2: Immunosuppressants Flashcards Preview

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Flashcards in 2: Immunosuppressants Deck (54):
1

what does immunopharmacology involve?

-production of vaccines and immunization
-treatment of inflammation
-autoimmune disorders
-allergies
-fungal, viral, and bacterial infections
-infections due to parasites
-cancer

2

what induces autoimmune diseases?

hyperactive T cell immune response

3

what causes immune suppression and incompetence?

hypoactive response of T cell immunity

4

role of each:
-helper T cells
-cytotoxic T cells
-suppressor T cells

helper: coordination of immune response
cytotoxic: remove virus-infected cells from the body
suppressor: temper immune response when it's overactive

5

purpose of immunosuppressants

inhibit normal immune response following organ transplantation or overactive immune response associated with autoimmune disorders

6

what part of the immune response do immunosuppressants work best for?

primary immune response
-efficacy depends on the type of immune response
-best results when treatment begun before exposure to Ag

7

define acute rejection

-occurs 24h to weeks post transplant
-mediated by T cells and cytokine release

8

how is immunosuppression achieved?

different classes of immunosuppressants that:
-decrease amount of lymphocytes
-divert lymphocyte traffic
-block pathways involved in lymphocytic response

9

classes of immunosuppressants

1. regulators of gene expression
2. alkylating agents
3. inhibitors of de novo purine synthesis
4. inhibitors of de novo pyrimidine synthesis
5. kinase and phosphatase inhibitors
6. protein immunosuppressants
7. others

10

what drugs are regulators of gene expression?

adrenocortical steroids - prednisone, prednisolone

11

what parts of immunosuppression are adrenocortical steroids used for?

induction and maintenance therapy

12

function of adrenocortical steroids

-reduce circulating lymphocyte levels
-block lymphocyte activation required for Ag presentation
-block T cell proliferation

(inhibit IL-2 gene expression, which is required for clonal expansion of B and T cells)

13

what drugs are alkylating agents?

cyclophosphamide

14

what drugs are inhibitors of de novo purine synthesis?

azathioprine, 6-mercaptopurine (first gen)
mizoribine, mycophenolate mofetil (MMF) (second gen)

15

what parts of immunosuppression are alkylating agents and purine synthesis inhibitors used for?

induction and maintenance

16

function of alkylating agents and purine synthesis inhibitors

-block or interfere with DNA/RNA synthesis and function
-prevent clonal expansion of B and T cells

17

chemically describe MMF

-ester prodrug -> active form: mycophenolic acid

18

function of MMF

inhibits inosinse 5'-monophosphate DH

19

side effects of MMF

GI shit and events related to bone marrow suppression (leukopenia, anemia, thrombocytopenia)

does NOT have CV risk or chronic nephrotoxic secondary effects

20

what drugs are inhibitors of de novo pyrimidine synthesis?

-brequinar
-leflunomide
-malononitrilamides

21

MOA of de novo pyrimidine synthesis

inhibit dihydroorotate DH

22

usefulness of the leflunomide derivative, FK778?

no benefit for using FK778 over MMF - also seems more difficult for patients to tolerate

23

what drugs are kinase and phosphatase inhibitors?

cyclosporine
tacrolimus
sirolimus/rapamycin

24

what parts of immunosuppression are kinase and phosphatase inhibitors used for?

induction and maintenance therapy (block signaling pathways that stimulate IL-2 production)

25

where does cyclosporine come from?

the fungus Tolypocladium inflatum Gams

26

how is cyclosporine administered? dosing?

