Drug Therapy of Gout
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Transcript of Drug Therapy of Gout
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Drug Therapy of Gout
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Drug therapy of gout
What Is Gout?
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Case presentation• 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• PMH of similar problems in right
ankle & left wrist
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Gout - acute arthritis
acute synovitis, ankle & first MTP
joints
The metatarsophalangeal articulations are the joints between the metatarsal bones of the foot and the proximal bones
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Gout - acute bursitis
acute olecranon bursitis
Bursitis is inflammation of the fluid-filled sac (bursa) that lies between a tendon and skin, or between a tendon and bone
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Gouty arthritis - characteristics• sudden onset• middle aged males• severe pain• distal joints• Intense
inflammation
• recurrent episodes• influenced by diet• bony erosions on Xray
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Monosodium urate crystals
polarized light red compensator
needle shape
negative birefringence
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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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Gouty arthritis - characteristics• sudden onset• middle aged males• severe pain• distal joints• intense
inflammation
• recurrent episodes• influenced by diet• bony erosions on
Xray• hyperuricemia
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Hyperuricemia
production excretion
hyperuricemia results when production exceeds excretion
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Hyperuricemiaproduction
excretion
net uric acid loss results when excretion exceeds production
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Chronic tophaceous gout
tophus = localized deposit of monosodium urate
crystals
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Gout - tophus
classic location of tophi on helix
of ear
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Gout - X-ray changesDIP (Distal interphalangeal joint) joint destructionphalangeal bone cysts
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Gout - X-ray changes
bony erosions
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Gout - cardinal manifestations
nephrolithiasis
nephropathy
arthritis tophi
HYPERURICEMIA
acute &
chronic
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Drug therapy of gout
The Role of Uric Acid in
Gout
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Uric acid metabolismcell
breakdowndietary 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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Gout - problems• excessive total body levels of uric acid
• deposition of monosodium urate crystals in joints & other tissues
• crystal-induced inflammation
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Treating acute gouty arthritis• colchicine• NSAID’s• steroids• rest, analgesia, ice, time
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Drugs used to treat gout
allopurinol
probenecid
febuxostat?
steroids
NSAID’s
colchicine
Acute Arthritis Drugs
Urate Lowering Drugs
rest + analgesia + time
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NSAID’s
•Indomethacin (Indocin) 25 to 50 mg four times daily•Naproxen (Naprosyn) 500 mg two times daily•Ibuprofen (Motrin) 800 mg four times daily•Sulindac (Clinoril) 200 mg two times daily•Ketoprofen (Orudis) 75 mg four times daily
Drugs used to treat gout
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Colchicine - plant alkaloid
colchicum autumnale
(autumn crocus or meadow
saffron)
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Colchicine• “only effective in gouty arthritis”• not an analgesic• does not affect renal excretion of uric
acid• does not alter plasma solubility of uric
acid• neither raises nor lowers serum uric acid
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Colchicine• Colchicine inhibits microtubule
polymerization by binding to tubulin, one of the main constituents of microtubules
• reduces inflammatory response to deposited crystals
• diminishes PMN phagocytosis of crystals• blocks cellular response to deposited crystals
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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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Colchicine - indications
Dose Indication
high treatment of acute gouty arthritis
low prevention of recurrent gouty arthritis
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Colchicine - toxicity• gastrointestinal (nausea, vomiting,
cramping, diarrhea, abdominal pain)• hematologic (agranulocytosis,
aplastic anemia, thrombocytopenia)• muscular weakness
adverse effects dose-related & more common when patient has renal or hepatic disease
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Gout - colchicine therapy• more useful for daily prophylaxis (low
dose)prevents recurrent attackscolchicine 0.6 mg qd - bid
• declining use in acute gout (high dose)
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Hyperuricemia - mechanisms
hyperuricemia
excessive production
inadequate excretion
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Urate-lowering drugs
net reduction in total body pool of uric acid
block production
enhance excretion
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Gout - urate-lowering therapy• 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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Drug therapy of gout
Drugs That Block Production of Uric Acid
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Uric acid metabolismcell
breakdowndietary intake
purine bases
hypoxanthine
xanthine
uric acid
xanthine oxidase
catalyzes hypoxanthine to xanthine & xanthine to
uric acid
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Allopurinol (Zyloprim™)• inhibitor of xanthine oxidase• effectively blocks formation of uric
acid• how supplied - 100 mg & 300 mg
tablets• pregnancy category C allopurinol
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Allopurinol - usage indications• management of hyperuricemia of
gout• management of hyperuricemia
associated with chemotherapy• prevention of recurrent calcium
oxalate kidney stones
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Allopurinol - common reactions• diarrhea, nausea, abnormal liver
tests• acute attacks of gout• rash
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Allopurinol - serious reactions• fever, rash, toxic epidermal necrolysis• hepatotoxicity, marrow suppression• vasculitis• drug interactions (ampicillin, thiazides,
mercaptopurine, azathioprine)• death
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Stevens-Johnson syndrome
target skin lesionsmucous membrane erosionsepidermal necrosis with skin detachment
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Allopurinol hypersensitivity• extremely serious problem• prompt recognition required• first sign usually skin rash• more common with impaired renal
function• progression to toxic epidermal necrolysis
& death
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Febuxostat• recently approved by FDA (not on market)• oral xanthine oxidase inhibitor• chemically distinct from allopurinol• 94% of patients reached urate < 6.0 mg/dl• minimal adverse events• can be used in patients with renal disease
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PEG-uricase• investigational drug• PEG-conjugate of recombinant
porcine uricase• treatment-resistant gout• uricase speeds resolution of tophi• further research needed
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Drug therapy of gout
Drugs That Enhance Excretion of Uric Acid
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Uricosuric therapy• probenecid• 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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Uricosuric therapy• moderately effective• increases risk of nephrolithiasis• not used in patients with renal
disease• frequent, but mild, side effects
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Uricosuric therapy• contra-indications
history of nephrolithiasiselevated urine uric acid levelexisting renal disease
• less effective in elderly patients
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Choosing a urate-lowering drug
hyperuricemia
excessive production
inadequate excretion
xanthine
oxidase inhibito
r
uricosuric agent
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Drug therapy of gout
Case Presentation
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Case presentation - therapyNSAID
steroid
colchicine (low-dose)
allopurinol
NSAID
days 1-10 days 11-365 days 365+