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Fluroquinolones - Coggle Diagram
Fluroquinolones
FLUROUINOLONES
MOA
FQ enter the bacterium by passive diffusion through water-filled protein channels (porins) in the outer membrane.
Inhibit the replication of bacterial DNA by interfering with the action of DNA gyrase and topoisomerase IV during bacterial growth and reproductionExplanation:
- The individual strands of double-helical DNA must be separated to permit DNA replication or transcription
- Separates strands result in 'over-winding' or excessive positive super-coiling of DNA at the point of separation (separation fork)
- DNA gyrase - bacteria enzyme, responsible for the continuous introduction of negative supercoils into DNA
- Inhibition of DNA gyrase leads to supercoiling and DNA breaks
- Topoisomerase IV is the second site blocked by the FQs; it is required by bacteria for cell division
- Topoisomerase:
- change the configuration or topology of DNA by nicking, pass-through and resealing mechanism;
- but they do not change the DNA's primary sequence;
- it has been implicated in the process of segregating newly replicated DNA
- FQs binds to both the enzymes, form a complex that inhibits the resealing step, causes cell death by inducing cleavage of the DNA
Gram+ve organisms - inhibition of DNA gyrase is more significant than topoisomerase IV
Gram-ve organisms - the opposite is true
Mammalian cells also possess topoisomerase II, same action as topoisomerase IV, however, very low affinity for FQs
Antibacterial spectrum
2nd generation
- Expanded gram-ve activity & some activity on gram+ve
- Active against typical organisms: Mycoplasma pneumonia and Chlamydia pneumoniae
3rd generation
- Expanded gram-ve activity
- Show improved activity against atypical organisms
- Specific gram+ve bacteria
1st generation
- Moderate gram-ve activity
- Achieve minimal serum conc.
- Restricted to treatment of uncomplicated urinary tract infections
4th generation
- Improved gram+ve coverage
- Maintains gram-ve activity
- Gains anaerobic coverage
Pharmacokinetics
Absorption
- Norfloxacin: 35-70% oral absorption; other FQs: 85-90% oral absorption
- IV for ciprofloxacin, levofloxacin, ofloxacin is available
- Interfere absorption by:
- Sucralfate - antacids containing aluminium or magnesium
- dietary supplements containing iron or zinc
- calcium and other divalent cations
Fate
- Bind to plasma proteins: 10-40%
- Well distributed in tissues and body fluids
- Low penetration of CSF for Ofloxacin
- Accumulates in macrophages & polymorphonuclear leukocytes
- Excreted by renal route
Adverse Reactions
- Gastrointestinal - nausea, vomiting, diarrhea
- CNS - headache, dizziness
- Pts with CNS disorders (epilepsy) must be treated cautiously
- Phototoxicity - pts are advised to apply sunscreens
- Connective tissues problems - possible articular cartilage erosion (arthropathy)
- FQs should be avoid in pregnancy, nursing mother, child <18y/o
Contraindications
- Moxifloxacin may prolong QTc interval -
- should not used in pts who are predisposed to arrhythmia
- pt taking anti-arrhythmic medications
Drug Interactions
- Interacts with antacids and cations on absorption
- Ciprofloxacin and Ofloxacin - increase serum level of theophylline by inhibiting its metabolism
- 3rd- & 4th - generations may raise the serum levels of warfarin, caffiene, cyclosporin
Uses
- Resistance respiratory infections - Ciprofloxacin is effective in treating infectious unresponsive to B-lactam antibiotics
- Anthrax - Ciprofloxacin is drug choice for postexposure prophylaxis and treatment of anthrax
- Gonorrhea - Ciprofloxacin active in infectious due to penicillinase-producing and non-penicillinase producing strains
- Gastrointestinal tract infections - Ciprofloxacin is highly efficacious in treating acute diarrhea illness due to enteric pathogens
- Urinary tract infections - Ciprofloxacin and Norfloxacin are effective in treating uncomplicated and complicated UTI
Mechanism of resistance
- Plasmid-mediated transferable resistance X occur
- Chromosomal mutation producing a DNA gyrase or topoisomerase IV with reduced affinity for FQs
- Reduced permeability/increased efflux of these drugs across bacterial membranes
- Increasing resistance among Salmonella, Pseudomonas, Staphylococci, gonoccoci and pneumococci
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