Fluroquinolones 01 01-19
- 1. Quinolones & Fluroquinolones Dr Uma Advani Assistant Professor pharmacology SMS Medical College , Jaipur.
- 2. To be discussed • Introduction • Quinolones • Structure activity relationship of quinolones & fluroquinolones (FQs) • Mechanism of action & resistance • General features of fluroquinolones • Classification of Fluroquinolones • Pharmacokinetics of fluroquinolones • Antimicrobial spectrum & therapeutic applications • Unique features of different fluroquinolones • Adverse effects & drug interactions • Contraindications & precautions • Summary
- 3. Introduction • A group of synthetic antibacterial agents mainly effective against gram negative organisms • Nalidixic acid first member introduced in 1964 for urinary and GIT infections • Synthetic fluorinated analogs of nalidixic acid: are fluoroquinolones (FQs) with extended spectrum and systemic effects in 1980s. • FQs are BACTERICIDAL, act by interfering with DNA replication. Since then many synthesized with useful spectrum.
- 4. Nalidixic acid: The first quinolone, nalidixic acid, was isolated as a by-product of the synthesis of chloroquine Less potent ,limited spectrum Active against gram negative bacteria – E.coli, Proteus, Klebsiella, Enterobacter, Shigella Inhibits bacterial DNA gyrase, Bactericidal Resistance develops rapidly Pharmacokinetics: Absorbed orally Metabolized in liver, highly protein bound, excreted in urine, half life – 8 hrs. Concentration in urine is lethal to common urinary pathogens (20 – 50 times that in plasma) Quinolones
- 5. Nalidixic acid Adverse effects : GI upset, rashes Neurological toxicity (in children) – headache, vertigo, drowsiness, visual disturbances, seizures Hemolysis in G6PD deficiency Indication: Urinary antiseptic Diarrhoea caused by E.coli, Proteus, Shigella, Salmonella Ampicillin resistant Shigella enteritis (cont..,) Quinolones
- 6. T h e carboxyl group at position 3 and ketone group at tposition 4 are essential for antimicrobial activity. Substitution at position 6 with a fluorine moiety markedly increase antibacterial activity against G+ve, G-ve , Mycoplasma and chlamydia.. Addition of a piperazine ring at position 7 on fluoroquinolones increases tissue and bacterial penetration and improves spectrum of activity to include Pseudomonas ( e.g. Ciprofloxacin) Structure of quinolones & FQs (Short for 4-oxo-1,4-hydroquinoline)
- 7. Structure activity relationship of quinolones & fluroquinolones(FQs) Modify napthyridone into quinolone Add fluorine Add a piperazine (cont..,)
- 8. 1980 – Fluoroquinolones Fluorination of the quinolone structure at position 6 and introduction of a piperazine substitution at position 7 Highly potent Broad spectrum Better tissue penetration Resistance less Structure of FQs (cont..,)
- 9. 1.They block bacterial DNA synthesis by inhibiting bacterial topoisomerase Ⅱ (DNA gyrase) in gram negative bacteria) and topoisomerase Ⅳ in gram positive bacteria. 2. Inhibition of DNA gyrase prevents the relaxation of positively supercoiled DNA that is requiredfor normal transcription and replication. 3. Inhibition of topoisomerase Ⅳprobably interferes with separation of replicated chromosomal DNA into the respective daughter cells during celldivision. Mechanism of action of FQs :
- 10. Mechanismof action: DNA- Enzyme- FQ complex 4. The gyrase is composed of two A subunits and two B subunits. The A subunits can cut one of double strands of the DNA .This is an ATP- dependent reaction. The energy is provided by B units. 5. FQs are inhibitor of A subunits. Therefore, the action of gyrase is inhibited and DNA replication or transcription is blocked as result of the death of bacteria. (cont..,)
- 11. Mechanism of Resistanceto Quinolones&FQ 1.Due to a. One or more point mutations in the quinolone binding region of the target enzyme b. A change in the permeability of the organism 2. DNA gyrase is the primary target in E coli, with single-step mutants exhibiting amino acid substitution in the A subunit of gyrase. 3.Topoisomerase Ⅳ is a secondary target in E coli that is altered in mutants expressing higher levels of resistance. (cont..,)
- 12. 4.In staphylococci and streptococci, the situation is reversed, topoisomerase Ⅳ is the primary target, and gyrase is the secondary target. 5.Resistance to one fluoroquinolone, particularly if of high level, generally confers cross-resistance to all other members of this class. (cont..,) Mechanism of Resistanceto Quinolones & FQs
- 13. (cont..,) Mechanism of Resistanceto Quinolones&FQs
- 14. General features of FQs • Rapidly bactericidal & high potency • Long post antibiotic effect on pseudomonas & enterobacteriaceae • Attain high levels in body fluids & tissues • Diarrhea and antibiotic-associated colitis unusual • Low frequency of mutational resistance • Active against many β-lactam & aminoglycoside resistant bacteria • Less active at acidic pH
- 15. Classification of FQs First generation: introduced in 1980 with one fluro substitution Norfloxacin Ciprofloxacin Ofloxacin (only as ophthalmic in the United States) Pefloxacin
- 16. Second-generation: In 1990s with additional fluro & other substitution extending antimicrobial spectrum to gram positive bacteria ,anaerobes and longer half life. Levofloxacin Moxifloxacin Gemifloxacin Prulifloxacin Lomefloxacin Sparfloxacin Finafloxacin (cont..,) Classification of FQs
- 17. Pharmacokinetics of FQs: Prototype : Ciprofloxacin • Oral given, well absorbed, be impaired by divalent cations, including those in antacid • Distributed widely in body fluids and tissues but CSF & aqueous levels are low • Urinary & billiary concentrations are 10-50 fold higher than plasma • Less active in acidic pH • Pass placenta reach to the fetus, • Biotransformation of the drugs in the liver • Most eliminated by renal, either tubular secretion or glomerular filtration.
