Editing Paracetamol (section)

==Pharmacology==
===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" />

===Pharmacokinetics===
After being taken by mouth, paracetamol is rapidly absorbed from the [[small intestine]], while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach's emptying and absorption, but the total amount absorbed stays the same.<ref>{{cite journal |vauthors=Prescott LF |title=Kinetics and metabolism of paracetamol and phenacetin |journal=British Journal of Clinical Pharmacology |date=October 1980 |volume=10 |issue = Suppl 2 |pages=291S–298S |pmid=7002186 |pmc=1430174 |doi=10.1111/j.1365-2125.1980.tb01812.x}}</ref> In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.<ref name="pmid7039926">{{cite journal |vauthors=Forrest JA, Clements JA, Prescott LF |title=Clinical pharmacokinetics of paracetamol |journal=Clin Pharmacokinet |volume=7 |issue=2 |pages=93–107 |date=1982 |pmid=7039926 |doi=10.2165/00003088-198207020-00001 |s2cid=20946160}}</ref>

Paracetamol's [[bioavailability]] is dose-dependent: it increases from 63% for 500{{nbsp}}mg dose to 89% for 1000{{nbsp}}mg dose.<ref name="pmid7039926"/> Its plasma terminal elimination half-life is 1.9{{ndash}}2.5 hours,<ref name="pmid7039926"/> and [[volume of distribution]] is roughly 50{{nbsp}}L.<ref name=Graham_2013>{{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 |date=June 2013 |volume=21 |issue=3 |pages=201–232 |doi=10.1007/s10787-013-0172-x |pmid=23719833|s2cid=11359488 }}</ref> Protein binding is negligible, except under the conditions of overdose, when it may reach 15{{ndash}}21%.<ref name="pmid7039926"/> The concentration in serum after a typical dose of paracetamol usually peaks below 30{{nbsp}}μg/mL (200{{nbsp}}μmol/L).<ref name=rosen/> After 4 hours, the concentration is usually less than 10{{nbsp}}μg/mL (66{{nbsp}}μmol/L).<ref name=rosen>{{cite book|title=Rosen's Emergency Medicine – Concepts and Clinical Practice |vauthors = Marx J, Walls R, Hockberger R |publisher=Elsevier Health Sciences|year=2013|isbn=9781455749874}}</ref>

[[Image:Metabolism of paracetamol.png|class=skin-invert-image|thumb|right|upright=2|Important pathways of paracetamol metabolism]]

Paracetamol is [[drug metabolism|metabolized]] primarily in the liver, mainly by [[glucuronidation]] and [[sulfation]], and the products are then eliminated in the urine (see the Scheme on the right). Only 2{{ndash}}5% of the drug is excreted unchanged in the urine.<ref name="pmid7039926"/> Glucuronidation by [[UGT1A1]] and [[UGT1A6]] accounts for 50{{ndash}}70% of the drug metabolism. Additional 25{{ndash}}35% of paracetamol is converted to sulfate by sulfation enzymes [[SULT1A1]], [[SULT1A3]], and [[SULT1E1]].<ref name="pmid23462933">{{cite journal |vauthors=McGill MR, Jaeschke H |title=Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis |journal=Pharm Res |volume=30 |issue=9 |pages=2174–87 |date=September 2013 |pmid=23462933 |pmc=3709007 |doi=10.1007/s11095-013-1007-6}}</ref>

A minor metabolic pathway (5–15%) of oxidation by [[cytochrome P450]] enzymes, mainly by [[CYP2E1]], forms a toxic metabolite known as [[NAPQI]] (''N''-acetyl-''p''-benzoquinone imine).<ref name="pmid23462933"/> NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with [[glutathione]]. The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by a large amount of formed NAPQI, and NAPQI binds to [[mitochondria]] proteins of the liver cells causing [[oxidative stress]] and toxicity.<ref name="pmid23462933"/>

Yet another minor but important direction of metabolism is deacetylation of 1{{ndash}}2% of paracetamol to form [[p-Aminophenol|''p''-aminophenol]]. ''p''-Aminophenol is then converted in the brain by [[fatty acid amide hydrolase]] into [[AM404]], a compound that may be partially responsible for the analgesic action of paracetamol.<ref name=Graham_2013/>