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Pharmacology > Immunomodulators > Flashcards

Immunomodulators Flashcards

1
Q

What are the 7 classes of immunosuppressant drugs?

A

1) glucocorticoids/steroids
2) proliferation inhibitors and anti-metabolites
3) immunophilin-binding drugs (inhibitors of T cell signaling pathways)
4) antibodies for induction immunosuppression
5) misc drugs to treat relapsing remitting MS
6) passive immunization Ig
7) immune checkpoint inhibitors

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2
Q

Define hyperacute rejection

A

cause by pre-existing reactive antibodies

occurs within minutes of transplant

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3
Q

Define acute rejection

A

6-12 months post transplant

T cell mediated

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4
Q

Define chronic rejection

A

months to years

due to fibrosis causing damage to graft blood vessels

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5
Q

What type of rejection is targeted by immunosuppressants?

A

acute

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6
Q

What are the two things that need to be matched prior to transplant?

A

1) ABO blood type compatible

2) HLA matched

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7
Q

What are the 4 principles of transplantation?

A

1) appropriate patient and donor prep and selection
2) multi-tiered approach to immunosuppression
3) potential initial immunosuppression (decreases potential toxicity of immunosuppressants)
4) drugs should be reduced or withdrawn if toxicity exceeds benefits

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8
Q

What is the MOA of steroids?

A

glucocorticoids bind to receptors in the cytoplasm and translocate to the nucleus to bind to target genes and influence their expression (INHIBIT critical immunoregulatory genes to inhibit immune response)

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9
Q

When are steroids indicated?

A
  • standard immunosuppressive therapy to prevent organ graft rejection (along with others)
  • high dose IV to combat acute rejection episodes and treatment of cytokine release syndrome
  • treats autoimmune diseases (RA, lupus, MS, IBD, asthma, psoriasis)
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10
Q

What are the side effects of steroids?

A 
hyperglycemia, hyperlipidemia, obesity 
developing diabetes
osteopenia
cataracts
poor wound healing
mania and psychosis
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11
Q

Why do steroids need to be tapered?

A

to avoid adrenal crisis (need to teach the adrenals how to make steroids again)

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12
Q

What percentage of transplant patients stay on steroids after 1 year post transplant?

A

80%

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13
Q

What are the 2 proliferation inhibitors and anti-metabolites?

A

azathioprine

mycophenolate mofetil

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14
Q

What does azathioprine do?

A

inhibit lymphocyte proliferation

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15
Q

What activates azathioprine?

A

glutathione (converts it from prodrug to 6-mercaptopurine)

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16
Q

What 3 things can azathioprine affect?

A

1) inhibits de novo purine biosynth
2) leads to apoptosis
3) inhibits T cell and CD28/Rac1 costimulation

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17
Q

What are 2 indications for azathioprine?

A

1) prophylactic prevention of graft rejection post organ transplant
2) autoimmune diseases (RA, Crohn’s, MS)

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18
Q

What are the adverse effects of azathioprine

A

diarrhea, leukopenia, hepatotox

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19
Q

What are the important drug interactions for azathioprine?

A

allopurinol and febuxostat (xanthine oxidase inhibitors used to treat gout)
due to increased levels of 6-MP

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20
Q

What is the MOA of mycophenolate mofetil (MMF)?

A

reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) type II which is used to make purine nucleotides

IMPDH is selectively expressed in lymphocytes so MMF selectively blocks lymphocyte prolif

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21
Q

What are the indications of MMF?

A

on label: prevent graft rejection

off label: autoimmune disorders

22
Q

What is a potentially very dangerous adverse effect of MMF?

A

progressive multifocal leukoencephalopathy (caused by reactivation of JC virus)

23
Q

What are the contraindications of MMF?

A

pregnancy or fertile patients

24
Q

In addition to MMF and azathioprine, what are 3 other anti proliferative drugs for immunosuppression?

A

1) methotrexate (treat RA)
2) cyclophosphamide (treat most severe diseases)
3) chlorambucil

25
Q

What are the immunophilin binding drugs/inhibitors of T cell signaling pathways?

A

calcineurin inhibitors (cyclosporin and tacrolimus)

mTOR inhibitors (sirolimus and everolimus)

26
Q

What are 3 indications of calcineurin inhibitors?

