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

This quiz covers the features and effects of nonsteroidal anti-inflammatory drugs, specifically ketoprofen and diflunisal, including their mechanism of action and adverse effects.