Pharmacology of Peptic Ulcer Disease Flashcards
Proton Pump Inhibitors ending
-prazole
PPI Mechanism
Prodrugs, unstable in acid, converted to reactive tetracyclic sulfenamides
Sulfenamides then interact with sulfhydryl (thiol) groups on cysteine residues of gastric H+/ K+ ATPase to form a covalent disulfide bond.
Covalent modification of the H+/K ATPase inhibits the activity of the proton pump and thereby prevents acid secretion.
Inhibit growth of Helicobacter pylori
PPI Enteric Coating Formulation (Capsule, Powder, Tablets)
Why provide an enteric coating?
capsules = omeprazole, esomeprazole, lansoprazole, and dexlansoprazole
powder granules = lansoprazole
tablets = omeprazole, pantoprazole and rabeprazole
Oral ormulations of these drugs are enteric coated to prevent premature activation.
PPIs (ex: omeprazole) are normally mixed with what to form oral suspicions?
NaHCO3
PPI IV Formulation - when are these used?
(esomeprazole, pantoprazole, lansoprazole)
For patients in whom oral administration is not suitable, or who require immediate relief from acid.
What drug is best taken 30 min before a meal?
PPIs - due to both the cephalic and gastric phases of stomach acid secretion.
Concurrent use with ______ might decrease the effectiveness of PPIs.
Concurrent use with acid decreasing drugs (H2 blockers, somatostatin analogue) might decrease the effectiveness of PPIs.
PPI Metabolism
Hepatic CYP3A4, CYP2C19 are responsible for PPI metabolism.
What race of people are susceptible to polymorphisms in CYP2C19 which increases PPI efficacy/toxicity?
Asians
In what case would be see a decrease in clearance of PPIs?
Substantial reduction in clearance of PPIs tend to occur in hepatic diseases.
Omeprazole, lansoprazole are especially significant.
PPI Drug Interactions
1) Decreased CYP2C19 leads to what?
2) PPI-induced low pH
Decreased CYP2C19, decreases the clearance of disulfiram, phenytoin, clopidogrel etc.
PPI-induced low pH decreases bioavailability of oral ketoconazole, ampicillin esters, iron salts etc.
All of the PPIs are prodrugs that require activation in the _____ environment of the _______.
All of the PPIs are prodrugs that require activation in the acidic environment of the parietal cell canaliculus.
In order for acid secretion to resume after taking a PPI, what must happen?
The parietal cell must synthesize new H+/K ATPase molecules, a process that requires approximately 18 hours.
Why are PPIs preferred for the treatment of peptic ulcer disease when there is accompanying H. pylori?
They contribute to eradication of the infection by inhibiting the growth of H. pylori.
PPI decreases bioavailability of oral ___?
Ketoconazole, ampicillin esters, iron salts.
Main two risks of using PPIs?
Induction of Cancer
Risk of gastric carcinoid tumors with prolonged used of PPI, due to enterochromaffin-like cells (ECL) hyperplasia
Vitamin B12 deficiency
Use of omeprazole maybe associated with decreased absorption of vitamin B12 and subsequent symptoms of its deficiency.
How can PPIs cause ZE?
Because gastric acid is a physiologic regulator
of gastrin secretion by G cells in the gastric antrum, the
decreased acid secretion caused by proton pump inhibitor therapy leads to increased gastrin release. The trophic effects of gastrin can induce hyperplasia of ECL cells and parietal cells in the gastric mucosa.
Patients
with Zollinger-Ellison syndrome usually develop ECL and
parietal cell hyperplasia.
Omeprazole Pharmokinetics - What kind of binding? What is the half-life?
95% plasma proteins binding
Plasma t½ range from 0.5 – 1hr, but effect last for 3-5days
Clinical Uses of Omeprazole
Short-term (4-8weeks) treatment/maintenance of esophagitis
GERD, gastric and duodenal ulcers, pathologic acid hyper-secretory conditions, adjunct therapy for H. pylori associated duodenal ulcers
OTC relief of heartburn
ADEs of Omeprazole
Well tolerated, but abdominal pain, constipation, flatulence and nausea may occur in some patients.
