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Respiratory Medicine Midterm > Protein Synthesis Inhibitors - 50 S ribosome > Flashcards

Protein Synthesis Inhibitors - 50 S ribosome Flashcards

1
Q

Macrolides

A

Erythromycin
Clarithromycin
Azithromycin

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2
Q

Ketolides

A

Telithromycin

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3
Q

Erythromycin

A

Esters absorbed well

Acid labile, poor oral absorption

Activity spectrum: mainly gram + cocci, treponema pallidum

Use in patients with PCN allergy

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4
Q

Clarithromycin

A

T1/2 - 3-4 hr

good intestinal absorption

Activity spectrum - extended gram - and chlamydia, legionella, pneumophilia, moraxella

has active metabolite

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5
Q

Azithromycin

A

T1/2 = 40 hr

Good intestinal absorption

Activity spectrum - same + more gram -
Drug of choice for legionnaire’s disease

Has active metabolite, least drug-drug interactions

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6
Q

Telithromycin

A

T1/2 = 10 hr

Good intestinal absorption

Activity spectrum - covers MDR S. pneumoniae

has active metabolite

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7
Q

Organisms macrolide antibiotic active against

A

gram +: S. aureus (except MRSA), group A, B, C, G streptococcus

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8
Q

Major indications of macrolines/ketolides in CAP

A

S. pneumoniae
Hemophilus spp
Moraxella catarrhalis

Atypical:
Legionella pneumophila
Chlamydiphila pneumonia
Mycoplasma

Distribute into and concentrate in body tissues and phagocytic cells where concentrations are greater than in plasma

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9
Q

MOA of macrolides and ketolides

A

irreversible bind 50 S subunit of bacterial ribosomes

bacteriostatic

Inhibit translocation step of protein synthesis –> inhibition of bacterial protein synthesis

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10
Q

Mechanisms of resistance to Macrolides

A

Methylation of ribosome
-Methylases encoded by erythromycin ribosome methylase genes (ERM-A, -B, -C…) alter macrolide binding to ribosome –> high level of resistance

Macrolide efflux pumps - mef E genes, pump macrolides out of cytosol –> mid-level resistance

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11
Q

Organisms intrinsically resistant to macrolides due to decreased permeability of the outer cell envelope

A

Enterobacteriaceae
Pseudomonas spp
Acinetobacter spp

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12
Q

Adverse Effects and clinical complications of macrolides and ketolides

A

GI: N/V/D

Hepatotoxicity - rare, serious

  • cholestatic jaundice - erythromycin astrolabe (hypersensitivity)
  • fatal hepatotoxicity - telithromycin

Cardiac - QTc interval prolongation - rare, serious

Drug-Drug: CYP3A interaction

Reversible hearing loss

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13
Q

QT interval prolongation with macrolides and telithromycin

A

intrinsic arrhythmogenic capability via blockade of the Ikr channel - inward rectifying K+ channel

Prolonged cardiac depolarization - prolonged QT interval - increases risk for torsades de pointes arrhythmias

Erythromycin>clarithromycin and azithromycin

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14
Q

Erythromycin with CYP3A4 inhibitors

A

Erythromycin alone associated with 2 fold risk of sudden cardiac death

5 fold increase if taking CYP3A4 - elevates circulating erythromycin levels

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15
Q

Category B Macrolides

A

Erythromycin
Azithromycin

Safest macrocodes in pregnancy

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16
Q

Macrocodes and CYP450 drug-drug interactions

A

Erythromycin and clarithromycin interact with inhibition of hepatic CYP3A enzymes

Azithromycin minimal effects on hepatic enzymes and fewer documented drug interactions

17
Q

Lincosamides

A

Clindamycin

18
Q

Clindamycin properties

A

similar to erythromycin - site and MOA, mech or resistance, efficacy vs non-enteric gram + cocci

19
Q

Antimicrobial spectrum of Clindamycin

A

anaerobes - primary clinical use

  • abdominal anaerobic infections associated with trauma
  • bacteroides fragilis
20
Q

Main adverse event of clindamycin

A

pseudomembranous colitis caused by C. diff

  • manage with:
  • metronidazole
  • vancomycin PO
21
Q

Management of toxin production of MRSA

A

MRSA harbor Panton-Valentine leukocidin (PVL) toxin

Alpha-toxin and SEB - (S. aureus enterotoxin B) - higher in CA-MRSA than hospital acquired MRSA
-community acquired more virulent

Use Clindamycin or Linezolid, do not increase toxins

22
Q

Chloramphenicol

A

Broad spectrum, activate against gram + and -

Restricted to life-threatening infections where there is no alternative - meningitis infections

23
Q

Lethal toxicities of Chloramphenicol

A

Aplastic anemia - idiosyncratic, life-threatening, occur after stopped. Pt with G6PD deficiency

Gray Baby Syndrome - developmental origins, penetrates human cells and disrupt mitochondrial protein synthesis

  • Abdominal distension, D/V, dusky gray color
  • circulatory collapse and death
  • drug concentration dependent - impaired glucuronidation in neonates and impaired renal clearance
24
Q

Development of clearance enzymes in neonates

A 
Sulfating - day 5
Acetylation day 20
Glomerular filtration day 30
Glucuronidation - day 60
Conjugation day 90 - glucose, GSH
Tubular secretion - day 180
25
Q

Kernicterus related to sulfonamides

A

Neonatal encephalopathy due to bilirubin displacement and poor bilirubin clearance

26
Q

Gray baby syndrome related to chloramphenicol

A

abdominal distension, D/V, dusky gray color, circulatory collapse and death

  • drug concentration dependent
  • impaired glucuronidation in neonates
  • impaired renal clearance
27
Q

Intestinomicina

A

contains chloramphenicol
people with anemia and other low blood cell counts at greater risk of injury of death from using this anti-diarrheal drug

28
Q

MOA of Chloramphenicol

A

binds to 50S ribosomal subunit, inhibits peptide transferase step of protein synthesis

Bacteriostatic

Enter host cells and impair host mitochondrial protein synthesis which produces toxicity

29
Q

Chloramphenicol Resistance

A

enzymatic modification by acetyltransferase (CAT)

30
Q

Linezolid

A

Oxazolidinones

used when organisms are vancomycin resistant

protein synthesis inhibitor

bacteriostatic

High levels are present in lungs

Binds to 50 S ribosomal subunit and interferes with binding to initiation complex

31
Q

Linezolid clearance and toxicity

A

Non-enzymatic oxidation - not CYP450 substrate, inhibitor or inducer

Renal clearance

Long term use increases ALT, decreases platelets, MAO interaction, peripheral neuropathy

Respiratory Medicine Midterm (11 decks)

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