Lecture 17 (after midterm 2)

Question 1

Bacterial functions in the human body

Answer 1

1) Maturation of the immune system and gut physiology
2) Synthesis of vitamins and metabolites
3) Digestions of complex glycans derived from food (fibers)
4) Protection from intestinal infection (Clostridioides difficile)

Question 2

Effect of Gut microbiota on drugs

Answer 2

Can metabolize drugs activating, inactivating or toxifying them

Question 3

What is Peptic Ulcer disease

Answer 3

Where the mucosal epithelium is exposed to acid and pepsin
Affects the upper GI tract (stomach, duodenum, and lower esophagus)

Question 4

What induces the formation of ulcers

Answer 4

Excess acid production or impaired barrier function that overwhelms the defense mechanisms in the GIT

Question 5

What are first line treatments for Peptic Ulcer Disease (PUD)

Answer 5

Proton pump inhibitors (given the cause is NOT a bacterial infection)
If caused by Helicobacter pylori, use antimicrobial treatment

Question 6

Possible causes of Peptic Ulcer Disease (PUD)

Answer 6

NSAIDs, stress and chronic illnesses, and Helicobacter pylori infection (bacterial infection)

Question 7

What is Gastroesophageal Reflux disease (GERD)

Answer 7

A dysfunctional relaxation of the lower esophageal sphincter, allowing reflux of acidic gastric contents from the stomach into the esophagus

Question 8

What can Gastroesophageal Reflux Disease (GERD) lead to

Answer 8

Inflammation, bleeding, ulcerations, and Barret esophagus

Question 9

What is Barrett esophagus

Answer 9

Reorganization of the cell lining of the esophagus in response to acid damage
A premalignant condition
Associated with high incidence of transition to cancer

Question 10

GERD treatment

Answer 10

Proton pump inhibitors, histamine (H2) receptor antagonists, and dopamine antagonists (increase the tone of the lower esophageal sphincter)

Question 11

Function of Antisecretory drugs

Answer 11

Prevent secretion of gastric acid in the stomach by parietal cells

Question 12

How is gastric acid secreted

Answer 12

By an ATPase proton pump
Pumps protons into gastric lumen

Question 13

Which molecules induce gastric acid secretion by parietal cells

Answer 13

Acetylcholine, gastrin, and histamine

Question 14

Mechanism of gastric acid secretion by Acetylcholine

Answer 14

Acetylcholine is released from vagus nerve terminals–>Acetylcholine binds the M3 muscarinic receptor on parietal cells–>parietal cells secrete gastric acid

Question 15

Mechanism of gastric acid secretion by Gastrin

Answer 15

Gastrin is released from G cells (in stomach)–> Gastrin then binds to CCK2 receptors or gastrin receptors on parietal cells–>parietal cells secrete gastric acid

Question 16

Mechanism of gastric acid secretion by Histamine

Answer 16

ECL (enterochromaffin-like cells) synthesize histamine–>histamine then binds to H2 receptor on parietal cells

Question 17

2 pathways of gastric acid secretion

Answer 17

Direct and indirect pathways

Question 18

Direct pathway of gastric acid secretion

Answer 18

Acetylcholine, gastrin, and histamine bind DIRECTLY to their respective receptors (M3 muscarinic receptors, CCK2 or gastrin receptors, and H2 receptors) on parietal cell’s membrane to SYNERGISTICALLY stimulate acid secretion

Question 19

Indirect pathway of gastric acid secretion

Answer 19

Acetylcholine and gastrin bind to their receptors on ECL cells to stimulate secretion of histamine–>histamine then stimulates parietal cells to secrete gastric acid

Question 20

Inhibition of Acetylcholine release to inhibit gastric acid secretion

Answer 20

ex. Propantheline
Inhibition by a Muscarinic (cholinergic) antagonist

Question 21

Pathway of acetylcholine gastric acid secretion

Answer 21

Acetylcholine released by vagus nerve–> acetylcholine acts on M3 muscarinic receptor (a GPCR)–>activates phospholipase C that converts PIP2 to IP3–>IP3 releases Ca2+ from ER and activates Protein kinase C–>Ca2+ release and Protein kinase C open ATPase proton pump–>release gastric acid

