This topic covers the general aspect of Heaptotoxicity

1. HEPATOTOXICITY DUE TO
CARBON TETRACHLORIDE
ACETAMINOPHEN
ETHANOL AND
AFLATOXINS
FARAZA JAVED
MPHIL PHARMACOLOGY

2. HEPATOTOXICITY
Hepatotoxicity refers to liver damage. Certain
medicinal agents, when taken in overdoses and
sometimes even when introduced within therapeutic
ranges, may injure the organ.
Chemicals that cause liver injury are called
hepatotoxin.

3. 1- CARBON TETRA CHLORIDE
Carbon tetrachloride was widely used as a
cleaning solvent, fire extinguisher agent, and
anthelmintics.
Because of its liver toxicity and known
carcinogenicity in animals, its role has become
limited; it is now used mainly as an
intermediate in chemical manufacturing.

4. MECHANISM OF TOXICITY
Carbon tetrachloride is a potent hepatic and renal
toxin. The mechanism is thought to be a result of
a toxic free-radical intermediate of metabolism.
(CCl4) undergoes hepatic reductive metabolism
to CCl3 and CCl3OO free radicals toxic
intermediates which may initiate hepatocellular
damage..
Chronic use of metabolic enzyme inducers such as
phenobarbital and ethanol increase the toxicity of
carbon tetrachloride. Carbon tetrachloride is a
known animal and suspected human carcinogen.

5. SIGN & SYMPTOMS
 Nausea
 Vomiting
 Dizziness
 Depression of conscious level
 Cardiac Arrythmias
 Coma
 Hapatic necrosis
 Renal Damage

6. MANAGEMENT
 Remove the subject from exposure area.
 Maintain normobaric or hyperbaric oxygen.
 In case of ingestion administer activated
chahrcoal.
 Ipecac induced vomiting may be useful for initial
treatment.
 N-acetylcysteine may minimize hepatic and renal
toxicity by providing a scavenger for the toxic
intermediate.

7. 2- ACETAMINOPHEN
Acetaminophen is a widely used drug found in
many over the counter and prescription
analgesics medication.
In adults, toxicity may occur by ingestion of greater
than 7.5-10g (24 regular strength or 15 extra
strength caplets or tablets) over a period of 8
hours or less.

8. MECHANISM OF TOXICITY
Acetaminophen is metabolized in the liver by
conjugation to non-toxic glutathione. The
conjugated product is eliminated in the urine.
But in an acute overdose, the liver's normal
glutathione reserves are depleted; the excess
acetaminophen is then metabolized to highly
toxic metabolite: N-acetyl-p-benzoquinone
(NABQI). NABQI is very reactive causing
hepatocellular death and subsequent massive
liver cell necrosis.

9. SIGN & SYMPTOMS
 Anorexia
 Nausea
 Vomiting
 Altered mental status
 Increased Transaminase level
 Heaptic failure
 Renal failure

10. MANAGEMENT
 Ipecac Syrup
 Activated Charcoal
 N-Acetyl Cysteine (loading dose is 150mg/kg in
200ml of 5% dextrose infused over 15-60 minutes).
 Mehtionine can also be given.

11. 3- ETHANOL
Commercial beer, wine, and liquors contain various
amounts of ethanol. Ethanol is also found in a variety
of perfumes, mouthwashes, many food flavorings (eg,
vanilla, almond, and lemon extracts), pharmaceutical
preparations (eg, elixirs), and many other products.
Ethanol is frequently ingested recreationally and is the
most common co-ingestant with other drugs in suicide
attempts. Ethanol may also serve as an antidote in
the emergency treatment of methanol and ethylene
glycol poisonings.

12. MECHANISM OF TOXICITY
Ethanol is also oxidized in liver by an ethanol-
inducible cytochrome P-450 enzyme that converted
the contents to toxic radicals. Induction also results
in energy wastage and increased production of
acetaldehyde that results in injury to cells and
mitochondria with a striking impairment of oxygen
utilization.
Acetaldehyde also causes glutathione depletion and
lipid peroxidation, and stimulates hepatic collagen
synthesis, thereby promoting fibrosis and cell
damage.

13. SIGN & SYMPTOMS
 Euphoria
 Impairment of balance & muscle coordination
 Nausea
 Vomiting
 Hypoglycemia
 Ketoacidosis
 Respiratory Depression
 Pale, bluish, cold and clammy skin due to insufficient
oxygen
 Coma

14. MANAGEMENT
 Protect the airway and provide supportive treatment.
 Don’t induce vomiting or activated charcoal
 Give glucose & thiamine to treat alcoholic ketoacidosis
 Correct hypothermia with gradual rewarming
 No specific antidote available
 Perform hemodylasis for efficient ethanol removal.

15. 4- AFLATOXINS
The aflatoxins are a group of structurally related toxic
compounds produced by certain strains of the fungi
Aspergillus flavus and A. parasiticus.
Aflatoxicosis is poisoning that results from ingestion of
aflatoxins in contaminated food. Among 18 different
types of aflatoxins identified, major members are
aflatoxin B1, B2, G1 and G2. Aflatoxin B1 is the most
toxic and most prevalent among this family.

16. MECHANISM OF TOXICITY
The major target for the toxicity of aflatoxins is the
liver. Oxidation by cytochrome P450, aflatoxins
then bind to DNA or proteins and impair their
functions. Aflatoxins produce necrosis of liver
cells, damage to mitochondria, and proliferation
of bile ducts. Aflatoxin also suppress the immune
system of the body.

17. SIGN & SYMPTOMS
 Vomiting
 Abdominal Pain
 Mental Impairment
 Convulsion
 Hemorrhaging
 Disruption of food digestion & metabolism
 Liver damage
 Coma

18. MANAGEMENT
 The FDA’s goal for aflatoxins has been to minimize
contamination by the cause.
 Provide supportive treatment.
 There is no specific antidote for toxicity of
aflatoxins. Timely administration of methionine
(200 mg/kg) and sodium thiosulfate (50 mg/kg), at
eight hour intervals, is proven to be of therapeutic
value.

19. REFERENCES
Kent R, and Olson M .Poisoning and Overdose. 3rd Edition.
California, San Francisco.
Jerrold B, and Frank P. Poisoning and toxicology handbook. 4th
Edition. Newyork, United State America.
Anthony R, and Jeffery S. Guidelines for the management of
Acetaminophen overdose. 2004.
R. P. Tiwari, T. C. Bhalla, S. S. Saini, G. Singh and D. V. Vadehra.
Mechanism of action of aflatoxin. J. Biosci., Vol. 10:1, 1986, pp.
145-151.