Antimetabolite Drugs

Mechanism of Action

Antimetabolites disrupt DNA/RNA synthesis by mimicking or inhibiting nucleotide precursors. They interfere with the production or function of nucleotides required for cell division. Key targets include purines (adenosine, guanine), pyrimidines (thymine, cytosine), and folate pathways essential for nucleotide production.

Key Targets

• Purines: Interference can block adenosine/guanine production.

• Pyrimidines: Inhibition affects thymine/cytosine formation.

• Folate: Inhibiting dihydrofolate reductase (DHFR) reduces DNA synthesis.

Types & Examples

Indications

• Methotrexate: Rheumatoid arthritis, psoriasis, ectopic pregnancy, leukaemia, lymphoma

• Mercaptopurine: Maintenance therapy for acute lymphoblastic leukaemia (ALL)

• Fluorouracil (5-FU): Colorectal and breast cancers, solid tumours

Contraindications

• Severe hepatic or renal impairment

• Active infection or severe immunosuppression

• Pregnancy (high teratogenic risk, especially with methotrexate)

• Known hypersensitivity to the drug

Management of Toxicity

• Methotrexate

  • Folinic acid (leucovorin) rescue to replenish folate stores

  • Alkalinise urine (IV sodium bicarbonate) to enhance methotrexate excretion

  • Glucarpidase for severe methotrexate toxicity (breaks down drug)

• Purine & Pyrimidine Antagonists

  • Myelosuppression → transfusions, G-CSF for neutropenia

  • Hepatotoxicity → monitor liver function, adjust doses accordingly

  • Fluorouracil → watch for hand-foot syndrome (palmar-plantar erythrodysaesthesia); may require dose reduction and supportive care

Notes

• Methotrexate:

  • Regularly monitor renal function, LFTs, and FBC.

  • Avoid NSAIDs and penicillins (can reduce renal clearance, raising toxicity risk).

• Fluorouracil:

  • Hand-foot syndrome (erythema, pain) responds to early intervention (dose adjustment, topical creams).