FIGURE 1 Chemical structure of acetaminophen

Acetaminophen was first synthesized in 1877 by Harmon Northrop Mors by reducing of p-nitrophenol by acetic acid (Refat et al., 2017). Despite of strong controversy regarding its safety and efficacy, it was not introduced for clinical use till 1950 when it first introduced as a combination with aspirin and caffeine known as trigesic (Refat et al., 2017). In 1963, acetaminophen became more popular as analgesic drug, and was added to British Pharmacopoeia (Refat et al., 2017; Krenzelok, 2009). Acetaminophen was approved by FDA in 2009 with warring of its combination with other analgesics (Krenzelok, 2009).

Acetaminophen acts either directly by inhibition of cyclooxygenase (COX) enzyme, or indirectly through its metabolite N-arachidonoylphenolamine (AM404) which activate cannabinoid receptors (CB1R and CB2R) and transient receptor potential cation channel subfamily member 1 (TRPV1) (Ohashi & Kohno, 2020; Ayoub, 2021). Acetaminophen is mainly blocks COX-2 (Kanchanasurakit et al., 2020).

Membrane phospholipid is converted to arachidonic acid (AA) by the action of phospholipase A2 (PLA2), this pathway is inhibited by corticosteroids (Al-Kuraishy et al., 2022). AA by the action of prostaglandin (PG) H2 synthase COX is converted to PGG2, this pathway is inhibited by acetaminophen and NSAIDs (Ferrer et al., 2019). Furthermore, PGG2 is converted to PGH2 by the action of PG H2 synthase peroxidase, this pathway is inhibited by acetaminophen only (Angelis et al., 2021|) (Figure 2).