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Drug Action IV > Fluroquinolones (MC) - Block 2 > Flashcards

Fluroquinolones (MC) - Block 2 Flashcards

1
Q

What are the primary targets of quinolones?

A

G+: Topoisomerase IV
G-: DNA gyrase

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2
Q

What is the function of DNA gyrase and topoisomerase IV?

A

DNA gyrase: removes/unwinding supercoils
Topoisomerase IV: removes/separation catenanes

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3
Q

What is the cooperative bidnign model?

A
  1. Drug binds to cleaved sDNA and traps enzymes
  2. 4 quinolone molecules bind cooperatively to DNA via H-bonds to DNA bases
  3. Quinolones stack forming pairs
  4. Quinolones aggregate (1 and 8 positions)

Gyrase Tyr122 mutants can’t cleave DNA but can still bind to quinolones
* sDNA is not necessary for target

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4
Q

What is the Mg2+ bridge model?

A
  1. Drug binds to DNA phosphates -> chealation by Mg2+
  2. Quinolone stacks onto bases
  3. Quinolone indues conformational change in gyrase-DNA complex

Cleavage of DNA is not necessary for binding

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5
Q

What is responsible of DNA segementation?

A

Tyrosyl

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6
Q

Describe the activity of quinolones?

A
  1. Bacteriocidal (concentration-dependent)
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7
Q

ADR of quinolones?

A
  1. Proconvulsant (N/V)
  2. Joint erosion
  3. Phototox
  4. Tendon rupture
  5. QT prolongation
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8
Q

What causes resistance in quinolones?

A
  1. Efflux mediated in G-
  2. Mutation of target enzyme in G+
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9
Q

What became a major structural component of quinolones?

A
  1. F on C6
  2. Piperizine at C7
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10
Q

What are the med chem driveers for fluoroquin development?

A
  1. Increase G+ coverage
  2. Decreasing phototox
  3. Improving F
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11
Q

SAR of quinolones?

A
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12
Q

How do quinolones get metabolized?

A
  1. Cleaving the pipirizine ring -> inactivation
  2. Phase 2 conjugation (glucoronide)
  3. CYP1A2
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13
Q

What is the pharmacophore of fluoroquines?

A

Piperazine ring

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14
Q

Activity of quinolones IIa?

A
  1. MRSA
  2. Pneumococcus
  3. Cipro -> P. aeruginosa
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15
Q

Activitiy of IIIa

A
  1. Pneumococcal
  2. Balanced renal and hepato billiary elimination
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16
Q

Activity of IIIb?

A

Pneumococcal (potent)

17
Q

What are your respiratory quinolones?

A
  1. Ciprofloxacin
  2. Levofloxacin
  3. Moxifloxacin
18
Q

What quinolones tend to have the best activity?

A
  1. Moxifloxacin
  2. Gemifloxacn
19
Q

Descrie the PK of quinolones?

A
  1. Zwitterionic -> decreased water solubility
  2. CNS distribution (Fluror increases lipophillic) -> stimulation GABAa binding -> irritability
  3. Derivatives are phototox
  4. Chelation of metals can decrease absorption
20
Q

What is the best for P. aeuriginosa?

A

Ciprofloxacin

21
Q

What is used in CAP and nosocomial pneumonia?

A

Levaquin

22
Q

Describe the coverage of moxiloxacin?

A
  1. Nonrenal clearance (hepato billiary system, no renal dose, CI in hepatic failure)
  2. MDRSP
23
Q

Why was gatifloxacin removed from the market?

A

Hyperglycemia in diabetics
* available as eyedrops

24
Q

What is the most potent of quinolones?

A

Gemifloxacin
* no longer on the market

25
Q

How are most quinolone eliminatd?

A

renal (tubular secretion or glomerular filtration)

26
Q

Why are quinolone rarely used in children?

A
  1. Growing cartilage -> arthropathy

Used in children with pseudomonal infections with CF)

27
Q

What are the forms of quinolone resistance?

A
  1. Mutation to parC gene that encodes for topoisomerase IV
  2. Mutation to qyrA gene that encodes the A subunit of the type II topoisomerase DNA gyrase
28
Q

Describe types of resistance pertaining to efflux?

A

Mutations that inactivate a repressor of marA (decreases translation of ompF-porin protein)
* Upreg of efflux, downreg of porins

29
Q

What is QNR?

A
  1. Plasmid resist found in ESBL
  2. Most common ABX resistance mechanisms
  • Encodes a 219 aa protein that binds to gyrase adn topoisomerase -> protects bacteria from drug binding

Drug Action IV (28 decks)

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