Immunosuppressants Flashcards
clinical uses of immunosuppressants
organ transplant rejection, graft vs host disease, autoimmune disorder, recalcitrant inflammatory disease
what is calcineurin
t cell selective immunosuppressant
mechanism of calcineurin
binds to cyclophilin, and cyclophilin complex inhibits calcineurin from inducing dephosphorylation. prevents nuclear translocation of TF, inhibit cytokine gene transcription and synthesis, inhibit (primarily) T cell and B/CTL proliferation
adverse effect of ciclosporin
三高, nephrotoxicity, neurotoxicity, gum hyperplasia
what is sirolimus
mTOR inhibitor (immunosuppressant)
mechanism of action of sirolimus
binds to FKBP , and FKBP complex binds and inhibits mTOR kinase activity p70S6K, activates repressor activity 4EBP1 and initiates growth arrest from G1 phase. Inhibits IL2 cytokine mediated proliferation of T and B cells
adverse effects of sirolimus
三高, thrombocytopenia
with ciclosporin: may impair renal function
advantages of sirolimus
antiproliferative
anti-angiogenic
name 2 cytotoxic immunosuppressants
azathioprine
mycophenolate mofetil (MMF)
mechanism of action of azathioprine
–> 6-mercaptopurine (6MP) –> 6-methyl-MP –> 6-thioguanine (6TG)
6TG is a structural analog and impedes DNA & RNA synthesis, inhibits de novo purine synthesis –> decrease lymphocyte proliferation
effectiveness of azathioprine
SE: bone marrow depression, anemia, leukopenia, thrombocytopenia, bleeding, GI toxicity, neoplasia
effective in renal transplant and some autoimmune disorders using triple therapy (ciclosporin + steroid + azathioprine)
mechanism of action of MMF
converted into mycophenolic acid, inhibits IMPDH (preferentially inhibits type II > type I) –> inhibit de novo pathway of purine (guanosine nucleotide) synthesis
effectiveness of MMF
more selective anti-proliferative effects for T/B cells, less bone marrow depression and GI toxicity than azathioprine, suppresses Ab formation by B cells, inhibits recruitments of leukocytes to graft sites.
SE: diarrhoea, neutropenia, anemia, hypertension
what is fingolimod
sphingosine 1 phosphate receptor agonist
mechanism of action of fingolimod
phosphorylated to give FTY720P, which targets at S1PR (GPCR) as an agonist and activates S1P1, 3, 4 and 5R. (nonspecific)
S1P1R activation leads to receptor downregulation, preventing lymphocyte egress from lymph nodes and decreases circulating auto-aggressive lymphocyte infiltration into CNS
