6 Quinolones

Quinolones, Folic Acid Antagonists
and Urinary Tract Antiseptics
Lec. 6
Assistant. Prof. Dr. Inssaf IH. Al-Shemmary

1. Fluoroquinolones (DNA Gyrase Inhibitors)
Classification of the Fluoroquinolones
1. First generation (Nalidixic acid): It's non –fluorinated quinolone
with a narrw spectrum, has a moderate activity against gram –ve
usually confined to the urinary tract.
2. Second generation (Ciprofloxacin, Norfloxacin, Ofloxacin):They

have activity against systemic aerobic gram –ve infections, and gram
+ve and atypical organisms such as Chlamydia, Mycoplasma
3. Third generation (Levofloxacin, Gatifloxacin, Sparfloxacin):These

agents retain expanded gram –ve activity and improved activity
against atypical organisms and specific gram +ve bacteria.
4. Fourth generation (moxifloxacin): This agent act against gram +ve,

gram –ve and anaerobic organisms.
Mechanism of Action
The fluoroquinolones enter the bacterium by passive diffusion
through water-filled protein channels (porins) in the outer
membrane. Once inside the cell, they inhibit the replication of
bacterial DNA by interfering with the action of DNA gyrase
(topoisomerase II) and topoisomerase IV during bacterial growth
and reproduction. Binding of the quinolone to both enzyme and the
DNA forms a ternary complex that inhibits the resealing step, and
can cause cell death.
Clinical uses of Ciprofloxacin

1. urinary tract infections even when caused with multi resistant
bacteria such as Pseudomonas.
2. Bacterial diarrhea caused by E. coli and other bacteria.
3. Typhoid fever.
4. Resistant TB.
5. Eradication of Meningococci from carriers.
6. Prophylaxis and treatment of Anthrax.
7. Resistant Respiratory infections (not pneumonia or sinusitis).
8. Pseudomonal infections associated with cystic fibrosis.
Pharmacokinetics
Fluoroquinolones are administered orally, IV. Ingestion of the
drugs with sucralfate, antacids or dietary supplements containing
iron or zinc can interfere with the absorption of these antibacterial
drugs. All the fluoroquinolones distribute well into all tissues and
body fluids. They are excreted by the renal route.
Adverse effects
1. GIT disorders: The most common adverse effects of the
fluoroquinolones are nausea, vomiting, and diarrhea.
2. CNS problems: headache and dizziness.
3. Phototoxicity: Patients taking fluoroquinolones are advised to
avoid excessive sunlight and to apply sunscreens.
Contraindications: Moxifloxacin may prolong the QT interval
and, thus, should not be used in patients who are predisposed to
arrhythmias. Also should be avoided in pregnancy, in nursing
mothers, and in children under 18 years of age,
Drug interactions: interfere with antacids. Ciprofloxacin
can increase the serum levels of theophylline by inhibiting its
metabolism.
2. Folic Acid Antagonists
Folic Acid Antagonists (sulfonamides, trimethoprim)
Sulfonamides
Sulfa drugs differ from each other by chemical, physical
properties and pharmacokinetics. Sulfa drugs are bacteriostatic.
Mechanism of Action
In many microorganisms, folic acid is synthesized from p-
aminobenzoic acid (PABA), pteridine, and glutamate. All the
sulfonamides currently in clinical use are synthetic analogs of PABA.
Because of their structural similarity to PABA, the sulfonamides
compete with this substrate for the bacterial enzyme, dihydropteroate
synthetase. They thus inhibit the synthesis of bacterial folic acid, in
turn inhibit synthesis of purines and pyrimidine ,result in inhibit
synthesis of DNA.
Actions of sulfonamides and trimethoprim.
Antibacterial spectrum
Sulfa drugs are active against selected enterobacteria in
the urinary tract, toxoplasmosis and chloroquine-resistant
malaria, streptococci, staphylococci.
Resistance
Resistance is generally irreversible and may be due to
1. An altered dihydropteroate synthetase.
2. Decreased cellular permeability to sulfa drugs.
3. Enhanced production of the natural substrate.
Classification of Sulfonamides
Sulfonamides can be divided into three major groups:
1. Oral absorbable: The oral absorbable sulfonamides can be
classified on the basis of their half-lives to:
a. Short acting: e.g. sulfisoxazole.
b. Intermediate acting: e.g.Sulfadiazine, sulfamethoxazole.
c. Long acting: e.g. sulfadoxine
2. Oral nonabsorbable: e.g. Sulfasalazine
3. Topical: e.g. Sodium sulfacetamide.

