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Anti-Inflammatory & Immunosuppressive Drugs 2

Anti-Inflammatory & Immunosuppressive Drugs 2. I-3 Fall 2012. 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 2012

  2. The Inflammatory Cascade Immunophilin ligands, mycophenolatemofetil, 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 • “Rapalogs” • Everolimus • Temsilolimus

  4. Immune Cell Activation Immunophilin ligands

  5. Immunophilin Ligands Inhibit T-Cell Activation or Proliferation

  6. Immunophilin Ligands: Adverse effects Neuropathy Nephrotoxicity (cyclosporine) Hypertension Hyperglycemia Hyperlipidemia Hirsutism gingival hyperplasia cholelithiasis Opportunistic infections !!! Dose reduction Combination Rx Or use Tacrolimus

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

  8. A Theoretical Framework for Other Immunosuppressants

  9. Blocking Rapid Cell Division Cyclophosphamide Inhibits de novo GMP synthesis

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

  11. Clinical Use of Immunosuppressants in Transplantation

  12. Biologic Products

  13. Biologic Products • Exquisitely selective • Less side effects compared to cytotoxic drugs • Now standard in algorithm to manage RA Challenges • Pharmacokinetic: Parenteral • Cost • Long-term toxicity ? • Antigenicity • Oversight

  14. Target: TNF alpha • Adalimumab: Humanized Fab fragment certolizumab golimumab

  15. Target: TNF alpha • Adverse effects • increased risk of infection (reactivation of tuberculosis) • GI upset • local reactions at the injection site • Antibody formation

  16. Clinical Benefit in RA Lancet 372(9636):375-82, Aug 2008; 1 year of therapy

  17. Other Disease Modifying Antirheumatic Drugs (DMARDS) Note: MTX is also a DMARD. We will revisit the cytotoxic drugs used in RA, including MTX in the M3 block

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

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

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

  21. Allopurinol Inhibits Uric Acid Production Xanthine oxidase Xanthine oxidase Hypoxanthine Xanthine Uric acid Irreversible Reversible Adverse Effects Acute gout rash hematologic reactions drug interactions (with drugs that rely on xanthine oxidase for metabolism) Xanthine oxidase Allopurinol Alloxanthine Febuxostat

  22. 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 anti-TNF drugs, are very selective in their action and present unique challenges. • Treatment of acute gout is with anti-inflammatory drugs; prevention of more attacks is with colchicine and/or decreasing production of uric acid (allopurinol/febuxostat) or increasing uric acid excretion (probenecid).

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