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Antibiotics > Protein Synthesis Inhibitors > Flashcards

Protein Synthesis Inhibitors Flashcards

0
Q

Bacterial ribosomes

A

70s
30s and 50s subunits
50s subunits have 23s rRNA
30s subunits have 16s rRNA

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1
Q

Human ribosomes

A

80s

40s and 60s subunits

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2
Q

Protein synthesis inhibitors selective toxicity

A

Human ribosomes are different from bacterial ribosomes. Drugs selectively target bacterial ribosomes. However, at higher drug concentrations, drugs can bind to human ribosomes.
TCN and aminoglycosides: taken up by active uptake=> contributes to selective toxicity b/c it does not occur in human cells

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3
Q

50s protein synthesis inhibitors

“Buy AT 30, SELL at 50”

A

MaCROlides and Ketolides (ErythROMYCIN, ClarithROMYCIN, AzithROMYCIN, TelithROMYCIN)
LINcosamide (cLINdamycin)
Streptogramin (Quinupristin/Dalfopristin)
OxaZOLIDone (LineZOLID)
Chloramphenicol

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4
Q

30s protein synthesis inhibitors

“Buy AT 30, SELL at 50”

A

Tetracyclines (Tetracycline, Doxycycline, Minocycline)
Glycyclines (Tigecyclin)
Aminoglycosides (Streptomycin, Tobramycin, Gentamicin, Amikacin, Neomycin)

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5
Q

Tetracyclines

A

Inhibit bacterial protein synthesis by binding to 30s subunit and preventing binding of aminoacyl tRNA to mRNA complex. TCN interacts with 16s rRNA
Bacteriostatic
Broad spectrum: gram (+/-), spirochete a, mycoplasms, rickettsiae, and chlamydiea
Therapeutic uses: cholera, *Lyme disease, Rocky Mountain spotted fever, mycoplasma pneumonia (atypical: no cell wall so PCN won’t work), *management of acne

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6
Q

Tetracycline bacterial resistance

A

Common. Plasma mediated. Cross resistance w/in drug class (if resistant to Doxycycline, will also be resistant to Minocycline)
Decreased TCN accumulation:
-Reduced permeability
-Increased efflux: tetK gene (E. Coli and S. Pneumoniae have gene)
Altered target (tetM)
-Production of ribosomal protection protein–>displaces TCN from target. Cross resistance occurs
Enzyme inactivation (tetX): not common
-Inactivate TCN in presence of NADPH and O2

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7
Q

6-deoxy TCN drugs

A

Doxycycline and Minocycline

6-deoxy: more lipophilic, increases oral absorption, increases acid stability

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8
Q

TCN physio-chemical properties

A

Conjugated double bonds give yellow color=> accumulates in teeth and bones. Avoid in kids developing permanent teeth
Amphoteric: exists as acid or base
Chelation with polyvalent metal ions: form insoluble complexes
Phototoxicity from C7-chloro group

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9
Q

Do not administer TCN with…

A 
Milk
Iron
Vitamins
Bismuth salts
Antacids
Vitamins
Metal ions
Hemetics
Cholestyrmine or cholestipol
Take TCN one hour before or two hours after taking any of the above
Oral absorption is impaired by food or meds containing di or trivalent metal ions (except doxycycline and Minocycline-->can still chelate but absorption not affected)
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10
Q

Chemical stability of TCN

A

Dimethylamino group must be in alpha orientation ( essential for activity)
TCN undergoes epimerization between pH 2-6. Can change orientation and make inactive
Or it can undergo dehydration at C6, than epimerization. The 4-epianhydroTCN is inactive but toxic to kidneys leading to Fanconi syndrome. Doxycycline and Minocycline are free of this toxicity b/c of 6-deoxy structures.

