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THURSDAY NIGHT IS HEALTH CARE CHANGE NIGHT, a weekly Health Care Series (cross-posted at ePluribusmedia.  I have been invited to contribute this installment.  I originally was going to post about high fructose corn sweetener, but between the time of the invitation and now FDA came out with a new warning about acetaminophen.

Acetaminophen is one of the most widely used pain and fever relievers in the United States.  Much of the widespread use has to do with the fact that it causes less stomach upset and GI bleeding than aspirin or ibuprofen.  It is not linked to Reye Syndrome as is aspirin, making it a good choice for children and teens with flu.  Another very large reason for widespread use is heavy marketing.

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However, acetaminophen has a very dark side.  According to CDC, right at half of all cases of acute liver failure (ALF) in the United States is directly caused by acetaminophen.  I will not be as geeky in this post as I normally am in my regular Sunday evening series, Pique the Geek, where we try to delve fairly deeply into the science of various topics.  However, some scientific and historical background is necessary to understand the process of liver toxicity produced by this material.

In 1887 a drug called phenacetin was first marketed for fever and pain. It is actually made from acetaminophen and is metabolized in the body to it.  It was withdrawn from the United States market in 1983 due to concerns over carcinogenicity.  However, acetaminophen had already replaced it in a large share of the market.  The reason that phenacetin was used for so long had to do with sloppy research in the early 20th century.

Acetaminophen was first introduced in 1953 by Winthrop, but in 1955 McNeil began marketing Tylenol Children's Elixir, and the Tylenol brand is still probably the most widely recognized brand name in the United States.  Now it outsells aspirin, and I believe this is a dangerous situation.

All medications are eliminated from the body, mostly as metabolites of the parent drug.  The major site of metabolism is the great chemical factory of the body, the liver.  There are three major pathways, two of them harmless.  The first one is addition of glucuronic acid (a sugar derivative) in the liver, producing a metabolite that is nontoxic and is eliminated by the kidneys.  It is thought that, in MOST people, about 40% of the drug is eliminated that way.

A second pathway, also harmless, is addition of sulfate in the liver, forming a water soluble metabolite that is carried away by the liver.  In MOST people this accounts for around 20% to 40% of the total load.

The third pathway, accounting for about 15% of drug clearance, involves the cytochrome P450 set of liver enzymes (the ones that are increased by drinking alcohol).  A toxic intermediate called NAPQI is formed, and that is cleared by combination with the natural antioxidant glutathione and eliminated by the kidneys.  Here is where the problem arises.

NAPQI is highly reactive and combines with the lipids in liver cell membranes, killing the cells.  When combined with gluatathione, it becomes nontoxic, but glutathione is essential for liver protection from the thousands of other reactive oxidizing agents that it processes constantly.  Reduction of glutathione thus also damages the liver, since it is not available to protect the liver from other bad actors.

In most people, the recommended dose of acetaminophen does not cause any outward sign of trouble.  However, there are behaviors that increase sensitivity towards toxicity.  As mentioned before, moderate to heavy alcohol intake induces the very enzyme that is responsible for the "bad" pathway, so drinkers are naturally more susceptible.  Besides, alcohol in large doses is a liver toxin in its own right, so that is a double whammy.

Another risk factor is fasting and low protein diets.  Since glutathione is derived from protein, restriction of protein intake reduces its availability, thus decreasing its protective effect on the liver.

A third risk factor may be caffeine.  Some fairly recent work is consistent with the hypothesis that caffeine induces a liver enzyme that also causes the production NAPQI, presumably Cytochrome P450.  Now this is problematic for a couple of reasons.  First, many folks drink a lot of coffee.  Second, caffeine is often added to painkiller medications to increase their potency.  Some of these combinations include acetaminophen.

There are also other drugs that induce these enzymes, particularly anticonvulsants.  The barbiturates are potent inducers, and a few combination products contain a barbiturate, a narcotic, and acetaminophen.

In most normal people with no other risk factors, four grams of acetaminophen will show up on liver function tests after a few days for about a third of the population.  Well, four grams a day is the maximum recommended dose for Tylenol Extra Strength products according to the Tylenol website.  So, recommended doses affect liver function in one third of people with no other risk factors.  This is not good.

Six grams a day for two days can cause significant liver function disturbances in normal (that is, no other risk factor) individuals.  Now, I know a lot of folks who have the attitude, "if two tablets will help, three will help more."  Here is how we start getting into trouble.

But there is a more insidious overdose danger.  There are so many products that contain acetaminophen that it is easy to take an overdose and not even suspect it.  Many of them are over the counter, and many others are prescription drugs.  This is, in my opinion, the greatest threat for overdose.  I carefully read the labels of any OTC materials that I buy (and I do not get that many) to assure that they do not have any acetaminophen in them.  I use aspirin or ibuprofen for pain (I recently burnt my fingers severely as readers of Pique the Geek are aware) and the ibuprofen was very welcome.  I choose not to take acetaminophen in any form, and am fortunate that I tolerate aspirin and ibuprofen well.

