Quinolones Chemische Eigenschaften,Einsatz,Produktion Methoden
Beschreibung
The quinolone antimicrobials comprise a group of synthetic substances possessing in common an
N-1-alkylated 3-carboxypyrid-4-one ring fused to another aromatic ring, which itself carries other
substituents. The first quinolone to be marketed (in 1965) was nalidixic acid. Nalidixic acid and cinoxacin are
classified as first-generation quinolones based on their spectrum of activity and pharmacokinetic properties.
While still available, they are considered to be minor urinary tract disinfectants that are effective primarily
against certain susceptible Gram-negative bacteria. Thus, the quinolones were of little clinical significance
until the discovery that the addition of a fluoro group to the 6-position of the basic nucleus greatly increased
the biological activity.
Acquired resistance
Resistance to the quinolones is becoming more frequent and is associated with spontaneous mutations in
two genes (gyrA and gyrB) that encode for the quinolone target protein, DNA gyrase. A single step mutation
can lead to low-level resistance, whereas mutations in both genes lead to high-level resistance. This
mechanism of resistance would be expected to produce cross-resistance within the class of quinolones. In addition, there are suggestions that resistance may be associated with an increase in drug efflux or a
decrease in outer membrane permeability affecting drug influx. Such a mechanism of resistance would be
expected to be more common in Gram-negative organisms with a more complex cell wall than in
Gram-positive organisms with its cell envelope.
Pharmazeutische Anwendungen
The pyridone-b-carboxylic acid derivatives or quinolones comprise a large and expanding number of synthetic compounds. Since the first analog, nalidixic acid, was synthesized in 1962, many types have been reported based on a few common structures: most are 1,8 naphthyridone or quinoline derivatives.
Changes to various parts of the molecules confer different properties and this is the basis of the variation in activity of various members of the group.
The first 4-quinolone, nalidixic acid, is a 1,8-naphthyridinone with a narrow spectrum of activity, chiefly against Enterobacteriaceae. Several compounds with improved antibacterial activity were subsequently synthesized. These included pipemidic acid, which expanded the spectrum to include weak activity against Pseudomonas aeruginosa, and piromidic acid, which exhibited useful activity against Staphylococcus aureus. Further development led to the discovery in the late 1970s of fluorine-substituted derivatives with much enhanced intrinsic activity against both organisms, a group now known as the fluoroquinolones. Numerous fluoroquinolones with altered
pharmacokinetic properties and additional improvements in spectrum, including in some cases useful activity against Mycobacterium tuberculosis and M. leprae, became available in the next 30 years. Current research efforts are directed to overcome problems of
resistance, which is increasingly encountered in both Gram-positive and Gram-negative bacteria.
Mechanism of action
The quinolones are rapidly bactericidal, largely as a consequence of inhibition of DNA gyrase and
topoisomerase IV, key bacterial enzymes that dictate the conformation of DNA. The Escheri chi a coli
chromosome is a single, circular molecule of approximately 1 mm in length, whereas the cell is only 1 to 3
μm long. Thus, the DNA molecule must be dramatically compacted in a conformationally stable way so that it can fit. Using the energy generated by adenosine triphosphate (ATP) hydrolysis, the molecule is
progressively wound about itself in a positive super coil.
Pharmakokinetik
The fluoroquinolones are well absorbed following oral administration, with excellent bioavailability. The
maximum plasma concentration usually is reached within a few hours, and the drugs are moderately bound to
plasma protein, leading to comparatively long half-lives. Earlier quinolones were rapidly
excreted into the urine, which limited their therapeutic application to urinary tract infections, whereas the
newer drugs are distributed to alveolar macrophages, bronchial mucosa, epithelial lining fluid, and saliva,
improving the use in various systemic infections. Several studies have suggested that the ratio of mean peak
plasma concentration to MIC and the 24-hour area under the curve to MIC may correlate with therapeutic
outcomes. If this proves to be true, it could greatly help the clinician in choosing the appropriate drug and
dosing schedule.
Clinical Use
The quinolones therapeutically fall into one of four classifications. The specific drugs within
each classification include nalidixic acid and cinoxin as first-generation agents, with utility limited to
uncomplicated urinary tract infections. The second-generation quinolones include norfloxacin, lomefloxacin,
enoxacin, ofloxacin, and ciprofloxacin. Whereas norfloxacin is used mainly for urinary tract infections (Enterobacter sp., Enterococcus sp., or Pseudomonas aerugi nosa), ciprofloxacin also is used for prostatitis,
upper respiratory tract infections, bone infections, septicemia, staphylococcal and pseudomonal
endocarditis, meningitis, sexually transmitted diseases (gonorrhea and chlamydia), chronic ear infections,
and purulent osteoarthritis.
Nebenwirkungen
The quinolone class is associated with more side effects than the β-lactam and macrolide classes but,
nonetheless, see very widespread medicinal use.
Among the side effects associated with quinolones is a proconvulsant action, especially in epileptics, but
this is mainly associated with the first-generation agents. Other CNS problems include hallucinations,
insomnia, and visual disturbances. Some patients also experience diarrhea, vomiting, abdominal pain, and
anorexia. These effects are most common with trovafloxacin. The quinolones are associated with erosion of
the load-bearing joints of young animals.
Quinolones Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
