- suppress t-cell mediated immunity - important for transplant rejection and automimunity - complex with cycophillin - cytoplasm protein in cells --> binds calcineurin-->prevents NFAT transcrtiption factor from entering nucleus ===> no IL 2 = no t-cell maturation

- prophylaxis for Kidney, liver, heart, and other organ transplant - tx of graft vs host disease - Rheumatoid arthritis that doesnt respond to methotrexate - psoriasis - not given prior to renal transplants = nephrotoxic

-Renal dysfunction -hirsutism - HTN - hyperlipidemia - tremor hands and feet - dont drink with grapefruit drinkis = inc cyclosporin concentrations

- neprotox (careful with renal transplants) - HTN - diabetes melitus (neg effect on beta cells) - neurotox - do not take with grapefruit juice = dangerousl high blood oncentrations bc CYP3A enzymes inhibited

Immunosuppressant Flashcards by Art F

Define: Prednisone Equivalent doses nomenclature?

-A 5 mg prednisone dose has equivalent effect to other short, long, or intermediate acting glucocorts regardless of concnetration

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glucocorticoids

-MOA?

1) genomic effects: direct to DNA = inhibit gene expression = fewer immune and inflammatory cytokines
2) non-genomic: cell signalling pathways affected - rapid immune suppression via signalling (cant be genomic bc that is slow change)

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Glucocorticoid effects:

rapid dec in periph blood lymphs
downreg pro inflammatory cytokines IL1, IL6 TNF-a, interferon-y
inhibit IL2 = needed for T-cell maturation
reduce neutrophil chemotaxis and lysosomal enzyme release
LITTLE EFFECT ON HUMORAL

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Glucocorticoid therapeutic uses:

prevent/treat transplant rejectino (combo therapy)
treat Graft v hot disease with BM transplant
block first dose cytokine storm in transplant recipeints by tx with muromonab-CD3 and antithymocyte globulin
tx autoimmune disorder… long list

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Glucocorticoids AE:

1) disabling/life threatening
- growth retardation
* **-inc risk inf
- poor wound healing
- HTN
- avascular necrosis of bone
- cataracts
- hyperglycemia
* **-adrenal crisis upon rapid discontinuation

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Prevent rapid withdrawal or reduced doses of glucocorticoid AE how?

-use combined glucocorticoid calcineurin inh protocols

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Low dose glucocorticoid definition:

less than or equal to 7.5mg of prednisone equiv per day

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Medium dose glucocorticoid definition:

greater than 7.5 mg, but less than or equal to 30mg prednisone equiv per day

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High dose glucocorticoid definition:

greater than 30mg but less than or equal to 100mg prednisone equiv per day

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Very high dose glucocorticoid definition:

> 100mg prednisone equiv per day

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Pulse therapy glucocorticoid definition:

greater than 250mg prednisone equiv per day for 1 day or a few days

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Cyclosporine

-type?

Calcineurin inhibitors

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Cyclosporine

-MOA?

suppress t-cell mediated immunity - important for transplant rejection and automimunity
complex with cycophillin - cytoplasm protein in cells –> binds calcineurin–>prevents NFAT transcrtiption factor from entering nucleus ===> no IL 2 = no t-cell maturation

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Cyclosporine

-Uses:

prophylaxis for Kidney, liver, heart, and other organ transplant
tx of graft vs host disease
Rheumatoid arthritis that doesnt respond to methotrexate
psoriasis
not given prior to renal transplants = nephrotoxic

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Cyclosporine

-AE?

*-Renal dysfunction
*-hirsutism
HTN
hyperlipidemia
tremor hands and feet
dont drink with grapefruit drinkis = inc cyclosporin concentrations

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Tacrolimus

-type?

Calcineurin inh

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Tacrolimus

-MOA?

-binds FK-binding protein –> binds calcineurin –> prevents translocation of NFAT to nucleus –> no IL-2

(similar to cyclosporin)

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Prefered calcineurin inh bc easier to monitor blood concentration (cyclosporin or tacrolimus)?

Tacrolimus

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Tacrolimus

-uses?

-prophylaxis of allograft rejection in solid organ transplantation

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Tacrolimus

- AE?

neprotox (careful with renal transplants)
HTN
diabetes melitus (neg effect on beta cells)
neurotox
do not take with grapefruit juice = dangerousl high blood oncentrations bc CYP3A enzymes inhibited

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Azathioprine

-what is it?type?

anti-proliferative/metabolic agent

- purine antimetabolite –> inh lymphocyte proliferation

Azathioprine

-MOA?

1) metabolized 6-MP –> comvereted to other stuff–> this other stuff incorporated into DNA ==> inh lymph proliferation
2) blocks de-novo synth of purine
- -> lymphs do not have a significant pure salvage pathway

Azathioprine

-AE?

