The most popular painkiller on the planet has been poisoning people
By Mike Wehner @MikeWehner
November 1st, 2020 at 10:13 AM
Got a headache? How about back pain? Maybe a fever? Don’t worry, there’s a magical pill that will take care of all those things… if only for a short while. It’s acetaminophen (or paracetamol), and it’s sold under various brand names like Tylenol and included in multi-drug combo pills like Excedrine. It’s long been considered the safest way to alleviate pain, but new research suggests it may not be quite as innocent as it seems.
The main issue with the drug, despite being a safe medication, is that people take its safety for granted and begin using it in higher and higher dosages and for extended periods of time. Overdose of the medication can result in poisoning that damages the liver and can even lead to death.
The research focuses on recent data showing a clear increase in the number of poisoning cases resulting from acetaminophen and the various pills that contain it. “It is a very safe drug, but only for short-term pain relief and as long as the daily dosage does not go above the recommended range,” Andrea Burden, co-author of the study, said in a statement.
The data the researchers used is specific to Switzerland, but the trend of increased poisonings appears to be much more widespread, and the cause is likely the same across the board. The medication is available easily over the counter, and while directions make it clear that those with pain of various types should be using only the lowest effective dosage, they tend to ignore those guidelines and take higher dosages. For patients that the drug doesn’t work well for, that means taking quite a bit more than the safe dose.
More:
https://bgr.com/2020/11/01/acetaminophen-safety-tylenol-paracetamol/
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Most of the people I know who take acetaminophen have some type of liver problem 
. I consider myself lucky that I never liked it.
For arthritis. Guess I'll have a shorter but less painful life
Here's a paper from 1985 describing the mechanism of the toxicology, which involves the oxidation product N-acetyl-p-benzoquinone imine: The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+.
Here's a picture of what is involved:
The toxicology is generally only very serious at very high doses, as p-450 oxidation to the quinoylimine is not the major metabolic pathway, and can be in many cases irreversible, although prompt treatment with S-acetylcysteine can ameliorate the toxicity.
I generally avoid acetaminophen, although under some circumstances I will take it, being careful to adhere to the recommended dose levels.
I generally like to take aspirin for pain and for inflammation, because taking aspirin makes me contemplate the chemistry of the eicosanoids, a marvelous cascade of the arachidonic inflammatory pathway. Targeting that pathway has provided some very problematic medicinal chemistry, specifically with the Vioxx and Celebrex cases of COX-2 inhibitors.
A lot of work around the world has been conducted to develop injectable aspirin to treat heart attacks. It is not a simple thing to do.
Aspirin, one of the world's first synthetic drugs, is still the world champion drug, even though it has well known anti-coagulation properties and can thus cause bleeding and in rare cases hemorrhaging. I take it fairly regularly, and I am always struck by its beauty and simplicity as well as its effectiveness.
