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

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. List of Abbreviations: AM404, N-(4-hydroxyphenyl)-arachidonamide; CB1R, Cannabinoid receptor-1; Cmax, Maximum concentration; CNS, Central nervous system; COX, Cyclooxygenase; CSF, Cerebrospinal fluid; ED₅₀, 50% of maximal effective dose; FAAH, Fatty acid amidohydrolase; IC₅₀, 50% of the maximal inhibitor concentration; LPS, Lipopolysaccharide; NSAIDs, Non-steroidal anti-inflammatory drugs; PGE₂, Prostaglandin E₂; TRPV1, Transient receptor potential vanilloid-1.