Lecture 6: Pharmacology of Peptic Acid Flashcards
What are the causes of PUD?
PUD includes inflammatory mucosal disorders of the upper GI tract and can involve any of the upper GI organs For example i. esophagus = reflux esophagitis ii. stomach iii. duodenum ulcer
What are the environmental factors (CAT) that lead to PUD?
- Caffeine
- Alcohol
- Tobacco
What are the three types of receptors in the parietal cell?
- histamine receptor (H2)
- acetylcholine (M3 subtype) receptor
- Gastrin/CCK-B receptor
Each receptor has own ligand
What 3 things that contribute to H+ in
Parietal cells?
- gastrin
- acetylcholine
- histamine
What are the key characteristics of the
H/K ATPase?
- ATP dependent
- rate of secretion of HCL depends
Completely on proton pump
What are the key characteristics of pepsin?
Aggressive factor #2
Derived from pepsinogen
A protease secreted by chief cells
Ability to damage the GI tract is pH dependent
Inactivated at pH > 4.0
IRREVERSIBLY inactivated at pH > 6
Too much pepsin can digest proteins on surface epithelium
What is the mechanism by which H. pylori promotes PUD?
MULTIFACTORIAL
Aggressive factor 3
Modifies NH3 with urease
Can increase acid output (antrum) or decrease acid output with increased gastrin output
Induces inflammation due to increase of COX-2
Decreased mucosal defenses
What prostaglandins are produced by COX?
PGE1 and PGE2
Fucked up by NSAIDS
What are the key factors for Bile?
Aggressive factor 5
Can be damaging to GI tract even in the absence of acid
-this effect is counterintuitive since bile neutralizes acid
-the reflux of bile into the stomach/esophagus is usually prevented
Injury from bile (bile gastritis) mainly occurs in patients who have had surgery in which pylorus has been disrupted (pyloroplasty)
What produces bicarbonate?
- Brunner’s glands
- stomach/duodenal surface epithelial cells
- mucus neck cells
What do prostaglandins E1 and E2 do?
Protective factors
- enhance other cytoprotective mechanisms
- increase bicarb
- increase mucous thickness
- increase mucosal blood flow (because of increase in vasodilation)
- Reduces production of H+ (receptor on parietal cells)
How do we inhibit acid production?
- Histamine (H2) receptor antagonists
2. Proton pump inhibitors
What are types of H2 receptor antagonists?
- Cimetidine (TAGAMET)
- Ranitidine (ZANTAC)
- Nizatidine (AXID)
- Famotidine (PEPCID)
What is Tagamet?
A H2 antagonist
Decreases H+ production by parietal cells
What is zantac?
A H2 antagonist
Decreases H+ production by parietal cells
What are characteristics of H1 antagonists?
Allergy medications
What are the characteristics of H2 antagonists?
Doesn’t do shit for allergies Only decrease acid production 1. rapidly absorbed and quick onset 2. p450 hepatic metabolism 3. renal excretion 4. elevates pH to inactivate pepsin
What are the adverse effects of Tagamet (cimetidine)?
Binds to P450 so it is CONTRAINDICATED in drugs that use P450 to be broken down, such as
i. warfarin
2. diazepam
Why do H2 antagonists may fail?
Because they leave two receptors (acetylcholine and gastrin) unopposed so not as effective
What are the types of Proton pump inhibitors?
- Omeprazole (Prilosec)
- Lansoprazole (Prevacid)
- Rabeprazole (Aciphex)
- Pantroprazole (Protonix)
- Esomeprazole (Nexium)
What is Prilosec?
A proton pump inhibitor
Omeprazole
What is the MoA of PPIs?
IRREVERSIBLY blocks H/K atpase which leads to them being permanently inactivated
This means that new atpase has to be synthesized
Much more effective
What are the key characteristics of PPIs?
- Intentionally delivered as prodrugs formulated within an acid resistant coating
- outer layer is dissolved in alkaline medium
- lipophilic prodrug is inactive at neutral/alkaline pH
- PPIs diffuse readily across lipid membranes and acidified compartments
What happens once PPI reaches parietal cell?
- Trapped by binding to H+
- Activated by coupling to sulfonated group (Sulfon)
- Activated form with Sulfon and H+ will bind to the H/K pump
