1. Dr. Laila M. Matalqah Ph.D. Pharmacology
Antibacterial Inhibitors of Nucleic acid Function or Synthesis General Pharmacology M212
Dr. Laila M. Matalqah
Ph.D. Pharmacology

2. Inhibitors of Nucleic acid Synthesis Fluoroquinolones
MOA: Inhibit bacterial DNA synthesis by inhibiting:
DNA gyrase (topoisomerase II) in G- bacteria
DNA gyrase (topoisomerase IV) in G+ bacteria
Bactericidal - concentration-dependent killing.
Effective against G-ve organisms
Enterobacteriacea
Pseudomonas species,
H. influenzae, Moraxella catarrhalis, Legionellaceae,
chlamydia, and mycobacteria
Effective in the treatment of gonorrhea but not syphilis.
Activity against some anaerobes - sparfloxacin, gatifloxacin, and moxifloxacin.
They lower the incidence of postsurgical urinary tract infections (UTIs).
cross-resistance with other antimicrobial drugs
rare, but this is increasing in the case of multidrug-resistant organisms.

3. Generation Drug Names Spectrum
1st
nalidixic acid
Gram(-) but not Pseudomonas species
2nd
norfloxacin
ciprofloxacin
ofloxacin
Gram(-) (including Pseudomonas species), some Gram(+) (S. aureus) and some atypicals
3rd
levofloxacin
sparfloxacin
gemifloxacin
Same as 2nd generation with extended Gram(+) and atypical coverage
4th
moxifloxacin
Same as 3rd generation with broad anaerobic coverage
Trovafloxacin first designed as a novel therapeutic approach to MRSA infections but was withdrawn in 1999 due to liver toxicity and death

4. Fluoroquinolones Ciprofloxacin
Systemic infection, useful in treating infections caused by many Enterobacteriaceae and other G- bacilli.
An alternative to more toxic drugs (e.g. aminoglycosides).
Drug of choice for prophylaxis and treatment of anthrax.
Useful for Urinary tract infection (UTI)
The most potent of the fluoroquinolones for P.aeruginosa infections
in treating resistant tuberculosis
traveler's diarrhea caused by E. coli
C. Examples of clinically useful fluoroquinolones

5. Fluoroquinolones Norfloxacin Levofloxacin
Not effective in systemic infections.
Uses: complicated and uncomplicated UTIs and prostatitis.
Levofloxacin
Primarily used in the treatment of prostatitis due to E. coli
sexually transmitted gonorrhea diseases (excepting syphilis).
Very good activity against respiratory infections due to S. Pneumoniae.

6. Fluoroquinolones Moxifloxacin
It has enhanced activity against gram-positive organisms (for example, S. pneumoniae) and also has excellent activity against many anaerobes.
It has very poor activity against P. aeruginosa.
Moxifloxacin does not concentrate in urine and is not indicated for the treatment of UTIs.

7. Fluoroquinolones - PK Absorption:
Only 35 to 70 percent of orally administered norfloxacin is absorbed, compared with 85 to 95 percent of the other fluoroquinolones
Intravenous preparations of ciprofloxacin and levofloxacin are available
antacids (with Al or Mg), or dietary supplements (with Zn or Fe, divalents) – decrease absorption
Distribution
Levels are high in bone, urine, kidney, and prostatic tissue (but not prostatic fluid), and concentrations in the lung exceed those in serum.
Execration:
excreted by the renal route.
once-daily dosing
I.v. preparations of ciprofloxacin, levofloxacin, gatifloxacin, and ofloxacin are available. Binding to plasma proteins 10 – 40 %.

8. Fluoroquinolones – S/E
GIT: nausea, vomiting, diarrhea
CNS:
headache and dizziness or light-headedness.
Patients with epilepsy – CAUTION???
Phototoxicity:
Discontinue therapy at the first sign of phototoxicity.
Hepatotoxicity:
Connective tissue problems
C/I in pregnancy, in nursing mothers, and in children under 18 years??
Can cause articular cartilage erosion
In adults - they can infrequently cause ruptured tendons.
Sparfloxacin and moxifloxacin prolong the QT interval so C/I in patient with arrythmia
Contraindications:
Sparfloxacin and moxifloxacin (prolong the QT interval) - not use in those who are predisposed to arrhythmias or are taking antiarrhythmics.

