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GASTROINTESTINAL PHYSIOLOGY
ENTERIC NERVOUS SYSTEM
Smooth muscle: All smooth muscle is innervated by the autonomic nervous system
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o No Striations: Thin and thick filaments run through in a random order
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o Plasticity: Smooth muscle is able to stretch to a greater length and compress to a shorter length than
skeletal
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o Slow, Sustained contraction as compared to skeletal muscle
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This is the type of smooth muscle found in Ciliary Muscle
and Ductus Deferens
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o Sparse innervation compared to multi-unit muscle
o Functional Syncytium: Gap junctions allow intercellular communication
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 High basal resting potential (-57 mV -vs- -80 mV) as compared to skeletal muscle
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SMOOTH MUSCLE CHANNELS:
o Electromechanical Channels: Channels that transduce electrical activity, in one form or another, to
mechanical activity of actin and myosin
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SMOOTH MUSCLE CONTRACTION:
o Ca+2 enters cell ------> Calmodulin then activates Myosin Light-Chain Kinase (MLCK) ------> MLCK
then phosphorylates myosin, turning it on and enabling it to interact with actin ------> contraction occurs
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SLOW-WAVES: The basal electrical tone of smooth muscle
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Also called the Basal Electrical Rhythm (BER)
Magnitude of change is 5 - 15 mV, caused by entrance of Na+ into cell
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Basal Rhythm in Different Regions: Remember these waves are only electrical -- not mechanical
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In the duodenum, 30-40% of slow-waves are associated with Ca+2 as
Ca+2 is added to the cells
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Activity can go on without any CNS
input
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o SUBMUCOSAL PLEXUS: Located in the submucosa, just outside the Muscularis Mucosae
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They are the
origin of short reflexes (not involving the CNS) that go through the two GI plexes in the enteric NS
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 The Vagus carries both afferents (70%!) and efferents
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o INTESTINO-INTESTINAL (short) REFLEX: Generally inhibitory, involving only the Enteric NS, and
completely independent of the Autonomic NS
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They work primarily by presynaptic inhibition, thus
inhibiting release of ACh
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 Norepinephrine binds to alpha1-Adrenoreceptors on parasympathetic nerve terminals and
thereby inhibit the release of ACh
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o Norepinephrine decreases GI-Motility when it acts on smooth muscle
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o VASOACTIVE INTESTINAL PEPTIDE (VIP): Acts directly on smooth muscle to cause smooth
muscle relaxation
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 VIP is in local neurons, and is released when Vagal Fibers excite these inhibitory neurons to
cause relaxation: Vagus (Excitatory synapse) ------> Turn on VIP neurons (Inhibitory synapse) -----> Relaxation
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Depending on the nerve, whenever
the ACh and NorE are released, so will the other substances be released
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Luminal contents will cause basal contractility without any nervous influence at all
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PARALYTIC ILEUS: Loss of GI contractility
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Post-Operative (Physiologic) Ileus is a very common occurrence with abdominal surgeries

TYPES OF MOTILITY:
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PERISTALSIS: Propulsion of material in the aboral (away from mouth) direction
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o Peristalsis occurs by segmental hyperpolarization followed by depolarization of muscle
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This is
mediated by VIP / NO
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 Contraction of the muscle occurs proximal to the bolus, in order to propel the bolus forward
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RHYTHMIC SEGMENTATION: Mixing and churning of materials without propelling them forward in the tract
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o Tonic Contraction is myogenic -- it doesn't depend on innervation
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All of below serve regulatory (as opposed to digestive) functions
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o STRUCTURE: Active part of peptide is on carboxy-end
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 PENTAGASTRIN Drug that mimics Gastrin, containing the last four residues in gastrin, and
therefore containing similar biological activity
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o FNXNS:
 It stimulates release of HCl in Parietal Cells
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 Intestinal Resection: If you cut out part of the intestine, higher levels of Gastrin will
result
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Primary negative feedback mechanism
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CHOLECYSTOKININ (CCK): Endocrine and neural
o STRUCTURE: Biological activity is contained in last seven residues on carboxy-end, with last four
residues in common with Gastrin, and with a protective NH2 on the carboxy terminus
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o Distribution: CCK is made from I-CELLS
o FNXNS:
 Stimulates contraction of the gall bladder
 Stimulates secretion of pancreatic enzymes
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The presence of CCK indicates that
the duodenum is currently full and gastric emptying should be slowed
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SECRETIN: Endocrine and neural
o Distribution: Secretin comes from S-CELLS in the duodenum
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o REGULATION:
 Secretin-release is stimulated by acid in the Duodenum
