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Pharmacology Infectious Disease > Antibacterials: Protein Synthesis Inhibitors > Flashcards

Antibacterials: Protein Synthesis Inhibitors Flashcards

1
Q

What are the 6 major classes of protien synthesis inhibitors? What parts of the ribosome do they attack?

A

Aminoglycosides - 30S
Tetracyclines - 30S

Clindamycin - 50S
Chloremphenicol - 50S
Erythromycin (macrolides) - 50S
Linzolid - 50S

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2
Q

Which protein synthesis inhibitor classes are bacteriostatic? Which are bacteriocidal?

A

All bacteriostatic Except:
Linzolid - Variable
Aminoglycosides - Bacteriocidal

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3
Q

Where in protein synthesis do each of the protein synthesis inhibitors act?

A

Aminogycosides - Block initiation complex formation
Tetracyclines (Tet1 A site tRNA-anticodon/codon) & Chloremphenicol (Peptidyl Transferase) - Prevent transpeptidation/peptide bond formation.
Macrolides, Clindamycin - Block translocation

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4
Q 
What are the general uses for each class of protein synthesis inhibitor? 
Aminoglycosides, Tetracyclines, Clindamycin, Chloremphenicol, Macrolides, Azithromycin
A

Aminoglycosides - Severe G- rod infections
Tetracyclines - Broad spectrum, Intracellular infections, ACNE
Clindamycin - Anaerobes above the diaphragm
Chloremphenicol - No other alternative. Developing countries (CHEAP), meningitis, bacterial conjunctivitis.
Macrolides - G+, Atypical pneumonia, Chlamydia
Azithromycin - Greater G- activity than other macrolides

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5
Q

Erythromycin comes in two modified forms. What are these forms, and how do they improve drug utility?

A

Estolate - better oral bioavailability. NOT in liver pts.

Ethyl succinate - better oral bioavailability. Flavored for peds.

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6
Q

What are two protein synthesis inhibitors that are metabolized by the liver’s P450 system? How does this affect dosing?

A

Clindamycin & Macrolides

Adjust dosing in liver pathology patients.

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7
Q

What are the toxicities associated with Macrolides in adults?

A

GI upset - Acid inactivation to ketal.

Steven-Johnson Syndrome (hypersensitivity, epidermal necrosis)

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8
Q

What two protein synthesis inhibotor groups are contraindicated in pregnancy or breast feeding and why?

A

Macrolides - pyloric stenosis

Tetracyclines - Ca2+ chelation disrupts bone and teeth growth (brown discoloration - permanent and progressive)

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9
Q

Why would you use clarithromycin or azithromycin rather than erythromycin?

A

Reduced GI upset & Better bioavailability:
Clarithromycin - C6 methoxy gp blocks ketal formation
Azithromycin - N-methylation blocks ketal formation; once a day dosing; greater G- activity.

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10
Q

How does resistance to macrolides develop?

A
  1. Hydrolase degradation
  2. Methylation or A–> G mutation of 50S (2058 site)
  3. Efflux pump
    * *use and S. pneumoniae resistance are correlated
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11
Q

Which protein synthesis inhibitors are synthesized by Streptomyces?

A

Tetracyclines
Clindamycin
Chloremphenicol
Macrolides

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12
Q

Clindamycin is realted to what two other protein-synthesis inhibitors by binding site? Why is this important?

A

Clindamycin, Erythromycin, and chloremphenicol all bind same site on the 50S ribosomal subunit.
Important because of cross-resistance (2058 mutation) competitive binding for that site if co-administered.

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13
Q

What is special about the tissue distribution of Clindamycin?

A

Penetrates the CNS

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14
Q

What toxicity is associated with Clindamycin? How is this managed?

A

Pseudomembranous colitis from C. diff., megacolon. Treat with Metranidazole or Vancomycin.

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15
Q

What are two important tips for taking Tetracyclines?

A
  1. CHELATION: Don’t take with divalentcation-contatining products (Milk, Antacids, Iron) or take those 2 hrs bfore taking the medicine.
  2. PAIN ON INJECTION: (thrombophlebitis); insoluble calcium complex formation.
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16
Q

What is one use of EDTA?

A

Taken w/ Tetracycline to reduce PAIN ON INJECTION. Competes with Tetracycline for Ca2+ chelation. - prevents insoluble complex formation.

17
Q

What are the two toxicities associated with Tetracyclines? What causes these?

