FLURO QUINOLONESfor MBBS studentsppt.ppt
- 2. COMPETENCY & SPECIFIC LEARNING OBJECTIVES • COMPETENCY - PH1.42, PH1.43 The student should able to Describe the Antibacterial spectrum, MOA, resistance, Uses & adverse effects of Fluoroquinolones
- 3. SPECIFIC LEARNING OBJECTIVES At the end of the class, the student should able to: • Classify Fluoroquinolones (FQ) with examples. • Describe the mechanism, spectrum, resistance and pharmacokinetics of FQ. • Describe the clinical uses, adverse effects, interactions and contraindications of FQ. • Compare and contrast between I & II generation FQ
- 4. Quinolones – accidental discovery Quinine Chloroquine Mefloquine Quinolones 1960’s GEORGE LESHER & Co workers Distillate of chloroquine
- 5. QUINOLONES SYNTHETIC ANTIMICROBIALS QUINOLONE STRUCTURE GRAM NEGATIVE BACTERIA FLUORINATED COMPOUNDS – ALSO GRAM POSTIVE ONES.
- 6. N N O H3C CH3 COOH Nalidixic acid N N H N F O CH3 CO2H Norfloxacin - Noroxin® Ciprofloxacin - Cipro® N N H N F O CO2H STRUCTURE
- 7. NALIDIXIC ACID SPECTRUM – Gram negative bacteria. E. Coli, proteus, klebsiella, Enetrobacter, Shigella. BACTERICIDAL DRUG metabolism – liver t1/2 – 8 hours. excretion – urine. 1.Resistance – rapid 2.Potency –low 3.Spectrum – limited 4.Resistance – high 5.For gi&urinary infections 6.Tissue levels - low HIGH CONCENTRATION – URINE ( 20 – 50 TIMES)
- 8. ADVERSE EFFECTS GIT, rashes. Neurological – headache, drowsiness, vertigo, visual disturbances, seizures. Long term use – Parkinsonism like symptoms. Leucopenia, biliary stasis. Phototoxicity - Rare G6PD deficiency – Hemolysis. C/I - INFANTS.
- 9. USES URINARY ANTISEPTIC. DIARRHOEA – proteus, E.coli, shigella, salmonella. Ampicillin resistant shigella enteritis.
- 10. FLUROQUINOLONES Quinolones with one or more substitutions. I Generation - 1980 II Generation -1990 N N H N F O CH3 CO2H Norfloxacin - Noroxin® Ciprofloxacin - Cipro® N N H N F O CO2H
- 11. Quinolones Fluoroquinolone (1970’s) - Fluorine addition at C 6 - increased activity against the DNA gyrase - increased penetration into the bacterial cell Ciprofloxacin introduced Piperazine group was added to C-7 Improved gram -ve & +ve coverage Better serum and tissue levels 1st quinolone to be used for conditions other then UTI’s 1987
- 12. FLUROQUINOLONES I Norfloxacin II Lomefloxacin Ciprofloxacin Sparfloxacin Ofloxacin Levofloxacin Pefloxacin Moxifloxacin Gatifloxacin III Gemifloxacin Plurifloxacin Sitafloxacin, Pazufloxacin Balofloxacin
- 13. MECHANISM OF ACTION Inhibit DNA gyrase DNA Topoisomerase IV
- 14. DNA gyrase MECHANISM OF ACTION
- 15. Fluoroquinolone: Mechanism of Action Cell Wall Cell Membrane DNA Gyrase DNA Topoisomerase IV fq fq fq fq fq fq fq Fluoroquinolone DNA Excessive positive supercoiliing DNA digestion
- 16. MECHANISM OF ACTION DNA gyrase Nicks double stranded DNA. Introduce negative supercoils. Reseals the nicked ends. Prevents excessive positive supercoiling RESISTANCE MUTATION OF DNA gyrase - Reduce affinity to FQs. Reduced permeability of drugs
- 17. Efflux Pump Chrosomal mutation Resistance to FQ Altered DNA gyrase Altered Topoisomerase IV
- 18. CIPROFLOXACIN MOST POTENT DRUG Aerobic gram negative bacilli Enterobactericeae Neisseria HIGHLY SUSCEPTIBLE E. Coli Neisseria K. Pneumoniae H. influenza Enterobacter H. ducreyi S. Typhi & other salmonella C.jejuni Shigella Y. enterocolitica Proteus. V. cholerae
- 19. MODERATIVELY SENSITIVE Pseudomonas S. Aureus ( MRSA) S. Epidermidis branhemella catarrhalis legionalla Brucella Listeria Mycobact. Tuberculosis LOW S. Pyogens. Faecalis, mycoplasma Clamydia Mycobact. Kansasii / avium
- 20. SPECIAL FEATURES Rapid bactericidal activity High potency Long post – antibiotic effect Mutational resistance – Low frequency Plasmid type mutants – Low Intestinal streptococci & anaerobes – Protected. Against β lactam & aminoglycoside resistant bacteria Acidic pH - Less active
- 22. PHARMACOKINETICS Oral absorption good. food delays absorption. High tissue penetrability Lung, sputum, muscle, bone, prostate & phagocytes concentration – high. Excretion – glomerular filtration, tubular secretion. Urinary / biliary concentration - 10-50 fold more
- 23. ADVERSE EFFECTS safety - good. GIT - Nausea, vomiting, bad taste, anorexia. CNS - Headache, dizziness, restlessness, anxiety, insomnia, impairement of concentration & dexterity, tremor. Seizures – rare. (?GABA RECEPTOR binding) Skin - Rash, pruritis, photosensitivity, urticaria, swelling of lips etc., Tendonitis & tendon rupture. bothers
- 24. C/I – PREGNANCY ARTHROPATHY -- IMMATURE ANIMALS CARTILAGE DAMAGE (?) Drug interactions Inhibits metabolism – Theophylline (CYP 450 1A2) Caffeine Warfarin NSAIDS enhance fluroquinolones toxicity Antacids, sucralfate, Iron salts – Reduce absorption of FQs.
