Methotrexate

Question 1

What is the core mechanism of action of methotrexate?

Answer 1

Methotrexate is a folate analogue that competitively inhibits dihydrofolate reductase, preventing the conversion of dihydrofolate to tetrahydrofolate and reducing purine and thymidylate synthesis.

Question 2

How does low-dose methotrexate work in inflammatory disease?

Answer 2

At low weekly doses it inhibits AICAR transformylase, leading to adenosine accumulation which has anti-inflammatory effects, suppresses T-cell activation, reduces cytokine production and limits lymphocyte proliferation.

Question 3

What is the mechanism of high-dose methotrexate in oncology?

Answer 3

At high doses it directly inhibits nucleotide synthesis causing cytotoxicity and apoptosis of rapidly dividing malignant cells, often combined with folinic acid rescue.

Question 4

What are the clinical indications for methotrexate?

Answer 4

Inflammatory arthritis such as rheumatoid arthritis, psoriasis and chemotherapy for acute lymphoblastic leukaemia.

Question 5

What are the common adverse effects of methotrexate?

Answer 5

Mucositis, myelosuppression, pneumonitis and liver fibrosis.

Question 6

What are the features of methotrexate-induced pneumonitis?

Answer 6

It presents with acute or subacute non-productive cough, dyspnoea, malaise and fever, usually within the first year of therapy, and resembles hypersensitivity pneumonitis.

Question 7

Does methotrexate cause pulmonary fibrosis?

Answer 7

Current long-term studies do not support an association between methotrexate and pulmonary fibrosis.

Question 8

What are the pregnancy precautions for methotrexate?

Answer 8

Women and men should avoid conception for at least 6 months after stopping methotrexate.

Question 9

How often is methotrexate taken?

Answer 9

Methotrexate is taken weekly, not daily.

Question 10

What monitoring is required for patients on methotrexate?

Answer 10

FBC, U&E and LFTs should be checked before starting, weekly until stable and then every 2–3 months.

Question 11

Why is folic acid prescribed with methotrexate?

Answer 11

Folic acid 5 mg weekly is given more than 24 hours after methotrexate to reduce toxicity without reducing therapeutic effect.

Question 12

What is the usual starting dose of methotrexate?

Answer 12

7.5 mg once weekly, usually using the 2.5 mg tablets to reduce dosing errors.

Question 13

Which drugs interact dangerously with methotrexate?

Answer 13

Trimethoprim and co-trimoxazole increase the risk of marrow aplasia, and high-dose aspirin reduces methotrexate excretion and increases toxicity.

Question 14

What is the treatment for methotrexate toxicity?

Answer 14

Folinic acid (leucovorin) is the treatment of choice.