Immunosuppressants Flashcards
Why did allograft transplants become widespread in 1983?
cyclosporine - it replaced steriods and azathioprine
What has been a new therapy?
ATG
Induction?
drugs given at time of transplantation, relatively intense, prolonged use
Maintenance?
lower potency, tolerable in chronic use
Rescue?
intense and effective. chronically intolerable, applied in response to rejection
What does maintenace therapy usually involved?
3 drugs: CNI, anti-proliferative, and steriods
What does an anti-CD3 ab do?
prevents T cell activation
What does an antiCD28 ab do?
blocks co-stimualtory signal so no activation of T cells so apoptosis
Anti-CD25 ab?
prevents adjacent T cell from becoming activated by IL2 so diminished T cell clonal expansion
mTOR inhibition?
normally activated by IL2 so w/ inhibition prevents cell cycle
anti CD52 ab?
binding of mAb identifies cell for lysis
Calneurin normal roles?
APC interacts w/ TCR and increase ctoplasmic Ca –> calmodulin –> calneurin activated. controls nuclear access of NFAT via dephosphorylation to activate IL2 genes
CNI effect?
prevention of upregulation of IL2
CDRs w/ Fab reiong can do what?
antagonism or signalling
F2 region of mAb can do what?
complement fixation or bind Fc receptors for ADCC
What are cell surface drugs?
Muronomab, Basiliximab, Daclizumab, Rabbit ATG, Alamtuzumab, Belatacept
What does Muronomab do?
mAb, depletes T cells, binds CD3, IV
What does Basiliximab and Daclizumab do?
mAb, bind CD25 (IL2 receptor), take via IV
What does Rabbit ATG do?
depletes T cell and has many Ags, IV
What does Alamtuzumas do?
mAb, depletes T cells, binds CD52
What does Belatacept do?
mAb, depletes T cells, binds oto CD28
What are so regular issues of cell surface drugs?
risk of opporunitistic infections so give them prophylactic drugs to prevent infection. Secondary malignicies and cytokine release syndrome
What are side effects of Muronomab?
angioedmea, hypovolemia, pulmonary edema
What is special about Belatacept?
don’t give in EBV negative patients
What are the two CNI drugs?
take IV/PO
- cyclosporine + cyclophilin
2. tacrolimus + FKBP12
Side effects of CNI drugs?
- renal toxicity - increased CK, BUN
- sometimes difficult to differentiate kidney rejection from drug toxicity
- CV, neurotoxicity, ginival hyperplasia, hypertrichosis, HTN
How do corticosteriods work?
IV/PO
Bind to Gr and translocate to nucleus and bind to CBP, recruit HDAC2 to deacetylate histones to decrease gene expression of inflammatory genes
Adverse effects of steriods?
chronic use associated w/ a lot of problems
- protein metabolism dysfunction, hypercorticism, hyperglycemia, increased DM, neurologic effects due to cell surface receptor, skin strophy, impairs wound healing
What is a mTOR inhibitor?
sirolimus
how does sirolimus work?
PO only
binds FKBP12 and inhibits signal transduction and clonal proliferation of T cells (second phase activation).
- no effect on calcineurin activity, synergistic w/ cyclosporine
- drug targets also expressed in nonimmune cells - side effects
- prevents clonal expansion and B cell differentiation into Ab producing cells
side effects of sirolimus?
hepatotoxicit, renal toxicity, HTN, anemia, etc
What are cell cycle disruptors?
- micophenolate mofetil
- Azathioprine
- Cyclophosphamide
- Methotrexate
How does micophenolate mofetil work?
IV/PO
inhibits IMP DH and prevents DNA synthesis and affects S phase
What cells are primarily affected by MM?
T and B cells - can’t make GMP through salvage pathway
- blocks secondary Ab responses, inhibits T cell proliferation, no chromosomal breaks
What is the most common side effect of MM?
GI tract
How does azathioprine work?
IV/PO
metabolic products = 6MP and 6 thioGTP
-6thioGTP blocks co-stimulation of Tcells and promotes apoptosis in IL2 stimulated memory T cells
Category D?
regards to potential for birth defects
Azathioprine
Side effects of azathioprine?
- . skin cancer - avoid UV
- monitor CBC and liver E’s, take pregnancy test before taking drug, dose reduction is impaired TPMT
How do cyclophosphamides work?
pro-drug that needs to be activated
- alklyating agent that cross links DNA
- lymphogenic drug that affects B cells more than T cells
Adverse effects of cyclophosphamides?
CV and pulmonary issues, pulmonary fibrosis and interstitial pneumonaie
Methotrexate basics?
DHF reductase inhibitor, effluxed by ABC transporters, and polymorphisms in genes affect efficacy and toxicity, S phase inhibition
How does methotrexate work?
converted to MTXPG via GGH. MTXPG impedes folate and inhibits de nove pyrimidine synthesis so AICAR builds up. AICAR inhibts ADA and AMP deaminase – adenosine accumulates
What does adenosine do?
Binds to receptors on monocytes and macrophages and decreases IL12, TNF alpha, MIP1a, and NO and increases secretion of anti-inflammatory IL10 and VEGF
Adverse effects of Methotrexate?
hematologic effects, high liver enzymes, heptatoxicity, neurologic syndrome, TERATOGEN, acute reactions
What are maintenace drugs?
steriods, CNI, Azathioprine, mycophenolate, and sirolimus
What are induction drugs?
Basiliximab, daclizumbas, muromonab, ATG (all cell surface targets)
Drugs and pregnancy and lactation?
Cat D and X - never give
Cat C and B - give w/ cation
-don’t give most of the cells during breastfeeding
What 2 drugs causes cytokine release?
- alemtuzumab
- muromonab
- TGN1412
