QUINOLOES DIVYA KALE PPT

1. QUINOLONES
BY
DIVYA G. KALE
VIDYABHARTI COLLEGE OF PHARMACY
AMRAVATI

2. CONTENTS
 Introduction
 History
 Classification
 Mechanism of action
 Resistance
 Pharmacokinetics
 Uses
 Adverse effects
 Interaction

3. INTRODUCTION
 The quinolones are a family of synthetic ,broad spectrum antibiotic
with bactericidal activity.
 The term quinolones refers to potent synthetic chemotherapeutic
antibacterial agent.

4. 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

5. CLASSIFICATION
 Quinolones (1st generation)
Highly protein bound
Mostly used in UTI
 Fluoroquinolones (2nd ,3rd ,4th generation)
Modified 1st generation quinlones
Not highly protein bound
Wide distribution to urine and other tissues
Limited CSF penetration

6. CLASSIFICATION

7. 1st Generation Quinolones
 The first –generation agents include cinoxacin and nalidixic acid ,which are
the oldest and least often used quinolones.
 Because minimal serum levels are achieved ,use of these drug has been
restricted to the treatment of uncomplicated urinary tract infections .
 They are some susceptible to the development of bacterial resistance.
 These agents are not recommended for use in patients with poor renal
function because of significantly decreased urine concentrations.

8. 2nd Generation Quinolones
 The second generation quinolones have increased gram negative activity , as
well as some gram positive and atypical pathogen coverage .
 Compared with first generation drugs ,these agents have broader clinical
applications in the treatment of complicated urinary tract infections and
pyelonephritis , sexually transmitted diseases, selected pneunomonies and
skin infections
 They include ciprofloxacin , lomefloxcin , norfloxacin ,ofloxacin ,and
enoxacin
 Ciprofloxicin and ofloxacin are most widely used because of their avalibility in
oral and intravenous formulations.

9. 3rd Generation Quinolones
 The third- generation quinolones currently include levofloxacin, gatifloxacin
,moxifloxacin and sparfloxacin .
 These agents are separated into a third class because of their expanded
activity against gram positive organisms ,particularly penicillin-sensitive and
penicillin –resistant S. pneumoniae ,and atypical pathogens such as
mycoplasma pneumoniae and chlamydia pneumoniae .
 Although the third generation quinolones retain broad gram negative
coverage ,they are less active than ciprofloxacin against pseudomonas species

10.  Because of their expanded antimicrobial spectrum,they are useful in the
treatment of community acquired pneumonia ,acute sinusitis and acute
exacerbations of chronic bronchitis.
 The FDA recommends that all of these drugs should be avoided in patients
who are taking drugs that are known to prolong the QT interval , such as
tricyclic antidepressants, phenothiazines and class I antiarrhythmics. In
contrast , levofloxacin does not affect the QT interval .

11. 4th Generation Quinolones
 Trovafloxacin , the current member of the fourth generation class ,adds
significant antimicrobial activity against anaerobes while maintaining the
gram positive and gram negative actitivty of the third generation quinolones
.It also retains activity against pseudomonas species comparable to that of
ciprofloxacin .
 Because of concern about hepatotoxicity ,trovafloxacin therapy should be
reserved for life or limb – threatening infections requiring inpatient treatment
and the drug should be taken for no longer than 14 days .

12. In Development
 Delafloxacin (developmental code name RX-3341) is a fluoroquinolone
antibiotic being developed .
 It is more active than other quinolones against Gram –Positive bacteria.
 Phase II clinical trials have been completed and phase III trial for ACUTE
BACTERIAL SKIN AND AKIN STRUCTURE INFECTIONS (ABSSSI) is due to begin .

13. FLUOROQUINOLONES

14. FLUOROQUINOLONES
 The fluoroquinolones are a relatively new group of antibiotics .
 They were first introduced in 1986 ,but they are really modified quinolones ,a
class of antibiotics ,whose accidental discovery occured in the early 1960s .

15. MECHANISM OF ACTION

16. Mechanism of action
 It blocks bacterial DNA synthesis by
Inhibition of bacterial Topoisomerase II (DNA Gyrase )
Inhibition of Topoisomerase IV
Inhibition of ATP dependent DNA gyrase ;which nicks double stranded DNA,
introduces negative supercoils and then reseals the nicked ends .This is required
to prevent excessive positive supercoiling of DNA strands when they separate to
permit replication or transcription.

17.  Inhibition of DNA gyrase also prevents the relaxation of posititvely supercoiled
DNA .
 Inhibition of DNA nicking –closing enzyme responsible for DNA enlongation
,which leads to break in double stranded DNA.
 Inhibition of topoisomerase IV interferes with the separation of replicated
chromosomal DNA into respective daughter cells during cell division .

18.  The critical imbalance in cellular metabolism resulting from the inhibition of
enzymes precipitates a sequence of cellular events which may lead to:
Premature cell division
Delayed cell division
Total failure of cell division leading to lysis of the cell

21. RESISTANCE
 Resistance appears to be the result of :
 Alteration in the quinolones enzymatic targets (DNA gyrase ) decreased outer
membrane permeability or the development of efflux mechansims .
 One or more point mutations in the quinolone binding regions of the target
enzymes ( Topoisomerase ) or from a change in the permeability of the
organism.

