Pharmacology - Drugs Used In Gout

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Classes of Drugs Used in Gout

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1. Management of acute attacks of gouty arthritis
- goal = control pain via drugs that limit joint inflammation

2. Long-term management of chronic gout
- goal = achieve normal conc of plasma urate by using drugs that either decrease synthesis of urate or increase excretion rate of urate

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Management of Acute Gout

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Agents that suppress leukocyte recruitment and activation:
- NSAIDs
- Colchicine
- Glucocorticoids

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NSAIDs

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- first-line drugs for acute gout
- Indomethacin most often used
- Aspirin = contraindicated (b/c it competes w/ uric acid for the organic acid secretion mechanism in the proximal tubule of the kidney)
- AE: bleeding, salt/water retention, renal insufficiency
- COX-2 selective inhibitors potentially useful b/c they may decrease risk of GI bleeding

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Colchicine

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MOA: binds to tubulin preventing formation of microtubules --> disrupts cell fxn like mobility of granulocytes so decreases their migration into area
- Also blocks cell division by disrupting the mitotic spindle
- Also inhibits synthesis and release of leukotrienes
- Must be admin within 24-48 hrs of onset of attack to be effective
- AE: DIARRHEA, nausea, vomit, abd pain; chronic: myopathy, neutropenia, aplastic anemia, alopecia
- should NOT be used in pregnancy
- b/c of diarrhea not as good as NSAIDs

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Glucocorticoids

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- powerful anti-inflammatory and immunosuppressive effects
- widespread AE when given systemically, so are used in tx of acute polyarticular gout or when there are contraindications (ex renal insufficiency) to other therapies
- Acute attack of gout in single joint that is unresponsive to NSAIDs or colchicine --> depot preparations of a glucocorticoid injected directly into site of inflammation

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Management of Chronic Gout

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Agents that lower plasma urate concentration
- Via decreasing uric acid synthesis
-- Allopurinol

- Via enhancing uric acid excretion (uricosuric agents)
-- Probenecid
-- Sulfinpyrazone

- Via enhancing uric acid metabolism
-- Rasburicase

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Allopurinol

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- decreases uric acid synthesis
- MOA - inhibition of xanthine oxidase (via comp inhibition of last two steps of uric acid biosynthesis)
- facilitates dissolution of tophi & prevents dev't/progression of chronic gouty arthritis by lowering uric acid conc below limit of solubility
- formation of uric acid stones disappears --> prevents dev't of nephropathy
- acute attacks of gouty arthritis can occur during early months of tx so an NSAID or colchicine is coadmin for first 4-6 months

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Allopurinol - AE

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- AE: HS rxn (skin rash) which rarely --> Steven Johnson syndrome
- pts who get a rash should stop drug

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Allopurinol - Drug Interactions

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- Mercaptopurine (anticancer drug) and Azathioprine (immunosuppressant) are purine analogues that are metabolized by xanthine oxidase
- if xanthine oxidase is inhibited by allopurinol, toxic levels of these drugs can occur
- dose reduction of drugs is required

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Uricosuric Agents - MOA

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- urate reabsorption: first step is uptake from tubular fluid by a transporter that exchanges urate for either an organic or an inorganic anion
- uricosuric drugs compete w/ urate for the brush-border transporter, thereby inhibiting its reabsorption via the urate-anion exchanger system

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Probenecid

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- uricosuric agent
- concomitant colchicine or NSAIDs are indicated for early in the course of therapy to avoid precipitating attack of gout
- should NOT be used in pts w/ nephrolithiasis or w/ overproduction of uric acid
- inneffective in pts w/ renal insufficiency
- b/c it inhibits secretion of most anions, dose of other drugs excreted this way should be reduced
- low-dose aspirin may antagonize probenecid action

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Probenecid - AE

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- mild GI irritation (caution in pts w/ history of peptic ulcer)

- HS rxn (usually mild)

- liberal fluid intake needed to minimize risk of renal stones

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Sulfinpyrazone

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- uricosuric agent
- rarely used today
- ineffective in pts w/ renal insufficiency
- AE: GI irritation (more frequent than probenecid), HS rxns (less frequent), depression of hematopoiesis
- shouldnt be used in pts w/ underlying blood dyscrasias
- liberal fluid intake should be maintained to minimize risk of renal stones

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Sulfinpyrazone - Drug Interactions

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- Sulfinpyrazone inhibits warfarin metabolism --> serious bleeding can occur

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Thiazide diuretics & Immunosuppressant agents (ex cyclosporine) effects on urate excretion

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- thiazide diuretics and immunosuppressant agents (ex cyclosporine) impair urate excretion and thereby increase the risk of gout

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Rasburicase

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- agent that enhances uric acid metabolism
- uricase is an enzyme found in other mammals that oxidizes uric acid to allantoin which is soluble and easily excreted by the kidney
- in cancer chemo, rapid lysis of tumor cells --> liberate free nucleotides --> increase plasma urate ; called tumor lysis syndrome and it can cause massive renal injury
- rasburicase is a recomb version of Aspergillus uricase

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Rasburicase - Uses

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- Indicated for initial management of elevated plasma uric acid levels in pediatric pts w/ leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy