Pathophysiology of gout
Gout is characterized by high levels of uric acid in blood, which may lead to deposition of sodium urate crystals in tissues like joints & kidney
Sodium urate is the end product of purine metabolism
Deposition of urate crystals initiates inflammatory proc
Acute vs. chronic gout
Management of acute gout involves pain relief & control of joint inflammation (NSAIDs, colchicine, glucocorticoids)
Management of chronic gout involves decreasing plasma urate concentration to normal levels (allopurinol, probenecid, sulfinpyrazone, rasbur
NSAIDs
First line treatment of acute gout
Indomethacin is most common, other NSAIDs also effective
Aspirin is contraindicated
NSAIDs (adverse effects)
Bleeding, salt/water retention, renal insufficiency
Adverse cardiovascular effects (coxibs)
Aspirin & gout
Aspirin is contraindicated in gout because it competes with uric acid for secretion in the proximal tubule of the kidney (at low doses)
Colchicine (MOA)
Binds to tubulin, inhibiting polymerization & formation of microtubules, thereby disrupting cellular functions & division
Also inhibits synthesis & release of leukotrienes
Colchicine (clinical uses)
Alleviates the pain of acute gout
Not to be used in pregnancy
Use with caution in patients with hepatic, renal, or cardiovascular disease
Colchicine (adverse effects)
Nausea, vomiting, abdominal pain, diarrhea
Myopathy, neutropenia, aplastic anemia, alopecia
Glucocorticoids
Powerful anti-inflammatory & immunosuppressive effects
Used in treatment of acute polyarticular gout or when there are contraindications to other therapies
Injected directly into site of inflammation as depot preparation
Allopurinol
Purine analog
Eventually lowers uric acid concentration below solubility limit
Used for treatment of chronic hyperuricemia
Coadministered with NSAID or colchicine in first 4-6 months to reduce the attacks of acute gout caused by increased mobilization of
Allopurinol (MOA)
Competitive inhibitor of last 2 steps of uric acid synthesis (catalyzed by xanthine oxidase)
Allopurinol (adverse effects)
Hypersensitivity (skin rashes), may progress to Steven-Johnson syndrome (rare)--all patient with cutaneous reaction should discontinue drug
Allopurinol (drug interactions)
Anticancer drug mercaptopurine & immunosuppressant azathioprine are also purine analogs which are metabolized by xanthine oxidase-->administration of allopurinol requires dose reduction in those drugs due to increased metabolite levels in body
Uricosuric agents
Increase the rate of excretion of uric acid
Ex. probenecid, sulfinpyrazone
Probenecid
Used in treatment of chronic hyperuricemia
Coadministered with colchicine or NSAIDs in early therapy to avoid precipitating acute attack of gout
Ineffective in patients with renal insufficiency
Probenecid (MOA)
Competes with urate for reabsorption transporter in tubules of kidneys, shifting the balance between renal excretion & formation of urate
Probenecid (contraindications)
Not to be used in patients with nephrolithiasis or overproduction of uric acid
Probenecid (cautions)
Inhibits secretion of most anions (reduce dose of other drugs excreted by this pathway)
Aspirin may antagonize action
Probenecid (adverse effects)
Mild GI irritation (caution in patients with history of peptic ulcer)
Hypersensitivity
Must maintain liberal fluid intake to prevent renal stones
Sulfinpyrazone
Used in treatment of chronic hyperuricemia (rarely now)
Ineffective in patients with renal insufficiency
Sulfinpyrazone (MOA)
Competes with urate for reabsorption transporter in tubules of kidneys, shifting the balance between renal excretion & formation of urate
Sulfinpyrazone (adverse effects)
GI irritation (more than probenecid)
Hypersensitivity (less than probenecid)
Depression of hematopoiesis (do not use in patients with underlying blood dyscrasias)
Must maintain liberal fluid intake to prevent renal stones
Sulfinpyrazone (drug interactions)
Inhibits warfarin metabolism (can lead to serious bleeding)
Rasburicase
Produced in animals, not humans
Used for initial management of elevated plasma uric acid in pediatric patients with leukemia, lymphoma, or solid tumors where anticancer therapy causes tumor lysis & hyperuricemia
Rasburicase (MOA)
Enzyme which oxidizes uric acid to allantoin, which is easily excreted by the kidney