Treatment For Gout

TREATMENT FOR GOUT


TREATMENT FOR GOUT

Introduction to Gout:

  • Characterized by elevated serum uric acid level.
  • Uric acid with low water solubility precipitates in joints, kidney & subcutaneous tissues.
  • Secondary hyperuricemia occurs.

2 mechanisms for secondary hyperuricemia:

1. Due to excessive uric acid production:

  • Eg: breakdown of proteins & nucleic acids during cancer chemotherapy).

2. Due to decreased uric acid excretion:

  • Eg: Use of thiazides, loop diuretics, ethambutol, clofibrate.

TREATMENT OF GOUT

Acute GOUT

Chronic GOUT

  • NSAID’s
  • Colchicine
  • Steroids
1. Drugs decreasing uric acid synthesis:

  • Purine based: Allopurinol.
  • Non-purine based: Febuxostat.

2. Drugs increasing uric acid secretion:

  • Probenecid
  • Sulfinpyrazone
  • Benzbromarone

3. Drugs increasing uric acid metabolism:

  • Rasburicase
  • Pegloticase

TREATMENT OF ACUTE GOUT:

  • Drugs: NSAID’s, Colchicine & Steroids.

Important drug details:

1. NSAIDs:

  • Indomethacin – DOC – Due to better tolerability.
  • Aspirin: Not preferred due to hyperuricemia.
  • Tolmetin: Ineffective.

2. Colchicine:

  • More effective & faster acting than NSAIDs.
  • Rarely used due to high toxicity.
  • MOA:
    • Acts by inhibiting granulocyte migration into inflamed joint.
    • Causes metaphase arrest.
  • Adverse effects:
    • Diarrhea – Most common & dose-limiting toxicity.
    • Cause kidney damage, myopathy & bone marrow depression.
  • Indications:
    • Prophylaxis of recurrent attacks of gout arthritis –
      • Daily colchicine dosage
    • In urate-lowering therapy –  
      • Suppresses gout attacks.
      • Due to abrupt change in serum uric acid precipitation.

3. Steroids:

  • Intra-articular corticosteroids used in refractory cases.

NEW ADVANCEMENTS:

  • IL-1 inhibitors:
    • Drugs: Anakinra, canakinumab & rilonacept.
    • Efficient for acute gout management.
    • Not FDA-approved.

TREATMENT OF CHRONIC GOUT:

Main strategy:

  • Decreasing serum uric acid –
    • By decreasing its synthesis.
    • By increasing its excretion & metabolism.

I) Drugs decreasing uric acid synthesis:

  • Drugs:
    • Purine based: Allopurinol.
    • Non-purine based: Febuxostat.

Individual drug description:

1. Allopurinol:

  • A newer hypoxanthine analog.
  • MOA: 
    • Decreases uric acid production, by inhibiting xanthine oxidase enzyme.
    • Metabolized by xanthine oxidase enzyme to alloxanthine.
    • Alloxanthine – Long acting inhibitor of xanthine oxidase.
  • Uses:
    • DOC for chronic gout in inter-critical period (between two acute attacks).
    • Combined with anticancer drugs – To decrease secondary hyperuricemia.
    • As an adjuvant to sodium stibogluconate in kala-azar treatment.
  • Drug interactions:
    • Dosage of 6-Mercaptopurine & azathioprine decreased on combination with allopurinol –
      • Since both are metabolized by xanthine oxidase.
    • Dose adjustment required in renal failure.
  • Contra-indications:
    • Acute Gout – 
      • Due to inhibitory effect of uric acid on cytokines release.
      • Also reduced uric acid aggravates inflammation.
  • Adverse effect:
    • Precipitation of acute gout attack (Most frequent)
    • Allopurinol hypersensitivity – Strong association with HLA–B*5801.
    • Drug rash (in 20% of patients) – Combined use of allopurinol & ampicillin.

2. Febuxostat:

  • Non-purine drug.
  • Administered without dose adjustment.
  • Causes abnormal liver function tests.

II) Drugs increasing uric acid excretion:

  • Also referred as “Uricosuric drugs”.
  • Drugs: Probenecid, sulfinpyrazone & benzbromarone.
  • MOA:
    • Acts as competitive inhibitors of uric acid reabsorption in proximal tubules.
  • Probenecid: Combined with penicillins, decreasing their renal excretion.
  • Contraindications:
    • Creatinine clearance is <50ml/min.
    • History of nephrolithiasis (uric acid or calcium stones).
    • Evidence of uric acid overproduction (> 800 mg of uric acid in a 24-hour urine collection).
  • Concurrent supply of abundant fluids & urinary alkalinizers advised –
    • Prevent uric acid crystal precipitation in kidney tubules.
    • Ineffective in presence of renal damage.

III) Drugs increasing uric acid metabolism:

  • Drugs: Rasburicase & Pegloticase.
  • Administered by i.v. route.
  • Indications: Only in patients with chronic gout refractory to other treatments.

Individual drug description:

  • Rasburicase:
    • Recombinant urate oxidase.
  • Urate oxidase (uricase):
    • An enzyme metabolizing insoluble uric acid to soluble allantoin in birds.
    • Absent in humans.
  • Pegloticase:
    • Drug is pegylated to increase duration of action.

Exam Important

  • Secondary hyperuricemia can occur due to excessive uric acid production or decreased uric acid excretion.
  • Drugs decreasing uric acid synthesis include Allopurinol & Febuxostat.
  • Allopurinol is a Purine based drug.
  • Febuxostat is a Non-purine based drug.
  • Drugs increasing uric acid secretion include Probenecid, Sulfinpyrazone & Benzbromarone.
  • Drugs increasing uric acid metabolism include Rasburicase & Pegloticase.
  • Indomethacin is DOC for acute GOUT, due to better tolerability.
  • Aspirin is not preferred for treatment of acute gout due to hyperuricemia.
  • Colchicine is more effective & faster acting than NSAIDs, useful for the treatment of GOUT.
  • Colchicine causes metaphase arrest.
  • Diarrhea is the most common & dose-limiting toxicity of colchicine.
  • Daily doses of Colchicine is used for prophylaxis of recurrent attacks of gout arthritis & also for urate-lowering therapy for suppressing gout attacks.
  • Main strategy for treatment of chronic gout includes decreasing serum uric acid, by decreasing its synthesis & by increasing its excretion & metabolism.
  • Allopurinol decreases uric acid production, by inhibiting xanthine oxidase enzyme.
  • Allopurinol is metabolized by xanthine oxidase enzyme to alloxanthine.
  • Alloxanthine is a long-acting inhibitor of xanthine oxidase.
  • Allopurinol is a DOC for chronic gout in inter-critical period (between two acute attacks).
  • Allopurinol is combined with anticancer drugs, to decrease secondary hyperuricemia.
  • Allopurinol is used as an adjuvant to sodium stibogluconate in kala-azar treatment.
  • Dosage of 6-Mercaptopurine & azathioprine decreased on combination with allopurinol, since both are metabolized by xanthine oxidase.
  • Allopurinol dose adjustment required in renal failure.
  • In acute gout, allopurinol is contraindicated, due to inhibitory effect of uric acid on cytokines release.
  • Most frequently allopurinol precipitates acute gout attack.
  • Uricosuric drugs includes probenecid, sulfinpyrazone & benzbromarone, competitively inhibiting uric acid reabsorption in proximal tubules.
  • Concurrent supply of abundant fluids & urinary alkalinizers advised for Probenecid, to prevent uric acid crystal precipitation in kidney tubules.
  • Rasburicase is a recombinant urate oxidase.
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