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

•  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

    • "Gout, acute tophaceous, gross"

      "Acute, tophoceous gout of the hand, with nodular deposits of urates in the intraphalangeal and phalangeal-metacarpal joints." Ó 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 (isolated from autumn crocus)

  • Pharmacokinetics:  colchicine

    • Readily absorbed following oral route administration

    • Peak plasma levels:   two hours

    • Drug metabolites:   intestinal tract and 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

• 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 and 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 and 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 and Lange, 1996, pp 223-226.