Protein Synthesis Inhibitors Flashcards
1
Q
What is a ribosome?
A
large nucleoprotein complex that catalyzes the ordered polymerization of amino acids
2
Q
What directs the ribosome to order the amino acids? What is the term for this?
A
mRNA template (mRNA translation)
3
Q
How can drugs target bacterial ribosomes while not affecting human ribosomes?
A
Structural difference (70s prokaryote vs. 80S Eukaryote)
4
Q
What are the three steps in protein synthesis?
A
Initiation, Elongation, termination
5
Q
Which step of protein synthesis do most current protein synthesis inhibitors target?
A
Elongation
6
Q
How do aminoglycosides inhibit protein synthesis?
A
Promote premature termination
7
Q
What are the five protein synthesis inhibitors?
A
Aminoglycosides, tetracyclines, chloramphenicol, macrolides and clindamycin
8
Q
Tetracyclines are named how?
A
number of fused rings: Tetra = 4, Doxy = 2, and Mino = 1
9
Q
What helps tetracycline’s effect on bacteria?
A
Bacteria concentrate tetracyclines inside the cell, eukaryotes and resistant bacterial do not
10
Q
How are human and bacterial ribosomes different? Similar?
A
Bac: 70S (30s and 50s)
Human Cytoplasm: 80S (40s and 60s)
Human mito: 70S (30s and 50s)
11
Q
Describe the process of adding amino acids.
A
Peptidyl site–>AA join in A-site (30s subunit)–> Amino and carboxyl ends react to form bond–> ribosome translates so new peptide is in P-site, A-site now vacant for new AA and process repeats
12
Q
Are tetracyclines bactericidal?
A
No, bacteria start to grow again once stop taking tetracycline
13
Q
What is the spectrum of Tetracycline?
A
Broad: G+, G-, aerobe, anaerobe and atypical bacteria
14
Q
What are atypical bacteria and three examples?
A
No cell wall and may cross human cell membrane; rickettsiae, mycoplasma, & chlamydia
15
Q
How do tetracyclines inhibit protein synthesis?
A
Bind to the 30S ribosomal subunit and inhibit binding of amino acylated tRNA to A site of ribosome
16
Q
Basis for selectivity for tetracyclines?
A
Tetracyclines are concentrated inside bacterial cells by an active transporter in bacterial cytoplasmic membrane; human cells do not concentrate the tetracyclines
17
Q
Of Tetracycline, Doxycycline, and Minocycline: which has the lower bioavailability and higher risk of superinfection in the gut?
A
Tetracyclines
18
Q
What inhibits the absorption of Tetracyclines?
A
Divalent and trivalent cations (Ca, Mg, Al, Fe). Think of tetracycline binding to bone. Do not take w/ milk, kaopectate, pepto-bismol, iron meds, or Ca2+ supplements. Take 1-2 hrs prior to a meal. Potent chelator
19
Q
Of tetracycline, doxycycline and minocycline: which are the most lipophilic and are therefore more easily distributed?
A
Tetracycline and doxycycline
20
Q
What is a characteristic of tetracyclines that is useful in the treatment of adults with periodontal disease?
A
Concentrate in gingival crevicular fluid
21
Q
What is the distribution of TC’s?
A
Diffuse easily across cell membrane, volume of distribution (everywhere b/c in water), [ ] in CSF is much lower than plasma, excreted in milk, binding to structures actively calcifying and [ ] in skin/GCF
22
Q
Of Tetracycline, doxycycline, and minocycline: which has the shortest halflife and therefore must be dosed more often during the day?
A
Tetracycline (4/day) and minocycline/doxycycline (1-2/day)
23
Q
Of tretracycline, doxycycline, and minocycline: which is eliminated unchanged in the urine?
A
Tetracycline
Minocycline and Doxycyclines undergo hepatic
metabolism and excretion and renal excretion
24
Q
When is tetracycline contraindicated?
A
Pregnant women and children less than 8. Uptake and concentrates in developing bones and teeth
25
3 common side effects of tetracycline?
