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

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Presentation on theme: "Anti-Inflammatory & Immunosuppressive Drugs 2 I-3 Fall 2012."— Presentation transcript:

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

2 The Inflammatory Cascade Inflammation (redness, edema, warmth, pain, tissue destruction) Inflammatory mediators Leukocyte & endothelial cell activation Tissue injury Adaptive immune system Innate immune system Perceived threatInfection Immunophilin ligands, mycophenolate mofetil, DMARDs, anti-TNF, etc. Anti-gout drugs

3 Immunophilin Ligands Cyclosporine Sirolimus Tacrolimus “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 is Non-Overlapping Toxicity DrugDose-Limiting Toxicity Cyclosporine & tacrolimus Nephrotoxicity, neurotoxicity (CYP interactions for cyclosporine) Sirolimus Myelosuppression, hepatic tox, hypertriglyceridemia MycophenolateGI irritation, myelosuppression All these drugs increase the risk of infection and lymphoma

11 Clinical Use of Immunosuppressants in Transplantation

12 Biologic Products

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

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

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

16 Clinical Benefit in RA MethotrexateEtanercept 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

17 Other Disease Modifying Antirheumatic Drugs (DMARDS) DrugDose-Limiting Toxicity HydroxychloroquineGI 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

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

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

20 Manipulating Serum Uric Acid Levels (Allopurinol, febuxostat)

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