NSAIDs toxicity

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. 

NSAIDs are used as the first-line treatment of rheumatoid arthritis, osteoarthritis, systemic lupus erythematosis and other inflammatory diseases, and are thus amongst the most widely used dtugs in the developed world. This widespread use inevitably entailed a considerable associated morbidity, in particular a high incidence of gastric toxicity. In the USA alone, perforations, ulcers and bleeds lead to the hospitalisation of 100,000 patients per year, and about 15% of these die while under intensive care. 

There is an increased risk of toxicity of MTX when administered with the NSAIDs, salicylates, oral antidiabetic drugs, phenytoin, tetracycline, and probenecid. There is an additive bone marrow depressant effect when administered with other drug known to depress the bone marrow or with radiation therapy. There is an increased risk for nephrotoxicity when MTX is administered with other drug that cause nephrotoxicity. When penicillamine is administered with digoxin, decreased blood levels of digoxin may occur. There is a decreased absorption of penicillamine when the dmg is administered with food, iron preparations, and antacids. 

Plasma digoxin levels may decrease when the drug is administered with bleomycin. When bleomycin is used witii cisplatin, there is an increased risk of bleomycin toxicity Pulmonary toxicity may occur when bleomycin is administered with other antineoplastic drugs. Plicamycin, mitomycin, mitoxantrone, and dactino-mycin have an additive bone marrow depressant effect when administered with other antineoplastic drugs. In addition, mitomycin, mitoxantrone, and dactinomycin decrease antibody response to live virus vaccines. Dactinomycin potentiates or reactivates skin or gastrointestinal reactions of radiation therapy There is an increased risk of bleeding when plicamycin is administered witii aspirin, warfarin, heparin, and the NSAIDs. 

NSAIDs can induce a number of other adverse reactions, including bleeding disorders, anemia, thrombocytopenia, erythema nodosum, erythema multiforme, fixed drug eruptions, toxic epidermal necrolysis, Stevens-Johnson syndrome, leukocytocla-sitc vasculitis, recurrent fever with exanthema and, of course, the well-known gastric cytotoxicity. 

Non-selective NSAIDs [those that inhibit both cyclooxygenase-1 and -2 (COX-1 and COX-2)] cause gastric mucosal damage by two primary mechanisms (1) a direct toxic interaction and (2) systemic pharmacologic actions. 

NSAIDs are classified as non-selective (they inhibit COX-1 and COX-2) or selective (they inhibit only COX-2) based on degree of cyclooxygenase inhibition. COX-2 inhibition is responsible for anti-inflammatory effects, while COX-1 inhibition contributes to increased GI and renal toxicity associated with non-selective agents. Since the antiplatelet effect of non-selective NSAIDs is reversible, concurrent use may reduce the... 

NSAIDs are associated with gastrointestinal, renal, hepatic, and central nervous system toxicity and may increase blood pressure. NSAIDs that are selective for the cyclooxygenase-2 (COX-2) isozyme are less likely to cause gastrointestinal complications but may increase the risk of cardiovascular events. They are no more effective than nonselective NSAIDs. Selective agents should be reserved for patients at high risk of gastrointestinal complications and low risk for cardiovascular events. 

Acetaminophen may worsen kidney function and increase blood pressure.1516 Nevertheless, acetaminophen remains the preferred analgesic for mild to moderate pain in patients with hypertension or kidney disease owing to the greater risks associated with NSAID use.17 Monitoring specifically for these toxicities generally is unnecessary. 

Elucidation of the activities of individual COX isoforms led to the development of drugs that selectively inhibit the inducible form of the enzyme, COX-2. Thus COX-2 inhibitors were expected to minimize NSAID gastrointestinal toxicity and antiplatelet effects (see Fig. 55-3).19 A common misconception is that COX-2 inhibitors are more effective than nonselective NSAIDs in relieving pain and inflammation. In clinical trials, patients experienced similar levels of pain relief with COX-2 inhibitors and nonselective NSAIDs. 

Animal studies indicate that the pathogenesis of NSAID small intestinal toxicity involves multiple interactions dependent on enterohepatic circulation, epithelial permeability, neutrophil infiltration and bacterial infection [233]. Several investigations [234-238] have suggested that bacterial flora may play a role in the pathogenesis of NSAID bowel injury and Robert and Asano [239] did show more than 25 years ago that germ-free rats are resis-... 

Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of therapy because of their excellent efficacy and minimal toxicity with shortterm use. There is little evidence to support one NSAID as more efficacious than another, and three drugs (indomethacin, naproxen, and sulindac) have FDA approval for this indication (Table 1-1). 

Acetaminophen is usually well tolerated, but potentially fatal hepatotoxicity with overdose is well documented. It should be used with caution in patients with liver disease and those who chronically abuse alcohol. Chronic alcohol users (three or more drinks daily) should be warned about an increased risk of liver damage or GI bleeding with acetaminophen. Other individuals do not appear to be at increased risk for GI bleeding. Renal toxicity occurs less frequently than with NSAIDs. 

Selection of an NSAID depends on prescriber experience, medication cost, patient preference, toxicities, and adherence issues. An individual patient should be given a trial of one drug that is adequate in time (2 to 3 weeks) and dose. If the first NSAID fails, another agent in the same or another chemical class can be tried this process may be repeated until an effective drug is found. Combining two NSAIDs increases adverse effects without providing additional benefit. 

NSAIDs are modestly effective for reducing the frequency, severity, and duration of migraine attacks, but potential GI and renal toxicity limit daily or prolonged use. 

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