This lecture covers acetaminophen or Tylenol toxicity. It explain why too much acetaminophen can cause liver toxicity, especially in people who frequently drink alcohol. Please give a thumbs up or leave a comment if you like.
Where you’re going to see most of your exam questions in regard to toxic metabolism is with acetaminophen toxicity so here’s a picture i took of a side of a sedum in ofin or a tylenol bottle it’s called tylenol cold and the question here is is why are we getting this warning and this is the warning that i am referring to it says if you consume three or more alcoholic
Drinks every day ask your doctor whether you should take acetaminophen or other pain relievers or fever reducers now this line is essentially crap what we care about is this line right here whether or not we should take acetaminophen so you might be thinking well if you’re a chronic alcoholic you might be inducing the p450 enzymes and therefore the levels of
Acetaminophen in your body would be decreasing and this pain medication wouldn’t work and that is probably correct to some degree but that’s not the answer what’s happening is we’re inducing p450 and therefore we’re going to make more toxic metabolites of acetaminophen so this leads to toxic metabolites and that is the problem so let’s start with just a little
Background information on acetaminophen it is the most widely used analgesic and antipyretic in the united states a pain reliever and a fever reducer and it is an over-the-counter medication so it is very safe if used in therapeutic ranges but at the same time it is the number one cause of acute liver failure in the united states and part of this could be people
Are knowingly overdosing on acetaminophen but the other reason is that they put acetaminophen in many drugs then it’s not always very clear that it has tylenol in it so here’s an example of you know tylenol cold it has the phenol efrain but acetaminophen is mixed into it you see acetaminophen in a lot of pain medications a lot of cold medications and so patients
Can unknowingly trying to treat some of their symptoms take a lot more acetaminophen than they anticipated and so what we’re interested in in this lecture is one acetaminophen toxicity but to how chronic alcoholism or you know can lead to some of this toxicity and so we’ll look at p450 induction and how something called depleted glutathione play a major role in
This toxicity so the pathogenesis here first point we need to understand is that by nature acetaminophen is not does not form toxic metabolites about 95 percent of it 95 percent here is conjugated by phase two enzymes to non-toxic form so glue quran id or sulfate so acetaminophen sulfate is non-toxic it doesn’t cause a problem but about 5% of acetaminophen this
Is number two here is metabolized by p450 enzymes into a reactive toxic intermediate and that’s this guy right here and so this toxic intermediate you actually should know the name for it it has an abbreviation and a p q i– and looking over to the left here this is n acetyl p benzoquinone amine and so having this the the formation of na p qi is really what is
Causing problems now this is where the alcoholism fits in if we are inducing these p450 enzymes this is the chronic alcoholic etoh user or if they’re using other p450 enzyme inducers we are going to form more of this na p qi and this is what is toxic so this next point i’m going to make here is we make this toxic compound in a non-alcoholic or in a small overdose
All of this toxic compound can be conjugated to glutathione which is g sh this is glutathione into a non-toxic conjugate and we can get rid of it but if these glutathione stores are depleted in a repeated overdose or if they are overwhelmed in the setting of p450 induction from chronic alcoholism or a very large overdose then this na pqi will bind to solve hydral
Groups on hepatic cells so let’s right here solve i drill groups and when it binds to this this eventually leads to cell death so by knowing this we can help provide an antidote in the setting of large overdose or a repeated overdose if we give an acetyl cysteine well this acts as a self hydral group donor it binds to this na pqi so that it doesn’t bind to these
Proteins and thus it forms a non toxic metabolite that we can get rid of so the reason we can’t just give gsh is because it can’t get into the cells very well now i want to make a quick point here looking into some of this data liver disease itself does not cause hepatic cell death does not increase your risk i should say it like this liver disease itself does
Not increase your risk for a patek cell death due to acetaminophen and the reason here is that with liver disease you’re also going to have less p450 enzymes and therefore you’re going to make less of this na pqi the real issue here is with depleted gsh so when people are taking acetaminophen in multiple forms and not realizing it now all of these points here are
Incredibly high yield and before we go here i want to point out some of these clinical signs of liver toxicity after an overdose the reason you should know these is that in an exam prompt these are going to be some of the things they’re gonna make you say ding ding ding there is liver toxicity here for a patient who’s taken a bunch of acetaminophen the first point
I want to make is unless it’s a very large overdose you don’t see these signs of liver toxicity immediately it’s going to take one to two days for these signs to become apparent and this is because we during this time the glutathione stores are being depleted once those stores are depleted we start seeing right upper quadrant tenderness this is where the liver is
Right we’ll see elevated liver enzymes these cells are dying and releasing the ast and alt and then we’ll also see jaundice because the liver is not able to get rid of the bilirubin the bilirubin in the body and so that will have they might say it as jaundice or a change in the skin color so this is acetaminophen toxicity an incredibly high yield and important topic
Transcribed from video
Acetaminophen or Tylenol Toxicity – Lect 19 – Pharmacology By Areo Saffarzadeh