Staining of teeth and altered rates of bone growth, GI disturbances, & phototoxic skin reactions
26
Out of the tetracyclines, which two drugs have the lowest risk of pseudomembranous colitis? Which is the DOC for treating PC?
Doxycycline and minocycline; vancomycin or metranidazole
27
What are the two ways GI disturbances can occur via tetracyclines?
Direct effect on enterocytes or indirect effect by causing disturbances in GI flora
28
Teeth staining is reversible/irreversible, dose dependent/non-dose dependent?
Irreversible and dose-dependent
29
What is the superinfection and its symptoms that can be caused by tetracycline (doxycycline has reduced risk)?
Pseudomembranous colitis due to superinfection by C. difficile (bloody stools)
30
What can be a rare side effect from treating a meningococcal infection with minocycline?
Vestibular toxicity: dizziness, vertigo
31
What do doxycycline and minocycline do in the blood and what consideration must be made?
Depress plasma prothrombin. If pt on anticoagulation therapy, dosing may need to be reduced
32
What can outdated tetracyclines cause (rare)?
Nephrotoxicity (Fanconi syndrome-proximal tubule toxicity)
33
What is a rare adverse effect from tetracyclines in pregnant women?
Hepatotoxicity (after large oral doses)
34
Why don't we use a tetracycline with a penicillin?
Tetra is bacteriostatic, so it will reduce the amount of cell wall synthesis penicillin targets (reducing its bacteriocidal effectiveness)
35
Tetracyclines are DOC for the treatment of what infections (9)?
Mycoplasma pneumonia, Rickettsia, Borrelia, Chlamydia, Vibrio, Combo therapy for H. pylori ulcer, acne, and gonorrhea/syphilis in those with penicillin allergies
36
What drug is commonly used for the eradication of the meningococcal carrier state (treating people who have come in close contact with someone who has meningitis)?
Minocycline
37
What is a dental specific use of tetracycline?
Chronic periodontal disease: Systemic or topical
38
What is Periostat?
Doxycycline (20mg tab bid, p.o.). Systemic therapy of advanced periodontal disease for up to 1 year.
39
What is Arestin?
Topical minocycline to be placed in periodontal pocket for up to 3 weeks release
40
What drug is predominantly used as a collagenase inhibitor?
Periostat (doxycycline)
41
What other periodontal problem can tetracyclines be used to treat (as an alternative to penicillin)
ANUG
42
Protein synthesis inhibitor that is isolated from Streptomyces soil bacteria?
Chloramphenicol
43
What is the major side effect associated with Chloramphenicol?
Aplastic anemia
44
Aplastic anemia associated with Chloramphenicol is an example of …?
Idiosyncratic toxicity (characteristic peculiarity)
45
Though Chloramphenicol is similar to tetracycline in its spectrum of activity, how is it different (mechanism of action)?
Binds to 50S bacterial ribosome and inhibits ribosomal peptidyltransferase; blocks "transpeptidation" reaction
46
What is the antimicrobial spectrum of chloramphenicol?
Just like Tetracycline: Broad: Gram +, gram -, anaerobes (excellent), atypical bacteria
47
What is Gray Baby Syndrome?
Neonate symptom that showed infants do not have mature hepatic drug metabolizing system (Chloramphenicol requires hepactic metabolism)
48
T/F. Chloramphenicol does not cross into the CNS well.
False. Reaches therapeutic [ ] in brain, CSF and crosses cell membranes
49
What character of Chloramphenicol makes it useful in treating bacterial meningitis?
Lipophilic and crosses blood brain barrier
50
2 blood dyscrasias associated with Chloramphenicol?
1. ) predictable, dose dependent depression of bone marrow cell proliferation
2. ) non-predictable, non-dose dependent risk of aplastic anemia that can occur even months after off Chloramphenicol
51
What is the good thing about the depressed bone marrow cell depression caused by Chloramphenicol?
It goes away once Chloramphenicol is stopped
52
Why does chloramphenicol cause depressed bone marrow cell depression/
Not as selective as tetracyclines and causes mitochondrial protein synthesis problems; also inhibits cytochrome C oxidaase, ubiquinone, cytochrome C reductase and protein translocating ATPase
53
When is Chloramphenicol indicated for treatment?
