2: B-lactams Flashcards Preview

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Flashcards in 2: B-lactams Deck (44):
1

G(+) vs. G(-): color on gram stain

G(+): dark purple (crystal violet)
G(-): light pink (safranin)

2

G(+) vs. G(-): can drugs penetrate the outer layer?

G(+): drugs penetrate outer layer
G(-): drugs can't penetrate outer layer, but some use porins

3

G(+) vs. G(-): where are B-lactamases located?

G(+): excrete B-lactamases through cell wall (need more)
G(-): B-lactamases confined to periplasmic space

4

G(+) vs. G(-): thickness of PG layer?

G(+): thick PG
G(-): thin PG

5

G(+) vs. G(-): number of membranes?

G(+): one membrane
G(-): two membranes (more lipoidal)

6

G(+) vs. G(-): L-Lys or DAP in PG?

G(+): L-Lys
G(-): DAP

7

B-lactam MOA

penicillin resembles D-Ala-D-Ala -> acylates Ser of PBP to form a stable product, inactivating PBP

8

what gives B-lactam ring its reactivity? 2 reasons

1. carbonyl: tetrahedral intermediate 90* compressed angle -> 109* angle
2. B-lactam carbonyl is more like a ketone carbonyl (N lone pair doesn't overlap with C=O) -> more reactive

9

why don't bacterial PBPs react with host protein?

bacteria have D-Ala; human proteins do not

10

4 mechanisms of resistance to B-lactmas

1. decreased cell uptake
2. mutant PBPs
3. efflux pump
**4. bacterial B-lactamases (hydrolyze B-lactam ring)

11

what percent of people are allergic to B-lactams?

6-8% of US

12

cause of B-lactam allergenicity

due to drug acting as hapten and acylating host proteins

13

range of sx from B-lactam allergy

rash (urticaria) to anaphylaxis

14

why can't B-lactams be structurally altered to reduce allergenicity?

b/c allergenicity originates in pharmacophore

15

how can you test for B-lactam allergy?

topical wheal and flare test

16

is penicillin degradation in acid reversible or not? what can catalyze degradation?

irreversible
-catalyzed by heavy metal ions

17

3 major degradation products of penicillin and mechanism of degradation

1. benzylpenicillenic acid (eliminate a sulfhydryl from 2nd intermediate)
2. Benzylpenillic acid (complex hydrolysis w/ ankemeric assistance)
3. Benzylpenicilloic acid (basic solution (-OH))

18

how can penicillins be stabilized against degradation?

make R group more electronegative -> nucleophilicity of carbonyl is reduced

19

effect of serum protein binding on penicillins

-reduces bioavailability b/c less [free drug]
-protects from degradation b/c degradation occurs on drugs in solution
-does not change half life b/c fast dissociation rates/ renal excretion rate = limiting factor

20

how does lipophilicity of R group change serum protein binding?

more lipophilic R = more highly protein bound

21

excretion of penicillin

rapid:
-biliary
-renal: 10% glomerular filtration, 90% tubular secretion via anionic mechanism

22

what happens to half life of penicillin if administered to patient with kidney disease?

increase half life

23

how can one target the anionic mechanism of penicillin excretion to increase its half life?

administer penicillin with probenecid

24

Benzylpenicillin (Pen G): R group

-benzyl R group

25

Benzylpenicillin (Pen G): B-lactamase sensitive?

yes

26

Benzylpenicillin (Pen G): activity

G(+) cocci + N. gonorrhea, H. influenzae

drug of choice for treatment of more stuff than any other antibiotic

27

Benzylpenicillin (Pen G): admin

p.o. - large dose
parenteral = most effective

28

Benzylpenicillin (Pen G): toxicity/contraindications

-acute allergic reaction
-don't give with significant history of asthma/allergies

29

Methichillin: R group

ortho methoxy groups

30

Methichillin: B-lactamase sensitive?

no - steric hindrance of methoxyls prevents nucleophilic attack on C=O

31

Methichillin: admin

injection only (unstable in acid, so no oral)

32

Methichillin: activity

narrow - mostly for B-lactamase producing S. aureus

33

Methichillin: toxicity/contraindications

-inducer of B-lactamase, so only use when required

34

Methichillin: resistance mechanism

PBP2 (mutation in gene mecA)

35

Cephapirin: structure

cephalosporin w/ 6-member ring w/ S
-acetate at position 3

36

Imipenem: structure

carbapenem
-S replaced by methylene (greater ring strain)

37

Imipenem: B-lactamase sensitive? sensitive to anything else?

no - inhibits B lactamases

but, hydrolyzed by renal dehydropeptidase-1 (can be overcome when given w/ cilastatin)

38

Imipenem: activity

G(+) and G(-)
-serious infections of gut, GU tract, bone, skin, endocardium

"magic bullet" - combo w/ cilastatin has broader activity than any other US antibiotic

39

Imipenem: admin

parenteral

40

Imipenem: toxicity/contraindications

good B-lactamase inducer, so only use when required

41

aztreonam: structure

-synthetic monobactam
-sulfamic acid in place of C=O

42

aztreonam: activity

almost completely G(-) - especially those by penicillin resistant dudes acquired in hospitals

43

aztreonam: toxicity/contraindications

-cross allergenicity only reported with ceftazidime (same R group)

44

aztreonam: what makes the B-lactam ring more reactive?

electronegativity of sulfamic acid