title: Paracetamol (Acetaminophen): mechanisms of action.
abstract: Paracetamol has a central analgesic effect that is mediated through activation of descending serotonergic pathways. Debate exists about its primary site of action, which may be inhibition of prostaglandin (PG) synthesis or through an active metabolite influencing cannabinoid receptors. Prostaglandin H(2) synthetase (PGHS) is the enzyme responsible for metabolism of arachidonic acid to the unstable PGH(2). The two major forms of this enzyme are the constitutive PGHS-1 and the inducible PGHS-2. PGHS comprises of two sites: a cyclooxygenase (COX) site and a peroxidase (POX) site. The conversion of arachidonic acid to PGG(2) is dependent on a tyrosine-385 radical at the COX site. Formation of a ferryl protoporphyrin IX radical cation from the reducing agent Fe(3+) at the POX site is essential for conversion of tyrosine-385 to its radical form. Paracetamol acts as a reducing cosubstrate on the POX site and lessens availability of the ferryl protoporphyrin IX radical cation. This effect can be reduced in the presence of hydroperoxide-generating lipoxygenase enzymes within the cell (peroxide tone) or by swamping the POX site with substrate such as PGG(2). Peroxide tone and swamping explain lack of peripheral analgesic effect, platelet effect, and anti-inflammatory effect by paracetamol. Alternatively, paracetamol effects may be mediated by an active metabolite (p-aminophenol). p-Aminophenol is conjugated with arachidonic acid by fatty acid amide hydrolase to form AM404. AM404 exerts effect through cannabinoid receptors. It may also work through PGHS, particularly in areas of the brain with high concentrations of fatty acid amide hydrolase.
authors.affiliation: Department of Anaesthesiology, University of Auckland, Auckland, New Zealand. briana@adhb.govt.nz
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Anderson
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D044262:Prostaglandin H2 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D016861:Cyclooxygenase Inhibitors; D043882:Receptors, Cannabinoid; D011982:Receptors, Prostaglandin; D016718:Arachidonic Acid; D009569:Nitric Oxide; D000082:Acetaminophen; D044262:Prostaglandin H2; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C466421:cyclooxygenase-3