Mascara Nitrogen Mustards

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jcu1
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257911
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Mascara Nitrogen Mustards
Updated:
2014-01-24 11:05:56
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  1. Cell Cycle
    • M - chromosomes segregated and divided (cell divides)
    • G1 - components for DNA replication synthesized
    • S - replication of DNA
    • G2 - cell prepares to divide
  2. transferring alkyl groups onto DNA
    nucleophil on DNA displaces leaving group on the alkylating agent
  3. Alkylating agent classes
    • Nitrogen mustards
    • ethyleneimine
    • alkyl sulfonates
    • nitrosoureas
    • triazenes
    • platinum coordination complexes
  4. Nitrogen mustards agents
    • mechlorethamine
    • cyclophosphamide
    • ifosfamide
    • melphalan
    • chlorambucil
    • bendamustine
  5. Ethyleneimine agents
    thiotepa
  6. Alkyl sufonates agents
    busulfan
  7. nitrosoureas agents
    • carmustine
    • lomustine
  8. triazenes agents
    • dacarbazine
    • temozolomide
  9. platinum coordination complexes
    • carboplatin
    • cisplatin
    • oxaliplatin
  10. cyclophosphamide route of admin
    • po
    • iv
  11. ifosfamide route of admin
    iv
  12. melphalan route of admin
    • iv
    • po
  13. chlorambucil route of admin
    • po
    • continuously on chronic basis
  14. bendamustine route of admin
    iv
  15. chemical structure of nitrogen mustards
    • Bis(chloroethyl) groups
    • rest of mlcl determines physical properties and affects transport, distribution, and reactivity
  16. nitrogen mustard activation
    • non-enzymatic
    • to aziridinium intermediate
  17. historical use of mechlorethamine
    • MOPP regimen for hodgkin's lymphoma
    • Stanford V
  18. what has mechlorethamine been replaced by and why?
    • cyclophosphamide
    • less secondary malignancies and infertility
  19. uses of mechlorethamine
    • NHL (non-hodgkins)
    • intracavitary injection in metastatic tumors
    • cutaneous T-cell lymphoma
  20. mechlorethamin AEs
    • myelosuppresion (dose-limiting)
    • emtogenicity (very high)
    • infertility
    • vesicant
    • secondary malignancy
  21. how to avoid extravasation with mechlorethamine
    use sodium thiosulfate
  22. mechlorethamine clinical pearls
    • use within 1 hr of reconsitution (fast hydrolysis and demethylation in solution)
    • slow IV push
  23. melphalan uses
    • multipe myeloma
    • autologous stem cell transplatn in elderly pts
    • unresectable epithelia ovarian cancer
  24. if melphalan given before a autologous transplant?
    impairs ability to harvest adequate quantity of stem cells
  25. melphalan AEs
    • myelosupression
    • infertility
    • secondary malignancy

    • less common:
    • pulmonary fibrosis
    • interstitial pneumonitis
    • rahses
    • cardiac arrest
  26. melphalan emetogenicity
    very low
  27. mechlorethamine emetogenicity
    very high
  28. mephalan clinical pearls
    • take tabs on empty stomach
    • store tabs in fridge
    • use IV solution within 60 min of reconsititution
  29. primary use of chorlambucil
    chronic lymphocytic leukemia
  30. chlorambucil uncommon uses
    • hodgkin's lymphoma
    • non hodgkin's lymphoma
  31. chlorambucil AEs
    • infertility
    • secondary malignancies

    • less common:
    • seizures (with pulsing dose)
    • tremor, muscle twitching, agitation, confusion
    • ataxia
    • pulmonary fibrosis
    • hepatotoxicity
  32. chlorambucil emtogenicity
    very low
  33. chlorambucil monitory
    weekly CBCs
  34. chlorambucil clinical pearls
    • take on empty stomach
    • keep in fridge
    • mildest treatment with least toxicities
  35. chlorambucil brand name
    Leukeran
  36. melphalan brand name
    Alkeran
  37. Leukeran generic name
    chlorambucil
  38. Alkeran generic name
    melphalan
  39. most used nitrogen mustard
    cyclophosphamide
  40. cyclophosphamide use
    all types of cancers (breast, CLL, NHL, acute lymphoblastic leukemia, multiple myeloma)
  41. cyclophosphamide AEs
    • myelosuppresion
    • alopecia
    • infertility
    • N/V
    • mucositis
    • hemorrhagic cystitis

