FLUOROQUINOLONES: FROM STRUCTURE TO ACTIVITY AND TOXICITY
CONTENTS: 1.INTRODUCTION 2.MECHANISM OF ACTION 3.CHEMISTRY AND ACTIVITY 4.TOXICITY 5.SAR 6.PHARMACOKINETICS 7.DRUG INTERACTIONS.
SYNTHESIS OF NALIDIXIC ACID:
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 infections Uncomplicated/complicated UTI Anthrax exposure and prophylaxis Unique Qualities: Binds divalent cations (i.e. Ca & Mg) which decreases absorption -- Increased effects of warfarin ADRs QTC prolongation, torsades de pointes, arrhythmias Nausea, GI upset Interstitial nephritis Not inclusive list of indications; patients at risk for tendon effects (>60 yo, renal failure, dialysis, concomitant corticosteroid therapy, dyslipidemia); weakest quinolone against MSSA
SYNTHESIS OF CIPROFLOXACIN:
CIPROFLOXACIN SYNTHESIS ( Cont):
STRUCTURE OF SPARFLOXACIN :
SYNTHESIS OF SPARFLOXACIN:
SYNTHESIS OF SPARFLOXACIN (Cont):
STRUCTURE OF TROVAFLOXACIN:
TOXICITY ASSOCIATED WITH FLUOROQUINOLONES GI: nausea, vomiting, diarrhea, abdominal pain CNS: dizziness, sleep disturbance, confusion, seizure Liver: hepatitis, liver failure Kidney: hematuria, crystalluria, nephritis, renal failure Musculoskeletal: tendinitis, arthropathy, tendon rupture Cardiovascular: hypotension, tachycardia with QTc changes Skin: rash, pruritis, photosensitivity Endocrine: disturbance in glucose homeostasis
SAR of Quinolones 1,4-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.
SAR continued... Isosteric substitution of carbon with nitrogen still remains the activity.
SAR continued... N1-Substitution is necessary for antibacterial activity. Small alkyl or cycloalkyl groups increase it: cyclopropyl>ethyl>methyl
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
SAR continued... Ring fusion at C1and C8; C5 and C6; C6 and C7 or C7and C8 introduces active compounds:
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.
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.
Fluoroquinolone Drug Interactions: Ciprofloxacin and Levofloxacin Ciprofloxacin listed 36 different drug interactions Levofloxacin listed 11 drug interactions
Ciprofloxacin as the perpetrator drug Mechanism Drug CYP1A2 inhibition caffeine, clozapine, mexiletine, olanzapine, R-warfarin, rasagiline, ropinirole, ropivacaine, theophylline, tizanidine, duloxetine, zolmitriptan CYP3A4 inhibition cyclophosphamide, sildenafil, glyburide, cyclosporine Inhibition of organic ion transporters methotrexate, probenecid, procainamide, cimetidine Reduced enterohepatic recycling Ethinyl estradiol Lack of interaction Diazepam, ethanol Unknown isoniazid
Levofloxacin as the perpetrator drug Mechanism Drug Inhibition of organic ion transporters cimetidine, procainamide Lack of interaction digoxin, oxycodone, theophylline, AZT Unknown Cyclosporine, tacrolimus
Common interactions with both drugs Mechanism Drug Complexation of drug to fluoroquinolone antacids, iron salts, calcium salts, magnesium salts, zinc oxide, didanosine Disruption of normal gut flora warfarin Unknown Antidiabetics, NSAIDs, probenecid
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
CONCLUSION
References 1.PPT by F.VAN BAMBEKE & P.M .TULKENS . (WWW.sbimc.org-WWW.bvikm.org) 2.Wikipedia. Ciprofloxacin. 2008. 20 January 2009 <http://en.wikipedia.org/wiki/Ciprofloxacin>. 3. Synthesis of drugs from SURENDRA N.PANDEEYA (Vol :II) .
THANK U