Block 2: Immunosuppressive drugs: Calci, Cytokine
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- Which anti-cancer drugs are immunsupressive at low doses?
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Cyclophosphamide
Methotrexate
Vincristine - Calcineurin Inhibitors
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Cyclosporine
Tacrolimus
Pimecrolimus - Cyclosporine (Sandimmune) MA
- (-) activation and proliferation of CD4+ and CD8+ cells
- Which intracellular protein does Cyclosporine bind to?
- Cyclophilin
- What is the result of the Cyclosporine-Cyclophilin complex?
- Inhibition of Calcineurin--blocks translocation of transciption factor NF-ATc
- Why do you need NF-ATc?
- To make IL-2
- How do you administer Cyclosporin?
- Vehicle containing EtOH and oil, either i.v. or capsule
- 1/2 life of Cyclosporine
- 6 hours
- Metabolism of Cyclosporine
- Liver (CYP3A4)
- Because Cyclosporine is CYP3A4 mediated, what drugs will decrease it activity
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Phenytoin (anti-seizure)
Phenobarbital (anti-epilep)
Any P-450 inducers - What drugs will decrease Cyclosporine excretion
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Erythromycin
Ketoconazole
Amphotericin B
St. John's Wart - Toxicity of Cyclosporine
- Nephro, Neuro, Hypertension, hirsutism, hyperlipidemia, gigival hyperplasia
- Tacrolimus vs. Cyclosporine
- 50-100X more potent but LESS nephrotoxicity, shorter half life
- Use Tacrolimus
- Prevention of transplant rejection and atopic dermatitis
- MA of Tacrolimus
- Binds cytoplasmic protein (FKBP-12), complex (-) Calcineurin
- Adminstration of Tacrolimus
- Shorter half-life so 3 day loading of i.v. then orally 2X/day
- Toxicity of Tacrolimus
- Nephrotoxicity, neurotoxicity, GI distress, hyperglycemia, (-) of pancreatic B-cell fxn
- Use of Pimecrolimus and MA
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Atopic dermatitis
Also binds FKBP-12--inhibits calcineurin - Sirolimus (Rapamycin)
- Regulates cytokine response used to prevent rejection in renal transplant
- Other use of Sirolimus
- Prevention of neointimal proliferation and restensosis after stent placement in coranary arteries
- MA of Sirolimus
- Binds FKBP-12 BUT complex inhibits PI kinase related protein kinase mTOR
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Why do you need mTOR?
Mammalian Target Of Rapamycin - Modulate intracellar signaling pathways for genes involved in cell proliferation - no T or B cell proliferation
- Metabolism of Rapamycin
- CYP3A4
- Everolimus
- Sirolimus analogue, more predictable oral absorption
- Toxcities of Sirolimus (Rapamycin)
- Anemia, thrombocytopenia, hyperlipidemia, post-surgical lymphocoele
- Contraindication for Rapamycin
- After liver transplantation
- Mycophenolate mofetil
- Prodrug metabolized to mycophenolic acid (MPA)
- Use of Mycophenolate mofetil
- After renal or heart transplant
- Metabolism of Mycophenolate mofetil
- Liver esterases
- MA of MPA
- Inhibition of inosine monophosphate dehydrogenase--no de novo purine synthesis
- How does defective de novo purine synthesis impair immunity
- T and B cells rely on de novo syn. for their source of purines rather than HPRT salvage
- HPRT
- hypoxanthine guanine phosphoribosyl transferase
- Don't do this when using Mycophenolate mofetil
- Do admin with antacids with Mg or Al-- decreased absorption.
- Toxicity of of Mycophenolate mofetil
- leukopenia and diarrhea
- Leflunomide
- prodrug-- active metabolite (-) dihydroorotate dehydrogenase-- no pyrimidine biosynthesis
- Thalidomide (no their not kidding) Use
- Treatment of Erythema nodosum leprosum in patients w/ graft-vs.-host dz
- Toxicity of Thalidomide
- Peripheral neuropathy and NEVER GIVE TO PREGNANT WOMEN--IT'S A TERATOGEN