Immunosuppressants Flashcards
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
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)
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
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
Names of Glucocorticoids
Prednisone
Methylprednisolone
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
Calcineurin inhibitors
route of administration
metabolism
IV or oral
CYP450 3A
Calcineurin inhibitors
Clinical Usage
Calcineurin inhibitors
allograft transplantation (not effective in ongoing or acute rejection)
GVHD (used in combination with Methotrexate)
Psoriasis
RA
Calcineurin inhibitors
Black Box Warning
Calcineurin inhibitors
Skin cancer
increased risk of infection
nephrotoxicity
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
Calcineurin inhibitors
names
Calcineurin inhibitors:
Cyclosporine
Tacrolimus
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
Sirolimus
Black Box
Sirolimus
Liver and lung transplants
can also cause hypokalemia, thrmbocytopenia, anemia, leukopenia, GI effects, edema, hypertension
Sirolimus
Metabolism
Half-Life
Sirolimus
CYP450 3A and P-glycoprotein
(use caution if coadministered with cyclosporine and tacrolimus)
60 hours
Sirolimus
MOA
Sirolimus
suppresses cytokine mediated T-Cell proliferation.
Binds to FKBP and forms a complex. This complex binds and blocks mTOR.
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)
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)
RA
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
Rho (D) immune globulin
Clinical usage
Rho (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
