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 lightred compensator needle shape negative birefringence

Crystal-induced inflammation PMN is critical component of crystal-induced inflammation crystal deposition hyperuricemia protein binding receptor bindingcytokine release influx of PMN’s 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 production excretion hyperuricemia results when production exceeds excretion

Hyperuricemia production excretion 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 nephrolithiasisnephropathyarthritistophi HYPERURICEMIA 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 Year Prevalence 30% 0.6%

Serum uric acid levels & age

Uric acid end product of purine metabolism serum uric acid level dependent upon rate of uric acid production efficiency of renal uric acid excretion

Uric acid metabolism cell breakdowndietary intakepurine bases hypoxanthinexanthine 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 overproducersunderexcretors

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

Drugs used to treat gout allopurinol probenecid febuxostat steroids NSAID’s colchicine Acute Arthritis DrugsUrate Lowering Drugs rest + analgesia + time

Drugs used to treat gout Acute Arthritis Drugs allopurinol probenecid febuxostat? steroids NSAID’s colchicine Urate Lowering Drugs rest + analgesia + time

Benjamin Franklin ( ) 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

Crystal-induced inflammation PMN is critical component of crystal-induced inflammation crystal deposition hyperuricemia protein binding receptor bindingcytokine release influx of PMN’s crystals engulfed inflammation

Colchicine - indications DoseIndication hightreatment of acute gouty arthritis lowprevention 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 NSAID’s colchicine Acute Arthritis DrugsUrate 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 breakdowndietary intakepurine bases hypoxanthinexanthine 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 mg & 300 mg tablets pregnancy category C allopurinol

Chemical structures N N O N N allopurinol N HN O N NH hypoxanthinexanthine N N NH N HO OH

Uric acid metabolism cell breakdowndietary intakepurine bases hypoxanthinexanthine uric acid allopurinol inhibits xanthine oxidase 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 ComponentSerum 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 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 Just approved drug PEG-conjugate of recombinant porcine uricase treatment-resistant gout uricase speeds resolution of tophi Iv with significant toxicity issues

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 gouturicosuric renal diseaseallopurinol nephrolithiasisallopurinol high 24-hr UUAallopurinol elderlyallopurinol tophaceous goutallopurinol

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 – Rules of engagement 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 steroid colchicine (low-dose)allopurinolNSAID days 1-10days days 365+