Title

 

Authors

A. A. Mangoni¹, M. A. Crilly², K. M. Knights<sup>3

1</sup>Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom;
²Division of Applied Health Sciences, University of Aberdeen, Aberdeen, United Kingdom;
³Department of Clinical Pharmacology, School of Medicine, Flinders University, Adelaide, Australia.

 

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed, particularly in older patients, for the management of musculoskeletal disorders. Concerns about the safety of NSAIDs have sparked a fierce debate over the last decade. It is generally accepted that a) NSAIDs increase cardio-renal toxicity; and b) the inhibitory selectivity of NSAIDs towards the cyclooxygenase (COX) isoforms COX-1 and COX-2 (i.e. non selective NSAIDs, nsNSAIDs, vs. selective COX-2 inhibitors) defines their pharmacological characteristics and accounts for their cardio-renal toxicity. However, the results of recent pharmacoepidemiological studies suggest that the risk of cardio-renal toxicity imparted by NSAIDs is largely independent of COX selectivity, and relatively lower in the older population (1). Notwithstanding issues with the interpretation and dissemination of the available evidence on the association between NSAID use and cardio-renal toxicity, other mechanisms have been proposed to explain the adverse cardio-renal effects of NSAIDs beyond COX selectivity. An in vitro interaction between several nsNSAIDs and aldosterone glucuronidation has recently been demonstrated (2). Preliminary in vivo data support the potential role of this nsNSAIDs-aldosterone interaction in determining adverse vascular remodelling. It is likely that the whole concept of COX selectivity also needs revisiting. The availability of several different methods with their unique experimental conditions makes the direct comparison of NSAID inhibition data difficult. Invitro studies on NSAID-mediated COX inhibition need to consider additional factors such as the source of the enzyme, the K_m (Michaelis constant) of the endogenous substrate, the mechanism of NSAID inhibition, and the concentrations of substrates and the inhibitors used (3). However, published data generally describe the extent to which NSAIDs inhibit COX, rather than the mechanism of inhibition and the determination of kinetic inhibitor constants. Rigorous in vitro kinetic studies of NSAID inhibition of COX isoforms are the first necessary step prior to considerations of cell/tissue selectivity, variability in NSAID pharmacokinetics, and assessment of cardio-renal toxicity.    
 
(1) Mangoni AA, Woodman RJ, Gaganis P, Gilbert AL, Knights KM. Use of non-steroidal anti-inflammatory drugs and risk of incident myocardial infarction and heart failure, and all-cause mortality in the Australian veteran community. Br J Clin Pharmacol 2010; 69(6):689-700.
(2) Knights KM, Winner LK, Elliot DJ, Bowalgaha K, Miners JO. Aldosterone glucuronidation by human liver and kidney microsomes and recombinant UDP-glucuronosyltransferases: inhibition by NSAIDs. Br J Clin Pharmacol 2009; 68(3):402-412.
(3) Knights KM, Mangoni AA, Miners JO. Defining the COX inhibitor selectivity of NSAIDs: Implications for understanding toxicity. Expert Review of Clinical Pharmacology 2010; 3(6):769-776.