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Anti-Inflammatory & Immunosuppressive Drugs 2

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Presentation on theme: "Anti-Inflammatory & Immunosuppressive Drugs 2"— Presentation transcript:

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

2 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)

3 Immunophilin Ligands Cyclosporine Tacrolimus Sirolimus “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
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

11 Clinical Use of Immunosuppressants in Transplantation

12 Biologic Products

13 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

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

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

16 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

17 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

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

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

20 Manipulating Serum Uric Acid Levels
(Allopurinol, febuxostat)

21 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)

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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