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).