FLUOROQUINOLONES

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RECENT KNOWLEDGE ABOUT ALL GENERATION OF FLUOROQUINOLONES

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Quinolones and Fluoroquinolones Dr.Ashkarali T 1 st year MD pharmacology SMVMCH

TABLE OF CONTENTS:

TABLE OF CONTENTS Introduction and classification Mechanism of Action Antimicrobial spectrum Clinically useful fluoroquinolones Resistance of Fluoroquinolones Adverse drug reactions Drug interactions Contraindications Complications

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Introduction and Classification

Quinolones And Fluoroquinolones:

Quinolones And Fluoroquinolones The quinolones (Qs) and fluoroquinolones (FQs) are a family of broad-spectrum synthetic antimicrobial agents. The parent of the group is nalidixic acid , which was introduced in 1962 . The fluoroquinolones have a fluoro group attached the central ring system.

Quinolones And Fluoroquinolones Classification:

Quinolones And Fluoroquinolones Classification GENERATIONS DRUGS INCLUDED 1 st generation Nalidixic acid Cinoxacin (removed from clinical use) 2 nd generation Ciprofloxacin Enoxacin Norfloxacin Ofloxacin 3 rd generation Levofloxacin Grepafloxacin Sparfloxacin 4 th generation Moxifloxacin Trovafloxacin

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First-generation 1) Cinoxacin (Cinobac) 2) flumequine(Flubactin) --veterinary use 3) nalidixic acid (NegGram, Wintomylon) (genotoxic carcinogen) 4) oxolinic acid (Uroxin) 5) piromidic acid  (Panacid) 6) pipemidic acid (Dolcol) 7) Rosoxacin (Eradacil)

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Second-generation 1) ciprofloxacin(Alcipro,Ciprobay, Cipro,Ciproxin) 2) enoxacin(Enroxil, Penetrex) 3) fleroxacin(Megalone, Roquinol) 4) lomefloxacin (Maxaquin) 5) nadifloxacin(Acuatim, Nadoxin, Nadixa) 6) norfloxacin (Lexinor, Noroxin) 7) ofloxacin (Floxin, Oxaldin, Tarivid) 8) pefloxacin(Peflacine) 9) rufloxacin (Uroflox)

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Third-generation Unlike the first- and second-generations, the third-generation is active against streptococci. 1) balofloxacin (Baloxin) 2) grepafloxacin(Raxar) (removed from clinical use) 3) levofloxacin (Cravit, Levaquin) 4) pazufloxacin(Pasil, Pazucross) 5) sparfloxacin(Zagam) 6) temafloxacin(Omniflox) (removed from clinical use) [ 7) tosufloxacin(Ozex, Tosacin)

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Fourth-generation Fourth generation fluoroquinolones act at DNA gyrase and topoisomerase IV 1) clinafloxacin 2) Gatifloxacin (Zigat, Tequin) (Zymar -opth.) 3) gemifloxacin (Factive) 4) moxifloxacin 5) sitafloxacin( Gracevit)) 6) trovafloxacin(Trovan) 7) prulifloxacin(Quisnon)

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In development 1) garenoxacin (Geninax)(application withdrawn) 2) delafloxacin (An anionic fluoroquinoline in clinical trials) 3) JNJ-Q2 Completed Phase II for MRSA

Quinolones And Fluoroquinolones:

Quinolones And Fluoroquinolones Qs and FQs are bactericidal drugs. FQs enter into the host cells and therefore are active against intracellular pathogens such as Legionella spp ., Mycoplasma spp. and Chlamydia spp.

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MECHANISM OF ACTION

Quinolones And Fluoroquinolones Mechanism of action:

Quinolones And Fluoroquinolones Mechanism of action The fluoroquinolones work by inhibiting one or more of a group of enzymes called topoisomerase, enzymes needed for supercoiling, replication and separation of circular bacterial DNA. 1. DNA Gyrase is a topoisomerase II that catalyzes the negative supercoiling of the circular DNA found in bacteria. 2. Topoisomerase IV , on the other hand, is involved in the relaxation of the supercoiled circular DNA, enabling the separation of the interlinked daughter chromosomes at the end of bacterial DNA replication

Quinolones And Fluoroquinolones Mechanism of action:

Quinolones And Fluoroquinolones Mechanism of action

Quinolones And Fluoroquinolones Mechanism of action:

Quinolones And Fluoroquinolones Mechanism of action Gram-negative bacteria primary target is DNA gyrase. Gram-positive bacteria primary target is topoisomerase IV.

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ANTIMICROBIAL SPECTRUM

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A ntimicrobial spectrum of quinolones

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Example Antibacterial Spectrum Nalidixic acid Gram-negative bacteria: E. coli, Proteus spp, Klebsiella spp, Shigells spp. Have no activity against P . aeruginosa Ciprofloxacin Gram-negative including P . aeruginosa Gram-positive: only Staphylococcus spp. Have no activity against Streptococcus pneumonia. Atypical bacteria: Legionella spp. Levofloxacin Gram-negative Gram-positive. Improved activity against Streptococcus pneumonia Atypical bacteria. Improved activity against Mycoplasma spp., Chlamydia spp. Moxifloxacin Gram-negative Gram-positive including Streptococcus pneumonia Antianaerobic activity

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CLINICALLY USEFUL FLUOROQUINOLONES

Nalidixic Acid:

Nalidixic Acid Well absorbed from GIT. Partly metabolized in liver. P oor tissue penetration and low plasma levels . Cannot be used for the treatment of systemic infections. Excreted in urine. High urine concentration.

