Drug Therapy of Gout 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 The drugs used in treating gout make sense! We have excellent drugs for managing gout 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 acute synovitis, ankle & first MTP joints arthrocentesis Monosodium urate crystals polarized light red compensator needle shape
negative birefringence Crystal-induced inflammation PMN is critical component of crystal- induced inflammation crystal deposition hyperuricemia protein binding receptor binding cytokine release influx of PMNs crystals engulfed 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 nephrolithiasis nephropathy arthritis tophi HYPERURICE MIA acute & chronic Drug therapy of gout The Role of Uric Acid in Gout Hyperuricemia & gout Serum Uric Acid Level > 10 mg/dl < 7 mg/dl Annual Incidence 70 0.9 5-Year Prevalence 30% 0.6% Serum uric acid levels & age 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 10 20 30 40 50 60 Age (years) Gouty Male Normal Male Gouty Female Normal Female Uric acid metabolism cell breakdown dietary intake purine bases hypoxanthine xanthine uric acid 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 - mechanisms hyperuricemia excessive production inadequate excretion Hyperuricemia - mechanisms hyperuricemia overproducers underexcretors Classifying hyperuricemia serum uric acid level urine uric acid excretion (24-hour) overproduction underexcretion serum uric acid high high urine uric acid 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 NSAIDs steroids rest, analgesia, ice, time Drugs used to treat gout allopurinol probenecid febuxostat? steroids NSAIDs colchicine Acute Arthritis Drugs Urate Lowering Drugs rest + analgesia + time Drugs used to treat gout Acute Arthritis Drugs allopurinol probenecid febuxostat? steroids NSAIDs colchicine Urate Lowering Drugs rest + analgesia + time Benjamin Franklin (1706 - 1790) suggests gout sufferers use lEau 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 PMN is critical component of crystal- induced inflammation crystal deposition hyperuricemia protein binding receptor binding cytokine release influx of PMNs crystals engulfed 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 allopurinol probenecid febuxostat? steroids NSAIDs colchicine Acute Arthritis Drugs Urate Lowering Drugs rest + analgesia + time Hyperuricemia - mechanisms hyperuricemia excessive production inadequate excretion Urate-lowering drugs net reduction in total body pool of uric acid block production enhance excretion 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 cell breakdown dietary intake purine bases hypoxanthine xanthine uric acid xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid 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 O N N allopurinol N HN O N NH hypoxanthin e xanthine N N N H N H O O H Uric acid metabolism cell breakdown dietary intake purine bases hypoxanthine xanthine uric acid allopurinol inhibits xanthine oxidase allopurinol allopurinol oxypurinol 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 Component Serum Level Hypoxanthine Xanthine Uric acid 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 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 hyperuricemia excessive production inadequate excretion xanthine oxidase inhibitor uricosuric agent Urate-lowering therapy mild gout uricosuric renal disease allopurinol nephrolithiasis allopurinol high 24-hr UUA allopurinol elderly allopurinol tophaceous gout allopurinol Treating acute gout What is the role of urate- lowering 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 Dont mess with the uric acid level Dont 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 steroi d colchicine (low-dose) allopurinol NSAID days 1-10 days 11-365 days 365+ Reginald D Sanders, MD LSU Clinical Pharmacology Drug Therapy of Gout