1. Sulfonamides and Quinolones
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture 7
October 08, 2010

2. Targets of Antibiotic

3. Sulfonamides
Sulfamethoxazole
Trimethoprim
Cotrimoxazole 3

4. Sulfonamides Structural analoges of PABA Folate antagonist
Active against selected enterobacteria in the urinary tract
PABA-para-amino benzoic acid

5. Sulfonamides: Mechanism of Action
Prevent the synthesis of folic acid, which deprive the cell of essential cofactors for purine, pyrimidine and amino acid synthesis
Sulfamethoxazole
Purine, Pyrimidine: Backbone of A, T, C, G.
Cotrimoxazole
Trimethoprim

6. Sulfonamides: Pharmacokinetics
Well absorbed orally
Intravenous sulfonamides are generally reserved for patients who are unable to take oral preparations
Widely distributed to body compartment
Acetylation and glucuronidation are the most important metabolic pathways
Eliminated by glomerular filtration. Therefore, depressed kidney function causes accumulation

7. Sulfonamides: Adverse Effects
Frequently cause unwanted effects including hypersensitivity reactions such as rashes, fever and Stevens-Johnson syndrome
Sulfonamides are oxidants and can precipitate hemolytic anemia in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals
Stevens–Johnson syndrome: a life-threatening skin condition, in which cell death causes the epidermis to separate from the dermis
Hemolytic anemia: a form of anemia due to hemolysis, the abnormal breakdown of red blood cells (RBCs), either in the blood vessels (intravascular hemolysis) or elsewhere in the human body (extravascular).

8. Sulfonamides: Drug Interactions
Sulfonamides potentiate the action of sulfonylureas, oral anticoagulants, and phenytoin due to inhibition of metabolism
Sulfonylureas: drugs for diabetis millilus

9. Sulfonamides: Mechanisms of Resistance
Altered enzyme dihydropteroate synthetase resulting in decreased affinity for sulfonamides
Decreased uptake of drug
Increased PABA synthesis can overcome the inhbition by sulfonamides

10. Trimethoprim
A broad-spectrum antibacterial drug and has largely taken the place of co-trimoxazole in the treatment of urinary tract infections, acute and chronic bronchitis
MOA is same as Sulfonamides 10

11. Trimethoprim: Pharmacokinetics
Well absorbed, highly lipid soluble and widely distributed in the body
At least 65% is eliminated unchanged in the urine 11

12. Trimethoprim: Adverse Effects
Generally well tolerated but occasionally causes GI disturbances, skin reactions and, rarely, bone marrow depression
Can produce folate deficiency, that is megaloblastic anemia, leukopenia, and granulocytopenia
Bone marrow depression: abnornal breakdown of RBC; Megaloblastic anemia: inhibition of DNA synthesis in RBC; Leukopenia: decrease in the number of white blood cells; Granulocytopenia: A marked decrease in the number of granulocytes 12

13. Quinolones 13

14. Fluoroquinolones
Newer drugs offer greater potency, a broader spectrum of antimicrobial activity, and in some cases, a better safety profile than older quinolones and other antibiotics
The new compounds are more active against gram-positive organisms, yet retain favorable activity against gram-negative microorganisms 14

15. Fluoroquinolones: Mechanism of Action
Enter the cell by passive diffusion through porins in the outer membrane
Intracellularly, they inhibit the replication of bacterial DNA by interfering with the action of DNA gyrase during bacterial growth and reproduction
Binding of the quinolone to both the enzyme and DNA to form a ternary complex inhibits the rejoining step and can cause cell death by inducing cleavage of the DNA 15

16. Fluoroquinolones: Antibacterial Spectrum
Bactericidal, effective against gram-negative organisms such as the Enterobacteriaceae, Pseudomonas species, Haemophilus influenzae, and mycobacteria
Effective in the treatment of gonorrhea but not syphilis
Levofloxacin & moxifloxacin have good activity against some gram-positive organisms, such as S. pneumoniae
Ciprofloxacin and norfloxacin are active against aerobic gram-negative and atypical bacteria
Streptococcus 16

17. Fluoroquinolones: Pharmacokinetics
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, levofloxacin, and ofloxacin are available
Fluoroquinolones with longest half-lives (levofloxacin and moxifloxacin) permit once-daily dosing
Binding to plasma proteins ranges from 10 to 40 percent
Distribute well into all tissues and body fluids. Levels are high in bone, urine, kidney, and prostatic tissue
They are excreted by the renal route 17

18. Fluoroquinolones: Adverse Effects
GI: Common adverse effects are nausea, vomiting, and diarrhea
CNS Problems: Prominent CNS effects are headache and dizziness or light-headedness. Thus, patients with CNS disorders, such as epilepsy, should be treated cautiously
Phototoxicity: Advised to avoid excessive sunlight and to apply sunscreens
Connective tissue problems: Should be avoided in pregnancy, in nursing mothers, and in children under 18 years of age
Should be avoided in pregnancy, in nursing mothers, and in children under 18 years of age because articular cartilage erosion (arthropathy) occurs in immature experimental animals 18

19. Ciprofloxacin
Useful in treating infections caused by many Enterobacteriaceae and other gram-negative bacilli. For example, traveler's diarrhea caused by E. coli can be effectively treated
Drug of choice for prophylaxis and treatment of anthrax
Most potent of the fluoroquinolones for Pseudomonas aeruginosa infections
Also used as an alternative to more toxic drugs, such as the aminoglycosides
May act synergistically with β-lactams and is also of benefit in treating resistant tuberculosis
Anthrax is an acute disease caused by the bacterium Bacillus anthracis. Most forms of the disease are lethal, and it affects both humans and other animals. 19

20. Norfloxacin
Effective against both gram-negative (including P. aeruginosa) and gram-positive organisms in treating complicated and uncomplicated UTIs and prostatitis
Not effective in systemic infections 20

21. Levofloxacin
Used in the treatment of prostatitis due to E. coli and of sexually transmitted diseases, except syphilis
May be used as alternative therapy in gonorrhea
Due to its broad spectrum of activity, levofloxacin is utilized in a wide range of infections, including skin infections, acute sinusitis, acute exacerbation of chronic bronchitis, and community-acquired pneumonia
Levofloxacin has excellent activity against respiratory infections due to S. pneumoniae 21