45 terms


Neuronal Regulation of Gastric Secretion
- via ACh
Paracrine Regulation of Gastric Secretion
- via Histamine
Endocrine Regulation of Gastric Secretion
- via Gastrin
Origin of Ions: H+
- generated within the parietal cell from dissociation of water
Origin of Ions: Bicarbonate
- generated from exchange for Cl- from an exchange protein
Origins of Ions: K+
- pumped into the Parietal Cell from proton pump
Somatostatin inhibits
- histamine and gastrin release from their respective cells.
Effects on Protein kinases: histamine
- binds to Gs protein
- increases Cyclic AMP from ATP
Effects on Protein kinases: PGE2
- binds to Gi protein
- inhibits Cyclic AMP
Effects on Protein kinases: Acetylcholine
- binds to M3
- increases Ca2+
Effects on Protein kinases: Gastrin
- binds to CCK-2
- increases Ca2+
Stomach Protection
- increased blood flow
- secretion of gastric mucus
- secretion of bicarbonate ions by superficial gastric epithelial cells
H. pylori
- a gram negative bacteria
- most common cause of non-NSAID related PUD
- thrives in acidic environment by creating a buffer zone of NH4OH
H. pylori: virulence factors
- urease (acts as an antigen)
- endotoxins from cell wall
- lipase and protease that digest gastric mucosa
- immune response to bacteria causes inflammation and epithelial cell damage
- ultimately increases gastric acid secretion
H. pylori: reasons for increased gastric secretion
- increase in pH that stimulated G-cells
- decrease in somatostatin levels due to lower # of D cells that in turn relieves suppression of G cells
Restoring Balance: Injurious factors
- gastric acid
- pepsin
Restoring Balance: Defense factors
- bicarbonate
- mucin
- PG
Drugs that decrease gastric acid
- Muscarinic antagonists
- Histamine (H2) receptor antagonists
- Proton pump inhibitors (PPIs)
Drugs that enhance mucosal defense
- PG analogs (misprostol)
- Sucralfate
- Antacids
- Bismuth compounds
Muscarinic antagonists
- Pirenzepine and Tolenzepine
- Can reduce basal acid production by 40-50%
- Historically used to treat peptic ulcer diseases (but not in USA)
- Rarely used today worldwide
- Poor efficacy and undesirable anti-cholinergic side effects like dry mouth, blurred vision, photophobia and difficulty in urination
H2 Receptor Antagonists: General Characteristics
- Provided better symptom control and higher healing rates compared with antacids
- Cemetidine: prototype drug
- Less potent than PPIs
- Predominantly decrease basal acid secretion
- Better choice for treatment of duodenal ulcers
- inhibit gastric acid production by reversibly competing with histamine for binding to receptors on the basolateral membrane of parietal cells.
