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Pharm > Immunopharmacology > Flashcards

Immunopharmacology Flashcards

1
Q

What are the indications for glucocorticoids, Prednisone and Prednisolone?

A
  1. Immunosuppression
  2. prevent graft rejection
  3. prevent GvHD
  4. Treatment of cytokine releases syndrome
  5. treatment of autoimmune and inflammatory disease
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2
Q

What is the mechanism of action for glucocorticoids, Prednisone and Prednisolone?

A
  1. Activates the glucocorticoid receptor transcription factor
  2. modifies expression of cytokines and other immunoregulatory genes
  3. suppresses active immune response
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3
Q

What adverse effects of glucocorticoids, Prednisone and Prednisolone?

A
  1. Hyperglycemia
  2. Hypertension
  3. Hyperlipidemia
  4. obesity
  5. diabetes
  6. poor wound healing
  7. mania and psychosis
  8. increase risk of infections
  • dose should be gradually reduced to minimize adverse effects
  • do not withdraw abruptly
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4
Q

What are two proliferation inhibitors and antimetabolite drugs?

A
  1. azathioprine

2. mycophenolate mofetil

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5
Q

What is the mechanism of azathioprine?

A

A. azathioprine goes to
prodrug=6-mercaptopurine
using glutathione

B. 6-mercaptopurine–>6-TIMP using HGPRT

  1. 6-TIMP–>inhibits de novo purine biosynthesis
  2. 6-TGTP–>inhibits CD28/Rac1 T cell costimulation

3.

6-TGTP–> incorporated into DNA (single strand breaks/base mispairing) –> apoptosis

ALL lead to:
INHIBITION OF LYMPHOCYTE PROLIFERATION

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6
Q

What are the uses of azathioprine?

A
  1. prophylactic prevention of graft rejection following organ transplant
  2. severe autoimmune diseases and other immune-mediated diseases
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7
Q

What are adverse effects of azathioprine?

A
  1. diarrhea, nausea, and vomiting
  2. leukopenia and thrombocytopenia
  3. hepatotoxicity
  4. increased risk of infections
  5. increased risk of malignancy
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8
Q

What drugs interfere with azathioprine? what happens?

*****

A

allopurinol and febuxostat (used in the treatment of gout) inhibit xanthine oxidase which means more 6TIMP is made from 6 Mercaptopurine –>increased toxicity

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9
Q

What is the mechanism of action of the mycophenolate mofetil which is the prodrug of mycophenolic acid?
mycophenolate mofetil–>mycophenolic acid

A

Mycophenolic acid (MPA) is a non competitive reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH) type 2

  1. rate-limiting enzyme in the de novo synthesis of purine nucleotides (required for S phase of the cell cycle)
  • lymphocytes need this
  • IMPDH2 is selectively expressed in lymphocytes

–>MPA selectively inhibits lymphocyte proliferation

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10
Q

What are the indications for mycophenolate mofetil?

A

on label-prevent graft rejection following organ transplantation
off label-autoimmune diseases and immune mediated disorders

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11
Q

What are adverse effects of mycophenolate mofetil?

A
  1. diarrhea, nausea and vomiting
  2. leukopenia and anemia
  3. embryo/fetal toxicity-risk of first trimester loss and congenital abnormalities
  4. increased risks of infections
  5. increased risk of malignancies
    * **6. progressive multifocal leukoencephalopathy-rare but potentially fatal-caused by reactivation of JC virus *****
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12
Q

Who shouldn’t take mycophenolate mofetil?

A

women of childbearing age who want to become preg and men who wish to become fathers

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13
Q

What are calcineurin inhibitors?

A

cyclosporine and tacrolimus

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14
Q

What are the indications for the calcineurin inhibitors, cyclosporine and tacrolimus?

A
  1. immunosuppression
  2. prevent graft rejection
  3. to prevent gvHD
  4. treatment of autoimmune disease
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15
Q

What is the mechanism of action for the calcineurin inhibitors, cyclosporine and tacrolimus?

A
  1. inhibitory complexes of cyclosporine/cyclophilin and tacrolimus/FKBP bind and inhibit the activity of calcineurin (phosphatase activity)
  2. calcineurin is a critical signaling enzyme for t-cell
  3. calcineurin activates NFAT transcription factor by dephosphorylating it
  4. NFAT normally is responsible for the expression of numerous genes including the t cell growth factor IL-2

Inhibit Signal 1 and prevent T cell proliferation by inhibiting production of IL2

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16
Q

What are the adverse effects of calcineurin inhibitors cyclosporine and tacrolimus?

A
  • **1. nephrotoxicity
  • **2. hypertension
  1. neurotoxicity/tremor
  2. glucose intolerance (T>C)
  3. Hyperlipidemia (C>T)
  4. Hirsutism&Hypertrichosis (C)
  5. Alopecia (T)
  6. Hyperkalemia
  7. Hypomagnesemia
  8. Gum Hyperplasia (C)
  9. increased risk of infection
  10. increased risk of malignancy
17
Q

What are the drug interactions of cyclosporine/tacrolimus?

