Drug Therapy of Gout

1. Drug Therapy of Gout

2. What Is Gout? A medical condition caused by an increase in the level of uric acid >> urate crystals , causing inflammatory responses around some joints of the body ( Gouty arthritis )

3. Case presentation (Gouty arthritis) • 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

4. Gout - acute arthritis acute synovitis, ankle & first MTP joints Redness and swelling are noticed around those joints in particular The metatarsophalangeal articulations are the joints between the metatarsal bones of the foot and the proximal bones

5. Gout - acute bursitis acute olecranon bursitis Bursitis is inflammation of the fluid-filled sac (bursa) that lies between a tendon and skin, or between a tendon and bone

6. sudden onset middle aged males severe pain distal joints Intense inflammation recurrent episodes influenced by diet ( since uric acid level is influenced by our dietary intake of purines) bony erosions on Xray Gouty arthritis - characteristics

7. 1-polarized light 2-red compensator Monosodium urate crystals These crystals show : 1-needle shape 2-negative birefringence (Birefringence: double streams of light, usually in prisms, etc) Diagnosis is done by taking a biopsy from the synovial fluid and then examined either by:

8. crystal deposition (blood stream) hyperuricemia inflammation crystals engulfed influx of PMN’s (Macrophages ) protein binding receptor binding (Synovial joints ) cytokine release Crystal-induced inflammation (from gout to gouty arthritis ) PMN is critical component of crystal-induced inflammation

9. sudden onset middle aged males severe pain distal joints intense inflammation recurrent episodes influenced by diet bony erosions on Xray Hyperuricemia (always) Gouty arthritis - characteristics

10. production excretion Hyperuricemia hyperuricemia results when production exceeds excretion (either by over production or less excretion )

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

12. Chronic tophaceous gout tophus = localized deposit of monosodium urate crystals ** could also be in several places in the body

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

14. Gout - X-ray changes DIP (Distal interphalangeal joint) joint destruction phalangeal bone cysts

15. Gout - X-ray changes bony erosions

16. arthritis tophi acute & chronic chronic HYPERURICEMIA Nephrolithiasis (Kidney stones) nephropathy Gout - cardinal manifestations *kidneys should be functioning well in order to use classical treatment

17. Drug therapy of gout Treatment targets either : 1- Decrease Uric Acid Formation 2- Increase Uric Acid Excretion

18. purine bases dietary intake uric acid hypoxanthine cell breakdown xanthine Uric acid metabolism One method of reducing uric acid levels , is inhibition of the enzyme xanthine oxidase xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid

19. Renal handling of uric acid Fate of uric acid in kidneys : Uric acid • glomerular filtration • tubular reabsorption • tubular excretion • post-secretory reabsorption • net excretion Uric acid Uric acid Uric acid The goal of some Gout Drugs, is to Increase the net excretion of uric acid from the kidneys.

20. The goal of some Gout Drugs, is to Increase the net excretion of uric acid from the kidneys Non steroidal anti-inflammatory Drugs are sometimes used in the treatment of Gout ( cause increase in excretion ) Aspirin on the other hand is never used

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

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

23. steroids NSAID’s colchicine allopurinol probenecid febuxostat? Drugs used to treat gout Urate Lowering Drugs For chronic cases Acute Arthritis Drugs It’s a new drug that’s being developed rest + analgesia + time

24. Drugs used to treat gout • NSAID’s • Indomethacin (Indocin) 25 to 50 mg four times daily • Naproxen (Naprosyn) 500 mg two times daily • Ibuprofen (Motrin) 800 mg four times daily • Sulindac (Clinoril) 200 mg two times daily • Ketoprofen (Orudis) 75 mg four times daily *Don’t memorize the doses, just the names ** Remember that Aspirin is never used

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

26. Correction for the previous lecture Colchicine is used to prevent the polymerization of the cell’s cytoskeleton by binding to TUBULIN ( not Actin)

27. Colchicine • “only effective in gouty arthritis” ( it only works on the inflammation process , and has nothing to do with uric acid levels .) • 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

28. Colchicine • Colchicine inhibits microtubule polymerization by binding to tubulin, one of the main constituents of microtubules • reduces inflammatory response to deposited crystals • diminishes PMN phagocytosis of crystals • blocks cellular response to deposited crystals

29. 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

30. Colchicine - indications It’s better to use xanthine oxidase inhibitors for

31. Colchicine - toxicity • gastrointestinal (nausea, vomiting, cramping, diarrhea, abdominal pain) • hematologic (agranulocytosis, aplastic anemia, thrombocytopenia) • muscular weakness Associated with high doses : adverse effects dose-related & more common when patient has renal or hepatic disease

32. 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)

33. Colchicine - Cancers • Promising studies have recently shown that Colchicine could be used for treating tumors • HOW ? • Since Colchicine prevents the formation of microtubules , this could be useful in limiting the mitotic activity of tumors cell : by preventing the formation of mitotic spindles (microtubules .)

34. hyperuricemia excessive production inadequate excretion Hyperuricemia - mechanisms

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

36. 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 Xanthine Oxidase as an example

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

38. purine bases dietary intake uric acid hypoxanthine cell breakdown xanthine Uric acid metabolism xanthine oxidase catalyzes hypoxanthine to xanthine & xanthine to uric acid

39. allopurinol Allopurinol (Zyloprim™) • inhibitor of xanthine oxidase • effectively blocks formation of uric acid • how supplied - 100 mg & 300 mg tablets • pregnancy category C **Drugs are characterized according to their effects on pregnancy (fetus) into several categories A,B,C,D,X. A is the safest, X: completely dangerous and should not be given to pregnant women  **benefits from taking the drug must outweigh it’s risks in order for it to be used.

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

41. Allopurinol - common reactions • diarrhea, nausea, abnormal liver tests • acute attacks of gout • rash *Manufactures are obliged to put a special indication on each leaflet ( a BLACK BOX) , that explains the serious side effect for that particular drug e.g Isotretinoinis a highly teratogenic Drug that should have a BLACK BOX **For Allopurinol you might find that BLACK BOX sometimes , because certain people have shown to have allergy for it .

42. Allopurinol - serious reactions • fever, rash, toxic epidermal necrolysis • hepatotoxicity, marrow suppression • vasculitis • drug interactions (ampicillin(antibiotic), thiazides(diuretic ), mercaptopurine, azathioprine(anti-cancer) • death

43. Stevens-Johnson syndrome Another serious side effect , characterized by : Mucocutaenous ulcerations target skin lesions mucous membrane erosions epidermal necrosis with skin detachment Those side effects are treated by systemic corticosteroids

44. 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

45. 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

46. PEG-uricase (Polyethelene Glycol) • Uricase: enzyme that degrades uric acid  • investigational drug • PEG-conjugate of recombinant porcine uricase • treatment-resistant gout • uricase speeds resolution of tophi • further research needed

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

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

49. Uricosuric therapy • moderately effective • increases risk of nephrolithiasis • not used in patients with renal disease • frequent, but mild, side effects

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