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PR3151 > Pharmacology - Protein Synthesis Inhibitors > Flashcards

Pharmacology - Protein Synthesis Inhibitors Flashcards

1
Q

What are the categories of protein synthesis inhibitors?

A
  • Tetracyclines (+ tigecycline)
  • Aminoglycosides
  • Macrolides (+ clindamycin)
  • Linezolid
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2
Q

Which categories of protein synthesis inhibitors are 30S inhibitors and 50S inhibitors respectively?

A

30S: Tetracyclines, tigecycline, aminoglycosides
50S: Macrolides

Linezolid binds to 23S bacterial ribosomal RNA of 50S subunit

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3
Q

What is the mechanism of action of the tetracyclines and tigecycline?

A

Inhibits protein synthesis by binding reversibly to 30S subunit of bacterial ribosome - prevents binding of tRNA to A site of mRNA-ribosome complex, to provide bacteriostatic effect

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4
Q

How are the tetracyclines administered?
(exclude tigecycline)

A

PO
(doxycycline can be given IV, rarely)

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5
Q

How is tigecycline administered?

A

IV (poor PO F)

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6
Q

What is the spectrum of action of doxycycline?

A
  • Acne vulgaris
  • Anthrax (Bacillus anthracis)
  • Streptococcus pneumoniae
  • Haemophilus influenzae
  • MRSA SSTI
  • Rickettsia (Rocky Mountain spotted fever), Chlamydia, Mycoplasma pneumoniae, Vibrio cholerae, Yersinia pestis plague
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7
Q

How is doxycycline eliminated?

A

Excreted unchanged in bile and urine

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8
Q

What is the spectrum of action of tigecycline?

A

Active against MRSA, multidrug resistant streptococci, vancomycin resistant enterococci, Extended Spectrum B Lactamase Producing Gram Negative bacteria (esp useful against carbapenem resistant strains)

Not active against Proteus & Pseudomonas

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9
Q

How is tigecycline eliminated?

A

Not extensively metabolised, mainly by biliary/fecal

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10
Q

What are the adverse reactions associated with the tetracyclines and tigecycline?

A
  1. GI Discomfort - irritation of gastric mucosa, drink plenty of water to avoid, do not take immediately before going to bed
  2. Effects on calcified tissues - deposition in bone and primary dentition during calcification, may cause hypoplasia of teeth and temporary stunting of growth - contraindicated in children and pregnant women
  3. Hepatotoxicity
  4. Phototoxicity
  5. Vestibular dysfunction - dizziness, vertigo, tinnitus (esp minocycline)
  6. Renal SE - less w doxycycline
  7. Superinfection - CDAD and/or Pseudomembranous colitis, may be observed >2/12 post Abx Tx
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11
Q

How should the tetracyclines be taken?

A

Take on an empty stomach, but drink plenty of water to avoid stomach discomfort

Do not take immediately before lying down/going to bed

Avoid dairy products and other substances with divalent/trivalent cations eg antacids - forms non-absorbable chelates, decreasing absorption

Stay away from the sun and wear sunblock if you need to go out - this medicine may increase your risk of sunburn temporarily

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12
Q

What are the contraindications for the tetracyclines and tigecycline?

A

CONTRAINDICATION W PREGNANCY (D) AND YOUNG AGE - bind to tissues undergoing calcification, interferes w growth, statins teeth irreversibly

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13
Q

How does tigecycline differ from the tetracyclines?

A

Molecule is altered from minocycline to expand spectrum of activity & dec resistance from efflux pumps and ribosomal protection in bacteria

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14
Q

Can tigecycline be used for bloodstream infection?

A

No

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15
Q

The use of tetracyclines and tigecycline is contraindicated in which populations of patients?

A
  1. Pregnant women,
  2. Breastfeeding women
  3. Children less than 8 years of age
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16
Q

What is the mechanism of action of the aminoglycosides?

