Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action

Article


Ayoub, S. S. 2021. Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action. Temperature. 8 (4), pp. 351-371. https://doi.org/10.1080/23328940.2021.1886392
AuthorsAyoub, S. S.
Abstract

Paracetamol (acetaminophen) is undoubtedly one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰 screens demonstrate low potency on the inhibition of COX-1 and COX-2. 𝘐𝘯 𝘷𝘪𝘷𝘰 data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol.

KeywordsParacetamol; Acetaminophen; Cyclooxygenase; Pain; Thermoregulation
JournalTemperature
Journal citation8 (4), pp. 351-371
ISSN2332-8959
Year2021
PublisherTaylor & Francis
Accepted author manuscript
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File Access Level
Anyone
Supplemental file
License
File Access Level
Anyone
Digital Object Identifier (DOI)https://doi.org/10.1080/23328940.2021.1886392
Publication dates
Online16 Mar 2021
Publication process dates
Accepted01 Feb 2021
Deposited04 Jul 2023
Additional information

This is an original manuscript of an article published by Taylor & Francis in Temperature on 16 Mar 2021, available at: https://doi.org/10.1080/23328940.2021.1886392

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