2010-10-04_ Matthews_3[1] - Inhibitors of DNA and RNA...

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Unformatted text preview: Inhibitors of DNA and RNA Synthesis Direct and Indirect Inhibition Antifungals and Antimicrobials Nucleic acid replication Uncoiling of the helix Strand separation by breaking the hydrogen bonds between the complementary strands Unwinding enzymes called DNA helicases Parent DNA strands unwind and separate from one another Topoisomerases produce breaks in the DNA and then rejoin them in order to relieve the stress in the helical molecule during replication ( topoisomerase II = DNA gyrase) Topoisomerase IV responsible for decatenation of linked daughter DNA molecules DNA and RNA polymerases Nucleic acid replication Anti-Fungals Griseolfulvin Inhibits mitosis Systemic treatment of dermatophyte infections from Micosporum, Trichophyton unresponsive to topical treatment 5-Fluorocytosine (5-FC) Interferes with DNA synthesis via 5-Fluro derivative that inhibits thymidylate synthetase Cutaneous and mucocutaneous candidiasis and Candida UTI combine with amphotericin B for cryptococcal meningitis Total daily dose of 50-150mg/kg given over 4 doses Absorbed well orally and 90% excreted unchanged in urine, remaining in feces High incidence of adverse reactions: thrombocytopenia, agranulocytosis and aplastic anemia, nausea, vomiting Inhibits bacterial RNA polymerase Especially important in treatment of tuberculosis Used in combination to decrease creation of resistance Given orally Vd~1.6L/kg with 60-90% protein bound and enters CSF (50% of [serum]) Associated with liver disease in 0.6% of patients Immune reactions are dose and interruption of dose related Induces CYP450 3A4 and 2C9 and 2C19 Drug-drug interactions Rifampicin Inhibits Bacterial Transcription Quinolones: Fluoroquinolones Prototype = nalidixic acid Fluoroquinolones resulte from addition of fluorine at position 6 = Cipro Target enzymes for fluoroquinolones differ based on pathogen and specific drug structure DNA gyrase (topoisomerase II) Topoisomerase IV Bactericidal Fluoroquinolones Aerobic gram-negative activity, poor gram positive activity Treatment against S. aureus, P.aeruginosa Now reports of P.aeruginosa resistance Newer agents in relation to ciprofloxacin Less Pseudomonal coverage Better gram-positive coverage (levofloxacin, gatifloxacin, moxifloxacin) Anaerobic coverage More favorable PK (longer elimination t1/2) Rapid rise of resistance may limit effectiveness Altered DNA gyrase or membrane permeability Concentration-dependent killing (up to 30-60 x MIC) Fluoroquinolones Absorbed well orally and also given IV Treatment of UTI and chronic prostatitis (P.aeruginosa resistant to other treatments) Patients with CF pneumonia cause by P.a but not S....
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This note was uploaded on 12/03/2010 for the course PHAMACOLOG pcl470 taught by Professor Arnot during the Fall '10 term at University of Toronto- Toronto.

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2010-10-04_ Matthews_3[1] - Inhibitors of DNA and RNA...

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