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Pharma + > Quinolones > Flashcards

Quinolones Flashcards

1
Q

Intro

A

A. Aminoquinolines: e.g. chloroquine, primaquine (antimalarial drugs – see under antiprotozoals)
B. Hydroxy-(Halogenated-)quinolines: e.g. chlorquinaldole
C. Isoquinoline derivatives (e.g. papaverine, praziquantel)
D. Quinolone carboxilic acids Quinolone carboxylic acid derivatives are synthetic antimicrobial agents.

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2
Q

STRUCTURE EFFECT RELATIONSHIP

A

Antibacterial effect:
3. position: carboxyl attaching to
4. position: ketone site of action
Broader spectrum:
6. position: fluor
1. position: cyclopropyl, ethyl, fluorophenyl
5. position: NH2, CH3, fluor
7. position: piperazine, diazabicyclonil
8. position: fluor, methoxi, CIANO (8-ciano-quinolones)

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3
Q
  1. generation quinolones (4-quinolones)
A

Nalidixic acid, Oxolinic acid, Cinoxacin
Narrow spectrum; Gram-negatives, enteric bacteria =>moderate
SC, IM
Obsolete, for non-complicated UTI (rapid elimination via urine)

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4
Q
    1. generation fluoroquinolones
A 
Flumequine, Norfloxacin
Sus, Av=> GI, resp, UTI
\+ fish Aeromonas
Wider spectrum; Gram-negatives, enteric bacteria=> good
PO (not with food), SC, IM
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5
Q
    1. generation fluoroquinolones
A 
Pefloxacin, 
Ciprofloxacin,-Hu
Ofloxacin, 
Danofloxacin, -Lactating cows, Sus
Difloxacin, - dog, Bo (not PO) + Eq
Enrofloxacin, -Lactating cows, Sus, Poultry, SA+ Eq
Ibafloxacin, - SA, only PO
Marbofloxacin, - LA (not PO), SA + Eq
Orbifloxacin, -SA (only PO)
Sarafloxacin

PO (not with food), SC, IM
Wide spectrum, mainly fastidious G(-)
Gram-negatives => pronounced
P. aeruginosa => pronounced (mainly ciprofloxacin)
Gram-positives => moderate (Staph + Mycobacterium)
Intracellular pathogens => good
+ Mycoplasma, Chlamydia, Staph
Primarily resistant: obligate anaerobic bacteria, streptococci, enterococci

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6
Q
  1. generation fluoroquinolones (mainly Hu)
A

Balofloxacin,
Levofloxacin,
Sparfloxacin,
Temafloxacin,

PO, SC, IM
Gram-positives => good-pronounced 
Gram-negatives => good-pronounced 
P. aeruginosa => good-pronounced 
Intracellular  pathogens => pronounced
Same as Gen 2.2 + STREP
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7
Q
  1. generation fluoroquinolones (mainly Hu)
A 
Gatifloxacin,
Gemifloxacin, 
Moxifloxacin, 
Trovafloxacin, 
Pradofloxacin- SA (only PO)
Gram-positives => pronounced 
Gram-negatives => good-pronounced 
P. aeruginosa => good-pronounced 
Anaerobes => good-pronounced 
Intracellular pathogens => pronounced
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8
Q

MODE OF ACTION

A

BACTERICIDAL concentration-dependent! + Post-Antibacterial Effect /PAE/ 2-5 hrs.

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9
Q

RESISTANCE

A

Significant! Antimicrobial Advice Ad Hoc Expert Group (AMEG) B category
Chromosomal mutation. Its developing is relatively fast, when drugs are used „heavily”,
• Changes in gyrase A gene (gyr-A) resistance against 1st gen.
• Changes in both gyrase A and B gene (gyr-A, gyr-B) ) full resistance.
Frequent in zoonotic E. coli, Salmonella and Campylobacter strains.
- Chromosomal resistance stays for a long time
Other mechanisms:
• Membrane proteins (inhibited penetration)
• Increased bacterial efflux (membrane-proteins actively pump the drug out from bacteria) Cross resistance is complete within the groups (generations)! limitations?
Plasmid mediated resistance mechanism (qnr-gene) - recent
• reduced susceptibility (Enterobacteriaceae) – significance

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10
Q

PHARMACOKINETICS 1.

