LSU Clinical Pharmacology

1. LSU Clinical Pharmacology Drug Therapy of Gout Reginald D Sanders, MD

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

4. Drug therapy of gout What Is Gout?

5. Drug therapy of gout Case Presentation

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

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

11. Gout - acute bursitis acute olecranon bursitis

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

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

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

15. polarized light red compensator Monosodium urate crystals needle shape negative birefringence

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

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

18. production excretion Hyperuricemia hyperuricemia results when production exceeds excretion

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

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

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

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

23. Gout - X-ray changes bony erosions

24. arthritis tophi acute & chronic HYPERURICEMIA nephrolithiasis nephropathy Gout - cardinal manifestations

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

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

27. Serum uric acid levels & age

28. purine bases dietary intake uric acid hypoxanthine cell breakdown xanthine Uric acid metabolism 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 excessive production inadequate excretion Hyperuricemia - mechanisms

31. hyperuricemia overproducers underexcretors Hyperuricemia - mechanisms

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

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

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

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

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

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

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

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

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

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

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

44. Colchicine - indications

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

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

49. hyperuricemia excessive production inadequate excretion Hyperuricemia - mechanisms

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