A

1) prevent solid organ rejection (heart, kidney, liver, lungs)
2) prevent graft vs host in bone marrow transplant
3) treat autoimmune disease (severe psoriasis, severe RA, SLE, IBD, nephrotic syndrome)

27
Q

What is the MOA of immunophilins? cyclosporin binds to _________ while tacrolimus binds to _________

A

cyclophilin

FKBP

28
Q

What are cyclophilin and FKBP?

A

peptidyleprolyl isomerases but the biologic activity of these drugs is independent of that activity

instead the drug enzyme complex binds and inhibits calcineurin

29
Q

What does calcineurin do?

A

helps activate NFAT which is a TF responsible for expression of many genes including T cell growth factor IL2

30
Q

Cyclosporine inhibits or activates NFAT?

A

INHIBITS

31
Q

How are cyclosporine and tacrolimus metabolized?

A

extensively via CYP450 (strongly affected by drugs that inhibit or induce CYP3A4)

32
Q

What are the major adverse effects of cyclosporine and tacrolimus?

A

nephrotoxicity

hypertension

33
Q

What effects do CYP3A4 drugs have on graft rejection?

A 
inducers = increase likelihood
inhibitors = decrease likelihood
34
Q

What are the mTOR inhibitors?

A

Sirolimus and Everolimus

35
Q

What do sirolimus and everolimus bind to?

A

FKBP (inhibit mTOR kinase complex downstream cytokine and growth factor receptors like the IL2 receptor)

36
Q

what does mTOR do?

A

regulates protein synthesis, cell proliferation and survival

37
Q

Which drug is NOT recommended for liver and lung transplants?

A

sirolimus and tacrolimus (increases risk of hepatic artery thrombosis and anastomatic dehiscence)

38
Q

Which drugs are used in coronary stenting to inhibit restenosis by preventing cell proliferation?

A

sirolimus and everolimus

39
Q

What are contraindications for siroliumus and everolimus?

A

pregnancy

40
Q

What is the goal of induction therapy?

A

use of anti-lymphocyte antibodies to acutely inhibit T cell responses in the recipient at time of transplant

41
Q

Name 3 antibody induction reagents

A

1) rabbit anti-thymocyte globulin
2) alemtuzmab
3) basiliximab

42
Q

What is the best tolerated antibody induction reagent?

A

basiliximab

43
Q

What is the typical triple drug regimen started post-op after organ transplants?

A

glucocorticoid

cyclosporin and tacrolimus

an anti-proliferative drug

44
Q

What are 3 common risks of immunosuppression?

A

1) increased risk of infection
2) increased risk of malignancy
3) post-transplant lymphoproliferative disorder (ex: B cell hyperplasia caused by EBV that can develop into lymphoma)

45
Q

What are 4 drugs used in treatment of relapsing-remitting MS?

A

1) fingolimod (sequesters lymphocytes in lymph node preventing them from accessing CNS - risk of fatal bradycardia)
2) natalizumab (increased risk of PML)
3) Interferon beta
4) glatiramer acetate

46
Q

What is the goal of MS immunotherapy?

A

to prevent immune cells from accessing the CNS

47
Q

What are 3 forms of passive immunization?

A

1) IVIG (can treat pts with underlying immunodeficiency disorders)
2) Hyperimmune Ig (purified from individuals with high titers against a specific antigen like hepatitis B)
3) Rho(D) Ig (used to prevent hemolytic disease of newborn in Rh-neg women)

48
Q

What kind of drug is ipilimumab?

A

mAb specific for CTLA4 protein on activated T cells (prevents it from delivering negative signal to T cells keeping them functional and protecting them from conversion to TREGs)

49
Q

What are some indications in ipilimumab?

A

late stage melanoma

50
Q

What are adverse effects of ipilimumab?

A

over immune activation (like inflammation of skin, GI tract, liver, nerves, and adrenals)

51
Q

What are Pembrolizumab and nivolumab?

A

antibodies specific for negative regulatory PD1 expressed on T cells

(when PD1 is stimulated by its ligand PD-L1, it inhibits T cell activation)

52
Q

What is the goal of pemrolizumab and nivolumab?

A

block PD1/PD-L1 interactions preventing PD1 negative signaling leading to enhanced T cell immune response against the cancer cell

Pharmacology (21 decks)

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