Lecture 17 (after midterm 2) Flashcards
Bacterial functions in the human body
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)
Effect of Gut microbiota on drugs
Can metabolize drugs activating, inactivating or toxifying them
What is Peptic Ulcer disease
Where the mucosal epithelium is exposed to acid and pepsin
Affects the upper GI tract (stomach, duodenum, and lower esophagus)
What induces the formation of ulcers
Excess acid production or impaired barrier function that overwhelms the defense mechanisms in the GIT
What are first line treatments for Peptic Ulcer Disease (PUD)
Proton pump inhibitors (given the cause is NOT a bacterial infection)
If caused by Helicobacter pylori, use antimicrobial treatment
Possible causes of Peptic Ulcer Disease (PUD)
NSAIDs, stress and chronic illnesses, and Helicobacter pylori infection (bacterial infection)
What is Gastroesophageal Reflux disease (GERD)
A dysfunctional relaxation of the lower esophageal sphincter, allowing reflux of acidic gastric contents from the stomach into the esophagus
What can Gastroesophageal Reflux Disease (GERD) lead to
Inflammation, bleeding, ulcerations, and Barret esophagus
What is Barrett esophagus
Reorganization of the cell lining of the esophagus in response to acid damage
A premalignant condition
Associated with high incidence of transition to cancer
GERD treatment
Proton pump inhibitors, histamine (H2) receptor antagonists, and dopamine antagonists (increase the tone of the lower esophageal sphincter)
Function of Antisecretory drugs
Prevent secretion of gastric acid in the stomach by parietal cells
How is gastric acid secreted
By an ATPase proton pump
Pumps protons into gastric lumen
Which molecules induce gastric acid secretion by parietal cells
Acetylcholine, gastrin, and histamine
Mechanism of gastric acid secretion by Acetylcholine
Acetylcholine is released from vagus nerve terminals–>Acetylcholine binds the M3 muscarinic receptor on parietal cells–>parietal cells secrete gastric acid
Mechanism of gastric acid secretion by Gastrin
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
Mechanism of gastric acid secretion by Histamine
ECL (enterochromaffin-like cells) synthesize histamine–>histamine then binds to H2 receptor on parietal cells
2 pathways of gastric acid secretion
Direct and indirect pathways
Direct pathway of gastric acid secretion
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
Indirect pathway of gastric acid secretion
Acetylcholine and gastrin bind to their receptors on ECL cells to stimulate secretion of histamine–>histamine then stimulates parietal cells to secrete gastric acid
Inhibition of Acetylcholine release to inhibit gastric acid secretion
ex. Propantheline
Inhibition by a Muscarinic (cholinergic) antagonist
Pathway of acetylcholine gastric acid secretion
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
Inhibition of Histamine release to induce gastric acid secretion
ex. Cimetidine
Inhibition by a Histamine H2 receptor antagonist
Pathway of Histamine gastric acid secretion
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
How can histamine inhibition be overcome
By food-induced acid secretion via acetylcholine and/or gastrin
Inhibition of Parietal cells gastric acid secretion
ex. Omeprazole
Proton pump inhibitors
Direct inhibition by blocking ATPase proton pump
Function of Proton Pump inhibitors
Reduce acid secretion independent of how it is stimulated
Cannot be overcome
Pathway of Proton pump inhibition of gastric acid secretion
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
Mechanism of somatostatins in gastric acid secretion
Reduce gastric acid secretion by stimulating EP3 receptors (same inhibitory receptors as prostaglandins)
Omeprazole in neutral vs ionic form
Neutral–>may enter acidic vesicles
Ionic–>stuck in vesicle
What is omeprazole
Prodrug that is converted to active form by stomach acids
Mechanism of omeprazole
In active form
Omeprazole covalently and irreversibly binds the ATPase proton pump, inactivating it
When to use Proton pump inhibitors
ex. Omeprazole
1) NSAID-associated damage prevention
2) Prophylactic treatment to protect the gastric barrier against infections (Clostridium difficile)
Side effects of long term use of Proton Pump Inhibitors (PPIs)
ex. Omeprazole
Vitamin B12 deficiency and hypomagnesemia
Increased risk of osteoporosis and fractures
Effect of NSAIDs on prostaglandins
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
What do NSAIDs inhibit
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
Side effects of COX-2 selective NSAIDs
ex. coxib, celecoxib
Myocardial infarction and stroke
Effect of NSAIDs
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
Mechanism of Prostaglandin
Activate prostanoid receptors on parietal cells to decrease gastric acid secretion
Function of Prostaglandin analog
ex. Misoprostol
1) Increases secretion of mucus and bicarbonate
2) Enhances mucosal blood flow
3) Inhibits mucosal cell turnover to enhance mucosal defense
When to use Misoprostol (prostaglandin analog)
Labour induction of medical abortion
Side effect of Misoprostol
Frequent diarrhea
