Pharm: Immunosuppressants Flashcards
Immunosuppressive drugs acts To suppress T cells in two ways, or at two different stages/phases. What are they?
- to inhibit T cell activation
2. to inhibit clonal expansion of T cells
Regarding immunosuppressive regimens, induction refers to ___.
employing a high dose of immunosuppressant at the time of organ transplantation; toxic with prolonged dosing
Regarding immunosuppressive regimens, maintenance refers to ___.
employing a low dose of immunosuppressant for chronic use; not as toxic as induction/rescue doses but also not without side effects. Typically uses a triple-drug therapy with agents that act at different levels of the inflammatory cascade
Regarding immunosuppressive regimens, rescue refers to ___.
dose of immunosuppressant taken in response to a rejection episode; chronically intolerable
What is CD3 and what is the effect of blocking it?
CD3 is a component of the T cell receptor; blocking it prevents T cell activation
What is CD28-CD80-86 and what is the effect of blocking it?
CD28 is on the T cell, CD80-86 is on the APC; these proteins’ interaction is critical for co-stimulation so blocking it leads to a failure to fully active the T cell and it eventually apoptoses
What is calcineurin, and what is the effect of blocking it?
a phosphatase located within a T cell; it is responsible for activating a nuclear factor of activated transcription (NFAT). Without activity of NFAT, the T cell will not transcribe IL-2
Within the nucleus of a T cell, glucocorticoid drugs inhibit ____ of ____ genes, which diminished the T cell’s ability to release ____.
transcription; pro-inflammatory; IL-2
What is CD25, and what is the effect of blocking it?
CD25 is the receptor on the T cell surface that bind IL-2; blocking the CD25 receptor would remove the T cell’s ability to bind and respond to IL-2, thus diminishing clonal expansion
When a T cell is activated by IL-2, ____ is activated within the cell, initiating the cell cycling that is critical to ____ ____.
mTOR; clonal expansion
When polyclonal IgG is used on lymphocytes, the result is ____ of the lymphocytes via ___ and ___ (what mechanisms?).
depletion via complement-dependent opsonization and lysis
In general, the CDR/antigen-binding region of mAbs (monoclonal antibodies) binds to specific targets and causes ____ or ____.
antagonism or signaling
The Fc region of a mAb is composed of the hinge and constant domains of the heavy chains, and binds ____ receptors, and is also involved in ____ ____.
Fc receptors; complement fixation
mAbs can bind either to ____ or ____, ultimately preventing stimulation of the T cell.
receptors; ligands
What are the options when a mAb binds a receptor?
it can either prevent stimulation at the receptor, or induce signal transduction (superagonist)
What are the functions of mAbs controlled by the Fc region?
- complement-dependent cytotoxicity (CDC)
- antibody-dependent cell-mediated cytotoxicity (ADCC)
- antibody-dependent cellular phagocytosis
Just for fun: what are the nomenclature meanings of mAb drugs?
'o' = murine 'xi' = chimeric 'zu' = humanized 'u' = human -mab = monoclonal anitbody
True or false (and why?): Muronamab is a mAb drug that targets IL-2 and is lymphocyte depleting.
False - muronamab (OKT3) targets CD3.
True or false (and why?): Basilizimab is a mAb drug that targets Multiple targets and is lymphocyte depleting.
False - basiliximab (Simulect) targets IL-2 receptor (CD25) and IS NOT lymphocyte depleting. Alternatively rabbit ATG (Thymoglobulin) - which is a pAb - has multiple targets and is lymphocyte depleting.
What drug targets CD80/86 (B7)?
Belatacept, aka Nulojix, a mAB
What are the greatest risks to patients taking immunosuppressants? (Not side effects, but rather consequences of immunosuppression)
- opportunistic infections
- secondary malignancies - lymphomas, skin cancer, lymphoproliferative disorder (proliferation of B cells due to therapeutic immunosuppression after organ transplantation; some could mutate and cause lymphoma)
What is calcineurin, and what is its role in T cell signaling?
calcineurin is an intracellular phosphatase; when APCs interact with T cell receptors, Ca enters the cell and activates calcineurin; when activated it dephosphorylates NFAT; NFAT enters the nucleus and becomes a TF for gene products that active T cells (IL-2 and IFg) and B cells (IL-4)
What drugs inhibit calcineurin? What proteins does each associate with in order to carry out its inhibitory function?
cyclosporine - binds cyclophilin
tacrolimus - binds FK binding protein 12
Patients taking calcineurin inhibitors are at risk for dose/duration-dependent ____, but this is sometimes hard to differentiate from ____ ____.
nephrotoxicity; graft rejection
Mild-moderate HTN caused by increased sympathetic tone and renal vascoconstriction can be cause by what drug?
cyclosporine
What are the major side effects seen in patients taking cyclosporine?
