• Nonacetylated Salicylates:
    • Drug list:
      • Magnesium choline salicylate
      • Sodium salicylate
      • Salicylsalicylate
    • Properties:
      • effective anti-inflammatory agents
      • probably less effective analgesics compared to aspirin
      • poor cyclooxygenase inhibitors compared aspirin, suggesting that these drugs may be preferable, compared to aspirin, in patients with:
        •  asthma
        •  bleeding predisposition
        •  renal dysfunction (possibly -- requires close monitoring)

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Diflusnisal

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Other Nonsteroidal Anti-inflammatory Agents

  • Overview
    • Development of new drug stimulated by side effects, particularly gastric irritation associated with large dose salicylate use
    • Primary clinical target: rheumatoid arthritis or osteoarthritis; in addition to other indications.

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Chemistry

Diverse Classes

Drug Classes: Examples
propionic acid derivative ibuprofen
pyrrolealkanoic acid derivative tolmetin
phenylalkanoic acid derivative flubiprofen
indole derivative indomethacin
pyrazolone derivative phenylbutazone
phenylacetic acid derivative diclofenac
fenamate meclofenamate acid
oxicam piroxicam
naphthylacetic acid prodrug nabumetone

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  • Pharmacodynamics:NSAIDs
    • Newer NSAIDs: similar in mechanism to aspirin --
    • Mechanism of action: innovation of prostaglandin biosynthesis
    • Additional mechanisms possible:
      •  chemotaxis inhibition
      •  interleukin 1 down-regulation
      •  interference with calcium-mediated intracellular processes
    • Unlike aspirin:
      • reversible inhibitors of cyclooxygenase
      • variable COX-I 1 -- COX-II selectivity
        • Celecoxib (Celebrex) is an example of a nonsteroidal antiinflammatory drug that works as a result of prostaglandin synthesis inhibition (inhibition COX-II)
    • Some lipoxygenase synthesis inhibition
    • Indomethacin & diclofenac:
      • synthesis reduction -- prostaglandins; leukotrienes
    • Mechanism of Inflammation Reduction:NSAIDs
      1. decrease in granulocyte, basophils, mast cells mediator release
      2. decrease vessel sensitivity to bradykinin and histamine
      3. influence T lymphocytes lymphokine production
      4. reversal of vasodilatation
    • Properties: NSAIDs
      • analgesic
      • antipyretic
      • anti-inflammatory
      • platelet aggregation inhibition
      •  gastric irritation -- less gastric irritation compared aspirin
      •  nephrotoxicity

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  • Pharmacokinetics: NSAIDs
    • well absorbed
    • highly metabolized:
      • phase I +phase II
      • phase II alone: glucuronidation
    • Excretion: renal -- primary
      • biliary excretion/enterohepatic circulation
    • highly protein-bound (principally albumin)
    • Chemical issues:
      • some NSAIDs:
        • racemates (e.g. ibuprofen)
        • single enantiomer (e.g. naproxen)
        • no chiral center (e.g., diclofenac)

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Ibuprofen

  • Properties:ibuprofen
    • derivative phenylpropionic acid
    • rapidly cleared
    • highly protein-bound
    • high doses required for bolts anti-inflammatory as well as analgesic effects
    • highly hepatically metabolize; little excreted unchanged
    •  Gastrointestinal irritation/bleeding -- less frequent than with aspirin
    • Total anti-inflammatory effect: reduced if ibuprofen is used concurrently with aspirin
  •  Contraindications:ibuprofen
    • patients with nasal polyps
    •  angioedema
    •  aspirin sensitivity -- bronchospasm
  •  Side effects:ibuprofen
    • gastrointestinal
    • tinnitus
    • aseptic meningitis (associated with systemic lupus erythematosus)
    • headache

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Naproxen & Fenoprofen

  • Properties:Naproxen & Fenoprofen
    • Naphthylpropionic acid compound
    • plasma protein-bound
    • Naproxen:
      • urinary excretion -- inactive glucuronide
      • naproxen competes with aspirin for plasma protein mining sites
      • prolongs prothrombin time
      • relatively safe/GI upsets frequency: 20%-40%
    • Fenoprofen:
      • propionic acid derivative
      • Of the NSAIDs, most likely to cause (still quite rare): interstitial nephritis
      • requires frequent dosing (qid)
  •  Adverse Effects (Naproxen/Fenoprofen)
    • Adverse effects/drug interactions --similar to naproxen, (effects less common been seen with aspirin) including:
      •  nephrotoxicity
      • gastrointestinal upsets
      • peripheral edema
      • rash
      • pruritus
      •  CNS/cardiovascular effects
      • tinnitus

