BY:SONALI KANADE

KAUSHIK.N.KUCHERUCHA.J.KADMANEDIKSHA KANOJIYA

GUIDED BY : MR . AMJAD ALI

ORIENTAL COLLEGE OF PHARMACY , SANPADA,

NAVIMUMBAI.

DEFINITION:

The fluoroquinolones are a family of broad spectrum,

systemic antibacterial agents that have been used widely as

therapy of respiratory and urinary tract infections. 

BackgroundIn 1962 nalidixic acid was discovered by

George Lesher during synthesis of chloroquine and was named as Quinolone.

Fluoroquinolones were derived by adding fluorine atom in nalidixic acid.

Earlier quinolones were useful only for treatment of UTI.

Fluorinated derivatives achieve bactericidal levels in blood and tissues so they have improved antibacterial spectrum.

1. SAFER TO USE

2.HIGH POTENCY

3.NEW FLUOROQUINOLONES ARE BROAD IN SPECTRUM

4.DEEP PENETRATION IN TISSUES (but dose not cross BBB. Can enter the cell i.e intracellular organism)

5.GOOD ORAL ABSORPTION

FLUOROQUINOLONES ARE FIVE STAR DRUGS !!!

CLASSIFICATION

Generations Drugs Spectrum

1st(Quinolone)

Nalidixic acid Gram -ve but not Pseudomonas species

2nd

NorfloxacinCiprofloxacin Ofloxacin

Gram -ve(including Pseudomonas species), some Gram+ (S. aureus) and some atypicals

3rd

Levofloxacin Sparfloxacin MoxifloxacinGatifloxacin

Same as 2nd generation with extended Gram +ve and atypical coverage

4th*Trovafloxacin Same as 3rd generation

with broad anaerobic coverage

Structural relativity of fluoroquinolones

First generation fluoroquinolones

Nalidixic acid

ciprofloxacin Ofloxacin

Norfloxacin

Second generation fluoroquinolones

Moxifloxacin Gatifloxacin

Levofloxacin Sparfloxacin

Third generation of fluoroquinolones

Trovafloxacin

Fourth generation of fluoroquinolones

SYNTHESIS OF CIPROFLOXACIN USE RETROSYNTHESIS TECHNIQUE IT WOULD MAKE YOUR

LIFE EASY.. !

SYNTHESIS OF CIPROFLOXACIN

CIPROFLOXACIN

SYNTHESIS (CONT..)

Topoisomerase II : to convert the +ve supercoiling to –ve supercoiling. There by allowing the process of replication or the allows the action of DNA helicase to proceed.

Topoisomerase IV: to separate the entangled DNA so that its expression could be proceeded.

MECHANISM OF ACTION

Fluoroquinolones blocks the ligase action where in has no effect on endoneuclease action of the enzyme. Thus what the bacteria left with is fragments of DNA which cannot be expressed.

MECHANISM OF ACTION (cont..)Fluoroquinolones are bactericidal agents

They block bacterial DNA synthesis by inhibiting bacterial DNA gyrase and topoisomerase IV.

Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is required for normal transcription and replication

Cont….Inhibition of topoisomeraseIV interferes with

separation of replicated chromosomal DNA into the respective daughter cells during cell division.

They can enter cells easily via porins and are

used to treat intracellular pathogens (Legionella, pneumophila and Mycoplasma)

RESISTANCE Resistance is due to • one or more point mutations in the

quinolone binding region of the target enzyme

OR to a change in the permeability of the organism

Resistance to one FQL confers cross

resistance to all members of the class.

PharmacokinecticsWell absorbed orally with bioavailability 80-

95% almost equal to IVHalf life 3-10 hoursOral absorption impaired by divalent

actions(Antacids containing Mg, Ca or Al ).Most of fluoroquinolones eliminated by renal

mechanism so adjustment required in patients with creatinine clearance <50 ml/min.

Limited CSF penetration.

Distribution [Conc] > serum:

Prostate tissueStoolBileLungKidneys NeutrophilsMacrophages

[Conc] < serum: Prostatic fluidBoneCSF

Drug interactions Drugs increasing levels of FQL

FQL increasing the levels of :

Theophyline AntidepressantsNSAIDS Imipramine corticosteroids Caffene

TheophylineWarfarin (INR –monitored)

Adverse effects.Generally safe antibioticsG.I.T-nausea,vomiting,diarrhea and antibiotic

associated colitis have been reported.CNS-confusion,insomnia,dizziness,anxiety,and

seizures(displacement of GABA from its receptors).

CVS-torsade de pointes,prolonged QTc interval.May damage growing cartilage resulting in

arthropathy(but that’s reversible so may b used in psudomonal infections in C.F where benefit outweighs the risk.)

Cont.Tendonitis and tendon rupture is rare but

very serious.Phototoxicity-avoid excesive sun exposure.Leukopenia,eosinophilia (rare)Mild elevation in transaminases (rare)

Contraindication Childrens (not absolute)PregnancyLactationEpilepsyQTc prolongation

Commonly used Fluoroquinolones

Ciprofloxacin 2nd generation fluoroquinoloneMainly effective against G –ve bacteria :Enterobacteriacae H. influenzae M. catarrhalisCampylobacter Pseudomonas N. gonorrheaeIntracellular pathogensM. Tuberculosis Mycoplasma ChlamydiaLegionella BrucellaNot effective against G+ and anaerobes

Clinical uses1.Urinary tract infections (G- bacteria)2. Osteomyelitis due to P. aeruginosa 3. Gonorrhea4. Travellers’ diarrhea- ciprofloxacin

commonly used5. Tuberculosis6. Prostatitis7. Community- acquired pneumoniae 8. Diabetic foot infections ( P. aeruginosa )9.Anthrax

Usual duration is 7-14 days Available forms

Brand name : ciproxin(bayer),cycin.

Oral Parentral Opthalmic 100 mg 200 mg iv 3mg/ml

solution250 mg 400 mg iv 3.3mg/mg

ointment500 mg

Levofloxacin

3rd generation fluoroquinolone

Spectrum: Gram-ve, Gram+ve (S. aureus including MRSA & S. pneumoniae) and Legionella pneumophila, atypical resp. pathogens,

Mycobacterium tuberculosis

Indications:Chronic bronchitis and CAP• Nosocomial pneumonia Intra-abdominal infections

Cont. Adverse reaction.Blood glucose disturbances in DM patientsQTC prolongation, torsades de pointes, arrhythmiasNausea, GI upset Interstitial nephritis

Usual duration same 7-14 daysAvailable forms

Brand name:leflox,l-cyn,qumic

Oral Parentral Opthalmic 100 mg 5 mg/ml iv 5mg/ml

solution250 mg 25 mg/ml iv500mg

REFERENCE:- http://www.DrNajeebLectures.comhttp://en.wikipedia.org/wiki/QuinoloneWilson and gisvolds textbook of Organic

Medicinal and Pharmaceutical Chemistry, by JhonH.Block and Jhon M. Beale. Eleventh edition. Pgno 247-252.

Foye’s principles of Medicinal chemistry, by Thomas L. lemke, David A williams.