Anti-Inflammatory & Immunosuppressive Drugs 2

I-3 Fall 2011

Susan Masters, Ph.D.

The Inflammatory Cascade

Inflammation (redness, edema,warmth, pain, tissue destruction)

Inflammatory mediators

Leukocyte & endothelial cell activation

Tissue injury Adaptive immunesystem

Innate immunesystem

Perceived threat InfectionImmunophilin ligands,mycophenolate mofetil,DMARDs, anti-TNF, etc.

Anti-goutdrugs

Immunophilin Ligands

Cyclosporine

Sirolimus

Tacrolimus

Immune Cell Activation

Immunophilinligands

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 isNon-Overlapping Toxicity

Drug Dose-Limiting Toxicity

Cyclosporine & tacrolimus

Nephrotoxicity, neurotoxicity

(CYP interactions for cyclosporine)

SirolimusMyelosuppression, 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

• Pharmacokinetics• Parenteral• Cost (for long haul)• Long-term toxicity

Challenges

Drugs for Gout

Acute Treatment (Anti-inflammatory)

Chronic Treatment (Decrease serum urate, anti-inflammatory)

NSAIDS (indomethacin); corticosteroids

Low-dose colchicine, allopurinol, uricosuric drugs

Colchicine Inhibits Microtubule Assembly

Autumn Crocus

SirolimusMicrotubule

Tubulin dimer

Tubulin dimer bound to colchicine

Toxicity

DiarrheaExtraordinarily toxic in OD

Activated macrophage

Manipulating Serum Uric Acid Levels

(Allopurinol, febuxostat)

Allopurinol Inhibits Uric Acid Production

Hypoxanthine Xanthine Uric acid

Allopurinol Alloxanthine

Xanthineoxidase

Xanthineoxidase

Xanthineoxidase

Reversible Irreversible

Toxicity: Acute gout, rash, hematologic reactions, drug interactions

Febuxostat

Uricosuric Drugs Inhibit Renal Reabsorption of Uric Acid

UA

UA

UA

UA

UAUA

UAUA

Probenecid

90% of uric acid filtered at the glomerulus is reabsorbed in the proximal tubule

UA

UAToxicity: Acute gout, allergic rxtn

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)

Drug Dose-Limiting Toxicity

Hydroxychloroquine GI upset, rash, ocular damage

Sulfasalazine Myelosuppression, rash

LeflunomideDiarrhea, rash, hair loss, myelosuppression, hepatotoxicity

Gold saltsSkin disorders, myelosuppression, kidney damage

Mycophenolate Prevents GMP Synthesisin Lymphocytes

GTP

GMP

DNA

PRPP

Inosine monophosphate (IMP)

De novo pathway of purine synthesis

Salvage pathway of purine synthesis (lacking in lymphocytes)

Guanine GMP+

IMPdehydrogenase

Mycophenolic acid

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