- 25. THERAPEUTIC USES (1) UTI – complicated / uncomplicated - High cure rates. (2) Chancroid - 500 mg BD x 3 days. (3) Gonorrhoea - 500mg single dose. (4) Bacterial gastroenteritis –E.Coli Shigella Salmonella C. Jejuni Travellors diarrhoea (ETEC) Decrease stool volume – Cholera.
- 26. (5) TYPHOID - 1st drug of choice. 500 mg – 750 mg BD x 10 days. (or) 200 mg IV BD. advantages (1) quick defervescence (2) Relief of symptoms early. Complications, relapse – low (3) Prevention of carrier state Cidal action good penetration biliary / Intestinal concentration. For typhoid carriers. 750 mg BD – 4- 8weeks. 92% Eradication.
- 27. (6) Bone, soft tissue, gynaecological & wound infections – by resistant staphlococci. Gram negative bacteria. + metronidazole / clindamycin -- Diabetic foot. (7) Respiratory infections. Mycoplasma Legionella B. catarrhalis Inhalational anthrax - US FDA Tuleremia.
- 28. (8) Tuberculosis - Combination therapy - Resistant TB. (9) Gram negative septicaemias. Ciprofloxacin + III gen. cephalsporin /Aminoglycoside. (10) Meningitis - gram negative organisms Immunocompromised. CSF shunts. (11) Prophylaxis – Neutropenia / cancer patients. (12) Conjunctivitis – Gram negative bacteria. Topical therapy
- 29. NORFLOXACIN Less protent than ciprofloxacin Use – Urinary / genital tract infections. Bacterial diarrhoeas. PEFLOXACIN Methyl derivative of norfloxacin. More lipid soluble. Oral – complete absorption. High CSF concentration. T1/2 – long. Alternative to ciprofloxacin in typhoid.
- 30. OFLOXACIN Intermediate between ciprofloxacin & norfloxacin. More portent than cipro - gram positive & anaerobes. Chlamydia, mycoplasma.
- 31. PK – Lipid soluble Plasma concentration – High. Excretion – Urine ( unchanged) Use – Systemic & mixed infections. For chronic bronchitis. Respiratory / ENT infections. Gonorrhoea – 200mg single dose. Non gonococcal urethritis / cervicitis. TB / leprosy.
- 32. Levo isomer More activity – strep. pneumonia. - Gm + ve & Gm - ve TB, Anaerobes. OBA – 100% single dose. 500 mg oral For community acquired pneumonia. Exacerbation of chronic bronchitis. Sinusitis. Enteric fever. Pyelonephritis. Skin & soft tissue infection. LEVOFLOXACIN Difluronated quinolone Equal to Ciprofloxacin More active against gram negative bacteria & Chlamydia. T1/2 – long, single dose. Dose – 400mg 0.3% eye drops. Phototoxicity QTc prolongation LOMEFLOXACIN
- 33. Increased activity – gram positive bacteroide fragilis & anaerobes,mycobacteria. Phototoxic reactions Slight prolongation of QTc interval - 3% Dose : 200, 400 mg single dose 0.3% eye drops. • pneomonia • Exacerbations of chronic bronchitis • Sinusitis / ENT infections • Tuberculosis / leprosy • MAC infection – AIDS patients • Chlamydial infections SPARFLOXACIN Str.pnemonia Atypical respiratory pathogens Anaerobes Myco. Tuberculosis QTc prolongation. swelling of face. •Community acquired pneumonia. •Exacerbation of chronic bronchitis. • other URI/LRI. GATIFLOXACIN
- 34. MOXIFLOXACIN Long activity drug High activity – St. pneumoniae Other gram positive ones some anaerobes TB – most potent. Use – Pneumonia. Bronchitis. Sinusitis Otitis media Dose – 400 mg OD 0.5% eye drops.
- 35. CIPRO NORFL PEFL OFL 1.Oral bioavailability (%) 60-80 35-45 90-100 85-95 2. Plasma protein binding (%) 20-35 15 20-30 25 3. Vol. of distribution (L/kg) 3-4 2 2 1.5 4. Percent metabolized 20 25 85 5-10 5. Elimination t1/2 3-5 4-6 8-14 5-8 6. Routes of administration oral, i.v. oral oral, i.v. oral 7. Dose (mg BD) oral: 250-750 400 400 200-400 iv : 100-200 - 400 200
- 36. LEVO LOME SPAR GATI 1.Oral bioavailability (%) ~100 >90 90 96 2. Plasma protein binding (%) 25 10 40 20 3. Vol. of distribution (L/kg) 1.3 1.7-2.5 3.6 - 4. Percent metabolized 5 20 60 <5 5. Elimination t1/2 8 6-9 15-20 8 6. Routes of administration oral,i.v. oral oral oral,i.v. 7. Dose (mg BD) oral: 500 400 200-400 200-400 (OD) (OD) (OD) (OD) iv : 500 - - 200-400