Tetrahydrofolate Synthesis Inhibitors Flashcards
(25 cards)
first sulonamide
sulfanilamide
sulfonamides first used clinically
1933
Penicillin discovered first, but not used clinically until the 1940’s
Chemistry of sulfonamides
- S linked to benzene ring
- Amino group linked to the same benzene ring in para position
Antimicrobial activity and spectrum of sulfonamides
- bacteriostatic
- work against gram + and gram -
- resistance is common
- sensitive bacteria:
strep pyogenes
strep pneumoniae
haemophilus influenzae
What is tetrahydrofolate
- coenzyme for DNA synthesis: purine synthesis and 1C transfer rxns
- in humans, it is a 2-step reduction and folate must be taken up in diet or from gut bacteria
- Most bacteria synthesize their own
- if bacteria cannot make it, they cannot replicate = bacteriostatic
MOA of sulfonamides
- compete with PABA for dihydropteroate synthase
- competitive inhibition of the first step of tetrahydrofolate synthesis
Resistance to sulfonamides
- mutated dihydropteroate synthase with decreased affinity for sulfonamides (acquired resistance)
- decreased permeability or active efflux of drug
- alternative metabolic pathway
- increased production of substrate (PABA) -> inactivation of drug not observed
Sulfonamide specificity
- only bacteria that need to synthesize their own tetrahydrofolate are susceptible to these drugs
- some bacteria can use preformed folic acid and are not susceptible
- We take up folic acid from environment so we’re not susceptible
Rapidly absorbed and eliminated sulfonamides
PK: peak after 2-6 hours, t1/2 of 5-12 hours, gone after 1-3 days
Sulfisoxazole acetyl
tasteless formulation for kids
Silver sulfdiazine
used topically to prevent burn infections
How are acetylated forms of sulfonamides cleared?
- renally
- drink plenty of water
crystals can form in urinary tract (crystalluria)
Are sulfonamides used alone?
No, due to resistance. Used in combo to treat Nocardia infections (trimethroprim-sulfamethoxazole)
Toxicity
- observed in 5% of pts
- most common: crystalluria
- Hypersensitivity rxns < 3%
- anorexia, N/V (1-2%)
- hematopoietic disorders < 1%
Trimethoprim-sulfamethoxazole
- TMP-SMZ, Bactrim, Septra, Sulfatrim
- trimethoprim inhibits THIRD step in tetrahydrofolate synthesis
- synergistic with sulfamethoxazole
- THREE methoxy groups
MOA of trimethoprim
- competes with dihydrofolate for dihydrofolate reductase
- competitive inhibition of the third step of tetrahydrofolate synthesis
- humans use DHFR but it’s sufficiently different from bacterial
Definition of drug-drug synergy
Synergy in general:
the effect of two drugs given in combo is greater than just the additive effect of the two drugs
Synergy in pharmacology:
Less than half of the concentration of both drugs is necessary to yield an effect of 100% of each separate drug
Specificity of trimethoprim
- inhibits bacterial dihydrofolate reductase much more effectively than human dihydrofolate reductase.
- low toxicity
Active spectrum of TMP-SMZ
Gram + and Gram - ; combo effective against resistant drugs.
Ideal ratio of TMP-SMZ
1:20
What is pyrimethamine-sulfadiazine used to treat
toxoplasma gondii infections
What is pyrimethamine-sulfadoxine used to treat
plasmodium spp infections (malaria)
Resistance to TMP-SMZ
- Co-resistance is less likely than resistance to individual drugs
- resistant version of dihydrofolate reductase encoded in plasmid easily acquired, so resistance on the rise
What is TMP-SMZ used for
- UTI
- bacterial respiratory tract infections
- GI infections
- S. aureus (skin and soft tissue)
- Pneumocystis jiroveci (fungus that causes pneumonia)
- prophylaxis in neutropenic pts.
