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Anti-Inflammatory & Immunosuppressive Drugs 2 I-3 Fall 2012 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 “Rapalogs” •Everolimus •Temsilolimus Immune Cell Activation Immunophilin ligands Immunophilin Ligands Inhibit T-Cell Activation or Proliferation Immunophilin Ligands: Adverse effects Neuropathy Nephrotoxicity (cyclosporine) Hypertension Hyperglycemia Hyperlipidemia Hirsutism gingival hyperplasia cholelithiasis Opportunistic infections !!! Dose reduction Combination Rx Or use Tacrolimus Immune Cell Activation Mycophenolate mofetil, leflunomide, cytotoxic drugs A Theoretical Framework for Other Immunosuppressants Blocking Rapid Cell Division Cyclophosphamide Inhibits de novo GMP synthesis 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 Biologic Products 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 Target: TNF alpha • Adalimumab: Humanized Fab fragment certolizumab golimumab Target: TNF alpha • Adverse effects – increased risk of infection (reactivation of tuberculosis) – GI upset – local reactions at the injection site – Antibody formation Clinical Benefit in RA 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 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 Note: MTX is also a DMARD. We will revisit the cytotoxic drugs used in RA, including MTX in the M3 block 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 Tubulin dimer Activated macrophage Sirolimus Microtubule Autumn Crocus Toxicity Diarrhea Extraordinarily toxic in OD Tubulin dimer bound to colchicine Manipulating Serum Uric Acid Levels (Allopurinol, febuxostat) Allopurinol Inhibits Uric Acid Production Xanthine oxidase Hypoxanthine Xanthine oxidase Xanthine Uric acid Irreversible Reversible Xanthine oxidase Adverse Effects Acute gout rash hematologic reactions drug interactions (with drugs that rely on xanthine oxidase Allopurinol Febuxostat for metabolism) Alloxanthine 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).
