Sulfonamide Flashcards
Sulfa drugs
Contain sulfonamide group (SO2-N)
Bacterial Folate Synthesis
Folate required for thymidine/DNA synthesis
Mammalian cells use exogenous folate (diet): can transfer folate across cell membrane
Bacterial cells: no exogenous folate (must synthesize)
Uridine converted to thymidine by thymidylate synthase
Thymidine is necessary to synthesize DNA
THF is necessary for proper function of thymidylate synase (comes from folate)
Folate synthesis is a selective target for antibiotics b/c
Bacteria must synthesize folate themselves for thymidine synthesis (necessary for DNA synthesis)Human cells do not have same mechanism: receive folate from diet, which transfers across cell membrane
Bacterial Folate Synthesis
- PABA: Para-Amino-Benzoic-Acid combined with Pteridine by dihydropteroate synthase enzyme to synthesize dihyropteroic acid (which later becomes folate)
- Dihydropteroic acid is converted to Dihydrofolic Acid and finally Tetrahydrofolate (form of folate necessary for DNA synthesis). Generation of tetrahydrofolate is catalyzed by Dihydrofolate Reductase.
Which step of bacterial folate synthesis is inhibited by Sulfonamides?
Dihydropteroate Synthase
Which step of bacterial folate synthesis is inhibited by Trimethoprim and Pyrimethamine?
Dihydrofolate Reductase (catalyzes generation of tetrahydrofolate)
Trimethroprim and Pyrimethamine are often administered together with a sulfonamide antibiotic for
sequential block of folate synthesis pathway in bacteria.
Sulfanomides
Sulfamethoxazole (SMX)
Sulfisoxazole
Sulfadiazine
-Mimics PABA (benzene ring attached to nitrogen group)
-Competitively inhibits dihydropteroate synthesis
Bacterial resistance to sulfanomides
Increased PABA
Altered dihydropteroate synthase
Decreased uptake
Dapsone
Not a sulfonamide Competes with PABA for dihydropteroate synthase Two main uses: -Mycobacterium leprae (leprosy) -Pneumocystic jivoreci
Sulfanomides
Sulfamethoxazole (SMX)
Sulfisoxazole
Sulfadiazine
Sulfanomides are usually administered with
Trimethoprim -TMP-SMX (Bactrim) -Sequential block of THF synthesis Sulfadiazine -Silver sulfadiazine (cream) for burns Sulfadiazine and Pyrimethamine -Sequentially blocks THF synthesis -Used in toxoplasmosis (HIV)
Sulfonamide Toxicity
Hypersensitivity reactions in 3% of patients
Reactions linked to
-Arylamine (NH2) at N4 position
-Nitrogen ring attached to N1 nitrogen
Only sulfonamide antibiotics contain both features
Other sulfa drugs
Furosemide (loop diuretic) Probenicid (gout) Hydrochlorothiazide (thiazide diuretic) Acetazolamide (carbonic anhydrase) Sulfasalazine (IBD) Sulfonylurea (diabetes)
Sulfonamide adverse effects
Same as penicillins
Trimethroprim/Pyrimethamine MOA
Inhibit dihydrofolate reductase
Similar to structure of dihydrofolate
Trimethroprim/Pyrimethamine Toxicity
Preferentially inhibits bacterial DHF reductase
Some inhibition of human enzyme can occur
Inhibits DNA synthesis of rapidly dividing cells
Trimethroprim/Pyrimethamine Toxicity
Bone marrow suppression
-Pancytopenia: Megaloblastic anemia, leukopenia, decreased platelets
Can alleviate with leucovorin (folinic acid)
-Converted to THF
-Does not require dihydrofolate reductase
-Leucovorin rescue
Bactrim (TMP-SMX)
Combination is bactericidal Covers many gram (+) and gram (-) -Does not cover pseudomonas -Does not cover B. fragilis (and most anaerobes) Covers some fungi and parasites
Bactrim common uses
UTI (e. coli)
Pneumocystis pneumonia in HIV (Tx/prophylaxis)
Can Bactrim (TMP-SMX) be administered in pregnancy?
No
Risk of kernicterus from sulfonamide component
TMP component can disrupt folic acid metabolism
What is treatment of choice for Pneumocystis jirovecci
Bactrim (TMP-SMX)
However, hypersensitivity reactions are 6-25 higher in HIV
Alternative therapy needed instead: Dapsone, Pentamidine or Atovaquone (malaria drug)
