2009 gout pharmacology

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2009 gout pharmacology

  1. 1. LSU Clinical Pharmacology Drug Therapy of Gout Reginald D Sanders, MD
  2. 2. 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?
  3. 3. Drug therapy of gout We have excellent drugs for managing gout The drugs used in treating gout make sense!
  4. 4. Drug therapy of gout What Is Gout?
  5. 5. Drug therapy of gout Case Presentation
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. Case presentation What does he have? What can do we do about it?
  10. 10. Gout - acute arthritis acute synovitis, ankle & first MTP joints
  11. 11. Gout - acute bursitis acute olecranon bursitis
  12. 12. Gouty arthritis - characteristics • sudden onset • middle aged males • severe pain • distal joints • Intense inflammation • recurrent episodes • influenced by diet • bony erosions on Xray
  13. 13. Drug therapy of gout What Happens To Gout Patients & Why?
  14. 14. Gout - acute arthritis arthrocentesis acute synovitis, ankle & first MTP joints
  15. 15. Monosodium urate crystals needle shape negative birefringence polarized light red compensator
  16. 16. 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
  17. 17. Gouty arthritis - characteristics • sudden onset • middle aged males • severe pain • distal joints • intense inflammation • recurrent episodes • influenced by diet • bony erosions on Xray • hyperuricemia
  18. 18. Hyperuricemia pr ction odu e ti o n xcre hyperuricemia results when production exceeds excretion
  19. 19. Hyperuricemia produ ction excre t io n net uric acid loss results when excretion exceeds production
  20. 20. Chronic tophaceous gout tophus = localized deposit of monosodium urate crystals
  21. 21. Gout - tophus classic location of tophi on helix of ear
  22. 22. Gout - X-ray changes DIP joint destruction phalangeal bone cysts
  23. 23. Gout - X-ray changes bony erosions
  24. 24. Gout - cardinal manifestations tophi arthritis acute & chronic HYPERURICE MIA nephrolithiasis nephropathy
  25. 25. Drug therapy of gout The Role of Uric Acid in Gout
  26. 26. Hyperuricemia & gout Serum Uric Acid Level Annual Incidence 5-Year Prevalence > 10 mg/dl 70 30% < 7 mg/dl 0.9 0.6%
  27. 27. 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
  28. 28. Uric acid metabolism dietary intake xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid purine bases hypoxanthine xanthine uric acid cell breakdown
  29. 29. Renal handling of uric acid •glomerular filtration •tubular reabsorption •tubular excretion •post-secretory reabsorption •net excretion
  30. 30. Hyperuricemia - mechanisms excessive production inadequate excretion hyperuricemia
  31. 31. Hyperuricemia - mechanisms overproducers underexcretors hyperuricemia
  32. 32. 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
  33. 33. Gout - problems • excessive total body levels of uric acid • deposition of monosodium urate crystals in joints & other tissues • crystal-induced inflammation
  34. 34. Drug therapy of gout What Drugs Are Available For Treating Gout?
  35. 35. Treating acute gouty arthritis what strategies might be effective?
  36. 36. Treating acute gouty arthritis • colchicine • NSAID’s • steroids • rest, analgesia, ice, time
  37. 37. Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs colchicine allopurinol steroids probenecid NSAID’s febuxostat? rest + analgesia + time
  38. 38. Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs colchicine allopurinol steroids probenecid NSAID’s febuxostat? rest + analgesia + time
  39. 39. Benjamin Franklin (1706 - 1790) suggests gout sufferers use l’Eau Medicinale d'Husson (secret French medicine containing colchicine)
  40. 40. Colchicine - plant alkaloid colchicum autumnale (autumn crocus or meadow saffron)
  41. 41. 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
  42. 42. Colchicine • mechanism of action poorly understood • reduces inflammatory response to deposited crystals • diminishes PMN phagocytosis of crystals • blocks cellular response to deposited crystals
  43. 43. 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
  44. 44. Colchicine - indications Dose Indication high treatment of acute gouty arthritis low prevention of recurrent gouty arthritis
  45. 45. 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
  46. 46. Treating acute gout What is the role of colchicine in treating acute gouty arthritis?