Pharmacokinetics
1. Administration: After oral administration (absorbable), most
sulfa drugs are well absorbed via the small intestine. Oral
nonabsorbable Agents (Sulfasalazine), It is not absorbed when
administered orally or as a suppository and, therefore, used for
treatment of chronic inflammatory bowel disease (Crohn's disease
or ulcerative colitis). Topical Agents (Sodium sulfacetamide) as
ophthalmic solution or ointment is effective in the treatment of
bacterial infection.
2. Distribution: They are distributed widely to tissues and body

fluids. They can also pass the CNS, placenta and enter fetal
tissues.
3. Metabolism: The sulfa drugs are acetylated, primarily in the
liver. The product is devoid of antimicrobial activity but retains the
toxic potential to precipitate at neutral or acidic pH. This causes
crystalluria (stone formation) and, therefore, potential damage to
the kidney.
4. Excretion: Sulfa drugs are eliminated by glomerular filtration.
Adverse effects
1. Crystalluria: Nephrotoxicity develops as a result of
crystalluria. Adequate hydration and alkalinization of urine
prevent the problem by reducing the concentration of drug and
promoting its ionization.
2. Hypersensitivity: Hypersensitivity reactions, such as rashes,
angioedema.
3. Hemopoietic disturbances: Hemolytic anemia, Granulocytopenia
and thrombocytopenia.
4. Kernicterus: This disorder may occur in newborns, because sulfa
drugs displace bilirubin from binding sites on serum albumin. The
bilirubin is then free to pass into the CNS because the baby's blood-
brain barrier is not fully developed.
Contraindications: Due to the danger of kernicterus, sulfa drugs

should be avoided in newborns and infants less than 2 months of age
as well as in pregnant women.
Trimethoprim
Trimethoprim is a potent inhibitor of bacterial dihydrofolate
reductase.
Mechanism of Action
The active form of folate is the tetrahydrofolate acid (THFA) that is
formed through reduction of dihydrofolic acid by dihydrofolate
reductase. This enzymatic reaction is inhibited by trimethoprim,
leading to a decreased availability of the THFA coenzymes required for
purine, pyrimidine, and amino acid synthesis.
Antibacterial spectrum: similar to sulfa drug.

Pharmacokinetics
Because the drug is a weak base, higher concentrations of trimethoprim
are achieved in the relatively acidic prostatic and vaginal fluids. The
drug also penetrates the CSF.
Adverse Effects
megaloblastic anemia, granulocytopenia.
Cotrimoxazole
The combination of trimethoprim with sulfamethoxazole (ratio 1:5)
is called cotrimoxazole. The synergistic antimicrobial activity
result from its inhibition of two sequential steps in the synthesis of
THFA.
3. Urinary Tract Antiseptics/Antimicrobials

urinary tract antiseptics, including (methenamine, nitrofurantoin,
quinolone nalidixic acid). These drugs do not achieve antibacterial
levels in the circulation, but they are concentrated in the urine,
microorganisms at that site can be effectively eradicated.

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Quinolones, Folic Acid Antagonists

and Urinary Tract Antiseptics

Assistant. Prof. Dr. Inssaf IH. Al-Shemmary

2. Second generation (Ciprofloxacin, Norfloxacin, Ofloxacin):They

3. Third generation (Levofloxacin, Gatifloxacin, Sparfloxacin):These

4. Fourth generation (moxifloxacin): This agent act against gram +ve,

Clinical uses of Ciprofloxacin

2. Oral nonabsorbable: e.g. Sulfasalazine

3. Topical: e.g. Sodium sulfacetamide.

2. Distribution: They are distributed widely to tissues and body

Contraindications: Due to the danger of kernicterus, sulfa drugs

Antibacterial spectrum: similar to sulfa drug.

3. Urinary Tract Antiseptics/Antimicrobials

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