**Pharmacology: Lesson 6: Quinolone Antibacterial Drugs**

1. Potent Effects of Quinolones:

• Strong Effect on Aerobic Gram-Negative Bacteria: Quinolones are highly effective against aerobic Gram-negative bacteria, including E. coli, Klebsiella, Pseudomonas aeruginosa, Salmonella, Shigella, and many others.

2. Mechanism of Action of Quinolone Drugs:

• Inhibition of DNA Gyrase: Quinolones are potent inhibitors of DNA gyrase. DNA gyrase is an essential enzyme involved in DNA replication and transcription in bacteria. When DNA gyrase is inhibited, bacteria cannot replicate and multiply, leading to the inhibition of growth and destruction of bacteria.

• Inhibition of Topoisomerase (at high concentrations 100-1000 times): Quinolones can also inhibit topoisomerase at higher concentrations. Topoisomerase is an enzyme involved in regulating DNA structure and repairing damaged DNA.

3. Differences Between Quinolone Generations:

• Quinolone Generation 2 differs from Quinolone Generation 1 mainly in terms of position:

• Position 7: Increased amount of fluoro substituents, which increases antibacterial activity and half-life in the body.

• Positions 1, 8: Ring modification, which broadens the antibacterial spectrum.

• Characteristics of Quinolone Generation I compared to Generation II:

• Does not contain F (fluoro).

• Poor absorption, more metabolism.

• Narrow antibacterial spectrum: primarily against intestinal and urinary tract bacteria.

• Antibacterial Spectrum of Quinolone Generation II compared to Generation I: The antibacterial spectrum of Quinolone Generation II is broader, including Gram-positive bacteria.

4. Substituents on the Quinolone Ring:

• Position 1:

• Short alkyl substituents: Increase antibacterial activity.

• Position 2: Reduce or abolish activity.

• Position 3: Must be COOH (carboxylic acid).

• Position 4: The CO group must not be changed.

• Both positions 3 and 4 contribute to the main effect and side effects of quinolones.

• Positions 5, 6: Substitutions at positions 5 and 6 reduce antibacterial activity, but they can still create an effect if both positions are within the same ring.

• Position 6:

• Increased effect: F (fluoro), heterocycle.

• Reduced effect: Bulky groups.

• Position 7:

• Increased half-life: N-CH3 (methylamino).

• Reduced effect: Substitution with a piperazinyl group, except for the case where the piperazinyl group substitution provides a good effect on Pseudomonas aeruginosa.

• Position 8: Substitution with F (fluoro) provides a good effect.

5. Chemical Properties of Quinolones:

• Quinolones are organic bases.

• Quinolones are alkaloids: they precipitate with alkaloid reagents.

• Quinolones form chelates with metal ions.

• Quinolones have a C=O group: they react with sodium nitroprusside to give a red-purple color.

6. Some Common Quinolones and Their Effects:

• Fluoroquinolones: Broad antibacterial spectrum.

• Lomefloxacin, fleroxacin: Longest half-life.

• Ofloxacin: Excreted mostly unchanged through the kidneys.

• Strongest inhibition of Staphylococcus aureus.

• Enoxacin: Most significantly inhibits drug metabolism in the liver.

7. Drug Interactions:

• Oral medications taken together reduce the bioavailability of fluoroquinolones by 90%:

• Antacids.

• Iron-containing medications.

• Multivitamins.

• Sucralfate (Al3+).

• Didanosine.

• Reason: Quinolones bind to cations, reducing absorption into the body.

• Ciprofloxacin:

• Effective against most Gram-negative bacteria, including typhoid bacteria.

• Effective against Gram-positive bacteria except for Staphylococcus aureus and Streptococcus pneumoniae.

• Noteworthy side effects:

• Nervous system: dizziness, nausea, headache.

• Cartilage damage: particularly in children and the elderly.

• Photosensitivity.

• Drug interactions:

• Interaction with caffeine, theophylline: Reduces liver detoxification of caffeine and theophylline.

• Interaction with diazepam: Reduces metabolism, increasing the half-life of diazepam.

• Ofloxacin:

• Used to treat mild urinary tract infections, prostatitis, respiratory and skin infections, gonorrhea, chlamydia.

• The levorotatory isomer (levofloxacin) is more potent.

• Sparfloxacin:

• Indicated for pneumonia and severe infections in chronic bronchitis.

• Effective against Gram-positive bacteria sensitive to ciprofloxacin, methicillin-sensitive staphylococci.

• Ofloxacin: Used as eye drops.

• Flumequine: Quinolone transitional between Generation 1 and 2.

8. Notes:

• Quinolones can cause serious adverse reactions such as cartilage damage, photosensitivity, and mental disorders.

• Quinolones should not be used in children, pregnant women, or breastfeeding mothers.

• Use quinolones as directed by a doctor.

• Inform your doctor about any medications you are currently taking to avoid drug interactions.