Flashcards in 2: Clindamycin + Tetracyclines + Chloramphenicol Deck (44):
1
where does clindamycin come from?
lincomycin treated with chlorine + triphenylphosphine in acetonitrile
2
clindamycin MOA
-same as macrolides
-inhibits protein synthesis - binds 23S RNA at same site as erythro
*antagonism/cross resistance b/w clinda and erythro
3
clindamycin uses
-aerobic G(+) cocci (staph, strep)
-anaerobic G(-) bacilli (bacteroides, fusobacterium)
-bone infections w/ S. aureus
-severe acne
-bacterial vaginosis
-replaced penicillin for lung abscesses, anaerobic lung and pleural space infections
-MRSA
-IV w/ pyrimethamine + lucovorin for AIDS toxoplasma encephalitis
4
clindamycin admin
-capsules, oral suspension
-IV: clindamycin phosphate
-topical: clindamycin HCl/ clindamycin phosphate
5
clindamycin metabolism
CYPs in liver -> inactive sulfoxide + N-demethylated derivative
6
clindamycin PK:
-% absorbed?
-where it goes?
-excretion?
-half life?
-90% absorbed from GI
-penetrates CNS (tx of cerebral toxoplasmosis in HIV)
-excreted in urine/bile
-t1/2 = 1.5-5h
7
what happens to clindamycin in hepatic failure?
accumulates
8
clindamycin AE
-diarrhea
-pseudomembranous colitis (C. diff inherently resistant, treat w/ metronidazole or vancomycin)
-nausea
-vomit
-abdominal cramping
-rash (hypersensitivity)
9
where do tetracyclines come from?
broad spec from streptomyces (mummy bones)
10
tetracycline contraindications
form stable chelates w/ polyvalent metal ions (Ca2+, Al3+, Cu2+, Mg2+) -> insoluble:
-don't give w/ foods rich in Ca, antacids, hematinics w/ Fe
-give metals 1h before or 2h after tetracycline
-chelates Ca during tooth formation -> permanently gray/brown that worsens w/ time due to photo-oxidation rxn (don't give to kids)
-pain on injection due to formation of insoluble Ca complexes so now inject w/ EDTA to chelate Ca
11
describe epimerization of tetracyclines
deprotonation -> followed by reprotonation, but in opposite orientation, rendering it inactive
12
describe dehydration of tetracyclines
-tertiary benzylic -OH at C6 is antiperiplanar w/ proton at C5a -> set up for dehydration
-results in 4-epianhydrotetracycline (inactive, toxic)
13
describe toxicity of 4-epianhydrotetracycline
produces Fanconi-like syndrome: failrue of reabsorption mechanism in PCT
-electrolytes not reabsorbed -> water follows electrolytes -> increased urine output, dehydration, electrolyte imbalances
14
what two tetracyclines do not form the toxic intermediate? why?
minocycline, doxycycline
-do not have -OH at C6 position
15
what happens to tetracyclines in basic solution?
cleavage -> forms a lactone product that is inactive
16
tetracycline MOA
-binds 30S subunit, blocks anticodon-codon interaction in A site, resulting in termination of peptide growth
*does not overlap with erythromycin binding site
*can inhibit human protein synthesis, but eukaryotes don't have a tetracycline uptake mechanism, so usually not a problem
-binds in 6 different spots; Tet1 has highest occupancy
17
tetracyclines uses
-acne
-chlamydia (trachoma, psittacosis, salpingitis, urethritis, LGV)
-Rickettsia (typhus, RMSF)
-brucellosis
-spirochetes (borreliosis, syphilis, Lyme disease)
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tetracyclines structures
study cheat sheet
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tetracycline: contraindications
decrease oral absorption 50% if taken with food or milk
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tetracycline: original organism
strep aureofaciens
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demeclocycline: contraindications
decrease oral absorption 50% if taken with food or milk
22
demeclocycline: why slower dehydration than tetracycline?
2nd -OH at C6 -> secondary cation intermediate is less stable and has higher energy barrier to overcome
23
demeclocycline: original organism
strep aureofaciens
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minocycline: contraindications
decrease oral absorption 20% if taken with food or milk
25
minocycline: bioavailability
90-100% orally
26
minocycline: why no toxic intermediate?
no -OH at C6
27
minocycline: original organism
from demeclocycline
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minocycline: AE
vestibular toxicities
29
oxytetracycline: contraindications
decrease oral absorption 50% if taken with food or milk
30
oxytetracycline: bioavailability
60%, orally (not great therapeutically), but most hydrophilic tetracycline
31
oxytetracycline: original organism
strep rimosis
32
doxycycline: contraindications
decrease oral absorption 20% if taken with food or milk
33
doxycycline: bioavailability
90-100%, orally
34
doxycycline: why no toxic intermediate?
no -OH on C6
35
doxycycline: why is it the preferred tetracycline?
-good bioavailability
-lesser degree of absorption reduction w/ food/milk
-less GI sx
-no toxic intermediate
-t1/2 = 18-22h (once a day dosing)
36
where does chloramphenicol come from?
strep venezuelae
37
chloramphenicol MOA
-binds reversibly to 50@ at a site near the site for erythro/clinda (competitive binding interactions among these drugs)
-inhibits peptidyl transferase -> blocks peptide bond formation b/w P and A sites
38
chloramphenicol uses
-ointment/eye drops: bacterial conjunctivitis
-chloramphenicol Na succinate = prodrug for IV/IM admin:
-hydrolyzed to chloramphenicol in liver
-bacterial meningitis
-typhoid fever
-Rickettsial infections
-intraocular infections
39
why is it important that chloramphenicol is lipid soluble?
remains relatively unbound to plasma proteins -> penetrates into all tissues, including brain
40
chloramphenicol resistance: 3 mechanisms
1. decrease membrane permeability
2. mutation of 50S subunit
3. elaboration of chloramphenicol acetyltransferase (don't bind 50S)
41
chloramphenicol toxicity, worst one
aplastic anemia:
-rare, but generally fatal
-weeks to months post treatment
-highest risk w/ oral suspension
-lowest risk w/ eye drops
-keep blood levels
42
chloramphenicol toxicity, common ones
-bone marrow suppression due to impairment of mitochondrial fxn once you reach a cumulative dose of 20g (completely reversible)
-increased risk of childhood leukemia + risk increases with length of treatment
-adults: nausea, vomit, diarrhea (rare in kids)
43
chloramphenicol metabolism
turned into its glururonide in liver (inactive) -> excreted by kidneys
-therefore must decrease dose if decreased hepatic fxn
44