|Year : 2017 | Volume
| Issue : 1 | Page : 1-2
Nonsteroidal anti-inflammatory drugs: Is there a link between cardiovascular and renal adverse effects?
Regan E Sevinsky1, David W Stewart1, Sam Harirforoosh2
1 Department of Pharmacy Practice, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN, United States of America
2 Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Johnson City, TN, United States of America
|Date of Web Publication||1-Mar-2017|
Department of Pharmaceutical Sciences, Gatton College of Pharmacy, East Tennessee State University, Box 70594, Johnson City, TN 37614-1708
United States of America
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Sevinsky RE, Stewart DW, Harirforoosh S. Nonsteroidal anti-inflammatory drugs: Is there a link between cardiovascular and renal adverse effects?. J Integr Nephrol Androl 2017;4:1-2
|How to cite this URL:|
Sevinsky RE, Stewart DW, Harirforoosh S. Nonsteroidal anti-inflammatory drugs: Is there a link between cardiovascular and renal adverse effects?. J Integr Nephrol Androl [serial online] 2017 [cited 2023 Oct 3];4:1-2. Available from: http://www.journal-ina.com/text.asp?2017/4/1/1/201275
Both the clinical benefits and the adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are mediated by the inhibition of cyclooxygenase (COX) 1 and 2. COX-1 is expressed constitutively in tissues, whereas COX-2 is produced under periods of stress and inflammation. The physiologic function of COX-1 and COX-2 is to convert arachidonic acid to prostaglandins, thromboxane A2 (TXA2), and prostacyclins. These products influence multiple systems such as cardiac, immune, gastrointestinal (GI), renal, vascular, and pulmonary systems., COX enzymes are present in various locations throughout the body including the blood vessels where they produce vasodilatory prostacyclins and TXA2, which causes platelet aggregation. They are also present in the kidney where they help maintain renal blood flow and promote natriuresis, diuresis, and vasodilation through the production of prostaglandins. Inhibition of COX with the use of NSAIDs produces the well-known pain-relieving effects through decreased production of prostaglandins, which under physiologic conditions cause hyperalgesia., Although NSAIDs remain guideline recommended for arthritis and musculoskeletal conditions, the use of NSAIDs does not come without risk of side effects. Well-known adverse effects of NSAIDs include GI bleeding, as well as cardiovascular and renal function changes.,
Renal adverse effects of NSAIDs have been widely investigated and include acute kidney injury, chronic kidney injury, interstitial nephritis, sodium retention, and hyperkalemia.,,,,, There are a variety of proposed mechanisms for these adverse effects, which are likely multifactorial in nature. The primary recognized mechanism is a reduction in prostaglandin production with the use of NSAIDs. Because prostaglandin production in the kidney produces vasodilatory effects, the resultant vasoconstriction and subsequent reduction in renal blood flow causes insult to the kidney. Further, inhibition of prostaglandin synthesis in the kidney increases reabsorption of sodium and water in the collecting tubule. Recent research has also identified a potential link between acute tubular injury and activation of the complement system by ketoprofen.
While renal adverse effects may be more frequently cited by clinicians, cardiovascular adverse effects are also well established. The cardiovascular adverse effects attributed to NSAIDs include myocardial infarction, hypertension, and atrial fibrillation.,, In addition, a recent meta-analysis reported NSAID users being 17% more likely to develop heart failure compared to nonusers. Like the renal effects, the link between NSAID use and cardiovascular adverse effects is likely multifactorial. The historical cardiovascular risk associated with COX-2-specific inhibitors, as opposed to nonselective NSAIDs, was thought to be due to the preserved platelet aggregating function of TXA2. Recently, Nissen et al. challenged this by demonstrating, contrary to historical belief, the noninferiority of celecoxib, as a COX-2-selective inhibitor (COXIB), compared to ibuprofen and naproxen for cardiovascular safety. In addition, a meta-analysis found that rofecoxib was the only COXIB that showed an increase in cardiovascular events compared to other COXIBs and nonselective NSAIDs. Another proposed mechanism for increased cardiovascular risk is generation of reactive oxygen species in cardiac cells by NSAIDs. Production of reactive oxygen species with the use of NSAIDs leads to upregulation of specific signaling pathways, one of these being apoptosis. This programmed cell death could ultimately lead to cardiovascular damage and disease. In addition, inhibition of prostaglandins leads to vasoconstriction of the peripheral and renal vasculature with resultant reabsorption of sodium and water in the kidney, which may contribute to elevations in blood pressure and fluid retention.
While renal and cardiovascular adverse effects are often considered separately, a potential for a relationship may exist between the two when considering NSAID administration. These cardiorenal effects could be attributable to a reduction in prostaglandin production in the kidney and vasculature leading to a decrease in renal perfusion and an increase in systemic vascular resistance and retention of sodium and water., In a previous study, reduced sodium excretion was reported with both the use of COXIBs and nonselective NSAIDs in rats. All of these factors could contribute to hypertension, myocardial infarction, and overall cardiovascular risk associated with NSAID use.,, More recently, a novel explanation of the link between renal and cardiovascular side effects has been reported by Ahmetaj-Shala et al. The study investigated wild-type and COX-2−/− mouse tissue and discovered a gene predominantly present in the renal medulla associated with the regulation of nitric oxide synthase inhibitors and asymmetric dimethylarginine (ADMA). Mice that were COX-2−/− exhibited decreased endothelial nitric oxide responses and increased plasma ADMA, which confers a reduction in the cardioprotective effects of nitric oxide synthase. If the relationship between adverse cardiovascular and renal effects is directly related, the use of ADMA as a biomarker for cardiovascular risk and a link to renal COX-2 inhibition could be a useful clinical tool. Further research focused on this relationship is warranted given the high prevalence of both cardiovascular disease and NSAID use in most developed countries.
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