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Pharm - Exam #5 > Lecture #2 - Immunomodulation > Flashcards

Lecture #2 - Immunomodulation Flashcards

1
Q

Glucocorticoids

MOA

A 
Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of  Cytokine-
      release Syndrome
Treatment of a wide variety 
      of autoimmune and inflammatory
     diseases e.g. RA, SLE, asthma etc
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2
Q

Glucocorticoids

A 
Many Adverse effects
Hyperglycemia
Hypertension
Hyperlipidemia
Obesity
Diabetes
Poor wound healing
Mania & Psychosis
increased Risk infections
  • Glucocorticoid dose should be
    gradually educed to minimize
    adverse effects

Glucocorticoids should not
be withdrawn abruptly

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3
Q

Glucocorticoids (prednisone/prednisolone)

Clinical Uses

A 
Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of  Cytokine- release Syndrome
Treatment of a wide variety of autoimmune and inflammatory diseases e.g. RA, SLE, asthma etc
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4
Q

Azathioprine

MOA

A 
Prodrug
Converted to 6-MP by HGPRT
Inhibits de novo purine synthesis
Incorporated into DNA & causes SSB
     base mispairing  apoptosis
Inhibits CD28 co-stimulation
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5
Q

Azathioprine

  • Adverse
A

Leukopenia/thrombocytopenia
Hepatotoxicity
increased Risk infections
increased Risk malignancy

Interacts with anti-gout drugs
Allopurinol & Febuxostat
Leading to increased [Azathioprine] increased toxicity

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6
Q

Azathioprine

  • interactions?
A

Interacts with anti-gout drugs
Allopurinol & Febuxostat
Leading to increased [Azathioprine] increased toxicity

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7
Q

Azathoprine

Clinical use

A 
Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of autoimmune 
      diseases
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8
Q

Mycophenolate
Mofetil

MOA

A

Prodrug
Converted to mycophenolic acid
Inhibits inosine monophosphate
dehydrogenase II (IMPDH2
- selectively expressed in lymphocytes)
- Inhibition of purine nucleotide synthesis
- no salvage pathway in lymphocytes

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9
Q

Mycophenolate
Mofetil

Adverse

A 
Leukopenia/anemia
Teratogenic (Male/Female)
increased Risk infections
increased Risk malignancy
RARE- Risk of Progressive multifocal 
        leukoencepalopathy (PML)
- Fatal viral disease caused by 
	   reactivation of JC virus
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10
Q

Mycophenolate
Mofetil

  • clinical use
  • contraindications?
A 
Immunosuppression
To Prevent graft rejection
To prevent GvHD
Treatment of autoimmune 
      diseases

Contraindicated in pregnancy,
Women who wish to become
pregnant, and men who wish
to become fathers

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11
Q

What are the 2 calcineurin inhibitors?

A

Cyclosporine

Tacrolimus

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12
Q

Cyclosporine
Tacrolimus

drug class

MOA

A

calcineurin inhibitors

Cyclosporin and tacrolimus bind
cyclophilin and FKBP, respectively to form inhibitory complexes
Cyclophilin/cyclosporin and
FKBP/tacrolimis complexes inhibit the calcium-regulated phosphatase, calcineurin

Inhibition of calcineurin inhibits the activation of the NFAT transcription factor, which is involved in regulating the expression of IL-2 and multiple other immunoregulatory genes
Potently inhibit the T cell immune response by inhibiting Signal 1

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13
Q

What are the 2 main Adverse effects of Cyclosporine & tacrolimus

some others?

A

Nephrotoxicity****
Hypertension***

Neurotoxicity/Tremor
Glucose intolerance (T>C)
Hyperlipidemia (C>T)
Hypertrichosis (C)
Alopecia (T)
increased Risk infections
increased Risk malignancy
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14
Q

Cyclosporine
Tacrolimus

metabolized by what?

How do inducers and inhibitors effect them?

A 
Metabolized by CYP3A4
Many drug interactions
3A4 inhibitors promote 
-increased drug levels 
INCREASED risk of toxicity

3A4 inducers promote
DECREASED Drug levels
INCREASED risk graft rejection

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15
Q

Cyclosporine
Tacrolimus

clinical use

A 
Immunosuppression
To prevent graft rejection
To prevent GvHD
Treatment of autoimmune 
        diseases
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16
Q

What are the 2 mTOR inhibitors?

A

mTor Inhibitors

Sirolimus
Everolimus

Immunosuppression
To prevent graft rejection
           - NOT LUNG
           - NOT LIVER
To prevent GvHD
Included in arterial stents to
       inhibit restenosis
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17
Q

what 2 drugs cannot be used for lung or liver graft rejection?

A

sirolimus, everolimus

18
Q

sirolimus, everolimus

MOA

A

Drugs form complex with FBKP
FKBP/drug complexs inhibits
IL-2 mediated activation of mTor kinase
(T cell signal 2)
Inhibits IL-2 stimulated protein synthesis,
Cell proliferation and survival

19
Q

sirolimus, everolimus

adverse effects

A 
Hypertriglyceridemia
Hypercholesterolemia
increased Lung disease
increased Risk of diabetes
Anemia, thrombocytopenia, 
       & leukopenia
DEcreased Wound healing
Teratogenic
increased Risk infections
increased Risk malignancy
20
Q

sirolimus, everolimus

contraindications? MAIN?

A

Metabolized by CYP3A4
Many drug interactions

Contraindicated in:
     - Pregnancy
NOT RECOMMENDED
     - Lung transplantation
       (risk anastomotic dehiscence)
     - Liver transplantation
       (risk hepatic artery thrombosis)
21
Q

What drugs are contraindicated in pregnancy?

