Alkylating Agents

ALKYLATING AGENTS


ALKYLATING AGENTS

MOA:

  • All alkylating agents & related drugs (procarbazine, dacarbazine & platinum compounds) are CCNS drugs.
  • Acts both on resting & dividing cells.
  • Step 1: Alkylate nucleophilic groups on DNA bases – N7 of guanine is most susceptible for alkylation.
  • Step 2: Lead to base cross-linking, abnormal base-pairing & DNA strand breakage.

Common adverse effects:

  • Gastrointestinal distress, bone marrow suppression, alopecia, secondary leukemia & sterility.

Classification of alkylating agents:

Nitrogen mustards Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil
Ethylenimines Thio-TEPA, hexamethylmelamine (altretamine)
Alkyl sulfonates Busulfan
Nitrosoureas Carmustine, lomustine, streptozocin
Triazines Procarbazine, dacarbazine, temozolomide

IMPOTANT DETAILS ON INDIVIDUAL DRUG GROUP:

I) Nitrogen mustards:

1. Cyclophosphamide:

  • Powerful vesicant
  • Prodrug – Activated by hepatic biotransformation to aldophosphamide.
    • Acrolein – One of its degradation products.
    • Responsible for hemorrhagic cystitis – Characteristic adverse effect.
  • Use: DOC for Wegener’s granulomatosis.

Adverse effects:

  • Hemorrhagic cystitis (Characteristic) – Treated by mercapto ethane sulfonic acid (mesna).
  • May cause cardiac dysfunction, pulmonary toxicity & syndrome of inappropriate ADH secretion.

2. Ifosfamide:

  • Produces chloracetaldehyde & acrolein as metabolites.

Adverse effects:

  • HIGHER risk of neurotoxicity & hemorrhagic cystitis.
  • Chloracetaldehyde – Responsible for nephrotoxic.

3. Chlorambucil:

  • Spares myelocytes, used for CLL.

4. Mechlorethamine:

  • Powerful vesicant.
  • DOC in Hodgkin’s disease.

5. Melphalan:

  • DOC for multiple myeloma.

II) Nitrosoureas:

  • Drugs: Carmustine (BCNU), lomustine (CCNU), semustine (methyl CCNU) & streptozocin.
  • Highly lipid soluble.
  • Crosses blood-brain barrier.
  • Use: Treatment of brain tumors (gliomas).

Adverse effects:

  • Cause delayed neutropenia.

Streptozocin:

  • Destroys pancreatic beta-cells – Hence, indicated for islet cell tumors.
  • Minimum bone marrow toxicity.

III) Triazines:

Dacarbazine:

  • Primarily affects RNA & protein synthesis, unlike alkylating agent.

Procarbazine:

  • Most leukemiogenic.
  • Causes disulfiram-like-reaction with alcohol.
  • Causes CNS effects (hypnosis & vivid dreams).

IV) Alkyl sulfonates

Busulfan:

  • Mainly causes adrenal insufficiency, pulmonary fibrosis, skin hyperpigmentation & hyperuricemia.

Toxicities of alkylating agents:

Drug

Distinctive toxicity

Cyclophosphamide Alopecia, Hemorrhagic cystitis, SIADH
Ifosfamide Hemorrhagic cystitis, SIADH
Busulfan Pulmonary fibrosis, Hyperpigmentation, Adrenal insufficiency
Procarbazine Secondary leukemias, Disulfiram-like reaction, Behavioral changes, CNS depression

IMPORTANT POINTS ON HEMORRHAGIC CYSTITIS:

Drugs causing:

  • Cyclophosphamide
  • Ifosfamide

Metabolite responsible:

  • Acrolein – In Cyclophosphamide
  • Chloracetaldehyde – In Ifosfamide

Treatment:

  • Mesna.

Nitrogen mustard toxicity:

  • Decreased by GM-CSF.

Exam Important

  • Busulfan may cause pulmonary fibrosis.
  • Anti-cancer drug with disulfiram-like-action is with Procarbazine.
  • Toxicity of nitrogen mustards can be decreased by GM-CSF.
  • All alkylating agents & related drugs (procarbazine, dacarbazine & platinum compounds) are CCNS drugs.
  • N7 of guanine is most susceptible to alkylation.
  • Common adverse effects of all alkylating agents are gastrointestinal distress, bone marrow suppression, alopecia, secondary leukemia & sterility.
  • Mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil are all nitrogen mustards.
  • Busulfan is an alkyl sulfonate.
  • Carmustine, lomustine, streptozocin are all nitrosoureas.
  • Procarbazine, dacarbazine, temozolomide are catagorized under Triazines.
  • Cyclophosphamide is a powerful vesicant
  • Cyclophosphamide is a prodrug activated by hepatic biotransformation to aldophosphamide & its by-product includes Acrolein, responsible for its characteristic adverse effect, hemorrhagic cystitis 
  • Hemorrhagic cystitis, characteristic adverse effect of cyclophosphamide, is treated by mercapto ethane sulfonic acid (mesna).
  • Cyclophosphamide is DOC for Wegener’s granulomatosis.
  • Ifosfamide produces chloracetaldehyde & acrolein as metabolites.
  • Ifosfamide has HIGHER risk of neurotoxicity & hemorrhagic cystitis.
  • Chlorambucil is used for CLL.
  • Mechlorethamine, a powerful vesicant is DOC for Hodgkin’s disease.
  • Drugs like Carmustine (BCNU), lomustine (CCNU), semustine (methyl CCNU) & streptozocin are all Nitrosoureas.
  • Streptozocin destroys pancreatic beta-cells, hence indicated for islet cell tumors.
  • Dacarbazine primarily affects RNA & protein synthesis, unlike alkylating agent.
  • Procarbazine is most leukemogenic, causing disulfiram-like-reaction with alcohol & also cause CNS effects (hypnosis & vivid dreams).
  • Busulfan mainly causes adrenal insufficiency, pulmonary fibrosis, skin hyperpigmentation & hyperuricemia.
  • Alopecia, Hemorrhagic cystitis, SIADH are all caused by Cyclophosphamide.
  • Hemorrhagic cystitis, SIADH are all caused by Ifosfamide.
  • Pulmonary fibrosis, Hyperpigmentation, Adrenal insufficiency are all caused by Busulfan.
  • Secondary leukemias, Disulfiram-like reaction, Behavioral changes, CNS depression are all caused by Procarbazine.
  • Nitrogen mustard toxicity is decreased by GM-CSF.
Don’t Forget to Solve all the previous Year Question asked on ALKYLATING AGENTS

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