Pharmacology: Test 4: Antibiotics Iii Lec 65

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Inhibition of Nucleic Acid Synthesis: SULFONAMIDES; sulfisoxazole, sulfamethoxazole

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BROADSPECTRUM

bacteriostatic, structural analog and competitive antagonist of PABA at DIHYDROPTEROATE SYNTHASE, inhibiting synthesis of folic acid.

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Inhibition of Nucleic Acid Synthesis: SULFONAMIDES; sulfisoxazole, sulfamethoxazole -- Pharmcokinetics

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Four classes:

oral absorbable, non-absorbable, topical, long-acting

broad distr. crosses BB and placenta

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Inhibition of Nucleic Acid Synthesis: SULFONAMIDES; sulfisoxazole, sulfamethoxazole -- Pharmcokinetics -- RESISTANCE

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decreased influx
active efflux
increased production of PABA, decrease synthase sensitivity.

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Inhibition of Nucleic Acid Synthesis: SULFONAMIDES; sulfisoxazole, sulfamethoxazole -- Pharmcokinetics -- ADVERSE EFFECTS

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UT: crystalluria
hemolytic anemia, aplastic anemia, agranulocytosis

Hypersensitivity: STEVENS-JOHNSON syndrom, rashes, fever

Drug Intxn: potentiate effects of oral anticoagulants, sulfonylurea hypoglycemic agents and hydantoin antiseizure drugs

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Inhibition of Nucleic Acid Synthesis: BENZYLPYRIMIDINES (trimethroprim)

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Broad spectrum, bacteriostatic

selective inhibitor of DIHYDROFLATE REDUCTASE. (There is a mammalian form of this enzyme but less sensitive to inhibition by these drugs).

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Inhibition of Nucleic Acid Synthesis: BENZYLPYRIMIDINES (trimethroprim) -- Pharmacokinetics

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usually oral, iv with sulfamethoxazole, broad distribution crosses BBB and placenta.

Drug weak base so trapped in prostatic and vaginal fluid.

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Inhibition of Nucleic Acid Synthesis: BENZYLPYRIMIDINES (trimethroprim) -- RESISTANCE

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decrease influx

increase production of reductase, decreased sensitivity of reductase

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Inhibition of Nucleic Acid Synthesis: BENZYLPYRIMIDINES (trimethroprim) -- adverse effects

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megaloblastic anemia, leukopenia, granulocytopenia (prevented by simultaneous admin of follic acid).

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Inhibition of Nucleic Acid Synthesis: SULFAMETHOXAZOLE + TRIMETHROPRIM

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synergism from seq blockade of folate synthesis>> BECOMES BACTERICIDALL instead of bacteriostatic

AIDS PTS have high incidence of adverse effects i.e. CNS disturbance so give folinic acid

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Inhibition of DNA replication (Transcription): FLUOROQUINOLONES: ciprofloxacin, levofloxacin

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mostly gram neg, some gram positive.

Bactericidal

Inhibits DNA gyrase (Topoisomerase II) in Gram Neg, which prevents relaxation of pos supercoiled DNA req'd for transcription and replication.

Inhibits Topoisomerse IV in Gram Positive, and probably interferes with seperation of replicated DNA into daughter cells during cell division.

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Inhibition of DNA replication (Transcription): FLUOROQUINOLONES: ciprofloxacin, levofloxacin - pharmacokinetics

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good oral abs, impaired by dairy prod, antacids and divalent and trivalent cations,

broad distr. Clearance via renal

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Inhibition of DNA replication (Transcription): FLUOROQUINOLONES: ciprofloxacin, levofloxacin - MECH OF RESISTANCE

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decrease influx

decrease affinity for gyrase or topoisomerase IV.

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Inhibition of DNA replication (Transcription): FLUOROQUINOLONES: ciprofloxacin, levofloxacin -- Adverse Rxns

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Not routine in pregnancy, nursing mothers and children due to cartillage damage

GI: incl pseudomembranous colitis

Drug intxn: increase levels of theophylline

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Inhibition of DNA replication (Transcription): NITROIMIDAZOLES; metronidazole

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for Anaerobes, can be used for VRE C. difficile, also some aerobic bacteria

Inhibits DNA replication by: nitro group of nitrosohydroxyl amino moiety is reduce by an electron transport protein in anaerobic bacteria, the reduced drug causes strand breaks in DNA. Mammalian drugs unharmed b/c they lack the enzyme to reduce the nitro group of these drugs.

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Inhibition of DNA replication (Transcription): NITROIMIDAZOLES; metronidazole -- pharmcokinetics

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can be used IV, good oral bioavailability

metabolized by liver CYP3A4 and renal clearance.

reduce dosing in pts with reduced liver fxn.

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Inhibition of DNA replication (Transcription): NITROIMIDAZOLES; metronidazole -- adverse effects

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leukopenia, seizures and peripheral neuropathy

drug intxn: Barbiturates induce liver enzyme which decreases serum concentration

has disulfuram like rxn, interfering with alcohol metabolism

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Inhibition of DNA replication (Transcription): RIFAMYCINS (rifampin, rifaximin)

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binds non-covalently to DNA dependant RNA polymerase and inhibits RNA synthesis

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Inhibition of DNA replication (Transcription): RIFAMYCINS -- RIFAMPIN

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orally absorbed, good CNS penetration, deacylated in liver (ACTIVE METABOLITES).

adv effects: induces CYP3A4, dermatitis, RED ORANGE DISCOLORATION of urin, sweat, feces, tears.

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Inhibition of DNA replication (Transcription): RIFAMYCINS -- RIFAXIMIN

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for non-invasive E coli (traveler's diarrhea)

also shigella, salmonella, and other enteropathogens

Not absorbed from GI tract, most excreted in feces