nephrotoxicity, HTN, hirsutism, hypertrichosis, and gingival hyperplasia; then of course infections and secondary malignancies
Corticosteroids are a drug targeted at ____. Explain their MOA.
the nucleus: corticosteroid brought into cell, binds a cytosolic GR, complex moves into the nucleus, binds coactivators, and all together they inhibit HAT (histone acetyltransferase) AND recruit HDAC2 (histone deacetylase-2) to suppress activated inflammatory genes
Corticosteroids, in addition to inhibiting T cell activity, also produce ____, which is ____ production.
neutrophilia; increased
____ are one of the most potent classes of anti-inflammatory and immunosuppressive drugs that are available clinically.
corticosteroids
Adverse effects of corticosteroids include ____ as a result of their interaction with transcriptional regulation. They also cause neurologic issues because of their interactions with ____.
adverse metabolic effects; cell surface receptors
Sirolimus is an inhibitor of ____. It binds to ____ and causes ____ arrest.
mTOR; FK-binding protein 12; G1 phase
True or false: sirolimus has no effect on ____ activity, but is synergistic with ____.
calcineurin; cyclosporine
Sirolimus has what effect on B cells?
prevents their differentiation into antibody-producing cells, thereby decreasing the levels of IgM, G, and A
mTOR is not exclusively a component of immune cells. What implications does this have for patients taking sirolimus?
this means that sirolimus can inhibit mTOR elsewhere in the body, leading to ADEs with effects on non-lymphoid tumor cells, smooth muscle cells, hepatocytes, and fibroblasts
What are the major adverse effects of sirolimus?
dose-related HLD; azotemia (high N-containing components of blood); PE, DVT; anemia, leukopenia, thrombocytopenia, hypoK, diarrhea; HTN; hepatotoxicity including fatal hepatic necrosis; infections/tumors; renal toxicity
Mycophenolate mofetil is an inhibitor of ____ and thereby interrupts ____.
monophosphate dehydrogenase, DNA synthesis
*MDH converts inosine MP to guanosine MP in purine synthesis
Why does mycophenolate mofetil work primarily on T and B lymphocytes?
these cells can’t synthesize GMP sufficiently through the salvage pathway, so when mycophenolate mofetil interrupts GMP synthesis, it’s all over
What are the most common side effects of mycophenolate mofetil?
GI tract issues - constipation, diarrhea, dyspepsia, N/V; infections/tumors; myelosuppression occurs infrequently
Azathioprine is a cell cycle disruptor drug that undergoes extensive metabolic conversion to several products. Two of its products are 6-thioguanine TP and 6-thio-IMP. What is the MOA of these products?
6-thioguanine TP = blocks co-stimulation of T cells and promotes apoptosis in IL-2 stimulated memory T cells
6-thio-IMP = inhibts purine synthesis because this is a fraudulent purine which gets incorporated into DNA, resulting in cell cycle arrest
What drugs, when taken together with AZA, can increase AZA toxicity?
allopurinol; 5-aminosalicylates (because they inhibit TPMT, an enzyme needed for AZA metabolism)
____, a cell cycle disruptor, is a ___ requiring metabolic activation.
Cyclophosphamide; pro-drug
Describe the MOA of cyclophosphamide.
it’s an alkylating agent, producing DNA cross-links
Why does cyclophosphamide have its greatest effect on humoral immunity?
because it’s a lymphopenic drug, affecting more B cells than T cells
Methotrexate (MTX) is a ____ inhibitor.
DHF reductase
MTX is converted to ____ within the cell by ____. This product has three effects: 1)____; 2)____; 3)____.
MTXPG, GGH.
- impede generation of bioactive forms of folate
- inhibit de novo pyrimidine synthesis
- cause AICAR accumulation which inhibits ADA and AMP deaminase, causing adenosine accumulation
What is the effect of accumulated adenosine, as is the result of MTX activity?
adenosine, when bound to adenosine receptors on macrophages, decreases pro-inflammatory IL-12/TNF-a/MIP-1a/NO and increases anti-inflammatory IL-10/VEGF; it also suppresses IL-12 production by mature DCs which means diminished Th1 and increased Th2 development
Major side effects of MTX include:
diarrhea, N/V, pulmonary fibrosis, hematologic toxicity, hepatotoxicity, infections, neurologic syndrome, tertogen
(these are relatively infrequent but serious)
True or false: most immunosuppressant drugs have relatively significant interethnic differences in pharmacokinetics.
True - because of the different levels of CYP3A4 and P-gp (metabolizers) in the intestine and liver
Which organ has the best response to immunopharmacologic agents, and which has the least best response?
renal = best liver = least best
Induction of immunosuppression is commonly effected with which agents?
basiliximab or thymoglobulin
Maintenance of suppression often involves which drugs?
AZA, prednisone, cyclosporine
