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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 Adaptive immune system Tissue injury Anti-gout drugs Leukocyte & endothelial cell activation Inflammatory mediators Inflammation (redness, edema, warmth, pain, tissue destruction) Infection Innate immune system Immunophilin Ligands Cyclosporine Tacrolimus Sirolimus Immune Cell Activation Immunophilin ligands Immunophilin Ligands Inhibit T-Cell Activation or Proliferation Immune Cell Activation Mycophenolate mofetil, leflunomide, cytotoxic drugs A Theoretical Framework for Other Immunosuppressants Blocking Rapid Cell Division A Big Advantage of Multiple Agents is Non-Overlapping Toxicity Drug Dose-Limiting Toxicity Cyclosporine & tacrolimus Nephrotoxicity, neurotoxicity (CYP interactions for cyclosporine) Sirolimus Myelosuppression, hepatic tox, hypertriglyceridemia Mycophenolate GI irritation, myelosuppression All these drugs increase the risk of infection and lymphoma Clinical Use of Immunosuppressants in Transplantation New Kids on the Block: Biologic Products Challenges • Pharmacokinetics • Parenteral • Cost (for long haul) • Long-term toxicity Drugs for Gout Acute Treatment (Anti-inflammatory) NSAIDS (indomethacin); corticosteroids Chronic Treatment (Decrease serum urate, anti-inflammatory) Low-dose colchicine, allopurinol, uricosuric drugs Colchicine Inhibits Microtubule Assembly Activated macrophage Tubulin dimer Sirolimus Autumn Crocus Toxicity Diarrhea Extraordinarily toxic in OD Microtubule Tubulin dimer bound to colchicine Manipulating Serum Uric Acid Levels (Allopurinol, febuxostat) Allopurinol Inhibits Uric Acid Production Hypoxanthine Xanthine oxidase Xanthine Reversible Xanthine oxidase Uric acid Irreversible Xanthine oxidase Allopurinol Alloxanthine Febuxostat Toxicity: Acute gout, rash, hematologic reactions, drug interactions Uricosuric Drugs Inhibit Renal Reabsorption of Uric Acid 90% of uric acid filtered at the glomerulus is reabsorbed in the proximal tubule UA UA UA Probenecid Toxicity: Acute gout, allergic rxtn UA UA UA UA UA UA UA 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) Other Disease Modifying Antirheumatic Drugs (DMARDS) Drug Dose-Limiting Toxicity Hydroxychloroquine GI upset, rash, ocular damage Sulfasalazine Leflunomide Gold salts Myelosuppression, rash Diarrhea, rash, hair loss, myelosuppression, hepatotoxicity Skin disorders, myelosuppression, kidney damage Mycophenolate Prevents GMP Synthesis in Lymphocytes DNA GTP IMP dehydrogenase GMP Inosine monophosphate (IMP) De novo pathway of purine synthesis Guanine + PRPP Mycophenolic acid GMP Salvage pathway of purine synthesis (lacking in lymphocytes) How Do They Compare? Dose Cost (4 weeks, lowest dose) Lancet 372(9636):375-82, Aug 2008; 1 year of therapy Methotrexate Etanercept 10-20 mg once/wk PO 25 mg 2 injections/wk SC $55 $1,400