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Salivary Glands Esophagus Stomach
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1. An understanding of the physiologic role of salivary glands, the esophagus, and the stomach.
2. An understanding of the physiologic defects in esophageal reflux and dysmotility.
3. An understanding of how our knowledge of gastric physiology is exploited in the therapy of gastric disorders.
4. An understanding of the mechanisms underlying the treatment of peptic diseases.
Salivary gland; esophagus; stomach; antacids
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Grant’s Atlas, 1972
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Salivary Glands Gross anatomy ◦ parotid ◦ submandibular ◦ sublingual
Histology ◦ serous ◦ mucus ◦ mixed
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Salivary Gland Functions Lubrication ◦ Swallowing ◦ Speech ◦ Prevention of dental caries
Digestion
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Secretory Products (1,500 mls/day) ◦ Amylase ◦ Lipase ◦ Mucin ◦ Growth factors Nerve growth factor EGF ◦ Fluid and electrolytes
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Berne & Levy, Principles of Physiology, 1996
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Adapted from Am J Physiol 178:155 (1954)
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Regulation of Secretion
Regulation is via both the sympathetic and parasympathetic nervous systems
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Grant’s Atlas, 1972
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N Engl J Med (1997) 336:924-932
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Feldman: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease, 7th ed.
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Achalasia
- Loss of primary peristalsis - Elevated lower esophageal sphincter pressures
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Feldman: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease, 7th ed.
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Spastic Esophagus
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N Engl J Med (1997) 336:924-932
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N Engl J Med (1997) 336:924-932
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Spechler, S. J. N Engl J Med 2002;346:836-842
Endoscopic Photograph Showing Traditional, or Long-Segment, Barrett's Esophagus
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Grant’s Atlas of Anatomy, 1972
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Enteroendocrine cells - Ghrelin
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Stomach Anatomy Cardia
◦ mucus cells Fundus and Body
◦ mucus cells ◦ parietal cells
acid secretion and intrinsic factor ◦ chief cells
Pepsiniogen ◦ enteroendocrine cells
ghrelin
Antrum ◦ mucus ◦ enteroendocrine cells
gastrin,somatostatin
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Gastric Functions Storage Mechanical breakdown of food Exocrine secretion (~2,500 mls/day) ◦ Acid ◦ Pepsinogen ◦ Intrinsic Factor
Endocrine secretion ◦ Gastrin ◦ Ghrelin
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Grant’s Atlas of Anatomy, 1972
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Receptive Relaxation Stomach exhibits high compliance ◦ 1.5 L of air results in an increase of 10 mm Hg in
intraluminal pressure Dependent upon the vagus nerve ◦ Non-adrenergic, non-cholinergic control ◦ Dependent on nitric oxide
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Gastric Functions Storage Mechanical breakdown of food Exocrine secretion (~2,500 mls/day) ◦ Acid ◦ Pepsinogen ◦ Intrinsic Factor
Endocrine secretion ◦ Gastrin ◦ Ghrelin
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Grant’s Atlas of Anatomy, 1972
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300 ml starting volume
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Gastric Functions Storage Mechanical breakdown of food Exocrine secretion (~2,500 mls/day) ◦ Acid ◦ Pepsinogen ◦ Intrinsic Factor
Endocrine secretion ◦ Gastrin ◦ Ghrelin
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No acid, no ulcers Peptic ulcer disease affects up to 10% of
the population
Acid Secretion
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H+-K+:ATPase Expressed by parietal cells Intraluminal pH = 0.8 Cytosolic pH = 7.3 Proton gradient = 2,400,000
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H+-K+:ATPase Enzyme requirements ◦ ATP 1 ATP > 2 H+
◦ Potassium
Required on the luminal side ◦ Hydrogen Produced via carbonic anhydrase
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Sawaguchi, A. et al. J. Histochem. Cytochem. 2004;52:77-86
Light (A,B) and electron (C-E) micrographs of isolated rabbit gastric glands stimulated with histamine for 30 min
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Fundus
Body
Antrum
Parietal cells
Chief cells
G cells gastrin
pepsinogen
Intrinsic factor
HCl +
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Regulation of Acid Secretion Acetylcholine - vagal input Gastrin - G cells ◦ pH > 3, amino acids Phe, Trp
Histamine Inhibition of any one pathway will also
significantly affect stimulation by other agents.
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Ach Histamine Gastrin
Muscarinic Receptor H2 receptor
IP3, Ca2+ cAMP IP3, Ca2+
H+ secretion
Atropine Cimetidine
Omeprazole
(inhibits H+/K+ ATPase)
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Nature (1992) 360:458-461
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Nature (1992) 360:458-461
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Aspirin/NSAID ulcers Increase risk of ulcers with aspirin or NSAID
(non-steroidal antiinflammatory drugs) ◦ Mechanism of action may include the inhibition of
prostaglandin synthesis, which normally promotes mucus production. ◦ Analogs of prostaglandin E (misoprostil) are used to
reduce the incidence of NSAID ulcers. Acid inhibition is more commonly used now.
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Gastric Exocrine Protein Secretion
Mucus - lubrication and mucosal protection Intrinsic factor - binding and absorption of
vitamin B12. Produced by the same cells (parietal cells) that secrete acid.
Pepsinogen - activated by acid to pepsin, an endoprotease. Produced by the chief cells.
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Vitamin B12
• Methylation-facilitates 1-carbon transfers – conversion of homocysteine to methionine
• Intramolecular rearrangement – isomerization of methylmalonyl coenzyme A to succinyl CoA
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Feldman: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease, 7th ed.
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Intrinsic Factor represents the only major essential factor produced by the stomach ◦ Intrinsic Factor is essential for vitamin B12
absorption. ◦ Patients who undergo a gastrectomy must have
vitamin B12 replaced. Deficiency results in CNS and peripheral neuropathic
problems, megaloblastic anemia, etc.
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Pepsinogen Secreted by the chief cells as an in active
proprotein. Activated by cleavage in an acid environment. Cleaves at aromatic amino acids.
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Gastric Endocrine Protein Secretion
Gastrin Ghrelin
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Ulcer Disease Therapy
Ulcers occur only in the presence of acid
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Oral Antiacids Advantages of the oral antacids include
their low cost, rapid onset of action and absence of systemic adverse reactions. Disadvantages include that short duration of beneficial effects
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Oral Antacids Sodium bicarbonate (baking soda, Alka
Seltzer) Calcium carbonate (Tums, Os-Cal) Magnesium hydroxide (Mylanta) ◦ side effects: diarrhea
Aluminum Hydroxide ◦ side effects: constipation
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Anticholinergics Inhibit neural stimulation of acid secretion High incidence of side effects
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H2 receptor antagonist imidazole ring - related to histamine Competitive antagonists for histamine Rapidly absorbed with peak levels in 90min.
Not protein bound. T1/2 = 4-12 hours depending on formulation Excreted largely in the urine, which requires
dosage adjustments in renal failure
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Cimetidine Adverse reactions ◦ Anti-androgenic effects: gynecomastia ◦ Diarrhea, headache, dizziness ◦ inhibits the hepatic cytochrome P450 such that the
half-life of warfarin-containing anticoagulants, phenytoin, propranolol, nifedipine, and others may be longer
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PPI - Omeprazole Covalently binds to the pump in low pH First pass effect in the liver after intestinal
absorption ◦ Excreted in the urine (70%) and feces
Few significant adverse reactions ◦ Elevated risk of osteoporosis with chronic use.
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H. pylori
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