1. Sulfonamides and Quinolones
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture 7
February 18, 2013

2. Targets of Antibiotic ? ?

3. Folate Inhibitors Individual Sulfonamide Drugs
Sulfamethoxazole
Trimethoprim
Cotrimoxazole
Structural analoges of PABA
Folate antagonist
Active against selected enterobacteria in the urinary tract 3

4. 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. Dihydrofolic acid (dihydrofolate, vitamin B9) is a folic acid derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidines, which are building blocks of DNA and RNA, dihydrofolate reductase is targeted by various drugs to prevent nucleic acid synthesis
Cotrimoxazole

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

6. 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).
Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) is a cytosolic enzyme in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (such as erythrocytes) by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH).
Sulfonamides: Drug Interactions
Sulfonamides potentiate the action of sulfonylureas, oral anticoagulants, and phenytoin due to inhibition of metabolism

7. 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

8. Trimethoprim Pharmacokinetics Adverse Effects
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
Pharmacokinetics
Well absorbed, highly lipid soluble and widely distributed in the body
At least 65% is eliminated unchanged in the urine
Megaloblastic anemia: anemia with larger than normal RBC
Leukopenia: decrease in number of WBC
Granulocytopenia: abnormal low count of granulocytes (neutrophil, basophil, eosinophil)
Adverse Effects
Generally well tolerated but occasionally causes GI disturbances, skin reactions and, bone marrow depression
Can produce folate deficiency, that is megaloblastic anemia, leukopenia, and granulocytopenia 8

9. Quinolones 9

10. 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 10

11. 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
DNA Gyrase: an enzyme that relieves strain while double-stranded DNA is being unwound by helicase 11

12. 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 12

13. 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
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 13

14. Fluoroquinolones: Adverse Effects
GI: Nausea, vomiting, and diarrhea
CNS: Headache and dizziness or light-headedness
Phototoxicity: Avoid excessive sunlight and to apply sunscreens
Connective tissue: 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 14

15. 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. 15

16. Norfloxacin Levofloxacin
Effective against both gram-negative (including P. aeruginosa) and gram-positive organisms in treating complicated and uncomplicated UTIs and prostatitis
Levofloxacin
Used in the treatment of prostatitis due to E. coli and of sexually transmitted diseases, except syphilis
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 16