A

Dehydration and epimerization of drug in acid or old meds
Fanconi syndrome - failure to reabsorb in the PCT
GI upset

18
Q

How can the toxicities associated with Tetracyclines be avoided?

A

Use lower doses if possible. DON’T administer old meds. Med monitoring for epimerization.

19
Q

Other than tetracycline, what are 4 other tetracyclines, and why would you use them as opposed to tetracycline?

A
  1. Democycline - for SIADH; Demethylated C6 = secondary carbocation = slower dehydration and epimerization
  2. Minocycline - NO hydration or epimerization - Lacks C6 OH
  3. Doxycycline - NO hydration or epimerization - Lacks C6 OH, Fecally excreted, and once-a-day dosing.
  4. Oxytetracycline
20
Q

Chloremphenicol is often only used in developing countries because it is a cheap drug. However, it has serious side effects. What toxicities are associated with chloremphenicol?

A

Aplastic anemia - Rare and Fatal
Bone marrow suppression - reversible
Gray Baby Syndrome

21
Q

What is Gray Baby Syndrome? What causes it and why?

A

Babies are gray ashen color, limp, and hypotensive. Cuased by Chloremphenicol. Neonates have underdeveloped UDP-glucuronyl transferases in their livers and can’t metabolize chloremphenicol.

22
Q

How is resistance to chloramphenicol developed?

A

Acetyltransferase enhancement - acetylation inactivates the drug.

23
Q

Name 7 Aminoglycosides. What is the general use for aminoglycosides? Any special uses for the 7 named?

A 
AMINOGLYCOSIDES: Severe G- rod infections
Gentamicin - UTI, burns, osteomyelitis/septic arthritis
Tobramicin
Neomycin - Bowel surgery prophylaxis
Amikacin - Nosocomial
Kanamycin
Spectinomycin - N. gonorrhea
Streptomycin
24
Q

What is the mechanism(s) of action of aminoglycosides?

A
  1. Inhibit formation of initiation complex
  2. Block translocation from A–>P site
  3. Cause misreading of mRNA (impairs proofreading function –> wring AA in proteins –> cell membrane damage –> enhances permeability to more drug)
25
Q

What are aminoglycosides often paired with? What are the conditions of useing these agents together and why?

A

Paired with beta-lactam/penicillin - Synergism. Enhances cell uptake of aminoglycoside b/c of damaged cell wall. Don’t use in same solution or at same injection site - the combo of drugs will inactivate each other.

26
Q

What toxicities are associated with Aminoglycosides, and what do you do to treat the toxicities?

A 
Ototoxicity/Vestibulartoxicity - Permanent, Discontinue or lower dose
Nephrotoxicity  - Discontinue or lower dose
Neuromuscular blocade (curare-like effect) - Neostigmine, Calcium gluconate
27
Q

How has resistance developed to Aminoglycosides?

A

Bacterial transferase enzymes that inactivate by acetylation, phosphorylation, and adenylation.

28
Q

What are the three streptogramins and which are bacteriostatic vs. bacteriocidal?

A

Quinupristin - Bacteriostatic
Dalfopristin - Bacteriostatic
Synercid - 30% Quinu, 70% Dalfo - BACTERIOCIDAL

29
Q

What are two antibiotics that are effective against VanR E. faecium and MRSA?

A

Synercid (Streptogramin), Linezolid (Oxazolindinones)

30
Q

What is one contraindication for giving a streptogramin?

A

Taking other meds metabolized by CYP3A4 - streptoramins inhibit CYP3A4.

31
Q

What are the mechanisms of Quinupristin and Dalfopristin?

A

Quinupristin - Blocks peptide exit tunnel in ribosome

Dalfopristin - Blocks peptidyl transferase/peptide bond formation. (Same as chloremphenicol)

32
Q

Resistance to quinupristin has developed how?

A

quinupristin binds in same site as erythromycin and clincamycin = same 2058 ribosomal 50S mutation confers resistance.

33
Q

What are toxicities associated with linezolid?

A

Thrombocytopenia, myelosuppresion, anemia -> Candida infections. Lactic acidosis.

34
Q

What should not be consumed or taken with linezolid and why?

A

Linezolid = MAO inhibitor
Serotonin syndrome if taken with:
Serotonergic or adrenergic agents, Tyramine

35
Q

How has resistance to linezolid developed?

A

2576 mutation of site in 50S subunit where linezolid binds.

Pharmacology Infectious Disease (8 decks)

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