2. Hepatotoxic Drugs
CONTENTS
• Introduction
• Classification
• Mechanism of Liver damage
• Patterns of Injury
• Specific drug or toxin which leads to
hepatotoxicity.
• Screening methods
• References
3. Hepatotoxic Drugs
Introduction
• Liver plays a key role in detoxifying harmful
substances .
• Toxic hepatitis is liver inflammation due to
toxic chemicals, drugs or certain poisonous
mushrooms.
• Among patients with acute liver failure, drug-
induced liver injury is the most common
cause.
9. Hepatotoxic Drugs
Intrinsic Idiosyncratic
Incidence More common Less common 1%
Predictability Predictable Unpredictable
Dose related Dose dependent Dose independent
Latency period Short latency period Variable latency period
weeks or months
Type of injury Usually necrosis Necrosis or apoptosis
Associated Acute liver failure Rash, fever, eosinophilia
Examples Acetaminophen Isoniazid
Classification
10. Hepatotoxic Drugs
Classification
• Chronic hepatotoxicity
Failure of return of liver enzymes or
bilirubin to pre-DILI(Drug Induced Liver
Injury) baseline, and / or other signs or
symptoms of ongoing liver disease (e.g.,
ascites, encephalopathy,
portal hypertension, coagulopathy) 6 months
after DILI onset
12. Hepatotoxic Drugs
Pathogenesis
Direct cell stress, direct mitochondria impairment
and specific immune reactions
Reactive metabolites depletes GSH, covalently
binding to proteins, enzymes, lipids, nucleic acid
and other cell structures
13. Hepatotoxic Drugs
Pathogenesis
cause ATP depletion and increase in ROS, inhibits
β-oxidation, cause steatosis.
Damage mitochondrial DNA, interfere with the
replication process, causes the opening of MPT
If the drug metabolite acts as a hapten it binds
covalently with the liver protein perceived as
foreign by the immune system resulting in an
autoimmune attack on hepatocytes.
25. Hepatotoxic Drugs
Drug Chemical Class Discontinued Country
TienilicAcid
(Ticrynafen)
Loop Diuretics 1982 Germany, France, UK,
US, Others
Benoxaprofen (Oraflex) NSAIDS 1982 Germany, Spain, UK, US
Tolrestat
(Alredase)
Aldose Reductase Inhibitor 1996 Argentina, Canada, Italy,
Tolcapone (Tasmar) Catechol-O-Methyl Transferas
(COMT)
1998 European Union, Canada,
Australia
Bromfenac (Duract) NSAIDS 1998 US
Trovafloxacin (Trovan) Fluoroquinolones Antibiotics June 1999 European Union, US
Troglitazone (Rezulin) Antidiabetic And
Anti-inflammatory
2000 US, Germany
Ximelagatran
(Exanta)
Anticoagulant 2006 Germany
Sitaxentan Endothilin receptor antagonist 2010 Germany
Tacrine (Cognex) Anticholinesterase 2013 US *
26. List of marketed drugs capable of inducing hepatotoxicity caused by
mitochondrial dysfunction, which have received warnings from drug agencies
Drug Chemical class Regulatory action
Felbamate Anticonvulsant Restricted use
Pemoline CNS stimulant Restricted use
Acetaminophen Analgesic Warnings
Leflunomide Immunomodulator Restricted use
Nefazodone Antipsychotic Warnings
Nevirapine Antiviral Warnings
Pyrazinamide Antituberculosis Warnings
Rifampin Antituberculosis Warnings
Terbinafine Antifungal Warnings
Valproic acid Anticonvulsant Warnings
Zafirlukast Asthma Warnings
Hepatotoxic Drugs
28. Hepatotoxic Drugs
Liver injury markers Significance
Sorbitol dehydrogenase (SDH) Hepatocyte specific injury
Glutathione S-transferase alpha
(GSTα)
Centrilobular liver damage and
kidney damage
HMGB1 (High mobility group box 1) Necrosis marker
Glutamate dehydrogenase (GLDH) Mitochondrial disruption
Cytokeratin 18 fragments Marker of caspase cleaved
proteins in apoptotic cell death
M-30 Apoptosis marker
M-65 Total apoptosis and necrosis
marker
29. Hepatotoxic Drugs
Treatment:
No specific treatment exists for most kinds of
toxic hepatitis
• For most other cases of drug-induced toxic
hepatitis, stopping the medication is the only
treatment.
Supportive therapy- People with severe
symptoms are likely to receive supportive
therapy in the hospital, including intravenous
fluids and medication to relieve nausea and
vomiting.
Liver transplant-When liver function is
severely impaired, a liver transplant may be the
only option for some people
30. Hepatotoxic Drugs
FOLLOW UP:
• Chronic DILI occurs in about 15 – 20 % of cases
of acute DILI and requires long-term follow-up
• Subjects who presented with cholestatic DILI are
more likely to develop chronic DILI
• Chronic DILI resembles AIH and might respond
to steroids
31. Hepatotoxic Drugs
SCREENING METHODS
In vivo model
A. Non-invasive model
• a. Chemically induced hepatotoxicity
1. CCl4 induced
2. Thioacetamide induced
3. Dimethyl or diethyl nitrosamine induced
4. Aflatoxin induced
• b. Drug-induced hepatotoxicity
1. NSAID induced
2. Anticancer drugs induced
3. Antibiotic induced
4. Anti-TB drugs induced
32. Hepatotoxic Drugs
Non –invasive
• c. Radiation-induced hepatotoxicity
• d. Metal-induced hepatotoxicity
1. Mercury induced
• e. Diet-induced hepatotoxicity -Alcohol induced
High fat diet induced
B. Invasive model
Bile duct ligation
Portal vein ligation
33. Hepatotoxic Drugs
Carbon tetrachloride (CCl4)
Principle
In laboratory animals, for experimental study of
liver injury, CCl4 is most widely used hepatic toxicant.
