Fluoroquinolones

Question 0

Selective toxicity of fluoroquinolones

Answer 0

Topoisomerase II of mammalian cells is different from the topoisomerase II in bacterial cells. Drugs that target bacterial topoisomerases will not effect human topoisomerases

Question 1

Type II topoisomerase

Answer 1

DNA gyrase: relieve supercoils
-primarily acts on gram(-)
Topoisomerase IV: decatenation (unlink DNA)
-primarily acts on gram(+

Question 2

Fluoroquinolones MOA

Answer 2

Inhibit DNA gyrase and topoisomerase IV–>inhibit bacterial DNA replication
Antibacterial spectrum depends on classification of quinolone

Question 3

Fluoroquinolones mechanism of bacterial resistance

Answer 3

Alteration of target:
-DNA gyrase mutation in gyrA and gyrB genes
-Topoisomerase mutation in parC and parE genes
Insufficient accumulation of drug:
-reduced permeability
-enhanced efflux

Question 4

Synthetic drug classes

Answer 4

Fluoroquinolones and sulfonamides

Macrolides are also synthetic

Question 5

Fluoroquinolones SAR

Answer 5

Pharmacophore: carboxy-4-pyridine
-reduction of 2,3 db makes drug inactive
- substitution at C2 interferes with gyrase DNA complexation
C6 fluoro group increases antibacterial activity from increased bacterial cell penetration and lipophilicity
C8 fluoro group increases photosensitivity but gives better absorption.
C8 -OCH3 decreases photosensitivity
C7- heterocyclic ring increases antibacterial activity
- if piperazinyl ring: good antibacterial effect but CNS effects. Alkyl substitution on the ring decreases CNS effects
N-1-cyclopropyl broadens activity
Third ring in nucleus increases activity

Question 6

Fluoroquinolones with third ring to increase activity

Answer 6

Ofloxacin and levofloxacin

Question 7

As you go from 1st generation fluoroquinolones to 4th generation fluoroquinolones

Answer 7

Increase tissue penetration
Increases antibacterial spectrum/coverage
Increase therapeutic uses

Question 8

Fluoroquinolones

Answer 8

ADRs: crystalluria(take with plenty of water), CNS (HA, dizziness), phototoxocity(from fluoro groups), cardiotoxicity (QT prolongation), Tendonitis and muscle weakness (Black Box warning)
DDIs: qt prolonging drugs, sulfonylureas(hypo or hyperglycemia), corticosteroids(bone depleting effect), antacids and metal ions (chelation)->take metals one hour before or two hours after fluoroquinolones)