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Heme Pharm > Drug Induced Immunosuppression > Flashcards

Drug Induced Immunosuppression Flashcards

1
Q

Propylthiouracil

A

Anti‐thyroid drugs with Neutropenia as Side Effect

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2
Q

Atypical antipsychotics

• Clozapine; Olanzepine

A

Commonly used Medications with

Neutropenia as Side Effect

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3
Q

Dapsone

A

Dermatologic drugs with Neutropenia as Side Effect

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4
Q

Anti‐malarial drugs

• Amodiaquine

A

Commonly used Medications with

Neutropenia as Side Effect

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5
Q

Drug induced immunosuppression can occur via two mechanisms:

1)
2) Direct or Indirect toxicity to b)

A

1) Immune‐mediated neutropenia

b) bone marrow granulocyte precursors

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6
Q 
Drug induced immunosuppression mechanism:
Both mechanisms (immune mediated or direct/indirect toxicity to granulocyte precursors) are mediated by formation of 1) by 2);
A

1) reactive metabolites
2) NADPH oxidase/
Myeloperoxidase enzyme system

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7
Q

Drug induced immunosuppression mechanism:
reactive metabolites bind to 1) irreversibly causing production of either (a), or (b) against membrane
structure

A

1) neutrophil membrane
a) antibodies
b) anti‐neutrophil auto‐antibodies

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8
Q

Drug induced immunosuppression mechanism:
Immune mediate destruction vs. Direct/indirect toxicity
how much time until clinical presentation;

A

Days to Weeks ‐ following immune‐mediated destruction versus

months ‐ following direct/indirect toxicity

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9
Q

Drugs that cause direct damage to
myeloid precursors also do so via
1)

A

1) reactive metabolites

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10
Q

Clozapine is chlorinated to form “1)”
which bind covalently & irreversibly → Toxicity to
2)

A

1) Nitrenium ion

2) bone marrow precursors

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11
Q

Direct or Indirect toxicity to bone marrow granulocyte precursors:
Dapsone also is oxidized to form “1)” which causes toxicity via covalent &
irreversible binding to bone marrow precursors

A

1) Reactive

hydroxylamine

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12
Q

Anti-inflammatory Gene

Expression Inhibitors

A

Glucocorticoids

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13
Q

Calcineurin-inhibiting drugs

A

• Cyclosporine & Tacrolimus

Sirolimus

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14
Q

Anti-metabolites

A

Methotrexate

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15
Q

Alkylating

agents

A

Cyclophosphamide

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16
Q

monoclonal to B cells

A

Rituximab

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17
Q

monoclonal to T cells

A

Alemtuzumab

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18
Q

Steroids hormones; bind to receptors where? 1) to form glucocorticoid-glucocorticoid receptor (G-R complex); this complex translocates to the 2) and binds to 3); this can modulate 4;

A

1) cytosolic
2) nucleus;
3) GRE (Gluc. Response Element)
4) transcription, translation

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19
Q

Glucocorticoids MOA:
Induces 1) → ↓PLA2 (phospholipase A2)→ 2) → ↓Formation and Release of eicosanoids, e.g., PGI2 - blood vessels;
Down-regulates expression of cytokines (3))

A

1) lipocortins
2) ↓AA (Arachidonic acid) release
3) IL-1, IL-4 and TNF-α

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20
Q

A/E: how do glucocorticoids cause diabete mellitus (?

A

b/c glucocorticoids promote GLUCONEOGENESIS;

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21
Q

↓Resistance to infections, osteoporosis,

hypertension, ↑Appetite → Weight gain

A

glucocorticoids

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22
Q

↑Appetite → Weight gain

A

glucocorticoids

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23
Q

Avoid abrupt stoppage; taper dosage

slowly

A

glucocorticoids

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24
Q

In normal T-cells:
1) → ↑[Ca2+] complexes with calmodulin (Ca2+/Calmodulin)
-this complex activates 2)
2) is needed to dephosphorylate 3), which translocates to nucleus → IL-2 gene
transcription

A

1) T-cell activation
2) Calcineurin
3) NFATc

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25
Q

Calcineurin-inhibiting Drugs
Cyclosporine (Cs) cross into cytoplasm; bind to 1) to form complex 2); this complex binds to calcineurin and ↓Calcineurin phosphatase activity by
Ca2+/Calmodulin;
Result–. 3)

