LSU Clinical Pharmacology Drug Therapy of Gout Reginald D Sanders, MD Drug therapy of gout - overview •what is gout? •what happens to patients with gout & why? •what drugs are available for managing gout? •how are those drugs used? Drug therapy of gout We have excellent drugs for managing gout The drugs used in treating gout make sense! Drug therapy of gout What Is Gout? Drug therapy of gout Case Presentation 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 Gouty arthritis - characteristics • sudden onset • middle aged males • severe pain • distal joints • Intense inflammation • recurrent episodes • influenced by diet • bony erosions on Xray Drug therapy of gout What Happens To Gout Patients & Why? Gout - acute arthritis arthrocentesis acute synovitis, ankle & first MTP joints Monosodium urate crystals needle shape negative birefringence polarized light red compensator Crystal-induced inflammation hyperuricemia inflammation crystal deposition crystals engulfed protein binding influx of PMN’s receptor binding cytokine release PMN is critical component of crystal-induced inflammation Gouty arthritis - characteristics • sudden onset • middle aged males • severe pain • distal joints • intense inflammation • recurrent episodes • influenced by diet • bony erosions on Xray • hyperuricemia Hyperuricemia hyperuricemia results when production exceeds 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 Gout - cardinal manifestations tophi arthritis acute & chronic HYPERURICEMIA nephrolithiasis nephropathy Drug therapy of gout The Role of Uric Acid in Gout Hyperuricemia & gout Serum Uric Acid Level Annual Incidence 5-Year Prevalence > 10 mg/dl 70 30% < 7 mg/dl 0.9 0.6% Serum uric acid levels & age 13.0 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 Gouty Male Normal Male Gouty Female Normal Female 10 20 30 40 50 Age (years) 60 Uric acid metabolism dietary intake xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid purine bases hypoxanthine xanthine uric acid cell breakdown Renal handling of uric acid •glomerular filtration •tubular reabsorption •tubular excretion •post-secretory reabsorption •net excretion Hyperuricemia - mechanisms excessive production inadequate excretion hyperuricemia Hyperuricemia - mechanisms overproducers underexcretors hyperuricemia Classifying hyperuricemia •serum uric acid level •urine uric acid excretion (24-hour) serum uric acid urine uric acid overproduction high high underexcretion high normal/low 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 Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs colchicine allopurinol steroids probenecid NSAID’s febuxostat? rest + analgesia + time Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs colchicine allopurinol steroids probenecid NSAID’s febuxostat? 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 •“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 Colchicine •mechanism of action poorly understood •reduces inflammatory response to deposited crystals •diminishes PMN phagocytosis of crystals •blocks cellular response to deposited crystals Crystal-induced inflammation hyperuricemia inflammation crystal deposition crystals engulfed protein binding influx of PMN’s receptor binding cytokine release PMN is critical component of crystal-induced inflammation Colchicine - indications Dose Indication high treatment of acute gouty arthritis low prevention of recurrent gouty arthritis 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) Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs colchicine allopurinol steroids probenecid NSAID’s febuxostat? rest + analgesia + time Hyperuricemia - mechanisms excessive production inadequate excretion hyperuricemia Urate-lowering drugs block production enhance excretion net reduction in total body pool of uric acid 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 Uric acid metabolism dietary intake xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid purine bases hypoxanthine xanthine uric acid cell breakdown Allopurinol (Zyloprim™) •inhibitor of xanthine oxidase •effectively blocks formation of uric acid •how supplied - 100 mg & 300 mg tablets •pregnancy category C allopurinol Chemical structures N N HN N NH O hypoxanthine N N N HO O allopurinol N NH N N OH xanthine Uric acid metabolism dietary intake purine bases cell breakdown oxypurinol hypoxanthine allopurinol inhibits xanthine oxidase xanthine uric acid allopurinol allopurinol 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 Allopurinol effect allopurinol lowers serum uric acid levels Component Hypoxanthine Xanthine Uric acid Serum Level 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 Allopurinol - usage indications •management of hyperuricemia of gout •management of hyperuricemia associated with chemotherapy •prevention of recurrent calcium oxalate kidney stones 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 Allopurinol - common reactions •diarrhea, nausea, abnormal liver tests •acute attacks of gout •rash Allopurinol - serious reactions •fever, rash, toxic epidermal necrolysis •hepatotoxicity, marrow suppression •vasculitis •drug interactions (ampicillin, thiazides, mercaptopurine, azathioprine) •death Stevens-Johnson syndrome target skin lesions mucous membrane erosions epidermal necrosis with skin detachment 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 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 PEG-uricase •investigational drug •PEG-conjugate of recombinant porcine uricase •treatment-resistant gout •uricase speeds resolution of tophi •further research needed Drug therapy of gout Drugs That Enhance Excretion of Uric Acid Renal handling of uric acid •glomerular filtration •tubular reabsorption •tubular excretion •post-secretory reabsorption •excretion Uricosuric therapy •probenecid •blocks tubular reabsorption of uric acid •enhances urine uric acid excretion •increases urine uric acid level •decreases serum uric acid level Uricosuric therapy •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) Uricosuric therapy •contra-indications history of nephrolithiasis elevated urine uric acid level existing renal disease •less effective in elderly patients Choosing a urate-lowering drug excessive production inadequate excretion xanthine oxidase inhibitor uricosuric agent hyperuricemia Urate-lowering therapy •mild gout •renal disease •nephrolithiasis •high 24-hr UUA •elderly •tophaceous gout uricosuric allopurinol allopurinol allopurinol allopurinol allopurinol Treating acute gout What is the role of uratelowering drugs like allopurinol or probenecid in treating acute gouty arthritis? Urate-lowering therapy •no anti-inflammatory activity •can precipitate acute gout •can prolong attack of gout •advice? Gout - rule #309 Concept “Don’t mess with the uric acid level” Don’t change your urate-lowering therapy during an acute gout attack Gout - therapeutic problems •renal disease •nephrolithiasis •transplantation •allopurinol allergy Drug therapy of gout Case Presentation Case presentation - therapy NSAID NSAID steroid colchicine (low-dose) allopurinol days 1-10 days 11-365 days 365+ LSU Clinical Pharmacology Drug Therapy of Gout Reginald D Sanders, MD
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