Severe systemic infections not treatable with less- toxic drugs. E.g. Cephalosporing resistant typhoid (S. typhi) or Meningitis and pneumonia caused by H.influenza or B. fragilis
54
Aminoglycosides are important for treating what bacteria?
G- bacilli aerobes and Pseudomona (P. aeruginosa)
55
How must aminoglycosides be administered?
Parenteral (outside alimentary, normally IV or IM)
56
Do aminoglycosides have a high or low therapeutic index?
Low TI, so require monitoring
57
Are aminoglycasides bactericidal/static and narrow or wide spectrum?
Bactericidal and narrow spectrum
58
Are aminoglycosides useful against anaerobes?
No (don't affect atypical bacteria either)
59
Aminoglycoside mechanism of action?
Bind bacterial ribosome 30s subunit and inhibit protein synthesis
60
3 effects caused by aminoglycosides binding the 30S bacterial ribosome?
1. ) Inhibit initiation: accumulation of initiation complexes (streptomycin monosomes)
2. ) Misincorporation: misread mRNA = wrong amino acid inserted
3. ) Premature termination: premature protein release from mRNA
61
Why are Aminoglycosides poorly absorbed if taken orally?
Large size and charged so can't cross membrane
62
How are aminoglycosides excreted (2)?
Unchanged, rapidly by kidney (glomerular filtration)
63
What is the basis for selectivity of aminoglycosides? What does it depend upon? What inhibits aminoglycosides?
[ ] inside bacterial cells by a cytoplasmic membrane transporter; oxygen dependent (anaerobic environment or low pH inhibit)
64
2 toxicities associated with Aminoglycosides?
Ototoxicity and nephrotoxicity
65
How are aminoglycoside toxicity avoided (3)?
Avoid longer interval, monitored dosing, not in patients with impaired kidney function (elderly/young kids)
66
What makes bacteria resistant to aminoglycosides?
Aminoglycoside-metabolizing enzyme acquired from plasmids
67
Systemic infections that are treated by Aminoglycosides (6)?
Klebsiella, Proteus, E.coli, Enterobacter, Pseudomonas aeruginosa, Serratia
68
Why are Aminoglycosides NOT used at abscess sites?
Abscesses have anaerobes against which Aminoglycosides are ineffective
69
2 infections where aminoglycosides are administered along with penicillin?
Meningitis and Enterococcal endocarditis
70
Five uses of aminoglycasides by itself?
Pseudomonas aeruginosa, infections caused by gram - enterics, N. gonorrhea, or sterilization of gut prior to sx
71
Prototype aminoglycoside?
Gentamicin
72
This aminoglycoside is used in skin ointments or to sterilize bowel prior to GI surgery?
Neomycin
73
This aminoglycoside is used in pseudomonal infections?
Tobramycin
74
2 aminoglycosides that are back up drugs for Gram negative drug resistant infections?
Amikacin, netilimicin
75
Macrolides are what general antibiotic type and for what are they named?
Protein synthesis inhibitors and named for large Macrolide ring structure
76
Prototype Macrolide
Erythromycin
77
What drug does Erythromycin act like in its antibacterial activity?
Penicillin, which is a cell wall inhibitor
78
Name the 2 new macrolides that are semisynthetic with an extended spectrum and improved pharmacokinetics.
Azithromycin, clarithromycin
79
What are the 2 new macrolides, Azithromycin and Clarithromycin used for?
Alternatives to penicillins for prophylaxis of bacterial endocarditis
80
What structure in the Macrolide makes it easily hydrolyzed in the stomach and thereby inactivating a large part of the drug?
The Lactone Ring
81
Erythromycin spectrum of activity, bacteriostatic/cidal, bacteria active against
Narrow spectrum, Bacteriostatic, Gram Positive Cocci and bacilli
82
What is the spectrum of activity for Azithromycin and Clarithromycin?
Somewhat broader, lower activity against some Gram + (Strep and Staph) but includes activity against Gram negatives like H. influenza
83
What is the Macrolide mechanism of action?
