Fluoroquinolones

• Introduction
• Newer quinolones
• Pharmacological aspects of newer quinolones
• Major clinical applications
• Adverse effects
• Drug Interactions
• Pharmacological outline of Sparfloxacin
• Further Developements of Quinolones
• Conclusion

PHARMACOLOGICAL ASPECTS OF NEWER QUINOLONES:

Pharmacokinetics / Pharmacodynamics

1. Excellent oral absorption
2. Good tissue distribution
3. Excellent interstitial fluid concentration
4. Significant entry into phagocytic cells
5. Excellent urinary concentration on oral administration
6. Longer plasma half life and o/d drug regimen
7. [Grepafloxacin, Sparfloxacin, Trovafloxacin, Moxifloxacin,Gatifloxacin,Gemifloxacin and Sitafloxacin]

ABSORPTION

The absorption of quinolones are reduced by Antacids containing Al+++, Ca++, Mg++, and Fe++ salts and dairy products . Some of the quinolones are available for IV use viz., Ciprofloxacin, Ofloxacin.  Almost all the newer quinolones have excellent tissue distribution and attain high concentration in the interstitial fluid but only a few quinolones viz., Trovafloxacin, Ciprofloxacin, Pefloxacin, and Ofloxacin penetrate blood barrier. Protein binding varies to some extent.

Norfloxacin, Lomefloxacin & Gatifloxacin- Lowest binding

Trovafloxacin, Rulofloxacin & Clinafloxacin – Highest binding

EXCRETION

Similarly quinolones exhibit differences the route of elimination Viz.,

Predominanatly by by by Renal elimination include; Ofloxacin, Levofloxacin,Lomefloxacin,Rufloxacin, and Gatifloxacin.

While those predominantly by hepatic elimination include; Nalidixic acid,Pefloxacin,Sparfloxacin and Grepafloxacin.

DOSAGE AND ADMINISTRATION

Flouroquinolones exhibit concentration dependent killing and therefore adminsitered O/day,twice a day regimen. In animal models a 24 hour AUC/MIC (Area under the concentration-time curve/minimum inhibitory concentration) ratio to be the best predictor of bacterial killing in vivo. With the peak plasma concentration C_max / MIC ratio being important for some bacteria to prevent emergence of resistance during treatment. Human studies ( and animal models) with ciprofloxacin, Grepafloxacin, and Levofloxacin show that a 24 hrs AUC/MIC ratio of about 100, or a C_max / MIC ratio of about 10 gives maximum clinical and bacteriological efficacy. These values can be used to predict the efficacy of different agents against different pathogens , and to define" Pharmacodynamic Breakpoints".

DRUG REGIMEN

The dosage schedules for the following quinolones have “Break points” ranging from 0.25 to 1 namely.,

• Ciprofloxacin        500mg bd
• Norfloxacin        400mg bd
• Pefloxacin        200mg bd
• Ofloxacin        400mg/d or 200mg bd
• Fleroxacin        400mg/d
• Gatifloxacin        400mg/d
• Grepafloxacin        400mg/d
• Livofloxacin        500mg/d
• Lomefloxacin        400mg/d
• Moxifloxacin        500mg/d
• Sparfloxacin        200mg/d
• Trovafloxacin        200mg/d
• Sitafloxacin        100mg bd

MAJOR CLINICAL APPLICATION

Antibacterial efficacy of quinolones depends on;

Activity against the target enzyme DNA Gyrase

Uptake by the bacterial cell

Physicochemical properties like – Hydrophobicity

- Acid base properties and

- Affinity for divalent cations.

Quinolones primary target is DNA Gyrase(Topoisomerase II ) in many of the gram-ve organisms whereas in the case of gram+ve organisms Topoisomerase IV appears to be the primary target as is the case of Ciprofloxacin, Norfloxacin, and Sparfloxacin.

For Sparfloxacin in the case of Strerptococci pneumoniae ,DNA gyrase appears to be the primary target.

Peculiarly in case of Sitafloxacin both DNA Gyrase -Topoisomerase II & Topoisomerase IV appears to be the targets and hence it is expected that there is little or no chance for development of resistance.