Anti-ulcer agents

Question 1

What are the causes of peptic ulcers?

Answer 1

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

Question 2

What is the function of bicarbonate ions?

Answer 2

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

Question 3

How does the stomach protect itself from its own acidity?

Answer 3

• thick layer of mucus

- bicarbonate production which neutralizes acidity

Question 4

Why is hydrochloric acid important?

Answer 4

because proteases like pepsin need acidic conditions to work

Question 5

The release of gastric acid is stimulated by?

Answer 5

1. acetylcholine
2. gastrin
3. histamine

Question 6

What produces gastrin?

Answer 6

G cells in stomach antrum

Question 7

When is gastrin produced?

Answer 7

at the sight of food to secrete gastric juices

Question 8

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

Answer 8

H2 receptor

Question 9

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

Answer 9

histamine

Question 10

Why is gastrin not beneficial as a drug?

Answer 10

because it is a peptide and cannot be given orally

Question 11

Why is inhibiting acetylcholine useless?

Answer 11

• too many side effects

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

Question 12

How are peptic ulcers treated?

Answer 12

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

Question 13

What are antacids?

Answer 13

weak bases that are nonspecific

Question 14

What does histamine consist of?

Answer 14

1. imidazole
2. flexible chain
3. primary amine

Question 15

What is the function of the hydrophobic substituent?

Answer 15

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)

Question 16

What is the effect if there is no induced fit?

Answer 16

antagonist effect

Question 17

What is 4-methylhistamine?

Answer 17

a highly selective H2 agonist that acts as a conformational blocker

Question 18

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

Answer 18

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

Question 19

What is N-guanylhistamine?

Answer 19

H2 partial agonist

Question 20

Is guanidine or primary amine more basic and why?

Answer 20

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

Question 21

How is N-guanylhistamine a partial agonist?

Answer 21

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

Question 22

The agonist binding region requires what type of interaction?

Answer 22

ionic

Question 23

The antagonist binding region requires what type of interaction?

Answer 23

hydrogen bonding

Question 24

What is the advantage of the thiourea over the guanidine?

Answer 24

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

Question 25

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

Answer 25

neutral

Question 26

What is burimamide?

Answer 26

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

Question 27

What is the advantage of the chain extension in burimamide?

Answer 27

it is added so it can reach the antagonist region

Question 28

Was burimamide highly active or not?

Answer 28

not active enough

Question 29

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

Answer 29

tautomer 1

Question 30

What is the meaning of tautomerism?

Answer 30

the changing of positions of electrons and protons

Question 31

Tautomer number 1 of histamine can bind inside which receptors?

Answer 31

H2 receptors

Question 32

Tautomer number 1 of histamine can form which interaction?

Answer 32

hydrogen bonding

Question 33

What two modifications were applied to enhance tautomer 1 formation?

Answer 33

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

Question 34

What are the advantages of the methyl in metiamide?

Answer 34

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

Question 35

What are the advantages of the sulfur atom in metiamide?

Answer 35

1. it is an electron-withdrawing group | 2. suppresses the ionization of imidazole ring at physiological pH

Question 36

Is metiamide or burimamide more active?

Answer 36

metiamide

Question 37

What happened to the patients who took metiamide?

Answer 37

they suffered from kidney damage and granulocytopenia

Question 38

What was the problematic functional group in metiamide?

Answer 38

thiourea

Question 39

What is the first marketed H2 antagonist for peptic ulcer?

Answer 39

cimetidine

Question 40

How can we decrease the ionization of guanidine?

Answer 40

by adding an electron-withdrawing group like CN

Question 41

How was the guanidine analogue different from the urea analogue?

Answer 41

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

Question 42

Is guanidine's ionization essential for binding?

Answer 42

no

Question 43

Why was a methyl group added in cimetidine?

Answer 43

to make it more hydrophobic and thus decrease desolvation effect

Question 44

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

Answer 44

- electron-donating group | - selective for H2 receptor

Question 45

Why was the cyano group added in cimetidine?

Answer 45

to withdraw electrons and suppress ionization

Question 46

What is the effect of desolvation energy on binding?

Answer 46

the lower desolvation energy, the more the binding

Question 47

What is ranitidine?

Answer 47

the second marketed H2 antagonist

Question 48

How is ranitidine different from cimetidine?

Answer 48

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

Question 49

Compare ranitidine to cimetidine

Answer 49

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

Question 50

How are famotidine and nizatidine different from drugs before them?

Answer 50

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

Question 51

Are H2 antagonists safe and mostly free of side effects?

Answer 51

yes

Question 52

What are the four most used H2 antagonists?

Answer 52

cimetidine, ranitidine, famotidine, and nizatidine

Question 53

Do H2 antagonists inhibit all aspects of gastric secretion?

Answer 53

yes

Question 54

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

Answer 54

because of inhibition of drug metabolism (CYP450)

Question 55

How do proton pump inhibitors work?

Answer 55

by irreversibly inhibiting an enzyme complex called the proton pump

Question 56

Are H2 antagonists or proton pump inhibitors superior?

Answer 56

proton pump inhibitors

Question 57

How are proton pump inhibitors used?

Answer 57

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

Question 58

Why must protons be rapidly excreted out of the canaliculus?

Answer 58

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

Question 59

All PPIs have what kind of skeleton?

Answer 59

pyridyl methylsulphinyl benzamidazole skeleton

Question 60

All PPIs act as?

Answer 60

prodrugs

Question 61

Why do PPIs act as prodrugs?

Answer 61

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

Question 62

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

Answer 62

cysteine

Question 63

Why are proton pump inhibitors considered weak basic compounds?

Answer 63

because of pyridine

Question 64

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

Answer 64

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

Question 65

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

Answer 65

they are unionized weak bases and lipophilic in nature

Question 66

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

Answer 66

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

Question 67

Protonation triggers an ________ conversion, which activates the PPI.

Answer 67

acid-catalysed

Question 68

Why do PPIs have very few side effects?

Answer 68

because of their selectivity of action

Question 69

What was the first PPI to reach the market?

Answer 69

omeprazole which was marketed as losec

Question 70

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

Answer 70

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

Question 71

What is the S-enantiomer of omeprazole?

Answer 71

esomeprazole (nexium)

Question 72

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

Answer 72

it has better kinetics

Question 73

Is it possible to double the dose levels of esomeprazole?

Answer 73

yes

Question 74

Is it possible to double the dose levels of omeprazole?

Answer 74

no

Question 75

Benefits of esomeprazole?

Answer 75

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

Question 76

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

Answer 76

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

Question 77

How is H. pylori treated?

Answer 77

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