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 Leukocyte & endothelial cell activation Inflammatory mediators Inflammation (redness, edema, warmth, pain, tissue destruction)

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 Microtubule Autumn Crocus Toxicity Tubulin dimer bound to colchicine Diarrhea Extraordinarily toxic in OD

Manipulating Serum Uric Acid Levels (Allopurinol, febuxostat)

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

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

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) Dose-Limiting Toxicity Hydroxychloroquine GI upset, rash, ocular damage Sulfasalazine Myelosuppression, rash Leflunomide Diarrhea, rash, hair loss, myelosuppression, hepatotoxicity Gold salts Skin disorders, myelosuppression, kidney damage

Mycophenolate Prevents GMP Synthesis in Lymphocytes DNA GTP IMP dehydrogenase GMP Inosine monophosphate (IMP) 5-phosphoryibosyl-1-pyrophosphate (PRPP), xanthosine monophosphate; IMP is precursor to both GMP and AMP xanthosine monophosphate (convert ketone to amino group) Very clever in it selectivity. Not benign, but an important point is that it has different toxicity than other drugs. Mycophenolic acid De novo pathway of purine synthesis Guanine + PRPP GMP Salvage pathway of purine synthesis (lacking in lymphocytes)

How Do They Compare? Methotrexate Etanercept Dose 10-20 mg once/wk PO 25 mg 2 injections/wk SC Cost (4 weeks, lowest dose) $55 $1,400 Lancet 372(9636):375-82, Aug 2008; 1 year of therapy