NSAIDs: Ketoprofen and Diflunisal

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Ketoprofen:
  • Inhibits both COX and lipoxygenase
  • Concurrent administration of probenecid elevates ketoprofen levels and prolongs its plasma half-life
  • Not superior to other NSAIDs in clinical efficacy
  • Major adverse effects: GI tract and CNS
• Diflunisal:
  • Derived from salicylic acid, but not metabolized to salicylic acid or salicylate
  • Undergoes enterohepatic cycle with reabsorption of its glucuronide metabolite
  • Used in rheumatoid arthritis, cancer pain with bone metastases, and pain control in dental surgery
  • 2% diflunisal oral ointment is a clinically useful analgesic for painful oral lesions
• Flurbiprofen:
  • (S)(–) enantiomer inhibits COX non-selectively, also affects TNF-α and nitric oxide synthesis
  • Hepatic metabolism is extensive, with different metabolism of (R)(+) and (S)(–) enantiomers
  • Demonstrates enterohepatic circulation
  • Available in topical ophthalmic formulation for inhibition of intraoperative miosis
  • Adverse effect profile similar to other NSAIDs
• Ketorolac:
  • Promoted for systemic use mainly as an analgesic, not as an anti-inflammatory drug
  • Effective analgesic, used successfully to replace morphine in some situations
  • Given intramuscularly or intravenously, with an oral dose formulation available
  • When used with an opioid, may decrease the opioid requirement by 25-50%
  • Ophthalmic preparation available for ocular inflammatory conditions
  • Toxicities similar to those of other NSAIDs, with potential increased renal toxicity
• Nabumetone:
  • Converted to the active acetic acid derivative in the body
  • Given as a ketone prodrug that resembles naproxen in structure
  • Half-life of more than 24 hours permits once-daily dosing
  • Does not appear to undergo enterohepatic circulation
  • Renal impairment results in a doubling of its half-life and a 30% increase in the area under the curve
  • Other adverse effects mirror those of other NSAIDs
• Tolmetin:
  • Non-selective COX inhibitor
  • Efficacy and toxicity profiles similar to those of other NSAIDs, with exceptions:
    • Ineffective in the treatment of gout
    • May cause rare thrombocytopenic purpura
• Sulindac:
  • Reversibly metabolized to the active sulfide metabolite, which is excreted in bile and then reabsorbed from the intestine (enterohepatic cycling)
  • Inhibits the development of colon, breast, and prostate cancer in humans
  • Among the more severe adverse reactions, Stevens-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, and nephrotic syndrome have been observed
• Oxaprozin:
  • Has a very long half-life (50-60 hours)
  • Does not undergo enterohepatic circulation
  • Mildly uricosuric, making it potentially more useful in gout than some other NSAIDs
  • Otherwise, has the same benefits and risks as other NSAIDs

Choice of NSAID

• All NSAIDs, including aspirin, are about equally efficacious, with a few exceptions
• Tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs for ankylosing spondylitis
• NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness
• For example, the GI and renal side effects of ketorolac limit its use
• Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic
• For patients with renal insufficiency, non-acetylated salicylates may be best
• Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs

Acetaminophen

• Only over-the-counter non-anti-inflammatory analgesic commonly available in the United States
• Mechanism of analgesic action unclear
• Weak COX-1 and COX-2 inhibitor in peripheral tissues, which accounts for its lack of anti-inflammatory effect
• Evidence suggests that acetaminophen may inhibit a third enzyme, COX-3, in the CNS
• Effective for the same indications as intermediate-dose aspirin
• Useful as an aspirin substitute, especially in children with viral infections and in those with any type of aspirin intolerance
• Well absorbed orally and metabolized in the liver
• Half-life unaffected by renal disease
• Negligible toxicity in most persons, but dangerous hepatotoxin in overdose or with severe liver impairment
• Mechanism of toxicity involves oxidation to cytotoxic intermediates by phase I cytochrome P450 enzymes

Disease-Modifying Antirheumatic Drugs (DMARDs)

• Heterogeneous group of agents with anti-inflammatory actions in several connective tissue diseases
• Called disease-modifying drugs because some evidence shows slowing or even reversal of joint damage, an effect never seen with NSAIDs
• Called slow-acting antirheumatic drugs because it may take 6 weeks to 6 months for their benefits to become apparent
• Mechanisms of action complex, including:
  • Reducing the number of immune cells available to maintain the inflammatory response
  • Interfering with the activity of T lymphocytes, B lymphocytes, or macrophages
  • Inhibiting the action of tumor necrosis factor-α (TNF-α)
• Examples of DMARDs:
  • Cytotoxic drugs (e.g., methotrexate)
  • Sulfasalazine, hydroxychloroquine, cyclosporine, leflunomide, mycophenolate mofetil, abatacept
  • Biologic agents that inhibit the action of TNF-α (e.g., infliximab, adalimumab, etanercept)
  • Recombinant human interleukin-1 receptor antagonist anakinra
• Used in various rheumatic diseases, including rheumatoid arthritis, lupus erythematosus, arthritis associated with Sjögren's syndrome, juvenile rheumatoid arthritis, ankylosing spondylitis, and other immunologic disorders