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Therapeutics > Unit 2 > Flashcards

Unit 2 Flashcards

1
Q

Gram (+) vs Gram (-):
-Outer membrane
-B-lactamases
-Peptidoglycan
-AA residues
-Cross-linking

A

Outer membrane:
(+) - drugs can penetrate outer layers of cell wall, membrane blocks drugs, one membrane
(-) - Some drugs can get through porins of outer membrane, two membranes

B-lactamases:
(+) - Excreted through cell wall to outer membrane, requires more to be functional
(-) - Confined to periplasmic space

Peptidoglycan
(+) - thicker than (-)

AA residues:
Both have G/M alternating saccharides
(+) - Lysine residues
(-) - DAP

Crosslinking:
(+) - Bridge between L-lys strand and terminal of D-ala of 2nd molecule
(-) - Bridge between DAP residue of one strand and terminal D-ala

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2
Q

Transpeptidase mechanism

A

Serine hydroxyl group hits the amide linkage
Tetrahedral intermediate forms, D-ala residue eliminated
New peptidoglycan binds H2N to carbonyl of existing strand
Transpeptidase unbinds

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3
Q

Beta-lactam mechanism

Two factors for reactivity

Reason for varying responses to B-lactams

Why they do not react with host-cell proteins

A

BL mimics D-Ala group that transpeptidase wants to bind to and forms inactivated enzyme, and defective cell wall is the result

Highly strained 4 member ring with 90 angle N-C-C bond
Turning this carbonyl into a tetrahedral carbon changes it to a more relaxed 109
Steric inhibition by the non-bonded electrons in nearby nitrogen group makes it act as more of a ketone carbonyl than an amide

Different penicillin binding proteins

Bacteria have very unnatural D-ala residues

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4
Q

Non beta-lactamase forms of resistance to beta-lactams

Mechanism of B-lactamase

A

Decreased drug uptake
Mutation of PBP
Efflux pump

Hydrolysis of the B-lactam ring

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5
Q

Allergenicity of B-lactam rings:
-Mechanism
-Can it be modified?

A

Binds to host protein

No- caused by common pharmacologic portion of drug

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6
Q

Penicillin degradation mechanism (acidic condition)
Basic

A

H+ attacks carbonyl carbon. If the R group is more electronegative then the penicillin will be more stable in the acid

Other carbonyl carbon gets attacked by OH group

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7
Q

Protein binding:
-Penicillin with more _____ side chain will be more protein bound
-Protein binding reduces ______, does not change ______
-Protein binding protects from _____

A

Lipophilic

Bioavailability, t1/2

Degradation

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8
Q

Excretion
-How does the renal excretion
-Drug used to prolong half life of _____ penicillin

A

10% glomerular filtration
90% tubular secretion
-t1/2 increased for kidney disease
Two mechanisms, one for cation and one for anion
Can also be hepatically excreted

Anionic, Probenecid

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9
Q

PK:
-Desired concentration
-Where penicillins do not distribute
-Half lives of most penicillin
-Which drug is excreted hepatically

A

4-5x MIC. 2 ug/mL or higher, peak at 8-25

CSF, unless parenteral

0.5-2h

Nafcillin

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10
Q

Benzylpenicillin (Penicillin G):
-Structure
-Sensitivity to BL
-Administration
-Toxicity
-Spectrum

A

Has benzyl ring

Yes

Orally, but better parenterally

Acute allergic reactions

Gram (+) cocci plus Neisseria gonorrhoeae/hamophilus influenzae (both -)

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11
Q

Benzylpenicillin benzathine and benzylpenicillin procaine
-Mechanism
-Risk
-Mod/Severe

A

Lower solubility, releases slower from the IM injection site

IV can cause cardiac arrest

Moderately severe infections of upper respiratory tract, scarlet fever, skin/soft tissue
Streptococci/Pneumococci

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12
Q

Phenoxymethoxyl (Penicillin V)
-More stable in ____
-Structure that makes it more stable
-Spectrum of activity
-A bit less sensitive to ____

A

Acid/Stomach

Ether before the benzyl ring

Same as Pen G

BL

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13
Q

Methicillin:
-BL sensitivity and reason
-Route of administration and reason
-Spectrum

A

No
Steric inhibition via the phenyl ring on amide carbonyl

Removal

Injection, unstable to stomach acid due to electron donation by amide carbonyl increasing nucleophilicity

Narrow, too much resistance now
MRSA due to mutation in PBP, mecA gene produces PBP2A

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14
Q

Nafcillin:
-Structure
-Sensitivity
-Comparison to methicillin

A

Double ring R group

Not BL sensitive

Clinically identical, more stable in stomach acid

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15
Q

Oxacillin:
-Structure
-BL sensitivity
-Spectrum

A

Long chain with ring at end, chain can flip

No

Staphylococcus/Streptococcus
-Used for penicillin resistant staph aureus

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16
Q

The three BL resistant oral penicillins:
-Names
-Four points to know

A

All isoxazoles: Oxacillin, Cloxacillin, Dicloxacillin

Less potent against gram + that do not produce BL
Highly protein bound
Cross resistant with methicillin
Dicloxacillin the only one still used

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17
Q

BL resistant, broad spectrum, oral penicillins
-Drugs
-Spectrum
-Special structure

A

Ampicillin
Amoxicillin

Many gram - bacteria sensitive to this

NH2 group is protonated 50% at physiological pH, will increase polarity and allow better entrance through porins

Ampicillins have OH group on aromatic ring

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18
Q

Beta-lactamase inhibitors

A

Used in combination with B-lactamase sensitive penicillins

Acylate the serine hydroxyl group in the active site of beta-lactamase

Amox/clav - augmentin
Sulbactam/Ampicillin- Unasyn
Tazobactam/Piperacillin- Zosyn
Avibactam/Ceftazidine

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19
Q

What are cephalosporins synthesized from?

