Flashcards in GI disorder drugs: PUD drugs Deck (32):
Acid Peptic Diseases compromise of what?
1. Peptic Ulcer: gastric (pain increases with food and 70% due to H. pylori) and duodenal (pain decreases with food and 90% due to H. pylori)
3. ZES: zollinger-ellison syndrome (tumor of the pancreas)
What are the players in the pathology of a peptic ulcer?
Decreased mucosal resistance to acid
H. pylori infection
NSAIDS: due to COX inhibitor and direct irritation
Concurrent use of other drugs like warfarin and corticosteriods
Gastrinoma: gastrin secreting tumor aka ZES
Peptic diseases associated with ?
Erosion or ulceration of mucosal lining of GI tract
What are the therapeutic choices of PUD?
1. Antacids: neutralize gastric acid
2. H2 receptor blockers and PPI: proton pump inhibitors that reduce gastric acid secretion
3. Antimicrobial treatment to eradicated H. pylori infection
4. Mucosal protective agents: they augment mucosal surface defense
First up to discuss are the antacids for PUD, what are gastric antacids?
Weak bases that react with gastric HCl to form salt and water. The end result is increased gastric pH.
--provide QUICK relief of symptoms
Commonly used antacids are:
Magnesium hydroxide, aluminum hydroxide and calcium carbonate
What are the adverse effects of gastric (oral) antacids?
Magnesium hydroxide: produce Mg salt, which is very poorly absorbed and cause diarrhea
Aluminum hydroxide: reacts with HCl to form aluminum chloride, which is insoluble and cause constipation and hypophosphatemia
Calcium Carbonate: hypercalcemia, nephrolithiasis and constipation
What are the clinical correlates of oral antacids and drug absorption?
Increase oral absorption of weak bases (quinidine)
Decrease oral absorption of weak acids (warfarin)
Decrease oral absorption of Ca, Mg, Al molecules can chelate tetracycline
What factors enhance gastric acid secretion?
Fundamental agonists that control the gastric acid secretion:
histamine (H2 receptor) , acetylcholine (Cholinergic receptor) and gastrin
Final pathway of these compounds is activation of the H/K ATPase pump
What is the regulation of gastric acid secretion?
Acetylcholine ----- produces Ca2+ -- this acts on protein kinase activation
Histamine receptor activation stimulates Adenylyl cyclase activation and activates cAMP --- to protein kinase
Prostaglandin E2 receptor inhibition leads to cAMP activation
Gastrin activates Ca2+ ---- activates protein kinase
All of the Ca2+ and cAMP leads to protein kinase activation which activates the proton Pump --- H goes out and produces gastric acid and K comes in the cell
Receptor binding of what will diminish gastric acid production?
Prostaglandin E and somatostatin diminish gastric acid production (aka Octreotide)
What are the H2 receptor blockers?
---they are capable of reducing nearly 60-90% of basal secretion of gastric acid following a single dose. No effect on gastric emptying time
--they are reversible H2 receptor blockers
Inhibit the activation of cAMP through adenylyl cyclase
Which H2 receptor blockers are more potent?
--are longer acting and more potent than older cimetidine
What is the purpose of H2 receptor blockers?
--healing of duodenal, gastric ulcers and relieving GERD
Peptic ulcers recurrence is common after what?
After monotherapy with H2 antagonists is stopped
(normally given with ABX)
Preoperatively H2 receptor blockers are used for what?
Prevents aspiration pneumonia
--in ICU used for stress ulcer prevention
What are acute stress ulcers?
Associated with major trauma and in high risk patients in intensive care units
--usually treated with IV H2 receptor blocker injection
H2 receptor blockers are used as a prophylaxis
What are adverse effects of H2 blockers?
Cimetidine: antiandrogenic or prolactin stimulating effects (elevated serum prolactin levels and gynecomastia)
and inhibition of CYP450 enzymes (warfarin, procainamide, phynetoin, benzos, theophylline, imipramine and quinidine) and decreases libido and confusion in elderly ppl. Can cross BBB and placenta
Other H2 blockers: nausea, headache and dizziness
Cimetidine and ranitidine can decrease renal excretion of creatinine
Next sets of drugs for PUD are the proton pump inhibitors.
What is the mechanism of action of PPI?
After transportation into the parietal cell, PPIs are converted to the active form, which reacts with a cysteine residue of the H/K-ATPase, forming a stable covalent bond leading to irreversible inactivation of enzyme.
What are the clinical uses of PPI?
GERD, duodenal and gastric ulcers, multiple endocrine neoplasia (MEN1) or ZES
--they contribute in combination with ABX to eradication of H. Pylori
How should NSAID induced ulcers be treated?
--they support platelet aggregation and maintain clot integrity --- used in hemorrhagic ulcers
What is the effectiveness and Route of Administration of PPIs?
Effectiveness: PPIs can inhibit nearly 100% of gastric acid secretion with single daily dose
Route of Administration: IV or PO
What are the side effects of PPIs?
Usually well tolerated and rarely they can produce nausea or diarrhea
--remember that Omeprazole inhibits the metabolism of warfarin, clopidogrel, phenytoin, diazepam, and cyclosporine (through P450)
--prolonged therapeutic use of PPI and H2 blockers may decrease bioavailability of vitamin B12; digoxin and ketoconazole (because acid is required for their absorption)
Moving on to H. pylori and PUD, what are the ways to document this kind of infection?
1. Endoscopic biopsy of the ulcer margin
2. Serologic test
3. Urea breath tests
--eradication of H. pylori results in rapid healing of active peptic ulcers and low recurrence rates
Explain the steps in the urea breath test
1. Subjects are given urea labeled with 13C orally
2. H. pylori produces urease which hydrolyses the labelled urea to 13CO2 and ammonia
3. 13 CO2 is dissolved in the blood and transported to the lungs
4. Exhaled 13CO2 is analyzed. The presence of H. Pylori results in an increase in the ratio of 13CO2 to 12CO2 in expired breath
What are the first line antimicrobials for H. Pylori eradication?
Broad spectrum antibiotics: Tetracycline
What is the first line regimen for H. pylori eradication?
PPI + Clarithromycin + Amoxicillin (duration = 10-14 days and eradication rate = 70-85%)
PPI + Clarithromycin + Metronidazole (duration = 10-14 days and eradication rate = 70-85% )
Bismuth subsalicyclate + metronidazole + tetracycline + ranitidine or PPI (duration = 10-14 days and eradication rate is 75-90%) (not used as first line due to lack of compliance)
--PPI treatment extended for at least 4 weeks
Moving on to the Mucosal Protective Agents..
First is Sucralfate, which is a sulfated disaccharide used in PUD. What is the mechanism of action?
Drug undergoes polymerization and selective binding to necrotic tissue where it acts as a barrier to acid
--it also stimulates endogenous prostaglandin synthesis
Sucralfate is ineffective with action of H2 receptor blockers or PPI, why?
Sucralfate requires acidic pH to be activated therefore it should not be administered simultaneously with H2 blockers, PPI or other antacids
The next mucosal protective agent is Bismuth Subsalicylate. what is the MOA and therapeutic action?
--selectively binds to an ulcer and forms a coating and protects from acid and pepsin
---some antimicrobial effect on H. Pylori. needs to be administered along with metronidazole and tetracycline for ulcer healing due to H. pylori