Immunopharmacology Page 5

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Azathioprine
- Chemistry --imidazolyl derivative of mercaptopurine (6-MP; 6-mercaptopurine
  - structural analog
  - antimetabolite
- Primary use --azathioprine: immunosuppression
- prototype: cytotoxic immunosuppressive drugs
  - kill profilerative cells
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- Pharmacokinetic/Pharmacodynamics: azathioprine
  - well absorbed from the GI tract
  - metabolized to mercaptopurine (primarily)
  - xanthine oxidase converts azathioprine to 6-thiouric acid
    - patients on xanthine oxidase inhibitors (allopurinol for management of hyperuricemia)-- dosage reduction required to prevent toxicity
  - urinary excretion
  - small amounts of mercaptopurine and unchanged drug also renally excreted
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- Mechanism of Immunosuppression Action:azathioprine
  - interference with nucleic acid metabolism
    - reducing significant lymphoid cell proliferation following antigenic stimulation
  - Cytotoxic purine analogues: destroyed stimulated lymphoid cells
  - Blockade of:
    - cellular immunity
    - primary and secondary serum antibody responses
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- Clinical Use:azathioprine; mercaptopurine
  - renal allograft maintenance
  - effective/possibly effective-- management of:
    - acute glomerulonephritis
    - real component of systemic lupus erythematosus
    - rheumatoid arthritis
    - Crohn's disease
    - multiple sclerosis
    - prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura
    - autoimmune hemolytic anemias
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- Toxicities:azathioprine, mercaptopurine
  - bone marrow depression
    - leukopenia -- most common
      - anemia
      - thrombocytopenia
      - bleeding
  - Skin rashes
  - Drug fever
  - nausea & vomiting
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Cyclophosphamide
- alkylating agent
- very potent immunosuppressive agent
- induces tolerance for marrow/immune cell grafting (does not prevent later graft vs. host syndrome)
- kills proliferating lymphoid cells
  - alkylates some resting cells
- Lower doses (< 120 mg/kg):
  - Clinical Use: Efficacious for managing:
    - Autoimmune disorders
      - systemic lupus erythematosus
      - autoimmune hemolytic anemia
      - antibody-induced pure red cell aplasia
      - Wegener's gramulomatosis
    - Acquired factor XIII antibodies/bleeding disorders
- Adverse Effects:-- large doses
  - pancytopenia
  - hemorrhagic cystitis

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Vincristine
- Mechanism of action: microtubule depolymerization
  - Mitotic arrest at metaphase; interferes with chromosome segregation
- Clinical Use: Vincristine
  - immunosuppression: idiopathic thrombocytopenic purpura refractory to prednisone
  - useful in treating some other rapidly proliferating neoplasms
  - In combination with prednisone: induction of remission in children with acute leukemia
- Adverse Effects:vincristine
  - significant frequency of neurotoxic reactions
  - occasional: bone marrow depression

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Vinblastine
- Mechanism of action: microtubule depolymerization
  - may prevent mast cell degranulation (binding to microtubule units)
    - reduce histamine release
- Mitotic arrest at metaphase; interferes with chromosome segregation
- Clinical Use:Vinblastine
  - Systemic treatment of Hodgkin's disease
  - Lymphomas
- Adverse Effects: Vinblastine
  - nausea
  - vomiting
  - alopecia
  - bone marrow suppression

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Methotrexate (MTX)
- Mechanism of Action: Folic acid antagonist: acts at catalytic side of dihydrofolate reductase
- Polyglutamate: important in methotrexate action
- Tumor resistance to methotrexate:
  - decreased drug transport into the cell
  - altered dihydrofolate reductase enzyme -- lower affinity for methotrexate
  - decreased polyglutamate formation
  - quantitative increase in dihydrofolate reductase enzyme concentration in the cell (gene amplification, increased message)
- Adverse effects:methotrexate
  - Bone marrow suppression
  - Dermatologic
  - GI mucosa
  - Adverse effects reversed by leucovorin (citrovorum factor)
    - Leucovorin "rescue" may be used in cases of over dosage or in high-those methotrexate protocols
- Other uses:
  - Treatment of rheumatoid arthritis
  - In combination with a prostaglandin: induces abortion

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Dactinomycin
- IV administration; 50 percent remains unmetabolized.
- Mechanism of action: intercalation between guanine-cytosine base pairs
  - inhibits DNA-dependent RNA synthesis
  - blocks protein synthesis
- Clinical Uses:Dactinomycin
  - in combination with vincristine and surgery (may include radiotherapy) in treatment of Wilms' tumor
  - with methotrexate: maybe curative for localized or disseminated gestational choriocarcinoma.
  - May be useful in preventing acute renal transplant rejection
- Adverse Effects:Dactinomycin
  - Major dose limiting toxicity: bone marrow suppression (all blood elements affected -- particularly platelets and leukocytes)
    - occasional severe thrombocytopenia
  - nausea
  - vomiting
  - diarrhea
  - oral ulcers
  - Dactinomycin: immunosuppressive (patient should not receive live virus vaccines)
  - alopecia/skin abnormalities
  - interaction with radiation ("radiation recall")

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