Immunosuppressants Flashcards
What are the three general uses of immunosuppressants?
transplantations
Autoimmune diseases
Inflammatory diseases
What are grafts between identical twins called?
Isografts
What are allografts?
Grafts from other people
True or false: you can never truly induce remission of autoimmune diseases with immunosuppressants?
False
What are the four major classes of Immunosuppressants?
- Glucocorticoids
- Calcineurin inhibitors
- Anti-proliferative/antimetabolic agents
- biologicals
Malignancies with immunosuppressants usually have what etiology?
Latent viral infections
What are steroids, technically?
Compounds with a common ring structure
What are corticosteroids, technically?
Adrenal cortex steroids
What are the two major MOAs of glucocorticoids?
Genomic
Non-genomic
What are the genomic effects of glucocorticoids?
Binds to a cytosolic receptor, and translocates to the DNA (1% of genome) to alter transcription/translation
What are the non-genomic effects of glucocorticoids?
Can influence cell signalling pathways and intercalate into the cell membrane to alter ion transport
What are the effects of glucocorticoids?
- Rapid decrease in peripheral blood lymphocyte
- Downregulate IL-1, IL-6, IFN-g, TNF-a
What is the function of IL-2?
T cell proliferation
What is the effect of glucocorticoids on PMNs?
reduce chemotaxis and lysosomal enzyme release
What is the effect of glucocorticoids on humoral immunity?
Little
What is the effect of CD3?
***Cytokine storm
What are the adverse effects of glucocorticoids?
Growth retardation
Impaired wound healing
HTN
Hyperglycemia
Rapid withdrawal of glucocorticoids may result in what?
Glucocorticoid crisis
What is low, medium, high, and very high doses of glucocorticoids?
Low = (0, 7.5] mg
Med = (7.5, 30]
High = (30, 100]
Very high = (100, 250]
What is the half-life of prednisone?
5 hours (intermediate)
What are the two, short acting glucocorticoids?
Cortisone
Hydrocortisone
What are the four intermediate acting glucocorticoids?
Prednisone
Prednisolone
Methylprednisolone
Triamcinolone
What are the two long acting glucocorticoids?
Dexamethasone
Betamethasone
What is pulse therapy with glucocorticoid use?
Greater than 250 mg of prednisone for 1 day
What is the MOA of cyclosporine?
Suppress T cell-mediated immunity by forming a complex with cyclophilin, and prevent dephosphorylation of NFAT
What is the transcription factor that cyclosporine suppresses? What does this produce?
NFAT–leads to IL-2 production
What is the function of IL-12?
Th1 cell production
What is the function of IL-4?
Th2 cell production
What are the therapeutic uses for cyclosporine? Side effects?
Prophylaxis for kidney transplant, RA
Nephrotoxic, HTN, Hirsutism
What is the effect of grapefruit juice on cyclosporine? Tacrolimus?
Inhibits p450 enzyme, causing an increase in cyclosporine and tacrolimus
What is the MOA of tacrolimus? What are the therapeutic uses? Side effects?
calcineurin inhibitor, preventing NFAT phosphorylation
Prophylaxis of allograft rejection
Nephro/neurotoxic, HTN,
DM,
What is the MOA of Azathioprine?
Purine antimetabolite that is metabolized to 6-mercaptopurine to inhibit lymphocyte proliferation
What are the two purines?
A
G
Why is it that most cells can overcome Azathioprine actions, but lymphocytes cannot?
Lymphocytes do not have a salvage pathway
What are the therapeutic uses of Azathioprine? Adverse effects?
Organ transplant rejection
RA
Myelosuppression
Hepatotoxic
Azathioprine increases that susceptibility to what viral infections?
Varicella
HSVs
What is the MOA of Mycophenolate Mofetil?
Prodrug that is hydrolyzed to MPA, which inhibits inosine monophosphate dehydrogenase, which is required for the synthesis of guanine.
Inhibits T and B cells
What are the therapeutic uses, and side effects of mycophenolate?
Transplant rejection
SLE
CMV infections
Teratogenic
Leukopenia
What is the MOA of sirolimus?
Inhibits T lymph proliferation by binding to FKBP (same as tacrolimus), to inhibit mTOR, and cell cycle progression
What are the therapeutic uses, and side effects of sirolimus?
Renal transplant
Anemia
Hypokalemia
What is Antithymocyte globulin?
rabbit serum antibodies against human thymocytes
What is the CD protein that all T cells express?
CD3
What are the two mechanisms that Antithymocyte globulin uses to destroy thymocytes?
Complement mediated cytotoxicity
Inhibition of lymphocyte functions by binding surface molecules
What are the therapeutic uses, and side effects of Antithymocyte globulin?
Induction immunosuppression
TNF-a release (ILI)
Serum sickness
Anaphylaxis
Cytokine storm
What is the MOA of Muromonab-CD3?
Mouse antibodies against CD3 cause T lymphocyte depletion
What are the therapeutic uses, and side effects of Muromonab-CD3?
Reverse organ transplant rxn
Cytokine storm
Anaphylaxis
Will not work more than once (immune response)
What are the three Anti-TNF-alpha reagents?
Infliximab
Adalimumab
Etanercept
What is the MOA of Anti-TNF-alpha reagents?
Prevents TNF-alpha from binding to its receptors by binding directly to the cytokine
What is infliximab?
Anti-TNF alpha antibody
What is Adalimumab?
Recombinant human IgG1 monoclonal against TNF-a
What is Etanercept?
Ligand binding portion of human anti-TNF alpha fused to the Fc portion of human IgG1
What are the therapeutic uses, and side effects of Anti-TNF alpha reagents?
Crohn’s, UC
Increase risk of infx and malignancies
