(sulfonamide) ______ was inactive in vitro
But this is a prodrug of the active ________
Sulfanilamide (pharmacologically active) is used to treat ____ infections
MOA of sulfonamide antibiotics
Competitively inhibits the incorporation of PABA into folic acid
by inhibiting the enzyme dihydropteroate synthase
What reaction does dihydropteroate synthase catalyze?
What are the following steps in this pathway?
Dihydropteroate diphosphate -> Dihydropteroic acid
**next steps: conversion to DHF acid -> THF acid --> methyleneTHF acid --> Thymine --> DNA
Sulfonamides are bioisosteres of ____
There is a significant difference in ____ between PABA and sulfanilamide
What does this mean for the drug?
PABA = 6.5 Sulfanilamide = 10.4
This causes sulfanilamide to be 1000x more neutral as a drug
What two effects does attaching electron-withdrawing heteroaromatic rings to the sulfonamide nitrogen?
Increases ACIDITY = increased stability = increased potency**
This also decreases crystalluria in the urine
**essentially makes it more similar to the normal metabolite
Sulfonamides in general inhibit...
- Gram + and -
- Chlamydia trachomatis
- Enterics (e.coli, kleb, salmonella, shig, enterobact)
- some protozoa and fungi
Sulfamethoxazole combined with ____ is important for treatment of _______
PCP (in aids)
Trimethoprim inhibits _____
Most common sulfa
sulfisoxazole and sulfamethoxazole are mainly used to treat ________
What is triple sulfa and what does it treat?
1:1:1 mix of -benzamide, -acetamide, -thiazole
Treatment of Gardnerella vaginalis
Sulfasalazine is a____ that is not...
What is the metabolism?
prodrug, ...not absorbed well in GIT
**metabolized to sulfapyridine and 5-aminosalicylic acid
Long acting sulfonamide
Sulfadoxine is used with _____ to treat _____
(pyrimethamine inhibits DHFR in p. falciparum)
Sulfadiazine is used with _____ to treat _____
Sulfonamide derivative examples (3)
- Carbonic anhydrase inhibitors (acetazolamide)
- Thiazides (HCTZ)
- Hypoglycemic agents (tolbutamide)
Most commone AE's of sulfonamides (6)
- Drug fever
- Stevens-Johnson syndrome
- Hematopoietic disturbances (HA, AA, Granul, Thromb)
What three mutations can cause resistance to sulfonamides
Overproduction of PABA
Decrease in cell permeability
PK of TMP compared to SMX
distributed more rapidly than SMX
SMX distribution and clearance (description)
Why isnt SMX as widely distributed as TMP
Differences in lipophilicity
Tissue ratio of SMX:TMP
1:2 to 1:5
Short half life sulfas
Intermediate half life sulfas
Sulfa metabolism mechanism
VIa N-4 N-acetylation
(in some cases N-1 glucuronidation)
Toxic metabolites of sulfa
Hydroxylamine and nitroso metabolites
First gen Quinolones have limited ___ activity