Nalidixic Acid. Clinical Use:

Nalidixic Acid. Clinical Use Norfloxacin is effectives against gram –ve and gram +ve organisms in treating complicated and uncomplicated urinary tract infections and prostitis. Bacterial gastrointeritis caused by E. coli, Proteus spp, Klebsiella spp, Shigella spp.

Ciprofloxacin:

Ciprofloxacin The most potent of the fluoroquinolones for P . aeruginosa . Long post-antibiotic effect. Well absorbed from GIT. Administration: orally, IV. Excreted in urine. Potent CYP450 inhibitor

Ciprofloxacin. Clinical Uses:

Ciprofloxacin. Clinical Uses UTIs Intra-abdominal infections (peritonitis) Bacterial gastrointeritis Sepsis Skin/soft tissue infections Typhoid (ciprofloxacin is the first choice in typhoid fever) Tuberculosis Gonorrhea Conjunctivitis

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Ciprofloxacin. Clinical Uses

Levofloxacin:

Levofloxacin An isomer of Ofloxacin and has largely replaced it clinically. Very well absorbed from GIT. Administration: orally, iv. Excreted unchanged Long post-antibiotic effects. Long-acting (single daily dose) .

Levofloxacin. Clinical Uses:

Levofloxacin. Clinical Uses Mostly used for the treatment respiratory tract infections due to S. pneumonia (pneumonia, COPD exacerbation). Used in the treatment of prostitis due to E.coli and of sexually transmitted diseases, with the exception of syphilis. Used as an alternative in patients with gonorrhea. Additionally due to its broad spectrum activity, levofloxacin is utilized in wide range of infections, including skin infections, acute sinusitis,nosocomal pneumonia.

Moxifloxacin:

Moxifloxacin Long-acting (single daily dose). Long post-antibiotic effect. Mostly used for the treatment respiratory tract infections (pneumonia, COPD exacerbation). Used for the treatment severe bacterial infections including sepsis, peritonitis. The most potent fluoroquinolones against M. tuberculosis . Poor activity against P.aeruginosa.

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RESISTNACE OF FLUOROQUINOLONES

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ADVERSE DRUG REACTIONS

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Mechanism of toxicity interactions with different receptor complexes, such as blockade of the GABAa receptor complex within the central nervous system, leading to excitotoxic type effects and oxidative stress

Quinolones And Fluoroquinolones Adverse Effects:

Quinolones And Fluoroquinolones Adverse Effects Abnormalities of bone and cartilage formation. (Cause cartilage damage in weight bearing joints in animal studies) Qs and FQs are contraindicated in children under 18 and pregnant women!!!

Quinolones And Fluoroquinolones Adverse Effects:

Quinolones And Fluoroquinolones Adverse Effects Photosensitivity (photodermatitis) A void sun and U.V. radiation exposure during therapy !!!

Quinolones And Fluoroquinolones Adverse Effects:

Quinolones And Fluoroquinolones Adverse Effects Tendonitis/tendon rupture. A few cases of ruptures of the shoulder, hand and Achilles tendon have been reported. CNS: confusion, insomnia, fatigue, depression, somnolence, seizures. CVS: QT-prolongation.

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DRUG INTERACTIONS

DRUG INTERACTIONS:

DRUG INTERACTIONS Ciprofloxacin is a potent CYP450 inhibitor. I ncrease s plasma levels and toxic effects of anticoagulant s, digoxin , theophylline With theophylline warfarin and cyclosporine

DRUG INTERACTIONS:

DRUG INTERACTIONS FQs in combination with with class IA and class III antiarrhythmics prolong QT and may cause arrhythmias. Qs and FQs have no sinergistic effects with other antibiotic classes . A synergistic inhibitory effect of fluoroquinolones has been observed on the binding of the neurotransmitter GABA. With antiarrhythmics With other antibiotics

DRUG INTERACTIONS:

DRUG INTERACTIONS The conocmitant oral administeration of magnesium or Aluminium containing Antacids has been found to result in six to ten fold decreases in the absorption of oral quinolones. Studies have documented substantial reductions in quinolones bioavailability when co administered with sucralfate. With antacids With sucralfate

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CONTRAINDICATIONS

Contraindications:

Contraindications Fluoroquinolones are contraindicated in patients with known hypersensitivity reactions with any member of fluoroquinolones class of antimicrobial agents.

Contraindications:

Contraindications Fluoroquinolones generally should not be administered to patients younger than 18 years of age. Fluoroquinolones should not be administerd to pregnant or lactating women. Should not be given to arrythmic patient.

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COMPLICATIONS

Complications :

Complications Ophthalmia Venerea ": A dreadful complication of fluoroquinolone -resistant Neisseria gonorrhoeae . Fluoroquinolone antibiotics are associated with a wide spectrum of musculoskeletal complications that involve not only tendon but also cartilage, bone, and muscle.

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Qs FOR NATURE

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Veterinary use The quinolones have been widely used in agriculture, and several agents have veterinary, but not human, applications. danofloxacin (Advocin, Advocid) (for veterinary use) difloxacin (Dicural, Vetequinon) (for veterinary use) enrofloxacin (Baytril) (for veterinary use) ibafloxacin (Ibaflin) (for veterinary use) marbofloxacin (Marbocyl, Zenequin) (for veterinary use) orbifloxacin (Orbax, Victas) (for veterinary use) sarafloxacin (Floxasol, Saraflox, Sarafin) (for veterinary use)