A

1) cyclophilin (CyP)
2) cyclosporine-cyclophilin complex
3) NFATc is not dephosporylated and thus IL-2 is not produced;

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26
Q

Calcineurin-inhibiting Drugs: Tacrolimus (FK506)
FK506 cross into cytoplasm; bind to 1); forms complex 2);
this complex binds to calcineurin and ↓Calcineurin phosphatase activity by
Ca2+/Calmodulin;
Result–. 3)

A

1) FK-binding protein (FKBP)
2) FK (Tacrolimus)-FKBP complex
3) NFATc is not dephosporylated and thus IL-3; IL-4, IFN-γ is not produced

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27
Q

Tacrolimus vs. Cyclosporine: what do they inhibit, ultimately?

A

Tacrolimus → ↓IL-3; IL-4, IFN-γ

Cyclosporine–. IL-2

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28
Q

Tacrolimus vs. Cyclosporine potency

A

Tacrolimus 50-100x > potent vs Cs

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29
Q

Tacrolimus clinical use:

A

immunosuppressant for transplantation

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30
Q

hepato-, nephro-,

& neuro—toxicity; hypertension, hyperlipidemia

A

Cyclosporine; reason why use is limited;

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31
Q

Normally, IL-2 is activated; why is that important?

A

IL-2 stimulates mTOR which increases translocation of mRNAs that promote transition from G1 to S phase of cell cycle;

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32
Q

1) – a kinase that phosphorylates & regulates

activity of PHAS-1 and p70 S6 kinase

A

1) mTOR

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33
Q

Sirolimus (S) binds to FKBP → S-FKBP complex
→ ↓1) → ↓Protein synthesis (Translation) &
Arrest of 2)

A

1) mTOR

2) T-cell division in G1 phase

34
Q

IL-2 stimulates 1) which increases translocation of mRNAs that promote transition from 2) to 3) phase of cell cycle;

A

1) mTOR
2) G1
3) S

35
Q

Sirilomus clinical use:

A

Sirolimus-eluting stents - Approved for coronary artery

disease

36
Q

a/e:
– Hyperlipidemia
– Leukopenia
– Thrombocytopenia

A

Sirolimus

37
Q

Hyperlipidemia

A

Sirolimus

38
Q

what activates mTOR? and what does it do?

A

IL-2 stimulates mTOR which increases translocation of mRNAs that promote transition from G1 to S phase of cell cycle;

39
Q

reacts non-enzymically with sulfhydryl

compounds, e.g., glutathione

A

Azathioprine (AZA)

40
Q

Pro-drug for 6-Mercaptopurine

A

Azathioprine (AZA)

41
Q

Immunosuppressants in patients

with inflammatory bowel disease

A

Azathioprine (AZA)

42
Q

Prevention of graft versus host

disease

A

Methotrexate

43
Q

1) has anti-neutrophil; anti-T cell, &

anti-humoral effects

A

1) methotrexate

44
Q

Mycophenolic Acid and Mycophenolate Mofetil MOA

A

inosine monophosphate

dehydrogenase (IMPDH) inhibitor

45
Q

1) reversibly inhibits inosine monophosphate dehydrogenase (IMPDH), the enzyme that controls the rate of synthesis of guanine monophosphate in the de novo pathway of purine synthesis used in the proliferation of B and T lymphocytes

A

MPA or MMF;

Mycophenolic Acid and Mycophenolate Mofetil

46
Q

MPA or MMF → ↓IMPDH;

↓IMPDH–> ↓ 1) and ↑ 2)

A

1) guanosine levels

2) Adenosine levels

47
Q

Implications of ↓Guanosine levels:
• ↓Expression of 1)
• ↓ 2)levels, which regulates iNOS in neutrophils → ↓NO production by immune cells
[Endothelial cell NO production unaffected]

A

1) adhesion molecules

2) Hydrobiopterin [BH4]

48
Q

Mycophenolic Acid and Mycophenolate Mofetil NO production in immune cells vs. Endothelial cells;

A

NO production by immune cells

[Endothelial cell NO production unaffected]

49
Q

-Efficacious for autoimmune disease, e.g.,
autoimmune hemolytic anemia
– Initial therapy for lupus nephritis
– Tried successfully for myasthenia gravis

A

Clinical uses of MMF (Mycophenolate Mofetil):

50
Q

autoimmune hemolytic anemia

A

MMF (Mycophenolate Mofetil):l

51
Q

Leflunomide inhibits 1)→

inhibition of pyrimidine synthesis

A

1) dihydroorotate dehydrogenase

52
Q

pyrimidine synthesis is blocked by leflunomide; significance?

