Drug Induced Megaloblastic Anaemia

Folic food fortification tends to offset the hematological effect of vitamin B12, therefore there maybe neurological complications rather than anaemia.

Severe neurological compromise can lead to optic neuropathy, myelopathy and neuropsychiatric symptoms.

Pathogenesis of drug induced megaloblastic anaemia:


Folate and its role in purine and pyrimidine synthesis


Dietary folate (vitamin B9): 5-methyltetrahydrofolate (is the form which gets absorbed)

Folinic acid supplement: 5,10-methyltetrahydrofolate

Folic acid supplement: dihydrofolate

Okay, the above is a bit messy. Im not too good myself in the complicated biochem reactions, and I doubt many will waste an extra space in the brain to memorise it. Here’s the simplified version:

  • 5-methylTHF –> THF –> 5,10-methylTHF –> purine & pyrimidine –> recirculated back as DHF and THF –> cycle is repeated
  • Homocysteine –> methinone needs B12
  • Homocysteine –> cysteine needs B6 (Sixteine)
  • THF –> 5,10 methylTHF needs B6

A memory aid

  • Pyrimidine is longer so takes more from 5,10 methyl THF; from TETRA become DI-hydrofolate
  • Purine is shorter so takes less: from 5,10 methyl THF become only TETRA-hydrofolate

Drugs that block absorption of folate (absorbed in duodenum)

  • Alcohol
    – Direct toxic effects on gastric mucosa
  • Anticonvulsants
    – People taking anticonvulsants (especially phenytoin) have lesser folate than those who do not.
    – Multiple factors: increase in microsomal activity (results in increased use of folic acid), decreased absorption, structural resemblance to folate (competitive inhibition in absorption)

Drugs that block absorption of B12 (absorbed in terminal ileum)

  • Metformin
    – Cobalamin is absorbed by binding to the receptors in terminal ileum with the presence of calcium ions.
    – Metformin interfere with this process. b12 deficiency due to metformin can be overcome with calcium.
  • PPI
    – Vitamin B12 is less well absorbed in acidic condition since it is also a weak acid.
    – PPI also blocks the produiction of intrinsic factor from parietal cells.

Drugs that block the metabolic pathway of folic acid and B12

  • Methotrexate, trimethoprim – dihydrofolate reductase inhibitor
  • 5-FU – thymydilate synthase inhibitor
  • Most immunosuppresants: AZA, MMF, leflunomide
  • NO
    – Block activation of B12 for methionine synthase function, therefore causing accumulation of 5-methyltetrahydrofolate



  1. Charles S. Hesdorffer, M.D., and Dan L. Longo, M.D. Drug-Induced Megaloblastic Anemia. N Engl J Med 2015;373:1649-58

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