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71 Cards in this Set
- Front
- Back
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+supercoil vs. -supercoil
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+ = compact, low energy, hard to unzip
- = compact, high energy, easy to unzip |
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Action of Topo I
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-supercoil to relaxed
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Action of Topo II
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relaxed to -supercoil
requires energy cut, pass through, reanneal (DNA gyrase) |
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DNA-dependent-RNA-polymerase subunits
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sigma - recognizes promoter, falls off (initiation)
beta - phosphodiester bonds (elongation) beta' - runs the track (translocation) beta - reads stop codon (termination, poly U) alpha - connects beta's (structural) |
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how many bp are unwound at a time?
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17 bp
about 2 turns (1.6 turns) |
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Mechanisms to speed protein synthesis in bacteria
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multiple simultaneous translations of the same DNA
no nucleus, allows transcription and translation at the same time one mRNA has multiple gene copies bugs can make 3% of their total |
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Rifamycins - drugs
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rifampin
rifabutin rifapentine rifaximin Combinations - Rifamate: rifampin, isoniazid - Rifater: rifampin, isoniazid and pyrazinamide |
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Rifamycins - target/MOA
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beta-subunit of RNA polymerase
- polymerase binds - initiation complex forms (initial phosphodiester bonds) - blocks later phosphodiester bonds - blocks mRNA exit tunnel (can't leave past 1-2 bases) - irreversible |
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Rifamycins - static or cidal
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cidal (irreversible binding)
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Rifamycins - structure
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the whole molecule is the pharmacophore (cannot change it)
rifampin and rifapentine: tail from C rifabutin: tail from N and O |
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Rifamycins - side effects
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discoloration of skin and secretions (red-orange, chromophore)
hepatotoxicity, hepatitis - monitor LFT's - EtOH to debilitated to TB to rifampin arthralgia arthritis uveitis hypersensitivity (major problem esp w/ rifapentine) - thrombocytopenia - ARF - interstital nephritis - hemolytic anemia |
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Rifamycins - spectrum
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Mycobacterium (major use)
- M. tuberculosis - M. kansasii - M. avium G+ G- atypicals |
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Rifaximin - use/dosage
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GI infections (poorly absorbed)
- traveler's diarrhea - 200 mg po bid - hepatic encephalopathy - 1200 mg bid - diverticular disease - 400 mg bid x 7 days - prophylaxis for colon surgery - 600-800 mg qd for 3-5 days |
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Rifaximin - absorption
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very poor (use for GI infections)
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Rifaximin - elimination
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fecal route (97%)
undergo entero-hepatic recirculation |
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Rifamycins - protein binding
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high for rifampin, rifabutin, rifapentine
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Rifamycins - drug interactions
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potent induction of 3A4 and 2C8/9 (1A2, 2C19)
- rifampin = 100% - rifapentine = 85% - rifabutin = 40% issue in HIV treatment esp |
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Rifamycins - auto-induction
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Rifampin: yes
Rifabutin: yes Rifapentine: no (slight) |
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Rifampin - dosing
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many regimens
IV and PO 300 mg q8h 300 mg q12h 600 mg qd 600 mg twice weekly |
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Rifabutin - dosing
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150-300 mg daily
150-300 twice weekly |
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Rifapentine - dosing
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600 mg qw
less frequent dosing - helps with compliance - good for pts with liver issues |
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Rifamycins - half-life
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rifampin = 2-5h
rifapentine = 14-18h (qw dosing) rifabutin = 32-67h |
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Rifamycins - absorption
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rifampin = 60% (IV or PO)
rifabutin = 20% (PO) rifapentine = unknown (PO) |
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Rifamycins - uses
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tuberculosis (in combination, primary use)
other mycobacterium infections (MAC) meningitis prophylaxis (not much anymore) - N. meningitidis - H. influenzae Staph infection - endocarditis - MRSA - colonization Acinetobacter Brucellosis Rickettsia Q fever Leprosy (M. leprae) |
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Rifamycins - selectivity
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very poor binding to human polymerase (only at very high doses)
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Rifampin - resistance
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12 binding aa
12 possible mutations 11 resistant mutants known |
