Nonselective NSAIDs have potentially important gastrointestinal, renal, and cardiovascular effects. Adverse gastrointestinal effects include dyspepsia, peptic ulcer disease, and bleeding. Renal adverse effects include acute renal failure due to renal vasoconstriction, worsening of underlying hypertension, and electrolyte and fluid abnormalities. Additionally, the risk of renal cell cancer may be increased. Cardiovascular effects include interference by some agents with the antiplatelet activity of aspirin, an effect on coronary risk, and worsening of heart failure.
Elevations of serum aminotransferases (transaminases) are commonly associated with NSAID use. However, these elevations are generally mild and reversible, and liver failure is quite rare. Reactions may be more common with some NSAIDs (eg, sulindac, diclofenac, and aspirin) and in patients on other hepatotoxic medications or with certain disorders, including systemic lupus and juvenile inflammatory arthritis. The potentially offending agent should be discontinued if the aminotransferases rise to greater than three times the upper limit of normal, if there is a fall in serum albumin, or if the prothrombin time is prolonged.
Pulmonary reactions are uncommon; they include bronchospasm and pulmonary infiltrates with eosinophilia. Bronchospasm can result from the condition “aspirin-exacerbated respiratory disease” (AERD), which appears related to cyclooxygenase (COX)-1 inhibition. Patients with AERD may have concomitant chronic rhinosinusitis and nasal polyposis; inflammation affecting the entire respiratory tract may be difficult to distinguish in some patients from anaphylaxis. Anaphylaxis to NSAIDs has also been reported and is assumed to be an IgE-mediated immunologic reaction.
Nonselective NSAIDs have several important hematologic effects. The antiplatelet effects of NSAIDs, which are due to inhibition of COX-1, lead to diminished production of thromboxane A2, resulting in decreased platelet aggregation. NSAIDs should, thus, be avoided in patients with preexisting platelet defects and should be withheld preoperatively for at least four to five times the drug half-life. Chronic aspirin therapy slightly increases the risk of hemorrhagic stroke. Use of nonselective nonsalicylate NSAIDs together with warfarin may increase the international normalized ratio (INR) and may increase bleeding risk due to the additional antiplatelet effect. Aplastic anemia has been most strongly associated with some of the early NSAIDs (eg, phenylbutazone and indomethacin); neutropenia is seen in less than 1 percent of patients.
Central nervous system side effects of NSAIDs include aseptic meningitis, psychosis, and cognitive dysfunction. Tinnitus is a common problem, particularly with high doses of salicylates, but can occur with any NSAID. Tinnitus is typically reversible upon cessation of drug therapy and is a good warning sign to identify some of those patients who are developing high blood levels of the drug.
Various skin reactions may develop in association with the use of NSAIDs. Severe, potentially life-threatening reactions such as toxic epidermal necrolysis and the Stevens-Johnson syndrome are uncommon. Morbilliform rashes and urticaria are also seen.
A small increased risk of nonunion in patients with bone fractures has been reported with the use of nonselective NSAIDs or COX-2 selective agents. However, a causal relationship has not been proven, and the effect of these drugs on fracture healing in humans is uncertain.