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

Targets of Antibiotic ? ?

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

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

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

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

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 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

Quinolones 9

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

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

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

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

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

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

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