Hinz et al. 2008 found that COX-2 may be inhibited by paracetamol, and this is attributed to it's analgesic and antipyretic properties. However, there are other more recent claims from Andersson et al., 2011 that a toxic intermediate metabolite, NAPQI, may be acting on TRPA1-receptors in the spinal cord. Whilst I'm vaguely aware that the end goal is to affect prostaglandins, to me at least it remains unclear how that translates to painkilling.

There are also other theories I would imagine.

This exceedingly common drug seems shrouded in mystery. I know very little about pharmacology (evidently!), so some expert insight into the popular theories, and why they're popular, would be greatly appreciated.

  • What are the most popular theories in a nutshell?
    • Why are they a popular theory?
    • Which protein is targeted?
    • How does that inhibition introduce the analgesic and antipyretic properties?
  • Is it possible multiple theories are correct?

  • Why is so little known about paracetamol? Is it exceptionally difficult, or the norm in pharmaceutical research of relatively old effective drugs? If it ain't broken, why fix it!


1 Answer 1


What are the most popular theories in a nutshell?

To date, the mechanism of action of paracetamol is not fully understood. There are some experimental evidences, but it is difficult to put things togheter. It is now clear that paracetamol acts contemporaneously via at least three pathways:

  • The inhibition of cyclo-oxigenase (COX)

The main mechanism proposed is the inhibition of COX, it's highly selective for COX-2.
COX are molecules involved in the metabolism of arachidonic acid (aa). It catalyzes the reaction to form prostaglandin H2, a pro-inflammatory compound, from aa. Paracetamol, as other NSAIDs, block this step , thus reduce the amount of prostaglandin H2. The reduced amount of prostaglandin H2 in the CNS, lowers the hypothalamic set-point in the thermoregulatory centre.

The exact mechanisms by which COX is inhibited in various circumstances are still a subject of discussion.

Some authors state that paracetamol works by inhibiting the COX-3 isoform—a COX-1 splice variant—of the COX family of enzymes.
This variant is expressed mostly in brain, so it is the one supposed to be involved in the antalgic effect of this compound.

There is another physiopathologic possibility to explain its action, that is: paracetamol would block COX, but in an inflammatory environment where the concentration of peroxides is high, paracetamol itself is oxydated and thus inactive. When it founds a non inflammatory environment, such as CNS, it become reduced and thus active (it reduces temperature, it has anti-dolorific action, etc).

  • The modulation of the endogenous cannabinoid system, through its metabolite AM404, a compound that inhibits the reuptake of the endogenous cannabinoid/vanilloid anandamide by neurons.

The COX model can explain quite well the action of paracetamol, altought it has been demonstrated an important role of the endocannabinoid system aside of COX. When cannabinoid receptors are blocked with synthetic antagonists, paracetamol's analgesic effects are prevented. This is tought to be due by an active metabolite of paracetamol, that is called AM404 and inhibits the reuptake of anandamide.

Anandamide reuptake lowers synaptic levels of anandamide. This results in a more activated pain receptor (at least the main one, called TRPV1, or according to an old nomenclature: vanilloid receptor). The high levels of anandamine, due to inhibition of its reuptake, desensitise this receptor in a way similar to the capsaicine. Furthermore, this active metabolite (AM404) inhibits sodium channels, this chemical behaviour is shared with lidocaine and procaine, two common anesthetic drugs.

These two actions by themselves have been shown to reduce pain, and are a possible explanation of paracetamol's mechanism of action; but one other specific activity of this compound remains unexplained by these two models.

  • Serotonin receptor agonism.

It has been observed that this compound can reduce the social rejection in humans. This can't be explained with COX or type I endocannabinoid system modulation. Increase of social behavior in mice dosed with paracetamol, wich models a reduction of social rejection response in humansdoes not appear to be due to cannabinoid receptor type 1 activity. . In the animal model, it seems a result from serotonin receptor agonism.

  • Aside of this main features, some other evidences are in bibliography.

In 2011 a debate started on scientific journals. Some has found a hint to the analgesic mechanism of paracetamol, being that the metabolites of paracetamol e.g. NAPQI, act on TRPA1-receptors in the spinal cord to suppress the signal transduction from the superficial layers of the dorsal horn, to alleviate pain. This findings has been contested in a new hypothesis paper on how paracetamol might act. This second study concedes that NAPQI is the active metabolite but that this reactive compound should react not only with the thiol in TRPA1 but also with any other suitably available nucleophile that it happens to encounter. This broad interaction with thiol groups in cysteine proteases, like the ones that process procytokines, might be the targets giving rise to overall analgesic effects, changing the global cytokyne environment. Even if there are evidences of drug-body interaction with formation of active metabolites and there are some models of drug action, many things are not fully cleared and the debate is still open.

Why are they a popular theory?

Are popular because are based on experimental and clinical evidence. Also, this theories can model lot of the biological effects of this compound.

Which protein is targeted?

Not any time it can be possible to reduce a pharmacological interaction at this level. For instance, in one theory it inhibits an enzyme, the cyclooxygenase (COX); in one other model entire classes of molecules, the sodium channels, are modulated... Unfortunately many times, dealing with living organisms, it is not possible to offer an hard, mechanicistic explanation of things.

How does that inhibition introduce the analgesic and antipyretic properties?

In the COX inhibition model, the analgesic properties can be explained trough an affinity for COX3; and the antipyretic activity can be due to the reduced amount of prostaglandin E2 in the CNS, in the thermoregulatory centre it lowers the hypothalamic set-point. The endocannabinoid model can explain preety well the anti dolorific actions, as well as the serotonin receptor interaction the behavioral one.

Is it possible multiple theories are correct?

Yes, there is a substantial overlap between different regulatory systems, so that is straight to think that the same chemical (or some of its different active metabolites) can modulate different systems.

Why is so little known about paracetamol? Is it exceptionally difficult, or the norm in pharmaceutical research of relatively old effective drugs? If it ain't broken, why fix it!

Is it not that difficult topic! One can say that is as tricky as any clinical pharmacology topic. The problem is that many compound are clinically used as drugs even if their molecular functionig is unknown if they are safe and of proved usefullness. This is true for paracetamol as well as many other drugs, like a lot of anaesthetic agents as Propofol.


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