A
  1. sirolimus
  2. everolimus
  3. Mycophenolate
    Mofetil
  4. methotrexate
  5. cyclophasphomide
  6. Chlorambucil
22
Q

Rabbit
anti-thymocyte
globulin

MOA

ADVERSE (2 main!)

A

Rabbit polyclonal antibodies specific
For human lymphocytes
Depletes lymphocytes from blood

  1. Cytokine release syndrome
  2. Leukopenia
23
Q

Alemtuzamab

MOA

adverse (3 MAIN)

A

Binds to CD52 expressed on T cells, B cells, macrophages,
NK cells & granulocytes
Depletes cells from blood by
Ab-mediated lysis

  1. Cytokine release syndrome
  2. Leukopenia
  3. Can take > 1 yr for immune system to recover
24
Q

What 2 drugs can cause cytokine release syndrome

A

Alemtuzamab

Rabbit
anti-thymocyte
globulin

25
Q

IVIG

Clinical

MOA

A
  1. Prevention of hemolytic disease
    of the newborn in inewborns born
    To Rh- females
  2. Purified Ig to Rh (D) antigen
    Given to Rh- mother at 28 weeks & 72 hr
    post pregnancy to deplete any fetal RBC in
    maternal blood to prevent the mother from
    generating an immune response to fetal RBC
26
Q

Hyperimmune Ig

Clinical

MOA

A

1.To provide rapid specific antibody immunity
to specific viruses and/or toxins

2.Purified Ig to specific antigens purified
from healthy volunteers
Given IV to patient in order to promote clearance
of virus/toxin

27
Q

Ipilimumab

CLinical
MOA

ADVERSE

A

1.Treatment of late stage melanoma

  1. Antibody specific for CTLA4
    Antagonizes the negative regulatory CTLA4 protein
    responsible for downregulating activated T cells
    Enhances T cell responses
  2. Potential for RARE autoimmune
    response
    (can be fatal)
28
Q

Pembrolizumab/Nivolumab

Clinical

MOA

A

1.Treatment of late stage melanoma

  1. Antibody specific for the PD1 protein, which is a
    negative regulatory receptor expressed on activated
    T cells that is responsible for downregulating T cell responses
    The PD1 ligand PD-L1 is expressed on tumor cells- this is a mechanism for tumor cells to avoid the immune response
    Antibody drugs block PD1/PD1-L1 interactions blocking the
    inhibitory signal and leading to enhanced tumor immune responses
29
Q

Methotrexate

Clinical
MOA

A
  1. Treatment of autoimmune disease
    - especially Rheumatoid arthritis

2.Inhibition of dihydrofolate reductase
to inhibit lymphocyte proliferation
Indirect mechanism of immunosuppression

30
Q

Methotrexate

adverse

A 
Renal toxicity
Hepatic toxicity
GI toxicity
Lung disease
BM suppression
Neurotoxicity
teratogenic

**Contraindicated in pregnancy

31
Q

Cyclophosphamide

Clinical

MOA

A

1.To Prevent graft rejection
To prevent GvHD
Treatment of severe cases of autoimmune disease

  1. Alkylation chemotherapeutic agent
    Crosslinks DNA, RNA & proteins
    Inhibits cell proliferation
    Promotes apoptosis
32
Q

Cyclophosphamide

adverse

A 
BM suppression
GI toxicity
increased Risk infections
increased Risk malignancy
Teratogenic (Male/Female)

Contraindicated in pregnancy,
Women who wish to become
pregnant, and men who wish
to become fathers

33
Q

Chlorambucil

MOA

Clinical

A
  1. Alkylation chemotherapeutic agent
    Crosslinks DNA, RNA & proteins
    Inhibits cell proliferation
    Promotes apoptosis

2.Sometimes used in the
treatment of severe
autoimmune diseases

34
Q

Chlorambucil

adverse

contrindication

A 
BM suppression
GI toxicity
increased Risk infections
increased Risk malignancy
Teratogenic (Male/Female)
35
Q

Fingolimod

Clinical

MOA

A

Treatment of Relapsing-Remitting
Multiple sclerosis

Sphingosine analog
Binds to S1P receptor to promote sequestration of lymphocytes in the
lymph node, thereby preventing lymphocyte entry to CNS

36
Q

What are the 4 drugs used in the tx of MS?

A
  1. fingolimod
  2. natalizumab
  3. interferon beta
  4. glatiramer acetate
37
Q

fingolimod

adverse effects (2 serious, 2 others)

A

Bradyarrhythmia
Atrioventricular block
increased Risk VZV infection (potentially fatal)
increased Risk malignancy

38
Q

Natalizumab

MOA

CLINICAL

A
  1. Binds alpha4 integrin adhesion molecule
    Prevents entry of lymphocytes into the CNS

2.Treatment of Relapsing-Remitting
Multiple sclerosis

39
Q

Natalizumab

ADVERSE

A

INCREASED risk of PML- especially if: - prior use of immunosuppression

  • seropositive for JC virus
  • chronic treatment
40
Q

Interferon Beta

MOA

CLINICAL

A 
1. Activates IFN beta receptors
Alters expression of pro-inflammatory
 gene expression
Inhibits entry of inflammatory cells
into CNS

2.Treatment of Relapsing-Remitting
Multiple sclerosis

41
Q

Glatiramer Acetate

MOA

Clinical

A
  1. Polymer of 4 amino acids found in MBP
    Production of specific suppressor T cells
    that suppress inflammation in the CNS

2.Treatment of Relapsing-Remitting
Multiple sclerosis

Pharm - Exam #5 (4 decks)

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