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

Adverse Drug Effects

1. Gastro Intestinal Tract – All quinolones have varying degrees of  GIT irritation ranging from mild nausea to severe gastritis which can be limited by administering ½ hr after food. Antacids / Divalent cations /H2 antagonists reduce GIT absorption and hence should not be used for treating GIT adverse effects.

2. Central Nervous System effects- The mechanism is not known probably interfering with GABA activity ? A direct pharmacological effect.

• The Pharmacodynamic Drug interactions with NSAIDs manifest sometimes as convulsions (enoxacin X fenbufen)
• The Pharmacokinetic drug- drug interaction with Theophylline.
• Sparfloxacin is devoid of proconvulsant activity
• Proconvulsant activity with
• Pefloxacin enoxacin Ofloxacin Norfloxacin Cinoxacin
• Ciprofloxacin Nalidixic acid etc.,

3. Cardio Vascular System Toxicity :- Both Sparfloxacin and Grepafloxacin are implicated in producing QT prolongation syndrome often mild but assumes significance when administered together with other agents like antiarrythmics, Macrolides, Cisapride, Azole antifungals, H1 antagonists like astemizole,cetrizine, terfinadine etc.,

4. Phototoxicity: Skin reactions like erythema,  pruritus, urticaria and rashes with phototoxicity are often associated. Sun burns occur when exposed to UV rays of UVA 320-400nm especially transmitted by the clouds & window  panes.        Sparfloxacin, Lomefloxacin Fleroxacin, show increased incidence of phototoxicity while Trovafloxacin, Grepafloxacin, and Moxifloxacin have reduced potential for Phototoxicity. Quinolones exhibit Photomutagenic & even photocarcinogenic effect in animals.. The underlying mechanism appears to be due to the formation of photodegradation products leading to the generation of reactive oxygen species.  In this context Newer quinolones are synthesized with chiral modification. It is not definite whether Tocopherols have any protective effect on phototoxicity.

5. Arthropathy- Interest has been focussed on proteoglycan synthesis and  mitochondrial function. Occurrence of this adverse effect precludes the use of very good antibacterials in paediatrics.

Human data from the experience with 3 compound have revealed that Nalidixic acid has poor tissue penetrability and hence did not manifest chodrotoxicity and in the case of ciprofloxacin and norfloxacin there was reduced AUC and therefore low systemic exposure. In case of Pefloxacin with 5-10 times higher systemic exposure ( Higher AUC) is well known to be associated with high incidence of arthropathy in humans because the drug affects articular cartilage & epiphyseal growth plate. The importance of this toxicity is that it is irreversible and manifest later after the drug is discontinued. The use of Nalidixic acid in UTI and ciprofloxacin in cystic fibrosis (pseudomonal) are officially permitted to be used in paediatrics. Recently many clinical studies revealed that newer quinolones might appear to be safer for paediatric use.

Review of 31 reports involving 7045 paediatric patients use of  Ciprofloxacin,Nalidixic acid,Pefloxacin,Norfloxacin, Ofloxacin in paediatric cystic fibrosis, no arthropathy was observed.  

Similarly the use of Norfloxacin, Trovafloxacin, and Ciprofloxacin in shigellosis, Salmanellosis, Meningococcal meningitis showed in incidence of arthropathy in paediatric group. Trovafloxacin, Gatifloxacin, Clinafloxacin, and Moxifloxacin appears more promising for paediatric use.

Further studies are planned in selected paediatric age groups with quinolones before concluding for official use of quinolones (except those already approved) in paediatric infections.

6.Tendinopthy - In 1991 Flouroquinolone associated Tendinopathy and tendon rupture have been reported. More than 1000 cases of quinolone induced tendinitis have been reported as per French surveillance in 1997. Clinically manifested as congestion and /or inflammation and oedema of tendon leading to pain and swelling and in more than 50% of cases it was bilateral and then tendon ruptures. 400 cases with in 18 months of treatment with Ofloxacin, Norfloxacin, Ciprofloxacin and Pefloxacin. In more than 70% patients aged 60yrs or above and in 10% of patients receiving concurrent steroid medication. Achilles tendon rupture reported to have occurred 120 days after the start of treatment and can occur even after withdrawal of the drug. Pathologically there was ultrastructure alteration in tendinocytes. In animals ,Mg deficiency aggravated tendinopathy.

Drug Interactions:

Primary drug- Quinolones. Interact with

X Warfarin = enhanced anticoagulation

X H2 Antagonists =  quinolone absorption

X Cyclosporin = toxicity

X Rifampicins = decreases serum concentration of quinolone

X NSAIDs = Convulsions

X Insulin & oral hypoglycemics = hypoglycemia.