  47. 47. 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)
  48. 48. Drugs used to treat gout Acute Arthritis Drugs Urate Lowering Drugs colchicine allopurinol steroids probenecid NSAID’s febuxostat? rest + analgesia + time
  49. 49. Hyperuricemia - mechanisms excessive production inadequate excretion hyperuricemia
  50. 50. Urate-lowering drugs block production enhance excretion net reduction in total body pool of uric acid
  51. 51. 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
  52. 52. Drug therapy of gout Drugs That Block Production of Uric Acid
  53. 53. Uric acid metabolism dietary intake xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid purine bases hypoxanthine xanthine uric acid cell breakdown
  54. 54. Allopurinol (Zyloprim™) • inhibitor of xanthine oxidase • effectively blocks formation of uric acid • how supplied - 100 mg & 300 mg tablets • pregnancy category C allopurinol
  55. 55. Chemical structures N N HN N NH O hypoxanthine N N N HO O allopurinol N NH N N OH xanthine
  56. 56. Uric acid metabolism dietary intake purine bases cell breakdown oxypurinol hypoxanthine allopurinol inhibits xanthine oxidase xanthine uric acid allopurinol allopurinol
  57. 57. 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
  58. 58. Allopurinol effect allopurinol lowers serum uric acid levels Component Hypoxanthine Xanthine Uric acid Serum Level
  59. 59. Allopurinol What are the clinical consequences of blocking production of uric acid?
  60. 60. 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
  61. 61. Allopurinol - usage indications • management of hyperuricemia of gout • management of hyperuricemia associated with chemotherapy • prevention of recurrent calcium oxalate kidney stones
  62. 62. 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
  63. 63. Allopurinol - common reactions • diarrhea, nausea, abnormal liver tests • acute attacks of gout • rash
  64. 64. Allopurinol - serious reactions • fever, rash, toxic epidermal necrolysis • hepatotoxicity, marrow suppression • vasculitis • drug interactions (ampicillin, thiazides, mercaptopurine, azathioprine) • death
  65. 65. Stevens-Johnson syndrome target skin lesions mucous membrane erosions epidermal necrosis with skin detachment
  66. 66. 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
  67. 67. 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
  68. 68. PEG-uricase • investigational drug • PEG-conjugate of recombinant porcine uricase • treatment-resistant gout • uricase speeds resolution of tophi • further research needed
  69. 69. Drug therapy of gout Drugs That Enhance Excretion of Uric Acid
  70. 70. Renal handling of uric acid •glomerular filtration •tubular reabsorption •tubular excretion •post-secretory reabsorption •excretion
  71. 71. Uricosuric therapy • probenecid • blocks tubular reabsorption of uric acid • enhances urine uric acid excretion • increases urine uric acid level • decreases serum uric acid level
  72. 72. 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)
  73. 73. Uricosuric therapy • contra-indications history of nephrolithiasis elevated urine uric acid level existing renal disease • less effective in elderly patients
  74. 74. Choosing a urate-lowering drug excessive production inadequate excretion xanthine oxidase inhibitor uricosuric agent hyperuricemia
  75. 75. Urate-lowering therapy • mild gout • renal disease • nephrolithiasis • high 24-hr UUA • elderly • tophaceous gout uricosuric allopurinol allopurinol allopurinol allopurinol allopurinol
  76. 76. Treating acute gout What is the role of uratelowering drugs like allopurinol or probenecid in treating acute gouty arthritis?
  77. 77. Urate-lowering therapy • no anti-inflammatory activity • can precipitate acute gout • can prolong attack of gout • advice?
  78. 78. Gout - rule #309 Concept “Don’t mess with the uric acid level” Don’t change your urate-lowering therapy during an acute gout attack
  79. 79. Gout - therapeutic problems • renal disease • nephrolithiasis • transplantation • allopurinol allergy
  80. 80. Drug therapy of gout Case Presentation
  81. 81. Case presentation - therapy NSAID NSAID steroid colchicine (low-dose) allopurinol days 1-10 days 11-365 days 365+
  82. 82. LSU Clinical Pharmacology Drug Therapy of Gout Reginald D Sanders, MD

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