1) BONE MARROW SUPPRESSION
- leukopenia, anemia, thrombocytopenia
2) liver tox
3) inc susceptibility to HSV and VZV
4) Inc risk of cancer -lymphoma

NEED TO MONITOR CBC AND LIVER FUNCTION!

Azathioprine

-uses:

1) prevention of organ transplant rejection
2) severe cases of rheumatoid arthritis
3) some CD, MS, and prednisone resistant antibody mediated idiopathic thrombocytopenic purpura and autoimmune hemolytic anemias

Mycophenolate mofetil - type? - characteristics probably not worth knowing?

- Anti-proliferative/metabolic agent - newer than azathioprine - delayed release tablet releases drug in intestines

Mycophenolate mofetil | -MOA?

- prodrug = rapidly hydrolyze to mycophenolic acid (MPA) - MPA - selective inh of inosine monophos dehydrogenase --> need to de-novo synth of guanine nucleotides - B and T cells use this path and have no salvage compared to other cells

Azothioprine inh? | Mycophenolate mofetil inh?

- blocks de-novo synth of purines | - blocks denovo synth of guanine

Mycophenolate modefil | -uses?

- prophylaxs of transplant rejection - combo with glucocorticoids and calcineurin inh - lower doses of glucocortcoids needed - off label to treat lupus

Mycophenolate Modefil | -AE?

-hematologic issues -GI usual ^^(better than azathioprine) -inc infection with CMV -congenital abnormalities - cleft lip, heart defects and pregnancy loss

Inc risk of CMV infectin with? Inc risk of VZV and HSV inf with?

- Mycophenolate Modefil | - Azathioprine

Serolimus - type? - use?

- Anti-proliferative/metabolic | - protects kidney from nephro toxic effects of calcineurin inh - combo therapy!

Serolimus | -MOA?

- binds FKBP (like tacrolimus) --> BUT NOT INHIBITING CALCINEUIN - INSTEAD binds to protein kinase mTOR ==> stops cell cycle progression in lymphocytes (G1 to S)

mTOR inh=

serolimus

Serolimus | -uses?

- prophylaxis of organ transplant rejection IN COMBO with glucocorticoids and a reduced dose of calcineurin inh - good in renal transplant patients that cant tolerate calcineurin inh bc of kidney toxicity

Serolimus | -AE?

- delayed wound healing* - hypokalemia - anemia,leukopen,thrombocytop - GI - inc risk of infections - increase cancer - lymphoma

Antithymocyte globulin | -what is it?

-rabbit serum containing purified gama globulin specific to human thymocytes

most commonly used llymphocyte depleting agent?

antithymocyte globulin

Antithymocyte globulin | -MOA?

-basically antibodies that bind a whole bucnh of inflammatory and growth factors on T-LYMPHOCYTES ESP CD3!!!! NEED CD3 TO MAKE T_CELLS WORK- we get rid of this To get rid of: -Complement mediated cytotox = lysing lymphocytes inh of lymph funcitons by bindibg to cell

Antithymocyte lobulin | -USES?

- induction immunosuppression - after transplant - prophylactic immunosuppression - tx of acute rejection of solid organ transplants IN COMBOwith other drugs

Antithymocyte globulin AE:

- fever chlls and that shit - serum sickness - anaphylaxis - leukopenia and thrombocytop - malignancy -lymphoma probs - infection

Muromonab-CD3 | -type/info?

- biological - from mouse | - CD3 is important for T-cell activation!!

Muromonab-CD3 | -MOA?

-antibodies againsts CD3 Functionally get rid of lymphocytes: bind CD3 on membrane Literally get rid of lymphocytes complement mediated destruction

Great for glucocorticoid resistant organ transplant reaction episodes?

muromonab-CD3

Muromonab Cd3 | -uses:

- glucocorticoid resistant organ transplant reaction episodes - repeat treatment course with drug not useful = human makes antibody for the mouse antibodies

Muromonab CD3 | -AE?

-cytokine storm: within 30 min inflammatory cytokines tnf-a and interferon-y = chills, fever... that shit --> helps to give glucocorticoid first - vomit, diarrhea,, tha shit - anaphylaxis, pumonary arrest....

Anti-TNF-alpha reagents | -drugs in this category?

- inflixmab - adalimumab - etanercept -good for treating conditions with TNF-alpha mediated inflammation (CD and Rheum arthritis)

Anti-TNF-alpha reagents | -MOA?

-bindsTNF-alpha = prevent from binding its receptor

Infliximab - derived from?

-chimeric human constant region and mouse variable (binding) region

Adalimumab - what is it?

-recomb human IgG1 monoclonal

Etanercept - what is it?

contains ligand-bidning portion of a human TNF-alpha receptor fused to Fc proteion of IgG1 (part antibody part TNF-a) ALL HUMAN

Anti-TNF-alpha reagents | -uses:

-rheumatoid arthritis -CD -UC plaque psoriasis

anti-TNF-a reagent AE?

- inc risk for serious infections | - inc risk for lymphomas and other malignancies