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Drug Action IV > Macrolides (MC) - Block 1 > Flashcards

Macrolides (MC) - Block 1 Flashcards

1
Q

Describe the structure of macrolides?

A
  1. Macrolactone (14-16 memmbered) ring to where certain components are areas of instability
  2. Attachment of 2 sugars:
    * 3’ cladinose sugar
    * 5’ desosamine sugar
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2
Q

What is the purpose of the desosamine sugar?

A

Salt formed through interactions is used to increase solubility

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3
Q

What acids increase solubility when combined with desosamine? Decrease solubility?

A

Glucoheptonic and lactobiononic acids

Laurylsulfate, stearic, estolate, EES

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4
Q

What portion of the macrolide forms a salt?

A

Desosamine sugar

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5
Q

What process inactivates macrolides?

A

Rapid acid-catalyzed internal cyclic ketal formation in the GIT

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6
Q

Descibe the acid instibility of macrolides

A
  1. OH serves as a nucleophile to O=
  2. In the presence of stomach acid, carbon with 2Os become anomeric
  3. 2nd OH attacks the anomeric carbon
  • Instability accounts for GI disturbances, prokinetic effects, cramping
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7
Q

Describe the MOA of macrolides?

A
  1. Interferes with ribosomal protein synthesis by binding to 23S rRNA in polypeptide exit tunnel adaject to peptidyl transferase center with in 50S subparticle
  2. Overall, prevents the growing peptide from becoming larger -> dissociation of peptidyl tRNA molecules
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8
Q

What are the binding sites of macrolides?

A
  1. Domain V at A2058 and A2059 in 50S
  2. Domain II at A752
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9
Q

Macrolide sites are occupied by? How is this bad?

A

Clindamycin, lincomycin, chloramphenicol, and streptogramin B antibiotics -> extensive cross resistance

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10
Q

What happens if you remove the cladinose sugar from the macrolide structure?

A

Methylation of sugar reduces binding to domain V of 23S -> 100 fold decrease in biological activity

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11
Q

What ABX classes produce incomplete bacterial proteins?

A

Macrolides and tetracyclines

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12
Q

What are macrolides target area?

A

50S ribosomal subparticle and inhibits translocation of aminoacyl-t-RNA (plug the export hole)

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13
Q

Resistance is primarily a result of ___? Against macrolides?

A

R factor enzymes
* Macrolides methylate a specific A2058 residue on their own rRNA

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14
Q

Apart from the formation of resistant A2058 residues, what other methods of resistance does bacteria have against macrolides?

A

Mutation of adenine to guanine within domain V A2058
* Results in a 10000 fold reductio of binding capacity of erythromycin and clarithromycin to the 23S rRNA

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15
Q

Why are macrolides used for G- bacteria?

A

Other ABX have decreased ability to penetration the cell membrane, macrolide, however, target their isolated ribosomes

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16
Q

What are the mechanisms of macrolide resistance?

A
  1. Associated with an A to G mutation at A2058-(Domain V)
    * 10,000 fold reduction in binding of erythromycin and clarithromycin
  2. Associated with methylation of A2058
    * Reduced binding of erythromycin and clarithromycin
17
Q

How can you prevent macrolide resistance?

A

Strong binding of Ketolides (e.g. telithromycen) prevents these resistance mechanisms

18
Q

What are the therapeutic uses for macrolides?

A
  1. Treatment of upper and lower respiratory tract and soft-tissue infections caused by G+ bacteria -> lang post ABX effect
  2. STDs
  3. Mild systemic infections:
    * Respiratory tract (CAP, Otitis media, AECB)
19
Q

Some macrolide derivatives are ___? ADRs involved?

A

Propropulsive through stimulation of gastrin production
ADR: hyperperistalsis -> GI cramps

20
Q

Describe macrolides spectrum of activity?

A
  1. Excellent G+ activity
  2. Acitive against many atypical organisms
  3. Poor G- activity because its inability to penetrate the cell wall (except for H. influenzae)
21
Q

What is a popular prodrug macrolide?

A

Erythromycin estolate: C2 propionyl ester and N-lauryl sulfate salt

21
Q

What is a ADR of erythromycin estolate?

A

Ilosone can cause cholestatic jaundice and must be replaced by another nonmacrolide ABX

22
Q

Describe the formulation of erythromycin ethyl succinate?

A

Mixed double ester pro-drug
* Oral suspension
* One carboxyl of sucicnate esterifies the C2 hydroxyl of erythromycin and the otehr ethanol

23
Q

What is erythromycin stearate?

A
  1. Very insoluble salt form of erythromycin
    * Water insolubility helps to mask the taste
    * Enhances stability in stomach
24
Q

What is erythromycin lactobionate?

A

Salt enhances solubility -> injections

25
Q

How does clarithromycin differ from Erythromycin?

A
  1. Produced synthetically by the 6-O methylation of erythromycin -> preventing internal ketal formation (acid stable)
  2. Enhanced lipophilicity of clarithromycin -> lower and less frequent dosing
26
Q

What are the outcomes of clarithromycin first pass metabolism?

A

Extensive and saturable:
1. FOrms a C14 OH analogue
2. Greater antimicrorbial potency than parent especially with H. influenzae

27
Q

Describe the metabolism of macrolide analogs?

A
28
Q

Descibe the structure of Azithromycin?

A
  1. 15 memebered lactone ring -> doesn’t form cyclic internal ketal (acid stabile)
  2. Azalide is formed by the semisyntheitc conversion of erythromycin
    * Carbonyl moeity absent
    * Ring-expanded analogue with an N-methyl group inserted between carbons 9 and 10
29
Q

Benefits of using Azithromycin?

A

Significant postantibiotic effcect against a number of pathogens -> first choice macrolide
* H. influenzae, Bordetella

30
Q

What is ketolide?

A
  • Contains no cladinose sugar
  • Agents that undergo oxidation of the 3-position from an alcohol to a ketone
31
Q

Types of ketolides?

A

Telithromycin

32
Q

How does the structure of Telithromycin contribute to its effectiveness?

A

Addition of the chain at C11/12 improves domain II binding:
1. No cladinose sugar -> reduced domain V
2. Strong binding to domain V and II reduces bacterial resistance

Drug Action IV (28 decks)

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