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11
Q

Distribution of TCN

A

Minocycline is only one that can penetrate CSF
All cross placenta and breast milk
All penetrate the enamel of unerupted teeth

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12
Q

TCN DDIs

A

Cyp inducers increase metabolism of doxycycline
PCN: decrease PCN bactericidal effect. TCNs are bacteriostatic. PCN works on cell walls and needs rapidly growing bacteria in order to work, TCN stops reproduction and growth
Retinoic acids: cerebral hypertension

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13
Q

Adverse effects of TCN

A 
GI upset
Photosensitivity
Chelation with metal ions
Depressed bone growth in neonates
Teeth discoloration in children
Hypersensitivity rxn: rash (Steven Johnson's syndrome)
Superinfection: from C. diff overgrowth
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14
Q

Glycycline (Tigecycline or Tygacil)

A

T-butylglycylamido group at C9 enhances bindings to 30s subunit (increase antibacterial activity)
Broad spectrum: gram (+/-) also MDR bacteria such as pseudomonas
Bacterial resistance: rare–>*avoids TCN resistance from enhanced affinity to binding site and t-butylglycylamido group provides steric hindrance to avoid efflux protein

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15
Q

Streptomyces suffix

Aminoglycosides

A

Mycin

I.e: neomycin, streptomycin

16
Q

Micromonospora suffix

Aminoglycosides

A

Micin

I.e. Gentamicin

17
Q

Structure of aminoglycosides

A

Amino sugars linked glycosidically
At least one aminohexose sugar: N-Methyl-L-glucosamine
Highly substituted 1,3-diaminocyclohexane ring (aminocyclitol): streptidine

18
Q

Aminoglycoside MOA

A

Inhibition of bacterial protein synthesis by binding to 30s ribosome subunit-> form a complex that is unable to initiate proper amino acid polymerization
Bactericidal
-blocks initiation of protein synthesis
-blocks further translation and elicits premature termination
-incorporation of incorrect Amino acid

19
Q

Aminoglycoside antibacterial activity

A

Only against aerobic bacteria (taken up by active uptake)
Broad spectrum: gram(+/-) bacteria but reserved for more serious gram (-)
Aminoglycosides and beta lactam Abx are synergistic (both bactericidal) but incompatible (Aminoglycoside Inactivates beta Lactam by opening up beta Lactam ring)

20
Q

Aminoglycoside bacterial resistance

A

Through horizontal gene transfer from resistant plasmids
N-acetylation
O-phosphorylation
O-adenylation
Bacteria resistant to Aminoglycosides may be susceptible to Amikacin b/c of 2-hydroxyaminobutyric acid tail Inactivates all modifying enzymes
Insufficient accumulation of drug: reduced permeability or enhanced efflux
Mutation of drug target: 30s ribosome

21
Q

PK of aminoglycosides

A

Poor oral absorption. Used Parenteral or topical
Neomycin black box warning: if applied on denuded skin in sufficient quantities it can lead to systemic toxicity
Short half life but post antibiotic effect
Ototoxicity and nephrotoxicity (similar to vancomycin, do not administer together)
Neuromuscular blockade

22
Q

Post antibiotic effect

A

See antibacterial effect even after [serum drug] concentration falls below MIC

23
Q

Macrolide and Ketolide structure

A

Large lactone ring
Ketone group
Glycosidically linked amino sugar (desosamine)
Neutral sugar linked either to amino sugar or to lactone ring (cladinose)

24
Q

Erythromycin water soluble salts

A

Lactobionate. Parenteral

Erythromycin itself is weakly basic and water insoluble, make with salts to make soluble

25
Q

Erythromycin water insoluble salts

A

Estolate. Oral masks taste
Stearate. Oral masks taste
Ethylsuccinate. Oral pediatric formulations
Erythromycin itself is weakly basic and water insoluble, make with salts to make soluble
ADR: incidence of cholestatic jaundice with estolate and ethylsuccinate

26
Q

Erythromycin

A

Acid instability leads to ketal formation (Inactivates drug)
-prevent by using coated tablets or structural modification
Unpleasant taste
-use water insoluble or ester formulations to mask taste, reduce acid instability(ketal formation), and decrease gut cramps (from ketal formation)
Moderate PPB shortest half life
Hepatic metabolism to inactive metabolite

