Drugs used in the Management of Gout

  • Introduction, Disease definition, Etiology:
    •  Familial metabolic disease: recurring acute arthritic arthritis -- caused by monosodium urate deposition in joints and cartilage
    • Monosodium urate deposition associated with:
      • chronic hyperuricemia
      • monosodium urate deposition
      • periodic, recurrent arthritic attacks -- location:lower extremity
    •  Untreated: progression may occur to polyarticular destructive disease
      • Uric acid urolithiasis/urate nephropathy: frequency = 20%
    • Typically, chronic elevation of plasma urate: necessary for gout
      • 20% to 30% of patients: normal serum puree during acute attack
    • Chronic uricemia crystallization joint urate deposit formation acute arthritis
    • Multiple causes of hyperuricemia

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  •  Clinical Manifestation: gout
    • chronic hyperuricemia: may be associated with prolonged period without clinical evidence
    • Asymptomatic time frame may end with:
      • sudden onset -- first gouty attack
      • appearance of subcutaneous tophaceous deposits
      • urolithiasis-- may be associated with hematuria
    • Usual patient: --
      • male
      • between 40 and 60 years of age
      • experiences sudden onset, occurring in early-morning, of excruciating pain that the first metatarsophalangeal joint;

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    • Acute episodes may become more frequent and polyarticular
      • Progression may occur:
        • chronic inflammation (appearing like rheumatoid arthritis)
        • disease may be associated with general symptoms-- fever, stiffness, myalgias, polyarthralgias.
    • Differential diagnosis-- alternatives:
      •  infectious arthritis (including, gonococcal arthritis)
      •  Other crystal-induced arthropathies:
        1. calcium pyrophosphate deposition (pseudogout)
        2. hydroxyapatite deposition disease
        3. microcrystalline corticosteroid-induced arthropathy
        4. trauma

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Pharmacological Treatment

  • Mechanistic Basis: management of gout
  • Sequence of Pathophysiological Events:
    1. phagocytosis by synoviocytes of urate crystals
    2. Synoviocytes release:
      • prostaglandins
      • interleukin 1 (IL-1)
      • lysosomal enzymes
    3. These chemotactic mediators attract:
      • polymorphonuclear leukocytes into the joint space associated with enhancement of the ongoing inflammatory process
    4. Increased numbers of mononuclear phagocytes (macrophages):
      • enter the joint
      • ingest urate crystals
      • release additional inflammatory mediators
  • This sequence suggests most effective drugs would be those that suppress different phases of the inflammatory process (leukocyte activation)

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 Colchicine

  • Overview:colchicine
    • alkaloid (isolated from autumn crocus)
  • Pharmacokinetics:colchicine
    • readily absorbed following oral route administration
    • peak plasma levels: two hours
    • Drug metabolites: intestinal tract & urinary excretion
  • Pharmacodynamics: colchicine
    • Dramatic pain relief
    • Dramatic reduction of gouty arthritis (12-24 hours)
      • not associated with altered metabolism
      • not associated with altered urate excretion
      • not associated with other analgesic effects

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  • Mechanism of Action:colchicine
    •  binds to intracellular protein -- tubulin
    •  consequent inhibition of tubulin polymerization to form microtubules
    •  inhibition of leukocyte migration/phagocytosis;inhibition of leukotriene B4 formation.
  •  Indications for Clinical Use:colchicine
    • Effective in alleviating inflammation/pain associate with acute gouty arthritis
    • Colchicine: increased gout specificity compared to NSAIDs
    • Diarrhea, associated with colchicine: has led to NSAIDs being very frequently used instead
    • Colchicine preferred:
      • prophylaxis of recurring gouty arthritis
      • Prevention of acute Mediterranean fever

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  •  Adverse Effects:colchicine
    • Diarrhea (common)
    • nausea, vomiting, the bowel pain
    • Rarely: hair loss;bone marrow depression, peripheral neuritis, myopathy
    • Acute, very large colchicine doses (non-therapeutic):
      • bloody diarrhea, shock
      • hematuria, oligouria
      • CNS depression -- fatal
      • Supportive treatment indicated

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Nonsteroidal Anti-inflammatory Drugs in Gout

  • Overview:NSAIDs
    • Rationale: NSAIDs-
      • inhibit urate crystal phagocytosis
      • inhibit prostaglandin synthase
      • indomethacin:
        1. initial treatment (agent most often used currently)
        2. alternative to colchicine (treatment failure or excessive discomfort {diarrhea})
      • Many other NSAIDs have been used with success in managing acute gouty arthritis except:
        • aspirin
        • salicylates
        • tolmetin
      •  Oxaprozin should not be used in patients with uric acid stones because:
        • oxaprozin lowers serum uric acid, thereby increasing uric acid excretion in urine.

