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35 Cards in this Set

  • Front
  • Back
Drug‐induced Neutropenia
Entails the study of drugs that induce
neutropenia (↓Neutrophils) as side
(undesirable) effects
• May occur via either:
– ↓Granulocyte production or
– ↑Destruction
Two Basic Mechanisms
-Immune‐mediated, drug‐induced neutropenia
-Direct or Indirect toxicity to bone marrow granulocyte precursors
Mechanisms of D-I Neutropenia
1. Both mechanisms are mediated by formation of reactive metabolites by NADPH oxidase/
Myeloperoxidase enzyme system
2. The drug or its reactive metabolites bind to neutrophil membrane irreversibly causing
production of either (a) antibodies, or (b) anti‐neutrophil auto‐antibodies against membrane
3. Example 1: Propylthiouracil (PTU) →→→→ Propyl‐thioester/sulfinic acid/sulfonic acid →→
→→ Bind covalently to neutrophil membrane →→→→ Antibody/Auto‐antibody production
4. Example 2: Amodiaquine →→→→→ Mono‐desmethyl amodiaquine (reactive metabolite)
D-I Neutropenia, Clinical Presentation
Clinical presentation: Days to Weeks ‐ following immune‐mediated destruction versus
months ‐ following direct/indirect toxicity
D-I Neutropenia Treatment
Treatment: Withdraw offending drug agent; resolution take 1‐3 weeks after drug cessation
Clozapine

Dapsone
Drugs that cause direct damage to
myeloid precursors also do so via
reactive metabolites
Clozapine is chlorinated to form “Nitrenium ion”
which bind covalently & irreversibly → Toxicity to
bone marrow precursors
– Dapsone also is oxidized to form “Reactive
hydroxylamine” which causes toxicity via covalent &
irreversible binding to bone marrow precursors
• Presentation of direct/indirect toxicity takes months
Immuno‐suppressive Therapies

Drugs, biologics, & irradiation ‐
used primarily for immuno‐suppression as
therapeutic goal

Conditions prompting their use:
• Treatment of malignant disease
• Maintenance of tissue/organ transplant
• Prevention of graft‐versus‐host disease
• Treatment of some auto‐immune/connective tissue disease
Immuno‐suppressive Therapies

Two categories of Immuno‐suppressive drugs:
– Broad‐spectrum immuno‐suppression
• Glucocorticoids
• Cytotoxic chemotherapeutics
• Radiation therapy
– Selective targeting of cells & pathways of the immune system → Specific
therapeutic effects
• Monoclonal antibodies
Glucocorticoids

Steroids hormones; bind to:
– Cytosolic receptors → G-R complex;
translocate to the nucleus → bind to GREs
(glucocorticoid response elements (in promoter region of specific genes) → ↑ or ↓Regulation of
specific genes
Glucocorticoids

Broad anti-inflammatory effects
– Induces lipocortins → ↓PLA2→ ↓AA
(Arachidonic acid) release → ↓Formation and
Release of eicosanoids, e.g., PGI2 - blood vessels
– Down-regulates expression of cytokines (IL-1,
IL-4 and TNF-α)

PGI2 is a vasodilator
Glucocorticoids

Adverse effect:
• Long-term use → diabetes mellitus;
↓Resistance to infections, osteoporosis,
hypertension, ↑Appetite → Weight gain
• Avoid abrupt stoppage; taper dosage
slowly
Calcineurin-inhibiting Drugs
I. Cyclosporine (Cs) and Tacrolimus (FK506)

In Normal T-cells
T-cell activation → ↑[Ca2+]; Ca2+/Calmodulin → activates Calcineurin-mediated dephosphorylation of
NFATc (cytosolic Nuclear Factor of Activated T-cells)
– Activated NFAT translocates to nucleus → IL-2 gene
transcription
Calcineurin-inhibiting Drugs
I. Cyclosporine (Cs) and Tacrolimus (FK506)

Actions of Cs & FK506 (see A of diagram):
– Cs and FK506 cross into cytoplasm; bind to cyclophilin
(CyP) and FK-binding protein (FKBP), respectively
– Cs-CyP complex or FK-FKBP complexes bind to
Calcineurin → ↓Calcineurin phosphatase activity by
Ca2+/Calmodulin
– Tacrolimus...
– Cs and FK506 cross into cytoplasm; bind to cyclophilin
(CyP) and FK-binding protein (FKBP), respectively
– Cs-CyP complex or FK-FKBP complexes bind to
Calcineurin → ↓Calcineurin phosphatase activity by
Ca2+/Calmodulin
– Tacrolimus → ↓IL-3; IL-4, IFN-γ; 50-100x > potent vs Cs
– Tacrolimus – immunosuppressant for transplantation; use
of Cs: limited by adverse effects – hepato-, nephro-,
& neuro—toxicity; hypertension, hyperlipidemia
Sirolimus
Activation of IL-2 receptors → mTOR
(molecular target of rapamycin ) Phosphorylation
– mTOR – a kinase that phosphorylates & regulates
activity of PHAS-1 and p70 S6 kinase
• Sirolimus (S) binds to FKBP → S-FKBP complex
→ ↓mTOR → ↓Protein synthesis (Translation) &
Arrest of T-cell division in G1 phase
Sirolimus

