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Respiratory II > Pharmacology- Chen Macrolides > Flashcards

Pharmacology- Chen Macrolides Flashcards

1
Q

Where do macrolides act?

A

They are protein synthesis inhibitors that block the 50S subunit

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2
Q

What was the first macrolide?

A

Erythromycin

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3
Q

What do macrolides end in?

A

-thromycin

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4
Q

What do aminoglycosides end in?

A

-mycin

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5
Q

What subunits are bacterial ribosomes made up of?

A

A 70S subunit, which made up of a 50S and 30S subunit

The 50S subunit is further divided into 5S and 23S (r RNA and proteins)

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6
Q

Where is the binding site for macrolides?

A

the 23S rRNA

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7
Q

What subunits make up human ribosome?

A

It is an 80S subunit that is composed of a 60S and a 40S subunit

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8
Q

What is the MOA for Macrolides (eryhtromycin, clarithromycin, azithromycin)?

A
  • Binds the 50S ribosomal RNA polypeptide exit tunnel which is near the peptidyltransferase center
  • It inhibits transpeptidation and translocation step of protein synthesis (blocks the movement of the peptides from P to A)
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9
Q

What domain do macrolides have a higher affinity for?

A

-Domain V of 23S rRNA

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10
Q

Are macrolides bacteriostatic or bactericidal?

A
  • Bacteriostatic

- At higher drug concentrations it can become bactericidal for some organisms

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11
Q

What is the MOA of ketolides (telithromycin)?

A

-Binds to the 50S rRNA polypeptide and inhibits transpeptidation and translocation step of protein synthesis

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12
Q

What domains do ketolides have a higher affinity for?

A

Ketolides can bind domain V and also have a high affinity for domain II of 23S rRNA

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13
Q

If there is resistance that results in alteration of the structure of V, will macrolides work?, Ketolides?

A
  • Macrolides will not work because this is the only place that they bind
  • Ketolides will still work because they can also bind to the II domain as well
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14
Q

What are the 3 mechanisms of resistance to macrolides?

A
  1. Reduced permeability of the cell membrane or increased active efflux
  2. Modification of the ribosomal binding site
  3. Production of esterases that hydrolyze macrolides
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15
Q

Which mechanism of resistance is one of the most important for gram + organisms?

A

Reduced permability of the cell membrane or increased active efflux

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16
Q

What gene increases the activity of efflux pumps to get macrolides out of bacteria?

A

Macrolide efflux (mef) genes

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17
Q

Which types of antibiotics have no cross resistance with bugs that have macrolide efflux genes?

A

Ketolides (telithromycin), lincosamides (clindamycin), and streptogramins (quinupristin-dalfopristin)

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18
Q

Is cross resistance due to macrolide efflux genes complete between erythromycin and other macrolides?

A

Yes–> All macrolides are affected by this resistance

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19
Q

What is another important resistance mechanism for gram+ organisms?

A

Modification of the ribosomal binding site

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20
Q

What gene mediates modification of the ribosomal binding site?

A

Erythromycin ribosome methylase (erm) genes

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21
Q

How do the erm genes work?

A

They methylate an adenine residue in domain V of 23S rRNA and prevent binding of macrolides and ketolides here

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22
Q

How do ketolides overcome modification of the ribosomal binding site by erm genes?

A

They can bind domain II

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23
Q

Is modification of the ribosomal binding site a high level or low level resistance?

A

High level macrolide resistance

  • This confers resistnace to mechanistically similar compounds such as clindamycin and streptogramins (these share the same ribosomal binding site)
  • This methylates all of domain V
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24
Q

What gene mediates the production of esterases that hydrolyze macrolides?

A

Erythromycin esterase gene (ere)

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25
Q

How does the ere gene exert its affects?

A

Hydrolyzes the lactone ring of macrolides and inhibits macrolide activity

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26
Q

Why does erythromycin have to be administered with enteric coating?

A

Because erythromycin base is the only microbiologically active structure and the base is destroyed by stomach acid

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27
Q

What preparations is erythromycin given in?

A

Stearate and ester

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28
Q

Which macrolides are more acid stable and have greater oral bioavailability?

A

Clarithromycin, Azithromycin, and Telithromycin

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29
Q

Where are the levels of clarithromycin, azithromycin, and telithromycin greater than levels in the serum?

A

Lung tissue and alveolar macrophages

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30
Q

Do macrolides have good CSF penetration?

A

No

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31
Q

Which macrolide may require dose adjustments in patients with moderate to severe renal impairment?

A

Clarithromycin

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32
Q

Which macrolide is the choice for STD and why?

A

Asithromycin

-It has high tissue concentrations and a prolonged tissue halflife

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33
Q

Which macrolides are metabolized by CYP3A4?

A

Erythromycin, clarithromycin, telithromycin

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34
Q

Order the macrolides from most activity to least activity for gram + aerobes

A

Teli > Clari> Ery> Azi

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35
Q

Order the macrolides from most activity to least activity for gram - aerobes

A

Teli>Azi>Clari> Ery

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36
Q

What other pathogens are macrolides effective against?

A

Chlamydophilia pneumoniae

Mycoplasma pneumoniae

37
Q

What community acquired respiratory tract infections are macrolides used for?

A

Pharyngitis, otitis media, sinusitis, acute infective exacerbation of chronic bronchitis, community acquired pneumonia, pertussis, legionnaires disease

38
Q

Which conditions do you use Clari- and Azi- for?

A

Pharyngitis, otitis media, and sinusitis

39
Q

What do you use for an acute infective exacerbation of chronic bronchitis?

A

Clari

40
Q

What do you use for CAP?

A

Clari, Azi, Teli

41
Q

What do you use for pertussis or legionnaires disease?

A

Ery

42
Q

What non-respiratory conditions can macrolides be used for?

