Folic Acid Antagonists Flashcards
Name the three classes of folic acid antagonists
Sulfonamides, Trimethoprim, Co-trimoxazole
Describe the biosynthesis pathway of folic acid, which steps occur in microorganisms and humans, and explain its importance
Biosynthesis Pathway:
Microbes
1. Dihydropteroate Synthase:
Pteridine + PABA => Dihydropteroic acid
- Dihydrofolate Synthase:
Dihydropteroic acid + Glutamate => Dihydrofolic acid
Microbes and Humans
1. Dihydrofolate reductase:
Dihydrofolic acid + NADPH => Tetrahydrofolate
- Tetrahydrofolate cofactors / precursors are needed for the synthesis of amino acids, purines and thymidine in DNA, RNA and protein synthesis
Combination therapy of cotrimoxazole exerts what kind of effect?
Synergistic bactericidal effect
Sulfonamide mechanism of action - Which step of the pathway does it inhibit?
Competitively inhibit the action of dihydropteroate synthase
What makes a bacteria sensitive to the inhibitory effect of sulfonamides?
A bacteria is sensitive to sulfonamide action only if it is necessary for the bacteria to synthesise its own folic acid.
Bacteria that can use preformed folates are not affected. Hence, sulfonamides are sufficient but not necessary.
Why does sulfonamides alone exert bacteriostatic effect?
It is sufficient to compete with PABA for dihydropteroate synthase.
Sulfonamide action can be counteracted by higher PABA concentrations
Why are mammalian cells insensitive to sulfonamides?
Mammalian cells require preformed folic acid and cannot synthesise it
How are sulfonamides administered?
Oral - Well absorbed (Except sulfasalazine)
Sulfonamide distribution
Serum albumin bound
Distributed throughout bodily fluids including cerebrospinal fluid, placental barrier and fetal tissue
How are sulfonamides cleared and why are they nephrotoxic?
Hepatic acetylation and conjugation of sulfonamides retain the toxic potential to precipitate at neutral or acidic pH causing crystalluria
Eliminated by glomerular filtration and secretion in kidneys and in breast milk
4 Adverse Drug Events caused by sulfonamides and explain how the pharmacokinetic properties can lead to them
- Crystalluria (Nephrotoxicity) - Resolve by hydration: Due to hepatic acetylation retaining toxic potential to precipitate in neutral or acidic pH
- Hypersensitivity - Rash, SJS, angioedema: Due to presence of sulfur
- Hematopoietic disturbances - Hemolytic anemia in G6PD deficiency: G6PD enzyme has antioxidant properties by maintaining high levels of GSH and NADPH which protect cells from oxidative damage
- Kernicterus - Newborns with bilirubin entering CNS: Bilirubin displacement from serum albumin which becomes free to pass into the CNS
Sulfonamides can potentiate the effect of which drug
Warfarin
What patient population are sulfonamides contraindicated in?
Newborns, infants, pregnant women, breastfeeding
What does trimethoprim inhibit?
Dihydrofolate reductase
Trimethoprim MOA
Inhibit dihydrofolic acid reduction to tetrahydrofolate (active form) required for purine, pyrimidine and amino acid synthesis
Spectrum activity of Trimethoprim
Enterobacter spp, E coli, Klebsiella
How do bacteria become resistant to trimethoprim?
Reduced affinity for trimethoprim through alteration of dihydrofolate reductase in Gram negative bacteria
Trimethoprim is administered ________
Orally (Rapid)
What is an advantage of trimethoprim as a weak base?
It can achieve higher concentrations in relatively acidic prostatic and vaginal fluids
What does trimethoprim basicity mean for drug distribution?
Wide distribution into body tissues and fluids including CSF
Trimethoprim is eliminated by ________
renal excretion unchanged
Why is trimethoprim avoided in pregnancy?
Its adverse effect is that it causes folic deficiency affecting red blood cell synthesis, leading to megaloblastic anemia, leukopenia and granulocytopenia in pregnant patients having poor diets
How can folic acid deficiency be managed?
Administer folinic acid, a 5 formyl derivative of tetrahydrofolate that can readily convert to tetrahydrofolate without the need for reduction
Ratio of Cotrimoxazole
Trimethoprim:Sulfamethoxazole = 1:5
Cotrimoxazole trade name
Bactrim and Septra
Cotrimoxazole MOA
Inhibit two sequential steps in the synthesis of tetrahydrofolate
Cotrimoxazole is administered ____
Commonly oral but can be used IV in severe pneumonia and UTI when cannot take by mouth
Cotrimoxazole drug distrbution
Throughout the body
Acidic prostatic and vaginal fluids
Good CSF penetration and readily crosses BBB
Cotrimoxazole clearance
Parent and metabolites renally excreted
5 Clinical uses of Cotrimoxazole
- UTI (E coli) 1st line prophylaxis in recurrent UTI in women and penicillin allergies
- RTI (Haemophilus, Klebsiella)
- Toxoplasmosis
- MRSA skin and soft tissue infection (community-acquired)
- Pneumocystis Pneumonia (Pneumocystis jiroveci) in immunocompromised patients
Which trimesters of pregnancy should cotrimoxazole be avoided?
1st trimester in case of folate deficiency and last trimester in case of G6PD deficiency
6 Adverse Effects of Cotrimoxazole
Presence of Sulfur:
1. Skin reactions - Rash (Common)
2. Photosensitivity
3. Nausea and vomiting (Common)
4. Glossitis and Stomatitis
In G6PD deficiency:
5. Hemolytic anemia
Folic acid deficiency due to Trimethoprim:
6. Megaloblastic anemia, leukopenia, thrombocytopenia
Cotrimoxazole drug interactions
Phenytoin half-life increases
Warfarin effect enhanced