Bind to 50S bacterial ribosome subunit to inhibit ribosomal trasnlocase activity
84
What does inhibiting translocase activity of the 50S subunit mean?
Stops transfer of nascent peptide from A site to P site which stop the next amino acid from being added
85
Can Erythromycin be bacteriocidal?
Yes, dependent on [ ] of developing bad resistance
86
What is good about narrow spectrum in antibiotics?
Reduces the risk of developing bacterial resistance
87
What is the drawback of erythromycin method of delivery and how is it avoided?
Destroyed by stomach acid so give w/ enteric coating or as ester salt (estolate, state)
88
Major difference in Azithromycin and Clarithromycin from Erythromycin?
Azithromycin and Clarithromycin are not sensitive to stomach acid
89
If bacteria are resistant to Erythromycin, Azithromycin, Clarithromycin, what does that mean for other drugs that bind the 50S subunit?
Bacteria are most likely resistant to those as well
90
What are the other two 50S subunit binding protein synthesis inhibitor antibiotics?
Clindomycin and chloramphenicol
91
Of Eryhtromycin, Azithromycin, and Clarithromycin: which has the longest half-life?
Azithromycin (60-70 hrs)
92
Where do macrolides concentrate?
Macrophages
93
Azithromycin and Clarithromycin, due to their concentration in Macrophages, are useful against this opportunistic infection in HIV and immunocompromised pts.
Mycobacterium avium intracellulaire
94
Where is erythromycin metabolized?
Liver
95
What is the positive with the longer half-lives of Azithromycin and Clarithromycin?
Requires dosing only 1-2 times/day
96
Most common side effects of Macrolides (erythromycin, azithromycin, clarithromycin)?
GI Disturbances
97
What metabolism process do macrolides interfere with leading to their drug interactions?
Inhibit cytochrome P450 drug metabolism by liver
98
How is Azithromycin metabolized?
In urine and bile, so safe for person with liver disease (also infers why it has a longer half life)
99
Most common mechanism for resistance to Macrolides in bacteria?
Plasmids encoding erythromycin efflux transporters or methylation enzymes
100
What is a positive side effect of erythromycin?
Increases peristalsis so may help with patients that have problems with stomach emptying
101
What is Macrolide dosing for endocarditis prophylaxis that Dr. Ritter gave?
A/C: 500mg, 30-60mins before surgery
102
What is a rare risk factor associated with erythromycin? What pop'n is this important?
Cholestatic jaundice from ester salts of erythromycin interrupting bile flow; pregnant women
103
What Penicillin Class is Erythromycin similar to?
Penicillin G
104
What are the two ways bacteria gain resistance to macrolides?
1. Acquisition of met gene (erythromycin efflux transporter)
| 2. Acquisition of arm gene (methylates a base residue in the 23S RNA of the ribosome)
105
When would a macrolide be indicated (2 general)?
Pt w/ penicillin allergy or bacteria is penicillin resistant
106
What three infections are macrolides commonly used to treat?
Respiratory (pneumonia, sinusitis, and bronchitis), middle ear and skin
107
Prototype Fluoroquinolone?
Norfloxacin (limited distribution), then Ciprofloxacin
108
3 major advantages of Fluoroquinolones?
Oral effectiveness, Broad spectrum, and Safe
109
Ciprofloxacin (fluoroquinolone) :cidal/static, bacteria effective against?
Bactericidal and G+ and G-
110
Fluoroquinolone method of action?
Inhibit DNA replication by inhibiting bacterial enzymes topisomerase (Gram +) and DNA gyrase (-) which untwist DNA supercoil
111
Bacterial DNA gyrase is related to what in humans and what are their purposes?
Human DNA topoisomerases and relieve buildup of torsional strain during DNA replication
112
What is an administration consideration with fluoroquinolones?
Don’t take with dairy or antacids because they bind divalent and trivalent metal cations(like tetracyclines do as well)
113
Which fluoroquinolone is useful for the treatment of UTIs because it does not have as good tissue penetration as Ciprofloxacin and Ofloxacin?
Norfloxacin
114
What can block the excretion of fluoroquinolones?
