22 Ciprofloxacin Administration [Usual Dosage]: IV. Spectrum: Gram- aerobic rods, and Legionella pneumophila, and other atypicals. Poor activity against Strep. pneumoniae.Indications:-- Nosocomial pneumonia-- Intra-abdominal infectionsUncomplicated/complicated UTIAnthrax exposure and prophylaxisUnique Qualities:Binds divalent cations (i.e. Ca & Mg) which decreases absorption-- Increased effects of warfarinADRsQTC prolongation, torsades de pointes, arrhythmiasNausea, GI upsetInterstitial nephritisNot inclusive list of indications; patients at risk for tendon effects (>60 yo, renal failure, dialysis, concomitant corticosteroid therapy, dyslipidemia); weakest quinolone against MSSA
47 SAR of Quinolones1,4-dihydro-4-oxo-3-pyridinecarboxylic acid portion is necessary for the antibacterial activity.The pyridone ring must be attached to an aromatic ring, in which isosteric substitution of carbon with nitrogen still remaines the activity.
48 SAR continued...Isosteric substitution of carbon with nitrogen still remains the activity.
49 SAR continued...N1-Substitution is necessary for antibacterial activity. Small alkyl or cycloalkyl groups increase it: cyclopropyl>ethyl>methyl
50 SAR continued...Substitution at C2 position decreases the activity remarkably or changes the antibacterial characters.Substitution at C5 , C6 , C7 and especially at C8 has good effects on the activity.C6 fluorine substitution increases the activity prominently, That’s why quinolones are also called fluoroquinolones.Substituted or unsubstituted piperazinyl or pyrolidinyl groups at C7 increase the activity against p.aeroginosa
51 SAR continued...Ring fusion at C1and C8; C5 and C6; C6 and C7 or C7and C8 introduces active compounds:
52 Why Fluoroquinolones cause CNS toxicity? Tremor, sleep disorders, anxiety, and convulsions because of GABA antagonism at the receptor.Because of low penetration to brain this toxicity is rare.
54 How Fluoroquinolones cause metal comlexation? This occurs with cations such as Ca2+, Zn2+, Fe2+, Fe3+, Bi3+. That’s why there is an interaction between quinolones and mineral containing drugs.Since this complexes are water insoluble, and there are bivalent metal ions in the urine, fluoroquinolones cause crystalluria.
62 Fluoroquinolone Drug Interactions: Ciprofloxacin and Levofloxacin Ciprofloxacin listed 36 different drug interactionsLevofloxacin listed 11 drug interactions
63 Ciprofloxacin as the perpetrator drug MechanismDrugCYP1A2 inhibitioncaffeine, clozapine, mexiletine, olanzapine, R-warfarin, rasagiline, ropinirole, ropivacaine, theophylline, tizanidine, duloxetine, zolmitriptanCYP3A4 inhibitioncyclophosphamide, sildenafil, glyburide, cyclosporineInhibition of organic ion transportersmethotrexate, probenecid, procainamide, cimetidineReduced enterohepatic recyclingEthinyl estradiolLack of interactionDiazepam, ethanolUnknownisoniazid
64 Levofloxacin as the perpetrator drug MechanismDrugInhibition of organic ion transporterscimetidine, procainamideLack of interactiondigoxin, oxycodone, theophylline, AZTUnknownCyclosporine, tacrolimus
65 Common interactions with both drugs MechanismDrugComplexation of drug to fluoroquinoloneantacids, iron salts, calcium salts, magnesium salts, zinc oxide, didanosineDisruption of normal gut florawarfarinUnknownAntidiabetics, NSAIDs, probenecid
66 FLUOROQUINOLONES (In development ) METABOLISM:Most fluoroquinolones are metabolized in the liver and excreted in urine, reaching high levels in urine. Moxifloxacin (AVELOX) is eliminated primarily in bile.FLUOROQUINOLONES (In development )garenoxacin (Geninax)(Application withdrawn due to toxicity issues)delafloxacin