Drug Induced Immunosuppression Flashcards
Propylthiouracil
Anti‐thyroid drugs with Neutropenia as Side Effect
Atypical antipsychotics
• Clozapine; Olanzepine
Commonly used Medications with
Neutropenia as Side Effect
Dapsone
Dermatologic drugs with Neutropenia as Side Effect
Anti‐malarial drugs
• Amodiaquine
Commonly used Medications with
Neutropenia as Side Effect
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
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
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
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
Drugs that cause direct damage to
myeloid precursors also do so via
1)
1) reactive metabolites
Clozapine is chlorinated to form “1)”
which bind covalently & irreversibly → Toxicity to
2)
1) Nitrenium ion
2) bone marrow precursors
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
Anti-inflammatory Gene
Expression Inhibitors
Glucocorticoids
Calcineurin-inhibiting drugs
• Cyclosporine & Tacrolimus
Sirolimus
Anti-metabolites
Methotrexate
Alkylating
agents
Cyclophosphamide
monoclonal to B cells
Rituximab
monoclonal to T cells
Alemtuzumab
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
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
A/E: how do glucocorticoids cause diabete mellitus (?
b/c glucocorticoids promote GLUCONEOGENESIS;
↓Resistance to infections, osteoporosis,
hypertension, ↑Appetite → Weight gain
glucocorticoids
↑Appetite → Weight gain
glucocorticoids
Avoid abrupt stoppage; taper dosage
slowly
glucocorticoids
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
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;
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
Tacrolimus vs. Cyclosporine: what do they inhibit, ultimately?
Tacrolimus → ↓IL-3; IL-4, IFN-γ
Cyclosporine–. IL-2
Tacrolimus vs. Cyclosporine potency
Tacrolimus 50-100x > potent vs Cs
Tacrolimus clinical use:
immunosuppressant for transplantation
hepato-, nephro-,
& neuro—toxicity; hypertension, hyperlipidemia
Cyclosporine; reason why use is limited;
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;
1) – a kinase that phosphorylates & regulates
activity of PHAS-1 and p70 S6 kinase
1) mTOR
Sirolimus (S) binds to FKBP → S-FKBP complex
→ ↓1) → ↓Protein synthesis (Translation) &
Arrest of 2)
1) mTOR
2) T-cell division in G1 phase
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
Sirilomus clinical use:
Sirolimus-eluting stents - Approved for coronary artery
disease
a/e:
– Hyperlipidemia
– Leukopenia
– Thrombocytopenia
Sirolimus
Hyperlipidemia
Sirolimus
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;
reacts non-enzymically with sulfhydryl
compounds, e.g., glutathione
Azathioprine (AZA)
Pro-drug for 6-Mercaptopurine
Azathioprine (AZA)
Immunosuppressants in patients
with inflammatory bowel disease
Azathioprine (AZA)
Prevention of graft versus host
disease
Methotrexate
1) has anti-neutrophil; anti-T cell, &
anti-humoral effects
1) methotrexate
Mycophenolic Acid and Mycophenolate Mofetil MOA
inosine monophosphate
dehydrogenase (IMPDH) inhibitor
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
MPA or MMF → ↓IMPDH;
↓IMPDH–> ↓ 1) and ↑ 2)
1) guanosine levels
2) Adenosine levels
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]
Mycophenolic Acid and Mycophenolate Mofetil NO production in immune cells vs. Endothelial cells;
NO production by immune cells
[Endothelial cell NO production unaffected]
-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):
autoimmune hemolytic anemia
MMF (Mycophenolate Mofetil):l
Leflunomide inhibits 1)→
inhibition of pyrimidine synthesis
1) dihydroorotate dehydrogenase
pyrimidine synthesis is blocked by leflunomide; significance?
Lymphocytes depend on de novo pyrimidine synthesis for cell replication &
clonal expansion after immune cell activation
Lymphocytes depend on 1) for cell replication &
clonal expansion after immune cell activation
1) de novo pyrimidine synthesis
Depletion of pyrimidine pool → 1)
1) ↓Lymphocyte expansion
Leflunomide a/e
Diarrhea
Orally administered, highly toxic drug; alkylates DNA
Cyclophosphamide
Major effect on B-cell proliferation; can ↑T-cell responses
Cyclophosphamide
Acrolein → Risk of cancer; what is acrolein?
a metabolite of Cyclophosphamide
↑Risk of cancer, especially bladder cancer [due to high Acrolein (carcinogenic) concentration in urine]
Cyclophosphamide
TNF Secreted by 1);
TNF activates 2) and ↑ expression of
surface adhesion molecules → Leukocyte
adhesion & diapedesis
1) activated macrophages
2) endothelial cells
3)
activation of ECs & ↑ expression of
surface adhesion molecules → Leukocyte
adhesion & diapedesis
TNF
Positive feedback on monocytes & macrophages
→ ↑Cytokine (e.g., IL-1) secretion
TNF
non-specific (binds TNF-α and TNF-β) and inhibits both –
approved for rheumatoid arthritis
Etanercept
TNF-α-specific -
approved for rheumatoid arthritis, Crohn’s disease,
ulcerative colitis
Infliximab and Adalimumab
↑Risk of reactivating latent tuberculosis – screen
patients for TB; ↑Risk of demyelinating disease
TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab
↑Risk of demyelinating disease
TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab
IL-1–> generated by activated mononuclear cells & stimulates 1) production → ↑2) → ↑Cell proliferation
1) IL-6
2) Expression of adhesion molecules
required for recruitment of immune
cells to sites of inflammation
adhesion molecules
Blocks IL-1-induced metalloproteinase release from synovial fluid; used for RA patients;
Anakinra
Interleukin-1 (IL-1) inhibitors
Anakinra
Polyclonal antibodies such as 1) affect all lymphocytes &
cause general immunosuppression
– Can predispose to infection
Anti-thymocyte globulin (ATG)
Acute reaction (characterized by fever, or
even anaphylaxis) to treatment is common
due to high immunogenicity of 1)
Abs
1) polyclonal
a partially humanized anti-
CD20 antibody
Rituximab
Induction therapy for renal transplantation
Daclizumab and Basiliximab
Antibodies against CD25 – the high affinity IL-2
receptor (CD25 – expressed only on activated T-cells)
Daclizumab and Basiliximab
what is the IL-2 receptor and what drug inhibits it?
CD25; inhibited by Daclizumab and Basiliximab
Inhibits purine synthesis
Mycophenolate mofetil and Mycophenolic acid
Azothioprine
Mycophenolate mofetil and Mycophenolic acid efficacy
Mycophenolate mofetil (MMF) – with
↑oral bioavailability; Efficacy: MMF >
MPA
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;
rate-limiting enzyme in the synthesis of guanosine
IMPD–>Hinosine monophosphate
dehydrogenase
IMPDH: Two isoforms (Types 1 & 2)
– Type 2: expressed in 1) &
preferentially inhibited by IMPDH
1) lymphocytes
