Antimicrobial Agents (Sulfonamides and Quinolones)

Prof. R. K. DixitPharmacology and TherapeuticsK.G.M.U. Lucknowdixitkumarrakesh@gmail.com

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

Quinolones

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

Thanks