Acetaminophen Toxicity

Acetaminophen is one of the most commonly available over-the-counter analgesics, found in Tylenol and other pain relievers. It's possible, however, to ingest too much acetaminophen, and the consequences can be fatal. Acetaminophen overdose remains one of the leading causes of hepatic failure in America, due mainly to accidental overdose as patients are often unaware of the levels of acetaminophen they are ingesting. This very short article should serve as a beginners primer on acetaminophen's mechanism of toxicity.

Acetaminophen itself is not the toxic compound, however, which can also lead to some confusion. The compound responsible for the hepatoxicity associated with acute acetaminophen overdose is a highly reactive metabolite of acetaminophen.

When taking acetaminophen, most of it is metabolized into inactive metabolites in the liver by conjugation with sulfate and glucuronide. However, some of the drug is oxidized by the liver enzyme CYP2E1, which creates a chemical called NAPQI (N-acetyl-p-benzoquinone-imine). This chemical is the culprit behind acetaminophen's hepatoxicity.

With normal doses of acetaminophen, only a small amount of NAPQI is produced, and that amount is quickly and efficiently detoxified in the liver by glutathione. As the amount of acetaminophen ingested increases, however, the load on the sulfate and glucuronide responsible for the metabolism of acetaminophen also increases. Once a certain amount of acetaminophen is ingested, the sulfate and glucuronide can no longer metabolize the acetaminophen, and the rest is oxidized by CYP2E1, which creates an over-abundance of NAPQI. There is enough glutathione in the liver to handle small overdoses, but the more NAPQI that is produced, the greater the chance of all the glutathione being used up.

Once most of the glutathione is used (around 60% or so), no more NAPQI can be detoxified, and it is free to react with the liver cells, which often leads to liver damage and, less frequently, death.

The amounts of acetaminophen that are dangerous are highly dependent on the individual, but the following are the generally accepted guidelines:

The recommended maximum daily dose (ie: the most you should take in 24 hours) is 4g. The recommended maximum single dose (ie: the most you should take at once) is 2g. To put these numbers in perspective, a single regular strength Tylenol contains 325mg of acetaminophen. It should also be noted that going slightly over these levels isn't really too much cause for concern, as the liver is generally a resilient organ.

Hepatoxicity becomes something to worry about, though, when the patient reaches single doses in excess of 10g, or chronic doses greater than 5g. That's not to say that those doses are always fatal, but at these levels, the risk of serious toxicity is greatly increased.

As is to be expected, the above quoted doses depend on many things. For instance, toxic doses will be much lower if the patient consumes excessive amounts of alcohol, if they have a preexisting liver condition that would impair liver function (such as Hepatitis C), or if they have an overabundance of CYP2E1.

Depending on the severity of the overdose, symptoms can develop anywhere from 10-15 hours for severe cases, to up to a week for less severe cases. Some symptoms of acetaminophen overdose are severe pain in the upper right quadrant of the abdomen (just below the rib cage), profuse sweating, nausea, vomiting, anxiety, lethargy, and possible mild disorientation.

Warning and disclaimer: This introductory article should not be considered as medical advice. Any questions or concerns should be directed to your physician. If you believe you have taken an overdose of acetaminophen, please call your local Poison Control center, or go to the hospital. If treated promptly, acetaminophen overdoses can be quickly, easily, and efficiently treated.