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

Targets of Antibiotic

Sulfonamides Sulfamethoxazole Trimethoprim Cotrimoxazole 3

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

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

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

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).

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

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

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

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

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

Quinolones 13

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

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

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

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

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

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

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

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