Acetaminophen toxicity and overdose: current understanding and future directions for NAC dosing regimens

ABSTRACT

Introduction

Although N-acetyl-cysteine (NAC) has long been used for the treatment of acetaminophen poisoning/overdose, the optimal NAC dosing regimen for varying patterns or severity of the poisoning/overdose is still unknown.

Areas covered

Relevant literature was searched for in the MEDLINE (from 1964 until August 31^st, 2022), SCOPUS (from 2004 until August 31^st, 2022) and GOOGLE SCHOLAR (from 2004 until August 31^st, 2022) databases, without restriction in terms of publication date. The inclusion criteria were: original clinical studies reporting results, and studies investigating efficacy and safety of NAC dosing regimens in case(s) of overdose or poisoning with acetaminophen.

Expert opinion

For a more effective treatment of acetaminophen poisoning in the future, it will be crucial to advance the technology of measuring acetaminophen, its metabolites and NAC in the serum, preferably with the point-of-care technique, so that in real time it can be continuously assessed whether it is necessary to administer NAC, and further to increase the dose of NAC and extend the duration of its administration, or not.

KEYWORDS:

• Acetaminophen
• poisoning
• NAC
• dosing regimen

Article highlights

• Although acetaminophen is a safe drug in the recommended doses, when overdosed it is converted to the highly reactive metabolite benzoquinone, causing severe centrilobular necrosis.

• N-acetyl-cysteine (NAC), which replenishes hepatic glutathione, is used to treat acetaminophen overdose and poisoning.

• The common patterns of poisoning are: (1) acute intentional or accidental ingestion of immediate-release acetaminophen; (2) multiple (staggered) intentional or accidental ingestion of immediate-release acetaminophen; (3) acute intentional or accidental modified-release acetaminophen ingestion; (4) intentional or accidental ingestion of liquid form of acetaminophen by a child; (5) repeated supratherapeutic acetaminophen ingestion.

• The use of NAC and the duration of its administration are based on the estimated total acetaminophen dose, and repeated measurements of ALT and acetaminophen concentration.

• A few new biomarkers (microRNA-122, high mobility group box-1, full-length and caspase-cleaved keratin-18, ratio of AUC cytotoxic acetaminophen metabolites/AUC all acetaminophen metabolites) showed good results in predicting liver damage after acetaminophen overdose.

• Patterns of poisoning/overdose that include modified-release acetaminophen or repeated ingestion of immediate-release acetaminophen require repeated multiple measurements of acetaminophen and ALT concentrations in serum in order to adjust NAC dose and duration of administration.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the Serbian Ministry of Education, Science and Technological Development (Grant No 175007).