A

Lymphocytes depend on de novo pyrimidine synthesis for cell replication &
clonal expansion after immune cell activation

53
Q

Lymphocytes depend on 1) for cell replication &

clonal expansion after immune cell activation

A

1) de novo pyrimidine synthesis

54
Q

Depletion of pyrimidine pool → 1)

A

1) ↓Lymphocyte expansion

55
Q

Leflunomide a/e

A

Diarrhea

56
Q

Orally administered, highly toxic drug; alkylates DNA

A

Cyclophosphamide

57
Q

Major effect on B-cell proliferation; can ↑T-cell responses

A

Cyclophosphamide

58
Q

Acrolein → Risk of cancer; what is acrolein?

A

a metabolite of Cyclophosphamide

59
Q 
↑Risk of cancer, especially bladder cancer [due to
high Acrolein (carcinogenic) concentration in urine]
A

Cyclophosphamide

60
Q

TNF Secreted by 1);
TNF activates 2) and ↑ expression of
surface adhesion molecules → Leukocyte
adhesion & diapedesis

A

1) activated macrophages
2) endothelial cells
3)

61
Q

activation of ECs & ↑ expression of
surface adhesion molecules → Leukocyte
adhesion & diapedesis

A

TNF

62
Q

Positive feedback on monocytes & macrophages

→ ↑Cytokine (e.g., IL-1) secretion

A

TNF

63
Q

non-specific (binds TNF-α and TNF-β) and inhibits both –

approved for rheumatoid arthritis

A

Etanercept

64
Q

TNF-α-specific -
approved for rheumatoid arthritis, Crohn’s disease,
ulcerative colitis

A

Infliximab and Adalimumab

65
Q

↑Risk of reactivating latent tuberculosis – screen

patients for TB; ↑Risk of demyelinating disease

A

TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

66
Q

↑Risk of demyelinating disease

A

TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

67
Q

IL-1–> generated by activated mononuclear cells & stimulates 1) production → ↑2) → ↑Cell proliferation

A

1) IL-6

2) Expression of adhesion molecules

68
Q

required for recruitment of immune

cells to sites of inflammation

A

adhesion molecules

69
Q

Blocks IL-1-induced metalloproteinase release from synovial fluid; used for RA patients;

A

Anakinra

70
Q

Interleukin-1 (IL-1) inhibitors

A

Anakinra

71
Q

Polyclonal antibodies such as 1) affect all lymphocytes &
cause general immunosuppression
– Can predispose to infection

A

Anti-thymocyte globulin (ATG)

72
Q

Acute reaction (characterized by fever, or
even anaphylaxis) to treatment is common
due to high immunogenicity of 1)
Abs

A

1) polyclonal

73
Q

a partially humanized anti-

CD20 antibody

A

Rituximab

74
Q

Induction therapy for renal transplantation

A

Daclizumab and Basiliximab

75
Q

Antibodies against CD25 – the high affinity IL-2

receptor (CD25 – expressed only on activated T-cells)

A

Daclizumab and Basiliximab

76
Q

what is the IL-2 receptor and what drug inhibits it?

A

CD25; inhibited by Daclizumab and Basiliximab

77
Q

Inhibits purine synthesis

A

Mycophenolate mofetil and Mycophenolic acid

Azothioprine

78
Q

Mycophenolate mofetil and Mycophenolic acid efficacy

A

Mycophenolate mofetil (MMF) – with
↑oral bioavailability; Efficacy: MMF >
MPA

79
Q

MPA or MMF: primarily affects lymphocytes which rely on de novo purine synthesis;

A

1) de novo purine synthesis;

it also needs pyrimidines which is why Leflunomide works;

80
Q

rate-limiting enzyme in the synthesis of guanosine

A

IMPD–>Hinosine monophosphate

dehydrogenase

81
Q

IMPDH: Two isoforms (Types 1 & 2)
– Type 2: expressed in 1) &
preferentially inhibited by IMPDH

A

1) lymphocytes

Heme Pharm (13 decks)

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