Drug Therapy of Gout

Drug therapy of goutWhat Is Gout?

Case presentation55 y/o male12 hours pain in my big toe & anklewent to bed last night feeling finefelt as if had broken toe this morningPMH of similar problems in right ankle & left wrist

Gout - acute arthritisacute synovitis, ankle & first MTP jointsThe metatarsophalangeal articulations are the joints between the metatarsal bones of the foot and the proximal bones

Gout - acute bursitisacute olecranon bursitisBursitis is inflammation of the fluid-filled sac (bursa) that lies between a tendon and skin, or between a tendon and bone

Gouty arthritis - characteristicssudden onsetmiddle aged malessevere paindistal jointsIntense inflammation

recurrent episodesinfluenced by dietbony erosions on Xray

Monosodium urate crystalsneedle shape

negative birefringence

Crystal-induced inflammationPMN is critical component of crystal-induced inflammation

Gouty arthritis - characteristicssudden onsetmiddle aged malessevere paindistal jointsintense inflammation

recurrent episodesinfluenced by dietbony erosions on Xrayhyperuricemia

Hyperuricemiahyperuricemia results when production exceeds excretion

Hyperuricemianet uric acid loss results when excretion exceeds production

Chronic tophaceous gouttophus = localized deposit of monosodium urate crystals

Gout - tophusclassic location of tophi on helix of ear

Gout - X-ray changesDIP (Distal interphalangeal joint) joint destructionphalangeal bone cysts

Gout - X-ray changesbony erosions

Gout - cardinal manifestations

Drug therapy of goutThe Role of Uric Acid in Gout

Uric acidend product of purine metabolism

serum uric acid level dependent uponrate of uric acid productionefficiency of renal uric acid excretion

Uric acid metabolismxanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid

Renal handling of uric acidglomerular filtrationtubular reabsorptiontubular excretionpost-secretory reabsorptionnet excretion

Gout - problemsexcessive total body levels of uric acid

deposition of monosodium urate crystals in joints & other tissues

crystal-induced inflammation

Treating acute gouty arthritiscolchicineNSAIDssteroidsrest, analgesia, ice, time

Drugs used to treat goutAcute Arthritis DrugsUrate Lowering Drugsrest + analgesia + time

NSAIDs

Indomethacin (Indocin) 25 to 50 mg four times dailyNaproxen (Naprosyn) 500 mg two times dailyIbuprofen (Motrin) 800 mg four times dailySulindac (Clinoril) 200 mg two times dailyKetoprofen (Orudis) 75 mg four times daily Drugs used to treat gout

Colchicine - plant alkaloidcolchicum autumnale(autumn crocus or meadow saffron)

Colchicineonly effective in gouty arthritisnot an analgesicdoes not affect renal excretion of uric aciddoes not alter plasma solubility of uric acidneither raises nor lowers serum uric acid

ColchicineColchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubulesreduces inflammatory response to deposited crystalsdiminishes PMN phagocytosis of crystalsblocks cellular response to deposited crystals

Crystal-induced inflammationPMN is critical component of crystal-induced inflammation

Colchicine - indications

DoseIndicationhightreatment of acute gouty arthritislowprevention of recurrent gouty arthritis

Colchicine - toxicitygastrointestinal (nausea, vomiting, cramping, diarrhea, abdominal pain)hematologic (agranulocytosis, aplastic anemia, thrombocytopenia)muscular weaknessadverse effects dose-related & more common when patient has renal or hepatic disease

Gout - colchicine therapymore useful for daily prophylaxis (low dose)prevents recurrent attackscolchicine 0.6 mg qd - bid

declining use in acute gout (high dose)

Hyperuricemia - mechanisms

Urate-lowering drugs

Gout - urate-lowering therapyprevents arthritis, tophi & stones by lowering total body pool of uric acidnot indicated after first attackinitiation of therapy can worsen or bring on acute gouty arthritisno role to play in managing acute gout

Drug therapy of goutDrugs That Block Production of Uric Acid

Uric acid metabolismxanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid

Allopurinol (Zyloprim)inhibitor of xanthine oxidaseeffectively blocks formation of uric acidhow supplied - 100 mg & 300 mg tabletspregnancy category C

Allopurinol - usage indicationsmanagement of hyperuricemia of goutmanagement of hyperuricemia associated with chemotherapyprevention of recurrent calcium oxalate kidney stones

Allopurinol - common reactionsdiarrhea, nausea, abnormal liver testsacute attacks of goutrash

Allopurinol - serious reactionsfever, rash, toxic epidermal necrolysishepatotoxicity, marrow suppressionvasculitisdrug interactions (ampicillin, thiazides, mercaptopurine, azathioprine)death

Stevens-Johnson syndrometarget skin lesionsmucous membrane erosionsepidermal necrosis with skin detachment

Allopurinol hypersensitivityextremely serious problemprompt recognition requiredfirst sign usually skin rashmore common with impaired renal functionprogression to toxic epidermal necrolysis & death

Febuxostatrecently approved by FDA (not on market)oral xanthine oxidase inhibitorchemically distinct from allopurinol94% of patients reached urate < 6.0 mg/dlminimal adverse eventscan be used in patients with renal disease

PEG-uricaseinvestigational drugPEG-conjugate of recombinant porcine uricasetreatment-resistant gouturicase speeds resolution of tophifurther research needed

Drug therapy of goutDrugs That Enhance Excretion of Uric Acid

Uricosuric therapyprobenecidblocks tubular reabsorption of uric acidenhances urine uric acid excretionincreases urine uric acid leveldecreases serum uric acid level

Uricosuric therapymoderately effectiveincreases risk of nephrolithiasisnot used in patients with renal diseasefrequent, but mild, side effects

Uricosuric therapycontra-indicationshistory of nephrolithiasiselevated urine uric acid levelexisting renal diseaseless effective in elderly patients

Choosing a urate-lowering drugxanthine oxidase inhibitoruricosuric agent

Drug therapy of goutCase Presentation

Case presentation - therapy

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