Sulfonamides and Quinolones Flashcards
what is prontosil?
prodrug of the active sulfonamide, p-aminobenzenesulfonamide
sulfamonide MOA
competitively inhibit dihydropteroate synthase, preventing incorporation of PABA into folic acid nucleus
(bioisosteres of PABA)
why do sulfonamides not affect human cells?
mammal cells use preformed folates in diet, while some bacteria make their own folic acid
alternate sulfonamide MOA
antimetabolite: some strains use drug as a substrate, but then the product is not capable of the next rxn
can sulfonamide action be reversed?
yes- increase [PABA]
describe PABA vs. sulfanilamide activity at physio pH
- why is this a problem?
- how it is overcome?
PABA pKa 6.5 -> anion at physio pH
sulfanilamide pKa 10.4 -> weak acid a physio pH
fix by attaching an e- withdrawing heteroaromatic ring to acidify the sulfonamide N and increase potency (due to electronegativity of R + resonance stabilization of anion)
what side effect does the increase in acidity of sulfonamides with a more EN R group mediate?
increased acidity causes decreased incidence of crystalluria
specific names of 9 sulfonamide drugs
sulfisoxazole sulfacetamide sulfabenzamide sulfamethizole sulfamethoxazole sulfathiazole sulfadiazine acetyl sulfisoxazole
sulfasalizine (different MOA)
general uses of sulfonamides
G(+) and G(-) Nocardia Chlamydia some protozoa/fungi E. coli Klebsiella Salmonella Shigella Enterobacter
how are sulfonamides normally given? what is one example and what is it used for
combinations: Bactrim (TMP-SMX)
- used for AIDS pneumocystis
MOA of TMP (trimethoprim)
inhibits DHFR, a sequential step in the THF synthesis pathway past where sulfamethoxazole works on DHPS
most popular sulfonamide and use?
sulfisoxazole - UTIs
sulfamethoxazole use
UTIs
what is the triple sulfas combination and what does it treat?
1: 1:1 sulfabenzamide, sulfacetamide, sulfathiazole
- used for Gardnerella vaginalis
what are the triple sulfas also combined with? what does this treat?
triple sulfas + phenylpropanolamine-pheniramine p.o.
-sinus/throat infections
pheniramine = antihistamine to decrease inflammation
what sulfonamide is different than the rest? why and what does it treat?
prodrug is not well-absorbed by GI: bacteria metabolize it to 5-aminosalicylic acid (anti-inflammatory)
- used for ulcerative colitis and Crohn’s disease
- SE: irritates gastric mucosa, but not as badly as other salicylates
sulfadoxine use
long-acting: prevents/treats malaria (inhibits falciparum DHFR)
what is sulfadoxine often combined with and what is this combo called?
sulfadoxine + pyrimethamine = Fansidar
sulfadiazine use
first line chemo for acute toxoplasmosis
AE of sulfonamides: general mechanisms
- cross allergenic
- these drugs used for more than abx activity:
- CAIs (acetazolamide)
- thiazides (ydrochlorothiazide)
- furosemide
- sulfonyurea hypoglycemic agents (tolbutamide)
most common AE of sulfonamides
allergies: rash, photosensitivity, drug fever
rare AE of sulfonamides
Stevens-Johnson syndrome crystalluria and hematopoietic disturbances anorexia nausea vomit
three mechanisms of sulfonamide resistance
- overproduction of PABA
- decrease affinity of DHPS for drug
- decrease cell permeability to drug
how common is sulfonamide resistance? implications?
common- no longer used as single-use dudes
mechanism of resistance to TMP
plasmid borne version of DHFR
TMP PK:
- absorption?
- distribution?
- half life?
- clearance?
