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Antimicrobial Agents (Sulfonamides and Quinolones)
Prof. R. K. DixitPharmacology and TherapeuticsK.G.M.U. [email protected]
ObjectivesAfter completion of this lecture you will be able to
– Know about sulphonamides• Types (Classification)• MOA• Combination with Trimethoprim or Pyrimethamine• Uses• ADRs, DDI, and Contraindications• Special points
– Know about Quinolones• Types (Classification)• MOA• Uses• ADRs, DDI, and Contraindications• Special points
Quinolones and FluoroquinolonesHave Quinolone structure
Nalidixic acid is first member
Fluorination of Quinolones - Fluoroquinolones
Gram negative mainly (Plus gram positive New FQs)
N to P
•MOA- (Queen stops gyrating dancers)
•In gram negative – •Inhibition of DNA gyrase enzyme (Inhibit negative super coiling)
•In gram positive – •Inhibition of Topoiosmerase IV – Inhibition of nicking and separation of daughter DNA strands after DNA replication (Inhibition of Decatenation)
•The malformed DNA is digested by Exonucleases
Why not human cells affected ?Mammalian cells have Topoiosmerase II
Resistance-Due to mutation in chromosomes
Altered DNA gyrase and Topoisomerase IVReduced permeability for drugIncreased efflux of drug
MembersQuinolones• Nalidixic acid
FluoroquinolonesNew Generations• Lomefloxacin• Levofloxacin • Prulifoxacin• Sparfloxacin • Gatifloxacin • Gemifloxacin• Moxifloxacin • Trovafloxacin• Alatrofloxacin• Finafloxacin
FluoroquinolonesFirst GenerationCiprofloxacinNorfloxacinPefloxacinOfloxacin
Second
Third
Fourth
MAN Can SPOT Good Life
Moxifloxacin AlatrofloxacinNorfloxacinCiprofloxacinSparfloxacin PefloxacinPrulifoxacinOfloxacin• Trovafloxacin• Gatifloxacin • Gemifloxacin• Lomefloxacin• Levofloxacin
Nalidixic Acid- •Gram negative, (Narrow spectrum)•Bactericidal, •Acts by DNA gyrase inhibition, •Highly protein bound, •High concentration is in Urine •Neurological toxicity(vertigo, visual and seizures)
•Haemolysis in G-6PD deficiency• Used as
•Urinary antiseptic, •Bacterial Diarrhea.
Don’t give with Nitrofurantoin (Antagonism)
First generation FQsCiprofloxacin-
•Long Post Antibiotic Effect (PAE) •Less active at acidic pH• Interacts with food and calcium •High tissue penetrability ( Except BBB) •High conc. in urine and bile
•CNS side effects are common, •Tendonitis and tendon rupture
•Drug Interaction- •Inhibition of metabolism of other drug,•Chelation•QT interval prolongation
USES- (Extended spectrum)CNSI, MFI, OI, ENTI, RTI, GITI, UTI, PID, STDs, SBI Nosocomial InfectionsSepticaemiaTuberculosis- MDR TB and XDR TBTyphoid
Treatment 2 weeks Prevention of carrier state 2 monthsOther drugs-
Other FQs Cephalosporins ,Ceftriaxone (Fastest)Chloramphenicol Cotrimoxazole Ampicillin
Norfloxacin – Less potent, Primarily used for UTI and GIT infections,
Ofloxacin- Highly active against Mycobacterium leprae
Pefloxacin –Methylated derivative of Norfloxacin, Oral bioavailability is 100%
Second Generation FQs
Lomefloxacin – •Once a day dose
Levofloxacin – •Levo-isomer of Ofloxacin, •Oral absorption is 100% •Single daily dose •Minimal drug interactions
Sparfloxacin – • Enhanced action against Chlamydia, • Maximum half life and Plasma Protein Binding• Second line Anti-tubercular drug • MAC in AIDS, Leprosy • No interaction with Theophylline and Warfarin, • Photoxicity • Single daily dose, • May prolong Q-T interval ( Avoid with Cisapride,
TCAs, Phenothiazines, Anti-arrhythemics, Hypokalemia)
Gatifloxacin – •Prolongs Q-T interval, •Unexpected Hypo or Hyperglycemia in Diabetes mellitus patients. ( Withdrawn )
Moxifloxacin – •Most potent FQ against M. tuberculosis. •Can prolong Q-T interval, •Phototoxic
Trovafloxacin – •Hepatotoxic (Reserved and maximum of 15 days Tt.)
Alatrofloxacin - Prodrug of TrovafloxacinFinafloxacin, Prulifoxacin, Gemifloxacin
Elimination of Fluoroquinolones
Renal•Norfloxacin•Ofloxacin•Ciprofloxacin•Lomefloxacin•Levofloxacin•Gatifloxacin
Hepatic•Pefloxacin•Moxifloxacin•Trovafloxacin•Sparfloxacin•Gemifloxacin
Fluoroquinolones safe in renal failure
PefloxacinMoxifloxacinTrovafloxacin
Miscellaneous points about Quinolones•No FQs effective against spirochaetes
•Ofloxacin and Pefloxacin are effective against M. leprae
•Moxifloxacin is the only FQ NOT used in UTI as its concentration is poor in urine
•Levofloxacin, Moxifloxacin, Gemifloxacin, Gatifloxacin, Sparfloxacin have good
activity against S. pneumonia and also
called Respiratory FQs. They also have good activity against anaerobes
•Chronic Prostatitis Tt. Ciprofloxacin for 1 to 2 months
•Gonorrhea- Tt. Single dose Ciprofloxacin 500mg
•Chlamydia trachomatis- Ciprofloxacin one week or single dose Azithromycin
Summary• Sulphonamides
– Act by inhibition of folic acid synthesis– Combined with Trimethoprim– Produce Stevens Johnson Syndrome– Prolonged use may produce hypothyroidism, goitre,
arthritis and drug fever
• Quinolones– Act by inhibition of DNA gyrase or Topoiosmerase IV– Have extended spectrum– Have chelating and enzyme inhibition property– Used for multiple infective diseases