Pyrimethamine + Co-trimoxazole or Sulphonamides
Serious pancytopenta and megaloblastic anaemia have been described in patients under treatment with pyrimethamine and either co-tnmoxazole or other sulphonamides.
A woman taking 50 mg pyrimethamine weekly as malarial prophylaxis, developed petechial haemorrhages and widespread bruising within 10 days of starting to take co-trimoxazole (320 mg tnmethopnm + 800 mg sulphamethox azole daily). She was found to have gross megaloblastic changes and pancytoperua addition to being obviously pale and ill. After withdrawal of the two drugs she responded rapidly to hydroxycobalamine and fohc acid, with chloro-quine as malarial prophylaxis.
Similar cases have been described in other patients taking pyrimethamine with co-trimoxazole or sulphafurazole. Another case has been referred to elsewhere involving a sulphonamide.
Uncertain, but a reasonable surmise can be made Pyrimethamine and tnmethopnm are both diamino-pynmidines and both selectively inhibit the actions of the enzyme dihydrofolate reductase which is concerned with the eventual synthesis, amongst other compounds, of the nucleic acids needed for the production of new cells. The sulphonamides inhibit another part of the same synthetic chain. The adverse reactions seen would seem to reflect a gross depression of the normal folate metabolism caused by the combined actions of both drugs. Megaloblastic anaemia and pancytopenia are among the adverse reactions of pyrimethamine and, more rarely, of co-tnmoxazole taken alone In theory this should not occur but in practice it clearly does so occasionally.
Importance and management
Information seems to be limited to the reports cited, but the interaction appears to be established Its incidence is unknown. Concurrent use need not be avoided but the authors of the report cited advise that co-tnmoxazole should be prescribed with caution and haematological cover to patients given pyrimethamine or proguanil for malarial prophylaxis and further caution in the tropics because of the folate deficiency associated with pregnancy and malnutrition in children. The manufacturers of co-trimoxazole support this in advising that if the dosage of pyrimethamine is high the blood picture should be monitored regularly.