# Antimetabolites

> Antimetabolites for MBBS Pharmacology — methotrexate leucovorin rescue, 5-FU, cytarabine, purine analogues and toxicity map.

- Canonical URL: https://prepelephant.com/topics/mbbs/pharmacology/antimetabolites
- Exam / course: MBBS · Subject: Pharmacology
- Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team
- First published: 2026-10-02
- Last updated: 2026-10-02
- How to cite: "Antimetabolites", PrepElephant, https://prepelephant.com/topics/mbbs/pharmacology/antimetabolites

## 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.