Post on 23-Dec-2015
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