Question 22

Inhibition of Histamine release to induce gastric acid secretion

Answer 22

ex. Cimetidine
Inhibition by a Histamine H2 receptor antagonist

Question 23

Pathway of Histamine gastric acid secretion

Answer 23

Histamine released by ECL–>histamine acts on H2 receptor (GPCR)–>activates adenylyl cyclase–>increases synthesis of cAMP–> high [cAMP] activates Protein Kinase A–> Protein Kinase A directly opens ATPase proton pump–>releases gastric acid

Question 24

How can histamine inhibition be overcome

Answer 24

By food-induced acid secretion via acetylcholine and/or gastrin

Question 25

Inhibition of Parietal cells gastric acid secretion

Answer 25

ex. Omeprazole Proton pump inhibitors Direct inhibition by blocking ATPase proton pump

Question 26

Function of Proton Pump inhibitors

Answer 26

Reduce acid secretion independent of how it is stimulated Cannot be overcome

Question 27

Pathway of Proton pump inhibition of gastric acid secretion

Answer 27

Direct Prostaglandin E2 binds to EP3 receptor (inhibitor) on parietal cells-->EP3 receptor inhibits adenylyl cyclase-->less cAMP produced-->decreased gastric acid secretion Indirect Prostaglandin E2 reduces histamine release from ECL cells and gastrin release from G cells

Question 28

Mechanism of somatostatins in gastric acid secretion

Answer 28

Reduce gastric acid secretion by stimulating EP3 receptors (same inhibitory receptors as prostaglandins)

Question 29

Omeprazole in neutral vs ionic form

Answer 29

Neutral-->may enter acidic vesicles Ionic-->stuck in vesicle

Question 30

What is omeprazole

Answer 30

Prodrug that is converted to active form by stomach acids

Question 31

Mechanism of omeprazole

Answer 31

In active form Omeprazole covalently and irreversibly binds the ATPase proton pump, inactivating it

Question 32

When to use Proton pump inhibitors

Answer 32

ex. Omeprazole 1) NSAID-associated damage prevention 2) Prophylactic treatment to protect the gastric barrier against infections (Clostridium difficile)

Question 33

Side effects of long term use of Proton Pump Inhibitors (PPIs)

Answer 33

ex. Omeprazole Vitamin B12 deficiency and hypomagnesemia Increased risk of osteoporosis and fractures

Question 34

Effect of NSAIDs on prostaglandins

Answer 34

NSAIDs reduce the number of prostaglandins which leads to 1) Increase in acid production 2) Decrease in mucus and bicarbonate production 3) Decreased blood flow 4) Increased risk of ulcers

Question 35

What do NSAIDs inhibit

Answer 35

Cyclooxygenase 1 and 2 responsible for the synthesis of prostaglandins COX1--> constitutively expressed, produces gastric prostaglandins responsible for mucosal integrity COX2--> induced by inflammatory stimuli

Question 36

Side effects of COX-2 selective NSAIDs

Answer 36

ex. coxib, celecoxib Myocardial infarction and stroke

Question 37

Effect of NSAIDs

Answer 37

1) Create local injuries in gastric epithelial cells (due to accumulation) 2) Weak acids so may cross cell membranes and enter gastric epithelial cells 3) Ionized in cytoplasm so may get trapped and accumulate causing cell damage

Question 38

Mechanism of Prostaglandin

Answer 38

Activate prostanoid receptors on parietal cells to decrease gastric acid secretion

Question 39

Function of Prostaglandin analog

Answer 39

ex. Misoprostol 1) Increases secretion of mucus and bicarbonate 2) Enhances mucosal blood flow 3) Inhibits mucosal cell turnover to enhance mucosal defense

Question 40

When to use Misoprostol (prostaglandin analog)

Answer 40

Labour induction of medical abortion

Question 41

Side effect of Misoprostol

Answer 41

Frequent diarrhea