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Fluoroquinolones - target/MOA
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DNA gyrase and Topo IV
attacks GyrA and ParC subunits can attack one or both (two changes for resistance) |
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Fluoroquinolones - static or cidal
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cidal (DS breaks)
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Fluoroquinolones - resistance
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alteration of target sites (GyrA, gyr-b, ParC, Par-e) (major mechanism)
efflux pumps (NorA) impermeability |
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Fluoroquinolones - target site mutations
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major mechanism
altered GyrA (major) or GyrB (minor) - main source of resistance - Quinolone Resistance Determining Region (QRDR) in E. coli altered ParC (major) or ParE (minor) - less common (20-25%) - grl gene range of resistance (inc MIC to full resistance) must have both alterations for full pneumococcal resistance resistance to older drugs doesn't mean resistance to new (4th gen) 4th gen effects a balanced amount of the two targets |
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Fluoroquinolones - efflux pumps
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seen in G+ and G-
NorA for hydrophilics (norflox, cipro, oflox) does not work for hydrophobics (sparflox, tovaflox, moxiflox) low level resistance synergistic with other forms reserpine = pump inhibitor |
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Fluoroquinolones - SAR-4
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4-oxo-dihydropyridine (ketone) is essential
fused aromatic heterocycle is essential |
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Fluoroquinolones - SAR - N1
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key to PK and potency
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Fluoroquinolones - SAR - N1 R group
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needs to be an alkyl or aryl
cyclopropyl or di-F-phenyl give max activity can be part of a ring with C8 |
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Fluoroquinolones - SAR - Cipro v. Norflox
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Norflox N1 = ethyl
Cirpo N1 = cyclopropyl Norflox = UTI Cipro = skin, soft tissue, bone etc |
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Fluoroquinolones - SAR - C2
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no changes (H only)
interferes with gyrase binding |
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Fluoroquinolones - SAR - C3 and C4
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C3 COOH and C4 ketone perform chelation
- gyrase binding - cell entry (antacids) |
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Fluoroquinolones - SAR - C5
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G+ but lose potency
(not sure what Davis is talking about) |
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Fluoroquinolones - SAR - C6
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need small electronegative (F)
FLUOROquinolones needed for gyrase binding |
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Fluoroquinolone - SAR - C7
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potency and spectrum
needs a saturated heterocycle 5-member pyrrolidine (1 N) = G+ 6-member piperazine (2 N) = G- 6-member fused to 5-member = G+ and G- |
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Fluoroquinolone - SAR - C8
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spectrum and resistance developmet
-OCH3 hits both targets (gen 4) |
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Fluoroquinolone - drugs/generations
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Nalidixic acid (Negram) (1st) - don't really need to know
Ciprofloxacin (2nd) Levofloxacin (3rd) Moxifloxacin (4th) Gatifloxacin (4th) Gemifloxacin (4th) |
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Fluoroquinolone - generation characteristics
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1st - G-, poor tissue penetration (UTI)
2nd - G-, good tissue penetration 3rd - G+ and atypicals 4th - G+ and anerobes loose G- and gain G+ as you progress |
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Fluoroquinolone - spectrum
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G- aerobes
- P. aeruginosa (po Cipro and po Levaquin) Intestinal pathogens - Salmonella - Shigella G+ aerobes - includes PCN-resistant - MSSA (not MRSA) pneumococcus (newer ones) Atypicals (intracellulars) (newer ones) Mycobacterium (newer ones) |
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Pseudomonas resistance mechanisms and bugs affected
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chromosomal AmpC beta-lactamase
- penicillins - cephalosporins - monobactams reduced AG transport - AG mutations in topo II and/or IV - fluoroquinolones impermeability (no OprD protein) - carbapenems efflux pumps (all drugs) - fluoroquinolones - penicillins - cephalosporins - monobactams - carbapenems - AG |
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Efflux pump parts
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LPS (outer membrane exit)
- Opr - M, J, N periplasm (linker lipoprotein) - Mex - A, C, E cytoplasmic membrane pump - Mex - B, D, F |
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Efflux pump types and their place in drug selection
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Four primary pumps
- ABM - CDJ - EFN - XYM Cipro and Levaquin activate all of the pumps Recognize resistance patterns based on pumps |
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Fluoroquinolone - resistance patterns
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increased use b/c of recommendation for pneumococcal use, spread to G- (pseudomonas)
increased use = increased resistance decreased use = decreased resistance exposure to FQ for one infection leads to resistant gut flora can latter effect other sites |
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Fluoroquinolone - absorption
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well absorbed
