Sulfonamides (MC) - Block 1 Flashcards
Describe the MOA of sulfonamides?
Inhibts DHPS -> inhibiting folate synthesis by competiviely inhibiting pABA
- antimetabolite of PABA
What is the MOA of trimethoprim?
Inhibits DHFR to prevent the recycling of folate
* antimetabolite of dihydrofolic acid
Describe the SAR of sulfonamides
- N4 unsubstitued or capable of regeneration of NH2
- No substitution on aromatic ring
- Acidic proton on N1
How is a sulfonamide metabolized?
Aniline undergoes acetylation (phase 2 conjugation)
* CYP2C9 forms N4 hydroxy metabolite
* Decreases in slow acetylators
What gene encodes for DHPS?
folP gene
Drug resistant DHPS is encded by ___?
sul genes
* contain point mutation in flexible loop domain -> no longer binding to sulfonamide
Describe the therapeutic effects of Bactrim?
Sulfonamide is bacteriostatic, however, combination with trimethoprim makes the drug bactericidal
Where is a common source of sulfonamide resistance?
the flexible loop domains of the binding sites of PABA
How are more susceptible to bactrim allergies?
Slow acetylators
How is sulfonide eliminated?
Glomerular filtration and tubular secretion
How causes sulfonamide allergy?
Nor really from sulfer:
* IGE mediated type 1 rx: Reactive nitroso compound covalently binds to cystein residues on proteins (haptans)
* Non type 1 rx: Nitrosos can bind to T cells -> maculopapular eruptions (SJS)
What is the function of DHFR inhibitors? Types?
- Prevents the conversion of THF
- Prevents formation of essential purines and DNA
Ex: trimethoprim (less efficient in inhibitng mammalian) and primethamine (selective towards protozoan DHFR)
Why do we give Bactrim?
Both drugs make eachother better in terms of lowering MIC
What causes resistance for DHFR inhibitors?
- Reduced cell permeability
- Overproduction of DHFR
- Altered DHFR -> reduced drug binding
TMP and SMX ratio of fomrulations?
1:5
Plasma - 1:20
