The document discusses hepatotoxicity, or liver injury caused by chemicals. The liver is the primary site of drug metabolism and many drugs can cause liver damage. Hepatotoxicity can be direct, through overdose, or idiosyncratic, through hypersensitivity reactions. Liver function tests are used to detect abnormalities and extent of damage. Several drugs are described that can cause hepatotoxicity through different mechanisms, such as paracetamol causing centrizonal necrosis, isoniazid causing multilobular necrosis, and halothane causing an immune response through metabolite binding. Regular monitoring of liver enzymes is recommended when taking hepatotoxic drugs.

4. HEPATOTOXICITY
• Liver is the Primary site for the metabolic process to
occur.
• Most of the drugs undergo metabolism mainly in the
liver.
• Hepatotoxicity implies liver injury caused due to
chemicals.
• Liver injury may follow the inhalation, ingestion, or
parenteral administration of a number of
pharmacologic and chemical agents.
• Chemical agents include industrial toxins such as
carbon tetrachloride, trichloroethylene, yellow
phosphorous.

5. • Hepatotoxicity is of two types:
direct toxic type
idiosyncratic type
• Direct toxic type: dose dependent and results
in morphological abnormalities.
• Idiosyncratic type: not dose dependent, and
may appear shortly after exposure of drugs.
Results in hypersensitivity reactions: rash
arthralgia, eosinophilia etc.

6. For the detection of abnormalities and extent of liver
damage Liver function tests(LFTs) are performed:

7. • Acute Hepatocellular Injury
• Characterized by:
– Marked elevation in ALT and AST
– Normal or minimally elevated alkaline phosphatase
– Bilirubin variably increased-----›worse prognosis.
Cholestatic Injury: Reduction in bile flow due to
– Reduced secretion
– Obstruction
Biochemically:
– Elevated Alk phosphatase
– Elevated GGT
– Elevated 5 NT

8. Hepatotoxic drugs
1. Drugs that cause hepatic damage in
overdosage:-
 Centrizonal necrosis : Paracetamol.
 Hepatocellular necrosis : Salicylates(aspirin).
 Fatty changes and hepatic failure :
Tetracyclines.
 Jaundice & elevated serum bilirubin:
androgens, OCP, rifampin.

9. 2. Drugs causing hepatic damage at therapeutic
dose by hypersensitivity reactions:
 Acute hepatocellular necrosis:
Halothane,Valproate, Isoniazid,Methyldopa
 Cholestatic Jaundice: Phenothiazines, oral
Hypoglycemic agents(chlorpropramide,
tolbutamide, glibenclamide), Antithyroid
drugs like Carbimazole and Antibiotics:
erythromycin
 Appears within 4 weeks of dosing and
recovery.

10. 3. Drug inducing hepatic damage by continued
therapy:
 Chronic active hepatitis: methyldopa,
isoniazid, dantrolene, nitrofurantoin.
 Hepatic fibrosis/cirrhosis: alcohol and
methotrexate.

11. 4. Drug inducing delayed hepatic damage even
after stoppage of the drugs:
 Benign liver tumor by high dose of anabolic
steroids.
 Hepatocellular carcinoma: OCP(Oral
Contaceptives) used for more than 5 years.

12. Other Drugs causing hepatotoxicity
• Pyrazinamide
• Sulphonamides
• Amiodarone
• Androgens
• Nevirapine
• Phenytoin

13. Paracetamol
• Used as analgesics and antipyretic agents.
• Therapeutics doses: 325-650mg every 4-6
hours.
• Total daily doses should not exceed 4000mg
per day.
• Dose > 7.5 g of paracetamol results in hepatic
toxicity.

14. Tetracyclines
• Antibiotics
• Hepatic toxicity develops on receiving of dose
> 2g per day.
• Pregnant women are more susceptible to
tetracycline induced hepatic damage.

15. Isoniazid(INH)
• Anti tubercular drug.
• Severe hepatic damage on exposure to this drugs.
• Damage occurs within weeks to months after the
therapy.
• Characteristics pathological process is multilobular
necrosis in liver.
• Acetylhydrazine, metabolite of isoniazid causes hepatic
damage.
• Hepatotoxicity is age dependent.
• Plasma transaminase levels are elevated.
• Stop the therapy after diagnosis of hepatic damage.
• Patients should be evaluated every month for the
symptoms of hepatic injury.

16. Pyrazinamide
• Anti tubercular drug
• Dose dependent and idiosyncratic hepatotoxicity.
• Therapeutic dose: 15-30mg orally in 3-4 divided
doses
• If daily dose > 3g, signs and symptoms of hepatic
diseases appear.
• Patients should undergo hepatic function tests
before the drug is administered.
• If hepatic damage appear – stop therapy.

17. Methyldopa
• Centrally acting anti hypertensive drug.
• Transient increase in plasma alanine
aminotransferase.
• Hepatitis appear within 3 months of starting the
drug.
• Hepatitis is duration dependent i.e. hepatic
dysfunction is reversible with discontinuation of
drug and recur if it is given again.
• Screening for hepatotoxicity is done by
determination of gamma glutamyl transpeptidase
or alanine aminotransferase, at about 3 weeks
and 3 months after initiation of therapy.

18. Erythromycin estolate
• Macrolide antibiotics
• Causes cholestatic hepatitis.
• Symptoms appear after 10-20 days of
treatment.
• Characterized by nausea, vomiting, abdominal
cramps, followed by leucocytosis,
eosinophillia, peripheral infiltration of
neutrophils and eosinophils.
• Mild elevation of serum aspartate
aminotransferase.

19. Phenytoin
• Idiosyncratic type.
• Phenytoin causes severe hepatitis like liver
injury leading to fulminant hepatic failure.
• Arene oxides, metabolite of phenytoin binds
covalently with hepatic macromolecules
leading to hepatic injury.
• Symptoms of hepatic injury include: fever,
rash, leukocytosis and eosinophilia.

20. Halothane
• Inhalational anesthetics
• Repeated administration, results in
hepatotoxicity.
• Halothane metabolism yields trifluoroacetic
acid, which reacts covalently with proteins in
liver cells
• Fluoroacetylated liver proteins initiate an
immune response.
• This immune response cause damage to
hepatic cells resulting in halothane hepatitis.

21. Sulphonamides
• Diffuse necrosis of liver due to direct drug
toxicity.
• Hepatocellular dysfunction appear 3-5days
after drug administration.
• Stop treatment after appearance of
symptoms.