Clinical Use/ Adverse Effects
• Clinical use:
– Sirolimus-eluting stents - Approved for coronary artery
disease
• Adverse effects:
– Hyperlipidemia
– Leukopenia
– Thrombocytopenia
• Clinical use:
– Sirolimus-eluting stents - Approved for coronary artery
disease
• Adverse effects:
– Hyperlipidemia
– Leukopenia
– Thrombocytopenia
Cytotoxic Agents – Antimetabolites
(Uses: Immunosuppression & Antineoplastic chemotherapy)
Examples
Azathioprine,
Methotrexate, Mycophenolate
Azathioprine (AZA)
– Pro-drug for 6-Mercaptopurine
-Slow-release from AZA; reacts
non-enzymically with sulfhydryl
compounds, e.g., glutathione
– < Efficacious than
Mycophenolate for long-term
survival of kidney allografts

– Immunosuppressants in patients
with inflammatory bowel disease
Methotrexate (MTX)/Uses
– Immune-mediated diseases, e.g., RA
– Prevention of graft versus host
disease
• Folate-independent anti-inflammatory
effect (unknown mechanism
– Perhaps via increasing adenosine (A) levels
– A→ Neutrophil adhesion/Phargocytosis,
& ROS generation (→ anti-inflammatory
effect)
– Cytotoxic action → Apoptosis of activated CD4 and CD8 T cells
• MTX has anti-neutrophil; anti-T cell, &
anti-humoral effects
MPA = inosine monophosphate
dehydrogenase (IMPDH) inhibitor
MPA or MMF
Mycophenolic Acid & Mycophenolate Mofetil
MPA or MMF → ↓IMPDH
Mycophenolic Acid & Mycophenolate Mofetil
MPA or MMF → ↓IMPDH
Leflunomide

Mech
Leflunomide inhibits dihydroorotate dehydrogenase →
inhibition of pyrimidine synthesis
– Lymphocytes depend on de novo pyrimidine synthesis for cell replication &
clonal expansion after immune cell activation
– Depletion of pyrimidine pool → ↓Lymphocyte expansion
Leflunomide

Adverse effects:
Diarrhea
Leflunomide

Clinical uses:
– Currently approved for rheumatoid arthritis
– Efficacious for other immune disease, e.g., myasthenia gravis,
lupus erythematosus
Cyclophosphamide, CyP

Effect
Orally administered, highly toxic drug; alkylates DNA
• CyP→ Hydroxylated intermediates by hepatic CYP
• → Phosphoramide mustard (PhM; active product) + Acrolein
• PhM + DNA → Cytotoxic effects; Acrolein → Risk of cancer
• Major effect on B-cell proliferation; can ↑T-cell responses
• Particularly used for disorders of humoral immunity, e.g., systemic lupus
erythematosus
Cyclophosphamide, CyP

Adverse Effects
Severe and widespread
• Leukopenia, cardiotoxicity, & ↑Risk of cancer, especially bladder cancer [due to
high Acrolein (carcinogenic) concentration in urine]
Cyclophosphamide (CyP)

Resistance to CyP may be caused by
↑DNA repair; ↓Drug permeability, and/or reaction of drug with glutathione or
other thiol-containing molecules
TNF (tumor necrosis factor):
TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab
– Secreted by activated macrophages →
multiple pro-inflammatory effects
– TNF → activation of ECs & ↑ expression of
surface adhesion molecules → Leukocyte
adhesion & diapedesis
– Positive feedback on monocytes & macrophages
→ ↑Cytokine (e.g., IL-1) secretion
TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

Adverse effects:
↑Risk of reactivating latent tuberculosis – screen
patients for TB; ↑Risk of demyelinating disease
TNF-α Inhibitors: Etanercept, Infliximab, Adalimumab

Uses
– Etanercept – non-specific (binds TNF-α and TNF-β) –
approved for rheumatoid arthritis
– Infliximab and Adalimumab – TNF-α-specific -
approved for rheumatoid arthritis, Crohn’s disease,
ulcerative colitis
II. Interleukin-1 (IL-1) inhibitors
IL-1 – generated by activated mononuclear cells & stimulates IL-6
production → ↑Expression of adhesion molecules → ↑Cell
proliferation
– IL-1 Receptor antagonist → ↓IL-1 activity

Anakinra
Anakinra

Effect and adverse reactions
• A recombinant form of IL-1 receptor antagonist (IL-1ra)
• Blocks IL-1-induced metalloproteinase release from synovial fluid
• Adverse effects:
• Neutropenia
• ↑Susceptibility to infection
Antibodies - Polyclonal
• Anti-thymocyte globulin (ATG)
– Derived from animal sera, e.g., rabbits following
injection with human thymocytes
• ATG targets all T cells → Broad
immuno-suppression
– Inhibit T lymphocytes & cause their lysis →
Inhibition of cell-mediated immune reactions
(e.g., graft rejection; delayed hypersensitivity)
• Polyclonal Ab affect all lymphocytes &
cause general immunosuppression
– Can predispose to infection
• Acute reaction (characterized by fever, or
even anaphylaxis) to treatment is common
due to high immunogenicity of polyclonal
Abs
Muromonab
Muromonab-CD3, anti-CD3
• Mouse monoclonal antibody against human
CD3 (a cell-surface signaling molecule for
activation of T-cell receptor)
• Body produces antibody against Mouse antibody (a
foreign protein
Rituximab
– a partially humanized anti-
CD20 antibody (approved for rheumatoid arthritis)
• CD20 – expressed on surface of all mature
B cells; Rituximab → depletion of
circulating B cells
Daclizumab and Basiliximab
– Induction therapy for renal transplantation
– Antibodies against CD25 – the high affinity IL-2
receptor (CD25 – expressed only on activated T-cells)
• Anti-CD25 antibody = specific activated T-cells targets