Quinolones

Pharmacology

1. Dr.Zulcaif Ahmad

2. The Quinolones
The Quinolones
The quinolones are really not antibiotics. By definition, an
antibiotic means something that's produced by another
living substance. That's the real definition. We have a lot
of chemotherapeutic antimicrobials that have activity
against organisms for which we loosely use the term
antibiotic, but they're really chemicals.

3. History
A group of synthetic antibacterial agents mainly
effective against G-ve
Nalidixic acid first member introduced in 1964 for
urinary and GIT infections
Its congeners Oxolinic acid and rosoxacin with
more potency in 1970s
Second generation called fluoroquinolones with
extended spectrum and systemic effects in 1980s
Since then many synthesized with useful spectrum.

4. Chemistry of Quinolones
They are
synthetic
fluorinated
analogs of
nalidixic acid.

5. Basic Structure of 4-quinolones
(Short for 4-oxo-1, 4-hydroquinoline)

6. The carboxyl group at position 3 and ketone group at
position 4 are essential for antimicrobial activity.
Substitution at position 6 with a fluorine moiety
markedly increase antibacterial activity against G+ve,
G-ve , Mycoplasma and chlamydia..
Addition of a piperazine ring at position 7 on
fluoroquinolones increases tissue and bacterial
penetration and improves spectrum of activity to
include Pseudomonas ( e.g. Ciprofloxacin,
Enrofloxacin

8. Generations
Researchers divide the quinolones into generations based
on their antibacterial spectrum. The earlier-generation
agents are, in general, more narrow-spectrum than the
later ones, but no standard is employed to determine
which drug belongs to which generation. The only
universal standard applied is the grouping of the non
fluorinated drugs found within this class (quinolones)
within the 'first-generation' heading.

9. Classification of Quinolones
First-generation
cinoxacin
flumequine
nalidixic acid
oxolinic acid
piromidic acid
pipemidic acid
rosoxacin

10. Second-generation
The second-generation class is sometimes subdivided into "Class 1" and "Class
2".
Ciprofloxacin
enoxacin
fleroxacin
lomefloxacin
nadifloxacin
norfloxacin
ofloxacin (only as ophthalmic in the United States)
pefloxacin

11. Third-generation
Unlike the first- and second-generations, the third-generation is active against
streptococci.
balofloxacin
grepafloxacin
levofloxacin
pazufloxacin
sparfloxacin
temafloxacin
tosufloxacin

12. Fourth-generation
Fourth generation fluoroquinolones act at DNA gyrase and topoisomerase IV.
This dual action slows development of resistance.
clinafloxacin
gatifloxacin
gemifloxacin
moxifloxacin
sitafloxacin
trovafloxacin
Prulifloxacin
 In development
garenoxacin (Geninax)(application withdrawn due to toxicity)
delafloxacin

13. Antimicrobial effects of Quinolones
a.Broad spectrum
a. First-generation, G
-
aerobic bacteria;
b. Second-generation, more activity
against G
-
aerobic bacteria;
c. Third-generation, fluoroquinolones,
possess excellent G
-
activity & moderate to good
activity against G
+
bacteria, anaerobes,

14. Summary of antimicrobial spectrum of quinolones

15. Typical therapeutic applications of ciprofloxacin.

16. Mechanism of action
1.They block bacterial DNA synthesis by inhibiting
bacterial topoisomerase (
Ⅱ
DNA gyrase) and
topoisomerase .
Ⅳ
2. Inhibition of DNA gyrase prevents the relaxation of
positively supercoiled DNA that is required for normal
transcription and replication.
3.Inhibiton of topoisomerase probably interferes with
Ⅳ
separation of replicated chromosomal DNA into the
respective daughter cells during cell division.

18. Mechanism of action
4.The gyrase is composed of two A subunits and
two B subunits. The A subunits can cut one of
double strands of the DNA .This is an ATP-
dependent reaction. The energy is provided by B
units.

