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medicinal chem > Anti-ulcer agents > Flashcards

Anti-ulcer agents Flashcards

1
Q

What are the causes of peptic ulcers?

A
  1. Stress, alcohol, and diet
  2. The use of nonsteroidal anti-inflammatories (NSAIDS)
  3. The presence of a bacterium called Helicobacter pylori .
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2
Q

What is the function of bicarbonate ions?

A

trapped in the mucus to create a pH gradient within the mucus layer

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3
Q

How does the stomach protect itself from its own acidity?

A
  • thick layer of mucus

- bicarbonate production which neutralizes acidity

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4
Q

Why is hydrochloric acid important?

A

because proteases like pepsin need acidic conditions to work

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5
Q

The release of gastric acid is stimulated by?

A
  1. acetylcholine
  2. gastrin
  3. histamine
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6
Q

What produces gastrin?

A

G cells in stomach antrum

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7
Q

When is gastrin produced?

A

at the sight of food to secrete gastric juices

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8
Q

The local hormone histamine stimulates the release of gastric acid by interacting with what type of histamine receptor?

A

H2 receptor

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9
Q

Of acetylcholine, gastrin, and histamine, which compound’s inhibition ended up useful?

A

histamine

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10
Q

Why is gastrin not beneficial as a drug?

A

because it is a peptide and cannot be given orally

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11
Q

Why is inhibiting acetylcholine useless?

A
  • too many side effects

- inhibiting acetylcholine will result in inhibiting acetylcholine everywhere in the body

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12
Q

How are peptic ulcers treated?

A
  • H2 histamine antagonists
  • Proton pump inhibitors (PPIs).
  • Antacids
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13
Q

What are antacids?

A

weak bases that are nonspecific

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14
Q

What does histamine consist of?

A
  1. imidazole
  2. flexible chain
  3. primary amine
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15
Q

What is the function of the hydrophobic substituent?

A
  1. to occupy a hydrophobic pocket within the binding site
  2. to prevent the target protein from switching on into the active conformational structure (the one that gives a biological response)
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16
Q

What is the effect if there is no induced fit?

A

antagonist effect

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17
Q

What is 4-methylhistamine?

A

a highly selective H2 agonist that acts as a conformational blocker

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18
Q

What is the function of the methyl in 4-methylhistamine?

A

the methyl forces histamine to stay in the active conformational structure that fits the H2 but not the H1

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19
Q

What is N-guanylhistamine?

A

H2 partial agonist

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20
Q

Is guanidine or primary amine more basic and why?

A

guanidine because once it forms the conjugate acid it can be stabilized by resonance

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21
Q

How is N-guanylhistamine a partial agonist?

A

it can fit two different binding sites (agonist and antagonist)

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22
Q

The agonist binding region requires what type of interaction?

A

ionic

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23
Q

The antagonist binding region requires what type of interaction?

A

hydrogen bonding

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24
Q

What is the advantage of the thiourea over the guanidine?

A

it forms only a hydrogen-bonding interaction so it fits the antagonist and not the agonist region.

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25
Q

Is thiourea an acidic, neutral, or a basic functionality?

A

neutral

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26
Q

What is burimamide?

A

highly specific competitive histamine H2 antagonist that is 100 times more potent than N-guanylhistamine in inhibiting gastric acid release

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27
Q

What is the advantage of the chain extension in burimamide?

A

it is added so it can reach the antagonist region

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28
Q

Was burimamide highly active or not?

A

not active enough

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29
Q

Which tautomer form of imidazole is the one that fits the binding site?

A

tautomer 1

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30
Q

What is the meaning of tautomerism?

A

the changing of positions of electrons and protons

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31
Q

Tautomer number 1 of histamine can bind inside which receptors?

A

H2 receptors

32
Q

Tautomer number 1 of histamine can form which interaction?

A

hydrogen bonding

33
Q

What two modifications were applied to enhance tautomer 1 formation?

A

1) Inserting an electronegative atom (sulfur) in the side chain.
2) Inserting an electron-donating group (methyl) at position 4 of the imidazole ring

34
Q

What are the advantages of the methyl in metiamide?

A
  1. increased basicity
  2. enhances tautomer 1 and increases selectivity for H2 receptor
  3. electron-donating group
35
Q

What are the advantages of the sulfur atom in metiamide?

A
  1. it is an electron-withdrawing group

2. suppresses the ionization of imidazole ring at physiological pH

36
Q

Is metiamide or burimamide more active?

A

metiamide

37
Q

What happened to the patients who took metiamide?

A

they suffered from kidney damage and granulocytopenia

38
Q

What was the problematic functional group in metiamide?

A

thiourea

39
Q

What is the first marketed H2 antagonist for peptic ulcer?

