Received: 1 May 2020
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Revised: 9 July 2020
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Accepted: 2 August 2020
DOI: 10.1111/1440-1681.13392
REVIEW ARTICLE
Paracetamol – An old drug with new mechanisms of action
Grzegorz W. Przybyła1
| Konrad A. Szychowski2
| Jan Gmiński2
1
Medical Faculty, University of Opole,
Opole, Poland
Abstract
2
Paracetamol (acetaminophen) is the most commonly used over-the-counter (OTC)
Department of Lifestyle Disorders and
Regenerative Medicine, University of
Information Technology and Management in
Rzeszow, Rzeszow, Poland
Correspondence
Konrad A. Szychowski, Department of
Lifestyle Disorders and Regenerative
Medicine, University of Information
Technology and Management in Rzeszow,
Sucharskiego 2, 35-225 Rzeszow, Poland.
Email: konrad.szychowski@gmail.com
Funding information
University of Information Technology and
Management in Rzeszow, Grant/Award
Number: DS 503-07-02-21
drug in the world. Despite its popularity and use for many years, the safety of its
application and its mechanism of action are still unclear. Currently, it is believed that
paracetamol is a multidirectional drug and at least several metabolic pathways are
involved in its analgesic and antipyretic action. The mechanism of paracetamol action
consists in inhibition of cyclooxygenases (COX-1, COX-2, and COX-3) and involvement in the endocannabinoid system and serotonergic pathways. Additionally, paracetamol influences transient receptor potential (TRP) channels and voltage-gated
Kv7 potassium channels and inhibits T-type Cav3.2 calcium channels. It also exerts
an impact on L-arginine in the nitric oxide (NO) synthesis pathway. However, not all
of these effects have been clearly confirmed. Therefore, the aim of our paper was to
summarize the current state of knowledge of the mechanism of paracetamol action
with special attention to its safety concerns.
KEYWORDS
acetaminophen, COX-1, COX-2, COX-3, paracetamol
1 | I NTRO D U C TI O N
Prostaglandins are mainly mediators of inflammatory pain.7,8 The
enzymes responsible for the synthesis of these mediators are called
Paracetamol (which is a recommended international nonpropri-
cyclooxygenases.9 In 1971, John Vane identified the first cycloox-
etary name of acetaminophen (acetyl-p-aminophenol, APAP)), was
ygenase (COX-1).10 This discovery helped explain the mechanism
synthesized in 1878 by Morse and first introduced into medicine
of action of aspirin, which has been extensively used since 1899 as
1-3
Initially, it
an analgesic and anti-inflammatory drug.10 Afterwards, in 1991, Xie
was rarely used in favor of phenacetin. However, after discovering
et al at Daniel Simmons's laboratory, Brigham Young University, dis-
that paracetamol is the main metabolite of phenacetin with better
covered the second cyclooxygenase (COX-2).11,12 Interestingly, the
tolerance vs. phenacetin nephrotoxicity, in the 1950s paracetamol
structure of the COX-2 enzyme did not differ substantially from the
as an antipyretic/analgesic by Von Mering in 1893.
replaced phenacetin in use
4-6
and has become a widespread drug
since then.
previously discovered COX-1.13 However, they have different clinical
significance.14,15 Finally, in 2002, Chandrasekharan et al discovered
Abbreviations: 2-AG, 2-arachidonoylglycerol; 5-HT, 5-hydroxytryptamine; AA, arachidonic acid; ADHD, attention deficit hyperactivity disorder; AEA, N-arachidonoylethanolamine;
AM404, N-arachidonoylphenolamine; APAP, N-acetyl-p-aminophenol acetaminophen; Cav3.1, isoform of T-type voltage-gated calcium channel (T-channels); Cav3.2, isoform of T-type
voltage-gated calcium channel (T-channels); Cav3.3, isoform of T-type voltage-gated calcium channel (T-channels); CB1, cannabinoid receptors type 1; CNS, central nervous system;
COX, cyclooxygenase; COX-1, cyclooxygenase-1; COX-2, cyclooxygenase-2; COX-3, cyclooxygenase-3; CYP450, cytochrome P450; DRG, dorsal root ganglion; FAAH, fatty acid amido
hydrolase; GABA, gamma-aminobutyric acid; GluR1, ionotropic glutamate receptor; iNOS, inducible nitric oxide synthase; LPS, lipopolysaccharides; NAPQI, N-acetyl-pbenzoquinoneimine; NF-κB, nuclear factor kappa B; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NS-398, N-(2-cyclohexyloxy-4-nitrophenyl)
methanesulfonamide; NSAIDs, nonsteroid anti-inflammatory drugs; OTC, over-the-counter; PAG, periaqueductal gray; p-BQ, p-benzoquinone; PG, prostaglandin; PGD2, prostaglandin
D2; PGE 2, prostaglandin E2; PGF2, prostaglandin F2; PGG2, prostaglandin G2; PGH2, prostaglandin H2; PGHS, prostaglandin endoperoxide-H synthase; PGI2, prostacyclin I2; pH, power of
hydrogen or potential for hydrogen; POX, peroxidase; PSD95, postsynaptic density protein 95; RTX, resiniferatoxin; RVM, rostral ventromedial medulla; SC560, (5-(4-chlorophenyl)-1(4-methoxyphenyl)-3-trifluoromethyl pyrazole); SNAP, S-nitroso-N-acetylpenicillamine; Syp, synaptophysin; THC, tetrahydrocannabinol; Trkb, tropomyosin receptor kinase B; TRP,
transient receptor potential; TRPA1, transient receptor potential channel subfamily ankyrin-1; TRPV1, transient receptor potential channel subfamily vanilloid-1; TRPV4, transient
receptor potential channel subfamily vanilloid-4; TTA-A2, (R)-2-(4-cyclopropylphenyl)-N-(1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl) acetamide; TXA 2, thromboxane A 2; TXB2,
thromboxane B2; WIN 55,212-2, (R)-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate.
Clin Exp Pharmacol Physiol. 2021;48:3–19.
wileyonlinelibrary.com/journal/cep
© 2020 John Wiley & Sons Australia, Ltd
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