- can be given in IV route to critically ill patients
Examples of H2RA's
- Cemetidine (Tagamet), prototype
- Ranitidine (Zantac)
- Famotidine (Pepcid)
- Nizatidine (Axid)
- differ mainly in pharmacokinetics and propensity to cause drug interactions
H2RA's: Adverse Effects
- generally well tolerated
- <3% incidence of side effects
- diarrhea, headache, drowsiness, fatigue, muscular pain
- some drugs long-term can cause reduced sperm count/impotence in men
- no major teratogenic effect
- inhibits CYP enzymes (1A2, 2D6, 2C9, 3A4) and ↑ serum levels of variety of other drugs
H2RA with most drug interactions
- Cimetidine
- also causes reduced sperm count
H2RA: Therapeutic use
- promote healing of gastric and duodenal ulcers
- treatment of uncomplicated GERD
Proton Pump Inhibitors
- the most potent suppressors of gastric acid secretion
- benzimidazole derivatives
- the best gastric acid suppressors
- can diminish basal and stimualted acid production by 80-95%
PPIs: Examples
- Omeprazole (Prilosec), prototype
- Esomeprazole (Nexium)
- Lansoprazole (Prevacid)
- Rabeprazole (Aciphex)
- Pantprazole (Protonix)
- these are prodrugs
- lipophilic compounds with weak base activity
- requires acidic environment to be activated
- diffuse into parietal cells of stomach and accumulate in the acidic canalicui (pH~1)
- irreversible inactivation via activated sulphenamide
- Acid secretion resumes only after new pump molecules are synthesized
PPIs: prolonged suppression
- due to irreversible inactivation
- therapeutic doses reach steady state after 4-5 days of continuous dosing
- these drugs have a powerful but slow onset of action: 24-40% inhibition on first day and ~80% inhibition after 4 days
Preventing Degradation of PPIs in gastric lumen
- can be bypassed through IV solutions
- oral dosage forms:
a) enteric coated cpasules
b) enteric coated granules for suspension
c) enteric coated tablets
d) powdered drug combined with sodium bicarbonate
PPIs: Adverse Effects
- generally well tolerated
- common side effects include nausea, constipation, flatulence, abdominal pain
- metabolized by CYP enzymes (2C19, 3A4): interact with warfarin, diazepam and cyclosporine
- prolonged use can cause hypergastrinemia
- rebound hypersecretion upon discontinuation
- might promote gastrointestinal tumors
- ~25 years of world wide use without emergence of major safety concerns.
PPIs: Therapeutic Uses
- promote healing of gastric and duodenal ulcers
- treatment of GERD and erosive esophagitis
- mainstay in pathological hypersecretory conditions (Zollinger-Ellison Syndrome)
- some are used for NSAID associated gastric ulcers in patients who continue NSAID use
- some are safe for children
Misoprostol: MOA
- synthetic PG analog of PGE1
- binds to EP3 receptors in parietal cells:
a) lowers cAMP
b) lowers gastric secretion
- Oral doses significantly inhibit basal acid (~85%) and food stimulated acid (~75%)
Misoprostol: Adverse effects
- diarrhea with or without abdominal pain in ~30% of patients
- can cause exacerbations of IBS
- contraindicated during pregnancy
Misoprostol: Therapeutic Uses
- FDA approved to prevent NSAID-induced mucosal injury
- rarely used due to unwanted side effects
Sucralfate: MOA
- sulfated polysaccharide
- some have Al(OH3) added
- in pH <3, these molecules cross-link to produce a viscous, sticky polymer
- this polymer can adhere to epithelial cells and ulcers for up to 6h after single dose
- inhibits hydrolysis of mucosal proteins by pepsin (Cytoprotective Agent)
- also stimulates local PG production
Sucralfate: Adverse effects
- constipation is most common
- Al can be absorbed, so avoid in renal impairment
- can inhibit absorption of other drugs including phenytoin, digoxin, cimetidine, and ketoconazole
Sucralfate: Therapeutic uses
- diminished use to treat acid-peptic diseases
- used in critically ill patients for prophylaxis of stress ulcers
Antacids: MOA
- largely replaced by more effective and convenient drugs
- generally salts of weak bases that neutralize gastric acid to produce salt and water
- Alter gastric and urinary pH and thereby the ADME properties of various drugs
Anatacid: Examples
- Calcium Carbonate (CaCo3)
- Aluminum Hydroxide (Al(OH)3)
- Magnesium Hydroxide (Mg(OH)2)
Carbonate antacids: SE
- can cause belching, flatulence, and nausea
Aluminum antacids: SE
- can cause constipation and can chelate other drugs
Magnesium antacids: SE
- can cause laxative effect and can chelate other drugs
Bismuth subsalicylate: MOA
- poorly understood
- Has anti-secretory, anti-inflammatory and anti-microbial effects
- As effective as cimetidine to treat peptic ulcers and given in combination with antibiotics to treat H.pylori infection.
- Good cytoprotective agent when used in combination with other gastric acid reducing agents