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 may lead to joint urate deposit formation and acute arthritis

  • Multiple causes of hyperuricemia

•  Clinical Manifestation: gout

  • Chronic hyperuricemia: may be associated with prolonged period without clinical evidence

  • Asymptomatic time frame may end with:

    • Sudden onset associated with 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

    • "Gout, acute tophaceous, gross"

      "Acute, tophoceous gout of the hand, with nodular deposits of urates in the intraphalangeal and phalangeal-metacarpal joints." (c) 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

    • 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

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)

•  Colchicine

  • Overview:  colchicine

    • Alkaloid

  • 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 microtubulesleads to 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

• 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 reduces urate pool size such that urate tophaceous deposits may be reabsorbed leading to arthritic relief with 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

  • 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 lead touric acid accumulation.

      •  This accumulation is 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%.

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.