A

Absorption
-(except 1st generation) Excellent absorption PO (food – delays time to peak), good bioavailability in monogastric species (very poor in adult cattle).
-Divalent or trivalent cations (e.g. Ca, Fe, Mg, Zn or Al) may reduce the absorption.
- SC., IM. good absorption
• Distribution - (except 1st generation)
- Excellent, very high Vd. High concentrations in bile, urine, prostate. Quinolones appear in milk.
- Good penetration through special barriers (CSF, ocular fluids)!
- Concentrated within phagocytic cells (reduction of survival of intracellular pathogens).

• Metabolism
- Partially metabolised (1st generation more complete).
- Metabolites may also be active. e.g. Enrofloxacin → Ciprofloxacin (deethylation of the ethyl group on the piperazine ring)
• Elimination
- Mainly via kidneys (tubular secretion) as active drug, partially with bile (e.g. inactive glucuronide ester).
- Enterohepatic recirculation, reduction of metabolite by gut-bacteria&raquo_space;> prolonged action
- In active form – urinary tract infections: E. coli, Klebsiella spp., Proteus spp., Pseudomonas spp. Staphylococcus spp.

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11
Q

Safety

A

-majority safe, 1st gen more toxic
• Long lasting administration and/or too large doses may increase the possibility of unwanted side-effects.
• During the administration of fluoroquinolones the risk-benefit ratio has to be considered
• Recent FQs are neither mutagenic nor teratogenic.
• Can decrease CYP3A- and CYP1A-mediated biotransformation by competitive inhibition

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12
Q

SIDE EFFECTS

A

Inhibition of load-bearing cartilage development (young animals & horses! )

  • Retinopathy (Fe!) leading to blindness (higher doses, enrofloxacin)
  • CNS-signs (Epilepsy! Quinolones may pre-dispose the seizure activity)
  • Dysbacteriosis (horses)
  • Others (observed mainly in human beings)
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13
Q

FLUOROQUINOLONES are synergistic with

A
  • betalactams
  • aminoglycosides
  • Vancomycin
    e.g. Staphylococcus aureus (Ciprofloxacin + Azlocillin; Levofloxacin + Oxacillin)
    Pseudomonas aeruginosa (Ciprofloxacin + Imipenem or Azlocillin or Amikacin)
    Enterococci (Ciprofloxacin + Imipenem or Ampicillin or Vancomycin)
    Expanded antibacterial spectrum with Metronidazole.
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14
Q

ANTAGONISTIC INTERACTIONS (Ciprofloxacin with):

A
  • Chloramphenicol - Rifampin
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15
Q

INTERACTIONS 2.

A
  • May increase anticoagulant effects of Warfarin
  • May increase Caffeine & Theophylline levels (liver)
  • May increase Cyclosporine levels
  • May prolong QTc if used concomitantly with antiarrhythmics (e.g., class IA and III agents) or with Cisapride
  • May increase risk of CNS stimulation and convulsions if used with NSAIDs
  • May lead to hypoglycaemia and/or hyperglycemias if used concomitantly with oral hypoglycemics or insulin
  • Gatifloxacin; increased serum Digoxin levels
  • Probenicid may increase Ciprofloxacin levels (kidney)
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16
Q

CLINICAL USAGE (INDICATIONS)

A
  • Urinary tract infections
  • Gastrointestinal infections (resistance!) 1st only
  • Respiratory infections
  • Mycoplasmosis!
  • Soft tissue infections, pyoderma
  • Osteomyelitis
  • Prostatitis
  • Eye infections
  • Gingivitis, periodontitis
  • Meningitis, meningoencephalitis
17
Q

HYDROXYQUINOLINES

A

A group of synthetic compounds: Chloroquine Iodochlorhydroxyquin , Diiodohydroxyquin (iodoquinol), Chlorquinaldole Broxyquinoline Hydroxyquinoline

