symptoms:-
 Yellowing of the skin and whites of the
eyes (jaundice)
 Fatigue
 Loss of appetite
 Nausea and vomiting
 Weight loss
 Dark or tea-colored urine

7. MECHANISM OF DRUG INDUCED LIVER INJURY:
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8. 1.Initial Mechanisms of Toxicity: Direct Cell
Stress, Direct Mitochondrial Impairment,
and Specific Immune Reactions
2. Direct and Death Receptor-Mediated
Pathways Leading to Mitochondrial
Permeability Transition
3. Apoptosis and Necrosis
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10. PATTERNS OF LIVER INJURY
Patterns of drug-induced liver disease
Type of injury: Hepatocellular Cholestatic Mixed
ALT ≥ Twofold rise Normal ≥ Twofold rise
ALP Normal ≥ Twofold rise ≥ Twofold rise
ALT: ALP ratio High, ≥5 Low, ≤2 2-5
Examples
Acetaminophen
Allopurinol
Amiodarone
HAART
NSAID
Anabolic steroid
Chlorpromazine
Clopidogrel
Erythromycin
Hormonal
contraception
Amitriptyline,
Enalapril
Carbamazepine
Sulfonamide
Phenytoin
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Forms of liver toxicity:-
 Zonal Necrosis- This is the most common
type of drug induced liver cell necrosis
where the injury is largely confined to a
particular zone of the liver lobule.
 Hepatitis- Disease of the liver causing
inflammation.
 Cholestasis- Cholestasis is a condition
where bile cannot flow from the liver to the
duodenum.
 Steatosis- Steatosis is a condition
characterised by the build up of fat within
the liver, sometimes triggering inflammation
of the liver

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• Granuloma- A granuloma is one of a
number of forms of localized nodular
inflammation found in tissues.
• Vascular lesions- They result from
injury to the vascular endothelium.
• Neoplasm- Neoplasm or tumor, tissue
composed of cells that grow in an
abnormal way.

14. GENETIC AND NONGENETIC RISK
FACTORS
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15. Drugs causing Liver damage
 Acetaminophen:-(Paracetamol, also
known by the brand name Tylenol and
Panadol) is usually well tolerated in
prescribed dose but overdose is the
most common cause of drug induced
liver disease and acute liver failure
worldwide.
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16.  Nonsteroidal anti-inflammatory drugs-
Aspirin, phenylbutazone, ibuprofen,
sulindac, phenylbutazone, piroxicam,
diclofenac and indomethacin.
 Glucocorticoids- Glucocorticoids are so
named due to their effect on carbohydrate
mechanism. they promote glycogen
storage in liver. The classical effect of
prolonged use both in adult and paediatric
population is steatosis.
 Isoniazid- Isoniazide (INH) is one of the
most commonly used drug for tuberculosis;
it is associated with mild elevation of liver
enzymes in up to 20% of patients and
severe hepatotoxicity in 1-2% of patients 16

17.  Natural products- Amanita mushroom,
particularly the destroying angels,
aflatoxins.
 Industrial toxin- Arsenic, Carbon
tetraChloride, Vinyl Chloride.
 Herbal and alternative remedies- Ackee
fruit, Camphor, Pyrrolizidine alkaloids,
Horse chestnut leaf, Valerian, Comfrey
(often used in herbal tea).
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Images showing liver damage

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Ultrastructural Images

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1. Donald Blumenthal; Laurence Brunton; Keith Parker; Lazo, John S.; Iain Buxton
(2006). Goodman and Gilman's Pharmacological Basis of Therapeutics Digital
Edition.McGraw-Hill Professional. ISBN 0-07-146804-8.
2. PMC- Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity
Stefan Russmann, Gerd A Kullak-Ublick and Ignazio Grattagliano
3. William M. Lee, M.D. Drug-Induced Hepatotoxicity. N Engl J Med 2003; 349:474-
85.
4. Aashish Pandit, Tarun Sachdeva and Pallavi Bafna. Drug-Induced Hepatotoxicity: A
Review Journal of Applied Pharmaceutical Science 02 (05); 2012: 233-243
Wikipedia: http://en.wikipedia.org/wiki/Liver_disease
Medicine Net: http://www.medicinenet.com/liver_disease/article.htm
References

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