Immunosuppressants Flashcards by Reina Lopez

What is the MOA for Glucocorticoids?

they bind to the Glucocorticoid receptor and the glucocorticoid response element (GRE) and regulates transcription

This leads to decreased circulating lymphocyte levels and suppresses some subsets of T cells and antigen stimulation of T cell proliferation (T-cell production, IL2 production) and inhibits the function of phagocytes

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what is the clinical use for glucocorticoids?

prevent rejection (prophylaxix)

at high doses you can treat acute rejection episodes

GVHD

and autoimmune diseases (acute glomerular nephritis, autoimmune hemolitic anemia)

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Glucocorticoids

Adverse Effects

Endo: decreased hormone release

eye: glaucoma/cataracts

moon facies

buffalo hump

easy bruising

poor wound healing

Muscle wasting

renal system (fluid retention, electrolyte imbalances)

reduced fertility

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One of the most serious adverse effects of glucocorticoid use:

Osteoperosis

d/t increased bone resorption and decreased bone formation

decreased calcium absorption from gut

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Names of Glucocorticoids

Prednisone

Methylprednisolone

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Calcineurin inhibitors

MOA

Calcineurin inhibitors

decrease IL-2 transcription

Cyclosporine binds to cyclophillin

Tacrolimus binds to FKBP.

NFAT-P isn’t dephosphorylated which is required for interleukin synthesis

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Calcineurin inhibitors

route of administration

metabolism

IV or oral

CYP450 3A

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Calcineurin inhibitors

Clinical Usage

Calcineurin inhibitors

allograft transplantation (not effective in ongoing or acute rejection)

GVHD (used in combination with Methotrexate)

Psoriasis

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Calcineurin inhibitors

Black Box Warning

Calcineurin inhibitors

Skin cancer

increased risk of infection

nephrotoxicity

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Calcineurin inhibitors

what causes acute nephrotoxicity?

Calcineurin inhibitors cause acute nephrotoxicity thru vasoconstriction of afferent and efferent glomerular arterioles

the amount of vasoconstriction is dose related and usually reversible

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Calcineurin inhibitors

names

Calcineurin inhibitors:

Cyclosporine

Tacrolimus

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What are the cardiologic effects of Calcineurin inhibitors?

What effect does it have on K+?

Calcineurin inhibitors cause a moderate increase in

BP.

Calcineurin inhibitors can cause hyperkalemia because of the reduced efficiency of urinary K+ secretion. Can be life threatening with concurrent administration of an ACEi

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Sirolimus

Black Box

Sirolimus

Liver and lung transplants

can also cause hypokalemia, thrmbocytopenia, anemia, leukopenia, GI effects, edema, hypertension

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Sirolimus

Metabolism

Half-Life

Sirolimus

CYP450 3A and P-glycoprotein

(use caution if coadministered with cyclosporine and tacrolimus)

60 hours

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Sirolimus

MOA

Sirolimus

suppresses cytokine mediated T-Cell proliferation.

Binds to FKBP and forms a complex. This complex binds and blocks mTOR.

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Azathioprine

MOA

Azathioprine

inhibits DNA synthesis during the S phase

azathioprine is converted to 6-MP which decreases the purine nucleotide pool which is needed for DNA replication (required in general but especially after antigen stimulation)

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Azathioprine

what type of cells are most sensitive?

Azathioprine

proliferating cells (stimulated lymphoid cells) are most sensitive

T-Cells

but azathioprine depresses both cell mediated and antibody mediated reactions

Azathioprine

route of administration:

metabolism

Azathioprine

Oral

Metabolized by CYP450

inactivation is by Xanthine oxidase

Azathioprine

Black Box

Azathioprine

Increased risk of neoplasia (mutagenic)

can also cause GI toxicity at higher doses and Bone Marrow suppression (leukopenia is common)

Cyclophosphamide

MOA

Cyclophosphamide

prevents cell division by cross-linking DNA strands and decreasing DNA synthesis

Cyclophosphamide

clinical usage

Cyclophosphamide

immunosuppression is off-lable

used as an anticancer agent

Methotrexate

MOA

Methotrexate

irreversibly binds to and inhibits dihydrofolate reductase (DHFR)

Methotrexate

Clinical Usage

Methotrexate

GVHD (extensively)

Psoriasis

Methotrexate

Adverse Reactions

Pregnancy category X

Hepatotoxicity

Death

Induces Lung Disease

Mycophenolate mofetil MOA

Mycophenolate mofetil noncompetitive inhibitor of IMPDH (important for guanine synthesis) selectively inhibits T and B lymphocyte proliferation

Mycophenolate mofetil Clinical Usage

Mycophenolate mofetil administered with glucocorticoids maintenance of immunosuppression (has mostly replaced azathioprine for maintenance immunosuppression following organ transplants)

Mycophenolate mofetil Black Box

Mycophenolate mofetil **Malignancies** **Pregnancy (Category D)** may also cause bone marrow depression and GI upset

Anti-Thromocyte globulin (ATG) MOA

Anti-Thromocyte globulin (ATG) purrified gamma globulin from the serum of rabbits immunized with human thymocytes **cytotoxic antibodies against T lymphocytes**

Anti-Thromocyte globulin (ATG) Clinical Usage:

Anti-Thromocyte globulin (ATG) Acute rejection episodes Steroid resistant rejections

Anti-Thromocyte globulin (ATG) Adverse effects

allergic type reactions local pain and erythema

Muromonab-CD3 (OKT3) MOA

Muromonab-CD3 (OKT3) monoclonal Ab directed against CD3 on surface of human thymocytes and mature T cells causing the internalization of T cell receptor

Muromonab-CD3 (OKT3) Clinical Usage

Muromonab-CD3 (OKT3) acute organ transplant rejection depletion of donor bone marrow of T-cells prior to transplant (Minimise GVHD)

Muromonab-CD3 (OKT3) Adverse effects

Muromonab-CD3 (OKT3) Allergic responses Chills Fever Wheezing Cytokine storm

What is a cytokine storm?

Cytokine storm common to many antibody drugs that target lymphocytes, results from activation of T cells and release of T cell cytokines before the antibody-coated T cells can be cleared by macrophages. It typically occurs after the first few doses and the symptoms dissipate as T cells are eliminated premedicate with glucocorticoids, diphenhydramine, acetaminophen

Daclizumab and Basiliximab MOA

Daclizumab and Basiliximab monoclonal antibodies to part of IL-2 receptor (CD25) **IL-2 antagonist** but the mechanism isn't well understood Daclizumab- Humanized IgG1 Basilizimab- chimeric mouse-human IgG1

Daclizumab and Basiliximab Clinical usage

Daclizumab and Basiliximab **prophylasis against acute rejection** used in combination with cyclosporin and corticosteroids

Rh_o(D) immune globulin Clinical usage

Rh_o(D) immune globulin administered to pregnant women to prevent alloimmunization of Rh (-) mothers who may potentially have a fetus who is Rh (+)

What is the most common immunosuppressant for acute renal allograft rejection?

High dose corticosteroids are the first line therapy for acute renal allograft rejection. 2nd is Anti-T cell antibody therapy

What is the prophylaxis treatment for GVHD?

methotrexate + cyclosporine

What is the treatment for GVHD?

glucocorticoids are the most effective treatment option 2nd line agents include: cyclosporine, tacrolimus, antithymocyte globulin