Definition & Class
- Structural analogs of normal metabolites (folates, purines, pyrimidines).
- Interfere with DNA/RNA synthesis by mimicking or blocking normal biochemical pathways.
- Cell cycle–specific: Most act in the S-phase.
Subclasses & Examples
| Subclass | Examples (Generic → Brand) | Mechanism of Action | Key Clinical Notes |
|---|---|---|---|
| Folate Antagonists | Methotrexate (Trexall®), Pemetrexed (Alimta®), Pralatrexate (Folotyn®) | Inhibit dihydrofolate reductase (DHFR) or related folate enzymes → block thymidylate/purine synthesis | MTX needs leucovorin rescue (HDMTX); renal clearance; mucositis & nephrotoxicity major risks |
| Pyrimidine Analogs | 5-Fluorouracil (Adrucil®), Capecitabine (Xeloda®), Cytarabine (Ara-C), Gemcitabine (Gemzar®), Azacitidine (Vidaza®), Decitabine (Dacogen®) | Mimic pyrimidines → inhibit DNA polymerase, thymidylate synthase, or incorporate into DNA/RNA | 5-FU bolus → myelosuppression; infusion → HFS & mucositis. Cytarabine HiDAC → cerebellar toxicity & conjunctivitis. Gemcitabine → flu-like symptoms, pulmonary toxicity |
| Purine Analogs | 6-Mercaptopurine (Purinethol®), 6-Thioguanine, Fludarabine, Cladribine (Leustatin®), Clofarabine (Clolar®) | Mimic purines → incorporated into DNA/RNA & inhibit enzymes in purine metabolism | 6-MP interacts with allopurinol/febuxostat (XO inhibitors). Fludarabine & Cladribine → profound immunosuppression. Clofarabine → pediatric ALL |
Class-Wide Toxicities
- Myelosuppression (dose-limiting for most).
- GI: nausea, vomiting, mucositis, diarrhea.
- Alopecia (less frequent vs. anthracyclines/taxanes).
- Organ-specific toxicities:
- MTX → renal & hepatic
- 5-FU/capecitabine → HFS, mucositis, diarrhea
- Cytarabine → cerebellar toxicity, ocular toxicity
- Purine analogs → prolonged immunosuppression
Key Pharmacist Pearls
- Supportive measures:
- MTX → leucovorin rescue + hydration + urine alkalinization.
- Pemetrexed/Pralatrexate → folic acid & B12 supplementation.
- 5-FU/capecitabine toxicity antidote → uridine triacetate.
- Cytarabine HiDAC → steroid eye drops prophylaxis.
- Purine analogs (fludarabine, cladribine) → PJP & antiviral prophylaxis.
- Pharmacogenomics:
- 6-MP → TPMT & NUDT15 deficiency → ↑ risk of life-threatening myelosuppression.
- 5-FU/capecitabine → DPD deficiency → ↑ severe toxicity.
- Drug–drug interactions:
- MTX ↑ toxicity with NSAIDs, PPIs, penicillins.
- 6-MP ↑ toxicity with allopurinol/febuxostat (need dose ↓).