Downloaded from http://ard.bmj.com/ on October 25, 2016 - Published by group.bmj.com Review Paracetamol and cyclooxygenase inhibition: is there a cause for concern? Burkhard Hinz,1 Kay Brune2 1Institute of Toxicology and ABSTRACT a central cyclooxygenase isoform, derived from the Pharmacology, University of Paracetamol is recommended as fi rst-line therapy same gene as COX-1 and referred to as cyclooxyge- Rostock, Rostock, Germany 5 6 2Department of Experimental for pain associated with osteoarthrosis and is one nase 3, have meanwhile been rejected. and Clinical Pharmacology and of the most widely used over-the-counter analgesic Instead, several data published during the past Toxicology, Friedrich Alexander drugs worldwide. Despite its extensive use, its mode few years suggest a tissue-dependent inhibitory University Erlangen–Nürnberg, of action is still unclear. Although it is commonly effect of paracetamol on the activity of both cen- Erlangen, Germany stated that paracetamol acts centrally, recent data tral and peripheral cyclooxygenase enzymes. In Correspondence to imply an inhibitory effect on the activity of peripheral view of the current debate concerning the safety Professor Burkhard Hinz, prostaglandin-synthesising cyclooxygenase enzymes. In of cyclooxygenase inhibitors, these fi ndings raise Institute of Toxicology and this context paracetamol has been suggested to inhibit several questions with respect to hitherto underes- Pharmacology, University of both isoforms in tissues with low levels of peroxide by timated cyclooxygenase-dependent side-effects of Rostock, Schillingallee 70, D-18057 Rostock, reducing the higher oxidation state of cyclooxygenase paracetamol, which has long been regarded as a safe Germany; enzymes. Two recent studies have also demonstrated alternative to traditional non-steroidal anti-infl am- burkhard.hinz@med. a preferential cyclooxygenase 2 (COX-2) inhibition by matory drugs (NSAID) and latterly also to selective uni-rostock.de paracetamol under different clinically relevant conditions. COX-2 inhibitors. In the present review attempts This review attempts to relate data on paracetamol’s have been undertaken to relate the data on the Accepted 10 September 2011 inhibitory action on peripheral cyclooxygenase enzymes cyclooxygenase inhibitory potency of paracetamol Published Online First 28 October 2011 to the published literature on its anti-infl ammatory to the published literature on its anti-infl ammatory action and its hitherto underestimated side-effects action and, more importantly, side-effects possibly elicited by cyclooxygenase inhibition. As a result, a related to inhibition of cyclooxygenase enzymes. pronounced COX-2 inhibition by paracetamol is expected to occur in the endothelium, possibly explaining its MODE OF CYCLOOXYGENASE INHIBITION cardiovascular risk in epidemiological studies. A careful The pathway leading to the generation of prosta- analysis of paracetamol’s cardiovascular side-effects glandins has been elucidated in detail. Within this in randomised studies is therefore strongly advised. On process, the cyclooxygenase enzyme (also referred the basis of epidemiological data showing an increased to as prostaglandin H (PGH) synthase) catalyses gastrointestinal risk of paracetamol at high doses or the fi rst step of the synthesis of prostanoids by when co-administered with classic cyclooxygenase converting arachidonic acid into PGH2, which is inhibitors, paracetamol’s long-term gastrointestinal the common substrate for specifi c prostaglandin impact should be investigated in randomised trials. synthases. The enzyme is bifunctional, with fatty- Finally, paracetamol’s fast elimination and consequently acid cyclooxygenase activity (catalysing the con- short-lived COX-2 inhibition, which requires repetitive version of arachidonic acid to prostaglandin G2 dosing, should be defi nitely considered to avoid (PGG2)) and prostaglandin hydroperoxidase activ- overdosage leading to hepatotoxicity. ity (catalysing the conversion of PGG2 to PGH2) (fi gure 1). Whereas traditional NSAID and selective COX-2 Paracetamol is one of the most widely used over- inhibitors inhibit cyclooxygenase by competing the-counter antipyretic and analgesic drugs world- with arachidonic acid for entering the cyclooxyge- wide. It is recommended as fi rst-line therapy for nase reaction,7 8 paracetamol has been suggested to pain associated with osteoarthrosis.1 Although dis- act as a reducing agent within the peroxidase site. In covered over 100 years ago and extensively used brief, paracetamol quenches a protoporphyrin radi- for over 50 years, its mode of action is still a matter cal cation. The latter generates the tyrosine radical of debate. For more than three decades it was com- in the cyclooxygenase site that