Levo = 99% Moxi = 90% Cipro = 75% Gemi = 71% |
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Fluoroquinolone - distribution/penetraions
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large Vd
excellent tissue penetration urinary concentrations highest with gati and levo |
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Fluoroquinolone - elimination
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Renal: cipro, levo
Hepatic (not P45): moxi, gemi |
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Fluoroquinolone - renal adjustment
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Cipro
Levo |
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Fluoroquinolone - dosing
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not stepdown therapy
Cipro - 100, 250, 500, 750 mg po q12h - 200, 400 mg IV q12h - 400 mg IV q8h - XR 500, 1000 mg q24h Levo - 250, 500, 750 mg po/IV q 24h Moxi - 200, 400 mg po/IV q24h Gemi - 160, 320 mg po q24h lower doses for UTIs but not Gemi and Moxi (not renally eliminated) |
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Fluoroquinolone - drug interactions
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Divalent/trivalent cations
- Al, Ca, Mg, Fe - sucralfate (has Al) - enteral feedings - 2h before or 4h after Phosphate binder (Renagel) Didanosine (has bicarb) May or may not have methylxanthin metabolism |
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Fluoroquinolone - side effects
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typically mild and self-limited
rarely require DC most common: GI and rash tendinitis (do not use in runners) QTc prolongation hepatotoxicity (trovafloxacin) CNS effects (trovafloxacin - dizziness) arthropathy (do not use in preg or kids) Photosensitivity (sparfloxacin, clinafloxacin) |
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Fluoroquinolone - serious but rare AEs
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TDP
thrombocytopenia increased INR/PT hepatitis acute allergic rxn gatafloxacin effects - severe hypoglycemia - severe hyperglycemia - tendon rupture |
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Characteristics of TDP inducers
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Ikr blockers
CYP450 3A4 substrates |
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Drug classes which prolong QTc
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anesthetics
antiarrhythmics (amiodarone) antimicrobials 3A4 substrates - antidepressants - antihistamines - antipsychotics |
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Antimicrobials that induce TDP
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one alone is fine, but multiple drugs or drugs + risk factors are worrisome
FQ - levo - moxi Azoles - ketoconazole - itraconazole - fluconazole Macrolides - erythromycin - clarithromycin Ketolides - telithromycin Pentamidine Cotrimoxazole |
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TDP risk factors
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despite knowing risk factors, cannot predict in whom it will occur
female hypokalemia hypomagnesemia heart failure or LV dysfunction ischemic heart disease bradycardia drug interactions competitions for P450 |
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Fluoroquinolone - cardiovascular toxicity?
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possible class effect
caution in pts with cardiac disease and electrolyte abnormalities avoid use in pts with TDP risk factors or taking other inducing agents |
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Fluoroquinolone - uses
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EVERYTHING
UTI prostatitis pyelonephritis skin and soft-tissue G- osteomyletitis CAP and HAP URTI GI infection intra-abdominal infection STD mycobacterial disease |
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Gemifloxacin - use/spectrum
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G+ including PCN/Cipro resistant S. penumo
targets II and IV (N at C8 is same as OCH3) approved for CAP and bronchitis Legionella Mycoplasma Strep S. pneumo |
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Metronidazole - target/MOA
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cleaves bacterial DNA
nitro groups reduced to reactive radicals |
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Metronidazole - selectivity
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aerobic organisms (aerobes and people) don't reduce nitros to radicals
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Metronidazole - spectrum
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G+ and G- anaerobes and protozoa
Bacteroides Gardnerella vaginalis Fusobacterium Peptococcus Peptostreptococcus Clostridium Trichomonas vaginalis Giardia lamblia Entamoeba histolytica |
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Metronidazole - absorption
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well absorbed
similar levels between IV and PO not affected by food |
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Metronidazole - penetration
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large Vd
good penetration crosses BBB (meningitis, abscesses) |
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Metronidazole - elimination
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metabolized in liver
excreted by kidneys (parent and 5 metabolites) removed by HD requires renal adjustment b/c 1 metabolite is nephrotoxic |
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Metronidazole - side effects
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antabuse rxn with alcohol
GI (most common) hematologic (neutropenia) CNS - rare but most serious - PN, confusion, seizures mutagenicity/carciongenicity - pregnancy category B - avoid in first trimester - enters breast milk well |
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Metronidazole - uses/dosing
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antibiotic-associated colitis
- 250 mg po qid or 500 mg po tid (IV or PO) anaerobic infection - 500 mg po tid, 500 mg IV q6-12h trichomonas vaginitis - 2g single dose or 500 mg po bid amebiasis - 750 mg po or IV tid giardiasis -250 mg po bid or tid |
