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Transcript
Anti-Inflammatory &
Immunosuppressive Drugs 2
I-3 Fall 2011
Susan Masters, Ph.D.
The Inflammatory Cascade
Immunophilin ligands,
mycophenolate mofetil,
DMARDs, anti-TNF, etc.
Perceived threat
Adaptive immune
system
Tissue injury
Anti-gout
drugs
Leukocyte & endothelial cell activation
Inflammatory mediators
Inflammation (redness, edema,
warmth, pain, tissue destruction)
Infection
Innate immune
system
Immunophilin Ligands
Cyclosporine
Tacrolimus
Sirolimus
Immune Cell Activation
Immunophilin
ligands
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 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
Clinical Use of Immunosuppressants in
Transplantation
New Kids on the Block: Biologic Products
Challenges
• Pharmacokinetics
• Parenteral
• Cost (for long haul)
• Long-term toxicity
Drugs for Gout
Acute Treatment (Anti-inflammatory)
NSAIDS (indomethacin); corticosteroids
Chronic Treatment (Decrease serum urate, anti-inflammatory)
Low-dose colchicine, allopurinol, uricosuric drugs
Colchicine Inhibits Microtubule Assembly
Activated
macrophage
Tubulin dimer
Sirolimus
Autumn Crocus
Toxicity
Diarrhea
Extraordinarily toxic in OD
Microtubule
Tubulin dimer bound
to colchicine
Manipulating Serum Uric Acid Levels
(Allopurinol, febuxostat)
Allopurinol Inhibits Uric Acid Production
Hypoxanthine
Xanthine
oxidase
Xanthine
Reversible
Xanthine
oxidase
Uric acid
Irreversible
Xanthine
oxidase
Allopurinol
Alloxanthine
Febuxostat
Toxicity: Acute gout, rash, hematologic reactions, drug interactions
Uricosuric Drugs Inhibit Renal
Reabsorption of Uric Acid
90% of uric acid filtered at
the glomerulus is reabsorbed
in the proximal tubule
UA
UA
UA
Probenecid
Toxicity: Acute gout, allergic rxtn
UA
UA
UA
UA
UA
UA
UA
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
Leflunomide
Gold salts
Myelosuppression, rash
Diarrhea, rash, hair loss,
myelosuppression, hepatotoxicity
Skin disorders, myelosuppression,
kidney damage
Mycophenolate Prevents GMP Synthesis
in Lymphocytes
DNA
GTP
IMP
dehydrogenase
GMP
Inosine monophosphate (IMP)
De novo pathway of purine synthesis
Guanine
+
PRPP
Mycophenolic acid
GMP
Salvage pathway of purine synthesis (lacking in lymphocytes)
How Do They Compare?
Dose
Cost (4 weeks, lowest dose)
Lancet 372(9636):375-82,
Aug 2008; 1 year of therapy
Methotrexate
Etanercept
10-20 mg once/wk
PO
25 mg 2 injections/wk
SC
$55
$1,400