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Block 5 Drugs > Antibiotics-Protein synthesis inhibitors > Flashcards

Antibiotics-Protein synthesis inhibitors Flashcards

1
Q

What is the coverage spectrum of Penicillin?

A

Some gram negative bacteria and all gram positives

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2
Q

What is the coverage spectrum of Cephalosporins?

A

Gram negatives and gram positive bacteria

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3
Q

What are the major differences between eurkaryotes and prokaryotes?

A

1) Prokaryotes have cell walls whereas eukaryotes do NOT
2) Prokaryotes use 30s/50s ribosomes whereas eukaryotes use 40s/60s ribosomes
3) Prokarytoes DON’T need preformed folate for RNA/DNA synthesis

  • remember that both prokaryotes and eukaryotes use topoisomerase but drugs are often more sensitive to bacterial topoisomerase
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4
Q

What are the general features of antibiotics that inhibit protein synthesis?

A

1) Selective to bacterial ribosomes
2) Have broader spectrum than ß-lactams - all bacteria need protein synthesis to grow
3) Bacteriostatic (with the exception of one group): affect reproduction > integrity (allows the immune system to take over)

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5
Q

Which antibacterial acts by inhibiting action at 30S and 50S subunit of the ribosome?

A

Aminoglycosides

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6
Q

Which antibacterial acts by inhibiting action at the 30S subunit of the ribosome?

A

Tetracyclines

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7
Q

Which antibacterials act by inhibiting the action of the 50S subunit of the ribosome?

A

(i) Macrolides
(ii) Clindamycin
(iii) Linezolid

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8
Q

What are the mechanisms of aminoglycosides?

A

1) Binds to two receptor sites => 16S RNA, 23S RNA and other ribosomal proteins
2) Leads to wrong base incorporation and misreading of mRNA
3) Translocation (30S binding) and recycling blocked (50S binding)

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9
Q

What additional mechanism does streptomycin have over other aminoglycosides?

A

Streptomycin can block initiation

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10
Q

Are aminoglycosides bacteriostatic or bactericidal?

A

Aminoglycosides are bactericidal unlike most other protein synthesis inhibitors
- however at low concentrations it is bacteriostatic

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11
Q

Why are aminoglycosides bactericidal?

A

Aminoglycosides transport easily into bacterial cells:

  • Passive diffusion through the porin channels of the outer membrane
  • Energy-dependent, rate-limiting transport through the plasma membrane (inhibited under anaerobic conditions)

Cytotoxicity:
- Drug-induced mutated proteins inserted into the plasma membranes enhance uptake of the drug

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12
Q

What is the most common cause of aminoglycoside resistance?

A

Inactivating enzymes (acetylases, adenylases )

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13
Q

What are other methods of aminoglycoside resistance?

A

1) Membrane impermeability
2) Mutation of the binding site
3) Methylation of rRNA

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14
Q

What is the historic use of streptomycin?

A

Mycobacterium TB (not used in US any more)

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15
Q

What is the coverage of gentamicin and tobramycin?

A

1) Aerobic gram negative rods

2) Gram positive if synergy with beta lactams

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16
Q

What group of bacteria are resistant to aminoglycosides?

A

Anaerobes are resistant

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17
Q

What is the best way to administer aminoglycosides?

A
  • Poor oral absorption (poorly distributed to tissues)

- IV and IM

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18
Q

What is the post antibiotic effect of aminoglycosides for gram negative aerobes?

A

Significant post-antibiotic effect (GN aerobes only):

-Drug keeps acting although the microbe is no longer exposed to it

19
Q

What are the major side effects of aminoglycosides?

A

1) Nephrotoxicity (acute tubular necrosis)
2) Ototoxic (auditory and vestibular)
- high-pitched sounds affected first, irreversible
3) Bone marrow suppression
4) Muscle weakness
5) Allergic reactions - rashes

20
Q

What is concentration dependent killing?

A

Concentration dependent killing -exposure to higher concentration of the drug is more efficient (even if it is short); there is no benefit of longer exposure

21
Q

What drugs exhibit concentration dependent killing?

A

1) Aminoglycosides
2) Fluoroquinolones
3) Metronidazole

22
Q

What is time dosing dependent killing?

A

TDK - you need longer exposure (e.g., frequent dosing)

23
Q

What are dosing considerations for aminoglycosides?

A

Extended (EID, once daily) interval dosing to reduce toxicity.

