Antimetabolites
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Direct answer
Antimetabolites are structural mimics of normal metabolites that fraudulently occupy folate, purine and pyrimidine synthesis enzymes, killing cells in S phase. Methotrexate inhibits dihydrofolate reductase and is rescued by leucovorin; fluorouracil blocks thymidylate synthase; cytarabine terminates DNA chain elongation in acute myeloid leukaemia; the purine analogues mercaptopurine and fludarabine corrupt DNA and RNA synthesis. Myelosuppression and mucositis are the class burden, with signature additions — methotrexate pulmonary toxicity, cytarabine cerebellar toxicity, allopurinol-mercaptopurine interaction.
What you must remember
- Methotrexate competitively inhibits dihydrofolate reductase, depleting reduced folates needed for thymidylate and purine synthesis; high-dose protocols demand leucovorin rescue, alkalinised urine and hydration.
- Methotrexate spans oncology — acute lymphoblastic leukaemia, choriocarcinoma, osteosarcoma — and low-dose weekly therapy for rheumatoid arthritis and psoriasis; toxicity is mucositis, myelosuppression, hepatic fibrosis and an interstitial pneumonitis.
- Fluorouracil is converted intracellularly to FdUMP, irreversibly inhibiting thymidylate synthase; mucositis, diarrhoea, myelosuppression and the palmar-plantar hand-foot syndrome are characteristic, and leucovorin potentiates its binding; capecitabine is its oral prodrug.
- Cytarabine, a pyrimidine nucleoside analogue, incorporates into DNA and terminates chain elongation — the backbone of acute myeloid leukaemia induction; high doses cause cerebellar dysfunction and conjunctivitis, prevented by steroid eye drops.
- Gemcitabine treats pancreatic, biliary and lung cancer with flu-like infusion reactions and prominent thrombocytopenia.
- Purine analogues: mercaptopurine maintains childhood acute lymphoblastic leukaemia — allopurinol blocks its xanthine-oxidase-mediated clearance, demanding mercaptopurine dose reduction; thiopurine methyltransferase deficiency predisposes to marrow aplasia.
- Azathioprine, the immunosuppressive prodrug of mercaptopurine, inherits the same allopurinol interaction; fludarabine causes long-lasting lymphopenia needing irradiated blood products to prevent transfusion-associated graft-versus-host disease; cladribine is the hairy-cell leukaemia drug of choice.
Common confusion
Methotrexate and leucovorin are mislabelled antidote-and-poison in the wrong order — leucovorin rescues normal cells by bypassing the blocked enzyme, so it must never be given with low-dose methotrexate for rheumatoid arthritis, where it simply abolishes efficacy. The allopurinol-mercaptopurine interaction is also forgotten, with fatal marrow aplasia the price.
Exam-focused takeaway
Theory answers should organise by pathway — folate, purine, pyrimidine — with mechanism, one disease and one toxicity per drug. Viva examiners ask how leucovorin rescue works and why allopurinol demands mercaptopurine dose cuts. MCQs test thymidylate synthase inhibition, hand-foot syndrome with fluorouracil and capecitabine, cytarabine cerebellar signs, TPMT and the irradiated-blood rule after fludarabine.
Frequently asked questions
How does leucovorin rescue work in methotrexate toxicity?
It supplies reduced folates that bypass the blocked dihydrofolate reductase step, rescuing normal marrow and mucosa — hence its role in high-dose protocols and accidental overdose.
What is the interaction between allopurinol and mercaptopurine?
Allopurinol inhibits xanthine oxidase, which normally degrades mercaptopurine, so levels and marrow toxicity rise unless the mercaptopurine dose is substantially reduced.
Which antimetabolite causes hand-foot syndrome?
Fluorouracil and its oral prodrug capecitabine, producing tender palmar-plantar erythema and desquamation.
What neurotoxicity follows high-dose cytarabine?
Cerebellar dysfunction — ataxia, dysarthria and nystagmus — more common in older patients and with renal impairment, alongside conjunctivitis prevented by steroid eye drops.
Why do fludarabine patients need irradiated blood products?
Persistent lymphopenia impairs immune rejection of transfused lymphocytes, risking transfusion-associated graft-versus-host disease, prevented only by irradiating cellular products.