Fluoroquinolones PDF

fluoroquinolones By / Dr. Ali khames abd el twab Lecturer of pharmacology and toxicology  Quinolones are synthetic antibacterials  Nalidixic acid in the early 1960s→→→→modification of the quinolone nucleus →→→expanded the spectrum of activity, improved pharmacokinetics, and stabilized co...

fluoroquinolones By / Dr. Ali khames abd el twab Lecturer of pharmacology and toxicology  Quinolones are synthetic antibacterials  Nalidixic acid in the early 1960s→→→→modification of the quinolone nucleus →→→expanded the spectrum of activity, improved pharmacokinetics, and stabilized compounds against common mechanisms of resistance.  Due to these enhancements, quinolone antimicrobials were rapidly integrated into human and agricultural medicine→→ Unfortunately, overuse resulted in rising rates of resistance in gram-negative and gram-positive organisms, Mechanism of action of quinolones : Inhibitis DNA gyrase (topoisomerase 2 ) and topoisomerase 4 causing failure of DNA replication and DNA breakage → cell lysis DNA gyrase is responsible for reducing torsional stress ahead of replicating forks by breaking double-strand DNA and introducing negative supercoils. Topoisomerase IV assists in separating daughter chromosomes once replication is completed. Fluoroquinolones bind to these enzymes and interfere with DNA ligation. This interference increases the number of permanent chromosomal breaks, triggering cell lysis. fluoroquinolones have different targets for gram- negative (DNA gyrase) and gram-positive organisms (topoisomerase IV), resulting in rapid cell death In place of DNA gyrase or topoisomerase IV, the mammalian cells possess an enzyme topoisomerase II (that also removes positive supercoils) which has very low affinity for FQs— hence the low toxicity to host cells. Helicases are proteins that use the energy of ATP hydrolysis to open (via hydrogen bonds breaking) double- stranded DNA, RNA, or RNA–DNA hybrids into two single strands.→The replication fork * is a region where a cell's DNA * double helix has been unwound and separated to create an area where DNA polymerases and the other enzymes involved can use each strand as a template to synthesize a new double helix. An enzyme called a helicase * catalyzes strand separation →→DNA polymerase is responsible for the process of DNA replication, during which a double-stranded DNA molecule is copied into two identical DNA molecules. Scientists have taken advantage of the power of DNA polymerase molecules to copy DNA molecules in test helicase unwinds the two strands for use as templates by DNA Polymerase, which synthesizes the new copy. This unwinding alters twist and generates positive torsional stress ahead of the replication fork Generations of fluoroquinolones spectrum Accumulation in macrophages and polymorphonuclear leukocytes results in activity against intracellular organisms such as Listeria,Chlamydia, and Mycobacterium.  Drug-drug interactions 1- quinolones + theophylline 2- quinolones + warfarin  Folate antagonists Folic acid is a coenzyme essential in the synthesis of ribonucleic acid (RNA), DNA, and certain amino acids. In the absence of folate, cells cannot grow or divide.  Humans use dietary folate to synthesize the critical folate derivative, tetrahydrofolic acid. By contrast, many bacteria are impermeable to folate derivatives, and rely on their ability to synthesize folate de novo  sulfonamides Sulfa drugs were among the first antibiotics used in clinical practice. Today, they are seldom prescribed alone (due to resistance ) except in developing countries, where they are employed because of low cost and efficacy. Mechanism of action  Spectrum Sulfa drugs have in vitro activity against gram- negative and gram positive organisms. Common organisms include: Enterobacteriaceae,Haemophilus influenzae, Streptococcus spp., Staphylococcus spp., and Nocardia.  Pharmacokinetics Absorption  Most sulfa drugs are well absorbed following oral administration An exception is sulfasalazine Topical silver sulfadiazine creams for burns Distribution Sulfa drugs are bound to serum albumin in circulation and widely distribute throughout body tissues (kernicterus). Sulfa drugs penetrate well into cerebrospinal fluid (even in the absence of inflammation) and cross the placental barrier to enter fetal tissues. Metabolism Sulfa drugs are acetylated and conjugated primarily in the liver. The acetylated product is devoid of antimicrobial activity but retains the toxic potential to precipitate at neutral or acidic pH,This causes crystalluria and potential damage to the kidney. Adverse effects 1. Crystalluria: Nephrotoxicity may develop as a result of crystalluria →→Adequate hydration and alkalinization of urine,Solved by reducing the concentration of drug and promoting its ionization. 2. Hypersensitivity: Hypersensitivity reactions, such as rashes, angioedema, or Stevens-Johnson syndrome, may occur. 3. Hematopoietic disturbances: Hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD} deficiency. Granulocytopenia and thrombocytopenia can also occur. agranulocytosis, aplastic anemia, and other blood dyscrasias. 4. Kernicterus: Bilirubin-associated brain damage (kernicterus} in newborns?? because sulfa drugs displace bilirubin from binding sites on serum albumin. The bilirubin is then free to pass into the CNS, because the blood-brain barrier is not fully developed.  Drug interactions : CYP2C9 ,plasma protein binding (↑↑the level of warfarin , phenytoin and methotrexate) Excretion : methenamine + sulphonamide → crystalluria??? Contraindications: should be avoided in newborns and infants less than 2 months of age, as well as in pregnant women at term.  Trimethoprim Concentrated in prostate and urine. Causes megaloplastic anaemia,granulocytopenia (the effects of folic acid deficiency) this can be reversed by simultaneous administration of folinic acid which does not enter bacteria. Hyperkalemia (due to potassium sparing effects) →C.I with ACEIs  Co-trimoxazole The combination of trimethoprim with sulfamethoxazole, called co-trimoxazole ,shows greater antimicrobial activity than equivalent quantities of either drug used alone.  Indications of co-trimoxazole gastrointestinal infections Cotrimoxozole is useful in the treatment of shigellosis and non-typhoid salmonella prostate and urinary tract infections Trimethoprim concentrates in prostatic and vaginal fluids, making it effective in treating infections at these sites. respiratory infections Cotrimoxozole is effective against H. influenzae. pneumocystis carinii pneumonia This is a common opportunistic infection complicating AIDS. Cotrimoxozole is the most effective therapy.  URINARY TRACT ANTISEPTICS fluoroquinolones and cotrimoxazole were the first line treatment but resistance gives the chance to another agents methenamine, nitrofurantoin, and fosfomycin due to 1-their efficacy against common pathogens 2-high concentrations in the urine. A. Methenamine (hexamine ,urotropine) Mechanism of action Methenamine salts are hydrolyzed to ammonia (use should be avoided in hepatic insufficiency) and formaldehyde in acidic urine (pH ≤ 5.5). Formaldehyde denatures proteins and nucleic acids, resulting in bacterial cell death.  Clinical tips Methenamine is formulated either as mandelate or hippurate ?? Methenamine is combined with a weak acid (for example, hippuric acid) to maintain urine acidity and promote production of formaldehyde Nitrofurantoin Mechanism of action inhibiting DNA and RNA synthesis. Susceptible organisms include E-coli, Klebsiella spp., Enterococcus spp., and Staphylococcus spp. Common adverse events include nausea, vomiting, and diarrhea. Use of the microcrystalline formulation decreases the incidence of gastrointestinal toxicity. Rare complications of therapy include pulmonary fibrosis, neuropathy, and autoimmune hepatitis. These events are observed with prolonged exposure greater than 1 month ,Especially in patients with impaired renal function.