Drug Induced Immunosuppression

Question 1

Propylthiouracil

Answer 1

Anti‐thyroid drugs with Neutropenia as Side Effect

Question 2

Atypical antipsychotics

• Clozapine; Olanzepine

Answer 2

Commonly used Medications with

Neutropenia as Side Effect

Question 3

Dapsone

Answer 3

Dermatologic drugs with Neutropenia as Side Effect

Question 4

Anti‐malarial drugs

• Amodiaquine

Answer 4

Commonly used Medications with

Neutropenia as Side Effect

Question 5

Drug induced immunosuppression can occur via two mechanisms:

1)
2) Direct or Indirect toxicity to b)

Answer 5

1) Immune‐mediated neutropenia

b) bone marrow granulocyte precursors

Question 6

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

Answer 6

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

Question 7

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

Answer 7

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

Question 8

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

Answer 8

Days to Weeks ‐ following immune‐mediated destruction versus

months ‐ following direct/indirect toxicity

Question 9

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

Answer 9

1) reactive metabolites

Question 10

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

Answer 10

1) Nitrenium ion

2) bone marrow precursors

Question 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

Answer 11

1) Reactive

hydroxylamine

Question 12

Anti-inflammatory Gene

Expression Inhibitors

Answer 12

Glucocorticoids

Question 13

Calcineurin-inhibiting drugs

Answer 13

• Cyclosporine & Tacrolimus

Sirolimus

Question 14

Anti-metabolites

Answer 14

Methotrexate

Question 15

Alkylating

agents

Answer 15

Cyclophosphamide

Question 16

monoclonal to B cells

Answer 16

Rituximab

Question 17

monoclonal to T cells

Answer 17

Alemtuzumab

Question 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;

Answer 18

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

Question 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))

Answer 19

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

Question 20

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

Answer 20

b/c glucocorticoids promote GLUCONEOGENESIS;

Question 21

↓Resistance to infections, osteoporosis,

hypertension, ↑Appetite → Weight gain

Answer 21

glucocorticoids

Question 22

↑Appetite → Weight gain

Answer 22

glucocorticoids

Question 23

Avoid abrupt stoppage; taper dosage

slowly

Answer 23

glucocorticoids

Question 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

Answer 24

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

Question 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)

Answer 25

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

Question 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)

Answer 26

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

Question 27

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

Answer 27

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

Question 28

Tacrolimus vs. Cyclosporine potency

Answer 28

Tacrolimus 50-100x > potent vs Cs

Question 29

Tacrolimus clinical use:

Answer 29

immunosuppressant for transplantation

Question 30

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

Answer 30

Cyclosporine; reason why use is limited;

Question 31

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

Answer 31

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

Question 32

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

Answer 32

1) mTOR

Question 33

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

Answer 33

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

Question 34

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

Answer 34

1) mTOR 2) G1 3) S

Question 35

Sirilomus clinical use:

Answer 35

Sirolimus-eluting stents - Approved for coronary artery | disease

Question 36

a/e: – Hyperlipidemia – Leukopenia – Thrombocytopenia

Answer 36

Sirolimus

Question 37

Hyperlipidemia

Answer 37

Sirolimus

Question 38

what activates mTOR? and what does it do?

Answer 38

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

Question 39

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

Answer 39

Azathioprine (AZA)

Question 40

Pro-drug for 6-Mercaptopurine

Answer 40

Azathioprine (AZA)

Question 41

Immunosuppressants in patients | with inflammatory bowel disease

Answer 41

Azathioprine (AZA)

Question 42

Prevention of graft versus host | disease

Answer 42

Methotrexate

Question 43

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

Answer 43

1) methotrexate

Question 44

Mycophenolic Acid and Mycophenolate Mofetil MOA

Answer 44

inosine monophosphate | dehydrogenase (IMPDH) inhibitor

Question 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

Answer 45

MPA or MMF; | Mycophenolic Acid and Mycophenolate Mofetil

Question 46

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

Answer 46

1) guanosine levels | 2) Adenosine levels

Question 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]

Answer 47

1) adhesion molecules | 2) Hydrobiopterin [BH4]

Question 48

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

Answer 48

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

Question 49

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

Answer 49

Clinical uses of MMF (Mycophenolate Mofetil):

Question 50

autoimmune hemolytic anemia

Answer 50

MMF (Mycophenolate Mofetil):l

Question 51

Leflunomide inhibits 1)→ | inhibition of pyrimidine synthesis

Answer 51

1) dihydroorotate dehydrogenase

Question 52

pyrimidine synthesis is blocked by leflunomide; significance?

Answer 52

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

Question 53

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

Answer 53

1) de novo pyrimidine synthesis

Question 54

Depletion of pyrimidine pool → 1)

Answer 54

1) ↓Lymphocyte expansion

Question 55

Leflunomide a/e

Answer 55

Diarrhea

Question 56

Orally administered, highly toxic drug; alkylates DNA

Answer 56

Cyclophosphamide

Question 57

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

Answer 57

Cyclophosphamide

Question 58

Acrolein → Risk of cancer; what is acrolein?

Answer 58

a metabolite of Cyclophosphamide

Question 59

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

Answer 59

Cyclophosphamide

Question 60

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

Answer 60

1) activated macrophages 2) endothelial cells 3)

Question 61

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

Answer 61

TNF

Question 62

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

Answer 62

TNF

Question 63

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

Answer 63

Etanercept

Question 64

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

Answer 64

Infliximab and Adalimumab

Question 65

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

Answer 65

TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

Question 66

↑Risk of demyelinating disease

Answer 66

TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

Question 67

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

Answer 67

1) IL-6 | 2) Expression of adhesion molecules

Question 68

required for recruitment of immune | cells to sites of inflammation

Answer 68

adhesion molecules

Question 69

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

Answer 69

Anakinra

Question 70

Interleukin-1 (IL-1) inhibitors

Answer 70

Anakinra

Question 71

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

Answer 71

Anti-thymocyte globulin (ATG)

Question 72

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

Answer 72

1) polyclonal

Question 73

a partially humanized anti- | CD20 antibody

Answer 73

Rituximab

Question 74

Induction therapy for renal transplantation

Answer 74

Daclizumab and Basiliximab

Question 75

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

Answer 75

Daclizumab and Basiliximab

Question 76

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

Answer 76

CD25; inhibited by Daclizumab and Basiliximab

Question 77

Inhibits purine synthesis

Answer 77

Mycophenolate mofetil and Mycophenolic acid | Azothioprine

Question 78

Mycophenolate mofetil and Mycophenolic acid efficacy

Answer 78

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

Question 79

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

Answer 79

1) de novo purine synthesis; it also needs pyrimidines which is why Leflunomide works;

Question 80

rate-limiting enzyme in the synthesis of guanosine

Answer 80

IMPD-->Hinosine monophosphate | dehydrogenase

Question 81

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

Answer 81

1) lymphocytes