What are the effects of acetaminophen (paracetamol) toxicity?

From the Guidelines

Paracetamol toxicity should be treated with N-acetylcysteine (NAC) as soon as possible, ideally within 8 to 10 hours of ingestion, in patients with possible or probable risk for hepatotoxicity as determined by the Rumack-Matthew nomogram. The management of paracetamol overdose is crucial to prevent severe hepatotoxicity and mortality. According to the study by Rumack et al 1, NAC should be administered to patients with acute acetaminophen overdose who have a possible or probable risk for hepatotoxicity. The Rumack-Matthew nomogram is used to determine the risk of hepatotoxicity based on the serum paracetamol level and the time of ingestion.

Key Considerations

• The standard NAC regimen involves a loading dose of 150 mg/kg over 1 hour, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours.
• Toxicity risk assessment depends on the serum paracetamol level plotted on the Rumack-Matthew nomogram, with treatment indicated if levels fall above the treatment line.
• Paracetamol toxicity occurs because the liver's detoxification pathways become saturated during overdose, leading to the accumulation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which depletes glutathione and causes hepatocellular damage.
• Early symptoms may be minimal or nonspecific (nausea, vomiting), while liver damage typically manifests 24-72 hours post-ingestion with elevated liver enzymes, coagulopathy, and potential progression to acute liver failure.
• Risk factors increasing susceptibility include malnutrition, chronic alcohol use, and certain medications that induce cytochrome P450 enzymes.
• Supportive care, monitoring of liver function, and early consultation with a poison control center or toxicologist are essential components of management, as shown in the study by Smilkstein et al 1.

Treatment Approach

• NAC treatment should be initiated as soon as possible, ideally within 8 to 10 hours of ingestion, to reduce the incidence of severe hepatotoxicity and mortality.
• Patients with no risk for hepatotoxicity as determined by the Rumack-Matthew nomogram do not require NAC treatment.
• The study by Prescott et al 1 showed that the incidence of severe hepatotoxicity was related to the time to first treatment with NAC, with patients treated within 8 hours having no severe hepatotoxicity and only 1 treated between 8 and 10 hours developing severe nonlethal hepatotoxicity.

From the FDA Drug Label

The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. VALUES ABOVE THE SOLID LINE CONNECTING 200 MCG/ML AT LEAST 4 HOURS WITH 50 MCG/ML AT 12 HOURS ARE ASSOCIATED WITH A POSSIBILITY OF HEPATIC TOXICITY IF AN ANTIDOTE IS NOT ADMINISTERED.

Paracetamol toxicity is likely if the ingested quantity is 150 mg/kg or greater, or if plasma acetaminophen concentrations are above the solid line connecting 200 mcg/mL at 4 hours with 50 mcg/mL at 12 hours [ 2 ].

• Ingestion of 150 mg/kg or greater may result in hepatic toxicity.
• Plasma acetaminophen concentrations above the solid line are associated with a possibility of hepatic toxicity if an antidote is not administered.

From the Research

Paracetamol Toxicity

• Paracetamol poisoning is common and potentially serious, with 158 cases (21%) out of 869 admissions for acute poisoning being caused by paracetamol 3
• The standard treatment for paracetamol poisoning is N-acetyl cysteine, which is effective in preventing liver damage if started early 3, 4
• Liver damage and death are associated with admission later than 15 hours after intake, highlighting the importance of prompt treatment 3

Treatment Options

• N-acetyl cysteine is the most commonly used antidote for paracetamol poisoning, and has been shown to reduce mortality in patients with acetaminophen-induced liver failure 4, 5
• Activated charcoal may also be effective in reducing the absorption of paracetamol, and may provide additional hepatoprotective benefits when used in conjunction with N-acetyl cysteine 6, 7
• Gastric lavage and ipecacuanha may also be used to prevent absorption, but their effectiveness is unclear and they may have a higher risk of adverse effects 5

Timing of Treatment

• Early treatment with N-acetyl cysteine is crucial in preventing liver damage, with treatment started within 15 hours of ingestion being most effective 3
• Administration of activated charcoal more than four hours after acetaminophen overdose may still provide additional patient benefit over NAC therapy alone 7

Outcome

• The outcome of paracetamol poisoning depends on the promptness and effectiveness of treatment, with liver damage and death being more likely if treatment is delayed 3, 5
• N-acetyl cysteine has been shown to reduce mortality in patients with fulminant hepatic failure, but the evidence is limited and further studies are needed to confirm its effectiveness 5