Pathophysiological aspects of nephropathy caused by non-steroidal anti-inflammatory drugs / Aspectos fisiopatológicos da nefropatia por anti-inflamatórios não esteroidais

Abstract Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used medications associated with nephrotoxicity, especially when used chronically. Factors such as advanced age and comorbidities, which in themselves already lead to a decrease in glomerular filtration rate, increase the risk of NSAID-related nephrotoxicity. The main mechanism of NSAID action is cyclooxygenase (COX) enzyme inhibition, interfering on arachidonic acid conversion into E2 prostaglandins E2, prostacyclins and thromboxanes. Within the kidneys, prostaglandins act as vasodilators, increasing renal perfusion. This vasodilatation is a counter regulation of mechanisms, such as the renin-angiotensin-aldosterone system works and that of the sympathetic nervous system, culminating with compensation to ensure adequate flow to the organ. NSAIDs inhibit this mechanism and can lead to acute kidney injury (AKI). High doses of NSAIDs have been implicated as causes of AKI, especially in the elderly. The main form of AKI by NSAIDs is hemodynamically mediated. The second form of NSAID-induced AKI is acute interstitial nephritis, which may manifest as nephrotic proteinuria. Long-term NSAID use can lead to chronic kidney disease (CKD). In patients without renal diseases, young and without comorbidities, NSAIDs are not greatly harmful. However, because of its dose-dependent effect, caution should be exercised in chronic use, since it increases the risk of developing nephrotoxicity.

Resumo Os anti-inflamatórios não esteroidais (AINEs) são medicamentos comumente utilizados, associados à nefrotoxicidade, sobretudo quando utilizados cronicamente. Fatores como idade avançada e comorbidades, que por si só já levam à diminuição da taxa de filtração glomerular, aumentam o risco de nefrotoxicidade dos AINEs. O principal mecanismo de ação dos AINEs é a inibição da enzima ciclooxigenase (COX), interferindo na conversão do ácido araquidônico em prostaglandinas E2, prostaciclinas e tromboxanos. Nos rins, as prostaglandinas atuam como vasodilatadoras, aumentando a perfusão renal. Essa vasodilatação atua como uma contrarregulação de mecanismos, como a atuação do sistema renina-angiotensina-aldosterona e do sistema nervoso simpático, culminando com uma compensação para assegurar o fluxo adequado ao órgão. O uso de AINEs inibe esse mecanismo, podendo causar lesão renal aguda (LRA). Altas doses de AINEs têm sido implicadas como causas de LRA, especialmente em idosos. A principal forma de LRA por AINEs é a hemodinamicamente mediada. A segunda forma de apresentação da LRA induzida por AINES é a nefrite intersticial aguda, que pode se manifestar com proteinúria nefrótica. O uso de AINEs em longo prazo pode ocasionar doença renal crônica (DRC). Nos pacientes sem doenças renais, jovens e sem comorbidades, os AINEs não apresentam grandes malefícios. Entretanto, por seu efeito dose-dependente, deve-se ter grande cautela no uso crônico, por aumentar risco de desenvolver nefrotoxicidade.

Anti-inflamatórios não esteroides: Efeitos cardiovasculares, cérebro-vasculares e renais / Nonsteroidal anti-inflammatory drugs: cardiovascular, cerebrovascular and renal effects