What PPI is safest to use in pregnancy?
Pantoprazole - category B. The others are category C.
What PPIs can be used to treat GERD in children?
Pantoprazole and Lansoprazole (also pregnancy category B)
Pantoprazole ADEs
Nausea, vomiting, xerostomia, abnormal liver function test, hepatitis may occur.
H2 blockers ending
-tidine
Does antihistamines have good or bad oral bioavailability?
Good oral bioavailability (with/without food).
Where are H2 blockers excreted? What is one indication for the adjustment of H2 block dose?
Minimal hepatic metabolism, excreted in urine
Must adjust dose in patient with renal insufficiency.
H2 Blockers suppress what?
Suppress basal acid release only, effective in nocturnal acid suppression, evening doses enough.
H2 Blockers’ absorption is decreased by what?
Antacids
Indications for H2 blockers
Indications: healing of gastric/duodenal ulcers, treat uncomplicated GERD, prevent stress-induced ulcers
Which H2 blocker should not be used in pregnancy?
Cimetidine
ADEs of H2 blockers
nausea, diarrhea, headaches, drowsiness and fatigue may occur
How does tolerance to H2 blockers develop?
Due to hypergastrinemia –> hyperplasia of ECL-cells –> increased tolerance.
What H2 blocker has a high propensity for drug interactions?
What are some ADEs of H2 blockers?
Cimetidine = high propensity for drug interactions
Cimetidine can cause galactorrhea (in women), gynecomastia, reduced sperm counts and impotence (in men)
All H2 blockers cross the placenta, secreted in breast milk, require caution in pregnant patients.
What is the prototypical Prostaglandin (PGE1) Analogue?
Misoprostol
Prostaglandin (PGE1) Analogue MOA
Synthetic analogue of PGE1, inhibits parietal cells via EP3 receptors
Enhance bicarbonate secretion, mucus production and blood flow within the gastric mucosa.
PGE1 analogues have higher _____, ______ plasma t½ and _____ oral bioavailability compared to PGE1.
PGE1 analogues have higher potency, longer plasma t½ and increase oral bioavailability compared to PGE1.
Side Effects of PGE1 analogues. When are their use contraindicated?
Diarrhea, may exacerbate inflammatory bowel disease,
Misoprostol (highly abortifacient) is contraindicated in pregnancy.
Antacids MOA
Neutralize stomach acid to form water and salts.
ADEs of Antacids
Constipation (aluminum) and diarrhea (magnesium)
Aluminum may bind phosphates in the GI, hypo-phosphatemia may lead to malaise, weakness and anorexia.
Magnesium antacids are contraindicated in patients with kidney diseases.
What antacids has a dual use? What antacids should be cautioned in HTN or hypervolemic patients?
Dual uses for calcium carbonate: antacid and calcium supplement.
Sodium bicarbonate use require caution in hypertensive patients or in hypervolemia.
Sucralfate MOA
Complex salt of sucrose, sulfate and aluminum hydroxide, minimal ability to alter pH.
Forms a viscous gel at low pH which binds to positively charged proteins, adheres to gastric epithelium.
Protect the gastric luminal surface from degradation by acid and pepsin.
Side effects of Sucrafate
May cause constipation, bind to drugs e.g. quinolones, phenytoin, and warfarin and limit their absorption.
Colloidal Bismuth MOA
Combine with glycoproteins, and mucus to form a barrier that protects ulcers from acid and pepsin.
Stimulates secretion of bicarbonate and prostaglandin.
Inhibits growth of H. pylori and helps to eradicate the infection.
Anti-Cholinergic Agents Members
Dicyclomine (also known as dicycloverine), a muscarinic receptor antagonists used to decrease parietal acid secretion.
Anti-Cholinergic Agents Indications and ADEs
Indications : For treatment of irritable bowel syndrome, less effective than PPIs or H2-blockers for reduction of acid secretion.
Adverse effects: Dry mouth, blurred vision, cardiac arrhythmias and urinary retention. Delirium may occur with high doses.
May cause rapid increases in libido after administration.