is responsible for monly stated that paracetamol acts centrally and is catalysing the oxygenation of arachidonic acid.9 10 at best a weak inhibitor of prostaglandin synthesis In view of the fact that hydroperoxides oxidise by cyclooxygenase 1 (COX-1) and cyclooxygenase the porphyrin within the peroxidase site, cyclooxy- 2 (COX-2).2 This concept is based on early work by genase inhibition by paracetamol is hampered by Flower and Vane3 who showed that prostaglandin high peroxide levels. Accordingly, Boutaud et al10 production in the brain is 10 times more sensitive to showed that high levels of peroxides overcome the inhibition by paracetamol than that in the spleen. inhibitory effect of paracetamol on the cyclooxy- Later it turned out that paracetamol elicits no mea- genase enzymes in diverse cells. As such, 12-hy- surable inhibition of prostaglandin formation in droperoxyeicosatetraenoic acid, a major product broken cell preparations, but a profound suppres- of platelets, completely reversed the inhibitory sion in intact cells (comprehensively reviewed in action of paracetamol on COX-1. Likewise, the Graham and Scott).4 Attempts to explain the phar- addition of peroxides to interleukin 1-stimulated macological action of paracetamol as inhibition of endothelial cells (as a model of a peroxide-enriched 20 Ann Rheum Dis 2012;71:20–25. doi:10.1136/ard.2011.200087 Downloaded from http://ard.bmj.com/ on October 25, 2016 - Published by group.bmj.com Review (the concentration that leads to 80% inhibition) on COX-2 in the human whole blood assay. However, due to its short half- life (approximately 2 h) paracetamol elicits a short-lived COX-2 inhibition only (fi gure 2). Thus, repetitive 1-g doses of parac- etamol have to be administered to provide a permanent 80% COX-2 inhibition necessary for pain relief. This fact has to be considered to avoid overdosages with this drug. By contrast, a greater than 95% COX-1 blockade that would be relevant for the inhibition of platelet function13 was not achieved (fi gure 2). Further experiments revealed that paracetamol elicits the most pronounced COX-2 inhibition in human whole blood when compared with the recombinant enzyme or freshly pre- pared human monocytes,11 thus confi rming the dependence of its potency as a COX-2 inhibitor on the oxidant/antioxidant status of the surrounding system. As a matter of fact, human plasma comprising various enzymatic and non-enzymatic antioxidant components may provide favourable conditions in this respect.14 In another study using a clinical model of tissue injury and acute infl ammation, outpatients received 1 g paracetamol before surgical removal of two impacted mandibular third molars and microdialysis was performed to collect infl ammatory transudate from the surgical site for the measurement of COX-1 and COX- 2-dependent prostanoid levels at the site of injury.15 Again, paracetamol was revealed as a selective inhibitor of COX-2- dependent prostaglandin E2 (PGE2) formation. INFLAMMATION Most pharmacological reference books depict paracetamol as a ‘pure’ analgesic without any anti-infl ammatory activity. This claim is largely based on early work showing that paracetamol does not suppress serious infl ammation associated with rheu- matoid arthritis.16 17 This lack of effect can now be explained by the high extracellular concentrations of arachidonic acid and per- oxide in the infl amed tissue, both of which diminish the effect Figure 1 Biochemical function of the cyclooxygenase enzyme and of paracetamol on prostaglandin synthesis.4 9 10 In line with pharmacological targets within its two activity sites. Paracetamol acid released from membrane phospholipids by the enzyme phospholipase this notion paracetamol does not decrease the concentration of A is converted by cyclooxygenase (also referred to as prostaglandin diverse prostanoids in the synovial fl uid of patients with rheu- 2 matoid arthritis.18 On the other hand, paracetamol decreases (PG) H synthase) to PGH2, the common substrate for specifi c prostanoid synthases. Cyclooxygenase is bifunctional, with fatty-acid tissue swelling following oral surgery in humans, with activity cyclooxygenase activity (catalysing the conversion of arachidonic acid similar to that of ibuprofen,19 20 implying that the drug is not to PGG2) and prostaglandin hydroperoxidase activity (catalysing the devoid of any anti-infl ammatory action. Moreover, the above- 15 conversion of PGG2 to PGH2). Traditional non-steroidal anti-infl ammatory cited study implies a signifi cant impact of COX-2 inhibition to drugs (tNSAID) and selective cyclooxygenase 2 inhibitors (coxibs) this response. In addition, a peripheral anti-infl ammatory action compete with arachidonic acid for entering the cyclooxygenase is supported by several experimental