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DoctorRx1986

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Though I am not a current pharmacy school student yet (I will be this fall), I have a question about the mechanism of action of the active ingredient in Tylenol, acetaminophen. I am currently working in a community pharmacy as a clerk and am absolutely fascinated by the idea of exactly how a drug works its effects in the body. I am very inquisitive and always asking the pharmacist question about one drug or another and searching things online. Anyway, it is my understanding that one of the most common analgesics, aspirin, works by inhibiting the cyclooxygenase 1 and 2 enzymes. These enzymes, when inhibited from working, fail to synthesize prostaglandins, which are responsible for inducing effects such as pain and inflammation. I have tried to look into the mechanism of action of acetaminophen, but I have a hard time finding it. Does acetaminophen also prevent prostaglandin synthesis and therefore alleviate pain? The only thing I've read about this drug is that it "elevates the pain threshold". However, that doesn't really tell me much and is too vague. Can any of you pharmacy students or pharmacists care to explain this? Thank you
 

XoQo

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[not a pharmacist, but came across your post and found it fascinating -- pharm students/professionals, please by all means chime in!]

what i recall from my pharmacology course (brief survey course) was that essentially the mechanism of acetaminophen is largely unknown. There have been a few recent papers regarding the mechanism:

http://www.ncbi.nlm.nih.gov/pubmed/15662292

in particular points out that


1.) acetaminophen thought to be weak prostaglandin inhibitor
2.) in vivo effect of acetaminophen simililar to the selective COX2s (i.e. vioxx)
3.) although acetaminophen suppresses prostaglandins, it somehow still fails to suppress inflammation of disorders like rheumatoid arthritis

3a.) Yet, somehow, it has been shown that acetaminophen DOES decrease swelling after oral surgery in humans and IS able to suppresses inflammation in *rodents*

4.) Theories that acetaminophen acts on the COX3 alternative splice form of cyclooxygenase in a clinically relevant manner have been disproven by genomic and kinetic analysis.

5.) There evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but this may be a secondary effect compared with its action on prostaglandin production



...again...it just seems that the big picture answer might be "we still don't know yet"
 

DoctorRx1986

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[not a pharmacist, but came across your post and found it fascinating -- pharm students/professionals, please by all means chime in!]

what i recall from my pharmacology course (brief survey course) was that essentially the mechanism of acetaminophen is largely unknown. There have been a few recent papers regarding the mechanism:

http://www.ncbi.nlm.nih.gov/pubmed/15662292

in particular points out that


1.) acetaminophen thought to be weak prostaglandin inhibitor
2.) in vivo effect of acetaminophen simililar to the selective COX2s (i.e. vioxx)
3.) although acetaminophen suppresses prostaglandins, it somehow still fails to suppress inflammation of disorders like rheumatoid arthritis

3a.) Yet, somehow, it has been shown that acetaminophen DOES decrease swelling after oral surgery in humans and IS able to suppresses inflammation in *rodents*

4.) Theories that acetaminophen acts on the COX3 alternative splice form of cyclooxygenase in a clinically relevant manner have been disproven by genomic and kinetic analysis.

5.) There evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but this may be a secondary effect compared with its action on prostaglandin production



...again...it just seems that the big picture answer might be "we still don't know yet"


Thanks for your reply. I figured acetaminophen does inhibit prostaglandin synthesis to an extent, but that no body knows for sure the true mechanism. I asked an intern at the pharmacy I work for and she wasn't really able to give me a response. Same thing with online resources...no specific explanation. But thanks for your insights. :thumbup::)
 
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WVUPharm2007

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A bunch of Germans proved last year that it is in fact a COX-2 inhibitor.
Roughly 80% or so inhibition of COX-2 and 50% inhibition of COX-1. Explains the pharmacodynamics of the drug quite well. It doesn't cause gastric pain and has NSAID like effects.

It was also more or less proven in some American pain therapy journal when they found that tylenol inhibited prostaglandin E2 without inhibiting thromboxane B2 last Summer.

I'll see if I can find the journals....
 

WVUPharm2007

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Here's the article from the journal PAIN from last July. Download here.

The abstract is as follows:
Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation.
Lee YS, Kim H, Brahim JS, Rowan J, Lee G, Dionne RA.

Pain and Neurosensory Mechanisms Branch, National Institute of Dental and
Craniofacial Research, Bethesda, MD, USA.

Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE2 and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2gene expression is up-regulated, suggests that acetaminophen is a selective COX-2inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses.

I can't find the article for the other one on any of my journal databases. The article is titled "Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man." appearing in FASEB...which is a journal that is obscure to me to say the least. Here is the Pubmed citation.
 

FutureRxDr

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I was under the impression that acetaminophen was actually a COX-3 (CNS) inhibitor. The other NSAIDS inhibit COX-1 and/or COX-2 and are therefore for inflammation and pain. Acetaminophen inhibits COX-3 and is mainly for pain, but not inflammation. Am I on the right track here?
 

WVUPharm2007

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I was under the impression that acetaminophen was actually a COX-3 (CNS) inhibitor. The other NSAIDS inhibit COX-1 and/or COX-2 and are therefore for inflammation and pain. Acetaminophen inhibits COX-3 and is mainly for pain, but not inflammation. Am I on the right track here?

It probably inhibits all three cycloxygenases to some degree. However, the degree to which it inhibits each one and how significant that is....you know. There is COX involved with inhibition of all those thromboxane and prostaglandins in the brain, but now they think that the CNS doesn't contribute to eicosanoid inflammatory signaling....or something like that....
 

xxfoolxx

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regarding COX-3, i was told it was a bunch of BS, and that it didn't exist. that theory was only developed because they couldn't come up with a definitive theory for the MOA of APAP. this comes from a professor at my school who identified the chemical compound of tramadol and is labeled as "tylenol man" by his colleagues because of his extensive work with APAP. as of now, i still have not heard about a definite MOA for APAP.
 

Jbuprepharm

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regarding COX-3, i was told it was a bunch of BS, and that it didn't exist. that theory was only developed because they couldn't come up with a definitive theory for the MOA of APAP. this comes from a professor at my school who identified the chemical compound of tramadol and is labeled as "tylenol man" by his colleagues because of his extensive work with APAP. as of now, i still have not heard about a definite MOA for APAP.

it's exists in dogs, on which one of the studies was conducted. But I haven't personally seen where they've found it (active anyway) in people
 

FutureRxDr

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Thanks for the info, I was just going off of what I learned in Biochem.
 
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