• CCl3, a toxic metabolite of CCl4, produced by Cytochrome
P-450 2E1 (CYPE2E1) in hepatocytes .
• This free radical then combines with cellular lipids and
proteins to form trichloromethylperoxyl radical which
induces an acute centrilobular necrosis .
• Histopathology studies showed that significant fibrosis
occurs after 2–4 weeks, severe bridging fibrosis after 5–7
weeks and cirrhosis after 8–9 weeks .
34. Hepatotoxic Drugs
Carbon tetrachloride (CCl4)
Procedure:
• Rats of either sex were fed with standard diet and
water and kept at a temperature (25 ± 2 C) and 12
h light/dark cycle.
• Hepatotoxicity was produced by CCl4
• At the last day of the study the animals were
anaesthetized and killed and the biochemical
parameter and histopathological studies were
performed.
35. Hepatotoxic Drugs
Non-steroidal anti-inflammatory drugs (NSAID) induced
Principle
• Paracetamol (PCM) hepatotoxicity consists of centrilobular
necrosis followed by congestion and failure.
• Cytochrome P450 2E1 (CYP2E1) and 3A4 (CYP3A4) converts
PCM to a highly reactive intermediary metabolite; N-acetyl-p-
benzo-quinone imine (NAPQI).
• Semiquinone radicals, obtained by one electron reduction of N-
acetyl-p-benzoquineimine covalently bind to macromolecules of
cellular membrane and increase the lipid peroxidation resulting
in the tissue damage.
36. Hepatotoxic Drugs
Non-steroidal anti-inflammatory drugs (NSAID)
induced
Procedure
• Rats of either sex were fed on standard chaw diet and
allowed to access to water ad libitum.
• They were allowed to acclimate for 12-h light/dark cycle
before use.
• Hepatotoxicity was produced by administration of PCM
with different doses (3 mg/kg, p.o. for 7 days–3 weeks) .
• The various parameters of hepatotoxicity were examined.
On the last day, the animals were anesthetized, blood
sample was collected, centrifuged and serum liver enzyme
activities were carried out.
37. Hepatotoxic Drugs
In vivo hepatotoxicity studies
• Toxicity testing in two animal species Rats and
Dogs another species may be chosen If the
compound is not bioavailable in the rat and dog
• The in vivo toxicity studies includes the following
• A rat acute toxicity study
• A rat repeated dose toxicity study
• A dog rising-dose tolerance study
38. Hepatotoxic Drugs
Acute toxicity study Repeated toxicity study Rising dose tolerance
study
Administer compound in a
single dose up to that which
induces lethality not exceeding
2000 mg/kg
Small number of animals (5/sex
per dose) are dosed daily
Determine plasma drug level
Small number of dogs
(1- 2/sex) are treated by
an “incrementation”
process
Monitor clinical signs as
bodyweight, food consumption
Clinical signs, bodyweight, food
consumption, clinical pathology
coagulation time, bilirubin,
transaminases and alkaline
phosphatases) necropsy with
histopathological examination
Same as in case of rat
but no necropsy.
39. Hepatotoxic Drugs
In vitro cytotoxicity screening assay
Numerous models are used for in vitro
hepatotoxicity studies, Isolated perfused
liver
Hepatocytes
Liver slices
Primary cultures of hepatocytes
Cell lines
41. Hepatotoxic Drugs
Conclusion
• Drug-induced hepatotoxicity is a significant clinical
problem.
• Current preclinical test systems for hepatotoxicity are
inadequate, reflecting our limited understanding of
mechanisms of drug toxicity, particularly the
“hypersensitivity” or “idiosyncratic” types of reactions
• The main challenge is to be able to detect drug induced
mitochondrial dysfunction during preclinical studies
41
42. Reference
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
43. Reference
• William M et.al., Drug-Induced Hepatotoxicity.
N Engl J Med 2003;349:474-85.
• Manf U et.al., Evaluation of the characteristics
of safety withdrawal of prescription drugs from
worldwide pharmaceutical markets-1960 to
1999. Drug Information Journal. Vol. 35, pp.
293-317,
• David et,al.,Hepatic Histological Findings in
Suspected Drug-Induced Liver Injury:
Systematic Evaluation and Clinical
Associations. HEPATOLOGY, Vol. 59, No. 2,
2014
44. Reference
• David et,al.,Hepatic Histological Findings in
Suspected Drug-Induced Liver Injury:
Systematic Evaluation and Clinical Associations
HEPATOLOGY, Vol. 59, No. 2, 2014
• Debra L. et,al.,Macrophages and Tissue Injury:
Agents of Defense or Destruction? Annu. Rev.
Pharmacol. Toxicol. 2011. 51:267–88
• Ganesh Singh et,al.,Animal models of
hepatotoxicity. Inflammation Research
· October 2015
