DRUGS USED IN GOUT

 Uric acid – major end product of purine metabolism

 Uricase
o Present in mammals (uric acid  allantoin)
o Absent in humans
 Treatment goals
o relieve acute gouty attacks
o prevent recurrent gouty episodes and urate lithiasis

PATHOPHYSIOLOGY

 Urate crystals activate NLRP3, resulting in release of prostaglandins and lysosomal enzymes by synoviocytes.
Attracted by these chemotactic mediators, polymorphonuclear leukocytes migrate into the joint space and
amplify the ongoing inflammatory process. In the later phases of the attack, increased numbers of mononuclear
phagocytes (macrophages) appear, ingest the urate crystals, and release more inflammatory mediators.

DRUGS

1. COLCHICINE
o An alkaloid isolated from the autumn crocus, Colchicum autumnale.
o Pharmacokinetics
 Peak plasma levels: 2 hours
 Half-life: 9 hours
 Excreted via GI and urine
o Pharmacodynamics
 Relieves pain within 12-24 hours
 MOA: Inhibition of tubulin polymerization and cell mitosis
 Binding to the intracellular protein tubulin, thereby preventing its polymerization into
microtubules
 Leading to the inhibition of leukocyte migration and phagocytosis
 Also inhibits the formation of leukotriene B4 and IL-1β
o Indications
 Used between attacks (the “intercritical period”) for prolonged prophylaxis
 Also used to treat and prevent pericarditis, pleurisy, and coronary artery disease, probably due
to its anti-inflammatory effect
o Adverse effects
 Diarrhea
 Nausea, vomiting, and abdominal pain
o Dosage
 0.6 mg one to three times daily
 For terminating a gouty attack, a regimen of 1.2 mg followed by a single 0.6-mg oral dose was as
effective as higher dose regimens, and adverse events were less frequent.
2. NSAIDS
o MOA
 Inhibiting prostaglandin synthase
 Inhibit urate crystal phagocytosis
o Aspirin
 At ≤2.6 g/d  causes renal retention of uric acid at low doses
 At >3.6 g/d  uricosuric
o Indomethacin
 Commonly used in the initial treatment of gout as a replacement for colchicine
 50 mg TID
 When response occurs, dosage is reduced to 25 mg three times daily for 5–7 days

o All other NSAIDs except aspirin, salicylates, and tolmetin have been successfully used to treat acute
gouty episodes.

3. URICOSURIC AGENTS
o Chemistry and Pharmacokinetics
 Excreted via kidneys
o Pharmacodynamics
 MOA: inhibit active transport sites for reabsorption and secretion in the proximal renal tubule
so that net reabsorption of uric acid in the proximal tubule is decreased

o With the ensuing increase in uric acid excretion, a predisposition to the formation of renal stones is
augmented rather than decreased
 Therefore, the urine volume should be maintained at a high level, and at least early in treatment,
the urine pH should be kept above 6.0 by the administration of alkali.

o Indications
 Allopurinol or febuxostat is contraindicated
 Tophi are present

o Adverse effects
 GI irritation
 Nephrotic syndrome has occurred after the use of probenecid

o Contraindications and Cautions

 Maintain a large urine volume to minimize the possibility of stone formation

o Dosage
 Probenecid: 0.5 g orally daily in divided doses, progressing to 1 g daily after 1 week
 Sulfinpyrazone: 200 mg orally daily, progressing to 400–800 mg daily
 Should be given in divided doses with food to reduce adverse GI effects
4. ALLOPURINOL
o Preferred and standard-of-care therapy for gout during the period between acute episodes

o Chemistry and Pharmacokinetics

 An isomer of hypoxanthine
 Half-life: 1-2 hours
 Allopurinol  (oxidized by xanthine oxidase)  ALLOXANTHINE, retains the capacity to inhibit
xanthine oxidase and has a long enough duration of action so that allopurinol is given only once a
day

o Indications
 First-line agent for the treatment of CHRONIC GOUT in the period between attacks and it tends
to prolong the intercritical period

o Adverse effects
 GI intolerance (including nausea, vomiting, and diarrhea), peripheral neuritis and necrotizing
vasculitis, bone marrow suppression, and aplastic anemia
 Hepatic toxicity and interstitial nephritis have been reported
 Pruritic maculopapular lesions occurs in 3%

o Contraindications and Cautions

 Allopurinol may also increase the effect of cyclophosphamide (chemo drug)
 Inhibits the metabolism of probenecid and oral anticoagulants
 May increase hepatic iron concentration

o Dosage
 Initial: 50–100 mg/d
 titrated upward until serum uric acid is below 6 mg/dL

5. FEBUXOSTAT
o Chemistry and Pharmacokinetics
 Half-life of 4–18 hours
 Metabolized in the liver
 Excreted via urine

o Pharmacodynamics
 Selective inhibitor of xanthine oxidase
 Reducing the formation of xanthine and uric acid without affecting other enzymes in the purine
or pyrimidine metabolic pathway

o Indications
 40 or 80 mg for the treatment of chronic hyperuricemia in gout patients

o Adverse effects
 Liver function abnormalities, diarrhea, headache, and nausea

o Dosage
 Starting dose: 40 mg daily
6. PEGLOTICASE
o Chemistry
 Recombinant mammalian uricase attached to methoxy polyethylene glycol (mPEG) to prolong
the circulating half-life and diminish immunogenic response

o Pharmacokinetics and Dosage

 8 mg every 2 weeks administered as an intravenous infusion
 Achieves a peak decline in uric acid level within 24–72 hours
 Half-life: 6-14 days

o Pharmacodynamics
 Urate oxidase enzyme converts uric acid to allantoin
 Should not be used for asymptomatic hyperuricemia

o Adverse effects
 Anaphylaxis
 Oral urate-lowering agents should be avoided in order not to mask the loss of pegloticase efficacy
 Nephrolithiasis, arthralgia, muscle spasm, headache, anemia, and nausea may occur
 Avoided in patients with G6PD  Uricase forms hydrogen peroxide causing hemolytic anemia