Introduction –
Acetaminophen, commonly known as paracetamol, is one of the world’s most common painkillers and is often recommended as one of the first treatments for pain, as it is safe for most people to take and side effects are rare. Not to be confused with non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol is an analgesic and has no anti-inflammatory properties, such as the ability to reduce oedema or cellular migration within the healing processes of the body (Jóźwiak-Bebenista and Nowak, 2014). However, when taken appropriately paracetamol does not affect the homeostatic production of constitutive prostaglandins (PGs) – a chemical that causes inflammation and swelling – and therefore, the production of PGs by blood platelet cells has no effect on blood coagulation or renal blood flow; this signifies that paracetamol is less likely than NSAIDs to irritate the lining of the stomach or the kidneys.
History of Paracetamol –
Paracetamol was synthesized in 1877 by Harmon Northrop Morse and was first used clinically by Joseph von Mering in 1887 (Mangus and Miller, 2005). Paracetamol, with a combination of aspirin and caffeine, was first introduced to the market in 1950 in the US under the name Triagesic. However, paracetamol was not introduced to the market as an individual analgesic until 1953 by Sterling-Winthrop Co. under the name of Panadol, available as a prescription only medication (POM) (Silverman et al. (1992).
Chemistry of Paracetamol –
The original method of synthesising paracetamol included the nitration of phenol with sodium nitrate, following in the reduction of p-nitrophenol with tin in glacial acetic acid to produce 4-aminophenol, where the amine is acetylated with acetic anhydride. (Ellis, 2002).
Pharmacodynamics and the Mechanism of Action in Humans –
The exact mechanism of action of paracetamol is not known, however one theory that has been studied within broken cell systems have shown that medicinal concentrations of paracetamol inhibit prostaglandin synthesis in intact cells in vitro, only when the levels of arachidonic acid (AA) are low. Under these conditions, PGs are largely synthesised by COX-2, demonstrating that like NSAIDs, the analgesia and antipyresis effects of paracetamol are dependent on its active metabolite (AM404) inhibiting the synthesis of PGs formed by the enzymatic activity of cyclooxygenase (COX), which therefore increases the body’s pain threshold. The AM404 metabolite has also been proven to directly activate the TRPV1 which inhibits pain signals in the brain. However, paracetamol does not inhibit the function of any cyclooxygenase (COX) enzymes outside the central nervous system (CNS) and so it not suitable as an anti-inflammatory drug. (Ghanem, Pérez, Manautou and Mottino, 2016).
Another theory comes from two independent groups (Zygmunt et al. and Bertolini et al.) who produced experimental evidence to demonstrate that the analgesic effects of paracetamol come from the indirect activation of cannabinoid CB1 receptors, by the acetaminophen metabolite (AM404) and endocannabinoid reuptake inhibitor, in the brain and spinal cord.
Experimental Evidence –
– preclinical in vivo (LIVE ORGANISMS) data
preclinical in vivo studies suggest that COX-3, a splice variant of COX-1, is the site of action of paracetamol, but genomic and kinetic exploration indicates that this selective interaction is unlikely to be clinically relevant as although the COX-3 isozyme is encoded by the same gene as COX-1, it is not functional in humans Furthermore, it has been demonstrated that paracetamol inhibits COX activity in brain homogenates more so than those from the spleen, for example the enzyme COX‐3 has been identified in the canine cerebral cortex of the brain. COX-3, when expressed in dogs, shares similar traits to both the COX-1 and COX-2 enzymes, produces pro‐inflammatory chemicals such as PGs, and is selectively inhibited by paracetamol. However, further research has implied that in both humans and rodents, the COX-3 enzyme encodes proteins with varied amino acid sequences compared to COX-1 and COX-2, and so COX-2-selective inhibitors react weakly with the COX-3 enzymatic site, because the active site is identical to that in COX-1. Moreover, the sites of COX-3 expression do not correlate with other sites associated with fever, and the protein should be present within the hypothalamus rather than the cerebral cortex. (Chandrasekharan et al. 2002). It is the current understanding that COX-3 does not play a role in PG-mediated fever and pain within humans and rodents and therefore, the mechanism(s) in animals and humans may differ.