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
effectiveness of fingolimod
used for multiple sclerosis
long T 1/2: 8days
SE: first dose bradycardia due to S1P1 activation in sinoatrial cells, hypertension, Gi upset, increased liver enzymes
mechanism of action of polyclonal Ab
side effects of polyclonal ab
cytokine storm
thrombocytopenia
leukopenia
serum sickness
mechanism of action of monoclonal ab
side effect of monoclonal ab
