58: Immunosuppressants Flashcards
adverse effects of immunosuppression include..
infectious disease
malignancy
MOA glucocorticoids
- genomic effects (bind to cytosolic receptor, translocate to nucleus and bind DNA –> change expression)
- non-genomic effects (influence signaling pathways, ion transport, rapid immunosuppressive effects (minutes))
effects of glucocorticoids
- rapid decrease in peripheral blood lymphocytes
- downregulate key pro-inflammatory cytokines
- inhibit IL-2 production by t cells (required for proliferation)
- reduce neutrophil chemotaxis and lysosomal enzyme release
- little effect on humoral immunity
therapeutic uses glucocorticoids
- transplant rejection
- graft v. host disease
- cytokine storm in transplant caused by treatment with muromonab CD3 and antithymocyte globulin
- autoimmune disorders
adverse effects glucocorticoids
- adrenal crisis upon rapid withdrawal
- cataracts
- avascular necrosis of bone
- poor wound healing
- growth retardation
- hyperglycemia
prednisone equivalent =
amount of prednisone or its equivalent
dosing glucocorticoids low medium high very high pulse
less than 7.5 mg per day 7.5 - 30 mg per day 30 - 100 mg per day greater than 100 mg per day greater than 250 mg prednisone equivalent per day for 1 day or a few days
MOA cyclosporine
suppresses t cell mediated immunity
forms a complex with cyclophilin which binds to calcineurin preventing the dephosphorlation of NFAT. NFAT cannot translocate to nucleus and cytokines including IL-2 does not occur
therapeutic uses cyclosporine
transplantation * not given renal because nephrotoxic
RA
psoriasis
combinations
adverse reactions cyclosporine
nephrotoxic HTN hyperlipidemia tremors of hands and feet swollen and painful gums hirsuitism skin cancer risk increased compared other immunosuppressives
grapefruit juice and cyclosporine
cyclosporine blood concentrations can be increased by juice through inhibition of microsomal enzyme CYP3A and p-glycoprtn multidrug efflux pump
preferred calcineurin inhibitor for transplantation due to ease of blood level monitoring
tacrolimus
similar MOA to cyclosporine
therapeutic use tacrolimus
prophylaxis of allograft rejection in solid-organ transplantation
adverse reactions tacroliums
nephrotoxicity hypertension DM neurotoxic grapefruit juice contra
purine antimetabolite used to inhibit lymphocyte proliferation
azathioprine
metabolized to 6-mercaptopurine –> purine synthesis blocked
lymphocytes don’t have a salvage pathway for purines
therapeutic uses for azathioprine
transplant rejection
RA
chron’s disease
adverse reactions azathioprine
bone marrow suppression: leukopenia, thrombocytopenia, anemia
hepatotoxicity
infection risk
cancer risk
MOA mycophenolate mofetil
prodrug hydrolyzed to selective inhibitor of inosine monophosphate dehydrogenase, required for de novo synthesis of guanine nucleotides –> selective inhibits lymphocyte proliferation because don’t have a salvage pathway
use for mycophenolate mofetil
prevent transplant rejection
combo therapy
treat lupus
adverse reactions mycophenolate mofetil
hematologic and GI
infections
congential abnormalities or spontaneous abortion with preggers
MOA sirolimus
inhibits t-lymphoctye proliferation by binding to FKBP simialr to tacrolimus
however, rather than inhibiting calcineurin, complex binds and inhibits mTor –> essential for cell cycle progression
therapeutic uses sirolimus
transplant rejections
renal transplant combo
characteristic antithymocyte globulin
rabbit serum containing purified gamma globulin specific to human thymocytes (antibodies to molecules on surface) including CD3)
–> complement mediated cytotoxicity or inhibition of lymphocyte function by binding to cell surface markers
therapeutic uses antithymocyte globulin
induction immunosuppression
prophylactic immunospurrpession
acute rejection
what can be used to combat the ‘cytokine storm’ from antithymocyte globulin?
glucocorticoids to prevent
see fever, chills, malaise
muromonab also has this side effect s
characteristics of muromonab-CD3
antibodies directed at CD3 cause the depletion of t lymphocytes therby causing immunosuppression
mouse antibody
therapeutic uses muromonab CD3
circulating t cells disappear from blood in minutes
used to reverse glucocorticoid-resistant organ transplant rejection
only can be used once (body figures it out)
chimeric monoclonal antibody containing a human constant region and murine variable region
infliximab
anti-TNFa reagent
recombinant human IgG1 monocolonal
adalimumab
anti-TNFa reagent
contains the lignad binding portion of human tNFa receptor fused to Fc portion of human IgG1
etanercept
anti-TNFa reagent
what does TNFa do?
inflammatory cytokine
implicated in pathogenesis of RA and crohns
