Package paracetamol with its antidote
Paracetamol overdose is the most common cause of acute hepatic failure. Hepatocytes become sensitive to paracetamol metabolites and inflammatory mediators1-3 when intracellular glutathione (GSH) is depleted due to paracetamol metabolism4. For this reason, many clinical conditions associated with GSH depletion place patients at greater risk of paracetamol toxicity, even at therapeutic paracetamol dosings. These predisposing conditions include chronic alcohol abuse, HIV, sepsis, multi-organ system failure, chemotherapy, other types of hepatic failure, certain metabolic diseases, and chronic CNS disease. In addition, patients without predisposing disease are at risk because over-the-counter cold remedies and similar preparations frequently contain paracetamol and represent sources of potential overdose due to excessive, concomitant or chronic use.
Importantly, Hawton, Townsend, Deeks, Appleby, Gunnell, Bennewith, and Cooper now report that morbidity and mortality from paracetamol overdose decreased in the years following UK legislation to restrict the package sizes of the drug5. However, as these authors note, restricting the package size did not completely resolve the problem.
N-acetylcysteine (NAC), which provides the cysteine necessary to replenish glutathione (GSH) depleted by paracetamol, is used to treat paracetamol overdose6,7.
Intravenous NAC treatment protocols are used in some regions. However, oral treatment protocols have been shown to be highly effective. Treatment is most effective when started soon after paracetamol ingestion8,9; delays should be avoided but are still common10. Therefore, we suggest that toxicity caused by intentional or unintentional paracetamol overdoses is best treated by prevention, i.e., by formulating or packaging paracetamol with sufficient amounts of NAC to largely prevent toxicity .
NAC preserves the antipyretic and analgesic properties of paracetamol. Therefore, co-administration should not interfere with paracetamol effectiveness. Further, since NAC has been used for many years at high doses with minimal (or no) toxicity, administration at the estimated doses together with paracetamol should not pose any safety issues. The disagreeable odor and taste characteristic of some NAC formulations, particularly those used clinically in the United States, would appear to be a problem. However, the contaminants responsible for the bad taste and odor are not present in appropriately manufactured NAC formulations. Our estimates indicate that including less than 200 mg of NAC per 500 mg of paracetamol would accomplish the necessary prevention of toxicity. Therefore, we foresee no obstacles to the introduction of NAC/paracetamol products. Efficacy of such formulations for preventing morbidity and mortality should be evaluated.
James P. Andrus, MD#
Lenore A. Herzenberg, PhD+
Leonard A. Herzenberg, PhD+
Stephen C. DeRosa, MD+
Departments of Pediatric Critical Care# and Genetics+,
Stanford University School of Medicine, Stanford, CA 94305-5318
Corresponding author: James Andrus,
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Competing interests: No competing interests