A

Increase=
Inhibitors of CYP3A4: grapefruit juice, azole antifungals, erythromycin/clarithromycin, verapamil, diltiazem

Reduce=
Inducers CYP3A4:
Rifampin, Carbamazepine, Phenobarbital, Phenytoin, St John’s wort

Other drugs that enhance nephrotoxicity:
NSAIDS

18
Q

methotrexate

A

anti-proliferative
Rheumatoid arthritis
contraindicated in pregnancy

19
Q

cyclophosphamide

A

anti-proliferative
prevent rejection and treat autoimmune
teratogenic

20
Q

chlorambucil

A

anti-proliferative
sever autoimmune
teratogenic

21
Q

What are the mTOR inhibitor drugs?

A

Sirolimus(rapamycin) and Everolimus (shorter hl)

22
Q

What is the mechanism of sirolimus and everolimus?

A

FKBP/sirolimus complex
inhibits mTOR kinase complex downstream of cytokine and growth factor receptors
e.g. IL2 receptor

SIGNAL 2

23
Q

What is sirolimus and everolimus indicated for?

A
  1. prophylactic prevention of graft rejection
    - NOT recommended for LIVER (hepatic artery thrombosis) transplants or LUNG transplants (anastomotic dehiscence)
  2. prevention of graft v host disease following bone marrow transplantation
  3. included in coronary stents to inhibit restenosis by preventing cell proliferation
24
Q

What are the adverse effects of everolimus and sirolimus?

A
  1. hypertriglyceridemia/hypercholesterolemia
  2. pulmonary edema/lung disease
  3. increased risk new onset diabetes
  4. hematologic-anemia, thrombocytopenia, leukopenia
  5. decreased wound healing
  6. increased risk of infection
  7. increased risk of malignancy
  8. teratogenic effects
25
What are the contraindications of everolimus and sirolimus?
pregnancy liver and lung transplant drug interactions by CYP3A4 similar to cyclosporine and tacrolimus
26
What is induction therapy?
anti-lymphocytic antibodies to acutely inhibit T-cell responses in the recipient at the time of transplantation 1. lymphocyte depleting Ab 2. Functional Inhibition of Ab
27
What are the two types of antibody induction agents that deplete T cells?
1. Rabbit Anti-thymocyte globulins (rTAG) - Fc-recptor mediated/complement dependent lysis and opsonization 2. Alemtuzumab - anti-CD52-expressed on t cells, b cells, macrophages, NK cells and granulocytes - can take 1 year for immune system to recover Adverse: Cytokine release syndrome**** Prolonged lymphopenia-increased infection
28
What is an antibody induction reagent that antagonizes?
Basiliximab (Daclizumab) - IL-2R antagonist that inhibits T-cell proliferation - not as effective as depleting antibodies - well tolerated but more rejection than with depleting agents
29
What are the steps to immunosuppressive therapy?
intraoperatively and 3-7 days post transplant=induction therapy triple drug regimens post opp 1. glucocorticoid 2. cyclosporine or tacrolimus 3. anti-proliferative drug Sirolimus/everolimus are sometimes used in place of cyclosporine/tacrolimus or anti-proliferative drug
30
What are 4 drugs that can be used to treat relapsing remitting multiple sclerosis?
1. Fingolimod - sequester lymphocytes in lymph node-cant enter CNS * *Risk of bradyarrhythmia and AV block * *increased risk of varicella zoster virus * *increased risk of malignancy 2. Natalizumab - block entry of lymphocyte into CNS * *Increased risk of PML-especially with prior use of immunosup drugs or seropositive JC virus 3. interferon beta - reduce the entry of inflammatory cells into CNS and reduce T-cell act 4. glatiramer acetate - promote production of specific suppressor T cell that migrate into brain and suppress inflammation
31
What are three immunoglobulins used for passive immunization?
1. IGIV - used for hypogammaglobulinemia 2. Hyperimmune Ig - similar to IGIV but individuals with high titer to a specific antigen 3. Rho Immune globulin - administered at 28 weeks of preg to Rh-negative women where the father is Rh+ - follow up dose post 72 hours
32
What are three immune checkpoint inhibitors? What are they indicated for?
1. Ipilimumab 2. Pembrolizumab/Nivolumab Treatment of late stage melanoma
33
What is the mechanism of Ipilimumab?
1. binds CTLA4 2. prevents CTLA4 from binding to CD80/86 3. prevents CTLA4 from delivering a negative signal 4. Leaves CD28 Co-stimulatory signal intact -->enhanced t-cell activation -in clinical trials for NSCLC, SCLC, prostate cancer and bladder cancer
34
What is the adverse effect of Ipilimumab?
-can result in severe and sometimes fatal adverse reactions due to immune activation eg. Inflammation of the skin, GI tract, liver, nerves, and adrenal glands
35
What is the mechanism of Pembrolizumab/Nivolumab?
used in metastatic melanoma and NSCLC 1. antibody for negative regulatory protein PD1 expressed on T cells - PD L1 is expressed on a variety of cell types including cancer cells-believed to be a mechanism by which cancer cells evade the immune system

Pharm (36 decks)

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