(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
FIrst gen quinolones are only useful for
Two examples of First gen quinolones
Second gen quinolone structure difference
Fluuorine ata C6
Heterocyclic ring (usually piperazine) at C7
Norfloxacin and levofloxacin shows a 40-100x poteny over nalidixic acid against...
most gram negatives incl. pseudomonas
Second gen quinolones have an extended activity against
G+ and mycoplasma
3rd and 4th gen quinolones often have _____
multiple Fluorine atoms
Best 3rd/4th gen for G-
Which quinolone is a last resort?
topoisomerases (TI) and gyrases cleave DNA by ...
carrying out nucleophilic attack on a phosphodiester linkage
--> one strand is free and one is enzyme linked
Nucleophile used by TI/gyrase
phenolic OH group of Tyrosine
TI-catalyzed reaction is _____
The equilibrium tends to favor...
in favor of the uncleaved DNA
Most common use for quinolones
Second and Third most common use for quinolones
Chlamydia trachomatis quinolones
ofloxacin + sparfloxacin
quinolone for N gonorrheae and H. ducreyi
First line for gonorrhea
Fourth and Fifth use for quinolones
Respiratory Tract Infections
Which quinolones WONT treat Bone, join, and soft tissue infections
____ is 50% effective as monotherapy in diabetic foot infections
Quinolones that have use against intraellular bacteria
Resistant organisms (to quinolones) have spontaneously occurring point utations in...
the A-subunit of DNA gyrase
(results in a 16-fold increase in MBC for fluoroquinolones)
Less common mutation for quinolone resistance
the B subunit of DNA gyrase
(results in a lower level of resistance)
Penetration of quinolone to gram negative bacteria is dependen on...
diffusion through porin channels (esp in E. coli and pseuomonas)
____ should be avoided when giving quinolones
Quinolones high or low oral BA?
Wide or narrow distribution?
High oral BA
Route of clearance for all quinolones (with one exception)
Renal and hepatic
(oxafloxacin is 95% renal)
Interstitial fluid concentrations __________ from 4-24 hours
Exceed serum concentrations
Quinolones form insoluble chelates with ______
Major inactive metabolite is the ______
glucuronide at the 3 carboxyl position
excreted in the urine
Most common AE for quinolones
Hallucinations and delirium an occur in patients who are also taking...
Quinolones are associated wih ____ (as an AE)
Why shouldnt you give quinolones to kids?
May damage growing cartilage and cause arthropathy (reversible)
Hyper/Hypoglycemia in diabetic patients
Exception to the "dont give to kids" rule for quinolones
Pseudomonal infections in kids with CF
(High mortality rate, benefits>risks)