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Toxicology Rounds

N-Acetylcysteine and Acetaminophen Toxicity

Two Common Misconceptions

Gussow, Leon MD

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    The standard protocol for treating acetaminophen (APAP) overdose calls for N-acetylcysteine (NAC) given as an oral loading dose of 140 mg/kg, followed by 17 doses of 70 mg/kg at four-hour intervals, a full three days of treatment. This schedule is so specific and has been used for so long that many emergency physicians take it as gospel, assuming it must have been precisely calibrated on the basis of exacting clinical studies. But it is useful to stop and ask, why 17 doses? Why not 18? Or 12? Once started on NAC, do most patients actually have to stay in hospital for 72 hours to complete the entire standard course?

    I recently attended a lecture by Barry Rumack, MD, in which he reviewed the history of how he and his colleagues devised the NAC regimen, which turns out to have originated not in hard science but from theoretical estimations, very educated guesswork, and regulatory fiat (J Toxicol Clin Toxicol 2002;40:3). They started with their knowledge of how APAP is handled by the liver. The majority is metabolized to nontoxic sulfate and glucuronide conjugates, which are excreted in the urine. After normal therapeutic dosing, a small amount of APAP (usually less than 5%) is transformed by the cytochrome P450 system to the metabolite NAPQI, that can rapidly react with and destroy nearby hepatic cells.

    Fortunately, the liver is able to detoxify NAPQI as long as it has an adequate supply of the tripeptide glutathione. After an overdose of APAP, however, the sulfate and glucuronide conjugation pathways become saturated, more NAPQI is formed, and the liver's stores of glutathione become depleted. When this happens, free NAPQI attacks structures on cell membranes, causing hepatonecrosis.

    In determining the recommended length of treatment and total cumulative oral dose of NAC, Dr. Rumack and his colleagues created calculations based on the half-life of APAP in overdose, the estimated absorption and turnover rate of glutathione, and the percent glutathione depletion expected to cause toxicity. They arrived at a total dose of 6 mg/kg/hr given over 20 hours. But because the Federal Drug Administration wanted a large safety factor built into the protocol before approving its use, both the calculated hourly dose and estimated length of treatment were essentially tripled. In addition, an oral loading dose was added so that high levels of NAC could be achieved quickly. Thus was born the familiar 72-hour schedule of 140 mg/kg followed by 70 mg/kg every four hours for 17 additional doses.

    When this was assessed in an open-label study of more than 2,500 patients, it proved very effective, especially if given early (N Engl J Med 1988;319:1557). Started within eight hours of acute ingestion, NAC completely prevented hepatotoxicity even if the initial plasma APAP concentration was very high. While not completely protective if started later, NAC still improved clinical outcome if given within eight to 24 hours after ingestion. It is important to note, however, that the 72-hour regimen has never been compared with shorter oral courses in a clinical trial.

    Three Days Unnecessary?

    It is reasonable to assume that in many cases, the complete three days of treatment with NAC may not be necessary. Because hepatic damage is caused by the metabolite NAPQI, which acts immediately after being formed from APAP, hepatotoxicity should not ensue if at any time after ingestion the APAP level is undetectable and liver enzymes are normal. In his historical review, Dr. Rumack stated that “the 72-hour oral NAC protocol is probably unnecessary in many cases where the drug has a shorter half-life and disappears before the full dosage is completed.”

    He went on to say, however, that we lack evidence proving the effectiveness of shorter treatment, and called for further studies. Unfortunately, given the large number of patients needed for adequate trials, such studies will probably never be done. Meanwhile, some poison centers have adopted a protocol in which NAC treatment is stopped at 36 hours after acute ingestion if at that time APAP is not detectable in the serum and there is no evidence of hepatotoxicity. A recent retrospective case series of 75 patients analyzed by Woo et al (Ann Emerg Med 2000;35:363) supported use of an abbreviated course of NAC in selected cases of acute APAP overdose.

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    Figure:
    Acetaminophen Metabolism

    Because much of the original research on treating APAP toxicity was limited to cases in which NAC was initiated within 24 hours of ingestion, it is often assumed that treatment is not effective if started later. Studies at Kings College Hospital in London, however, using an intravenous protocol have clearly shown that NAC improves survival and other outcome measures even if begun after onset of fulminant hepatic failure (Brit Med J 1991;303:1026). NAC has turned out to be a very versatile agent with myriad beneficial effects. It helps modify inflammation, enhances blood flow and oxygen delivery, and fights oxidant damage. It seems to improve outcome even in hepatic failure unrelated to APAP. NAC should be administered in cases of known or suspected APAP overdose even if time from ingestion is more than 24 hours or unknown.

    Our understanding of APAP toxicity and its treatment is evolving as medical knowledge improves, forcing re-evaluation of what has passed for conventional wisdom. The beliefs that all patients started on NAC must receive the full 72-hour course and that NAC is not effective treatment for APAP toxicity if started more than 24 hours after ingestion, are misconceptions based on outdated science. Understanding this, the use of this most valuable antidote can become more focused and efficient.

    © 2004 Lippincott Williams & Wilkins, Inc.