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Name the three receptors with the system that contribute to acid secretion.
- H2- Paracrine,
- CCK2/CCK-B - Endocrine
- Ach/M3 - neuroendocrine
M3, H2 and CCK2 receptors are found on which type of cell and where are they located?
the basolateral side of parietal cells found in the Fundus and Body of the stomach.
Active acid pumps are found where? Inactive?
- Active are on the surface
- Inactive within the cell
What type of Acid producing pump is in the parietal cell?
Name the gastric defense against acid into the esophagus.
Lower esophageal sphincter (LES)
Name the 4 gastric defenses against acid damage.
- Mucosal blood flow
- PGE2 and PGI2 stimulated mucus production
- PGE2 and PGI2 inhibit gastric acid secretion
- secretion of bicarbonate ions by gastric epithelial cells
PGE2 and PGI2 are inhibited by what 3 drugs?
Name the 6 classes of drugs used for treatment of PU and GERD.
- H2 receptor antagonists
- proton pump inhibitors (PPI)
- prostaglandin analogs
- bismuth compounds
Pathway of Ach/M3 receptor activation?
Pathway of H2 receptor activation?
Name the 4 H2 receptor antagonistson the market.
- Cimetidine (Tagamet)
- Ranitidine (Zantac)
- Famotidine (Pepcid)
- Nizatidine (Axid)
Why is Famotidine the most potent H2 receptor antagonist?
because of the sulfur atom in the forth atom side chain
Peak serum concentration of H2 antagonists?
1 to 3 hours
What percentage of an H2 antagonist is protein bound?
< 10% to 35 %
How are H2 antagonists metabolized and excreted?
by the liver, excreted in urine
H2 antagonists effectively suppress what type of acid secretion? By how much over a 24hr period?
nocturnal acid secretion, approximately 70%
Name the 3 therapeutic uses of H2 antagonists.
- promote healing of gastric and duodenal ulcers
- treat gastroesophageal reflux disease (GERD)
- prevent stress ulcers
What are some common side effects of H2 antagonists?
drowsiness, fatigue, muscular pain, diarrhea, constipation
What are some less common side effects of H2 antagonists under IV route of administration?
CNS effects like confusion, delirium, hallucinations, slurred speech and headache
What are some of the side effects associated with long term usage of Cimetidine?
- decreased testosterone binding to the androgen receptor
- inhibits a CYP that hydroxylates estradiol which results in galactorrhea, gynecomastia, reduced sperm count, and impotence.
H2 antagonists inhibit which CYPs? Which H2 antagonist especially?
- 1A2, 2C9, and 2D6
H2 antagonist tolerance can develop how fast?
Within 3 days
How can H2 antagonist tolerance produce secondary hypergastrinemia?
stimulates histamine release from enterochromaffin-like cells(ECL cells)
How much can PPIs diminish daily acid production?
80% to 95%
Name the six PPIs available on the market with their stereochemistry.
- Racemic- Omeprazole (Prilosec, rapine, Zegerid)
- S-Isomer- Esomeprazole (Nexium), Lansoprazole (Prevacid), Rabeprazole (Aciphex), Pantoprazole (Protonix)
- R-Isomer- Dexlansoprazole (Dexilant)
Where do PPIs diffuse into and where do they accumulate?
into parietal cells and accumulate in acidic secretory caniliculi
How are PPIs activated and trapped in the parietal cells?
proton-catalyzed formation of tetracyclic sulfenamide which form covalent bonds in the H/K ATPase
How long are PPIs effective and why for so long?
from 24-48 hrs because the irreversibly bind to the pump and it takes that long for new pumps to be generated
What is the plasma T1/2 of PPIs?
.5 to 2 hrs
What % of PPIs are protein bound?
Which CYP is effected by PPIs? And what is the effect?
CYP2C19 is inhibited and slows metabolism of the PPI.
Which PPIs does not inhibit CYP2C19?
Pantoprazole and Rabeprazole
Therapeutic uses of PPIs are?
- promote healing of gastric and duodenal ulcers
- treat GERD and esophagitis
- Drugs of choice for Zollenger-Ellison syndrome
- Lansoprazole for NSAID gastric ulcers
- DU associated with H.pylori infections
Side effects of PPIs are?
nausea, abdominal pain, constipation, flatulence, diarrhea, subacute myopathy, arthralgias, headaches, skin rashes
Drug interactions with PPIs are? Why?
- warfarin, diazepam, cyclosporin,
- inhibition of CYP2C19 and 3A4 may increase plasma levels
PPIs effect bioavailability for which drugs and how?
