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).