  • Form complexes with Fe-ions
  • Antibacterial (Gram+), antifungal, antiprotozoal
  • Poorly absorbed from GI (30-40%), glucuronide conjugate is extracted via kidneys.
  • For intestinal infections caused by bacteria/ protozoa (i.e Giardia, Amoebae).
  • Topically for skin infections caused by bacteria & fungi
  • Potentially neurotoxic when used for prolonged periods.
18
Q

NITROFURANS 1

A

Nitrofurantoin, Furazolidone

bright yellow-brownish substances
-bactericidal
Nitrofuran-reductase=> toxic metabolite, destroys DNA, ribosome
- Relatively broad-spectrum, mainly Gram(-), coliforms, Salmonella spp. Mycoplasma spp., Coccidia spp. and some other protozoa. ( not Proteus, Pseudomonas spp.)

19
Q

NITROFURANS 2

A

-well absorbed, furasolidone is decomposed by liver, quick excretion w/urine in active form (nitrofurantoin), The blood and tissue levels are usually too low
- Indications:
• Enteral infections (furasolidone)
• UTIs (dogs and cats) (nitrofurantoin)
• Topical (skin-) formulation
- Toxicity: low TI, toxic drugs - GI-irritation, Neurotoxicity, inhibition of BM. - Mutagenic, potentially carcinogenic (oxidative DNA damage) not intended for food producing animals.

20
Q

NITROIMIDAZOLES 1.

A

Metronidazole
Ronidazole /Dimetridazole,
Ipronidazole,
Tinidazole

In anaerobic conditions toxic metabolites (non-enzymatic reduction of the nitro group) destroy the DNA of bacteria or protozoa.

  • Spectrum: relatively narrow antibacterial spectrum, Obligate anaerobic bacteria!!
    Clostridium spp. Bacteroides spp. Fusobacterium spp. Brachyspira hyodysenteriae
    Protozoa!
    Trichomonas spp. Histomonas spp. Giardia spp. Amoeba spp.
21
Q

NITROIMIDAZOLES 2.

A
  • Kinetics: excellent absorption & tissue penetration to abscesses, BM, CSF, prostate, etc.
  • Metabolisation in liver (30%) oxidation (active metabolites) + glucuronid conjugates (inactive). - Elimination via kidneys.
  • Indications:
    • gingivitis, parodontitis, oral cavity infections
    • anal sacculitis
    • pseudomembranous colitis! (Cl. difficile, Cl. perfringens) (other antibiotics)
    •trichomonosis gardiosis! & histomonosis (treatment of blackhead, not anymore in turkeys)
    • Banned for Swine dysentery prevention ↔Table 2 !
22
Q

QUINOXALINES 1.

A

Carbadox,
Olaquindox

• Mode of action: Bactericidal
• Mechanism of action: transient reactive metabolites are formed => they destroy bacterial DNA (action is more pronounced under anaerobic condition)
• Sensitive microbes; mainly Gram- bacteria (E. coli, Proteus vulgaris, Pasteurella multocida, Salmonellas). Among Gram+ Clostiridia are highly sensitive + some strains of Strepto-, & Staphylococci, Chlamydia spp., Brachyspira hyodysenteriae, Protozoas
• Resistance in E.coli, R-plasmid mediated
• Indications: Porcine patients (pigs and hogs)*
- Feed additive 10-20 ppm (growth promotional effect)
- Prevention (treatment) of swine dysentery
*Not intended to use in food producing animals in EU & Canada

23
Q

QUINOXALINES 2.

A
  • Kinetics: absorption fast, near complete. Tmax within 1-2 hour. Extended distribution among the organs, large Vd. Elimination mainly via urine.
  • *Metabolites, types; short-living (transient), final! metabolites eliminate slowly (after 4-5 weeks)
  • Toxicity: low TI, toxic drugs (Carbadox more), Time and dose dependent inhibition of adrenal gland (zona glomerulosa). Decline in plasma aldosterone levels (hypoaldosteronism) at 2x higher dose or prolonged use.
  • *Mutagenic (genotoxic) effect. Carbadox is a known, Olaquindox is a possible carcinogenic (DNA damage) (MRL is not available for them, they are not in Table 1 or 2

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