Sulfonamides and Quinolones Flashcards Preview

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Flashcards in Sulfonamides and Quinolones Deck (58):
1

what is prontosil?

prodrug of the active sulfonamide, p-aminobenzenesulfonamide

2

sulfamonide MOA

competitively inhibit dihydropteroate synthase, preventing incorporation of PABA into folic acid nucleus
(bioisosteres of PABA)

3

why do sulfonamides not affect human cells?

mammal cells use preformed folates in diet, while some bacteria make their own folic acid

4

alternate sulfonamide MOA

antimetabolite: some strains use drug as a substrate, but then the product is not capable of the next rxn

5

can sulfonamide action be reversed?

yes- increase [PABA]

6

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)

7

what side effect does the increase in acidity of sulfonamides with a more EN R group mediate?

increased acidity causes decreased incidence of crystalluria

8

specific names of 9 sulfonamide drugs

sulfisoxazole
sulfacetamide
sulfabenzamide
sulfamethizole
sulfamethoxazole
sulfathiazole
sulfadiazine
acetyl sulfisoxazole

sulfasalizine (different MOA)

9

general uses of sulfonamides

G(+) and G(-)
Nocardia
Chlamydia
some protozoa/fungi
E. coli
Klebsiella
Salmonella
Shigella
Enterobacter

10

how are sulfonamides normally given? what is one example and what is it used for

combinations: Bactrim (TMP-SMX)
-used for AIDS pneumocystis

11

MOA of TMP (trimethoprim)

inhibits DHFR, a sequential step in the THF synthesis pathway past where sulfamethoxazole works on DHPS

12

most popular sulfonamide and use?

sulfisoxazole - UTIs

13

sulfamethoxazole use

UTIs

14

what is the triple sulfas combination and what does it treat?

1:1:1 sulfabenzamide, sulfacetamide, sulfathiazole
-used for Gardnerella vaginalis

15

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

16

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

17

sulfadoxine use

long-acting: prevents/treats malaria (inhibits falciparum DHFR)

18

what is sulfadoxine often combined with and what is this combo called?

sulfadoxine + pyrimethamine = Fansidar

19

sulfadiazine use

first line chemo for acute toxoplasmosis

20

AE of sulfonamides: general mechanisms

-cross allergenic
-these drugs used for more than abx activity:
-CAIs (acetazolamide)
-thiazides (ydrochlorothiazide)
-furosemide
-sulfonyurea hypoglycemic agents (tolbutamide)

21

most common AE of sulfonamides

allergies: rash, photosensitivity, drug fever

22

rare AE of sulfonamides

Stevens-Johnson syndrome
crystalluria and hematopoietic disturbances
anorexia
nausea
vomit

23

three mechanisms of sulfonamide resistance

1. overproduction of PABA
2. decrease affinity of DHPS for drug
3. decrease cell permeability to drug

24

how common is sulfonamide resistance? implications?

common- no longer used as single-use dudes

25

mechanism of resistance to TMP

plasmid borne version of DHFR

26

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

27

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

28

sulfonamide metabolism

metabolized by N-4 N-acetylation, sometimes N-1 glucuronidation -> inactive
-hydroxylamine + nitroso metaoblites toxic

29

division of humans in terms of sulfonamide metabolism

fast and slow acetylators-> affects metabolism

30

what are the four core structures of quinolones?

quinolone
cinnolone
1,8-naphthyridone
pyridopyrimidone

31

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

32

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

33

what is the most potent fluoroquinolone?

cipro!

34

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)

35

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

36

quinolone MOA

inhibits action of Topoisomerase II -> stabilization of cleavage complex, which blocks DNA religation

37

most common use for quinolones + which ones?

UTIs
-norfloxacin
-cipro
-ofloxacin
-nalidixic acid

38

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)

39

specific quinolones for gonorrhea

cipro (but resistance)
-now first line is ceftriaxone

40

specific quinolones for chlamydia

ofloxacin
sparfloxacin

41

specific quinolones for H. ducreyi

cipro

42

specific quinolones for prostatitis

norfloxacin
cipro
ofloxacin

43

specific quinolones for shigella

norfloxacin
cipro
ofloxacin

44

specific quinolones for cholera

decreases duration -norfloxacin

45

specific quinolones for S. pneumo

moxifloxacin

46

specific quinolones for CF exacerbations

fluoroquinolones

47

specific quinolones for bone/joint/soft tissue

fluoroquinolones except norfloxacin

48

specific quinolones for diabetic foot infections

Cipro!

49

specific quinolones for intracellular dudes

norfloxacin
cipro

50

5 mechanisms of resistance to quinolones

1. point mutations in A subunit of DNA gyrase (lower affinity)
2. mutations of B subunit of DNA gyrase (lower level resistance)
3. additive effects of A + B subunit mutations
4. efflux pumps
5. point mutations -> cross resistance

51

describe PK of quinolones

-good p.o. bioavaliability and absorption
-widely distributed (including CNS)
-renal + hepatic clearance (except oxafloxacin 95% renal)

52

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]

53

chemical reactions with quinolones?

form insoluble chelates with heavy metals

54

metabolism of quinolones

major inactive metabolite = glucuronide at 3C=O
-excreted in urine

55

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

56

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

57

specific AE of lomefloxacin

photosensitivity

58

specific AE of gatifloxacin

hyperglycemia or hypoglycemia in diabetics