Cirrhosis NSAIDs

Percutaneous Hver biopsy after each 1.5 g of total accumulated methotrexate dosage to detect hepatic fibrosis or cirrhosis not rehably predicted by semm aminotransferase tests are recommended (1,50). Concurrent use of NSAIDs may increase toxicity of methotrexate, although toxicity may be avoided if the dmgs are separated by 12 h. 

Selective bowel decontamination in acute pancreatitis Prevention of SBP in cirrhosis Prevention of NSAID intestinal injury Extra-GI indications Skin infections Bacterial vaginosis Periodontal disease... 

Acetyls alley lie acid was shown to prevent cirrhosis under certain experimental conditions [125]. Naproxen and indomethacin partially protected against LPS and D-galactosamine-in-duced hepatotoxicity [126] Acetylsalicylic acid and ibuprofen were also protective in endo-toxic shock [127]. Endotoxaemia is one of the complications in cirrhotic patients [128] and is probably caused by an impaired ability of the liver to take up and detoxify gut-derived LPS [116]. The presence of portosystemic shunts in cirrhotic patients may also contribute to this spill-over of LPS into the systemic circulation [129]. NSAIDs, however, are also reported to provoke deleterious effects on renal function in cirrhosis [130], and can therefore not be used in cirrhotic patients. Cell-specific delivery of NSAIDs to SECs and/or KCs may make application of these drugs in cirrhosis feasible by circumventing the renal side-effects. 

Uses Edema, HTN, CHF, h atic cirrhosis Action Loop diuretic -1- reabsorption of Na Cr in ascending loop of Henle distal tubule Dose 5-20 mg/d PO or IV 200 mg/d max Caution [B, ] Contra Sulfonylurea sensitivity Disp Tabs, inj SE Orthostatic -1- BP, HA, dizziness, photosens, electrolyte imbalance, blurred vision, renal impair Notes 20 mg torsemide = 40 mg furosemide Interactions t Risk of ototox W/ aminoglycosides, cisplatin t effects W/ thiazides t effects OF anticoagulants, antih5rpCTtensives, Li, salicylates X effects IT/barbiturates, carbamaz ine, cholestyramine, NSAIDs, phenytoin, phenobarbital, probenecid, dandehon EMS t Effects of anticoagulants monitor for S/Sxs tinnitus, monitor ECG for hypokalemia (flattened T waves) OD May cause HA, hypotension, hypovolemia, and hypokalemia give IV fluids symptomatic and supportive... 

Although colchicine is more specific in gout than the NSAIDs, NSAIDs (eg, indomethacin and other NSAIDs [except aspirin]) have replaced it in the treatment of acute gout because of the troublesome diarrhea sometimes associated with colchicine therapy. Colchicine is now used for the prophylaxis of recurrent episodes of gouty arthritis, is effective in preventing attacks of acute Mediterranean fever, and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis. Although it can be given intravenously, this route should be used cautiously because of increased bone marrow toxicity. 

Loop diuretics induce renal prostaglandin synthesis, and these prostaglandins participate in the renal actions of these drugs. NSAIDs (eg, indomethacin) can interfere with the actions of the loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis. 

These findings from special renal studies and the clinical trial data indicate that inhibition of Cox-2 does not eliminate the renal effects of NSAIDs because Cox-2-derived prostanoids are involved in normal renal function. However, the kidney contains considerably more Cox-1 than Cox-2, and the localization of the two isoforms is different It is not yet known whether the Cox-2 inhibitors will be safer in subgroups of patients prone to develop acute renal failure with NSAIDs, such as those patients with severe volume depletion, congestive heart failure, or hepatic cirrhosis with ascites (Bosch-Marce et al., 1999). Also, it is not known whether rare events, such as interstitial nephritis or papillary necrosis, will occur with long-term use of Cox-2 inhibitors, although studies in animals suggest that such events may be related to Cox-1 inhibition, since only Cox-1 is found in the papilla. Therefore, Cox-2 inhibitors may not produce these serious adverse effects (Khan etal., 1998). 

NSAIDs inhibit prostaglandin synthesis, and in so doing can reduce GFR in susceptible patients, including those with cirrhosis. A number of renal complications can occur, including acute renal failure. All NSAIDs have been associated with nephrotoxicity. There is a small amount of data suggesting that renal effects are less likely to occur with sulindac, but studies relate to short-term therapy only, and there have been case reports of acute renal failure developing in high-risk patients [4,27,35]. 

Various NSAIDs have been shown to reduce GFR in patients with cirrhosis. Decompensated cirrhotic patients with ascites have the highest risk [35, 36]. 

