DNA and Antimetabolites Flashcards
1
Q
what does DNA gyrase do
A
relieves supercoiling of prokaryotic DNA
2
Q
what does topoisomerase IV do
A
decatenation (unlinking) of interlinked chromosomes
3
Q
how to quinolones or fluoroquinolones work?
A
inhibit DNA gyrase and topoisomerase IV to kill prokaryotes
4
Q
how do quinolones enter
A
porin! gram -
5
Q
what is more important in gram-?
A
DNA gyrase
6
Q
what is more important in gram +
A
topoisomerase IV
7
Q
what are the respiratory fluoroquinolones?
A
- levofloxacin
2. moxifloxacin
8
Q
what fluroquinolones cover pseudomonas?
A
- ciprofloxacin
2. levofloxacin (has some)
9
Q
what is nalidixic acid?
A
fluoroquinolone that is not used clinically because it doesn’t reach systemic levels. only covers gram- in urine.
10
Q
nalidixic acid and resistance
A
if cultures reveal resistance to this, it is a short step to resistance to ciprofloxacin
11
Q
characteristic of ciprofloxacin
A
achieves systemic levels and covers gram- aerobes including pseudomonas
12
Q
what does levofloxacin cover
A
respiratory FQ so: s. pneumoniae m. pneumoniae c. pneumoniae l. pneumoniae some pseudomonas
13
Q
what does moxifloxacin cover
A
respiratory FQ so: s. pneumoniae m. pneumoniae c. pneumoniae l. pneumoniae some anaerobes (bacteroides) NO PSEUDOMONAS
14
Q
what is ciprofloxacin used for
A
gram- only for complicated UTI, prostatitis, anthrax, gram- ostomyelitis, pseudomonas
15
Q
why can moxifloxacin not be used for UTI?
A
it doesn’t accumulate in the urine, so not used for UTI
16
Q
what can moxifloxacin be used for?
A
ob/gyn/GI surgeries since it covers bacteroides
17
Q
what can levofloxacin, gemifloxacin and moxifloxacin be used for?
A
empirically as monotherapy for CAP, skin and soft tissue infections because cover gram- to varying degrees
can also be used for UTI (except not moxifloxacin)
18
Q
fluoroquinolones MOA
A
inhibition of topoisomerase leading to cleavage of DNA and cell death
are concentration dependent killers
19
Q
resistance against FQ
A
cross resistance among FQ
- mutations in topoisomerase (GyrA and GyrB genes)
- efflux pumps
- altered porin channels
20
Q
which FQ are available PO or IV?
A
- ciprofloxacin
- levofloxacin
- ofloxacin
- moxifloxacin
21
Q
kinetics of FQ
A
achieves high concentrations in most compartments except CNS (moxifloxacin has limited in urine)
22
Q
FQ and other cells
A
penetrates microphages and PMNs
23
Q
what limits absorption of FQ
A
chelation with dairy, antacids, iron formulations and Mg.
24
Q
which meds are you not to take with dairy
A
tetracyclines and FQ
25
ADE of FQ
1. chelation so don't use in pregnancy or children
2. photosensitivity
3. QTc prolongation
4. tendinitis
5. inhibition of CYP450
26
what does FQ inhibit
CYP450
27
why can FQ cause tendinitis
breaks down collagen and inhibits collagen repair processes. so could cause aortic dissection and ruptures too.
28
safety alerts for FQ
aortic dissection and rupture, hypoglycemia, mental disturbances
29
box alerts for FQ
tendinitis, exacerbation of myasthenia gravis, peripheral neuropathy and CNS effects
30
what do drugs that interfere with bacterial folate do?
bacteriostatic
31
what drugs interfere with bacterial folate?
1. sulfonamides and sulfones
| 2. trimethoprim and pyrimethamine
32
what folate inhibitors are usually combined?
SMX/TMP sulfamethoxazole/trimethoprim
33
which drugs are PABA analogs?
sulfonamides
34
what are the sulfonamides
sulfamethoxazole, sulfadiazine, sulfadoxine, sulfone
35
what drugs are dihydropteroate synthase inhibitors?
sulfonamides (this is a bacterial mechanism)
36
what drugs are dihydrofolate reductase inhibitors?
pyrimethamine, trimethoprim (this is a human mechanism)
37
spectrum of TMP/SMX
1. pneumocystic jiroveci
2. nocardia
3. enterobacteriacae like ecoli, klebsiella, enterobacter, proteus (important)
4. moraxella
5. hemophilus
6. community acquired MRSA (important)
7. c trachomatis
8. protozoa
38
what are the folate antagonists used for
UTI, pneumonia in immunocompromised, burns (topical), conjunctivitis (topical), leprosy (dapsone), malaria (pyrimethamine)
39
resistance of sulfonamides
cross resistance (if resistant to one of them, resistant to them all)
1. increased production of PABA (outcompetes)
2. alteration in dihydropteroate synthetase
3. decreased cellular permeability
40
resistance of trimethoprim
1. altered bacterial DHFR
| 2. increased bacterial expression of DHFR (makes its own not humans)
41
kinetics of sulfonamides
highly plasma protein bound which could cause kernicterus in neonates and pass into placenta
42
absorption of sulfonamides
sulfasalazine has poor absorption, used for GI
43
what do sulfonamides pass into
CNS, prostate, placenta
44
how are sulfonamides eliminated?
