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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
Q

What are the contraindications of everolimus and sirolimus?

A

pregnancy
liver and lung transplant
drug interactions by CYP3A4 similar to cyclosporine and tacrolimus

26
Q

What is induction therapy?

A

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
Q

What are the two types of antibody induction agents that deplete T cells?

A
  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
Q

What is an antibody induction reagent that antagonizes?

A

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
Q

What are the steps to immunosuppressive therapy?

A

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
Q

What are 4 drugs that can be used to treat relapsing remitting multiple sclerosis?

A
  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
Q

What are three immunoglobulins used for passive immunization?

A
  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
Q

What are three immune checkpoint inhibitors? What are they indicated for?

A
  1. Ipilimumab
  2. Pembrolizumab/Nivolumab

Treatment of late stage melanoma

33
Q

What is the mechanism of Ipilimumab?

A
  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
Q

What is the adverse effect of Ipilimumab?

A

-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
Q

What is the mechanism of Pembrolizumab/Nivolumab?

A

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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