## Diagnosis: Methotrexate-Induced Megaloblastic Anemia Methotrexate (MTX) inhibits dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate (THF). This causes functional folate deficiency and megaloblastic anemia, even when serum folate is low-normal. ## First-Line Prevention & Treatment: Folinic Acid (Leucovorin) **Key Point:** Folinic acid (5-formyl-THF, leucovorin) is the drug of choice for MTX-induced megaloblastic anemia because it **bypasses the DHFR block** and directly replenishes the THF pool. **High-Yield:** Standard dosing: - **5 mg orally once daily** on non-MTX days (e.g., if MTX given weekly, give folinic acid on days 2–7) - Alternative: 5 mg twice weekly on non-MTX days - This prevents and treats MTX-induced folate deficiency ## Why Folinic Acid (Not Folic Acid) in MTX Therapy? ```mermaid flowchart TD A[Folic Acid] -->|DHFR| B[Dihydrofolate] B -->|DHFR BLOCKED by MTX| C[❌ THF not formed] D[Folinic Acid] -->|Bypasses DHFR| E[THF] E -->|Directly available| F[✓ Nucleotide synthesis resumes] C --> G[Megaloblastic Anemia] F --> H[Normal Hematopoiesis] ``` | Feature | Folic Acid | Folinic Acid (Leucovorin) | |---------|---|---| | **Requires DHFR?** | Yes | No | | **Effective in MTX therapy?** | No (DHFR blocked) | Yes (bypasses block) | | **First-line for MTX prevention** | No | Yes | | **Cost** | Lower | Higher | | **Onset of action** | Slow | Rapid | **Clinical Pearl:** Folic acid is ineffective in MTX-induced deficiency because MTX blocks its conversion to THF. Folinic acid works because it is already in the active form (5-formyl-THF) and does not require DHFR. **Mnemonic:** **FOLINIC = Folinic for MTX** — Folinic acid is the rescue agent for methotrexate toxicity because it bypasses the DHFR block.
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