58: Immunosuppressants

Question 1

adverse effects of immunosuppression include..

Answer 1

infectious disease

malignancy

Question 2

MOA glucocorticoids

Answer 2

• 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))

Question 3

effects of glucocorticoids

Answer 3

• 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

Question 4

therapeutic uses glucocorticoids

Answer 4

• transplant rejection
• graft v. host disease
• cytokine storm in transplant caused by treatment with muromonab CD3 and antithymocyte globulin
• autoimmune disorders

Question 5

adverse effects glucocorticoids

Answer 5

• adrenal crisis upon rapid withdrawal
• cataracts
• avascular necrosis of bone
• poor wound healing
• growth retardation
• hyperglycemia

Question 6

prednisone equivalent =

Answer 6

amount of prednisone or its equivalent

Question 7

dosing glucocorticoids
low
medium
high 
very high 
pulse

Answer 7

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

Question 8

MOA cyclosporine

Answer 8

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

Question 9

therapeutic uses cyclosporine

Answer 9

transplantation * not given renal because nephrotoxic
RA
psoriasis
combinations

Question 10

adverse reactions cyclosporine

Answer 10

nephrotoxic
HTN
hyperlipidemia
tremors of hands and feet
swollen and painful gums
hirsuitism
skin cancer risk increased compared other immunosuppressives

Question 11

grapefruit juice and cyclosporine

Answer 11

cyclosporine blood concentrations can be increased by juice through inhibition of microsomal enzyme CYP3A and p-glycoprtn multidrug efflux pump

Question 12

preferred calcineurin inhibitor for transplantation due to ease of blood level monitoring

Answer 12

tacrolimus

similar MOA to cyclosporine

Question 13

therapeutic use tacrolimus

Answer 13

prophylaxis of allograft rejection in solid-organ transplantation

Question 14

adverse reactions tacroliums

Answer 14

nephrotoxicity
hypertension
DM
neurotoxic
grapefruit juice contra

Question 15

purine antimetabolite used to inhibit lymphocyte proliferation

Answer 15

azathioprine

metabolized to 6-mercaptopurine –> purine synthesis blocked

lymphocytes don’t have a salvage pathway for purines

Question 16

therapeutic uses for azathioprine

Answer 16

transplant rejection
RA
chron’s disease

Question 17

adverse reactions azathioprine

Answer 17

bone marrow suppression: leukopenia, thrombocytopenia, anemia
hepatotoxicity
infection risk
cancer risk

Question 18

MOA mycophenolate mofetil

Answer 18

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

Question 19

use for mycophenolate mofetil

Answer 19

prevent transplant rejection
combo therapy
treat lupus

Question 20

adverse reactions mycophenolate mofetil

Answer 20

hematologic and GI

infections

congential abnormalities or spontaneous abortion with preggers

Question 21

MOA sirolimus

Answer 21

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

Question 22

therapeutic uses sirolimus

Answer 22

transplant rejections

renal transplant combo

Question 23

characteristic antithymocyte globulin

Answer 23

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

Question 24

therapeutic uses antithymocyte globulin

Answer 24

induction immunosuppression
prophylactic immunospurrpession
acute rejection

Question 25

what can be used to combat the ‘cytokine storm’ from antithymocyte globulin?

Answer 25

glucocorticoids to prevent

see fever, chills, malaise

muromonab also has this side effect s

Question 26

characteristics of muromonab-CD3

Answer 26

antibodies directed at CD3 cause the depletion of t lymphocytes therby causing immunosuppression

mouse antibody

Question 27

therapeutic uses muromonab CD3

Answer 27

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)

Question 28

chimeric monoclonal antibody containing a human constant region and murine variable region

Answer 28

infliximab

anti-TNFa reagent

Question 29

recombinant human IgG1 monocolonal

Answer 29

adalimumab

anti-TNFa reagent

Question 30

contains the lignad binding portion of human tNFa receptor fused to Fc portion of human IgG1

Answer 30

etanercept

anti-TNFa reagent

Question 31

what does TNFa do?

Answer 31

inflammatory cytokine

implicated in pathogenesis of RA and crohns