PUD and GERD Med Chem (Dr. J) Flashcards
What are stimulatory signals for HCl secretion?
Histamine
Ach
Gastrin
When histamine binds to the H2 receptor, what kind of GPCR is stimulating the proton pump?
Gs (adenylyl cyclase, cyclic AMP, PKA)
When Ach binds to the M3 receptor, what kind of GPCR is stimulating the proton pump?
Gq (PLC, IP3, Ca2+)
When gastrin binds to the CCK2 receptor, what kind of GPCR is stimulating the proton pump?
Gq (PLC, IP3, Ca2+)
What is the core structure of PPIs?
pyridine and benzimidazole moiety liked by methylsulfinyl group
Which PPIs are racemic mixtures?
Lansoprazole
Omeprazole
Pantoprazole
Rabeprazole
PPIs are prodrugs activated by _______ ___________
acidic environment
What happens when PPIs are in an acidic environment before reaching the site of action?
can bind to other proteins—> inactivated drug
What is the target reaction when PPI reaches the site of action?
sulphenamide interacts covalently with the sulphydryl groups of cysteine residues in extracellular domain of the proton pump
How long does it take for new proton pump molecules to be synthesized after taking PPI?
24-48 hours
PPIs need enteric coating to reach site of action, what dosage forms can PPIs come in?
- capsules
- powder for suspension
- tablets
- IV
- enteric coated granules
How do we prevent degradation of PPIs by acid outside of the desired site of action?
eteric coating
How are PPIs metabolized?
CYP2C19 and CYP 3A4 (1st pass metabolism)
How many days does it take to achieve a 70 % inhibition of proton pumps?
2-5 days
What type of environment do DR and enteric coated tablets dissolve in?
alkaline pH
What is a bioisotere?
mimic natural ligand but inhibit its natural action
What is the MOA of H2RAs?
inhibit acid production by reversibly competing with histamine for binding of H2 receptors on the basolateral membrane of parietal cells
How much acid is suppressed by H2RAs in 24 hours?
70%
Why is Ranitidine recalled?
NDMA (a carcinogen) increases over time under normal storage conditions
What FG was added to ranitidine in order for NDMA not to form?
thiazole ring replaces furan
What is absorption of H2RAs enhanced by?
food
What is absorption of H2RAs decreased by?
antacids
When do serum concentrations of H2RAs peak?
1-3 hours
What neuro-endocrine cells are most prominent in acid-secreting regions of the stomach?
Enterochromaffin- like cells
What are the cytoprotective effects of Prostaglandin E2?
- Stimulation of mucin
- Stimulation of bicarbonate secretion
- increased mucosal blood flow
What does Misoprostol (EP3 agonist) on parietal cells result in?
decreased acid secretion (Gi mediated)
How can pepsin-mediated hydrolysis of mucosal proteins leading to mucosal erosion and ulcerations be inhibited?
sulfated polysaccharides (sucralfate)
How does sucralfate produce a physical and chemical barrier?
cross-linking produces a sticky polymer that adheres to epithelial cells and ulcer craters
Why does CaCO3 (antacid) produce more gas and pain as a side effect?
produces CO2 as a byproduct; can cause belching, distention, flatulence
How does food effect antacids?
Food elevates gastric pH to ~5 for ~1hour and prolongs the effects of antacids for ~2-3 hours
What properties of antacids can cause drug interactions?
Alter gastric and urinary pH
Antacids can _________ other drugs due to Mg2+ and Al3+
Chelate
Which type of ulcer is more dependent on intragastric pH?
H. Pylori
H.pylori is significantly less common in places with _______ socioeconomic status
High
When is H. Pylori usually contracted and how long does it last?
Early child hood; can be dormant for life
How is H.pylori able to adhere to epithelial cells?
Uses flagella to swim through the mucus layer of the stomach/ intestines where pH is near neutral
What mechanism does H.pylori use to protect itself from acidic environment?
Produces acid inhibitory protein that blocks acid secretion by parietal cells
How does H. Pylori lead to excessive production of cytokines and inflammation?
Release toxins
How does our immune system destroy the mucosa when trying to eradicate H. Pylori?
- Neutrophils leave capillaries and accumulate in areas of infection
- Release lysosomes for extracellular killing
- Destroys bacteria and mucous membranes of stomach
- Gastric acid causes ulcerations
How does chronic gastritis due to H. Pylori affect other systems in the body?
Production of gastrointestinal hormones (somatostatin, gastrin, ghrelin) and neurotransmitters
What other problems can chronic H. Pylori infection lead to?
MALT lymphoma
Intestinal metaplasia
Dysplasia
Gastric cancer