A

STDs, skin and soft tissue infections, H. Pylori infections, MAC in AIDS patients

43
Q

What STDs can only Azi be used for?

A

Uncomplicated urethritis or cervicitis and chancroid

44
Q

What do you use for chlamydial infections?

A

Ery, Azi

45
Q

What do you use for syphillis?

A

Ery

46
Q

Which drugs are used for skin and soft tissue infections?

A

Ery, clari, azi

47
Q

What drug is used for H. Pylori infections?

A

Clari

48
Q

Which drugs are used for MAC in aids patients?

A

Clari, azi

49
Q

What CV AE do macrolides cause?

A

QT interval prolongation

50
Q

What GI AE do macrolides cause?

A

N/V/D

51
Q

Which macrolide most commonly causes GI issues and why?

A

Ery because it is a direct agonist of motilin receptor

52
Q

What MSK AE do macrolides cause?

A

Myasthenia Gravis

53
Q

What ophthalmic AE do macrolides cause?

A

Abnormal vision and blurred vision

54
Q

What otic AE do macrolides cause and which one specifically does this?

A

Reversible ototoxicity- Ery

55
Q

What hepatic AE do macrolides cause?

A

Cholestatic hepatitis, hepatitis and liver toxicity, life-threatening liver failure (teli)

Other indications for teli were removed when it was realized that this drug can cause hepatitis and liver failure

56
Q

What drugs are contraindicated with ery, clari, teli?

A

Theophylline, warfarin, CCBs, cyclosporine

57
Q

Why does this contradiction exist?

A

Ery, clari and teli are oxidized by CYP3A4 to a metabolite which forms an inactive metabolite-enzyme complex by binding to the heme of the CYP3A4 enzyme–> This results in reduced clarance of other agents that are metabolized by CYP3A4

58
Q

How does ery, clari, and teli increase digoxin levels in the blood?

A
  1. Macrolides destroy the gut flora that normally metabolizes digoxin to inactive products
  2. Macrolides inhibit P-glycoprotein mediated renal secretion and excretion of digoxin (reduces elimination of digozin)
59
Q

What is the MOA for oxazolidinones (linezolid)

A

Binds to the 50S ribosomal RNA (rRNA) and interferes with the formation of the complex that associates mRNA, fmet-tRNA, and 50S ribosome which blocks protein synthesis

60
Q

Is there any cross resistance with other drug classes for linezolid?

A

No, it has a unique binding site

61
Q

Is linezolid bacteriostatic or bactericidal?

A

It is bacteriostatic, but at higher concentrations may become bactericidal

62
Q

What is the mechanism of resistance for linezolid?

A

Mutation of the linezolid binding site on 23S rRNA

63
Q

Is linezolid have good oral bioavailability?

A

Yes, it’s 100%

64
Q

Does linezolid affect CYP3A4?

A

No

65
Q

What hematologic AE are associated with linezolid?

A

Thrombocytopenia**

Also anemia and neutropenia in patients with underlying BM suppression

66
Q

What GI AE are associated with linezolid?

A

N/V/D

67
Q

What neurological AE are associated with linezolid?

A

Peripheral neuropathy

68
Q

What endocrine/metabolic AE are assocaited with linezolid?

A

Lactic acidosis

69
Q

What is the most common AE with linezolid?

A

Thrombocytopenia

70
Q

What are the respiratory uses for linezolid?

A

CAP and nosocomial pneumonia (this drug is very good for these)

71
Q

What are the non-respiratory uses for linezolid?

A

Skin and soft-tissue infections

Vancomycin-resistant enterococcus faecium infection

72
Q

When do we want to use linezolid?

A

As a last resort for multi-drug resistant infections

(We want to prevent bacteria from developing resistance to this

73
Q

What is warfarin predominantly metabolized by?

A

CYP3A4

74
Q

Why does warfarin dose need to be adjusted carefully when used with a macrolide?

A

Because it has a narrow therapeutic window and macrolides inhibit CYP3A4 thus messing with the normal metabolism of warfarin

75
Q

What % of digoxin is converted to inactive metabolites in 10% of the population by normal gut flora?

A

40%

76
Q

What do macrolides do to gut flora?

A

They reduce the number of normal gut flora

77
Q

What effect does macrolides reducing gut flora have on the metabolism of digoxin?

A

It reduces the conversion of digoxin to inactive metabolites and can increase digoxin toxicity

78
Q

What is one mechanism for digozin excretion?

A

Through secretion mediated by P-glycoprotein in the kidney

79
Q

What do macrolides do to P-glycoprotein and what is the implication of this for digoxin?

A

Macrolides inhibit P-glyoprotein mediated transport and increase serum levels of digoxin

80
Q

What are the 2 common presentations of myasthenia gravis?

A

Muscle weakness and ocular symptoms (diplopia and ptosis)

81
Q

What effect do macrolides have on myasthenia gravis?

A

They can unmask it

82
Q

Which macrolide was originally used for legionnaire’s disease?

A

Eryhtromycin

83
Q

Which macrolide is indicated for H. Pylori infections, upper and lower respiratory tract infections and MAC?

A

Clarithromycin

84
Q

Which macrolide is indicated for STDs and MAC and why?

A

Azithromycin

-Due to high tissue concentration and long tissue half life

85
Q

What domain is the ketolide telithromycin more selective for?

A

Domain II of 23S rRNA

86
Q

Why were other respiratory indications removed for telithromycin?

A

RIsk of hepatitis and high-mortality liver failure

87
Q

Why does linezolid have no cross resistance with other agents

A

It has a unique binding site on the 50S rRNA

88
Q

When should linezolid be used?

A

As a reserve antibiotic… used sparingly and as a last resort against multidrug-resistant infections

Respiratory II (8 decks)

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