- 18. Therapeutic applications o f F Qs Fluoroquinolones are extensively used treating general infection. a. Urinary tract infections, even when caused by multidrug-resistant bacteria, b. Intestinal and biliary tract infections c. Soft tissue infections d. Bone, joint and intra-abdominal infections e. Respiratory tract infections
- 19. CIPROFLOXACIN:(prototype): Highly effective against pseudomonas • Drug of choice for prophylaxis & treatment of Anthrax & prophylaxis of meningococcal meningitis. • Typhoid • UTIs • Tuberculosis • Bacterial gastroenteritis • Osteomyelitis & joint infections • Gonorrhea & chanchroid • Septicemia due to gram negative organisms • Respiratory infections especially due to Mycoplasma, H. influenza, Legionella • Prophylaxis of infections in neutropenic & cancer patients • Topical use: conjunctivitis Unique features of different FQs
- 20. NORFLOXACIN: Minimum oral bioavailability • Minimum Inhibitory concentration for gram negative bacteria is 8-10 times higher than that of ciprofloxacin. • Attains lower concentration in tissues • Less potent than ciprofloxacin • Primarily used in urinary & genital tract infections • For bacterial diarrheas it is good as anaerobic flora of the gut not affected. Unique features of different FQs (cont..,)
- 21. Unique features of different FQs PEFLOXACIN: • Methyl derivative of Norfloxacin • Completely absorbed, exhibits cumulation on repeated absorbtion • More lipid soluble, CSF concentration are higher than other FQs • Highly metabolized in liver to active metabolite • Dose needs to be reduced in liver disease but not in renal insufficiency • Preferred for meningeal infections • 200,400mg tablet available & injection 400mg/5ml to be used diluted in glucose solution but not in saline as it precipitates in presence of Chloride ions. (cont..,)
- 22. Unique features of different FQs OFLOXACIN: • Lipid soluble oral bioavailability is high • Food does not interfere its absorption • Oral tablet (200 & 400mg) & i.v.(200mg) • Largely excreted unchanged by kidney ,so dose need reduced in renal failure • Effective for gonococcal infection, including disseminated disease. • Occasionally used for treatment of tuberculosis and atypical mycobacterial infections • Suitable for eradication of meningococcal infections from carriers. • Highly effective in: leprosy, Chlamydial urethritis or cervicitis , atypical (Mycoplasma) pneumonia & Chronic bronchitis (cont..,)
- 23. SPARFLOXACIN: Excreted by both renal & hepatic Long half life Increased action against gram positive bacteria, Streptococcus, Staphylococcus, Enterococcus,Anaerobes & mycobacteria NOT effective against Peudomonas Indication: upper and lower respiratory tract infections. Highly effective in Tuberculosis, , Macobacterium Avium Complex, Leprosy Adverse effects: Phototoxic QT prolongation (cont..,)
- 24. MOXIFLOXACIN: Hepatic metabolism & biliary excretion Tablet & intravenous (400 mg) Indications: MDR tuberculosis, Bronchitis, pneumonia, otitis media, Urinary concentrations are low not suitable for UTI Contraindications : Primarily metabolised in liver, not used in liver disease Patients with Seizures & Patients receiving proarrythmic drugs as it prolong Q-T interval (cont..,)
- 25. FINAFLOXACIN: Activity increase in acidic pH Longer plasma half life ,once daily administration. Given orally or i.v. High safety profile no hepatotoxicity, renal toxicity , phototoxicity or cardiotoxicity. Indications: Active against gram positive,gram negative, anarobes & atypical pathogens. Indication: H.pylori eradication, UTI, community acquired pneumonia, severe exacerbation of COPD. Cystic fibrosis,complicated intraabdominal infections & skin infectionsTopical preparation for acute otitis externa by Pesdomonas & staphylococcus. Topical preparation for acute otitis externa by Pesdomonas & staphylococcus. (cont..,)
- 26. PRULIFLOXACIN: Newer 2nd generation FQ is prodrug of Ulifloxacin Broad spectrum active against gram positive & negative bacteria & many resistant strains Rapidly absorbed, excreted unchanged in urine Indication : Good efficacy in acute exacerbation of acute bronchitis & in uncomplicated UTI ( single dose of 600mg ) & complicated UTI Side effects: GI & CNS disturbance, but do not prolong Q-T interval. (cont..,)
