1.
ANTI-METABOLITES + CYTOTOXIC DRUGS: many of those used in cancer therapy can also inhibits B + T lymphocytes
2.
ANTIBODIES: ...
3.
basiliximab: another murine-human chimeric cd25 mab
4.
CALCINEURIN INHIBITORS: cyclosporine and tacrolimus
5.
describe anti-thymocyte globulins: - immunization of animals with human thymic lypmphocytes
- depelete thymocytes + block function by binding cell surface antigens
6.
describe daclizumab anti-cd25 mabs: humanized mabs against cd25 of IL2 receptors
- specific for activated and not resting T cells
7.
describe mycophenolate mofetil: ...
8.
describe the immunosuppresant activity of Glucocorticoids: widely used for allograft rejection, autoimmune disorders, arthritis, lupus, asthma, allergic disorders, etc
9.
describe the pharmokinetics of mycophenolate mofetil: absorbed rapdily + hydrolyzed to mycophenolic acid
10.
describe the toxicity of mycophenolate mofetil: leukopenia, diarrhea + vomitting
- increased infections, CMV/sepsis
11.
described anti-CD3 monoclonal abs: - raised against CD3 receptor on T cells
- depletes most T cells from blood and peripheral lymphoid organs
- reduces function of remaining T cells
12.
How do antibodies act as immunosuppressants: antibodies raised against lymphocyte cell surface antigens intefere with their activation + function of lymphocytes or causing depletion
13.
how is immunosuppressive therapy performed?: apply multi-tiered immunosuppressive therapy using several agents simultaneously
- each directed at different target to achieve synergy
- allows use of lower doses of each agent to limit tox.
14.
mTOR INHIBITORS (mammalian target of rapamycin): sirolimus (rapamycin) and everolimus
15.
what are the adverse effects of CD3 mabs: cytokine release syndrome (activation of T cells before destruction)
- hypersensitivity reactions
16.
what are the disadvantages to glucocorticoids: extensive use leads too
- growth retardation in children, Osteoporosis
- increased risk of infections, ulcers, hyperglycemia, HTN, diabtes
17.
what are the drug interactions of azathioprine?: metabolized by xanthine oxidase ( in liver + metabolizes purines)
- allopurinol inhibits xanthine oxidase and can lead to increase tox
18.
what are the drug interactions of calcineurins: interact with drugs that effect P450 enzymes
- interacts with sirolimus (mTOR inhibitor)
19.
what are the drug interactions of mTOR inhibitors: rapamycin interacts with cyclosporine to increase renal tox.
- admin of drug should be separated by time
20.
what are the drug interactions of mycophenolate mofetil?: administration with antacids (mg or al OH) decreases absorption
- no cholestyramine (prevents bile absorption)+ other drugs that effect enterohepatic circulation
21.
what are the pharmokinetics of cyclosporine: - very hydrophobic --> administered IV or capsule
1/2 life is 5-18hrs
- metabolized by liver, with hepatic dysfunction dosage adj required
22.
what are the side effects of anti-thymocyte abs: fever, chills + potentially hypotension (due to injection of foreign abs)
- slow injection, pretreat with corticosteroids, acetaminophen/antihistamine can minimize effects
- can cause leukopenia + thrombocytopenias
23.
what are the therapeutic uses of azathioprine: major agents for transplant rejection
- for those who dont respond to glucocorticoids or cyclosporine
- severe RA , crohns, and MS
24.
what are the therapeutic uses of mTOR inhibitors?: organ transplantation- used alone or with calcineurin inhibitors and glucocorticoids
- can be used topically
- rapamycin also in drug eluting stents to prevent restenosis
- anti cancer drug too
25.
what are the therapeutic uses of mycophenolate mofetil?: renal transplants
- combined iwth calcineurin inhibitors + glucocorticoids
- lupus, RA, dermatological disorders
26.
what are the use of tacrolimus: similar uses but much higher potency
27.
what are the uses for cyclosporine: transplantation of kidney, heart, liver, bone marrow, lung and pancreas
- monotherapy or with glucocorticoids
graft vs host disease + autoimmune disorders (psoriasis, RA, crohns)
28.
what are the uses for immunosuppressive drugs?: prevent graft rejection and for treatment of autoimmune diseases
29.
what are the uses of daclizumab: used as triad of drugs --> cyclosporine/tacrolimus + steroids + mycophenolate mofetil
30.
what is a thymocyte?: progenitor cells in thymus that mature into T cells
31.
what is azathioprine: purine anti-metabolite + prodrug of mercaptopurine
32.
what is the MOA of azathioprine: cleaved to mercaptopurine and converted to thio-GTP which can be incorporated into DNA
- inhibits cell proliferation causing death
33.
what is the MOA of cyclosporine: binds to cyclophilin and inhibits calcineurin thus preventing NFAT translocation
34.
what is the MOA of glucocorticoids: not well understood
- can inhibit expression of IL-1,2,6, TNF-alpha, and inteferon
35.
what is the MOA of mycophenolate mofetil: inhibitor of inosine monophosphate dehydrogenase --> critical for de novo synthesis of purines
- B and T cells highly dependent on this pathway
- suppresses lymphocytic prolif, migration, adhesion and ab formation
36.
what is the MOA of tacrolimus: binds to FKBP12 to inhibit calcineurin + prevent NFAT translocation --> IL-2 and T cell prolif
37.
what is the MOA of the mTOR inhibitors: complexes with FKBP12 and inhibits interaction with mTOR
- mTOR is a protein kinase --> role in expansion of B + T cells
38.
what is the pharmokinetics of azathioprine: well absorbed via GI tract, peaks at 1-2 hours
- excreted primarily via urine
39.
what is the pharmokinetics of the mTOR inhibitors?: rapamycin rapidly absorbed + high fat diet can increase peak level
- extensively metabolized by cpy3a4 and transported by P-glycoprotein
- difference between sirolimus and everolimus is everolimus has shorter 1/2 life
40.
what is the toxicity of azathioprine?: effects rapidly growing cells --> bone marrow, GI cells leading to leukopenia, thrombocytopenia, GI tox
- hepato tox
- mutagenic + carcinogenic
41.
what is the toxicity of cyclosporine and tacrolimus: main side effect is renal tox
other side effects --> hypertension, hyperlipidemia, hirsutism (cyclosporine), neurological s/e, diabetes (esp with glucocorticoids)
- risk of malignancy + opportunistic inf.
42.
what is the toxicity of mTOR inhibitors: dose dependent increase in serum cholesterol + TGs that may require statins
- myelosuppression (platelets, leuk, RBCs)
- opportunistic infections
43.
what is the use of anti-thymocyte abs: used in renal transplantation to delays use of calcineurin inhibitors
44.
what toxicity is associated with daclizumab: immunosuppression
45.
whats is the general MOA of calcineurin inhibitors: - activation of T cells receptors cause increase in intracellular calcium turning on phosphatase (calcineurin)
- calcineurin dephosphorylates NF-AT + travels to nucleus to increase IL-2 transcription
