HEPATOTOXICITY DUE TOCARBON TETRACHLORIDEACETAMINOPHENETHANOL ANDAFLATOXINS

FARAZA JAVEDMPHIL PHARMACOLOGY

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.

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.

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.

SIGN & SYMPTOMS

Nausea Vomiting Dizziness Depression of conscious level Cardiac Arrythmias Coma Hapatic necrosis Renal Damage

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.

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.

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.

SIGN & SYMPTOMS

Anorexia Nausea Vomiting Altered mental status Increased Transaminase level Heaptic failure Renal failure

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.

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.

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.

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

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.

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.

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.

SIGN & SYMPTOMS

Vomiting Abdominal Pain Mental Impairment Convulsion Hemorrhaging Disruption of food digestion & metabolism Liver damage Coma

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.

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.