Shit, I almost forgot to save this post. This one was done by yours truly:
Now I know why I've been able to gobble so many prescription painkillers without inflicting much damage at all to my liver. I've had people tell me "you should be dead", although to be fair they were fairly ignorant. Still, I've eaten a lot of fucking vicodin, why isn't my liver ruined? Furthermore, why does acetaminophen poison your liver at all? What can stop it, and what's used in treatment?
Well, check it. I originally got on this train of thought because my twacked out self was taking a cold shower, as I've been doing for years now, and thought it would be lulzy to make a thread in NFHC "Things I like while on meth" saying nothing except, "Taking an
[COLOR="Blue"]ice[/COLOR] cold shower." Because you know, it is really nice on speed, and it releases NEP as well as doing a few other interesting things that I'll write about on my site later...but I just wanted to let you guys know about something specific.
Cold showers may increase one of the body’s most powerful endogenous antioxidants: glutathione. While the body can make its own glutathione from other nutrients, our bodies cannot seem to utilize glutathione pills or capsules. Encouragingly, a study of winter swimmers hints that cold water therapy can stimulate increases in glutathione levels.
In fact, many of the antioxidants we ingest orally work by helping the body produce glutathione.
http://www.cold-showers.com/increase-glutathione-levels/^^That's obviously just some health related blog quoting from a doctor selling a book, but the study itself is legitimate. There is only
one study done on it.
Anyway, I had never heard of glutathione before and I looked it up...
very interesting stuff...but the most relevant is its relationship to acetaminophen:
GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, and mitochondria. However, it is also capable of participating in non-enzymatic conjugation with some chemicals, as in the case of N-acetyl-p-benzoquinone imine (NAPQI), the reactive cytochrome P450-reactive metabolite formed by paracetamol (or acetaminophen as it is known in the US), that becomes toxic when GSH is depleted by an overdose of acetaminophen.
Glutathione conjugates to NAPQI and helps to detoxify it, in this capacity protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI begins to react with the cellular proteins, killing the cells in the process. The preferred treatment for an overdose of this painkiller is the administration (usually in atomized form) of N-acetyl-L-cysteine, which is processed by cells to L-cysteine and used in the de novo synthesis of GSH.
Glutathione (GSH) participates in leukotriene synthesis and is a cofactor for the enzyme glutathione peroxidase. It is also important as a hydrophilic molecule that is added to lipophilic toxins and waste in the liver during biotransformation before they can become part of the bile. Glutathione is also needed for the detoxification of methylglyoxal, a toxin produced as a by-product of metabolism.
At this point we know two things: cold water increases Glutathione levels and that glutathione is directly responsible for protecting yr body from getting APAP poisoning. Let's add a few more details to flesh out our understanding...
NAPQI is an acronym for the chemical N-acetyl-p-benzo-quinone imine. It is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (also called acetaminophen). It is normally produced only in small amounts, and then almost immediately detoxified in the liver.
However, under some conditions in which NAPQI is not effectively detoxified (usually in case of paracetamol overdose), it causes severe damage to the liver. This becomes apparent after 3–4 days after ingestion and may result in death from fulminant liver failure several days after the overdose.
Okay, so now we have a basic understanding of
why it is that ingesting ass loads of APAP will kill you: APAP produces a toxic metabolite which in large amounts overwhelms to the body's natural defense against it.
The primary metabolic pathway for paracetamol is glucuronidation. This yields a relatively non-toxic metabolite, which is excreted into bile and passed out of the body. A small amount of the drug is metabolized via the cytochrome P-450 pathway (specifically CYP1A2 and CYP2E1) into NAPQI, which is extremely toxic to liver tissue, as well as being a strong biochemical oxidizer.
In a normal person, the majority of the paracetamol is metabolized by glucuronidation, and the small amount (approximately 10% of paracetamol dose) of NAPQI that is produced is immediately inactivated by conjugation with glutathione. This differs among special populations
I'm not exactly sure how far I'd trust wikipedia with numbers like "10%", it may or may not be true.
