1. FLUOROQUINOLONES:
FROM STRUCTURE TO ACTIVITY AND TOXICITY

2. CONTENTS:
1.INTRODUCTION
2.MECHANISM OF ACTION
3.CHEMISTRY AND ACTIVITY
4.TOXICITY
5.SAR
6.PHARMACOKINETICS
7.DRUG INTERACTIONS.

21. SYNTHESIS OF NALIDIXIC ACID:

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 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

23. SYNTHESIS OF CIPROFLOXACIN:

24. CIPROFLOXACIN SYNTHESIS ( Cont):

29. STRUCTURE OF SPARFLOXACIN :

30. SYNTHESIS OF SPARFLOXACIN:

31. SYNTHESIS OF SPARFLOXACIN (Cont):

33. STRUCTURE OF TROVAFLOXACIN:

44. 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

47. 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.

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 interactions
Levofloxacin listed 11 drug interactions

63. 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

64. Levofloxacin as the perpetrator drug
Mechanism
Drug
Inhibition of organic ion transporters
cimetidine, procainamide
Lack of interaction
digoxin, oxycodone, theophylline, AZT
Unknown
Cyclosporine, tacrolimus

65. 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

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

67. CONCLUSION

68. References
1.PPT by F.VAN BAMBEKE & P.M .TULKENS . (
2.Wikipedia. Ciprofloxacin January 2009 <
3. Synthesis of drugs from SURENDRA N.PANDEEYA (Vol :II) .

69. THANK U