1. 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?

2. Drug therapy of gout The drugs used in treating gout make sense! We have excellent drugs for managing gout

3. Drug therapy of gout What Is Gout?

4. Drug therapy of gout Case Presentation

5. 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

6. 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

7. 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

8. Case presentation What does he have? What can do we do about it?

9. Gout - acute arthritis acute synovitis, ankle & first MTP joints

10. Gout - acute bursitis acute olecranon bursitis

11. Gouty arthritis - characteristics sudden onset middle aged males severe pain distal joints Intense inflammation recurrent episodes influenced by diet bony erosions on Xray

12. Drug therapy of gout What Happens To Gout Patients & Why?

13. Gout - acute arthritis acute synovitis, ankle & first MTP joints arthrocentesis

14. Monosodium urate crystals polarized lightred compensator needle shape negative birefringence

15. 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

16. Gouty arthritis - characteristics sudden onset middle aged males severe pain distal joints intense inflammation recurrent episodes influenced by diet bony erosions on Xray hyperuricemia

17. Hyperuricemia production excretion hyperuricemia results when production exceeds excretion

18. Hyperuricemia production excretion net uric acid loss results when excretion exceeds production

19. Chronic tophaceous gout tophus = localized deposit of monosodium urate crystals

20. Gout - tophus classic location of tophi on helix of ear

21. Gout - X-ray changes DIP joint destruction phalangeal bone cysts

22. Gout - X-ray changes bony erosions

23. Gout - cardinal manifestations nephrolithiasisnephropathyarthritistophi HYPERURICEMIA acute & chronic

24. Drug therapy of gout The Role of Uric Acid in Gout

25. Hyperuricemia & gout Serum Uric Acid Level > 10 mg/dl < 7 mg/dl Annual Incidence 70 0.9 5-Year Prevalence 30% 0.6%

26. Serum uric acid levels & age

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

28. Uric acid metabolism cell breakdowndietary intakepurine bases hypoxanthinexanthine uric acid xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid

29. Renal handling of uric acid glomerular filtration tubular reabsorption tubular excretion post-secretory reabsorption net excretion

30. Hyperuricemia - mechanisms hyperuricemia overproducersunderexcretors

31. Classifying hyperuricemia serum uric acid level urine uric acid excretion (24-hour)

32. Gout - problems excessive total body levels of uric acid deposition of monosodium urate crystals in joints & other tissues crystal-induced inflammation

33. Drug therapy of gout What Drugs Are Available For Treating Gout?

34. Treating acute gouty arthritis what strategies might be effective?

35. Treating acute gouty arthritis colchicine NSAID’s steroids rest, analgesia, ice, time

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

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

38. Benjamin Franklin (1706 - 1790) suggests gout sufferers use l’Eau Medicinale d'Husson (secret French medicine containing colchicine)

39. Colchicine - plant alkaloid colchicum autumnale (autumn crocus or meadow saffron)

40. 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

41. Colchicine mechanism of action poorly understood reduces inflammatory response to deposited crystals diminishes PMN phagocytosis of crystals blocks cellular response to deposited crystals

42. 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

43. Colchicine - indications DoseIndication hightreatment of acute gouty arthritis lowprevention of recurrent gouty arthritis

44. 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

45. Treating acute gout What is the role of colchicine in treating acute gouty arthritis?

46. 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)

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

48. Hyperuricemia - mechanisms hyperuricemia excessive production inadequate excretion

49. Urate-lowering drugs net reduction in total body pool of uric acid block production enhance excretion

50. 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

51. Drug therapy of gout Drugs That Block Production of Uric Acid

52. Uric acid metabolism cell breakdowndietary intakepurine bases hypoxanthinexanthine uric acid xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid

53. Allopurinol (Zyloprim™) inhibitor of xanthine oxidase effectively blocks formation of uric acid how supplied - 100 mg & 300 mg tablets pregnancy category C allopurinol

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

55. Uric acid metabolism cell breakdowndietary intakepurine bases hypoxanthinexanthine uric acid allopurinol inhibits xanthine oxidase allopurinol oxypurinol

56. 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

57. Allopurinol effect ComponentSerum Level Hypoxanthine Xanthine Uric acid allopurinol lowers serum uric acid levels

58. Allopurinol What are the clinical consequences of blocking production of uric acid?

59. 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

60. Allopurinol - usage indications management of hyperuricemia of gout management of hyperuricemia associated with chemotherapy prevention of recurrent calcium oxalate kidney stones

61. 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

62. Allopurinol - common reactions diarrhea, nausea, abnormal liver tests acute attacks of gout rash

63. Allopurinol - serious reactions fever, rash, toxic epidermal necrolysis hepatotoxicity, marrow suppression vasculitis drug interactions (ampicillin, thiazides, mercaptopurine, azathioprine) death

64. Stevens-Johnson syndrome target skin lesions mucous membrane erosions epidermal necrosis with skin detachment

65. 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

66. 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

67. PEG-uricase Just approved drug PEG-conjugate of recombinant porcine uricase treatment-resistant gout uricase speeds resolution of tophi Iv with significant toxicity issues

68. Drug therapy of gout Drugs That Enhance Excretion of Uric Acid

69. Renal handling of uric acid glomerular filtration tubular reabsorption tubular excretion post-secretory reabsorption excretion

70. Uricosuric therapy probenecid blocks tubular reabsorption of uric acid enhances urine uric acid excretion increases urine uric acid level decreases serum uric acid level

71. 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)

72. Uricosuric therapy contra-indications history of nephrolithiasis elevated urine uric acid level existing renal disease less effective in elderly patients

73. Choosing a urate-lowering drug hyperuricemia excessive production inadequate excretion xanthine oxidase inhibitor uricosuric agent

74. Urate-lowering therapy mild gouturicosuric renal diseaseallopurinol nephrolithiasisallopurinol high 24-hr UUAallopurinol elderlyallopurinol tophaceous goutallopurinol

75. Treating acute gout What is the role of urate- lowering drugs like allopurinol or probenecid in treating acute gouty arthritis?

76. Urate-lowering therapy no anti-inflammatory activity can precipitate acute gout can prolong attack of gout advice?

77. 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

78. Gout - therapeutic problems renal disease nephrolithiasis transplantation allopurinol allergy

79. Drug therapy of gout Case Presentation

80. Case presentation - therapy NSAID steroid colchicine (low-dose)allopurinolNSAID days 1-10days 11-365days 365+