Folate synthesis inhibitors Flashcards
What is the mechanism of action of sulfonamides?
Competitive inhibitor of dihydropteroate synthase, preventing the conversion of PABA to dihydropteroic acid
Why are mammalian cells insensitive to sulfonamides?
Mammalian cells require preformed folic acid and are hence not affected by the inhibition of the folic acid precursors
What are the 3 folate acid synthesis inhibitors?
- Sulfonamide
- Trimethoprim
- Cotrimoxazole
What is the route of administration of sulfonamides?
Oral
How are the sulfonamindes eliminated?
Metabolized in the liver and eliminated by the kidney
What are the clinical indications for cotrimoxazole?
- UTI
- Pneumocystis pneumonia caused by P. jiroveci
- MRSA infections
- RTI caused by H. influenzae, K. pneumoniae & Moraxella catarrhalis
What are the adverse effects of taking sulfonamides?
- Crystalluria
- Hypersensitivity
- Haematopoietic disturbances
- Kernicterus
What is the effect of sulfonamides on warfarin?
Sulfonamide potentiates warfarin by displacing it from its albumin binding sites, increasing plasma conc. of warfarin
How do sulfonamides cause kernicterus?
Sulfonamides displace bilirubin from binding sites on serum bilirubin, allowing the bilirubin to enter the CNS of the foetus as BBB not fully developed
Which group of individuals are sulfonamides contraindicated in?
- Pregnant women
- Neonates & children < 2mths old
What is the route of administration of trimethoprim?
Oral; good oral bioavailability
Does trimethoprim penetrate the CSF?
Yes
How is trimethoprim eliminated?
Primarily renal clearance
What is the mechanism of action of trimethoprim?
Trimethoprim inhibits drihydrofolate reductase, preventing the reduction of dihydrofolic acid to its active form tetrahydrofolic acid.
This decreases the availability of tetrahydrofolate cofactors required for amino acid, purine & pyramidine synthesis
Should trimethoprim be given during pregnancy?
No. Cat C in pregnancy
What are the adverse effects of taking trimethoprim?
Folic acid deficiency
How to manage folic acid deficiency with trimethoprim?
Simultaneous administration of folinic acid
What is the mechanism of action of cotrimoxazole?
Inhibition of 2 sequential steps in the synthesis of tetrahydrofolic acid results in synergistic antimicrobial activity
What is the route of administration of cotrimoxazole?
Oral/IV
Does cotrimoxazole penetrate the CSF?
Yes
How is cotrimoxazole eliminated?
Renal clearance
What are the adverse effects of taking cotrimoxazole?
- Hypersensitivity
- GI symptoms
- Haemolytic anaemia in G6PD deficient patients
- Hyperkalaemia
What groups of individuals are cotrimoxazole contraindicated in?
- G6PD deficiency
- Infants < 2mths old
- Pregnant women
- Patients with folate deficiency
What are the indications for trimethoprim?
- UTI
- Bacterial prostatitis
What is the mechanism of action of nitrofurantoin?
Reduced by bacteria to highly active intermediate that inhibits various enzymes and disrupts the synthesis of proteins, DNA & RNA
What is nitrofurantoin indicated in?
UTI caused by E. coli & Enterococci
What is the route of administration of nitrofurantoin?
Oral
How is nitrofurantoin eliminated?
Rapid clearance into the urine
What are the adverse effects when taking nitrofurantoin?
- Colours urine brown
- Nausea, vomiting & diarrhoea
- Hypersensitivity
- Cholestatic jaundice & hepatotoxicity
- Patients with renal dysfunction may experience pulmonary & hepatic toxicities + peripheral neuropathies
- Leukopenia, haemolytic anaemia in G6PD deficient patients
Which groups of individuals is nitrofurantoin contraindcated in?
- Renal dysfunction
- Pregnant women & infants due to risk of haemolytic anaemia