- 27. LEVOFLOXACIN: L-isomer of ofloxacin Maximum oral bioavailablity, given orally or i.v. Excreted unchanged by kidney Indications : Upper and lower respiratory tract infections. Community acquired pneumonia : (Respiratory FQ) MDR TB, nosocomial infections Eye drops for bacterial conjunctivitis & corneal ulcer. (cont..,)
- 28. LOMEFLOXACIN: Similar to Ciprofloxacin ,more active against Gram negative bacilli & chlamydia Longer plasma half life ,once daily administration 400 mg tablet available & Topical eye drops available (0.3%) Side effect: Photo toxicity & Q-T prolongation Withdrawn in USA & other countries, available in India (cont..,)
- 29. Drug Oral bioavail.(%) Half life (hr) Dosage 0ral (mg) Excretion Remarks Ciprofloxacin 60-80 3-5 BD 250-750 Renal Action on aerobic Gram −ve bacteria Prulifloxacin 90 10-12 600 OD Unchanged Renal No Q-T prolongation Gemifloxacin 70 7 320 OD Renal & non renal ‘respiratory FQ’ Levofloxacin ~100 5-7 500 OD Renal ‘respiratory FQ’ Lomefloxacin 95 8 400 OD Renal phototoxic Moxifloxacin 85 10-15 400 OD Non renal ‘respiratory FQ’ Norfloxacin 35-45 4-6 400 BD Renal Lower systemic levels, used for UTI Ofloxacin 85-95 5-8 200-400 BD Unchanged Renal Use in leprosy & resistant TB (cont..,)
- 30. Trovafloxacin/Alatrofloxacin due hepatotoxicity restricted only to life threatening infections In addition in India: Pazufloxacin & Balofloxacin are available. Pazufloxacin:injectable 500mg intravenous infusion for lung & intraabdominal abscesses, peritonitis &nosocomial infections Balofloxacin: exacerbation of chronic bronchitis, community acquired pnemonia& UTI (cont..,)
- 31. Due to adverse effects like Gatifloxacin: QT prolongation & dysglycemia (increase or decrease blood sugar level: risky in diabetics) withdrawn from market. Temafloxacin: immune hemolytic anemia Grepafloxacin: cardiotoxicity: QT prolongation Clinafloxacin : phototoxicity
- 32. a. The most common effects are nausea, vomiting, and diarrhea. b. Headache, dizziness, insomnia, skin rash, occasionally. c. Photosensitivity occurs with lomefloxacin and pefloxacin. d. FQs may damage growing cartilage and cause an arthropathy. They are not used in patients under 18years of age. The arthropathy is reversible. e. FDA has issued warning regarding peripheral neuropathy f. Ciprofloxacin prophylaxis use in anthrax patients associated with damage to muscle ligament.
- 33. Drug interactions • Complexation with metallic ions (Fe, Al, Mg, Ca & Zn) - Common to all fluoroquinolones. - Chelation complexes provides the basis for their incompatibilities with antacids, hematinics, and mineral supplements containing divalent or trivalent metals • CYP1A2 inhibition: increase the levels of theophylline, warfarin & caffeine; especially by ciprofloxacin & pefloxacin ( Lomefloxacin, Levofloxacin & Sparfloxacin have no effect ) • NSAIDS: increase CNS toxicity of FQs; seizures may occur • FQs which prolong QTs interval should be used with caution those receiving class 1A, class III antiarrhythmic; erythromycin, TCAs etc.
- 34. Drug interactions with fluroquinolones (cont..,)
- 35. Contraindications & precautions: • Patients with seizures • Pregnancy & lactation • Children below 18 years • Drugs prolonging QT interval are contraindicated in patients of cardiac arrhythmia & in hypokalemia • Hepatic & renal failure
- 36. Summary FQs are fluorinated synthetic analogs of Nalidixic acid Good oral bioavailability & are primarily renal excretion Act by blocking DNA synthesis by inhibition of bacterial DNA gyrase & topoisomerase IV Mainly active against gram negative bacteria including pseudomonas. Resistant to T. Pallidum & Nocardia. Newer FQs are active against methicillin sensitive S. aureus & S. pneumonia & anaerobes Use cautiously with drugs prolonging QT interval Point mutations confer high degree of resistance with cross tolerance to other members