1. Anti-Inflammatory & Immunosuppressive Drugs 2
I-3 Fall 2011
Susan Masters, Ph.D.

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

4. Immune Cell Activation
Immunophilin
ligands

5. Immunophilin Ligands Inhibit T-Cell Activation or Proliferation

6. Immune Cell Activation
Mycophenolate mofetil,
leflunomide, cytotoxic drugs

7. A Theoretical Framework for Other Immunosuppressants

8. Blocking Rapid Cell Division

9. 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

10. Clinical Use of Immunosuppressants in Transplantation

11. New Kids on the Block: Biologic Products
Challenges
Pharmacokinetics
Parenteral
Cost (for long haul)
Long-term toxicity

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

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

14. Manipulating Serum Uric Acid Levels
(Allopurinol, febuxostat)

15. 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

16. Uricosuric Drugs Inhibit Renal Reabsorption of Uric AcidUA
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

17. 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)

18. 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

19. 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)

20. 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