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

    • 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)

• 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

• 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

• 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%.