19. Mechanism of action
5.Quinolones is an inhibitor of A subunits.
Therefore, the action of gyrase is inhibited and
DNA replication or transcription is blocked as
result of the death of bacteria.
6. Novobiocin is an inhibitor of the B subunit of
DNA gyrase and is active mainly against G
+

bacteria.

20. Mechanism of action
Quinolones and fluoroquinolones, eradicates bacteria by interfering
with DNA replication.
 shown to be toxic to eukaryotes.
Recent evidence has shown eukaryotic topoisomerase II is also a
target for a variety of quinolone-based drugs. Thus far, most of the
compounds that show high activity against the eukaryotic type II
enzyme contain aromatic substituents at their C-7 positions.

21. Quinolones can enter cells easily via porins and,
therefore, are often used to treat intracellular pathogens
such as Legionella pneumophila and Mycoplasma
pneumoniae.
 For many Gram-negative bacteria, DNA gyrase is the
target, whereas topoisomerase IV is the target for many
Gram-positive bacteria.

23. Resistance to Quinolones
1. Due to
a.One or more point mutations in the quinolone
binding region of the target enzyme
b.A change in the permeability of the organism
2. DNA gyrase is the primary target in E coli, with single-
step mutants exhibiting amino acid substitution in the
A subunit of gyrase.
3. Topoisomerase is a secondary target in E coli that is
Ⅳ
altered in mutants expressing higher levels of
resistance.

24. Resistance to Quinolones
4. In staphylococci and streptococci, the situation is
reversed, topoisomerase is the primary target,
Ⅳ
and gyrase is the secondary target.
5. Resistance to one fluoroquinolone, particularly if
of high level, generally confers cross-resistance to
all other members of this class.

25. Pharmacokinetics of
Quinolones
a.Oral given, well absorbed, be impaired by divalent
cations, including those in antacids,
b.Distributed widely in body fluids and tissues, pass
placenta reach to the fetus,
c.Biotransformation of the drugs in the liver
d.Most eliminated by renal, either tubular secretion
or glomerular filtration.

26. Effect of dietary calcium on the absorption of
ciprofloxaxin

27. Clinical uses of Quinolones
1.Nalidixic acid is only second-line drug
treating urinary infection with gram-
negative bacilli (Bacillus coli, Bacillus
proteus , etc).
2.Pipemidic acid not only is used treating
infection of urinary tract but also treating
intestinal and biliary tract infection with
sensitive bacteria.

28. Clinical uses of Quinolones
3.Fluoroquinolones are extensively used treating
general infection.
a.urinary tract infections, even when
caused by multifrug-resistant bacteria,
b.Intestinal and biliary tract infections
c.Soft tissue infections
d.Bone, joint and in intra-abdominal
e.Respiratory tract infections

29. Clinical uses of Quinolones
Ciprofloxacin and ofloxacin are effective for
gonococcal infection, including disseminated
disease. They are occasionally used for
treatment of tuberculosis and atypical
mycobacterial infections. They are suitable for
eradication of meningococci from carriers.

30. Clinical uses of Quinolones
Ofloxacin is effective for chlamydial
urethritis or cervicitis.
Ciprofloxacin is a second-line agent for
legionellosis.
Levofloxacin, sparfloxacin are used for
treatment of upper and lower
respiratory tract infections.

31. Drug interactions with fluoroquinolones

32. Adverse effects of Quinolones
a.The most common effects are
nausea, vomiting, and diarrhea.
b.Headache, dizziness, insomnia, skin
rash, occasionally.
c.Liver toxicity is rarely for
trovafloxacin.
d.Photosensitivity occurs with
lomefloxacin and pefloxacin.

33. Adverse effects of Quinolones
e.Fluoroquinolones may damage
growing cartilage and cause an
arthropathy. They are not used in
patients under 18 years of age. The
arthropathy is reversible. Since
fluoroquinolones are excreted in
breast milk, they are contraindicated
for nursing mothers.