Raja1

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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

H2RA: MOA

- 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)

PPIs: MOA

- 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

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