I strongly urge everyone to be aware of ingredients in all OTC and prescription medications.  You can tell from the label for OTC materials, but for prescription medications you pretty much have to look them up online of, better, to ask the pharmacist directly whether there is any acetaminophen in your prescription, and if so, how much.  If you have a prescription that contains the maximum recommended dose and unknowingly take the maximum dose of OTC acetaminophen, you are at eight grams a day right off the bat.

Another potential danger out there is for infants and children.  Modern medical practice is not to give aspirin to children under 18 for fever (it is OK for muscle pain or headache) because of Reye Syndrome.  Thus, until ibuprofen became available OTC, acetaminophen has been the drug of choice.  A common mistake is substituting infant's acetaminophen drops for children's acetaminophen elixir.  The drops are much higher in concentration and should be given only with the little dropper that comes with them.  Using the directions for the weaker elixir with the drops will overdose your toddler, so be sure not to get the dosages mixed up.

How do you know if you have been poisoned?  After a few hours you will begin to feel bad, sometimes just "run down" in general.  Nausea and vomiting and sweating is not uncommon.  Vomiting is a good thing, if any is left unabsorbed in your stomach.  After about eight hours the damage is done and if severe enough pain on the right side of the abdomen from swelling and liver enzymes are haywire.  Kidney failure may also begin.  After a few days, you are either going to get over it or not.  No treatment is effective if given much after eight hours, except for liver transplant.  Those are sort of hard to get, especially in the quick.

There is a very effective treatment if given within the first eight hours.  There is a drug called acetylcysteine that can be given by emergency department staff.  It is metabolized to glutathione, which we talked about earlier.  This replaces the depleted glutathione, the important antioxidant, and significantly reduces liver damage.  If you wait too long, though, the liver cells are already dead and this will not revive them.  It just protects the ones still living.

I should point out the difference between acute poisoning and chronic poisoning.  In acute poisoning (very high single dose event), then the emergency department can give you activated charcoal to absorb any drug not yet out of the GI track, the acetycysteine to protect the liver, and you will likely be OK, IF you get to the emergency department fast.  On the other hand, the chronic overdosage caused by taking more than the recommended amounts of the drug add up over the months and years and can not really be treated except for avoiding the drug altogether.

Here are my recommendations for acetaminophen:

o  Eliminate the drug in any combination product, prescription or OTC.  This one step would eliminate accidental overdose caused by not knowing that you are taking it twice (or more).  If acetaminophen is needed, then plain tablets or capsules can easily be added to the other drug.  For example, if you need Percocet, the physician can prescribe oxycodone tablets and acetaminophen tablets with dosage instructions for both.  It might be a little more trouble, but I believe that this one step would reduce cases of accidental overdose significantly.

o  Eliminate adverts for acetaminophen and products containing it in the popular media.  This may have some First Amendment issues, but we did it for tobacco on the TeeVee and radio.  The big drug houses have a vested interest in selling as much as they can.  I see more adverts for acetaminophen than for any other OTC drug.

o  Make acetaminophen a "behind the counter" drug, like pseudoephedride.  This way, a pharmacy employee would be available to counsel the purchaser on the dangers of acetaminophen overuse.  This is less extreme than the third suggestion, which I prefer, but likely to be more acceptable to people.

o  Make it prescription only.  I prefer this approach.  This is the most onerous way to reduce toxicity, but in this case both a physician and a pharmacist would be involved in counseling the patient about the dangers of this drug.  I am not saying to make it a controlled substance like opiates, but prescription like antibiotics.

Finally, here are my personal opinions about acetaminophen:

o  It is a dangerous drug that is way, way overadvertised and overused.

o  I choose not to take it in any form.  I check labels on everything that I buy.

o  I strongly recommend that adults who tolerate aspirin to use aspirin.  Ibuprofen is fine, too, for those who can tolerate it and is approved for children.  It is cheap, safe, and effective.  Naproxin is also a good choice for those who can tolerate it.

o  For those who can not tolerate aspirin, ibuprofen, or naproxin, take the lowest dosage consistent with relief for the shortest amount of time.  Do not drink any alcohol while you take acetaminophen.  This actually is only a partial fix, since the liver enzymes induced by alcohol are already there and take several weeks to go back to normal levels.  Do not use caffeine, and if you take antiseizure medication, or any medication for that matter, ask your physician what to do.  The only problem with that is that physicians are heavily influenced by the drug companies and sometimes do not have the best information available, but better than nothing.

I now conclude this installment.  I want to express my appreciation to TheFatLadySings for inviting me to guest host this evening.  I will stick around for a while for questions and comments.  Please visit my science series, Pique the Geek here on Kos and crossposted at docudharma, at 9:00 PM Eastern every Sunday evening.  The next installment will be about the psychedelic amphetamines as part of the series Drugs of Abuse.

Crossposted at docudharma.

Update:  Folks, it is after midnight now.  I appreciate the opportunity to post on this astute series tonight, and hope to do so again some day soon.  Thank everyone for the good comments and questions.  Please see me Sunday as indicated just two paragraphs above here.

Warmest regards,

Doc

 

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Originally posted to Translator on Thu Jun 11, 2009 at 05:58 PM PDT.

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