Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients. Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme. NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition. However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations. In addition, previously unpublished data stored in the sponsor's files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects. Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events. There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence. Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective. In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail.

NSAIDs depress prostaglandins synthesis through inhibition of COX-1 that is involved in maintaining cell integrity and COX-2 that, although presents particularly in the kidneys, is overexpressed in response to inflammation. Both the beneficial and side effects of NSAIDs are, therefore, through their inhibition of COX enzymes. Introduction of COX-2-selective inhibitors has improved the safety profile of the drugs with regard to their most common side effect which occurs at the gastrointestinal level but has not rendered them less cardio-nephrotoxic. Renal side effects of NSAIDs are rare, sometimes transient and often reversible upon drug withdrawal. The incident rate and the severity of the renal side effect, however, increase in patients with risk factors such as those with diabetes, heart failure, renal dysfunction and in the elderly. The side effects range from electrolyte retention and reduce glomerular filtration to nephritic syndrome and chronic renal failure. These effects are shared among NSAIDs with evidence of dose and exposure dependency. There is no known predictor for the nephrotoxicity. However, a relationship has been found between high plasma concentration and the renal adverse effect of NSAIDs. The usefulness of therapeutic drug monitoring in patients with risk factors needs to be explored.

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Aims In¯ammation reduces hepatic clearance of many drugs with unknown therapeutic consequences. This study was carried out to examine the effect of rheumatoid arthritis (RA) on the pharmacokinetics and pharmacodynamics of verapamil. Methods Eight RA patients were age-and sex-matched with eight healthy volunteers. The disease severity was assessed, and ECG, blood pressure and verapamil enantiomers concentrations were measured for 12 h post 80 mg oral verapamil. Serum interleukin-6 (IL-6) and nitrite (NO 2 ± ) were measured in predose samples. Results IL-6 and NO 2 ± concentrations were signi®cantly increased in parallel with disease severity. Oral clearance of both S-and R-verapamil was signi®cantly decreased by RA. While the unbound fraction of S-and R-verapamil decreased by 5 and 7-fold, respectively, the unbound AUC remained unchanged for the more potent enantiomer, S-verapamil. AUC of norverapamil enantiomers was increased 2±3-fold. Despite elevated serum drug concentrations in RA, the potential to prolong the PR-interval was signi®cantly reduced by one fold and the effect on the heart rate and blood pressure did not increase. Conclusions RA results in increased verapamil concentrations due likely to changes in protein binding, decreased clearance and/or altered hepatic blood¯ow. A signi®cant decrease in dromotropic effect, despite increased serum drug concentrations, may be attributed to receptor down regulation caused by pro-in¯ammatory cytokines and/or NO.