Os anti-inflamatórios não esteroides (AINEs) encontram-se entre os medicamentos mais prescritos em todo o mundo. Essa classe heterogênea de fármacos inclui a aspirina e vários outros agentes inibidores da ciclo-oxigenase (COX), seletivos ou não. Os AINEs não seletivos são os mais antigos, e designados como tradicionais ou convencionais. Os AINEs seletivos para a COX-2 são designados COXIBEs. Nos últimos anos, tem sido questionada a segurança do uso dos AINEs na prática clínica, particularmente dos inibidores seletivos da COX-2. As evidências sobre o aumento do risco cardiovascular com o uso de AINEs são ainda incompletos, pela ausência de ensaios randomizados e controlados com poder para avaliar desfechos cardiovasculares relevantes. Entretanto, os resultados de estudos clínicos prospectivos e de meta-análises indicam que os inibidores seletivos da COX-2 exercem importantes efeitos cardiovasculares adversos, que incluem aumento do risco de infarto do miocárdio, acidente vascular cerebral, insuficiência cardíaca, insuficiência renal e hipertensão arterial. O risco desses efeitos adversos é maior em pacientes com história prévia de doença cardiovascular ou com alto risco para desenvolvê-la. Nesses pacientes, o uso de inibidores da COX-2 deve ser limitado àqueles para os quais não há alternativa apropriada e, mesmo assim, somente em doses baixas e pelo menor tempo necessário. Embora os efeitos adversos mais frequentes tenham sido relacionados à inibição seletiva da COX-2, a ausência de seletividade para essa isoenzima não elimina completamente o risco de eventos cardiovasculares, de modo que todos os fármacos do largo espectro dos AINEs somente devem ser prescritos após consideração do balanço risco/benefício.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most often prescribed drugs in the world. This heterogeneous class of drugs includes aspirin and several other selective or non-selective cyclooxygenase (COX) inhibitors. The non-selective NSAIDs are the oldest ones and are called traditional or conventional NSAIDs. The selective NSAIDs are called COX-2 inhibitors. In recent years, the safety of NSAID use in clinical practice has been questioned, especially that of the selective COX-2 inhibitors. The evidence on the increase in cardiovascular risk with the use of NSAIDs is still scarce, due to the lack of randomized and controlled studies with the capacity of evaluating relevant cardiovascular outcomes. However, the results of prospective clinical trials and meta-analyses indicate that the selective COX-2 inhibitors present important adverse cardiovascular effects, which include increased risk of myocardial infarction, cerebrovascular accident, heart failure, kidney failure and arterial hypertension. The risk of these adverse effects is higher among patients with a previous history of cardiovascular disease or those at high risk to develop it. In these patients, the use of COX-2 inhibitors must be limited to those for which there is no appropriate alternative and, even in these cases, only at low doses and for as little time as possible. Although the most frequent adverse effects have been related to the selective COX-2 inhibition, the absence of selectiveness for this isoenzyme does not completely eliminate the risk of cardiovascular events; therefore, all drugs belonging to the large spectrum of NSAIDs should only be prescribed after consideration of the risk/benefit balance.

Cardio-renal effects of celecoxib versus ibuprofen in patients with arthritis

Arthritis is a common condition that co-exists in the elderly population. This condition leads to frequent administration of co-morbid Non Steroidal Anti-inflammatory drugs [NSAIDs]. To study cardio-renal toxicity of celecoxib versus ibuprofen in arthritic patients. Seven hundred ninety two arthritic patients were enrolled in the study for 6 months. Three hundred ninty six patients administered celecoxib, 400 mg twice a day; 396 patients administered ibuprofen 300 mg three times a day Effects measured included: investigator reported hypertension, edema, or congestive heart failure, and increases in serum creatinine or reduction in serum creatinine clearance, and changes in serum electrolytes. Celecoxib was associated with significant [P<0.05] lower incidence of hypertension and edema in comparison with ibuprofen. Systolic hypertension occurred significantly less [P<0.05] with celecoxib compared with ibuprofen. Serum creatinine was significantly increased [P<0.05] in patients treated with ibuprofen in comparison with celecoxib. Creatinine clearance was significantly lower [P<0.05] in cases treated with ibuprofen in comparison to celecoxib. Non significant changes in serum body electrolytes. The most important finding of this study was the lowering incidence of cardiorenal complications of celecoxib in comparison with ibuprofen

Can COX-2 inhibitor-induced increase in cardiovascular disease risk be modified by essential fatty acids?

