Nonsteroidal antiinflammatory drugs and the kidney

Nonsteroidal antiinflammatory drugs (NSAIDs) have potentially important renal adverse effects. With regard to renal adverse effects there is no indication of significant differences between conventional NSAIDs and selective COX-2 inhibitors. Their nephrotoxicity has been well documented. Many of the renal abnormalities that are encountered as a result of NSAIDs use can be attributed to the inhibition of prostaglandins synthesis. The release of prostaglandins is particulary importent in high-risk patients, including patients with severe heart disease, liver disease, preexisting renal disease, elderly and patients with volume depletion. The common complication of NSAID use is retention of sodium and edema formation due to increased reabsorption of sodium and water in the loop of Henle and hyperkalemie due to diminished renin secretion. Nonsteroidal antiiflammatory drugs can induce two different forms of acute renal failure. Decreased prostaglandin synthesis can lead to reversible renal ischemia and hemodynamically-mediated acute renal failure. Second form of acute renal failure is acute interstitial nephritis. This type of interstitial nephritis is often accompanied by nephrotic syndrome due to minimal change disease. Nephrotic syndrome after NSAIDs treatments may be also associated with membranous nephropathy. Another complication of NSAIDs treatment is modest rise of systemic blood pressure in some hypertensive patients due to increase in renal and systemic vascular resistence. In patients consuming excessive amount of NSAIDs over a prolonged period of years papillary necrosis can occur. Exposure to large quantities of NSAIDs can probably induce in some patients chronic renal insufficiency.     

非类固醇类抗炎药的小肠黏膜损害

非类固醇类抗炎药(NSAIDs)对胃十二指肠黏膜的损害十分突出,得到临床广泛重视。近年来随着诊断手段的不断发展,发现NSAIDs的小肠黏膜损害的发生率也不低。NSAIDs导致小肠黏膜损伤是一个复杂的多步骤的过程,可导致黏膜通透性增加、炎症、溃疡、出血、狭窄及穿孔等。目前尚无有效的防治方法。本文就NSAIDs导致的小肠黏膜损害作一综述。     

Nonsteroidal antiinflammatory drugs and lower gastrointestinal bleeding

To define the association of the ingestion of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin (ASA), and lower gastrointestinal bleeding (GIB) a retrospective, case-controlled study was undertaken of 188 patients admitted to three community hospitals in three cities with a diagnosis of lower GIB. Information was obtained about NSAID usage among these patients, and the data were compared with an age- and sex-matched control group of 185 patients admitted with a nongastrointestinal diagnosis, derived from a daily admission list. At the time of admission, in the New Jersey group, NSAID consumption was present in 26 of 90 (29%) patients with lower GIB compared with 16 of 90 (18%) of controls (P<0.05, odds ratio 1.88, 95% CI 1.2–3.1) whereas, in the South Carolina group 34 of 98 (35%) were taking NSAID compared with 18 of 95 (19%) of controls (P<0.01, odds ratio 2.27, 95% CI 1.2–4.4). These data indicate that there is a significantly increased rate of NSAID ingestion in patients admitted with lower GIB, implying that NSAID may unmask bleeding from a variety of lower gastrointestinal lesions.     

Nonsteroidal antiinflammatory drugs and dyspepsia in the elderly

Upper gastrointestinal tract symptoms are common in the elderly and, despite a paucity of data, nonsteroidal antiinflammatory drugs (NSAIDs) are believed to be important risk factors. We aimed to evaluate the association of NSAIDs with dyspepsia and heartburn in a population-based study. An age- and gender-stratified random sample of Olmsted County, Minnesota, Caucasian residents aged 65 years and older was mailed a valid self-report questionnaire; 74% responded (N=1375). Age- and gender-adjusted (to 1980 US Caucasian population) prevalence rates for NSAID use, dyspepsia (defined as pain located in the upper abdomen or nausea), and heartburn (defined as retrosternal burning pain) were calculated. Logistic regression analysis was used to estimate the association of dyspepsia and heartburn with potential risk factors adjusting for age and gender. The age- and gender-adjusted annual prevalences (per 100) of aspirin and nonaspirin NSAID use were 60.0 (95% CI 57.2,62.7) and 26.1 (95% CI 23.6,28.7), respectively. The annual prevalences of dyspepsia and heartburn were 15.0 (95% CI 12.9,17.0) and 12.9 (95% CI 10.9,14.8), respectively. Aspirin was associated with dyspepsia and/or heartburn (OR=1.6, 95% CI 1.2,2.2) as were nonaspirin NSAIDs (OR=1.8, 95% CI 1.3,2.6), but smoking and alcohol were not significant risk factors. Aspirin and nonaspirin NSAIDs are associated with almost a twofold risk of upper gastrointestinal tract symptoms in elderly community subjects.This work was supported in part by research grants AG09440 and AR30582 from the National Institutes of Health.     

