Acetaminophen/paracetamol is a great drug. It comes without a lot of the GI irritation problems of aspirin and other typical COX inhibitors. Unlike aspirin, it doesn't increase clotting time. No nagging feeling you're going to give your kid Reye's syndrome. However, it has an unusually low threshold for overdose, due to a quirk in its metabolism.
Most acetaminophen is conjugated to a sugar derivative and excreted. A small fraction, however, gets converted to a toxic metabolite: NAPQI.
NAPQI is a potent hepatotoxin - much at all and your liver is shot. As I intimated yesterday, glutathione provides reducing equivalents - this is another time it comes in handy. It can detoxify NAPQI. However, you've only got a limited pool of glutathione - generating these reducing equivalents in an oxidizing atmosphere is energetically "expensive" - think of it like running a fridge outside in summertime. So when you're out of glutathione, as in an overdose, you stop detoxifying NAPQI.
Liver failure due to acetaminophen overdose is maybe the saddest possible aspect of a failed suicide attempt. You can go for several (painful) days without a liver, and it takes awhile before jaundice and overt signs of liver failure begin to show in the first place.
So imagine this: you decide to commit suicide, or attempt suicide. Acetaminophen is readily available just about everywhere. Maybe you're subconsciously expecting the attempt to fail and it seems like a fairly benign choice. In whatever case, you take about 20 pills, go to sleep, and...wake up. Nothing seems wrong for several days - until the symptoms of liver failure set in, at which point your only option is a transplant.
For the curious and potential googlers: if you overdose on the stuff, there is a sizable window (hours) to take an antidote - which is just the amino acid N-acetylcysteine, which is reducing on its own and can replenish glutathione.
On the off chance of a suicidal googler: call 1-800-SUICIDE (800-784-2433) in the US, visit here for a comprehensive list. If you've already overdosed on acetaminophen, call 911 and get yourself to a hospital ASAP - this is one of the few drugs with a real "antidote," and the sooner you get it in you, the more liver damage you will prevent.
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Good stuff!
I would add-
It is generally accepted that 4gr of APAP in any 24 hour period is within safe limits for those with healthy liver function. However, alcohol consumption reduces this threshold. Chronic moderate to heavy drinkers should probably avoid APAP altogether. And, while 4gr is the recommended daily max., an acute toxic dose probably starts at around 8gr/single dose.
I just completed an autopsy report on a sad death resulting from an accidental acetaminophen OD. This was a kid of about 20 who had a relatively minor surgical procedure and was given a prescription for acetaminophen w/codeine for post-op pain - pretty standard order. Unfortunately it didn't cover his pain adequately, so he went to his FP the next day and got a prescription for Dilaudid. He died unexpectedly that night. When I did the autopsy, I thought he might have ODed on the Dilaudid, or even on a street drug. When the tox came back, he had high, but not lethal levels of codeine, therapeutic levels of acetaminophen and NO Dilaudid. No other substances either.Then I looked at the microscopic sections - his liver was completely shot. I figure that he took a big OD of APAP with Codeine within a few hours of surgery, which wiped out his liver after a couple of days. In the meantime, his pain settled enough the day before he died that he didn't need the Dilaudid, but kept taking the APAP and Codeine. He went to bed the night he died, probably feeling relatively OK. He never woke up. A tragic death.
Interested stuff...is this the only toxic metabolite?
Bruce-
That's a sad story for certain.
But, I do wonder if there could have been something else in the mix - like alcohol? Or, if he had tolerance to opiates that might have played-in as well?
There are some preparations of codeine/APAP that have really high amounts of APAP, i.e., 60/800. But he would have had to take 10-12 of those to push the APAP high enough to be toxic. On the other hand if he was a heavy drinker that might explain how lower doses could lead to toxicity.
You have a tough job!
I've known people to take 10 or 12 doses of a prescription painkiller in less than 24 hours. Some are sure they need 2 or 3 times what the doctor says, others just have a hard time being patient when in pain, and, like most people, think the pain will go away faster if they take another one.
I've also known many people to willfully ignore directions to not mix a drug with alcohol.
The APAP alcohol interaction is a very bad thing, IMO, as many people view APAP as the default painkiller, take as much or more than what the label lists as safe, and mix with alcohol, without a second thought.
So I'm not here to advertise a supplement by any means, but you should check out milk thistle extract and its active components, a group of flavonoids called silymarins. It is pretty amazing stuff, and also has the potential to protect against APAP toxicity. One mechanism by which it does this is stimulating production of GSH. I've read it has several other mechanisms for hepatoprotection, though I don't know a ton about it.... It's used in injectible form for Amanita (death cap) mushroom poisoning in some ER's, too! Plus, it's very non-toxic. Sweeeeet.