27
Q

Ketal form of erythromycin

A

Inactive
Causes gut cramps and loss of activity
C6 under acidic conditions will react with keto group

28
Q

Clarithromycin

A

Derivative of erythromycin
Structural modification to prevent ketal formation
C6-OH—>C6-OCH3 (methoxy group)
Used for gastric ulcers (H. pylori)
Hepatic metabolism to active 14-OH metabolite. Has longer T1/2 than parent compound
Low PPB

29
Q

Azithromycin

A

Structural modification to prevent ketal formation
N-methyl group inserted into the ring b/w C9 and C10–>azalide
Increased half life (*68 hours) and post antibiotic effect
High PPB but decreases at higher [drug]
Inactive metabolite from hepatic metabolism
First choice Macrolide especially for upper respiratory infections
Does not cause gut cramps b/c no ketal formation

30
Q

Macrolides MOA and antibacterial acitivity

A

Bind to 23s rRNA of 50s ribosomal subunit: blocks the polypeptide exit tunnel adjacent to peptidyl transferase
Upper and lower respiratory infections
Clarithromycin is used in combination for gastric ulcers (H. Pylori) Bacteriostatic, can be bactericidal at higher concentrations

31
Q

Macrolide resistance

A

Methylation of guanine residues of rRNA caused by erythromycin ribosomal methylase (erm) gene. Decreases antimicrobial binding
Drug efflux from Macrolide efflux A (mefA) gene
MLS phenotypes will have cross resistance from constitutive erm gene. (Will be resistant to macrolides, lincosamide and Streptogramin)

32
Q

Macrolide DDI

A

QT prolongation drugs (procainamide, amlodipine, ciprifloxacin or fluoroquinolones)
Inhibits CYP3A4

33
Q

Ketolides

Telithromycin

A

C6-methoxy group: acid stable, no ketal formation
Chain at C11/C12 increases binding to 23s rRNA increasing antibacterial activity
Oxidation at C3 from alcohol to keytone; loss of L-cladinose sugar at C3–>decreases antibacterial activity
Telithromycin is active against many erythromycin resistant microorganisms
ADR: hepatotoxicity and C/I in myasthenia gravis pts bc drug binds to cholinergic receptors decreasing muscle contraction

34
Q

Lincosamide

Clindamycin

A

Amino octoside
Chloro group at C7..->lipophilic
Weakly basic–>HCL salts increase oral absorption
R group substitutions:
-Phosphate ester (helps aid in solubilization for Parenteral formulations)
-Palmitate ester HCL (fatty acid, increase oral absorption)

35
Q

Clindamycin

A

Binds 50s ribosomal subunit
Metabolized by N-demethylation
Antibacterial activity: similar to macrolides
-primarily gram(+) and non spore forming anaerobic bacteria (actinomycetes and mycoplasma)
-excellent against P. acnes
ADE: GI discomfort, pseudomembranous colitis, Steven Johnson’s syndrome

36
Q

Oxazolidinone (know structure)

Linezolid (Zyvox)

A

MOA: binds 23s rRNA of 50s ribosomal subunit
Antibacterial spectrum against gram(+) bacteria especially VRE, MRSA, nosocomial and community acquired pneumonia, skin/skin structure infections

37
Q

Linezolid (Zyvox)

A

Resistance: mutation of 23s rRNA
ADE: myelosuppression
100% bioavailable after oral absorption.
It is and MAOI: caution with serotonergic drugs, SSRIs, and tayramine rich foods(cheese, wine). Can cause HTN crisis, serotonin syndrome, flushing, and headaches

38
Q

Chloramphenicol

A

MOA: inhibition of bacterial protein synthesis (binds 50s ribosomal subunit)
Antibacterial activity: broad spectrum
Resistance: R-factor enzymes acetylate drug
ADE: gray baby syndrome. Avoid in neonates

Antibiotics (4 decks)

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