Module 2: Acid Suppression Pharmacology Flashcards
Dr. Digavalli
Difference between Erosion and ulcers
Erosion: superficial lesions
Ulcer: deep lesions across layers
Complication of untreated ulcers
Bleeding and perforation (hole)
What may cause Barretts esophagus
-precancer stage
-chronic inflammation (esophagitis/gastritis) leading to epithelial changes (squamous to columnar)
What are the ways to protect the GI tract?
-epithelial cells secreting mucus and bicarbonate: buffer and protection
-prostaglandins, hydrogen sulfide, nitric oxide, trefoil factors: microcirculation and protection
-continuous regeneration of mucosal tissue
Function of prostaglandins and hydrogen sulfide
microcirculation and protection
Factors contributing to peptic ulcers
Imbalance between damaging and protecting factors
-H. pylori
-poorly functioning of the sphincter
-excessive use of NSAIDs, aspirin (inhibit COX enzyme and PG)
-dietary and lifestyle (alcohol, smoking, caffeine)
-stress
What are the damaging and protective factors?
-damaging: acid/pepsin/H.pylori/stress
-protecting: Prostaglandins, bicarbonate, hydrogen sulfide, mucosal repair
Which cells in the stomach produce acid?
Parietal cells
1.5l per day
How is the acid produced by parietal cells?
the enzyme carbon anhydrase (CA) converts CO2 to H2CO3 (carbonic acid)
H2CO3 dissociates to H+ and HCO3 (bicarbonate) -> goes into the blood as BUFFER after a meal (alkaline tide, exchange HCO3 with Cl-)
H+ is secreted into the gastric duct via the H+/K+ antiporter
Cl- diffuses from the blood (then through the parietal cell) into the gastric duct too
-> forms HCl- (acid)
What is secreted by Parietal cells and Chief cells?
-Parietal cells:
Chief cells: Pepsinogen
What is secreted by G cells and ECL cells?
G cells: Gastrin -> CCK B receptors
Enterochromaffin-like cells: Histamine -> H2 receptors
Postganglionic cholinergic neurons: ACh -> muscarinic M3 receptors
What is secreted by Goblet cells and D cells?
Goblet cells: Mucous (protection)
D cells: Somatostatin (inhibits acid secretion)
What is the role of histamine, ACh and gastrin in the stomach?
-histamine (via ECL) and ACh (via vagal/anticholinergic neurons) stimulate parietal cells
-gastrin stimulates acid secretion -> parietal cells and ECL
What are the functions of Somatostatin and gastrin?
Somatostatin (via D cells): inhibits ECL, G cells, and parietal cells
Drug formulation of Omeprazole
-enteric coated -> prevents early activation -> absorption
-Weak base pKa 4.5
-take on empty stomach (food reduces the bioavailability by 50%)
MOA of omeprazole
-Protonation and conversion into Sulphenamide intermediate
-irreversibly binds to proton pumps
Clinical use of PPIs
-GERD
-Peptic ulcer disease
-NSAID-induced ulcers
-Esophagitis
-Zollinger-Ellison syndrome
Side effects of PPIs
-Diarrhea, risk of C diff induced diarrhea
-Nausea
-Abdominal pain
-headache
-inhibit CYP450
-induce CYP450 (omeprazole, lansoprazole, pantoprozole)
Which of the PPIs induce CYP450?
-Pantoprazole
-Lansoprazole
-Omeprazole
Which molecule do PPIs interfere with?
absorption of Vitamin B12
-may worsen osteoporosis with long-term use (1-2y)
How are PPIs metabolized?
liver (CYP450) -> excreted through the urine and feces
Onset duration of PPIs
4 hours
Which PPIs can be administered IV?
Esomeparzole and Pantoprazole
MOA of H2 receptor antagonists
-competitive inhibition of H2 receptor on parietal cells -> decrease in gastric acid secretion
-protection for 10-12h
Clinical use of H2RA
-effective against nocturnal acid release
-prophylaxis for ulcers, GERD, heartburn
-GERD
-Zollinger-Ellison syndrome
-Peptic ulcer disease
Side effects of H2RA (Cimetidine)
-Headache
-Gynecomastia (blocks production of testosterone)
-inhibits P450 enzyme (except Famotidine)
-Vitamin B12 deficiency with long-term use
Side effects Famotidine
-Diarrhea
-Headache
-dizziness
-confusion in the elderly
How are H2RA eliminated?
-Metabolized in the liver (CYP450)
-excreted in the urine
What might be a consequence of prolonged acid suppression?
C. diff infection
Vitamin B12 deficiency
Antacids
-short onset, short duration
-sodium an calcium bicarbonate may cause bloating and belching
MOA of Antiacids
-directly buffers the acid -> forming a salt and water
-increases the gastric pH -> pH > 4 deactivates pepsin (protein degrading enzyme)
Clinical use of Antacids
-Symptoms of GERD, PUD, esophagitis, gastric hyperacidity
-safe for pregnant women
-works better for duodenal ulcers than in gastric ulcers
-calcium carbonate is helpful in hypocalcemia
-magnesium hydroxide is used as a laxative
Side effects of Antacids
-Aluminum hydroxide: constipation (elderly), not in patients with CKD, hypophosphatemia
-Calcium carbonate: Hypercalcemia, metabolic alkalosis
-Magnesium hydroxide: strong laxative effect -> diarrhea
-sodium bicarbonate: metabolic alkalosis
Which of the Antacids have poor oral bioavailability?
Aluminium hydroxide
Magnesium hydroxide
Which of the Antiacids cause bloating and belching?
Carbonate containing
-Sodium carbonate
-Calcium carbonate
Which of the Antacids cause metabolic alkalosis?
-Sodium bicarbonate
-Calcium bicarbonate
Which antacids should be avoided in CKD?
-Aluminium hydroxide
-Magnesium hydroxide
-also caution with sodium carbonate and calcium carbonate bc of metabolic alkalosis
aluminum and magnesium accumulation due to decreased kidney function
How does absorption of Antacids cause DDIs?
due to being administered in large amounts (grams) they easily bind (adsorb) to drugs given in mg (warfarin, digoxin)
Antacids DDI
-chelation with FQ, tetracyclines space with 3-4h
-reduces dissolution of weakly basic drugs, acid environment is needed (antivirals, conazole, tk inhibitors) and poorly soluble drugs
Use of Cytotec (Misoprostol)
-NSAID-induced and mucosal restoration
-increases local blood flow and bicarbonate buffering
-PGE1 (porstaglandin E1) analog
-can cause smooth muscle contraction -> contraindicated in pregnancy, SSRIs, anticoagulants, steroids
Use of Sucralfate
-forms a sticky wax-like coating on ulcers
-ulcer healing, PG secretion
-can interfere with phosphate absorption by binding to phosphate
Use of Bismuth Salicylate
-coats the ulcers
-stimulates mucous and PG synthesis
-antibacterial effect
-causes black tongue and black stool -> reacts with sulfide (Bisulfide) causing the black color
