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Topical Nonsteroidal Anti-inflammatory Drugs and Nephrotoxicity: Is There a Safer Option?

Based on limited data, the authors believe prescribers need to use the same precautions for topical NSAIDs that they use for other NSAID preparations.
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Prescription and over-the-counter (OTC) nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important component in

 the treatment of acute and chronic pain. The emergence of topical NSAIDs has generated controversial questions about their safety in patients with absolute or relative contraindications to orally administered NSAIDs. OTC NSAIDs generally are considered safe when they are used as directed, but extensive data showing evidence of renal dysfunction (changes in serum urea or creatinine levels, clinically diagnosed kidney disease, and renal failure) illustrates they can cause renal toxicity.1,2 Using non-oral routes of administration to achieve analgesia with reduced plasma concentrations may be an attractive alternative to systemic NSAID exposure, especially in patients who are at greater risk for NSAID-induced toxicity.  

Mechanism of Action of NSAIDs

The pharmacological effect of most NSAIDs is thought to be due to reversible cyclooxygenase 1 and 2 (COX-1 and COX-2) inhibition resulting in downstream inhibition of prostaglandin (PG) synthesis through the arachidonic acid pathway. Specifically, the rate-limiting step of arachidonic acid oxygenation is inhibited, preventing PG G2 and, ultimately, thromboxane A2 and PGE2 from being produced.3 Thromboxane A2 is a potent activator of platelets and a crucial component in the pain and inflammatory response.4 In addition, NSAIDs may exert their analgesic effect by a poorly understood central mechanism.5

Non-acetylated salicylates also may have effects on other inflammatory pathways, such as nuclear factor-κβ.6 Each available NSAID displays variable inhibitory selectivity and potency for the COX enzymes, which explains the different propensities for adverse effects (AEs) between the agents. Aspirin is the only irreversible COX inhibitor due to a covalent bond formed at the active site. The other commercially available NSAIDs are reversible, owing largely to noncovalent binding to COX active sites.3

Mechanisms of NSAID-Associated Toxicities

Gastrointestinal Toxicity

It is important to understand the mechanisms of the major AEs associated with oral NSAID use. The AE profiles of NSAIDs are thought to be based on their unique COX inhibition reactions. Data suggest that both COX (1 and 2) isoforms maintain gastric mucosa, therefore NSAIDs that block COX-1 are not more likely to cause ulceration and bleeding than COX-2 blocking agents.7 Other proposed explanations for NSAID-induced gastrointestinal ulceration and bleeding include a reduction in ATP levels and increases in free oxygen species, both of which alter the protective environment of the intestinal epithelial barrier.8

Cardiovascular Toxicity

COX-2 isoform inhibition has been directly linked to cardiovascular toxicity based on a meta-analysis of 114 double-blind, randomized controlled trials.1 COX-2 inhibition also was found to reduce the renal clearance of the major metabolite of PGI2 (prostacyclin).9 PGI2 and PGE2 both play a large role in vascular tone and, more importantly, platelet aggregation, which explains the increased incidence of cardiovascular AEs. Other proposed explanations for NSAID-associated cardiovascular toxicity includes COX-2 mediated inhibition of cardiac angiogenesis as well as attenuation of ATP-mediated stress priming within the cardiac myocyte following hypoxic insult.10

Renal Toxicity

NSAIDs have been linked to acute and chronic renal failure, tubulointerstitial nephritis, papillary necrosis, pre-renal azotemia, and acute tubular necrosis.11 The 2 primary PGs that modulate renal function are PGE2 and PGI2.12 PGE2 decreases sodium reabsorption in the loop of Henle. The decrease in sodium reabsorption is responsible for the natriuresis required to maintain adequate renal perfusion. At the distal nephron, PGI2 enhances potassium secretion through the renin-angiotensin system as it stimulates renin release.12

PGI2 also plays a major role in the vasodilation of the afferent arteriole, resulting in an increase in renal blood flow through the glomerulus.12 Inhibition of PGI2 or PGE2 inhibits renin release in the juxtaglomerular apparatus, decreasing glomerular filtration rates. Specifically, COX-2 inhibition has been found to decrease renin secretion from the macula densa induced by a decrease in NaCl.13

Along with these hemodynamic changes, NSAIDs can cause direct tubular damages. It is important to note that analgesic-induced nephrotoxicity (AIN) consists of a chronic renal papillary and medullary necrosis.14 This is direct damage to the renal physiology, unlike the pharmacodynamic effects of afferent arteriole dilation. NSAIDs may precipitate papillary necrosis due, in part, to decreases in blood flow to the renal medulla.15,16 To summarize, NSAID inhibition of the COX enzymes plays a multifactorial role in causing renal toxicities via hemodynamic changes and/or direct tubular damage.

Last updated on: September 27, 2017
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