Nonsteroidal antiinflammatory drugs and uncoupling of mitochondrial oxidative phosphorylation

Objective. There is a lack of correlation between cyclooxygenase (COX) inhibition and nonsteroidal antiinflammatory drug (NSAID)—induced gastrointestinal (GI) damage; it has been suggested that mucosal damage may be initiated by a “topical” action of NSAIDs involving mitochondrial injury. We evaluated the effect of a range of NSAIDs and related compounds on mitochondrial function and assessed the differences between them in relation to their physicochemical properties. Methods. Stimulation of respiration, as an indicator of mitochondrial uncoupling, was measured in isolated coupled rat liver mitochondrial preparations, using an oxygen electrode. Results. Conventional NSAIDs and acidic prodrugs all had stimulatory effects on mitochondrial respiration at micromolar concentrations (0.02–2.7 μM); higher concentrations were inhibitory. The uncoupling potency was inversely correlated with drug pKa (r = −0.87, P < 0.001; n = 12). Drugs known to have good GI tolerability, including modified flurbiprofen (dimeroflurbiprofen and nitrobutyl-flurbiprofen), nabumetone (a non-acidic prodrug), and non-acidic highly selective COX-2 inhibitors, did not cause uncoupling. Conclusion. The ability to uncouple mitochondrial oxidative phosphorylation is a common characteristic of antiinflammatory agents with an ionizable group. Modification or absence of an ionizable moiety reduces the effect on mitochondria and could lead to improved NSAID GI safety.     

Nonsteroidal antiinflammatory drugs and upper gastrointestinal hemorrhage in an urban hospital

Aspirin and nonsteroidal antiinflammatory drugs have been implicated in the pathogenesis of gastrointestinal hemorrhage. To evaluate their impact on inpatients, charts from Temple University Hospital with a discharge ICD-9 code which included upper gastrointestinal hemorrhage during a one-year period were reviewed. Aspirin and/or nonaspirin nonsteroidal antiinflammatory drug (NSAID) use was identified in 34 patients (19 daily users and 15 intermittent users). Sixty-seven patients who bled, but did not use these agents, served as controls. Daily NSAID users were older than intermittent users and controls (P<0.05). A higher frequency of bleeding ulcers was associated with NSAID use. Patients using NSAIDs spent more time in intensive care than controls (median 1 day vs 0 days). Daily users had a higher transfusion requirement (4 units) than non-users (0 units;P<0.05). This study suggests that NSAID use has a substantial impact on health care resource utilization in patients admitted to an urban hospital for upper gastrointestinal hemorrhage.This work was presented in part at the annual meeting of the American Gastroenterological Association, San Francisco, California, May 1992, and has appeared in abstract form (Gastroenterology 102:A98, 1992).This work was supported in part by G.D. Searle and Co.     

Nonsteroidal antiinflammatory drugs: Effect on pyloric sphincter and duodenogastric reflux

We have investigated the effect of nonsteroidal antiinflammatory drugs on canine pyloric sphincter pressure, mucosal potential difference (PD), and duodenogastric reflux in 5 dogs. Only intragastric aspirin at doses of 30 and 100 mg/kg caused a significant (P<0.05) decrease in pyloric sphincter pressure, an increase of duodenogastric reflux, and changed the mucosal PD. Neither intravenous aspirin, intragastric phenylbutazone, or intrarectal indomethacin produced these changes. The mechanism for the aspirin effect may be mediated by local pathways related to changes in mucosal PD. We postulate that increased duodenogastric reflux may be an aggravating factor for the gastric mucosal damage caused by intragastric aspirin.     

Nonsteroidal antiinflammatory drugs and a selective cyclooxygenase 2 inhibitor uncouple mitochondria in intact cells

OBJECTIVE: Uncoupling of isolated mitochondria by nonsteroidal antiinflammatory drugs (NSAIDs) has been considered relevant to the development of gastrointestinal (GI) side effects. We investigated the occurrence of NSAID-induced uncoupling of mitochondria in intact cells (rat thymocytes) compared with the effects of a selective cyclooxygenase 2 (COX-2) inhibitor. METHODS: Oxygen consumption and mitochondrial membrane potential were simultaneously measured amperometrically and by distribution of radioactive tracer molecules, respectively, in the presence and absence of pharmacologically relevant concentrations of the NSAIDs indomethacin and diclofenac and the selective COX-2 inhibitor SC-236. Analysis of data by a technique related to top-down elasticity analysis permitted assessment of the influence of these compounds on individual components of cellular energy metabolism. RESULTS: Indomethacin, diclofenac, and SC-236 increased proton leak in isolated mitochondria. Both diclofenac and SC-236 significantly stimulated proton leak in intact cells and simultaneously inhibited substrate oxidation and ATP turnover. Oxygen consumption rates of isolated cells remained unchanged over a wide concentration range of the drugs, despite significant effects on subsystems of cellular energy metabolism. CONCLUSION: NSAIDs and selective COX-2 inhibitors have significant and equally directed effects on cellular energy metabolism. They both uncouple mitochondrial respiration and inhibit substrate oxidation and ATP turnover. However, the topical effect and selective COX-2 inhibition may not be sufficient to cause NSAID-like damage to the GI tract.