A

Distorts ribosomal structure to
- block formation of initiation complex of ribosome
- cause misreading of codons as wrong amino acyl tRNAs are able to bind to A site to put the wrong amino acid in that position
- inhibit translocation

Diffuse through aq porin channels of outer membrane of Gram negative bacteria and transport across inner membrane by active transport - process may be inhibited by anaerobic conditions, pH, hyperosmolarity

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17
Q

List out the 5 aminoglycosides.

A
  • Gentamicin
  • Tobramycin
  • Amikacin
  • Streptomycin
  • Neomycin
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18
Q

How is gentamicin administered?

A

IV/IM/Intrathecal/Opthalmic/Topical

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19
Q

What is the spectrum of activity of gentamicin?

A

For serious Gram negative infections - E.coli, Klebsiella spp, Proteus mirabilis, ESBL producing E.coli and Klebsiella spp, Amp-C producing GNR

**should not use for Pseudomonas aeruginosa anymore, following CLSI breakpoints (amikacin instead)

Not effective as monoTx for Gram positive, better when used synergistically w cell wall active antibiotics

Can be combined w a penicillin/ceftriaxone to treat Enterobacteriacae eg Proteus, Klebsiella and other MDR Gram negatives as empiric Tx and to avoid resistance

Combined w penicillin for enterococcal endocarditis

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20
Q

What is the spectrum of activity of amikacin?

A

Active against Proteus, P. aeruginosa, Mycobacterium tuberculosis, and gentamicin resistant Klebsiella, Enterobacter and E. coli
Less active than gentamicin against Enterococci, ineffective against most Gram positive anaerobic strains

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21
Q

How is amikacin administered?

A

IM/IV/Intrathecal

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22
Q

How is streptomycin administered?

A

IM

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23
Q

What is the spectrum of activity of streptomycin

A

Primarily used in combination w other antimicrobials against TB and other mycobacterial diseases

24
Q

How is Tobramycin administered?

A

IM/IV/INH/
Opthalmic ointments & solutions

25
Q

Can the aminoglycosides penetrate the CSF?

A

Poorly

26
Q

How are the aminoglycosides excreted?

A

Renal, excreted unchanged in urine

(except neomycin: 97% unchanged in feces due to only being used by PO route)

27
Q

What are the adverse reactions associated with aminoglycosides

A
  1. Ototoxicity - from high peak plasma lvl,possibly irreversible
  2. Nephrotoxicity (monitor urea, Cr, renal panel) - proximal tubular cell retention disrupts calcium mediated transport processes, can range from mild & reversible to severe & potentially irreversible
  3. Neuromuscular paralysis - associated w rapid inc in conc or concurrent administration w neuromuscular blockers
28
Q

Aminoglycosides demonstrate synergism when combined with which class of antibiotics? Name one class.

A

Beta lactams

29
Q

What are the contraindications for aminoglycosides?

A
  1. Pregnant women,
  2. Patients suffering from myasthenia gravis because of the risk of prolonged neuromuscular blockade
  3. Patients with severe renal Impairment
30
Q

What are the 6 “NOs” in relation to aminoglycosides?

A
  1. No to protein synthesis
  2. Particularly active against aerobic Gram-Negative Organisms
  3. No to use during pregnancy
  4. No to oral administration
  5. No to CSF penetration
  6. Nephro- and Oto- toxicities
31
Q

What are the predisposing factors to nephro/ototoxicity?
(eg in the use of aminoglycosides?)

A
  • dose
  • duration of Tx > 5 days
  • concomitant use of other nephrotoxic drugs eg vancomycin
  • older age: due to reduced renal fn
  • genetic predisposition: ototoxicity occurs in patients w point mutations in mitochondrial DNA
32
Q

Name the 3 macrolides.

A

Erythromycin, Clarithromycin, Azithromycin

33
Q

How are the macrolides administered?

A

PO/IV
(Clarithromycin not administered IV)

34
Q

What is the spectrum of activity of erythromycin?

A

Effective against Atypicals and Gram-negatives
(Haemophilus influenzae coverage not strong)

Can be used against staphs and streps as an alternative

35
Q

What is the spectrum of activity of clarithromycin?

