Nitrogen mustards

• Nitrogen mustard is an alkylating agent that causes cross-linking between DNA strands, leading to cell death.
• Cyclophosphamide and Ifosfamide are prodrugs. They must be activated by CYP3A4 and CYP2B6.
• Examples of nitrogen mustards include mechlorethamine, cyclophosphamide, ifosfamide, chlorambucil, melphalan.
• Large fluid infusion and MESNA can used to prevent hemorrhagic cystitis.
• Acrolein is the metabolite of cyclophosphamide and ifosfamide. It has little antitumour activity. The major SE is hemorrhagic cystitis.
• At standard dose, they have little cardiac toxicity.

  At high dose, will cause severe myocarditis, exudative pericarditis, myocardial depression arrhythmias, and congestive HF.
• Cyclophosphamide has an additional immunosuppressant property to treat lupus nephritis.
• The side effects of cyclophosphamide include myelosuppression, hemorrhagic cystitis, syndrome of inappropriate ADH, alopecia, highly emetogenic, cardiotoxicity.

  Major SE includes alopecia and hemorrhagic cystitis.
• (Cyclophosphamide): Hemorrhagic cystitis more common in renally compromised and poorly hydrated patient.

  S&S includes gross hematuria (blood in urine).

  Management includes increase IVF, MESNA, total bladder irrigation.
• MESNA can help to decrease the risk of bleeding in patient with hemorrhagic cystitis.
• Ifosfamide has a higher risk of hemorrhagic cystitis compared to cyclophosphamide.
• S&S of hemorrhagic cystitis include dysuria, frequently urination

  Treatment of hemorrhagic cystitis include evacuation of clots, continuous bladder irrigation by using 1% alum, prostaglandins, or high dose tranexamic acid.
• The side effects of ifosfamide include hemorrhagic cystitis, leukopenia, neurotoxicity Fanconi syndrome, N&V, alopecia, hepatic enzyme elevations.

  Symptoms of leukopenia is WBC nadir, occurs between day 8 to 13; recovery usually be completed by day 17-18 of treatment cycle.

  Symptoms of neurotoxicity include encephalopathy (cerebellar ataxia - inability to coordinate muscle movement, mental confusion, complex visual hallucinations)

  Treatment of neurotoxicity is methylene blue / methylthioninium chloride.
• Fanconi syndrome is the impairment of proximal renal tubule of kidney function. It is irreversible, long lasting, and progressive. Symptoms of Fanconi syndrome include polyuria, metabolic acidosis, renal phosphate wasting.