Probenecid (used in war to prolong supplies of penicillin)
115
Huge Contraindiction for using fluoroquinolones?
Do not use in pregnant/nursing women or children under 18 due to potential to damage growing cartilage (Achilles tendon rupture)
116
Notable drug interaction for fluoroquinolones?
They increase plasma levels of warfarin
117
Quinolone (older group) that is used only for UTIs?
Nalidixic Acid
118
Large Glycopeptide druge whose most important use is treatment of Methicillin Resistant Staphylococcus infections (MRSA)?
Vancomycin
119
How are fluoroquinolones excreted?
Excreted unchanged in urine; reduce dose w/ renal insufficiency
120
Vancomycin bactericidal or static?
Vancomycin
121
Vancomycin method of action?
Inhibit cell wall synthesis but by different mechanism than penicillin
122
Vancomycin is DOC for?
Treating pseudomembranous colitis from clindamycin
123
2 methods of administration for Vancomycin and is it absorbed systemically?
IV or orally (125 mg 4/day) No systemic absorption
124
Vancomycin excretion?
Kidney
125
2 side effect risks from Vancomycin?
Ototoxicity, nephrotoxicity, thrombophlebitis and red man syndrome (degranulation)
126
Bacitracin mechanism of action?
Inhibit transport of building blocks of cell wall to outside cell membrane
127
Clinical use of Bacitracin?
Topical treatment of skin & eye bacterial infections
128
Bacitracin used in combo with what drugs normally?
Polymyxin B and Neomycin
129
Clindamycin is an alternative drug for what?
Alternative to amoxicillin for endocarditis prophylaxis
130
How is clindamycin similar to erythromycin? Different?
Activity against gram +, has high activity towards anaerobes
131
What is the MOA for clindamycin?
Protein synthesis inhibitor by binding 50S; same site as macrolides and chloramphenicol
132
T/F. Clindamycin is not absorbed well when taken orally.
F. Absorbed almost completely and penetrates deep into soft tissues, including bone
133
Clindamycin is DOC for?
Anaerobes and lung/pleural space infections (abscesses)
134
Clindamycin is good against anaerobes which makes it key treatment when?
late phase dental infections (bacteroides, prevotella, porphyromonas, fusobacterium)
135
Dosing of Clindamycin before surgery for endocarditis prophylaxis?
600 mg 30-60 min before surgery
136
3 protein synthesis inhibitor drugs that are alternatives to amoxicillin for prophylaxis of endocarditis?
Azithromycin, clarithromycin and clindamycin
137
Major risk with Clindamycin?
Antibiotic associated enterocolitis due to C. diff overgrowth (superinfection); drug can also accumulate in patients with hepatic failure
138
What is the drug used to treat the superinfection caused by Clindamycin?
Vancomycin (vancomycin vanquishes the turds)
139
2 drugs other than Nalidixic acid and Norfloxacin for UTIs?
Nitrofurantoin and methenamine
140
5 drugs used to treat M. tuberculosum?
Isoniazid, Ethambutol, Rifampin/Rifampicin, Pyrazinamide, and Streptomycin
141
3 major agents used to treat M. tuberculosum?
Isoniazid, Ethambutol, and Rifampin
142
The major agent used for M. tuberculosum?
Isoniazid
143
Isoniazid has hepatotoxicity when paired with what other Tb drug?
Rifampin/Rifampicin
144
Ethambutol mechanism of action?
Inhibits synthesis of tubercle bacilli cell wall component
145
What combination is used only in hospital settings? How work and how administered?
Imipenem-cilastatin; Beta-lactam in the carbapenem subclass, cell wall synthesis inhibitor and Cilastatin inhibits kidney enzyme that metabolizes imipenem; parenteral formulation
146
Rifampin mechanism of action
inhibits DNA-dependent RNA polymerase
147
Tb drug that is an inducer of hepatic microsomal drug-metabolizing enzymes leading to many drug-drug interaction?
Rifampin
148
Why use drug cocktail on Tb?
Tb is slow growing with high mutation and resistant rates
149
What two additional drugs are used for UTI?
Nitrofurantoin and methenamine
