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Understand gout, a form of arthritis, its symptoms, causes, and available drug therapies like colchicine and NSAIDs. Learn about hyperuricemia, uric acid metabolism, and the role of urate-lowering drugs. Discover how to effectively manage acute gout flares and reduce crystal-induced inflammation.
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Drug therapy of gout What Is Gout?
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
Case presentation • can barely walk (due to pain) • right elbow swollen • exam shows left first MTP joint & left ankle to be red, swollen & tender to touch • right elbow also swollen
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
Case presentation What does he have? What can do we do about it?
Gout - acute arthritis acute synovitis, ankle & first MTP joints
Gout - acute bursitis acute olecranon bursitis
sudden onset middle aged males severe pain distal joints Intense inflammation recurrent episodes influenced by diet bony erosions on Xray Gouty arthritis - characteristics
Drug therapy of gout What Happens To Gout Patients & Why?
arthrocentesis Gout - acute arthritis acute synovitis, ankle & first MTP joints
polarized light red compensator Monosodium urate crystals needle shape negative birefringence
hyperuricemia crystal deposition inflammation crystals engulfed protein binding influx of PMN’s receptor binding cytokine release Crystal-induced inflammation PMN is critical component of crystal-induced inflammation
sudden onset middle aged males severe pain distal joints intense inflammation recurrent episodes influenced by diet bony erosions on Xray hyperuricemia Gouty arthritis - characteristics
production excretion Hyperuricemia hyperuricemia results when production exceeds excretion
production excretion Hyperuricemia net uric acid loss results when excretion exceeds production
Chronic tophaceous gout tophus = localized deposit of monosodium urate crystals
Gout - tophus classic location of tophi on helix of ear
Gout - X-ray changes DIP joint destruction phalangeal bone cysts
Gout - X-ray changes bony erosions
arthritis tophi acute & chronic HYPERURICEMIA nephrolithiasis nephropathy Gout - cardinal manifestations
Drug therapy of gout The Role of Uric Acid in Gout
purine bases dietary intake uric acid hypoxanthine cell breakdown xanthine Uric acid metabolism xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid
Renal handling of uric acid • glomerular filtration • tubular reabsorption • tubular excretion • post-secretory reabsorption • net excretion
hyperuricemia overproducers underexcretors Hyperuricemia - mechanisms
Classifying hyperuricemia • serum uric acid level • urine uric acid excretion (24-hour)
Gout - problems • excessive total body levels of uric acid • deposition of monosodium urate crystals in joints & other tissues • crystal-induced inflammation
Drug therapy of gout What Drugs Are Available For Treating Gout?
Treating acute gouty arthritis what strategies might be effective?
Treating acute gouty arthritis • colchicine • NSAID’s • steroids • rest, analgesia, ice, time
steroids NSAID’s colchicine allopurinol probenecid febuxostat Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs rest + analgesia + time
Benjamin Franklin (1706 - 1790) suggests gout sufferers use l’Eau Medicinale d'Husson (secret French medicine containing colchicine)
Colchicine - plant alkaloid colchicum autumnale (autumn crocus or meadow saffron)
Colchicine • not only effective in gouty arthritis • some what effective in other arthropathies ie. pseudogout, sarcoid, etc. etc. • 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
Colchicine • mechanism of action poorly understood • reduces inflammatory response to deposited crystals • diminishes PMN phagocytosis of crystals • blocks cellular response to deposited crystals
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
Treating acute gout What is the role of colchicine in treating acute gouty arthritis?
Gout - colchicine therapy • more useful for daily prophylaxis (low dose) • prevents recurrent attacks • colchicine 0.6 mg qd - bid • declining use in acute gout (high dose)
steroids NSAID’s colchicine allopurinol probenecid febuxostat Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs rest + analgesia + time
hyperuricemia excessive production inadequate excretion Hyperuricemia - mechanisms
block production enhance excretion net reduction in total body pool of uric acid Urate-lowering drugs
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
Drug therapy of gout Drugs That Block Production of Uric Acid
purine bases dietary intake uric acid hypoxanthine cell breakdown xanthine Uric acid metabolism xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid
allopurinol Allopurinol (Zyloprim™) • inhibitor of xanthine oxidase • effectively blocks formation of uric acid • how supplied - 100 mg & 300 mg tablets • pregnancy category C
purine bases dietary intake oxypurinol uric acid hypoxanthine cell breakdown allopurinol allopurinol xanthine Uric acid metabolism allopurinol inhibits xanthine oxidase
Allopurinol effect allopurinol lowers serum uric acid levels
Allopurinol What are the clinical consequences of blocking production of uric acid?
Allopurinol • 90% absorption from the gut • metabolized to oxypurinol • once daily dosing • lowers serum uric acid levels • lowers urine uric acid levels • side effects rare, but potentially lethal