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GOUT
• 55 y/o male• 12 hours “pain in my big toe & ankle”• went to bed last night feeling fine• felt as if had broken toe this morning• similar problems in right ankle & left wrist
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Case presentation
• lab studies– serum uric acid = 11.5 mg/dl– 24-hour uric acid excretion = 300 mg
• left foot X-rays show bony erosion with overhanging edge, medial side of first metatarsal head
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Uric acid metabolism
cell breakdown
dietary intake purine bases
hypoxanthine
xanthine
uric acid
xanthine oxidase
catalyzes hypoxanthine to
xanthine & xanthine to uric
acid
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Renal handling of uric acid
•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory reabsorption
•net excretion
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Classifying hyperuricemia
• serum uric acid level• urine uric acid excretion (24-hour)
overproduction underexcretionserum uric acid high highurine uric acid high normal/low
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Crystal-induced inflammation
PMN is critical component of crystal-
induced inflammation
crystal deposition
hyperuricemia
protein binding
receptor binding
cytokine release
influx of PMN’s
crystals engulfed
inflammation
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Drugs used to treat gout
allopurinol
probenecid
Urate oxidase
steroids
NSAID’s
colchicine
Acute Arthritis Drugs
Urate Lowering Drugs
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Urate Lowering Drugs
• prevents arthritis, tophi & stones by lowering total body pool of uric acid
• not indicated after first attack• initiation of therapy can worsen or bring on
acute gouty arthritis• no role to play in managing acute gout
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Colchicine - plant alkaloid
colchicum autumnale
(autumn crocus or meadow saffron)
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Colchicine
• mechanism of action poorly understood???inhibits microtubule polymerization by bindingto tubulin, one of the main constituents ofmicrotubules
• reduces inflammatory response to depositedcrystals
• diminishes PMN phagocytosis of crystals• blocks cellular response to deposited crystals
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Colchicine adverse effect • Typical side effects of moderate doses may
include gastrointestinal upset, diarrhea, andneutropenia.
• High doses can also damage bone marrow,lead to anemia, and cause hair loss. All ofthese side effects can result from inhibition ofmitosis, which may include neuromusculartoxicity and rhabdomyolysisadverse effects dose-related & more common whenpatient has renal or hepatic disease
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Colchicine
• is an alternative for those unable to tolerate NSAIDs in gout.
• more useful for daily prophylaxis (low dose)– prevents recurrent attacks– colchicine 0.6 mg qd - bid
• declining use in acute gout (high dose)
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Allopurinol and Febuxostat
• Inhibitors of xanthine oxidase• effectively blocks formation of uric acid
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Uric acid metabolism
cell breakdowndietary intake purine bases
hypoxanthine
xanthine
uric acid
allopurinol inhibits
xanthine oxidase
allopurinoallopurinol
oxypurinol
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Allopurinol effects
Effect of Allopurinol on Total Serum Levels of Xanthine + Hypoxanthine
Normal 0.15 mg/dl
Allopurinol 0.35 mg/dl
saturation level of xanthine & hypoxanthine > 7 mg/dl
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Allopurinol
• once daily dosing• lowers serum uric acid levels• lowers urine uric acid levels• side effects rare, diarrhea, nausea, abnormal liver testsrash
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Allopurinol and Febuxostat
• Are relatively contraindicated withconcomitant use of theophylline andchemotherapeutic agents, namelyazathioprine and 6-mercaptopurine, becauseit could increase blood plasma concentrationsof these drugs, and therefore their toxicity.
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Allopurinol – black box warning
THIS IS NOT AN INNOCUOUS DRUG. IT IS NOT RECOMMENDED FOR THE TREATMENT OF ASYMPTOMATIC HYPERURICEMIA
ALLOPURINOL SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS OF AN ALLERGIC REACTION
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Urate oxidase
• uricase speeds resolution of tophi • Rasburicase acute hyperuricemia in patients
receiving chemotherapy.
• A PEGylated form of urate oxidase, egloticase, was FDA approved in 2010 for the treatment of chronic gout in adult patients refractory to "conventional therapy"
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Uricosuric therapyprobenecid
• blocks tubular reabsorption of uric acid• enhances urine uric acid excretion• increases urine uric acid level• decreases serum uric acid level
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probenecid
• moderately effective• increases risk of nephrolithiasis• not used in patients with renal disease• frequent, but mild, side effects• some drugs reduce efficacy (e.g., aspirin)
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Renal handling of uric acid
•glomerular filtration
•tubular reabsorption
•tubular excretion
•post-secretory reabsorption
•excretion