23. PHARMACOKINETICS
 Absorption : Well absorbed orally with bioavailability 80-90% Oral absorption
is impaired by divalent cations
 Distribution: Widely distributed in body fluids and tissues but limited CSF
penetration. It can pass the placenta reaching to the foetus
 Half life :3-8 hours in serum
 Elimination : 30-50% from urine by tubular secretion or glomerular filtration
and some amount in bile –faeces

24. USES
 RTI(Respiratory Tract Infection):
 EMPYEMA: The collection of pus in a cavity of the body ,especially in the
pleural cavity (the area between the lungs and the inner surface of the chest
wall )
 PNEUMONIA: Infection of the lungs that caused by bacteria , viruses , fungi or
parasites
 LUNG ABSCESS: Bacterial infection that occurs in the lung tissue causing tissue
to die and pus to collect in that space
 MENINGITIS :Inflammation of the lining of the brain and spinal cord

25.  UTI (Urinary Tract Infection) :
 PYELONEPHRITIS: A type of urinary tract infection (UTI) that affects one or
both kidneys caused by a bacterium mainly Escherichia coli or virus infection.
It causes the kidneys to swell and may permanently damage them.
 EPIDIDYMITIS: Inflammation of the epididymis, a tube near the testicles that
stores and carries sperm in men
 PROSTATITIS: Inflammation of the prostate gland due to a urine infection in
men
 CYSTITIS: Inflammation of the bladder usually caused by a urine infection in
women

26.  GIT (Gastro Intestinal Tract) infection :
ENTERIC FEVER : A potentially fatal multisystemic illness caused primarily by
Salmonella species
BACTERIAL DIARRHOEA : Cause by Campylobacter, salmonellae, and shigella
organisms
 Skin & soft tissue infections :
INFECTED ULCERS: Shallow wound that develops on the skin.
INFECTED BURNS: Red coloured and warm to touch due to an infection

27.  GONORRHEA : A venereal disease involving inflammatory discharge from the
urethra or vagina.
 CHANCROID: Bacterial infection that causes open sores on or around the
genitals of men and women
 TUBERCULOSIS: Infectious bacterial disease characterized by the growth of
nodules (tubercles) in the tissues, especially the lungs
 CONJUCTIVITIS: Inflammation of the outermost layer of the white part of the
eye and the inner surface of the eyelid

29. ADVERSE EFFECTS
 CNS (Central Nervous System)
 Quinolones may displace the neuro inhibitor GABA, resulting in CNS
stimulation
 Dizziness
 Headache
 Insomnia
 Restlessness
 Phototoxicity
 Skin damage after exposure to UV light due to toxic reactions.
 These included second-degree burns, discoloration and sometimes permanent
discoloration and scarring of the skin.

30. Cardiac Toxicity
 Torsades de pointe:
 paroxysm of ventricular tachycardia in which the electrocardiogram shows a
steady undulation in the QRS axis in runs of 5 to 20 beats with progessive
changes in direction. It is a most severe type of arythmia and can result in
death. It is most often associated with and preceeded by a prolongation of
the QT interval.

31. Gastrointestinal
 Depletion of magnesium and disruption of cellular enzyme function
 Disruption of mitochondrial function and energy production
 Other common side effects are:
Nausea
Vomiting
Anorexia
Diarrhea

32. INTERACTIONS
 NSAIDS:
Enhance the CNS toxicity of quinolones
 Theophylline, Caffeine or Warfrine
Plasma concentration is increased by Ciprofloxacin
 Antacid or Iron salts
Reduce the absorption of quinolones

33. CIPROFLOXACIN
 2nd generation fluoroquinolone
 Most potent fluoroquinolone against P. aeruginosa
 Not effective against Gram +ve and anaerobes
 Mainly effective against Gram –ve bacteria:
Enterobacteriacae
Campylobacter
Pseudomonas
 Intracellular Pathogen:
M. Tuberculosis
Chlamydia
Brucella

34.  CLINICAL USE:
 Urinary Tract Infections
 Travellers' diarrhoea
 Anthrax
 Diabetic foot infections
 UNIQUE QUALITIES:
 It binds to divalent cations which decreases absorption
 Because of its good penetration into bone, orally administered ciprofloxacin is
a useful alternative to parenterally administered antibiotics for the treatment
of osteomyelitis caused by susceptible organisms.

35. Marketed Preparations

37. LEVOFLOXACIN
 3rd generation fluoroquinolone
 Levo-isomer
 100% oral bioavailability
 Effective bacteria against Gram + ve and Gram- ve
 Also effective against Pathogen:
Legionella pneumophila
Atypical respiratory pathogens
Mycobacterium tuberculosis

38.  CLINICAL USE:
 Urinary tract infections
 Chronic bronchitis
 Nosocomial pneumonia
 Intra-abdominal infections
 UNIQUE QUALITY:
It binds to divalent cations which decreases absorption

40. References
 Monique Andersson and Alasdair MacGowan, Development of the quinolones
Journal of Antimicrob Cheratherapy (2003) 5t, Supot S 1-11001011/j/d212
 George Alcoy, Mechanams of Resistance to Quindies, Cocal Infectious
2005,415120-2005 by the infectious Dis Society of A
 David T. Bearden, Layer, Phim Mechanism of Action of and
 Het A, DO 30.039/2259) Moodyst, 2012. 2303-2311, Alteration of protein
cumples and pathways in genetic information Flow and some to stimulus
contribute to castan
 Michael A. Rohanski, Daniel J. Dwyer & James Coles Nature Reviews Microbial