Immunosupressents Flashcards
What are the poly clonal IgG against human T-lymphocytes?
Anthihymocyte globulin
Atgam; thymoglobulin
What are the co-stimulatory molecutles?
muromonab-CD3
Belatacept
What are the CD-25 inhibitors?
Daclizumab
Basiliximab
What are the CD52 inhibitors?
Alemtuzumab
What are the calcineurin inhibitors?
Cyclosporine
Tacrolimus
Pimecrolimus
What are the nuclear transcription inhibitors?
Methylprednisolone
What are teh mTOR inhibitors?
Sirolimus
What are teh cell cycle disruptors?
Mycophenolate mofetil
Azathioprine
MEthotr4exate
Cyclophosphamide
What is the point of cancer chemotherapy outside of anti-cancer?
controlling proliferation of T cell populations
release of what cytokine leads to T cell proliferation and clonal expansion?
IL-2
What is induction?
at time of transplantation; relatively intense; prolonged use of prohibitively toxic; may include donor specific transfusion or irradication as drug alternative
What is maintenance?
lower potency; tolerable in choric use; not with out side effects
ususally have tripple durg therapy
may recive only 1-2 drugs
can have long term toxicity
what are the three drugs uszed in maintenacne?
Calcineurin inhibitor
anti-proliferative
steroid
What is rescue?
intense, effective
chrinically intolerable; applied in response to rejeciton episode
What are the 9 ways to block T cell activation?
1) block CD3 tcell receptor
2) surface receptor target; CD28-CD80/86
3) inhibiting calcineurin– cant activate NFAT (nuclear factor of activated transcription)
4) block transcriptional regulation of pro-inflammatory genes
5) block CD25 with monoclonal antibodies
6) inhibiting mTOR
7) inhibit cell ceycle (2 ways)
- a) CD 52 recetpor– ADCC tagging
- b)target the Tcel lvia polyclonal IgG against human T-lymphocytes
what are the ways that monocolonal antibodies can act on a t-Cell?
antagonism
signalling
CDC
ADCC
What are the types of monoclonal antibodies?
murine
chimeric
humanized
human
What drugs act via antagonism?
Infliximab (ligand)
omalizumab (ligand)
natalizumab (receptor)
davlizumab (receptor)
What drug acts via signalling?
TGN1412 (acts as a CD28 superagonist)
What drug acts via CDC and ADCC?
Alemtuzumab
rituzximab
What are these patients recieving these drugs at risk for>
opportunistic infections and secondary maligancies, lymphoma and skin cancer
What are calcineurin inhibitors?
act by blocking calcineuring from activating NFAT, and not allowing it to enter the nucleus
which is the first phase of T-cell activation
functionally associated with ion channel regulation, receptor signalling, cell secretions etc
-each bind to specific proteins that aid in calcineurin fucntioning.
cyclosporine A - cyclophilin
tracrolimus to FK binding protein 12
Which of the calcineurins inhibitors is most potent?
tacrolimus compared to cyclosporine
what toxicity is related to calcinurine inhibitors?
Renal Toxicity doe/dependent nephrotoxicity HTN (cardiovascular) Neurotoxicity (Tacrolimus) gingival hyperplasia (cyclosporine) Secondary malignacies (lymphomas and skin cancer)
What is the mechanism of action for Cortiosteroids?
bind to the GR (glucocorticoid receptors) and the receptor-lingand complexes translocate to the nucleus and bind to coactivators to inhibit HAT in two ways.
What are the two ways of inhibiting HAT?
1) recruiting HDAC2 - reverses the histone acetylation (suppresion of inflammatory genes)
2) directl inhibition
What do the corticosteroids produce?
Neutrophila (^porduction; Vapoptosis)
Esoinopenia (^apoptosis)
monocytopenia (^apoptosis)
What are the adverse effects of corticosteroids?
-one of hte most potent classes of anti-inflammatory and immunosuppressive drugs
-protein metabolism dysfuntion (myopathy, impaired wound healing etc)
-increased susceptibility to infection
-hypercorticism (cushing’s sundrome)
-menstrual irregularity
-hyperglycemia
-hypercholesterolemia
etherosclerosis
fat embolism, thrombosis, thromboembolism, phlebittis
neurologic effects - insomnia, depression, anxiety
skin atrophy-
What is the mechanism of mTOR inhibitors?
bidns to FKBP12 (like tacrolimus) but inhibits activation of mammalian target of rapamycin (mTOR)
- inhibits second phase of activation: signal transduction adn clonal proliferation of T-cells
- prevents B-cell differentiation into antibody-producting cells, decreasing the levels of IgM, IgG, and IgA
What are mTOR inhibitors synergistic with?
cyclosporine (in vivo and in vitro)
What is a mTOR inhibitor and what are its adverse effects?
Sirolimus
-dose-related hyperlipidemia
thrombophlebitis, thromboembolism (pulomary DVT)
anemia, leukopenia, thrombocytopenia, hypokalemia, fecer and diarrhea
HYP
hepatotoxicity (fatal!!!!!)
opportunistic infections and secondary malignancies
What are the cell cycle disruptors?
micophenolate mofetil
azathioprine
cyclophosphamide
methotrexate
What is the mechanism of micophenolate mofetil?
a cell-cycle disruptor
blocks IMD and interupts DNA synthesase
affects primarity T adn B lymphocytes (cant synthesize GMP via salvage pahtway)
What are the side effects of micophenolate mofetil?
constipation, diarrhea, dyspepsia and nausea/vomiting
myelosuppression (neutropenia)- infrequently
infections and tumors
What are the advantages of mycophenolate mofetil?