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Flubiprofen

  • Properties:flubiprofen
    • propionic acid derivative
    • good synovial concentration
    • extensively metabolized; some enterohepatic recirculation
    • efficacy: similar to aspirin and other incidents
  • Clinical Use:flubiprofen
    • ankylosing spondylitis
    • rheumatoid arthritis
    • osteoarthritis
    • topical ophthalmic: inhibition of intraoperative miosis

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Ketoprofen

  • Properties: ketoprofen
    • propionic acid derivative
    • some inhibition of cyclooxygenase and lipoxygenase activity
    • Rapid absorption;
    • complete hepatic metabolism
    • effectiveness: equivalent to other NSAIDs & aspirin; not superior to other NSAIDs
  • Clinical Use/characteristics: ketoprofen
    • rheumatoid arthritis
    • osteoarthritis
    •  Major Adverse Effects: referable to the CNS & gastrointestinal tract

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Oxaprozin

  • Properties: Oxaprozin
    • propionic acid derivative
    • very long half-life -- once a day dosing
    • generally: similar benefits/adverse effects compared other NSAIDs
    • mildly uricosuric (maybe more useful in gout compared other NSAIDs)

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Diclofenac

  • Properties: Diclofenac
    • phenylacetic acid derivative (similar to flubiprofen and meclofenamate)
    • potent cyclooxygenase inhibitor -- following properties:
      •  anti-inflammatory
      •  analgesic
      •   antipyretic
    • Rapid absorption (oral dosing); half-life -- 1-2 hours
    • synovial fluid accumulation
    • better cyclooxygenase inhibitor compared to naproxen
  • Clinical Use/characteristics:Diclofenac
    • Chronic inflammatory conditions:
      •  rheumatoid arthritis
      •  osteoarthritis
    • Chronic musculoskeletal pain
    • Ophthalmic solution: prevention of postoperative ophthalmic inflammation
    •  Adverse effects (frequency -- 20%)
      • gastrointestinal disturbance
      • occult GI bleeding
      • gastric ulceration
      • transaminitis (increase serum amino transferase) occurs more frequently with diclofenac than with other NSAIDs

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Sulindac

  • Properties:Sulindac
    • sulfoxide prodrug
    • action metabolite: acetic acid derivative
    • effective form: sulfide derivative (following hepatic metabolism)
      • sulfide derivative excreted in bile-- reabsorbed from the intestine
      •  enterohepatic cycling accounts for 12-16 hour duration of action
  • Clinical Use: sulindac
    • Indications/Adverse Reactions:similar to other NSAIDs
    •  More serious reactions include:
      • Stevens-Johnson epidermal necrolysis syndrome
      • thrombocytopenia
      • agranulocytosis
      • nephrotic syndrome
      • cholestatic liver damage

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Tolmetin

  • Properties: tolmetin
    • pyrroleacetic acid derivative
    • Effective in juvenile & adult rheumatoid arthritis and osteoarthritis
    • short half-life; requires frequent administration
    • minimal/no enterohepatic circulation

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Etodolac

  • Properties: Etodolac
    • acetic acid derivative
    • well absorbed; good bioavailability; strongly bound to plasma proteins
    • similar to their NSAIDs (except for its pharmacokinetic properties)
    • possibly slightly less gastric toxicity (referencing ulcer disease)

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Nabumetone

  • Properties: Nabumetone
    • prodrug
    • ketone converted to acetic acid derivative
    • half-life: > 24 hours -- once-daily dosing
    • may be slightly less likely to cause gastrointestinal distress compared other NSAIDs

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Meclofenamate

  • Properties: Meclofenamate
    • fenamic acid derivative
    • short half-life
    • generally same adverse effect profile compared to other NSAIDs
      • causes increased oral anticoagulant effect
      •  contraindicated in pregnancy
      •  efficacy/safety: not establish in young children
      • treatment with meclofenamate should not exceed one-week
    • reasonable analgesic; less effective than aspirin in treating inflammation

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Piroxicam

  • Properties: Piroxicam
    • half-life: 40-80 hours; once-daily dosing or every other day
    • rapid absorption
    • primarily excreted as glucuronate conjugate
    • gastrointestinal upset: frequency = 20%
    • Other Adverse Effects:
      • dizziness
      • rash
      • headache
      • tinnitus
      • the dosages > 20 mg per day ® increased peptic ulcer incidence
    • Clinical Uses:piroxicam
      • ankylosing spondylitis
      • osteoarthritis
      • rheumatoid arthritis

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Primary Reference: Katzung, B. G. and Furst, D. E. Nonsteroidal Anti-Inflammatory Drugs; Disease-Modifying Antirheumatic Drugs; Nonopioid Analgesics; Drugs Used in Gout, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 578-602.
Lipsky, P.E. Rheumatoid Arthritis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1880-1888.
Agudelo, C.A. Gout in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton & Lange, 1996, pp 223-226.