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

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: golimumab 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 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

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 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 Tubulin dimer bound to colchicine Diarrhea Extraordinarily toxic in OD

Manipulating Serum Uric Acid Levels (Allopurinol, febuxostat)

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

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).