A

Effective against Atypicals and Gram-negatives
(mainly used against Haemophilus influenzae)

Can be used against staphs and streps as an alternative

Stronger coverage of atypicals than erythromycin

36
Q

What is the spectrum of activity of azithromycin?

A

More active than erythromycin against H. influenzae and Moraxella catarrhalis

Active against atypicals - preferred Tx for Chlamydia, gonorrhea (w ceftriaxone IM)

Can be used against staphs and streps as an alternative

37
Q

Can the macrolides penetrate the CSF?

A

Poorly

38
Q

How are the macrolides excreted?

A

Erythromycin and clarithromycin are metabolised heptically, excreted in bile

Azithromycin is largely eliminated unchanged in faeces via biliary excretion

39
Q

What are the adverse reactions associated with macrolides

A
  1. GI Distresss - Gastric upset most common (less w clarithro and azithro than erythromycin)
  2. Hepatotoxicity - caution w hepatic dysfunction
  3. Ototoxicity - transient deafness has been associated w high doses of erythromycin, irreversible sensorineural hearing loss with azithromycin
  4. May prolong QT interval, should use w caution in patients w pro-arrhythmic conditions (avoid as needed)
40
Q

Can the macrolides be used in pregnancy?

A

Yes (esp if beta-lactam allergic)

41
Q

Name 2 mechanisms via which bacteria may acquire macrolide resistance.

A

ERM gene expression, efflux pumps

42
Q

How is clindamycin administered?

A

PO/IV/TOP

43
Q

What is the spectrum of action of clindamycin?

A

Useful against anaerobic infections, incl penicillin resistant anaerobes, but also has some aerobic coverage

For Gram positives (albeit yellow) - MRSA/MSSA, Streptococcus

Good activity against oral pathogens

ALMOST ALL AEROBIC GRAM NEGATIVES ARE RESISTANT

44
Q

Can clindamycin penetrate the CSF?

A

Poorly

45
Q

How is clindamycin excreted?

A

Hepatic, metabolised to inactive products

46
Q

What are the adverse reactions associated with clindamycin?

A
  1. GI Sx - V/D, esophageal irritation, CDAD
  2. Skin rashes
47
Q

How should clindamycin be taken by oral route?

A

Take w a full glass of water to reduce esophageal irritation

48
Q

When does clindamycin exhibit cross resistance with the macrolides?

A

When the microbes acquire resistance by expressing erm methylases

Is not a substrate for macrolide efflux pumps

49
Q

What is the mechanism of action of linezolid?

A

Binds to bacterial 23S ribosomal RNA of 50S subunit to prevent formation of 70S initiation complex - inhibit peptide synthesis

50
Q

How is linezolid administered?

A

PO/IV

51
Q

What is the spectrum of action of linezolid?

A

Used against Gram positives - Listeria monocytogenes, staphylococci (incl penicillin resistant strains, MRSA, VRSA), streptococci (incl S. pneumoniae), enterococci (incl VRE)

**used sparingly since its newer and so powerful - try to slow down resistance formation

Not indicated for Gram negative

52
Q

Can linezolid penetrate CSF well?

A

Yes

53
Q

How is linezolid excreted?

A

Non-enzymatic oxidation to 2 inactive metabolites, 80% in urine

No need dose adjustments for renal and/or hepatic dysfunctions

54
Q

What are the adverse reactions associated w linezolid?

A
  1. GI Sx - N/D
  2. Headache
  3. Rash
  4. Thrombocytopenia if used for >10 days (monitor CBC)
  5. Serotonin syndrome - do not give within 2 weeks of SSRIs or MAOIs, avoid tyramine & histamine rich food
  6. Irreversible peripheral neuropathies and optic neuritis if used >28days
55
Q

What infections should linezolid not be used against regardless of microbe?

A

Catheter site or catheter-related bloodstream infections

56
Q

Name at least 2 key adverse effects associated with prolonged use of linezolid

A
  1. Irreversible peripheral neuropathies
  2. Optic neuritis
  3. Bone marrow suppression
57
Q

Which of the protein synthesis inhibitors are safe for use in pregnant women?

A

Macrolides and Clindamycin

PR3151 (14 decks)

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