Editing Paracetamol (section)

===Pharmacodynamics===

Paracetamol appears to exert its effects through two mechanisms: the inhibition of [[cyclooxygenase]] (COX) and actions of its metabolite [[N-arachidonoylphenolamine|''N''-arachidonoylphenolamine]] (AM404).<ref name=Ghanem2016>{{cite journal |vauthors = Ghanem CI, Pérez MJ, Manautou JE, Mottino AD |title = Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity |journal = Pharmacological Research |volume = 109 |pages = 119–31 |date = July 2016 |pmid = 26921661 |pmc = 4912877 |doi = 10.1016/j.phrs.2016.02.020 }}</ref>

Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting [[COX-1]] and [[COX-2]] enzymes and especially similar to selective [[COX-2 inhibitor]]s.<ref name="pmid23719833">{{cite journal |vauthors=Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF |title=The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings |journal=Inflammopharmacology |volume=21 |issue=3 |pages=201–32 |date=June 2013 |pmid=23719833 |doi=10.1007/s10787-013-0172-x |s2cid=11359488}}</ref> Paracetamol inhibits [[prostaglandin]] synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of [[arachidonic acid]] and [[Organic peroxide#Biology|peroxides]] is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.<ref name=Ghanem2016/><ref name="pmid23719833"/> The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the [[central nervous system]] and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.

The second mechanism centers on the paracetamol metabolite [[AM404]]. This metabolite has been detected in the brains of animals and [[cerebrospinal fluid]] of humans taking paracetamol.<ref name=Ghanem2016/><ref name="pmid29238213">{{cite journal |vauthors=Sharma CV, Long JH, Shah S, Rahman J, Perrett D, Ayoub SS, Mehta V |title=First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid |journal=J Pain Res |volume=10 |issue= |pages=2703–2709 |date=2017 |pmid=29238213 |pmc=5716395 |doi=10.2147/JPR.S143500 |doi-access=free }}</ref> It is formed in the brain from another paracetamol metabolite [[4-aminophenol]] by action of [[fatty acid amide hydrolase]].<ref name=Ghanem2016/> AM404 is a weak agonist of cannabinoid receptors [[Cannabinoid receptor type 1|CB1]] and [[Cannabinoid receptor type 2|CB2]], an inhibitor of [[endocannabinoid transporter]], and a potent activator of [[TRPV1]] receptor.<ref name=Ghanem2016/> This and other research indicate that the [[endocannabinoid system]] and TRPV1 may play an important role in the analgesic effect of paracetamol.<ref name=Ghanem2016/><ref name="pmid33328986">{{cite journal |vauthors=Ohashi N, Kohno T |title=Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action |journal=Front Pharmacol |volume=11 |issue= |pages=580289 |date=2020 |pmid=33328986 |pmc=7734311 |doi=10.3389/fphar.2020.580289 |doi-access=free |title-link = doi }}</ref>

In 2018, Suemaru ''et al''. found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the [[TRPV1]] receptors<ref name="Suemaru2018">{{cite journal |vauthors = Suemaru K, Yoshikawa M, Aso H, Watanabe M |title = TRPV1 mediates the anticonvulsant effects of acetaminophen in mice |journal = Epilepsy Research |volume = 145 |pages = 153–159 |date = September 2018 |pmid = 30007240 |doi = 10.1016/j.eplepsyres.2018.06.016 |s2cid = 51652230 }}</ref> and a decrease in neuronal excitability by [[Hyperpolarization (biology)|hyperpolarization]] of neurons.<ref>{{cite journal |vauthors = Ray S, Salzer I, Kronschläger MT, Boehm S |title = The paracetamol metabolite N-acetylp-benzoquinone imine reduces excitability in first- and second-order neurons of the pain pathway through actions on KV7 channels |journal = Pain |volume = 160 |issue = 4 |pages = 954–964 |date = April 2019 |pmid = 30601242 |pmc = 6430418 |doi = 10.1097/j.pain.0000000000001474 }}</ref> The exact mechanism of the anticonvulsant effect of paracetamol is not clear. According to Suemaru ''et al''., acetaminophen and its active metabolite [[AM404]] show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.<ref name="Suemaru2018" />