Update on Cyclooxygenase-2 Inhibitors

Abstract

Nonsteroidal anti-inflammatory drugs represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described side effects can limit their use. Cyclooxygenase-2 (COX-2) inhibitors were initially touted as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of nonspecific nonsteroidal anti-inflammatory drugs. However, in the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. This review summarizes the current state of knowledge about both renal and cardiovascular side effects that are attributed to COX-2 selective inhibitors.Clin J Am Soc Nephrol 1: 236 -245, 2006236 -245, . doi: 10.2215 N onsteroidal anti-inflammatory drugs (NSAID) are the most commonly used class of medications for the treatment of pain and inflammation and represent one of the most common classes of medications used worldwide, with an estimated usage of Ͼ30 million per day (1). Nonselective NSAID inhibit both constitutive cyclooxygenase-1 (COX-1) and inducible cyclooxygenase-2 (COX-2), the rate-limiting enzymes that are involved in production of prostaglandins and thromboxane. In addition to their role in inflammation, prostaglandins are important regulators of vascular tone, salt and water balance, and renin release, and nonselective NSAID exhibit adverse effects, including salt retention and reduced GFR, which may elevate BP or make pre-existing hypertension worse (2). It has been estimated that as many as 2.5 million Americans experience NSAID-mediated renal effects yearly (3). Risk factors that predispose to NSAID-induced renal functional alterations include age Ͼ65 yr, cardiovascular disease, diabetes, male gender, high NSAID dosage, and concurrent use of other nephrotoxic drugs (3). Up to 20% of patients who take nonselective NSAID and have more than one of these risk factors may manifest alterations in renal function.In addition to renal side effects, nonselective NSAID have long been known to predispose to gastrointestinal (GI) toxicity. It has been estimated that one third of patients who taking long-term nonselective NSAID develop endoscopically proven gastric or duodenal ulcers (4). The risk for serious bleeding from these lesions is somewhat lower, with approximately 100,000 hospitalizations for GI complications of NSAID (5). One study estimated that nonselective NSAID-induced GI abnormalities constitute the 15th leading cause of death in the United States (6). The premise that COX-1 performs cellular "housekeeping" functions for normal physiologic activity and is the predominant isoform expressed in platelets and the GI tract, whereas COX-2 acts at inflammatory sites, led to the development of COX-2 selective inhibitors. It also was originally hypothesized that the renal effects of nonselective NSAID were also linked to COX-...

Cyclooxygenase-2 Mediates Dialysate-Induced Alterations of the Peritoneal Membrane

“…We are aware that COX-2 inhibitors cannot be easily used in clinical practice, at least for long-term treatments, because major concerns about the cardiovascular safety of these drugs have been raised. 30 This issue is particularly important in patients with ESRD, which have prevalent cardiovascular risk 31 ; however, we believe that our results provide evidence about the feasibility of considering inflammation as a potential therapeutic target to ameliorate PD-related PM deterioration. Further studies of peritoneal inflammatory reaction will provide more specific interventions with minimum adverse effects on cardiovascular risk.…”

Drug-induced acid-base disorders

“…Renin inhibition can be triggered by simultaneous use of cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs; NSAIDs), leading to hyperkalemia and metabolic hyperchloremic acidosis [73,74]. Heparin impairs aldosterone synthesis as a result of direct toxicity to the zona glomerulosa, with inhibition of aldosterone synthase (adrenal 18-hydroxylase).…”

Medication Side Effects: Barriers to the Management of Fluid Intake

“…35,36 Other agents, such as non-steroidal anti-infl ammatories [NSAIDs], are known to affect fl uid balance in some users because of their infl uence on the release of renin, salt retention, and blood pressure regulation. 37,38 The Manley et al study noted frequent dialysis patient use of proton-pump inhibitors (PPIs), which is possibly a result in part of the need to treat the negative gastric side effects of NSAIDs. This has the potential to add further complication because certain PPIs can occasionally cause diarrhea and in rare cases cause colitis.…”