- Ketoconazole, itraconaxole, digoxin, and atazanavir
- altered pH of the stomach.
MOA of prostaglandin analogs
- binds EP3 receptor on parietal cells to stimulate Gi pathway to decrease intracellular cAMP
- decrease gastric acid secretion
- PGE2 stimulates Mucin and bicarbonate secretion
- increases mucosal blood flow
Name the prostaglandin analog used for the treatment of PU and GERD.
The addition of a methyl ester group at the C1 position has what kind of effect on a prostaglandin analog?
- increases potency
- increases duration of antisecretory effects
With the addition of a methyl group to C16 and transfer of a hydroxyl group from C15 to C16 will have what kind of effect of a prostaglandin analog?
- increases oral bioactivity
- duration of antisecretory action
Misoprostol has a peak plasma time of? T1/2 of?
peaks at 60 - 90 minutes, T1/2 of 20 - 40min
Indication of Misoprostol
prevent NSAIDs-induced mucosal injury
Common side effects of prostaglandin analogs are?
- Diarrhea, abdominal pain and cramps
- may cause exacerbations of inflammatory bowel disease.
A Contraindication of prostaglandin analogs? Why?
- during pregnancy
- increased uterine contractility
What is the MOA of Sucralfate?
- extensive cross linking at pH <4 produces a viscous sticky polymer that adheres to epithelial cells and ulcer craters.
- inhibits hydrolysis of mucosal proteins by pepsin.
- may stimulate local production of PGs and epidermal growth factor.
What is the duration of effectiveness of Sucralfate?
up to 6 hours
How do you administer Sucralfate?
on an empty stomach 1 hour before meals
Therapeutic use of Sucralfate?
- Prophylaxis of stress ulcers
- oral mucositis (radiation and aphthous ulcers)
- bile reflux gastropathy
- Radiation proctitis and solitary rectal ulcers
Common side effect of Sucralfate?
The use of what drugs should be avoided within 30 min of a dose of Sucralfate?
Sucralfate may inhibit absorption of which drugs? How do you avoid inhibition?
- Phenytoin, digoxin, ketoconazole, fluoroquinolone
- Take at least 2 hours after the administration of other drugs.
The two categories of Antacids with examples are?
- Potent antacids (NaHCO3, CaCO3, Mg(OH)2)
- Non-potent antacid (Al2+O3, Al(OH)3)
Define neutralizing capacity.
the quantity of 1 N HCL (in milliequivalents) to bring to pH 3.5 within 15 min. so the higher the number the more potent the antacid
Most potent to least potent antacid:
NaHCO3, CaCO3 > Mg2+ compound > Al3+ compound
Antacids pose a risk to patients with what conditions?
cardiac or renal failure
Common side effects of antacid are?
belching, nausea, abdominal distention, and flatulence
Why is the combination of Mg2+ and Al3+ effective for treatment?
Mg is rapid acting and Al is slow reacting providing balanced an sustained neutralizing capacity.
Magaldrate is a complex made of?
Why is magaldrate effective for sustained antacid relief?
it is poorly absorbed
True or False? Al3+ causes constipation while Mg2+ causes diarrhea.
Adverse effects of antacids in patients with renal insufficiency?
Absorbed Al3+ contributes to osteoporosis, encephalopathy and proximal myopathy
Define Milk-alkali syndrome.
alkalosis, hypercalcemia and renal insufficiency caused by large does of NaHCO3 or CaCO3 with milk
What are the ramifications of Milk-alkali syndrome?
reduced parathyroid hormone (PTH), phosphate retention, precipitation of Ca2+ slats in kidney (nephrolithiasis)
How do antacids (with Al3+ or Mg2+) render other drugs inutile?
chelation forming insoluble complexes that pass through the GI tract without absorption.
How do you prevent the chelation of drugs with antacids?
taking antacids 2 hours before or after other drugs
What 4 drugs are used to eradicate H. pylori and prevent ulcer recurrence?
- Bismuth (subsalicylate or subcitrate potassium)
The MOAs of the quadruple therapy for H. pylori consists of?
- coats ulcers and erosions
- promotes mucin and bicarbonate production
- significant antibacterial effects and bind enterotoxins
How does one develop GU or DU?
- failure of PGs protection of the gastric mucosa
- lack of mucus and bicarbonate
How does one develop GERD?
loss of lower esophageal sphincter tone
Treatments for GU/DU, GERD, H. pylori aim to do what?
- decrease gastric acidity
- enhance mucosal protection
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