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38 Cards in this Set

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Which anti-cancer drugs are immunsupressive at low doses?
Cyclophosphamide
Methotrexate
Vincristine
Calcineurin Inhibitors
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
Phenytoin (anti-seizure)
Phenobarbital (anti-epilep)
Any P-450 inducers
What drugs will decrease Cyclosporine excretion
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
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
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
In combo with cyclosporin or tacrolimus or in those w/calcineurin-inhibitor toxicity
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
Use of Mycophenolate mofetil
After renal or heart transplant
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