Medical Pharmacology Chapter 41:  Anti-inflammatory Agents

Nonsteroidal Anti-Inflammatory Drugs; Disease-Modifying Antirheumatic Drugs; Nonopioid Analgesics; Drugs Used in Gout

 

 

• 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)

• Diflusnisal

  • 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

• 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 and 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)

• 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

• Naproxen and Fenoprofen

  • Properties:Naproxen and 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

• 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

• Ketoprofen

  • Properties: ketoprofen

    • Propionic acid derivative

    • Some inhibition of cyclooxygenase and lipoxygenase activity

    • Rapid absorption;

    • Complete hepatic metabolism

    • Effectiveness: equivalent to other NSAIDs and aspirin; not superior to other NSAIDs

  • Clinical Use/characteristics: ketoprofen

    • Rheumatoid arthritis

    • Osteoarthritis

    • Major Adverse Effects: referable to the CNS and gastrointestinal tract

• 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)

• 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

• 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

• Tolmetin

  • Properties: tolmetin

    • Pyrroleacetic acid derivative

    • Effective in juvenile and adult rheumatoid arthritis and osteoarthritis

    • Short half-life; requires frequent administration

    • Minimal/no enterohepatic circulation

• 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)

• 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

• 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

• 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

      • Tnnitus

      • The dosages > 20 mg per day ® increased peptic ulcer incidence

    • Clinical Uses:  piroxicam

      • Ankylosing spondylitis

      • Osteoarthritis

      • Rheumatoid arthritis

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 and Lange, 1996, pp 223-226.