Nonsteroidal Antiinflammatory Drugs (NSAIDs)Rx

Indications: RA, juvenile idiopathic arthritis, osteoarthritis, ankylosing spondylitis, spondyloarthropathy, gout, pain

Mechanism of Action: Anti-inflammatory and antiplatelet properties are mediated by the inhibition of COX enzymes and decreased production of prostaglandins. Drugs that inhibit COX-2 are anti-inflammatory because they decrease the formation of prostaglandins by activated cells. Drugs that inhibit COX-1 decrease the production of thromboxane and thus decrease platelet activation. Because COX-1 contributes to the maintenance of gastric mucosa, blocking COX-1 increases the risk of peptic ulceration. NSAIDs are classified according to whether they inhibit both COX-1 and COX-2 (nonselective NSAIDs) or whether they are more selective for COX-2 and spare COX-1 (COX-2 selective NSAIDs or coxibs). Nonacetylated salicylates such as salsalate are weak inhibitors of COX, and their mechanism of action is poorly understood.

Contraindications: Hypersensitivity to NSAIDs, GI ulceration, hemorrhagic state, and last trimester of pregnancy (risk of premature closure of ductus arteriosus), severe renal impairment, heart failure, hyperkalemia,postoperative pain after CABG surgery

Precautions: Increased risk of MI and stroke. Fluid retention may aggravate heart failure and hypertension. Use with caution or avoid in patients at high risk of GI bleeding (i.e., previous GI bleeding, peptic ulcer, elderly, concurrent corticosteroid or warfarin treatment); if benefit outweighs risk, a nonselective NSAID with a proton pump inhibitor or misoprostol prophylaxis or a COX-2 selective drug should be used. Administer with food. Use with caution in asthma, bleeding disorders, and hepatic or renal disease. Can aggravate hypertension. Caution in elderly – increased risk of side effects.

Monitoring: Monitor hematocrit, creatinine, liver enzymes periodically (e.g., 1 month after starting and then every 3–6 months). In patients at high risk of renal impairment (diuretics, receiving ACE inhibitors, edematous states, heart failure, renal failure, diabetes), monitor renal function more closely after starting treatment.

Pregnancy Risk: Most NSAIDs category C, but category D in third trimester
Arthrotec-category X because of misoprostol

Adverse Effects
Common: GI irritation (dyspepsia, reflux, epigastric pain), rash, fluid retention, hypertension
Less common: GI ulceration, hemorrhage, gastric outlet obstruction, hepatitis with elevations of liver enzymes, hypersensitivity (anaphylaxis, asthma, urticaria, angioedema) particularly in patients with nasal polyps, exfoliative dermatitis, hematologic toxicity (agranulocytosis, anemia, leukopenia, thrombocytopenia), renal toxicity (interstitial nephritis, proteinuria, nephrotic syndrome, acute renal failure, hyperkalemia), CNS toxicity (dizziness, drowsiness, insomnia, nervousness), CV toxicity (stroke, MI), tinnitus, aseptic meningitis (particularly in SLE)

Drug Interactions
Anticoagulants: Increased hemorrhagic risk with anticoagulants and thrombolytics.
NSAIDs: Increased risk of GI side effects if combinations of NSAIDs used.
Aspirin: A nonselective NSAID such as ibuprofen taken before aspirin blunted the long-term antiplatelet effects of aspirin perhaps because ibuprofen blocked the access of aspirin to its binding site on the COX-1 enzyme. If patients took aspirin first and then ibuprofen, the long-term antiplatelet effects of aspirin were not altered. A COX-2 selective drug did not affect the antiplatelet effect of aspirin, irrespective of whether it was taken before or after aspirin.
Methotrexate: Increased levels of MTX with many NSAIDs, but with the MTX doses used in RA, usually not of clinical importance.
Cyclosporine: May increase risk of nephrotoxicity.
Diuretics: Decreased effects of thiazides and furosemide, increased renal toxicity with diuretics, increased risk of hyperkalemia with K+-sparing diuretics.
Lithium: Increased lithium levels.
Antihypertensive agents: Antihypertensive effect reduced.
Warfarin, novel anticoagulants and antiplatelet agents: Increased risk of bleeding.

Patient Instructions: Take with food. Discontinue and seek medical advice if unusual bleeding occurs.

Comments:  See individual NSAIDs for additional information. Most NSAID side effects are class-effects. Consider risk-benefit ratio before prescribing. Use lowest effective dose and shortest duration of therapy. The increased CV risk appears smaller with naproxen than other NSAIDs. Prophylax against GI ulcers and bleeds (usually with a PPI) in high-risk patients who cannot do without an NSAID.

BIBLIOGRAPHY

FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345:433–442. PMID:11496855