    • Less common:
    • SIADH
    • heart failure
    • secondary malignancies (AML, bladder cancer)
  42. cyclophosphamide emetogenicity
    dose-dependent and route dependent
  43. how to minimize risk of hemorrhagic cystis with use of cylcophosphamide
    • MESNA
    • forced diuresis
    • fluid intake >/2 2 L per day
    • take in morning to dec inc in nighttime bladder exposure to acrolein
  44. what metabolite causes hemorrhagic cystitis with use of cylcophosphamide?
    acrolein
  45. MESNA MOA
    • circulates in blood as inactive oxidized form (dimesna)
    • excrete into the urine and partially reduced to monomeric form
    • free sulfhydryl group inactivates acrolein (Michael rxn)
  46. ifosfamide chemical structure
    • isomer of cylcophosphamide
    • slower metabolism --> more chloracetaldehyde (encephalopathy)
  47. ifosfamide dosage form
    iv inpatient
  48. ifosfamide toxic metabolite
    • chloracetaldehyde
    • causing encephalopathy
  49. ifosfamide and MESNA
    mandatory
  50. ifosfamide uses
    • testicular cancer
    • sarcoma
    • non-hodgkins lymphoma
  51. ifosfamide AEs
    • hemorrhagic cyctitis
    • encephalophathy
    • myelosuppresion
    • N/V
    • infertility
  52. ifosfamide emetogenicity
    moderate
  53. risk factors for encephalopathy
    • hypoalbuminemia
    • renal dsfx
    • pelvic mass
    • hx of ifosfamide-induced encephalopathy
  54. sx's of encephalopathy
    • confusion
    • somnolence
    • coma
    • delirium
    • confusion
    • hallucinations
    • stupor
    • personality changes
    • twitching
  55. sometimes given to treat ifosfamide-induced encephalopathy
    methylene blue
  56. bendamustine chemical properties
    • water-soluble
    • amphoteric
    • bifunctional compound
  57. bendamustine chemical structure
    • not a pro-drug
    • benzimidazole ring has purine analog activity
  58. bendamustine cross resistance with other alkylators
    • not repaired by typical alkyltransferase enzymes
    • little cross-resistance
  59. bendamustine uses
    • common: NHL, CLL
    • other: mantle cell lymphoma, multiple myeloma
  60. bendamustine AEs
    • very well tolerated
    • myelosuppresion
    • skin reactions
    • infusion reactions
    • N/V
    • fatigue
  61. bendamustine metabolism
    CYP 1A2
  62. Bendamustine dose adjustment
    • avoid in CrCl <40 ml/min
    • avoid in moderate-severe hepatic impairment
  63. bendamustine drug-drug interaction
    • inhibitors of CYP 1A2:¬†cipro, fluvoxamine
    • inducers of CYP 1A2: omeprazole, smoking
  64. busulfan chemical workings
    • bifunctional alkylating agent
    • SN2 rxn
  65. busulfan especially toxic to:
    • myeloid cells¬†
    • hematopoietic stem cells
  66. historic use of busulfan
    chronic oral therapy for chronic myelogenous leukemia
  67. current use of busulfan
    allogenic stem cell transplantation combined with cylophosphamide or fludarabine
  68. busulfan route of admin and why
    • iv preferred over oral
    • dec in risk hepatic veno-occlusive disease (VOD)/sinosoidal obstruction syndrome (SOD)
    • avoid variation in bioavailability
  69. busulfan PK
    • distribution into CSF
    • hepatic metabolism (gluthione conjugation and CYP 3A4
  70. busulfan drug interactions
    • APAP (glutathione depletion
    • metronidazole
  71. busulfan AEs
    • seizures
    • pulmonary fibrosis
    • SOS/VOD
    • myelosuppression
    • secondary malignancies
    • N/V
  72. busulfan seizure prophylaxis
    • phenytoin
    • levetiracetam
    • benzodiazepine
  73. busulfan emetogenicity
    moderate

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