9. Fluoroquinolones Drug interactions:
↓ absorption: Al3+, Mg2+, and Ca2+ antacids
CYP450 inhibition: potential drug interactions
ciprofloxacin: increases serum level of theophylline (induce seizure),
3rd & 4th- generation fluoro. may increase serum level of warfarin, caffeine and cyclosporine

10. Inhibitors of Folate Synthesis and Metabolism
Sulfonamides
Sulfasalazine
Silver sulfadiazine*
Sulfamethoxazole
Sulfadiazine
Trimethoprim
Cotrimoxazole (Trimethoprim +Sulfamethoxazole )

12. Folic Acid Antagonists
Coenzymes containing folic acid
required for the synthesis of purines and pyrimidines
and other compounds necessary for cellular growth and replication.
In the absence of folic acid, bacteria cannot grow or divide.
Humans cannot synthesize folic acid and must obtain preformed folate as a vitamin from the diet.
Many bacteria are impermeable to folic acid, and must synthesize folate de novo.
Both compounds interfere with the ability of bacterium to divide.

13. FOLIC ACID ANTAGONISTS
Sulfonamides MOA:
inhibit the synthesis of folic acid – dihydropteroate reductase.
Trimethoprim MOA:
prevents the conversion of folic acid to its active, coenzyme form (tetrahydrofolic acid).
Both compounds interfere with the ability of bacterium to divide.

14. Sulfonamides Spectrum enterobacteriaceae, chlamydia
sulfadiazine in combination with pyrimethamine is the preferred form of treatment for toxoplasmosis and chloroquine-resistant malaria.
C. Resistance
Only organisms that synthesize their own folic acid are sensitive to the sulfonamides. Humans are not affected (as well as bacteria that do not synthesize folic acid).
Organisms resistant to one member of this drug family are resistant to all.
Resistance - irreversible, it may be due to altered dihydropteroate synthetase decreased cellular permeability to drugs enhanced production of the natural substrate, PABA.

16. Sulfonamides well absorbed after oral administration
Sulfasalazine (an exception) not absorbed orally
reserved for treatment of chronic inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis).
Intestinal flora split sulfasalazine into sulfapyridine and 5-aminosalicylate (anti-inflammatory effect)
Topically: creams of silver sulfadiazine - effective in reducing burn-associated sepsis.

17. Sulfonamides - PK Bound (in a different extent) to serum albumin
Distribution in the body, good penetration into CSF
They can pass the placental barrier – C/I.
Metabolism: acetylated in the liver.
crystalluria ("stone formation") and potential damage to the kidney.
Excretion by glomerular filtration
may also be eliminated in breast milk. c/I

18. Sulfonamides Well absorbed orally, short-acting: Sulfadiazine,
Sulfisoxazole
Sulfamethoxazole
Well absorbed orally, long-acting:
Sulfamethopyrazine
Poorly absorbed in GIT: Sulfasalazine (sulfapyridine)
Used topically: Silver sulfadiazine for burn infection

19. Sulfonamides - AE Hepatitis
Nephrotoxicity : a result of crystalluria
Adequate hydration and alkalization of urine is necessary
Note: It is contraindicated to use acidic drugs (salicylates) or food (oranges etc.) !!!
Hypersensitivity - common
rashes, fever, angioedema, anaphylactoid reactions,
Hepatitis

20. Trimethoprim Other folate reductase inhibitors:
inhibitor of bacterial dihydrofolate reductase;
antibacterial spectrum similar to SA.
May be used alone in the treatment of acute UTIs, and in the treatment of bacterial prostatitis and vaginitis.
Trimethoprim is fold more potent than SA.
Mostly compounded with sulfamethoxazole = co-trimoxazole.
Other folate reductase inhibitors:
pyrimethamine (used with SA in parasitic infections),
methotrexate (in cancer chemotherapy).
Resistance in G- bacteria
presence of altered dihydrofolate reductase with lower affinity for trimethoprim or overproduction of the enzyme
decrease drug permeability.

21. Trimethoprim Pharmacokinetics similar to sulfamethoxazole.
Adverse effects
folic acid deficiency
megaloblastic anemia, leukopenia, granulocytopenia – especially in pregnant women and patients with a poor diets
The blood disorders can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria.
nausea, vomiting, skin rashes

22. Cotrimoxazole Trimethoprim & sulfamethoxazole (1/5)→(1/20).
Combination is synergistic; bactericidal.
Greater antimicro.activity than either alone.
Effective in:
UTI.
RTI.
Prostatic & vaginal infections.
Pneumocystis pneumonia (IV).
Ampicillin-or chloramphenicol- resistant typhoid fever.

24. Cotrimoxazole Adverse effects
Gastrointestinal; N/V, glossitis, stomatitis
Dermatologic; Skin rash common & severe
Hematologic; Megaloblastic anemia, leukopenia, thrombocytopenia, hemolytic anemia in pts. deficient in G6PD.
Drug interactions; Warfarin, phenytoin??, methotrexate??