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Cyclo-oxygenase-2 Inhibitors and Renal Function
US Nephrology, 2007;1(1):15-8
AbstractSince the introduction of aspirin in 1898, non-steroidal anti-inflammatory drugs (NSAIDs) have become one of the most commonly used medications. The mechanism of action of these drugs is to inhibit cyclooxgenase (COX), the rate-limiting enzyme in prostaglandin synthesis. However, despite their beneficial analgesic, anti-inflammatory, and antipyretic properties, the side effects of NSAIDs (especially gastric intolerance) are not negligible.
Citation US Nephrology, 2007;1(1):15-8
In early 1990s, a second COX isozyme, COX-2, was discovered. It was suggested that COX-1 is constitutively expressed in many tissues (including the gastrointestinal tract, platelets, and kidneys) and is responsible for producing prostanoids that regulate normal housekeeping or physiological functions, while being inducible in response to a variety of evoking stimuli in different tissues and a mediator of inflammation and pain in certain diseases.1
Since aspirin and the other traditional NSAIDs inhibited both COX-1 and COX-2, more selective COX-2 inhibitors were developed with the expectation of avoidance of much of the toxicity of non-specific NSAIDs. However, Merck was forced to withdraw Rofecoxib (a COX-2 inhibitor) from the market in 2004 due to its potential cardiovascular (CV) risks to some patients. US Food and Drug Administration (FDA) advisers allowed Celebrex (another COX-2 inhibitor) to remain on the market, but asked makers of all prescription NSAIDs, including Celebrex, to alert patients to an increased risk of serious adverse CV events. In addition to their CV hazard, NSAIDs produce renal effects in 2.5 million Americans per year,2 and the influence of COX-2 inhibitors on renal function remains another major concern regarding their safety. This brief article discusses the renal effects of non-selective and selective COX-2 inhibitors based on pre-clinical data and pre- and post-market clinical trials.
Hemodynamic Effects of Cyclo-oxygenase-2 Inhibition from Pre-clinical Data
It is well known that prostaglandins (PGs) are important mediators of vascular tone, salt and water balance, and renin release. The rate-limiting COX enzyme (prostaglandin synthase G2/H2) initiates the metabolism of arachidonic acid (AA) to PGG2 and subsequently to PGH2, which is then further metabolized by tissue-specific isomerases to PGs (PGE2 and PGI2 are major metabolites in the kidney) and thromboxane (Tx) (see Figure 1). Due to their short half-life before being inactivated and excreted, PGs predominantly act locally in the area in which they are secreted. PGE2, PGI2, and PGD2 (expressed in vessels) are generally considered as vasodilators, while TxA2 and PGF2α are vasoconstrictors. PGs may influence renal blood flow (RBF) under some circumstances.3 PGE2 plays an important role in regulating sodium chloride (NaCl) and water reabsorption in medullary thick ascending limb and collecting duct 4, promoting diuresis and natriuresis. PGI2 and PGE2 activate the renin–angiotensin system (RAS) with a subsequent increase in aldosterone, which leads to the stimulation of renal potassium secretion. As mentioned above, traditional NSAIDs inhibit COX-1 and COX-2 non-selectively. Their depression of PG production exhibits analgesic, antipyretic, and antiinflammatory effects and induces potential side effects by affecting renal function, inducing water and salt retention, decreasing glomerular filtration rate (GFR), and elevating blood pressure (BP), hyponatremia, and hyperkalemia.
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