Selective COX-2 inhibitors increase the risk of myocardial infarction and stroke. This has been attributed to their ability to inhibit endothelial COX-2 derived prostacyclin (PGI2) but not platelet COX-1 derived thromboxane A2 (TXA2). On the other hand, aspirin blocks both COX-1 and COX-2 enzymes without decreasing PGI2 but blocks TXA2 synthesis that explains its beneficial action in the prevention of coronary heart disease (CHD). The inhibitory action of aspirin on COX-1 and COX-2 enzymes enhances the tissue concentrations of dihomo-gamma-linolenic acid (DGLA), arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). These fatty acids form precursors to PGE1, PGI2, PGI3, lipoxins (LXs), and resolvins that have anti-inflammatory actions. In contrast, increase in the concentrations of DGLA, AA, EPA, and DHA is much less with specific COX-2 inhibitors since they do not block the formation of eicosanoids through COX-1 pathway. COX-2 inhibitors interfere with the formation of LXs and resolvins that have neuroprotective and cardioprotective actions. EPA and PGI2 have anti-arrhythmic action. EPA, DHA, and AA augment eNO formation that prevents atherosclerosis. This suggests that COX-2 inhibitors increase cardiovascular and stroke risk by interfering with the formation of eNO, PGI2, LXs, and resolvins and implies that combining EFAs with COX-2 inhibitors could prevent these complications.

COX-2 selective nonsteroidal anti-inflammatory drugs: current status.

Since, their introduction, COX (cyclooxygenase enzyme)-2 specific inhibitors have become a rapidly growing segment of the prescription drug market. Researchers have recently focused on the potentially lethal side effects associated with their. FDA has banned the use of nimesulide (hepatotoxic) in pediatric patients and rofecoxib (cardiovascular complications) in both adults and children. COX-2 inhibitors may decrease vascular prostacyclin production and may tip the balance in favour of prothrombotic eicosanoids (thromboxane A2) and lead to increased cardiovascular thrombotic events. COX-2 inhibitors can also result into increase blood pressure, macular eruptions, urticaria, pseudoporphyria, erythema multiforme, oedema, worsening of heart failure, fatal allergic vasculitis and aggravation of doxorubicin-mediated cardiac injury. The COX-2 enzyme is also involved in the development of many organ systems, and its inhibition may lead to various congenital defects in neonates. It has been reported that COX-2 inhibitors also interfere with implantation, hence their use should be avoided in sexually active women at risk of pregnancy. However, presently the choice of COX-2 selective inhibitors for a particular patient should be based upon their relative efficacy, toxicity, concomitant drug use, concurrent disease states, hepatic and renal function and relative cost.

Efecto de diferentes dosis de asoirina sobre el precondocionamiento contra el atontamiento en ovejas / Effect of different doses of aspirin on preconditioning against stunning in conscious sheep

Se ha postulado que los antiinflamatorios no esteroides que actuan inhibiendo la ciclooxigenasa (COX) podrían tener efectos nocivos sobre el corazón. Recientemente se ha demostrado que los inhibidores de la COX-2 bloquean la protección por precondicionamiento tardío (PT). Se desconoce sin embargo, el efecto que pudiera tener la aspirina, el antiinflamatorio no esteroide más ampliamente utilizado en la clínica, sobre el PT en mamíferos grandes. La aspirina actúa inhibiendo las dos isoenzimas de la ciclooxigenasa (COX-1 y COX-2), siendo empleada en dosis altas como droga antiinflamatoria y en dosis bajas como agente antitrombótico.El propósito de este estudio fue analizar qué efecto tienen distintas dosis de aspirina sobre la protección delPT contra el atontamiento y las arritmias en ovejas conscientes. Se consideraron 5 grupos; control (C): 12 minde isquemia (I) y 2 hr de reperfusión (R); PT: 6 períodos de 5 min I-5 min R, 24 hr antes de la I de 12 min, ytres grupos igual que PT, pero con 1.5 (PTA1.5), 8 (PTA8) y 20 (PTA20) mg/kg de aspirina respectivamente, administrados 10 min antes de la primera I de precondicionamiento. Los resultados demostraron que la dosis antiinflamatoria de aspirina (20 mg/kg) fue capaz de inhibir el PT contra el atontamiento (C vs PTA20, NS),mientras que las dosis bajas (1.5 mg/kg) e intermedia (8 mg/kg) no afectaron la protección (C vs PT, PT1.5 yPT8, p<0.01). Asimismo, ninguna de las tres dosis alteró la protección contra las arritmias. Conclusión: Lasdosis antiagregantes plaquetarias de aspirina no producirían riesgo de inhibir la protección contra el atontamiento por PT, mientras que dosis antiinflamatorias elevadas serían perjudiciales. Como la aspirina se administró antes de los períodos precondicionantes, la inhibición de la cardioprotección sugiere que la COX actúacomo mecanismo gatillador del PT contra el atontamiento.

