• 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)

• Properties:diflusnisal

  • salicylic acid derivative

  • not metabolized to salicylate or salicylic acid

  • analgesic + anti-inflammatory activity

  • minimal antipyretic action

•  Clinical Uses:diflusnisal

  • pain

  • osteoarthritis

  • rheumatoid arthritis

• 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.

Chemistry

Diverse Classes

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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

  • 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)

• 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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• 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

• 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

• 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

• 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)

• 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

• 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

• Properties: tolmetin

  • pyrroleacetic acid derivative

  • Effective in juvenile & adult rheumatoid arthritis and osteoarthritis

  • short half-life; requires frequent administration

  • minimal/no enterohepatic circulation

• 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)

• 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

• 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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• 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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