FIGURE 2 Differential effect of acetaminophen and NSAIDs on the COX
pathway
Regarding the pharmacokinetic profile of acetaminophen, it orally active
and rapidly absorbed from small intestines, its absorption is reduced by
food (Souza et al., 2022). Peak plasma concentration of acetaminophen is
achieved within 20 minutes during fasting, and within 90 minutes when
taken after food (Brookhuis et al., 2021). The bioavailability of
acetaminophen is 63-89% depending on used doses, has high volume of
distribution about 50L, with minimal plasma protein binding (Spyker et
al., 2022).
Prolonged use of acetaminophen is associated with minimal adverse
effects, though its use during pregnancy increases risk of asthma in
offspring (Shaheen et al., 2019). However, the association between
acetaminophen use and risk of asthma is controversial (Sherbash et al.,
2020). The recommend daily dose of acetaminophen is 500mg-1g g/day.
Higher doses of acetaminophen lead to acute toxicity which causes acute
liver failure (Jaeschke et al., 2020). In addition, long-term use of
acetaminophen is associated with kidney impairment by 23% and kidney
cancer by 28% (Kanchanasurakit et al., 2020). Acetaminophen may
interact with different agents and drugs, for example prokinetic drugs
accelerate absorption of acetaminophen (Southren et al., 2021). As well,
enzyme inducer drugs such as rifampicin enhance acetaminophen toxicity
by activating the formation of N-acetyl-p-benzoquinone imine (NAPQI)
(Chowdhury et al., 2020). However, enzyme inhibitors such isoniazid
reduces the formation of NAPQI by 70% (Balhara et al., 2021). Of note,
85-95% of acetaminophen is metabolized to non-toxic metabolites, 5-15%
is metabolized to toxic metabolites which neutralized by hepatic
glutathione (Zacharia & Jacob, 2023). However, 1-2% of acetaminophen
is metabolized by deacetylation process to form p-aminophenol which
converted by brain fatty acid amide hydrolase (FAAH) to AM404 which has
different effect on the brain (Ogemdi, 2019) (Figure 3).