The document summarizes various drugs used for their anti-inflammatory and immunosuppressive properties. It discusses how immunosuppressants like cyclosporine, tacrolimus, and sirolimus inhibit T-cell activation and proliferation to prevent transplant rejection and treat autoimmune disorders. Newer biologic drugs targeting TNF are also mentioned. For gout, acute attacks are treated with anti-inflammatory drugs while prevention involves colchicine and allopurinol to decrease uric acid production or probenecid to increase uric acid excretion.

1. ANTI-INFLAMMATORY
&
IMMUNOSUPPRESSIVE
DRUG

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 threat Infection
Immunophilin ligands,
mycophenolate mofetil,
DMARDs, anti-TNF, etc.
Anti-gout
drugs

3. IMMUNOPHILIN LIGANDS
Cyclosporine
Sirolimus
Tacrolimus

4. IMMUNE CELLACTIVATION
Immunophilin
ligands

5. IMMUNOPHILIN LIGANDS INHIBIT T-
CELLACTIVATION OR PROLIFERATION

6. IMMUNE CELLACTIVATION
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
• Pharmacokinetics
• Parenteral
• Cost (for long haul)
• Long-term toxicity
Challenges

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

13. COLCHICINE INHIBITS MICROTUBULE
ASSEMBLY
Autumn Crocus
Sirolimus
Microtubule
Tubulin dimer
Tubulin dimer bound
to colchicine
Toxicity
Diarrhea
Extraordinarily toxic in OD
Activated
macrophage

14. MANIPULATING SERUM URIC ACID
LEVELS
(Allopurinol, febuxostat)

15. ALLOPURINOL INHIBITS URIC ACID
PRODUCTION
Hypoxanthine Xanthine Uric acid
Allopurinol Alloxanthine
Xanthine
oxidase
Xanthine
oxidase
Xanthine
oxidase
Reversible Irreversible
Toxicity: Acute gout, rash, hematologic reactions, drug interactions
Febuxostat

16. URICOSURIC DRUGS INHIBIT RENAL
REABSORPTION OF URIC ACID
UA
UA
UA
UA
UA
UA
UA
UA
Probenecid
90% of uric acid filtered at
the glomerulus is reabsorbed
in the proximal tubule
UA
UA
Toxicity: Acute gout, allergic rxtn

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)
Drug 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
GTP
GMP
DNA
PRPP
Inosine monophosphate (IMP)
De novo pathway of purine synthesis
Salvage pathway of purine synthesis (lacking in lymphocytes)
Guanine GMP
+
IMP
dehydrogenase
Mycophenolic acid