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Pharm block 2 > Protein synthesis inhibitors > Flashcards

Protein synthesis inhibitors Flashcards

1
Q

biochem reminder: In prokaryotic protein synthesis, how does it begin?

A

begins with initiation phase where 30S, 50S, incoming tRNA, and mRNA

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2
Q

Once the initiation phase of prokaryotic protein synthesis begins, describe the steps

A
  1. tRNA binds to A site of ribosomal subunits
  2. new AA transferred to P site to continue a growing chain
  3. incoming AA from A to the P site occurs for translocation to happen
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3
Q

What are the drug types that inhibit bacterial protein synthesis?

A

aminoglycosides

macrolides

tetracyclines

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4
Q

In what ways do aminoglycosides, macrolides, and tetracyclines inhibit protein synthesis?

A

at different locations

  • initiation phase
  • binding of tRNA
  • activites of peptidyl transferase (at P site)
  • cause inappropriate AA insertions into growing peptide chains (mis-reading errors)
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5
Q

What are the aminoglycosides?

A
  • amikacin
  • gentamicin
  • kanamycin
  • netilmicin
  • streptomycin
  • tobramycin
  • neomycin
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6
Q

What is the general mechanism of action for the aminoglycosides? What are the ways in which this is accomplished?

A

binding to the bacterial 30S subunit to interfere with protein synthesis

  1. interfere with formation of the initiation complex
  2. misread mRNA and miscode AA in growing peptide chain
  3. cause ribosomes to separate from mRNA
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7
Q

the blockade of movement of the ribosome may occur after formation of a single initiation complex, what is the result of this?

A

monosome =>mRNA chain with only a single ribosome

inefficienct protein synthesis

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8
Q

How are the aminoglycosides administered? are there any exceptions?

A
  • too water soluble so cannot be given orally
  • used parenterally

except in neonates, aminoglycosides due to high degree hydrophilicity

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9
Q

The amingoglycosides have short half-lives in systemic circulation. What is the side effect?

A

accumulation occurs in the inner ear and renal cortex

this accounts for nephrotoxic and otoxic side effects

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10
Q

What is the postantibiotic effect seen with aminoglycosides?

A

due to translational mechanism of action, microbes continue to die even as plasma levels of the drug decline

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11
Q

When are aminoglycosides used?

A

ONLY used in treating gram (-) infections

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12
Q

What organisms and in what way does resistance occur wrt aminoglycosides?

A

especially anaerobes => acquired resistance via alterations in receptor proteins on their ribosomes

this prevents aminoglycosides from binding

bacteria may enzymatically or post-translationally alter phosphorylation, acetylation, or adenylation

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13
Q

What drugs are considered tetracyclines?

A
  • tetracycline
  • minocycline
  • doxycline
  • demeclocycline
  • oxytetracycline
  • tigecycline
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14
Q

What is the mechanism of action for tetracyclines?

A

inhibit protein synthesis through reversible binding to bacterial 30S ribosomal subunits which prevent binding of new incoming AA (tRNA) to interfere with peptide growth

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15
Q

What are antibiotics designed to overcome 2 commone mechanisms of tetracycline resistance? why? What is the first antibiotic designated for these mechanisms?

A

glycylcyclines => tigecycline is first

  • resistance mediated by efflux pumps
  • ribosomal protection
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16
Q

Of all the tetracycline derivatives, which is most related to minocycline?

A

tigecycline

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17
Q

Tetracyclines are bacteriostatic for what organisms? How do the modes of penetration differ?

A

bacteriostatic against gram (-) and (+)

gram (-) => passive diffusion

gram (+) => active transport

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18
Q

Gastric absorption of the tetracyclines may be inhibited by what? when is the best time to administer them?

A
  1. chelation to divalent cations
  2. bile acid resins

on an empty stomach

19
Q

Of the tetracyclines, which would you prescribe a patient with renal dysfunction? why?