- absorbed 85-90%
- distributed more rapidly than sulfas
- T1/2 = 10-12h
- drug + inactive metabolites cleared in urine
SMX PK:
- distribution
- elimination rate
- half life
- widely distributed, including CSF (but not as distributed as TMP b/c differences in lipophilicity)
- rapidly eliminated
- T1/2 = 10-12h
sulfonamide metabolism
metabolized by N-4 N-acetylation, sometimes N-1 glucuronidation -> inactive
-hydroxylamine + nitroso metaoblites toxic
division of humans in terms of sulfonamide metabolism
fast and slow acetylators-> affects metabolism
what are the four core structures of quinolones?
quinolone
cinnolone
1,8-naphthyridone
pyridopyrimidone
first gen quinolones:
- activity?
- uses?
- examples?
activity: G(-), limited G(+)
- don’t get systemic [drug] that are useful
uses: lower UTIs
ex: oxolinic acid, nalidixic acid
second gen quinolones:
- how are they different from first gen?
- activity?
- examples?
diff: F at C6, heterocyclic ring (piperazine) at C7
activity: broader, more potent - more G(-) and G(+)
ex: norfloxacin, ciprofloxacin, levofloxcin
what is the most potent fluoroquinolone?
cipro!
3rd/4th gen quinolones:
- differences?
- activity?
- examples?
diff: multiple F atoms
activity: improved G(+), especially S. pneumo + still good G(-) (but none as good for G(-) as cipro)
ex: moxifloxacin (4), sparfloxacin (3)
which of the quinolones is a drug of last resort? why?
moxifloxacin: severe SE
- irreversible peripheral neuropathy
- tendon rupture
- acute liver failure
- Steven-Johnson syndrome
quinolone MOA
inhibits action of Topoisomerase II -> stabilization of cleavage complex, which blocks DNA religation
most common use for quinolones + which ones?
UTIs
- norfloxacin
- cipro
- ofloxacin
- nalidixic acid
other uses for quinolones?
- prostatitis
- STDs (gonorrhea, chlamydia, H. ducreyi)
- GI bugs (travelers, shigella, cholera)
- resp tract (S. pneumo, CF exacerbations)
- bone/joint/soft tissue
- intracell dudes (chlamydia, mycoplasma, legionella, brucella, TB)
specific quinolones for gonorrhea
cipro (but resistance)
-now first line is ceftriaxone
specific quinolones for chlamydia
ofloxacin
sparfloxacin
specific quinolones for H. ducreyi
cipro
specific quinolones for prostatitis
norfloxacin
cipro
ofloxacin
specific quinolones for shigella
norfloxacin
cipro
ofloxacin
specific quinolones for cholera
decreases duration -norfloxacin
specific quinolones for S. pneumo
moxifloxacin
specific quinolones for CF exacerbations
fluoroquinolones
specific quinolones for bone/joint/soft tissue
fluoroquinolones except norfloxacin
specific quinolones for diabetic foot infections
Cipro!
specific quinolones for intracellular dudes
norfloxacin
cipro
5 mechanisms of resistance to quinolones
- point mutations in A subunit of DNA gyrase (lower affinity)
- mutations of B subunit of DNA gyrase (lower level resistance)
- additive effects of A + B subunit mutations
- efflux pumps
- point mutations -> cross resistance
describe PK of quinolones
- good p.o. bioavaliability and absorption
- widely distributed (including CNS)
- renal + hepatic clearance (except oxafloxacin 95% renal)
quinolones: drug concentrations in different places after different times
after 2h: ISF [drug] are 50-100% of serum [drug]
4-24h: ISF [drug] > serum [drug]
CSF [drug] are 40-90% of serum [drug]
chemical reactions with quinolones?
form insoluble chelates with heavy metals
metabolism of quinolones
major inactive metabolite = glucuronide at 3C=O
-excreted in urine
AE of quinolones
- generally well tolerated
- nausea, vomit, diarrhea (most common)
- headache, dizzy (CNS)
- hallucinations, delirium, seizures, skin rash, liver fxn abnormal, tendonitis (rare)
- peripheral neuropathy w/ quins
contraindications of fluoroquinolones
-f’quins damage growing cartilage, cause reversible arthropathy
therefore, don’t give to patients less than 18 y/o, unless for CF patients w/ pseudomonas
specific AE of lomefloxacin
photosensitivity
specific AE of gatifloxacin
hyperglycemia or hypoglycemia in diabetics
