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Anti-Inflammatory & Immunosuppressive Drugs 2

Anti-Inflammatory & Immunosuppressive Drugs 2. I-3 Fall 2011 Susan Masters, Ph.D. The Inflammatory Cascade. Immunophilin ligands, mycophenolate mofetil, DMARDs, anti-TNF, etc. Perceived threat. Infection. Tissue injury. Adaptive immune system. Innate immune system. Anti-gout drugs.

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Anti-Inflammatory & Immunosuppressive Drugs 2

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  1. Anti-Inflammatory & Immunosuppressive Drugs 2 I-3 Fall 2011 Susan Masters, Ph.D.

  2. The Inflammatory Cascade Immunophilin ligands, mycophenolate mofetil, DMARDs, anti-TNF, etc. Perceived threat Infection Tissue injury Adaptive immune system Innate immune system Anti-gout drugs Leukocyte & endothelial cell activation Inflammatory mediators Inflammation (redness, edema, warmth, pain, tissue destruction)

  3. Immunophilin Ligands Cyclosporine Tacrolimus Sirolimus

  4. Immune Cell Activation Immunophilin ligands

  5. Immunophilin Ligands Inhibit T-Cell Activation or Proliferation

  6. Immune Cell Activation Mycophenolate mofetil, leflunomide, cytotoxic drugs

  7. A Theoretical Framework for Other Immunosuppressants

  8. Blocking Rapid Cell Division

  9. A Big Advantage of Multiple Agents isNon-Overlapping Toxicity All these drugs increase the risk of infection and lymphoma

  10. Clinical Use of Immunosuppressants in Transplantation

  11. New Kids on the Block: Biologic Products Challenges • Pharmacokinetics • Parenteral • Cost (for long haul) • Long-term toxicity

  12. Drugs for Gout Acute Treatment (Anti-inflammatory) NSAIDS (indomethacin); corticosteroids Chronic Treatment (Decrease serum urate, anti-inflammatory) Low-dose colchicine, allopurinol, uricosuric drugs

  13. Colchicine Inhibits Microtubule Assembly Activated macrophage Tubulin dimer Sirolimus Microtubule Autumn Crocus Toxicity Tubulin dimer bound to colchicine Diarrhea Extraordinarily toxic in OD

  14. Manipulating Serum Uric Acid Levels (Allopurinol, febuxostat)

  15. Allopurinol Inhibits Uric Acid Production Xanthine oxidase Xanthine oxidase Hypoxanthine Xanthine Uric acid Reversible Irreversible Xanthine oxidase Allopurinol Alloxanthine Febuxostat Toxicity: Acute gout, rash, hematologic reactions, drug interactions

  16. Uricosuric Drugs Inhibit Renal Reabsorption of Uric Acid UA 90% of uric acid filtered at the glomerulus is reabsorbed in the proximal tubule UA UA UA UA UA UA UA UA Probenecid Toxicity: Acute gout, allergic rxtn UA

  17. Summary • The immunosuppressants that are used to prevent transplant rejection and to treat autoimmune disorders inhibit T-cell function and proliferation • Newer biologic products, including ant-TNF drugs, are very selective in their action; • Treatment of acute gout is with anti-inflammatory drugs; prevention of more attacks is with colchicine and/or decreasing production of uric acid (allopurinol) or increasing uric acid excretion (probenecid)

  18. Other Disease Modifying Antirheumatic Drugs (DMARDS)

  19. Mycophenolate Prevents GMP Synthesisin Lymphocytes DNA GTP IMP dehydrogenase GMP Inosine monophosphate (IMP) Mycophenolic acid De novo pathway of purine synthesis + Guanine PRPP GMP Salvage pathway of purine synthesis (lacking in lymphocytes)

  20. How Do They Compare? Lancet 372(9636):375-82, Aug 2008; 1 year of therapy

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