Drug Induced Immunosuppression Flashcards Preview

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Flashcards in Drug Induced Immunosuppression Deck (81):
1

Propylthiouracil

Anti‐thyroid drugs with Neutropenia as Side Effect

2

Atypical antipsychotics
• Clozapine; Olanzepine

Commonly used Medications with
Neutropenia as Side Effect

3

Dapsone

Dermatologic drugs with Neutropenia as Side Effect

4

Anti‐malarial drugs
• Amodiaquine

Commonly used Medications with
Neutropenia as Side Effect

5

Drug induced immunosuppression can occur via two mechanisms:
1)
2) Direct or Indirect toxicity to b)

1) Immune‐mediated neutropenia
b) bone marrow granulocyte precursors

6

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

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

7

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

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

8

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

Days to Weeks ‐ following immune‐mediated destruction versus
months ‐ following direct/indirect toxicity

9

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

1) reactive metabolites

10


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

1) Nitrenium ion
2) bone marrow precursors

11

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

1) Reactive
hydroxylamine

12

Anti-inflammatory Gene
Expression Inhibitors

Glucocorticoids

13

Calcineurin-inhibiting drugs

• Cyclosporine & Tacrolimus
Sirolimus

14

Anti-metabolites

Methotrexate

15

Alkylating
agents

Cyclophosphamide

16

monoclonal to B cells

Rituximab

17

monoclonal to T cells

Alemtuzumab

18

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;

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

19

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

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

20

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

b/c glucocorticoids promote GLUCONEOGENESIS;

21

↓Resistance to infections, osteoporosis,
hypertension, ↑Appetite → Weight gain

glucocorticoids

22

↑Appetite → Weight gain

glucocorticoids

23

Avoid abrupt stoppage; taper dosage
slowly

glucocorticoids

24

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

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

25

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)

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

26

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)

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

27

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

Tacrolimus → ↓IL-3; IL-4, IFN-γ
Cyclosporine--. IL-2

28

Tacrolimus vs. Cyclosporine potency

Tacrolimus 50-100x > potent vs Cs

29

Tacrolimus clinical use:

immunosuppressant for transplantation

30

hepato-, nephro-,
& neuro—toxicity; hypertension, hyperlipidemia

Cyclosporine; reason why use is limited;

31

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

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

32

1) – a kinase that phosphorylates & regulates
activity of PHAS-1 and p70 S6 kinase

1) mTOR

33

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

1) mTOR
2) T-cell division in G1 phase

34

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

1) mTOR
2) G1
3) S

35

Sirilomus clinical use:

Sirolimus-eluting stents - Approved for coronary artery
disease

36

a/e:
– Hyperlipidemia
– Leukopenia
– Thrombocytopenia

Sirolimus

37

Hyperlipidemia

Sirolimus

38

what activates mTOR? and what does it do?

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

39

reacts non-enzymically with sulfhydryl
compounds, e.g., glutathione

Azathioprine (AZA)

40

Pro-drug for 6-Mercaptopurine

Azathioprine (AZA)

41

Immunosuppressants in patients
with inflammatory bowel disease

Azathioprine (AZA)

42

Prevention of graft versus host
disease

Methotrexate

43

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

1) methotrexate

44

Mycophenolic Acid and Mycophenolate Mofetil MOA

inosine monophosphate
dehydrogenase (IMPDH) inhibitor

45

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

MPA or MMF;
(Mycophenolic Acid and Mycophenolate Mofetil)

46

MPA or MMF → ↓IMPDH;
↓IMPDH--> ↓ 1) and ↑ 2)

1) guanosine levels
2) Adenosine levels

47

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

1) adhesion molecules
2) Hydrobiopterin [BH4]

48

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

NO production by immune cells
[Endothelial cell NO production unaffected]

49


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

Clinical uses of MMF (Mycophenolate Mofetil):

50

autoimmune hemolytic anemia

MMF (Mycophenolate Mofetil):l

51

Leflunomide inhibits 1)→
inhibition of pyrimidine synthesis

1) dihydroorotate dehydrogenase

52

pyrimidine synthesis is blocked by leflunomide; significance?

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

53

Lymphocytes depend on 1) for cell replication &
clonal expansion after immune cell activation

1) de novo pyrimidine synthesis

54

Depletion of pyrimidine pool → 1)

1) ↓Lymphocyte expansion

55

Leflunomide a/e

Diarrhea

56

Orally administered, highly toxic drug; alkylates DNA

Cyclophosphamide

57

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

Cyclophosphamide

58

Acrolein → Risk of cancer; what is acrolein?

a metabolite of Cyclophosphamide

59

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

Cyclophosphamide

60

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

1) activated macrophages
2) endothelial cells
3)

61

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

TNF

62

Positive feedback on monocytes & macrophages
→ ↑Cytokine (e.g., IL-1) secretion

TNF

63

non-specific (binds TNF-α and TNF-β) and inhibits both –
approved for rheumatoid arthritis

Etanercept

64

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

Infliximab and Adalimumab

65

↑Risk of reactivating latent tuberculosis – screen
patients for TB; ↑Risk of demyelinating disease

TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

66

↑Risk of demyelinating disease

TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

67

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

1) IL-6
2) Expression of adhesion molecules

68

required for recruitment of immune
cells to sites of inflammation

adhesion molecules

69

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

Anakinra

70

Interleukin-1 (IL-1) inhibitors

Anakinra

71

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

Anti-thymocyte globulin (ATG)

72

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

1) polyclonal

73

a partially humanized anti-
CD20 antibody

Rituximab

74

Induction therapy for renal transplantation

Daclizumab and Basiliximab

75

Antibodies against CD25 – the high affinity IL-2
receptor (CD25 – expressed only on activated T-cells)

Daclizumab and Basiliximab

76

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

CD25; inhibited by Daclizumab and Basiliximab

77

Inhibits purine synthesis

Mycophenolate mofetil and Mycophenolic acid
Azothioprine

78

Mycophenolate mofetil and Mycophenolic acid efficacy

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

79

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

1) de novo purine synthesis;

it also needs pyrimidines which is why Leflunomide works;

80

rate-limiting enzyme in the synthesis of guanosine

IMPD-->Hinosine monophosphate
dehydrogenase

81

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

1) lymphocytes