Renal prostaglandins are involved in the mechanism of action of diuretics. NSAIDs block the synthesis of prostaglandins and hence can reduce the effects of diuretics. The combination may also increase the risk of NSAID-induced nephrotoxicity [5]. Patients with cirrhosis and ascites are at a greater risk of this interaction. 

Many centres prefer to avoid using NSAIDs in any patient with liver disease because of their side-effect profile. However, if the liver disorder is purely cholestatic in origin and the disease has not progressed to cirrhosis and portal hypertension, NSAIDs may be an option. Any risk-benefit assessment should consider the potential risk of hepatotox-icity, albeit rare. There are no specific contraindications in this patient because they are not cirrhotic, do not have deranged clotting, and are unlikely to be at increased risk of deteriorating renal function. If deemed necessary an NSAID could be used cautiously. 

NSAIDs should be avoided in this patient, or indeed any patient with cirrhosis, because of their unfavourable side-effect profile ... 

The nonsalicylate NSAIDs can also affect renal function. Risk factors fc>r NSAID-induced acute renal failure include congestive heart feilure, glomerulonephritis, chronic renal insufficiency, cirrhosis, systemic lupus erythematosus, diabetes mellitus, significant atherosclerotic disease in the elderly and use of diuretics. NSAIDs can adversely affect cardiovascular homeostasis and can be a risk factor for the onset or exacerbation of heart feilure. 

However, these data are limited and must be interpreted with caution, since NSAIDs have significant toxic effects on the kidney only in patients at risk (that is those with volume depletion, heart failure, cirrhosis, intrinsic renal disease, and hypercalcemia), in whom the secretion of vasodilator prostaglandins is increased in an attempt to counteract the effect of increased renal vasoconstrictors, such as angiotensin II. 

Aspirin can increase the risk of variceal bleeding in patients with cirrhosis. In fact, according to a case-control study (147), patients with cirrhosis and esophageal or cardiac varices who take NSAIDs are three times more likely to have a first episode of variceal bleeding compared with similar patients who are not taking NSAIDs. 

In 125 patients with cirrhosis who were admitted to hospital with a first episode of bleeding related to esophageal or cardiac varices, compared with 75 patients with cirrhosis, but no previous or current history of variceal bleeding, who were admitted to the same hospitals, a questionnaire showed that more patients with a first episode of bleeding had used aspirin, either alone or in combination with other NSAIDs compared with controls (OR = 4.9). This increased risk of bleeding was seen only in patients with grade 2 or grade 3 varices. 

The actual risk of NSAID-associated acute renal dysfunction also continues to be the subject of controversy. There is adequate evidence that underlying renal insufficiency, congestive heart failure, or hepatic cirrhosis are conditions that carry a high risk of NSAID-related renal functional impairment. It is still not known whether old age is a risk factor, whether the risk of renal impairment varies with different NSAIDs, or whether renal function continues to deteriorate, stabilize, or even improve in affected patients with continued use of NSAIDs. Three cases of renal insufficiency caused by topical NSAIDs have been described (SEDA-18,100). 

Acute renal insufficiency has been reported after the use of rofecoxib in patients with predisposing conditions, such as chronic renal insufficiency, renal transplantation, heart disease, liver cirrhosis, and dehydration (2-5). COX-2 inhibitors should be used with great caution, if at all, in patients with medical problems that are associated with prostaglandin-depen-dent renal function. From this point of view they do not differ from traditional NSAIDs (6). 

To summarize patient a risk of NSAID-induced AKI. Frequency will be greater in patient populations with restricted renal blood flow, e.g. CHF, cirrhosis, nephrotic syndrome, shock. However, for absolute numbers, the elderly are probably most at risk since they are the primary group who take NSAIDs for re-heve rheumatic complaints [3]. 

The ability of sulindac to inhibit prostaglandin synthesis and impair renal function has been confirmed in a different high-risk group, namely patients with hepatic cirrhosis and ascites [82]. We have also identified the development of profound acute kidney injury in risk prone patients who received sulindac for several days to weeks. Collectively, these studies suggest caution in accepting any NSAID as being "renal sparing". 

Six of 12 females with normal renal function experienced at least a 10% decrease in GFR following a 3-day course of indomethacin (25 mg four times daily) (p<0.05). When misoprostol was added, four of these six NSAID-sensitive patients experienced no change in GFR. Misoprostol also blunted indomethacin-induced decreases in creatinine clearance and natriuresis in another at-risk group, patients with alcoholic cirrhosis and ascites [181]. 

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