N-acetylation and renal elimination
45
where does trimethoprim accumulate
weak base so accumulates in prostate and vaginal fluids
46
trimethoprim elimination
renally (primary)
47
what occurs with hypersensitivity reaction to sulfonamides
steven johnson syndrome (slough of skin)
48
what other sulfonamides are cross sensitive with SMX and SSD
1. diuretics (loop, thiazides, carbonic anhydrase inhibitors)
2. oral hypoglycemic sulfonylureas
3. celecoxib
4. bacitracin
49
ADE of sulfonamides
1. rash
2. crystalluria (drink a lot of fluid)
3. photosensitivity
50
what happens in neonates with sulfonamides
kernicterus -- displacement of bilirubin from albumin (jaundice)
51
what is stevens johnson syndrome
immune complex mediated hypersensitivity (type III but follows type IV)
52
when is steven johnson syndrome a risk
with slow acetylators, immunocompromised and pt with brain tumors/undergoing radiotherapy/with antiepileptics
53
what does steven johnson syndrome entail
skin and mucous membranes where apoptosis of keratinocytes cause separation of epidermis from the dermis. fas and Fas L, activated T cells.
54
area of SJS
minor form of toxic epidermal necrolysis (TEN) with less than 10% body surface area detachment
55
what is TEN
detachment of more than 30% of body surface area
56
what is a major problem for sulfonamides and sulfone?
hemolytic anemia in G6PD deficiency
57
ADE of trimethoprim
leukopenia and macrocytic anemia if chronic use since inhibiting mammalian DHFR
58
what drugs interfere with RNA polymerase
rifamycins
59
what is needed for bacterial transcription initiation
RNA polymerase
60
what is needed for bacterial transcription elongation
adding bases to chain via RNA polymerase
61
what is needed for termination?
dissociation of the DNA, RNA polymerase, and newly formed RNA
62
what do rifamycins do?
bind to beta subunit of RNA polymerase, which blocks elongation of the nascent RNA chain
63
what are the rifamycins
rifampin, rifabutin, rifapentine
64
MOA rifamycins
form very stable complex with RNA polymerase (very low affinity for human, even mitochondrial) to prevent elongation
65
rifamycin spectrum
love to kill bacteria in the phagosome, very broad including mycobacteria
66
what do rifamycin not cover
enterobacteraceae
67
resistance against rifamycin
spontaneous mutation of rpoB gene that is rapid and predictable
68
use of rifamycins (monotherapy)
monotherapy only in the prophylaxis of neisseria meningitidis or H influenzae meningitis
69
use of rifamycins (combination treatment)
TB, leprosy, bone infections, endocarditis
70
adverse effects of rifamycins
1. stains body fluids orange/red
2. powerful enzyme inducer (many drug interactions, decrease effects of other drugs)
3. hepatotoxic (hepatitis)
4. flu like hypersensitivity
71
MOA of rifamixin
inhibits DNA dependent RNA polymerase
72
spectrum of rifamixin
ecoli, possibly other enterobacteriaeceae and possibly e coli (narrow)
73
use of rifamixin
uncomplicated travelers diarrhea bc does not achieve therapeutic levels systemically
74
SE of rifamixin
not absorbed systemically, so minimal or local SE
75
which drugs generate ROS
metronidazole, nitazoxanide
76
MOA metronidazole
activated by pyruvate-ferredoxin oxireductase (PFOR) to its active reduced form, which is thought to bind DNA and proteins, leading to microbial death
77
spectrum of metronidazole
protozoa (giardia, trichomonas), anaerobes, H pylori
78
use of metronidazole
C diff except now use oral vancomycin 1st then a macrolide then metronidazole.
amoebic dyssenterty, amoebiasis, below the belt anaerobes
79
ADE of metronidazole with alcohol
inhibits aldehyde dehydrogenase making a disulfram reaction that makes you sick when you drink alcohol
80
ADE of metronidazole
leukopenia, thrombocytopenia, metallic taste, neurotoxic, ototoxic, neuopathy, inhibits warfarin metabolism
81
MOA nitazoxanide
activate by pyruvate ferredoxin oxidoreductase leads to formation of free radicals and ROS
82
SE nitazoxanide
very few SE or drug interactions
83
spectrum nitazoxanide
adjunct to antiretroviral therapy in cryptosporidium and giardia in kids
84
urinary tract drugs are
nitrofurantoin, methenamine, cranberry, phenazopyridine (AZO, pyridium)
85
MOA methenamine
forms formaldehyde at acidic pH so acts as antiseptic
86
MOA cranberry
inhibits adherence of uropathogens to uroepithelial cells (no real data)
87
contraindications for AZO/pyridium/phenazopyridine_
pt with creatine clearance less than 50
88
caution for AZO
max of 2 days of therapy or else causes hemolytic anemia leading to acute renal failure
89
what does AZO do to urine
changes urine from orange to red
90
MOA nitrofurantoin
reduced form damages DNA
91
spectrum of nitrofurantoin
e coli, enterococci
92
uses for nitrofurantoin
urinary tract only
93
what is best for nitrofurantoin
acidic urine is better effect for treatment and prophylaxis of uncomplicated UTI
94
ADE of nitrofurantoin
issue in G6PD!! causes anemia, hepatotoxic, neurologic disturbances
95
what drugs are issues in G6PD ?
sulfonamides and nitrofurantoin
96
what are the GI antibiotics?
1. neomycin
2. vancomycin (oral)
3. metronidazole (but will have systemic absorption)
4. rifamixin
5. fidoxamicin
6. bacitracin
7. some sulfonamides like sulfadiazine
97
what drugs should not be used in children for risk of discoloration of teeth and remodeling of bone?
tetracyclines and fluoroquinolones (both cause chelation)
98
what carbapenem has little activity against pseudomonas?
ertapenem
