Inflammation

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;

    • 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

  • 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

  •  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

Nonsteroidal Anti-inflammatory Drugs in Gout

  • Overview NSAIDS

  • Rationale:NSAIDS:

    • inhibition of urate crywstal phagocytosis

    • inhibition of prostaglandin synthase

    • Indomethacis is an initial treatment (agent most often used currently); it is an alternative to colchicine.  Other NSAIDs have been used in managing acute gouty arthritis with the exception of aspirin, salicylates and tolmetin.  Oxaprozin should not be used in patients with uric acid stones because oxaprozin lowers serum uric acid, thereby increasing uric acid excretion in the 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

  • Chemistry:uricosuric agents

    • Uricosuric drugs -- organic acids

    • Site of action: renal tubular anionic transport sites

  • Pharmacokinetics:uricosuric drugs

    • Probenecid: very slow metabolism; completely reabsorbed by renal tubules

    • Sulfinpyrazone (or active hydroxylase metabolite): rapid renal excretion

  • 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)

    •  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

 Allopurinol

  • Overview:allopurinol

    • Reduced uric acid synthesis by inhibiting xanthine oxidase

    • alternative to increasing uric acid excretion

  • Chemistry: allopurinol -- isomer of hypoxanthine

  • Pharmacokinetics:allopurinol

    • 80% absorbed after oral routes administration

    • allopurinol metabolized by xanthine oxidase ® alloxanthine, which also inhibits xanthine oxidase

  • 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

  • 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

  • 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%

  •  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.