Antimetabolites

Antimetabolites Overview - Stealthy Saboteurs

• Structural analogs of endogenous metabolites (folic acid, purines, pyrimidines).
• MOA: "Counterfeit" molecules. They substitute for or compete with normal metabolites, thereby:
  • Inhibiting critical enzymes in nucleotide synthesis.
  • Incorporating into DNA/RNA, leading to non-functional macromolecules & chain termination.
• Cell cycle specific: Primarily S-phase (DNA synthesis).
• Major Classes:
  • Folate Antagonists (e.g., Methotrexate)
  • Purine Analogs (e.g., 6-Mercaptopurine, Azathioprine, Fludarabine)
  • Pyrimidine Analogs (e.g., 5-Fluorouracil, Cytarabine, Gemcitabine)

⭐ Myelosuppression is a common and often dose-limiting toxicity for most antimetabolites. 📌 "Anti-Metabolites = Anti-Making (DNA/RNA)"; S-phase specific.

Folate Antagonists - Folate Foes

• Methotrexate (MTX): Primary folate antagonist.
  • MOA: Competitively inhibits Dihydrofolate Reductase (DHFR), blocking DHF $\rightarrow$ THF conversion. This ↓ thymidylate & purine synthesis. S-phase specific.
  • Uses:
    • Malignancies: ALL, lymphoma, choriocarcinoma, breast, head/neck, osteosarcoma.
    • Non-malignant: Rheumatoid arthritis, psoriasis, IBD, ectopic pregnancy.
  • Toxicity: Myelosuppression (dose-limiting), mucositis, hepatotoxicity, nephrotoxicity (crystalluria; prevent with hydration/urine alkalinization), pulmonary fibrosis, teratogenic.
  • Leucovorin Rescue: Folinic acid bypasses DHFR block, protects normal cells after high-dose MTX.
• Pemetrexed: Inhibits DHFR, Thymidylate Synthase (TS), GARFT. Uses: Mesothelioma, NSCLC.
• Pralatrexate: For peripheral T-cell lymphoma.

  ⭐ Myelosuppression is the most common dose-limiting toxicity of methotrexate.

Purine Analogs - Purine Punks

• MOA: Act as false purine metabolites.
  • Inhibit de novo purine synthesis (e.g., by inhibiting PRPP amidotransferase).
  • Incorporate into DNA/RNA → cause chain termination or dysfunction.
• Key Drugs & Primary Uses:
  • 6-Mercaptopurine (6-MP), Azathioprine (AZA - prodrug of 6-MP):
    • Acute Lymphoblastic Leukemia (ALL), immunosuppression (e.g., IBD, RA, transplants).
  • Fludarabine:
    • Chronic Lymphocytic Leukemia (CLL), Non-Hodgkin Lymphoma (NHL).
  • Cladribine (2-CDA):
    • Hairy Cell Leukemia (HCL), CLL.
  • Pentostatin:
    • HCL (inhibits adenosine deaminase).
• General Toxicities: Myelosuppression, GI distress (nausea, vomiting, diarrhea), hepatotoxicity.
• Drug-Specific Toxicities:
  • Fludarabine: Profound myelosuppression & immunosuppression (↑opportunistic infections), neurotoxicity.
  • Cladribine: Myelosuppression, neurotoxicity.

⭐ ⚠️ Allopurinol Interaction: Allopurinol (xanthine oxidase inhibitor) blocks the metabolism of 6-MP and Azathioprine, drastically ↑ their toxicity. Dose of 6-MP/Azathioprine must be reduced by ~75% when co-administered with allopurinol to prevent severe myelosuppression and pancytopenia.

Pyrimidine Analogs - Pyrimidine Pirates

• Mimic pyrimidines; disrupt DNA/RNA synthesis, targeting rapid cell division.

High‑Yield Points - ⚡ Biggest Takeaways

• Antimetabolites are S-phase specific cell cycle inhibitors.
• Methotrexate (MTX), a folate analog, inhibits DHFR; rescue with Leucovorin. Key toxicities: myelosuppression, mucositis.
• 5-Fluorouracil (5-FU), a pyrimidine analog, inhibits thymidylate synthase; potentiated by Leucovorin. Causes hand-foot syndrome.
• Cytarabine (ara-C) inhibits DNA polymerase; causes pancytopenia, cerebellar toxicity.
• 6-Mercaptopurine (6-MP) is a purine analog; its metabolism is inhibited by Allopurinol, increasing toxicity.
• Hydroxyurea inhibits ribonucleotide reductase, halting cells in S-phase.