Pre-emptive analgesia for laparoscopic surgery. a randomized, double-blind, placebo-controlled comparison between parecoxib sodium and tramadol

This study was performed to compare the preemptive effect of intravenous parecoxib vs intravenous tramadol as regards control of stress response to intubation and efficacy of analgesia, in adult patients undergoing laparoscopic surgery. Forty five adult patients ASA physical status I-II scheduled to undergo abdominal laparoscopic surgery were included in this study. Patients were randomly divided into three equal groups. Group I [n = 15] received parecoxib [40 mg iv]. Group II [n = 15] received tramadol [100 mg iv]. Group III [n = 15] received placebo [10 ml normal saline iv]. Anesthesia was induced 10 minutes later using propofol [2 mg/kg] and fentanyl [1-2 micro g/kg]. Tracheal intubation was facilitated using succinyl choline [1.5 mg/kg]. Maintenance of anesthesia was achieved using isoflurane [0.6% - 1.5% according to blood pressure] in a mixture of 50% N[2]O in oxygen. Intraoperative muscle relaxation was maintained using atracurium [0.5 mg/kg followed by 0.1 mg/kg every 20 min]. Mechanical ventilation parameters were adjusted to maintain end-tidal CO[2] [ETCO[2]] at normal levels. Surgery was performed using standard techniques. Catecholamine levels [adrenaline and noradrenaline] were measured 1 minute before and 1 minute after intubation. Heart rate [HR], systolic [SBP] and mean arterial blood pressures [MBP] were recorded 1 minute before, and then every 1 minute after intubation, for 5 minutes. Postoperatively, patients received a continuous infusion of iv morphine at a rate of 0.03 mg/kg/hr. When requested, an additional [rescue] dose of morphine was administered at a dose of 0.05 mg/ kg, to a maximum of one rescue dose per 6 hours. The time till request of the first rescue dose, the number of rescue doses given, and the total rescue morphine dose given were recorded. Patients were observed for the first 24 hrs after surgery for occurrence of nausea and/or vomiting, and pruritis. Data was recorded at 8 hour intervals [8, 16 and 24 hrs after surgery]. There were no intergroup differences as regards age, gender, height or weight. Time to intubation, duration of surgery, doses of propofol and fentanyl used were also similar in-between the groups. Catecholamine levels increased significantly from baseline after intubation in all groups [P < 0.05], but the increase was significantly less in group II [tramadol] than in group I [parecoxib], and both study groups showed a lesser increase compared to placebo [P < 0.05]. Relative to baseline, HR, SBP and MBP increased significantly after intubation in all groups. This increase was significantly greater in group III [P < 0.05]. The tramadol group showed a slightly lesser increase in HR, SBP and MBP compared to the parecoxib group [P < 0.05], but these differences were not clinically significant. Patients in the parecoxib group showed a longer time [median] to first request of rescue analgesia [11.6 hrs] as compared to the tramadol group [7.2 hrs]. Both groups were superior to placebo [3.9 hrs to rescue dose, P < 0.05]. A similar trend was shown in the number, and total dose of rescue morphine, in-between the groups. Nausea and/or vomiting was greatest in the tramadol group [P < 0.05], and more pronounced in all groups in the first 8 hours after surgery. Pruritis was an isolated finding in the tramadol, group; none of the patients in the other two groups complained of pruritis. Both parecoxib and tramadol are effective agents as preemptive analgesics for laparoscopic surgery. While tramadol can have a more stable hemodynamic profile, parecoxib provides a more intense analgesic effect, with a hemodynamic profile that is not clinically inferior to tramadol. The use of tramadol, however, can be associated with more side effects, such as nausea, vomiting, and pruritis