A

7-aminocephalosporanic acid

20
Q

What adds to the mechanism of cephalosporin?

A

Leaving group that facilitates ring opening

21
Q

MOA of cephalosporin resistance

A

Hydrolyzed by B-lactamases
If X group is electron attracting, it will make beta-lactamase more reactive

22
Q

Allergenicity of cephalosporins

A

Should be used with caution, if at all, with penicillin allergies

Fever and rashes

23
Q

Classification of cephalosporins
-Trend

A

Increased gram (-) coverage and decreased gram (+) coverage

24
Q

First generation
-Activity
-Structure of oral vs parenteral

A

Gram +

Substituents at C-3 for oral are not chemically reactive

25
Q

Second generation cephalosporins
-Activity
-Features (4)

A

Retain G+ activity, and add some G-

Carbamate side chain is less reactive towards hydrolysis with the electron donating NH
Oxime ether increases resistance to hydrolysis, syn is more resistant
Cefuroxime penetrates BBB
Prodrug of cefuroxime is available

26
Q

Third generation cephalosporins
-Activity
-Features

A

Big increase in G+

-Nearly all of them have an aminothiazole substituent with oxime at position 7 which is good for B-lactamases
-Charged pyridinium ring at C-3 is very good leaving group which activates the B-lactam ring
-Side chain carboxyl helps take out G-

27
Q

Fourth generation cephalosporins
-Activity
-Features

A

Retain spectrum of third gen, add in some that are resistant to gen3
They are also more active against gram+

Syn methoximino group at c7 reduces resistance on cefepime
N-methylpyrrolidine moiety is good leaving group and increase reactivity of B-lactam

28
Q

Fifth generation cephalosporins

A
29
Q

Carbapenems
-Original molecule too reactive to be used clinically (derivative of this drug that is used)
-Structural feature

A

Thienamycin: primary amino group attacks B-lactam ring, imipenem

Like penicillin, but sulfur group that is present on thiazoldine ring is replaced by methylene, greater ring strain

30
Q

Imipenem:
-What it inhibits
-What hydrolyzes this and how is is overcome?
-Dosage form

A

B-lactamases

Renal dihydropeptidase, cilastatin

Parenteral

31
Q

Meropenem:
-more highly resistant to _____
-Can be administered without _____
-Can be combined with ______ for complicated UTIs

A

Beta lactamases

Cilastatin

Vaborbactam

32
Q

Ertapenem has less ________ but has _____

A

Broad spectrum

Longer half-life

33
Q

Monobactam
-Drug
-Relevant group
-Spectrum
-Features (3)

A

Aztreonam (completely synthetic)

Sulfamic acid end taking place of C2 carboxyl group

Mostly severe G- infections

Electronegative sulfamic acid activates the B-lactam ring
No reported ross-allergenicity with penicillins or cephalosporins
Oxime ether increase resistance to B-lactamases

34
Q

Two glycopeptides

A

Vancomycin
Teicoplanin

35
Q

Vancomycin:
-MOA
-MIC required to be considered susceptible
-Resistance

Mechanism of vanc resistance

How is vanc eliminated

Vanc can be synergistically combined with

A

Inhibitor of Gram + cell wall biosynthesis
Steric hinderance by binding over the D-ala-D-ala end

4

usually last line of defense for multidrug resistant bacteria. Europe has showed som

D-ala-lactate mutation, vanc has much less affinity

90% by kidneys

Gentamicin

36
Q

Aminoglycosides bind to _____ causing a ____ mutation

A

30S ribosomal subunit
Frameshift

37
Q

Toxicities of aminoglycosides

A

Ototoxic (irreversible)
Nephrotoxic (reversible, more frequent if also taking loop diuretics)

37
Q

Three resistance mechanisms to AGS

A

Inactivation by acetylation, adenylation, phosphorylation

Altered ribosomes

Altered AGS uptake (goes away after drug is removed

38
Q

Penicillins/aminoglycosides used for _____
Streptomycin used for _______*
______ has retained antibiotic activity against hospital AGS resistant infections

A

Bacterial endocarditis

TB (only in combination)

Amikacin

39
Q

Amikacin

Tobramycin

Gentamicin used for ______

Orally used AGS

Streptomycin is used for _____ with _____

A

Joint/bone G- infections, also can be used topically, eye infections as well

Neomycin B/Paromomycin

TB, other antibiotics

40
Q

Macrolide abx structure

A

14-membered lactone rings with alternating methyl groups
Formed by acyl-carrier protein, via polyketide pathway
Desosamine and cladinose sugars are attached to ring
pKa is 8.8, can form salts (Glucoheptonic and lactobionic) that are more soluble

41
Q

How do macrolides work

A

Bind reversibly to the P site so the tRNA transfer cannot happen- involving 23S RNA

42
Q

Four mechanisms of resistance from macrolides

A

Lactone ester hydrolase induced hydrolyze macrolide

Drug induced production of RNA methylase that methylates part of 23S RNA on the 50S ribosome inhibiting the macrolide binding

Mutation of adenine to guanine at A2058, reduction in affinity to binding

Efflux pump

43
Q

______ inactivates erythromycin, this can be prevented with ______

Stable formulations

A

OH groups affected in acidic conditions, enteric coated formulation

6-OCH: clarithromycin

Amine analog: Azithromycin

44
Q

Erythromycin metabolism

Interaction, which drugs

Side effects

A

Demethylation in the liver

Inhibit CYP3A and other P450 enzymes, with erythromycin and clarithromycin

GI, allergies, jaundice, stenosis

45
Q
A

Therapeutics (6 decks)

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