Inhibitors of folate metabolism Flashcards
Why is folate a dietary supplement rather than tetrahydrofolate?
Because folate can enter cells whereas tetrahydrofolate can’t
Tetrahydrofolate is essential for C1 metabolism. True or false?
True
Why is the enzyme dihydropteroate synthetase a good antibacterial drug target?
Because humans don’t have this enzyme
What is the pka of para-aminobenzoic acid?
pKa 5
Prontosil was shown to be a prodrug for which drug?
Sulfanilamide
Why is diethylene glycol toxic?
Because the liver oxidises the hydroxyl groups to toxic aldehydes
Sulphanilimide mimics PABA, although not very well. True or false?
True
What is sulfadiazine used to treat?
Toxoplasmosis
Sulfadiazine is 75% ionised at physiological pH and so is 100x more active than sulfanilamide. True or false?
True
Folate metabolism is essential for DNA and RNA synthesis and is required for all C1 metabolism. True or false?
True
Inhibition of folate synthesis is used to treat bacterial infections, malaria, cancer, rheumatoid arthritis and other diseases. True or false?
True
What do bacteria make dihydrofolate from?
Pteridine
What do we make dihydrofolate from?
Folate
What is trimethoprim used for?
Sometimes antimalarial but principally to treat cystitis (UTI)
Typhoid fever
Chronic bronchitis
gonorrhoea in penicillin resistant patients
Why is trimethoprim selectively toxic?
Because its affinity for dihydrofolate reductase in bacteria is 50,000x stronger than for human dihydrofolate reductase
Co-trimoxazole is a combination of which two medicines?
Trimethoprim
Sulphamethoxazole
The chlorophenyl ring in pyrimethamine is more hydrophobic than trimethoprim. True or false?
True
The pyrimidine ring in pyrimethamine has DHFR activity. True or false?
True
Methotrexate also targets mammalian DHFR. What is it used for?
Anti-cancer agent used against rapidly proliferating tumours
Prolonged high doses of methotrexate lead to ______
Anaemia
In vivo, methotrexate has equal activity against bacterial DHFR and mammalian DHFR but in vivo, it is inactive against bacterial DHFR. True or false?
True
Why is methotrexate not active in bacteria?
Because it is too polar for passive diffusion
In very low doses, what is methotrexate used to treat?
Rheumatoid arthritis and inflammatory bowel disease
Methotrexate, in combination, is also used to terminate pregnancy, especially ectopic pregnancy. True or false?
True
Very severe reactions take place when methotrexate is taken with penicillin. Why?
Penicillin seems to inhibit elimination of methotrexate