A

cimetidine

40
Q

How can we decrease the ionization of guanidine?

A

by adding an electron-withdrawing group like CN

41
Q

How was the guanidine analogue different from the urea analogue?

A

the guanidine analogue was less active like urea but unlike urea it had no agonist activity

42
Q

Is guanidine’s ionization essential for binding?

A

no

43
Q

Why was a methyl group added in cimetidine?

A

to make it more hydrophobic and thus decrease desolvation effect

44
Q

What is the effect of the methyl connected to the imidazole in cimitedine?

A
  • electron-donating group

- selective for H2 receptor

45
Q

Why was the cyano group added in cimetidine?

A

to withdraw electrons and suppress ionization

46
Q

What is the effect of desolvation energy on binding?

A

the lower desolvation energy, the more the binding

47
Q

What is ranitidine?

A

the second marketed H2 antagonist

48
Q

How is ranitidine different from cimetidine?

A

cimetidine’s cyano group was swapped out for a nitro group to give ranitidine

49
Q

Compare ranitidine to cimetidine

A

Ranitidine has fewer side effects than cimetidine, a longer duration of action, and is 10 times more active

50
Q

How are famotidine and nizatidine different from drugs before them?

A

they have a thiazole ring (ring with sulfur) instead of imidazole

51
Q

Are H2 antagonists safe and mostly free of side effects?

A

yes

52
Q

What are the four most used H2 antagonists?

A

cimetidine, ranitidine, famotidine, and nizatidine

53
Q

Do H2 antagonists inhibit all aspects of gastric secretion?

A

yes

54
Q

Why must attention be given to possible drug interactions when using cimetidine?

A

because of inhibition of drug metabolism (CYP450)

55
Q

How do proton pump inhibitors work?

A

by irreversibly inhibiting an enzyme complex called the proton pump

56
Q

Are H2 antagonists or proton pump inhibitors superior?

A

proton pump inhibitors

57
Q

How are proton pump inhibitors used?

A

they are used on their own to treat ulcers that are caused by NSAIDs and in combination with antibacterial agents to treat ulcers caused by the bacterium H. pylori

58
Q

Why must protons be rapidly excreted out of the canaliculus?

A
  1. accumulation of protons inside parietal cells can lead to cell damage
  2. if the protons are accumulated they will go back to carbon dioxide
59
Q

All PPIs have what kind of skeleton?

A

pyridyl methylsulphinyl benzamidazole skeleton

60
Q

All PPIs act as?

A

prodrugs

61
Q

Why do PPIs act as prodrugs?

A

because they are activated when they reach the acidic canaliculi of parietal cells

62
Q

Once activated, PPIs bind irreversibly to exposed ______ residues of the proton pump and ‘block’ the pump

A

cysteine

63
Q

Why are proton pump inhibitors considered weak basic compounds?

A

because of pyridine

64
Q

What if the proton pump inhibitors were given orally without the enteric coating?

A

they will not be absorbed because of the positive charge that will make the drug highly polar and unable to pass

65
Q

How can PPIs cross the cell membrane of the parietal cell into the canaliculi?

A

they are unionized weak bases and lipophilic in nature

66
Q

Why does a 1000-fold accumulation occur in the canaliculi?

A

because of protonation and the ionized drug is too polar to cross back into the cell through the cell membrane

67
Q

Protonation triggers an ________ conversion, which activates the PPI.

A

acid-catalysed

68
Q

Why do PPIs have very few side effects?

A

because of their selectivity of action

69
Q

What was the first PPI to reach the market?

A

omeprazole which was marketed as losec

70
Q

Why is omeprazole (and other PPIs) much more active than H2 antagonists?

A

because they bind directly with the proton pump and they bind covalently not reversibly so that the parietal cell needs to synthesize new receptors

71
Q

What is the S-enantiomer of omeprazole?

A

esomeprazole (nexium)

72
Q

Why is the S-enantiomer of omeprazole superior to its R-enantiomer?

A

it has better kinetics

73
Q

Is it possible to double the dose levels of esomeprazole?

A

yes

74
Q

Is it possible to double the dose levels of omeprazole?

A

no

75
Q

Benefits of esomeprazole?

A
  • undergoes less hydroxylation
  • has a lower clearance rate
  • achieves higher plasma levels
  • can result in greater activity after doubling dose
76
Q

Why can bacterial cells contribute to the formation of stomach ulcers?

A

because they secrete proteins and toxins that interact with the stomach’s epithelial cells, leading to inflammation and cell damage

77
Q

How is H. pylori treated?

A

with a triple therapy of a PPI and at least two antibacterial
agents

medicinal chem (3 decks)

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