- blocks the secondary antibody responses mediated by memory B cells
- selective effect on lymphocyte proliferation, unlike azathioprine or methotrexate
- no chromosomal breaks
What is the mechanism of azathioprine?
extensive metabolic conversion: 6-mercaptopurine (anti-cancer drug), 6 thioguanine
-a purine antagoinst; 6thio-IMP converted to 6-thi-GMP and is incorporated into DNA and stops cell cycle
What is the mechanism of 6 thoguanine triphosphate?
blocks co. stimulation of T cells to promote apoptosis in IL-2 stimulated memory T cells.
- inhibits RAC1
- blocks CD28 co. stimulation
What category is azathioprine in?
D
What are the adverse effects of azathioprine?
-decreased warfarin leves (V INR values)
TPMT inhibiotn by 5-aminosalicylates (^ azathioprine toxicity)
-mild GI upset
^ risk of skin cancer, esp with UV exposure
What enzyme test should be done on patients who are going to take azathioprine and what should be canged due to the results?
TPMT enzyme levels check; with deficent levels, azathiprine dose should be reduced
What is the cyclophosphamide mechanism?
must be metabolically actiated
is an alkylating agent and produces DNA cross-linds (intrastrand adn interstrand)
-effects B cells more thand T cells
What are the adcerse effects of cyclophosphamide?
dose limiting toxicity of— Hematologic
hemorrhagi cysits due to acrolein (metabolic by product)
-CV adn pulmonary issues
-long term use– fertility issues
What is the mechanism of methotrexate?
- a diyhydrofolate reductase inhibitor
- polyglutamated in cytoplasm to increase retention
- cause accumulation of AICAR
What is the purpose of AICAR accumulation?
inhibits ADA and AMP deaminase– adenosine accumulation
What are the effects of adenosine accumulation?
anti-inflammatory via AR on cells like macrophages to V IL-12, TNF-alpha, MIP-1a, and nitric oxide,
also ^ IL-10 and VEGF (both anti-inflamnatory)
-also leads to decreased Th1 and Th2 developemnt due to IL-12 release by DCs
What does methotrexate inhibit?
s-phase specific inhition
-tissues with high rate of cellular division (most snesitive)
What are the toxic effects of MEthotrexate? and is premedication requried?
- darrhea, N/V - premedication may be necessary (5HT3 antagonist and corticosteroid)
- Hematologic Toxicity
- Elevated hepatic enxmes
- Hepatotoxisity
- infections and neurologic syndrome
- a teratogen
Corticosteroids Drugs: Mechanism Route of admistration Route of Excreation Useage (maintaince or indcution) establish organ rejection..?
1) predinsone; methylprednisolone
2) antiinflammatory; inhibition of IL-2 production
3) IV/PO
4) Hepatic
5) Maintenance immunotherapy
6) Established rejection pulsed high-dose
Calcineurin inhibitors Drugs: Mechanism Route of admistration Route of Excreation Useage (maintaince or indcution) establish organ rejection..?
1) Cyclosporine; Tacrolimus
2) IL-2 bloackade; ihibitionof T-lymphocyte activation adn proliferation
3) IV/PO variable
4) Hepatic (CYP)
5) Maintenance immunotherapy
6) Ineffective
IL-2 Recetptor antagonist Drugs: Mechanism Route of admistration Route of Excreation Useage (maintaince or indcution) establish organ rejection..?
1) Basiliximab; Daclizumab
2) bloackade IL-2 receptor
3) IV
4) -
5) Induction agents for > 70% of de novo transplantation
6) Ineffective
Anti-lymphocyte antibodies Drugs: Mechanism Route of admistration Route of Excreation Useage (maintaince or indcution) establish organ rejection..?
1) Muromonab; Thymoglobulin
2) Anti-CD3 antibody; Anti-thymocyte Globuline– Deplete CD3 and Cells
3) IV
4) -
5) Induction agents for > 70% of de novo transplantation
6) Established rejection
Cell cycle and mTOR inhibitors Drugs: Mechanism Route of admistration Route of Excreation Useage (maintaince or indcution) establish organ rejection..?
1) Azathioprine; mycopheonolate; sirolimus
2) purine antagonist; purine biosynthesis inhibiotr; inhibition of IL-2 driven cell-cycle progression
3) IV/ PO; sirolimus- PO only
4) A & M Renal; S Hepatic (CYP)
5) maintenacne immunotherapy
6) ineffective
what drugs are contranindicated in breastfeeding?
cyclosporine tacrolimu azathioprine methotrexate cyclophosphamide
What categorey is MTX? and what are the other cell cycle disruptors?
cat X; cat D
What are the three monoclonal antibodies that casue cyokine relase upon infusion?
alemtuzumab, muromonabe-CD3, and TGN1412
What does alemtuzumab recognize?
CD52 on T cells, efficient complement- dependent lysis of lymphocytes
What does Muromonabe target?
CD3 on Tcell receptor comples
What does TGN1412 targert?
CD28
What is TGN1412
a superagopnist, that co-stimulates activation of naive T cells
