1. ANTI-GOUT DRUGS

2. GOUT A familial metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints & cartilage.

3. GOUT

4. Treatment aims to:  Relieve acute gouty attacks - Colchicine, NSAIDs, corticosteroids  Prevent recurrent gouty episodes - Uricosuric agents - Allopurinol

6. CLASSIFICATION of antigout drugs 1. Colchicum alkaloids Colchicine 2. Nonsteroidal anti-inflammatory drugs Naproxen, indomethacin, phenylbutazone, ibuprofen 3. Uricosuric agents Probenecid, sulfinpyrazone 4. Urate synthesis inhibitors Allopurinol

7. COLCHICINE An alkaloid (colchicum autumnale) Relieves pain & inflammation of gouty arthritis in 12-24 hrs MOA  inhibits the polymerization of tubulin (a structural protein necessary for motility) - inhibits leukocyte migration  reduces the phagocytosis of urate crystals by leukocytes

8. Adverse Effects  Diarrhea - bloody  Nausea, vomiting & abdominal pain  Hair loss  Bone marrow depression  Peripheral neuritis  Myopathy  Acute intoxication: burning throat pain, bloody diarrhea, shock, hematuria  Fatal ascending CNS depression

9. NSAIDs:  Anti inflammatory ( inhibiting urate crystal phagocytosis) & analgesic effects  Indomethacin is most commonly used NSAID- uricosuric  All NSAIDs except aspirin, salicylates & tolmetin

10. URICOSURIC AGENTS PROBENECID SULFINPYRAZONE Organic acids MOA  inhibit the reabsorption of uric acid in the proximal part (S 2 ) of the nephron  may also reduce secretion of uric acid into the nephron (proximal tubule), but reduction of reabsorption is the dominant (& therapeutic) effect

11. Adverse effects  Gastrointestinal irritation  Rash  Nephrotic syndrome with probenecid  Aplastic anemia

12. ALLOPURINOL Standard of care therapy in the intercritical period Reduces total uric acid body burden MOA  Allopurinol is converted to alloxanthine by xanthine oxidase  Inhibits the production of less soluble uric acid by xanthine oxidase from more soluble xanthine & hypoxanthine

14. Pharmacokinetics 80-90% absorbed after oral administration short half-life(1-2hours),but metabolite alloxanthine (oxipurinol) has a half-life of about 15 hours

15. Adverse effects  Acute attacks of gouty arthritis (prophylactic treatment with NSAIDs or colchicine)  GI intolerance  Peripheral neuritis  Necrotizing vasculitis  Bone marrow depression  Aplastic anemia  Hepatic toxicity, Interstitial nephritis  Allergic skin reactions-exfoliative dermatitis  Cataract formation

16. Interactions  Inhibits the metabolism of 6- mercaptopurine and azathioprine so their dosage must be reduced by 75%  Prolongs t 1/2 of warfarin & probenecid (inhibits metabolism)  May enhance the bone marrow toxicity of cytotoxic drugs (cyclophosphamide) Caution: Safety in children & during pregnancy has not been established

17. FEBUXOSTAT Recently approved first non-purine inhibitor of xanthine oxidase Safe in renal disease as highly metabolized to inactive metabolites in the liver

18. GLUCOCORTICOIDS INTERLEUKIN-1 INHIBITORS- anakinra – under investigation

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