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Uricosuric Drugs

  • Overview:uricosuric drugs
    • Decreases total body urate pool in patients with tophaceous gout or those patients who experience increased frequency of gouty attacks.
    • Uricosuric agents should not be used in patients secreting large quantities of uric acid precipitate uric acid caliculi
    • Uricosuric drugs:
      • probenecid
      • sulfinpyrazone

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  • Pharmacodynamics:uricosuric drugs
    • Uric acid freely filtered (glomerulus)
      •  Both reabsorbed and secreted by proximal tubule middle segment.
      •  Uricosuric drugs (probenecid, sulfinpyrazone, large dose aspirin)space for influence active transport sites net proximal tubule uric acid reabsorption decreased
        • low-dose aspirin causes net uric acid retention by inhibiting secretory transporters should not be used for analgesia in gout patients
        • Secretion of other weak acids (e.g. penicillin) also reduced by uricosuric drugs
      •  Increased uric acid excretion urate pool size decreases urate tophaceous deposits may be reabsorbed (arthritic relief; bone remineralization)
      •  Note: increased renal uric acid excretion will increased likelihood of urate renal stone formation --
        • this risk can be minimized by insuring adequate urine volume and urine alkalinization (sodium bicarbonate)

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    •  Adverse Effects: probenecid & sulfinpyrazone
      • gastrointestinal irritation (sulfinpyrazone a little worse)
      • Probenecid: allergic dermatitis
      • Rash: either agent
      • Probenecid: nephrotic syndrome (rare)
      • Aplastic anemia -- both -- very rarely

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 Allopurinol

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  • Pharmacodynamics:allopurinol
    • Purine source -- mainly from:
      • amino acids
      • formate
      • carbon dioxide
    • Unincorporated purine ribonucleotides and those from nucleic acid degradation xanthine or hypoxanthine uric acid (oxidation step)
      •  last step: inhibited by allopurinol, leading to:
        • reduced plasma urate
        • reduced urate pool size
        • increased in xanthine and hypoxanthine levels -- both more soluble compounds

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  • Clinical Use/Issues:allopurinol
    • Probable long-term use for management of gout
    • Indications:
      • chronic tophaceous gout with enhanced tophi reabsorption when uricosuric agents are used
      • patients with gout when 24-hour urinary uric acid (on purine-free diet) > 600-700 mg
      • probenecid or sulfinpyrazone: cannot be used: adverse effect/allergic reaction/inadequate therapeutic effect
      • patients with recurring renal stones
      • patients with functional renal impairment
      • excessively high serum urate levels
    • Other Indications:
      • should be used prevent massive uricosuria following management of blood dyscrasia
      • antiprotozoal

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  • Adverse Effects:allopurinol
    • Increase risk of acute gouty arthritis early in allopurinol therapy as urate crystals move from tissue to plasma
    • Acute attacks may be prevented by using colchicine initially
      • alternatively: allopurinol may be used in combination with probenecid or sulfinpyrazone
    • Gastrointestinal disturbances: nausea, vomiting, diarrhea
    • Peripheral neuritis, necrotizing vasculitis, bone marrow depression, aplastic anemia (rarely)
    • Hepatic toxicity
    • Interstitial nephritis
    • Skin-reactive: puritic macropapular lesion: frequency 3%

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  •  Drug-Drug Interactions:allopurinol
    • increased effect of cyclophosphamide
    • inhibit probenecid & oral anticoagulants metabolism
    • may increase hepatic iron
    •  when chemotherapeutic mercaptopurines are being given concurrently, their dose must be reduced to about 25%.

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Primary References: 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.
Primary References:Agudelo, C.A. Gout in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton & Lange, 1996, pp 223-226.