Mechanisms of action of paracetamol and related analgesics

Authors: Graham G.G.¹; Scott K.F.²

Source: Inflammopharmacology, Volume 11, Numbers 4-6, 2003 , pp. 401-413(13)

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Abstract:

Paracetamol and salicylate are weak inhibitors of both isolated cyclooxygenase-1 (COX-1) and COX-2 but are potent inhibitors of prostaglandin (PG) synthesis in intact cells if low concentrations of arachidonic acid are available. The effects of both drugs are overcome by increased levels of hydroperoxides. At low concentrations of arachidonic acid, COX-2 is the major isoenzyme involved in PG synthesis when both COX-1 and COX-2 are present in cells. Therefore, paracetamol and salicylate may selectively inhibit PG synthesis involving COX-2 because the lower flux through this pathway produces lesser levels of the hydroperoxide, PGG₂, than the pathway involving COX-1. Apart from the lack of anti-inflammatory effect of paracetamol in rheumatoid arthritis, the clinical effects of paracetamol and salicylate are very similar and resemble those of the selective COX-2 inhibitors. A splice variant of COX-1, termed COX-3, may be a site of action of these drugs but, further work, particularly at low concentrations of arachidonic acid is required. We suggest that paracetamol, salicylate and, possibly, the pyrazolone drugs, such as dipyrone, may represent a distinct class of atypical NSAIDs which could be termed peroxide sensitive analgesic and antipyretic drugs (PSAADs).

Keywords: PARACETAMOL; ACETAMINOPHEN; SALICYLATE; DIPYRONE; PROSTAGLANDIN; COX-1; COX-2; COX-3; PEROXIDASE

Document Type: Review article

DOI: http://dx.doi.org/10.1163/156856003322699573

Affiliations: 1: School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia, Department of Clinical Pharmacology, St Vincent's Hospital, Darlinghurst, NSW 2010, Australia 2: School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia

Publication date: 2003-12-01