Acetaminophen Toxicity (Paracetamol Poisoning) Information

What is acetaminophen or paracetamol?

Acetaminophen or paracetamol is one of the most common agents used for intentional self-poisoning because of its easy availability. It is the active ingredient found in many over the counter (OTC) and prescription drugs used as an analgesic (pain reliever) or antipyretic (for reducing fever). Acetaminophen (paracetamol) is also found in combination with other drugs in various preparations.  N-acetylcysteine (NAC) is a specific antidote for paracetamol poisoning and is most effective when given within 8 hours of ingestion.

Acetaminophen Toxicity Dosage

The maximum daily dose recommended in adults is 4 g, and 90 mg/kg in children. Although it is a very safe drug when used in the correct doses, high doses can lead to toxicity. The most dreaded complication is acute liver failure. In adults, 150 mg/kg or 12 g may be fatal if not treated promptly. Toxicity may occur at lower levels in those with malnutrition, prolonged fasting, eating disorders, and chronic alcoholism. Overdosing may occur when wrong preparations are given to infants. It should be remembered that infant paracetamol drops are more concentrated than the elixir form hence much smaller doses are required when using drops instead of elixirs.

Acetaminophen Toxicity Mechanism

The chemical name of paracetamol or acetaminophen is N-acetyl-p-aminophenol (APAP). When taken orally, it is rapidly and completely absorbed from the stomach and small intestine. The rate of paracetamol absorption depends on the rate of gastric emptying. The absorbed acetaminophen (paracetamol) is metabolized by the liver and has a plasma half-life of 1.5 to 2.5 hours. Acetaminophen (paracetamol) metabolism is dependent on the age of the patient and the dose ingested.

Nearly 90% of the acetaminophen (paracetamol) is metabolized by the liver into glucuronide and sulfate conjugates, which are water soluble and are easily excreted through the kidneys. A small proportion remains unchanged and is excreted as such, while the remaining portion is metabolized into N-acetyl-p-benzoquinone-imine (NAPQI) which is a highly toxic metabolite. Glutathione binds NAPQI to make it non-toxic, which is then eliminated through the urine.

Acetaminophen Liver Toxicity

High doses of acetaminophen (paracetamol) can cause liver damage hence it is said to be hepatotoxic. When toxic doses of acetaminophen (paracetamol) are taken, metabolism by the liver is hampered, leading to a longer half-life. Sulfate conjugation is saturated hence NAPQI cannot be detoxified, which leads to liver necrosis (tissue death). Liver damage and death due to acetaminophen (paracetamol) poisoning is less common in children than in adults mainly because of the differences in the drug’s metabolism and its pathways of detoxification. Serious toxicity normally does not occur unless the dose is above 150 mg/kg.

Symptoms of Paracetamol (Acetaminophen) Poisoning

There may be no signs or symptoms initially even up to 24 hours, and when symptoms do appear they may be nonspecific in nature, such as

• Nausea.
• Vomiting.
• Abdominal pain.
• Malaise.
• Loss of appetite.

The more serious toxic effects may appear after 24 to 36 hours of severe poisoning, such as

• Hypotension (low blood pressure).
• Hypothermia (low body temperature).
• Abdominal pain.
• Sweating.
• Metabolic acidosis.
• Hypoglycemia (low blood glucose).
• Hypoprothrombinemia.
• Renal failure.
• Delirium.
• Convulsion.
• Jaundice (yellowish discoloration of the skin and conjunctiva).
• Coma.
• Liver failure may occur several days after ingestion. The outcome is poor in such cases.

Treatment of Paracetamol (Acetaminophen) Poisoning

Liver damage is the most dreaded complication of paracetamol overdose. Kidney failure may also occur. The sooner treatment can be started, the better the outcome.

• Emergency medical care should be sought immediately in case of suspected paracetamol overdose.
• General supportive measures such as intravenous fluids and oxygen.
• Gastric lavage if the patient comes within 1 hour of paracetamol overdose.
• Activated charcoal may be used if the patient is seen within 8 hours of paracetamol ingestion.
• Emergency measurement of paracetamol in the blood is essential in assessing the severity of poisoning.
• A single blood paracetamol level 4 hours after an overdose can indicate the potential risk of liver toxicity and specific antidote may be given based on this level.
• The specific antidote of choice is intravenous N-acetylcysteine. It must be given within 10 hours of ingestion to prevent or reduce acute liver damage. Further delay reduces its efficacy. If a patient comes more than 8 hours after an overdose, it is advisable to start with the antidote without waiting for the blood paracetamol level. Treatment can be stopped later if the paracetamol level in the blood is found to be below the treatment line.
• Oral methionine is an alternative antidote for paracetamol poisoning when N-acetylcysteine is not available.
• IV glucose to correct hypoglycemia.
• Liver function tests.
• Prothrombin time ratio to assess impending liver failure.
• Renal function tests.
• Charcoal hemoperfusion for fulminant liver failure.
• Hemodialysis for acute renal failure.
• Liver transplantation may be considered in case of acute liver failure.
• In case of a staggered overdose, where multiple doses have been taken over a period of several hours or days, measuring the blood paracetamol level will not be of much use. In such patients, N-acetylcysteine should be given if the dose of paracetamol ingested is more than 150 mg/kg body weight in any one 24-hour period or 75 mg/kg body weight in high risk patients, such as those on anticonvulsant drugs, chronic alcoholism, malnutrition, and eating disorders.
• Psychiatric assessment of the patient.
• Identification of patients with genuine suicidal tendencies.

Prevention of Paracetamol (Acetaminophen) Poisoning

• Educating the public and parents in particular about the importance of correct dosing and the potential risks associated with overdosing.
• Being particularly careful when using pediatric preparations for children as different acetaminophen (paracetamol) preparations come in different concentrations.
• Use of child-proof containers.
• Keeping all medication out of reach of children.
• Storage of medication in locked cupboards.
• Making people aware of the potential risks associated with using paracetamol and NSAID together or in those with chronic ethanol use.
• Use of combination tablets of the toxin and antidote, such as acetaminophen (paracetamol) and methionine.