What are the effects of paracetamol (acetaminophen) toxicity?

From the Guidelines

Acetaminophen toxicity should be treated with immediate administration of N-acetylcysteine (NAC) as soon as possible, ideally within 8 hours of ingestion, to reduce the incidence of severe hepatotoxicity and mortality. The treatment protocol for acetaminophen toxicity involves a loading dose of 150 mg/kg over 60 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 1. Blood tests should be obtained to measure acetaminophen levels, liver function tests, and coagulation studies.

Risk Stratification

The Rumack-Matthew nomogram can be used to determine the risk of hepatotoxicity in patients with a single known time of acetaminophen overdose within 24 hours of ingestion 1. However, for patients with unknown or unreliable ingestion history, extended-release or repeated supratherapeutic ingestions, the decision to treat with NAC should be individualized 1.

Repeated Supratherapeutic Ingestions

Repeated supratherapeutic ingestions of acetaminophen can result in hepatotoxicity, hepatic failure, and even death 1. Treatment with NAC is recommended for patients with serum acetaminophen concentrations of greater than or equal to 10 mg/mL or greater than normal aminotransferase concentrations (AST or alanine transaminase (ALT) .50 IU/L) 1.

Key Points

• Acetaminophen toxicity can cause liver damage through the production of a toxic metabolite called NAPQI, which depletes glutathione stores and causes hepatocellular necrosis 1.
• Early symptoms of acetaminophen toxicity may include nausea, vomiting, and abdominal pain, while later stages can progress to liver failure, encephalopathy, and death if untreated 1.
• Prevention involves careful adherence to recommended dosing guidelines and awareness that acetaminophen is found in many combination medications 1.
• NAC has been shown to limit hepatotoxicity in acetaminophen-toxic patients by several mechanisms, including serving as a sulfhydryl group donor, conjugating NAPQI into a nontoxic metabolite, and blunting the hepatocellular toxicity of NAPQI 1.

Treatment Recommendations

• Administer NAC to acute acetaminophen overdose patients with either possible or probable risk for hepatotoxicity as determined by the Rumack-Matthew nomogram to reduce the incidence of severe hepatotoxicity and mortality, ideally within 8 to 10 hours postingestion 1.
• Do not administer NAC to acute acetaminophen overdose patients with no risk for hepatotoxicity as determined by the Rumack-Matthew nomogram 1.
• Consider NAC for patients with hepatotoxicity thought to be due to acetaminophen and have a suspected or known acetaminophen overdose, including repeated supratherapeutic ingestions 1.

From the FDA Drug Label

Acetylcysteine injection is an intravenous antidote for the treatment of acetaminophen overdose. Acetaminophen doses of 150 mg/kg or greater have been associated with hepatotoxicity Acetylcysteine probably protects the liver by maintaining or restoring the glutathione levels, or by acting as an alternate substrate for conjugation with, and thus detoxification of, the reactive metabolite of acetaminophen.

Acetaminophen toxicity is treated with acetylcysteine, which is an intravenous antidote.

• Mechanism of action: Acetylcysteine maintains or restores glutathione levels, or acts as an alternate substrate for conjugation and detoxification of the reactive metabolite of acetaminophen.
• Treatment: Acetylcysteine is used to treat acetaminophen overdose, which can cause hepatotoxicity at doses of 150 mg/kg or greater 2.

From the Research

Acetaminophen Toxicity Mechanism

• Acetaminophen poisoning accounts for a disproportionate percentage of all toxic ingestions and can be life-threatening 3
• The hepatorenal toxicity of acetaminophen is mediated by a reactive metabolite normally detoxified by reduced glutathione 4
• If glutathione is depleted, covalent binding to macromolecules and/or oxidation of thiol enzymes can lead to cell death 4

Treatment of Acetaminophen Toxicity

• N-acetylcysteine (NAC) is the mainstay of treatment for acetaminophen-induced hepatotoxicity 3, 4, 5, 6
• NAC acts to detoxify acetaminophen by increasing the synthesis and availability of glutathione, which binds and inactivates the highly reactive and hepatotoxic acetaminophen metabolite N-acetyl-p-benzoquinoneimine 3
• Oral or intravenous NAC can mitigate acetaminophen-induced hepatorenal damage if given within 10 hours, but becomes less effective thereafter 4
• The US Food and Drug Administration has approved an intravenous formulation of NAC, allowing the treatment time to be decreased from 72 hours to 20 hours 3

Administration and Efficacy of NAC

• Co-administration of NAC and acetaminophen can efficiently block acetaminophen toxicity 7
• Oral NAC therapy is contraindicated in the presence of coma or vomiting, or if activated charcoal has been given by mouth 4
• Intravenous NAC is preferable for most patients with acetaminophen poisoning due to a shorter hospital stay, patient and doctor convenience, and concerns over the reduction in bioavailability of oral NAC by charcoal and vomiting 6
• Adverse reactions to intravenous NAC can occur, including anaphylactoid reactions, but are generally mild and do not prevent completion of treatment 4, 6

Outpatient Treatment and Prevention

• Outpatient NAC treatment for acetaminophen poisoning can be effective and may offer cost savings 5
• Self-administration of NAC in the home setting may be a viable option for patients with acetaminophen poisoning 5
• Co-formulation of acetaminophen and NAC may provide a convenient and effective way of preventing toxicity associated with large doses of acetaminophen 7