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Medicinal Chemistry > Lecture 24 > Flashcards

Lecture 24 Flashcards

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1
Q

What is the function of tetracyclines?

A

Block binding of AA-tRNA to A site

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2
Q

What is the function of macrolides?

A

Block translocation

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3
Q

What is the function of linezolid?

A

Prevents binding of fMet-tRNA

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4
Q

What is the function of fusidic acid?

A

Inhibits elongation factor G

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5
Q

What is the function of chloramphenicol?

A

Blocks peptide bond formation

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6
Q

What is important about the macrolide structure?

A

Have large macro-cyclic ring structure w/ a lactone and often w/ methyl/ethyl groups on alternating carbons in the ring

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7
Q

Macrolide rings come in ____ member varieties

A

14, 15, and 16

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8
Q

What is normally attached to the ring structure of macrolides and through which bonds?

A
  • At least one 6-membered amino-sugar and one 6 membered sugar
  • Glycosidic bonds
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9
Q

What do macrolides bind to?

A

50S subunit of bacterial ribosome, making interactions btwn proteins and 23S rRNA

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10
Q

Where are the most significant interactions btwn macrolides and 50S subunit of ribosome?

A

In the peptidyl transferase ring region of the 23S rRNA

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11
Q

Do macrolides block peptidyl transfer?

A

No

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12
Q

What effect do macrolides have on peptidyl transfer?

A

Binding in the peptidyl transferase region results in inhibition of translocation of aminoacyl-tRNA => preventing protein synthesis

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13
Q

Macrolides are substrates for _____

A

CYP 3A4 N-dealkylation

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14
Q

What is important about the spiroketal form of macrolides?

A
  • No antibiotic activity
  • Binds w/ high affinity to motilin receptors in the gut, stimulating smooth muscle contraction and increasing gut motility => diarrhea
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15
Q

What is erythromycin often used for w/ respect to the gut?

A

To increase gastric motility

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16
Q

What is significant about erythromycin base?

A

Poor water solubility and is acid labile

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17
Q

What is significant about erythromycin HCl?

A

Improved water solubility and is acid labile

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18
Q

What is significant about erythromycin ethylsuccinate?

A
  • Ester increases absorption of erythromycin compared to free base
  • Better tolerated
  • More acid stable than erythromycin
  • Absorbed as ethylsuccinate ester, so must be hydrolyzed for activity
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19
Q

What is significant about erythromycin estolate?

A
  • Propionic acid ester w/ lauryl sulfate counter ion
  • Improves absorption in gut
  • Better tolerated
  • Propionic acid ester must be hydrolyzed for activity
  • More acid stable than erythromycin
20
Q

Do esters of erythromycin cause less diarrhea?

A

No, as erythromycin is excreted in the bile back into the gut, the esters still cause diarrhea

21
Q

Which organisms is erythromycin effective against?

A
  • Some gram pos (strep. pyogenes and pneumoniae)
  • Variable activity against MSSA
  • Limited gram neg activity and some anaerobes
22
Q

When is erythromycin a good choice?

A

As an alternative where amoxicillin can’t be used due to an allergy

23
Q

Is erythromycin commonly used? Why or why not?

A

No, clarithromycin is used more often b/c has longer half life, and doens’t form spiroketal so doesn’t cause diarrhea

24
Q

What is clarithromycin used to treat and why?

A
  • Mycoplasma pneumoniae
  • Legionella pneumophila
  • Both bacteria lack a cell wall so beta-lactams are ineffective
25
Q

When is azithromycin used?

A
  • Same indications as clarithromycin

- As an alternative to penicillin’s like amoxicillin in the case of an allergy

26
Q

What is significant about azithromycin?

A

Extremely long half life, so need to give a loading dose

27
Q

What can macrolides cause inhibition of?

A

CYP 3A4 by competition for the enzyme

28
Q

What is the most important drug interaction w/ macrolides?

A

Warfarin

29
Q

What are some drug interactions w/ macrolides?

A
  • Carbamazepine
  • Cyclosporine
  • Theophylline
  • Warfarin
  • HMG-CoA reductase inhibitors
30
Q

What do tetracyclines bind to and what does this cause?

A
  • 16S rRNA of the 30S subunit of the bacterial ribosome

- Results in blocking the aminoacyl-tRNA from the A-site of the ribosome

31
Q

What bacteria are tetracyclines effective against?

A

Very broad spectrum (many gram pos and gram neg and anaerobes)

32
Q

___ properties of tetracyclines are essential for activity

A

Mg chelation

33
Q

Are chelates of tetracyclines well absorbed?

A

No

34
Q

What should be avoided and how long before and after taking tetracycline chelates?

A
  • Dairy products, antacids, and supplements w/ calcium, magnesium, iron, and aluminum
  • 1h before and 2h after dose
35
Q

What does calcium chelation of tetracyclines cause?

A

Causes tetracyclines to be incorporated into newly forming bones and teeth as tetracycline-calcium orthophosphated complexes => brown discolouration or streaks on teeth

36
Q

Are tetracyclines safe in pregnancy and lactation?

A

No, cross placenta and get into breast milk

37
Q

In which px should tetracyclines not be used?

A
  • Pregnant women

- Children 12 and under

38
Q

What are the 2 commonly used tetracyclines?

A

Doxycycline and minocycline

39
Q

What is the spectrum of doxycycline?

A
  • Activity against many gram pos, MRSA, and MSSA; many gram neg and anaerobes
  • Not against VRE or VRSA
  • Used as an alternative to amoxicillin when allergy is present and against mycoplasma pneumoniae and legionella pneumophila
40
Q

What is the spectrum of minocycline?

A
  • More broad than minocycline
  • Gram pos including MSSA and MRSA
  • More gram neg and anaerobes
  • Good alternative to amoxicillin when allergy is present and against mycoplasma pneumoniae and legionella pneumophila
41
Q

What is the spectrum of tigecycline?

A
  • All gram pos including MSSA, MRSA, and VRSA (not VRE)

- Most gram neg and anaerobes

42
Q

When is tigecycline used?

A

As a very last resort b/c of side effects

43
Q

What are some side effects of tetracyclines?

A

Erosions of epithelium => irritation to tissues and photosensitivity

44
Q

Which location is most susceptible to tetracycline side effects and how can this be prevented?

A
  • Esophagus

- Take dose w/ full glass of water and do not lie down for at least 1/2 hour after a dose

45
Q

How can a bacteria produce macrolide resistance?

A
  • Produce a gene that methylates the A2058 (causes steric hindrance for macrolide binding)
  • Mutation of A2058 to G (reduces # of potential H-bond interactions)
46
Q

What makes macrolides lethal for bacteria but harmless for humans?

A

Bacterial ribosomes have A2058 while human ribosomes don’t

Medicinal Chemistry (14 decks)

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