A

doxycycline

it is metabolized hepatically and excreted in the feces so it is the safest for renal disease

20
Q

How do gram (+) microbes acquire resistance?

A

actively pump the drugs out of the cells via an efflux pump

21
Q

How do gram (-) microbes acquire resistance?

A

alterations in outer membrane proteins that prevent tetracyclines from entering the microbe

22
Q

Which tetracycline drug is not affected by normal tetracycline resistance mechanisms?

A

tigecycline

23
Q

What is the mechanism of action for Chloramphenicol?

A

bacteriostatic

binds to the 50S subunit to block linkage of incoming AA to growing peptide chain by interfering with peptidyl transferase

24
Q

How is chloramphenicol metabolized?

A

glucuronidation

25
Q

Why should chloramphenicol not be given to infants or adults with hepatic disease?

A

it accumulates because it is inefficienctly glucuronidated resulting in “gray” syndrome

they will fail to eat, fail to thrive, become pale and cyanotic and have abdominal distention

26
Q

Lincosamides are protein synthesis inhibitors. What drug is associated and what is its mechanism of action?

A

clindamycin

binds to 50S ribosomal subunit and preventing translocation of incoming AA from ribosomal A site to P site

27
Q

What are the drugs associated wtih macrolides?

A
  • erythromycin base
  • erythromycin estolate
  • erythromycin stearate
  • erythromycin ethylsuccinate
  • clarithromycin
  • azithromycin
28
Q

What is the mechanism of action for macrolides?

A

inhibit protein synthesis by binding to same site on prokaryotic 50S as clindamycin and chloramphenicol bind

Macrolides prevent translocation of AA from A site to the P site

29
Q

Why must consideration be given when either/or clindamycin, chloramphenicol and macrolides are in any type of combination?

A

may interfere with one another and cross resitance may develop between these drugs

30
Q

Are macrlides bacteriostatic or bactericidal?

A

may be either depending on drug concentration

31
Q

How do microbes become resistant to macrolides?

A
  • permeability for macrolides is altered
  • methylate bacterial 50S ribosomal subunits
  • enzymatically destroy the drugs
32
Q

How should the erythromycins of the macrlides be administered?

A

associated with GI distress but minimized if taken with food

33
Q

What can the estolate salt of erythromycin cause in the liver?

A

may cause cholestatic hepatitis

  • elevted liver function enzymes
  • malaise
  • nausea
  • vomiting
  • abdominal cramps
  • jaundice
  • fever
34
Q

How can erythromycines potentiate the actions of other drugs?

A

inhibiting microsomal P450 3A4 metabolism leading to toxicity of other meds

35
Q

How can erythromycins affect the heart? What must you consider before administering them?

A
  • prolongs QT intervals on ECG
  • this leads to torsades de pointes (cardiac arrhythmia)

should not be combined with other meds that prolong the QT interval

36
Q

What two antibiotics prolong the QT interval and inhibit P450 3A4? What is the difference between them?

A
  • erythromycins
  • clarithromycin

clarithromycin has less GI distress

37
Q

Azithromycin is a macrolide. Describe how it works.

A

does NOT prolong QT interval

does NOT inhibit hepatic microsomal P450 enzymes

38
Q

What is the reason azithromycin is given in place of erythromycin?

A

minimal incidence of diarrhea

39
Q

When should azithromycin not be given instead of erythromycin?

A

if a patient has allergies to erythromycin

40
Q

What are the drugs for Ketolides?

A

telithromycin

41
Q

What is the mechanism of action of telithromycin?

A

inhibits protein synthesis by inhibiting the 50S ribosomal subunit similar to macrolides

binds to 2 separate domains w/in 50S ribosomal subunit

42
Q

Wrt resitance why does binding to 2 separate domains with the 50S subunit mean?

A

would require 2 different muations to develop resistance

43
Q

Why is telithromycin more difficult for bacteria to acquire resistance?

A

it is a poor substrate for bacterial efflux pumps

2 binding locations w/in 50S

Pharm block 2 (12 decks)

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