"Well, what if I'm a drinker?" you ask... "After all, generally when I pop pills I'm drinking, too..."
Too right.
Chronic alcoholics may not have enough glutathione to inactivate all of the NAPQI produced, and other populations may create more NAPQI than normal due to differences in P-450 enzyme activity. The primary concern, however, is ingestion of large amounts of paracetamol due to accidental or intentional overdose. Since the drug is available over the counter almost everywhere in the world, it is a common choice for suicide attempts, especially among those unfamiliar with the manner of death it causes.
A toxic dose of paracetamol usually varies between 4 g in special populations and 6 g in the average person. The lethal dose is usually between 10 g and 15 g, though concurrent alcohol intake will lower that figure significantly. When a toxic dose is ingested, the sheer quantity of the drug saturates the normal glucuronide pathway, causing large amounts of NAPQI to be produced. Some of this is conjugated with glutathione, but eventually the glutathione reserves in the liver are depleted. This leaves only NAPQI, which in these large quantities kills liver cells very effectively.
Ah, so basically it depletes the levels of glutathione and has free reign to be extremely toxic. Not cool! But then, this
must mean that the level of glutathione in yr body must correspond to the amount of APAP that can be safely ingested. As far as 10 grams being a lethal dose goes, I have eaten 10 & 11 grams of APAP in the form of various pain killers about 5 or 6 times now, and it didn't really effect me. My abdomen hurt for a little while but it went away. I was, however, taking cold showers at that time & have been for a while.
So, how do doctors treat a kid that swallows a bunch of pills (like Pope 1337 ;p) and kill himself? Easy: pump the kid full of the amino acids necessary for the body to make glutathione.
The preferred antidote for NAPQI poisoning (usually secondary to paracetamol poisoning) is acetylcysteine. It can be given in large amounts without side effects. The preferred route of administration is intravenous, but many hospitals in the United States still give the oral form. The amino acid methionine can also be used effectively as an antidote for NAPQI toxicity. These antidotes must be given within hours of the initial overdose to be useful. The antidote should be given as soon as possible, up to 8 hours post-ingestion. The sooner the antidote is administered, the better the prognosis. If given within two hours of overdose, the prognosis is excellent.
Well! Why even bother going to a doctor, eh? Now, note, just in case you have a habit of being an idiot or not having a very specific sense of humor,
do not take anything I say as serious medical advise. I don't want to be, nor will I be held responsible for what you do with what I write. Or in the words of the almighty Koton,
Hear these words and hear them well lest it be not absolutely crystalline.
That all these
things, these whimsies,
these profane musings shall be not held accountable for any deed
or insipid act for it is all but sweet sham and pasquinade amidst such locution that might persuade an ass or ignoramus or folly soul but to those who hear these words be they wise enough to hear then be they wise enough to penetrate.A contract has been hatched and your seal was duly noted.
Anyway, enough of that...
What I was trying to get at it is that's
strikingly obvious that this sort of information could be very handy for people that take prescription pain medicine. Why isn't an amino-acid supplement of some sort prepared along side their Rx of vicodin, percocet, codeine, or whatever? What foods are best to eat?
Forget them, then, it's fairly obvious that you can't rely on someone
else to keep you alive. Certain people may keep you from dying, but there is no one out that which serves the function of keeping you alive. Except maybe your mother.
Also, for people that are facing a severe depletion of glutathione, and could die within hours because of an APAP overdose...Why not at least
try soaking them in ice cold water? Try that for five minutes, every half hour...It could be the difference between life and death. Someone should try it with rats, or elves, or maybe a congressman.
All relevant links:
http://en.wikipedia.org/wiki/Glutathionehttp://www.cold-showers.com/increase-glutathione-levels/http://en.wikipedia.org/wiki/NAPQIhttp://en.wikipedia.org/wiki/Acetylcysteine
