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Antimetabolites - Antifolate

There drugs inhibit crucial enzymes involved in nucleotide synthesis. This includes the following drugs

Method of action
  • Dihydrofolate reductase is the enzyme that reduces folic acid this results in compounds which are vital to the production of nucleotides for DNA or RNA.
  • Methotrexate inhibits dihydrofolate reductase.
  • Pemetrexed inhibits thymidylate transferase.
  • Raltitrexed inhibits thymidylate synthase inhibitor.
  • Inhibition of these enzymes leads to a lack of nucleotides and incomplete DNA or RNA synthesis and thus cell replication stops.
Indications
Cautions
  • Monitor full blood count, urinalysis, renal and liver function tests every 2-3 months.2 Monitoring of plasma levels of methotrexate is recommended if high doses used.
  • Pemetrexed requires prophylactic folic acid and vitamin B12 supplementation.
Contraindications
  • Significant renal impairment as excreted in urine
  • Severe hepatic impairment
  • Avoid if presence of significant pleural or peritoneal fluid as can accumulate in these collections
  • Pregnancy
  • Breast feeding.
Important drug interactions
  • Antifolate effect enhanced by: nitrous oxide, sulfamethoxazole, trimethoprim
  • Excretion impaired by: NSAIDs (but can be used with care in rheumatoid arthritis), aspirin, ciprofloxacin, penicillins, probenicid, omeprazole
  • Reduced absorption by: neomycin
  • Increased risk of haematological toxicity by corticosteroids
  • Pulmonary toxicity of methotrexate enhanced by cisplatin.2

There is CSM advice regarding paying attention to strength of oral tablets and frequency of tablet taking of methotrexate - in some indications doses should be taken once weekly.7 If they are taken more frequently then there is a risk of toxicity.
Patients should receive detailed written information before starting treatment8

Adverse effects
  • Common side effects: mucositis and bone marrow suppression. Folate inhibition is the cause of mucositis and myelosuppression. This can be counteracted by the use of folate supplements in the form of folinic acid (calcium folinate or calcium levofolinate).
  • Gastrointestinal side effects (marked with raltitrexed).
  • Rare side effects: pneumonitis (methotrexate), skin rashes (pemetrexed).
Document references
  1. Shankar S, Handa R; Biological agents in rheumatoid arthritis. J Postgrad Med. 2004 Oct-Dec;50(4):293-9. [abstract]
  2. Summary of Product Characteristics - Methotrexate sodium tablets 2.5 mg, Wyeth Pharmaceuticals; electronic Medicines Compendium (14th Sep 2006)
  3. Summary of Product Characteristics - Alimta 500mg powder for concentrate for solution for infusion (pemetrexed disodium) Eli Lilly and Company Limited, electronic Medicines Compendium
  4. NICE Technology Appraisal; Mesothelioma - pemetrexed disodium. January 2008.
  5. Colorectal cancer (advanced) - irinotecan, oxaliplatin and raltitrexed, NICE Technology Appraisal (2005)
  6. Summary of Product Characteristics - Tomudex® (Raltitrexed) AstraZeneca UK Limited. electronic Medicines Compendium (25 Oct 2001)
  7. NPSA - Patient Safety Alert (3) - Reducing the harm of oral methotrexate (2004)
  8. NPSA - Patient Safety Alert (13) - Methotrexate (Jun 2006)
AcknowledgementsEMIS is grateful to Dr Gurvinder Rull for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2008.
DocID: 4180
Document Version: 3
DocRef: bgp26095
Last Updated: 24 Sep 2007
Review Date: 23 Sep 2008
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