  • Concentration-dependent killing
  • Toxicity both time and concentration dependent
  • Significant post-antibiotic effect (GN aerobes only)
  • Watch out for renal dysfunction
24
Q

What are the main aminoglycosides?

A

streptomycin, gentamicin, tobramicin, amikacin

25
Q

What are the main tetracyclines?

A

Doxycycline, teracycline, minocycline

26
Q

What is the mechanism of tetracyclines?

A

Binds to 30S subunit & blocks amino-acyl-tRNA binding resulting in the elongation block

27
Q

How does bacterial resistance to tetracyclines develop?

A
  • Reduced cell permeability-efflux pumps
  • Reduced binding to ribosomal 30S site
  • Inactivation by enzymes

*Rarely used in US because of resistance

28
Q

Describe the absorption of tetracyclines.

A
  • Well absorbed from the gut
    • reduced absorption with food and chelators e.g. Al(OH)3
  • Good tissue penetration (fairly large Vd)
  • Doxycycline - mainly hepatic metabolism
29
Q

What are the main side effects of tetracyclines?

A
  • Gastrointestinal intolerance (N/V/D)
  • Hepatotoxic
  • Skin photosensitivity
  • Never use in pregnancy, neonates, children- deposits in enamel of teeth and bone
  • Doxycycline is the only tetracycline that can be used in renal failure
30
Q

What are the primary macrolides?

A
  • Erythromycin
  • Azithromycin
  • Clarithromycin
31
Q

What is the mechanism of macrolides?

A

Binds to and block polypeptide release channel on 50S

32
Q

How does macrolide resistance develop?

A

1) Role of 23S rRNA- nucleotide 2058 (a part of 50S)
- Modification of A-2058 (chromosomal mutation or induction of methylase) leads to resistance
2) Efflux or reduced permeability
3) Mutation or modification of the binding site
4) Production of esterase (by Enteriobacteriaceae)

*Strep pneumoniae and Staph aureus are often resistant

33
Q

What are the principle uses of azithromycin?

A
  • Respiratory tract infections
  • Gram positive cocci, Mycoplasma, Legionella, Chlamydia, H. influenzae, Mycobacteria
  • Can be used in penicillin-allergic individual
34
Q

Describe the pharmokinetics of macrolides?

A
  • Well absorbed in the GI tract

- Hepatic metabolism

35
Q

What toxicity is associated with macrolides?

A
  • Allergy-skin rashes
  • Hepatitis 2-5%
  • Gastrointestinal upsets (N/V/D)
  • Ototoxic-especially in elderly
36
Q

What is the mechanism of clindamycin?

A
  • Binds to the 50S subunit on a 23S rRNA binding site and interferes with the peptide bond formation
  • Binding site partially overlaps with macrolides
37
Q

How does clindamycin resistance develop?

A
  • Mutual interference if co-prescribed with the macrolides

- Resistance mechanisms same as with macrolides

38
Q

What is the use/spectrum of clindamycin?

A
  • Used for skin and soft tissue infection + dental
  • Often used for deep seated infections (e.g intrabdominal infections) in combination with other agents
  • Bacteriostatic
  • Gram positive cocci (Staph. and Strep.)
  • Oral and bowel anaerobes (50% Bacillus fragilis)
39
Q

Describe the pharmacokinetics of clindamycin?

A
  • Well absorbed from the gastrointestinal tract
  • Good tissue penetration (large Vd) concentrated intracellularly
  • Hepatic metabolism
40
Q

What are the side effects of clindamycin?

A
  • Hypersensitivity reactions: skin rashes
  • Gastrointestinal intolerance: N/V/D but also pseudomembranous colitis (C.difficile)
  • Hepatotoxic-hepatitis
  • Bone marrow suppression - WBC
41
Q

What is the mechanism of Linezolid?

A
  • Binds to 23S rRNA of 50S at the A site

- Blocks formation of the initiation complex

42
Q

How does linezolid resistance develop?

A
  • Mutation of 23S rRNA binding site

- No cross-resistance with other drug classes

43
Q

What is the spectrum of linezolid?

A
  • Used to treat VRE, VRSA and MRSA
  • Wide range of gram positive organisms susceptible
    • Bacteriostatic against staph and enterococci
    • Bacteriocidal for most strep
44
Q

What are the side effects of linezolid?

A
  • Hematologic : leukopenia/thrombocytopenia & aplastic anemia
  • Gastrointestinal intolerance: N/V/D
  • Biochemical hepatitis

Block 5 Drugs (9 decks)

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