IV or p.o.
given 4-24h before transplant, continued after with lower doses at weekly intervals

27

where does cyclosporine concentrate?

in the red and white blood cells

28

PK of cyclosporine

metabolized by liver
mainly excreted in feces

29

toxicity of cyclosporine

renal (proximal tubule) - limiting factor
gingival (hyperplasia)
neuronal
some hepatic
may induce systemic HTN

30

MOA of cyclosporine

associates with calcineurin and inhibits its phosphatase activity, preventing translocation of NFAT members to nucleus, inhibiting production of lymphokines

also blocks JNK and p38 signaling pathways that are induced by antigen recognition in T cells

31

what is tacrolimus and where does it come from

macrolide abx from Streptomyces tsukubaensis

32

MOA of tacrolimus

binds cytoplasmic FK506 binding protein 12 (FKBP12), inhibiting phosphatase pathway of calcineurin

also inhibits JNK and p38 pathways

33

admin of tacrolimus

IV or p.o.
not as widely distributed as cyclosporine, but 100x as potent

34

PK of tacrolimus

metabolized in liver
mainly excreted in feces
produces similar toxicity to cyclosporine

35

what specific disease is tacrolimus proposed to be beneficial for?

myasthenia gravis, notably to reduce corticosteroid burden

36

where does sirolimus/rapamycin come from?

Streptomyces hygroscopicus

37

MOA of sirolimus

inhibits calcineurin (and blocka response of T cells to cytokines) by binding FKBP12

but complex formation with FKBP12 does not inhibit IL-2 production in contrast to what happens with other drugs in this class

38

admin of sirolimus

alone or in combo w/: cyclosporine, tacrolimus, or MMF
-efficacy improved when used with cyclosporine

39

what drugs are protein immunosuppressive drugs?

antilymphocyte globulins:
-muromonab-CD3
-daclizumab
-basiliximab

polyclonal antithymocyte globulin

anti-CD52 or anti-CD20 agents

belatacept

40

antilymphocyte globulin MOA

inhibit acute graft rejection by binding to lymphocyte surface proteins
-daclizumab/basiliximab = antiCD25 monoclonal Ab's for induction and induce less T cell depletion than other drugs
-muromonab = antiCD3 mouse monoclonal Ab that binds to T cell receptor-associated CD3 complex and alters T cells - used for induction and treatment of rejection

41

what is belatacept and what is it equivalent to?

a targeted immunosuppressant drug -costimulatory blocker

equivalent alternative to traditional calcineurin inhibitors for kidney transplant recipients and for replacement of calcineurin inhibitors over time

42

belatacept MOA

inhibits CD28-mediated T cell costimulation

high affinity mutant form of T-lymphocyte associated antigen 4-IgG1 (CTLA4Ig) that binds to CD80 and CD86 on APCs, blocking engagement of CD28 on T cells and preventing T cell activation

43

what is special about belatacept?

seems to specifically target immune rxn against transplants

44

AE of belatacept

anemia
neutropenia
UTI
headache
peripheral edema
more frequent post-transplant lymphoproliferative disorders compared to other immunosuppressants
high cost $$$
serious side effects in kids***

45

what are the two most widely studied costimulatory pathways for studying induction or maintenance of allograft tolerance?

CD28/B7 and CD40/CD154 pathways

46

what is rapamycine?

macrocyclic lactone from Streptomyces hygroscopicus

47

MOA of rapamycine

targets mTOR (key regulator of cell proliferation)

48

uses of rapamycine

-some for treatment of acute transplant rejection

****facilitates maintenance of cardiac and pulmonary transplants by preventing sm. mm. proliferation (in cardiac) and fibroblasts (in pulm) that are detrimental to the proper fxn of the transplanted organs

49

what is everolimus and what is it used for?

a drug similar to rapamycine- used for renal transplantation b/c little nephrotoxicity
-also being tried in patients with neoplasia and renal insufficiency

50

why can everolimus not replace calcineurin inhibitors?

b/c its use as sole "immunosuppressant" comes w/ de novo donor-specific alloantibodies associated with Ab-mediated rejection

so, proposed as a reduced dose in combo w/ calcineurin inhibitors

51

what is fingolimod?

FTY720 - synthetic small molecule related to myricin, a sphingosine analog

52

fingolimod MOA

reduced circulating T cells by driving them into lymphoid tissues

53

fingolimod uses

mainly for MS since it reduces infiltration of lymphocytes into the CNS

54

what can be used for rheumatoid arthritis?

TNF-a inhibitors