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It acts in endocrine, neural, and paracrine fashion
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GASTRIC INHIBITORY PEPTIDE (GIP): Endocrine
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Thus the effect is dosedependent, and a large (non-physiological) dose is required to elicit a response
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Greenwald thinks this effect is secondary importance because it is only
pharmacological
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VASOACTIVE INTESTINAL PEPTIDE (VIP): Primarily neural
MOTILIN: Endocrine
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GASTRIC RELEASING PEPTIDE (GRP) (Bombesin): Neural
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Its release is
Non-Adrenergic Non-Cholinergic
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ENKEPHALIN (an Opioid):
o FNXN: Decreases GI-motility by inhibiting the release of ACh
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o Higher CCK is especially marked during first trimester
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Gastrin
interacts with hypothalamus to somehow promote anabolic growth in infants
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 Resting pressure = 50-60 mm Hg to prevent swallowing of air
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o Body: Combination of skeletal and smooth muscle
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 Resting pressure = 30 mm Hg
 LES contractility is myogenic
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 VIP inhibition of LES is Non-Adrenergic, Non-Cholinergic (NANC)
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 Give a VIP-Antibody and the LES will no longer relax because inhibition has been
removed
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o Oral Phase: 1 second, voluntary
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It is stimulated by the presence of the slightest food or liquid
(saliva) in the back of the throat
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 Aspiration of food is prevented:
 Respiration is inhibited from this point forward
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Rather it is adduction vocal cords
that prevents food getting into trachea
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 RELAXATION of Lower Esophageal Sphincter occurs early in the swallowing reflex -- before the
end of peristalsis of the esophagus
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Types of peristalsis:
o PRIMARY PERISTALSIS: The initial peristalsis, initiated by the swallowing reflex
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It is initiated by distension of esophagus and mechanoreceptors on smooth muscle
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It doesn't need to open
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Failure of LES to relax due to lack
of VIP or because enteric system has been knocked out
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o SYMPTOMS:
 Distended esophagus because food can't easily get to stomach
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 Spastic uncoordinated contractions following meal
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Heartburn
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o Secondary peristalsis can help alleviate the symptoms by pushing unwanted chyme back into the stomach
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o Lying down after a meal (i
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lack of gravity) worsens the reflux
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It acts on ACh
receptors to amplify the effect of ACh
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Pressure increase with more food is gradual
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More food ------> distend stomach wall and activate mechanoreceptors
------> more VIP on stomach wall ------> relaxation
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o It controls the rate of Gastric Emptying, so duodenum doesn't get overloaded with bolus
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o This number represents the maximum number of contractions that can occur per minute
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o General Properties:
 Retropulsion: Stomach contractions originating at antrum and going backward, to prevent too
rapid of gastric emptying
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 Fats are slowest emptying of all substances
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 Isotonic contents empty before hypotonic contents
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o ENTERO-GASTRIC REFLEX: Negative feedback from duodenum will slow down the rate of gastric
emptying, by multiple mechanisms
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 Acid in duodenum ------> stimulate Secretin release ------> inhibit stomach motility via Gastrin
inhibition
 Fats in duodenum ------> stimulate CCK and GIP ------> inhibit stomach motility
 Hypertonicity in duodenum ------> (unknown hormone) ------> inhibit gastric emptying
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 Dumping (Gastric Emptying) Syndrome = TOO RAPID emptying, which can result from
resection of part of the stomach
 SYMPTOM: Too rapid emptying ------> hypertonic bolus in duodenum ------> pull fluid
in from circulation ------> Severe cardiac problems and hypovolemia
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It can cause nausea, heartburn, and
reflux
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It gets increasingly slower as you move through intestine
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The general movement of food
aborally is a result of the basal electrical rate
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If you give tetrodotoxin to kill all the nerves, you still
get motility
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Atropine
has no effect on it
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Distension on colonic side of sphincter ------> sphincteral contraction ------> bolus is prevented from
moving backward
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HAUSTRATIONS: Slow segmental movements that move food very slowly through colon
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Mass Movements result from GASTRO-COLIC REFLEX: Food entering into stomach can cause much more
rapid and forceful peristalsis in colon, ultimately resulting in defecation
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happen in the morning
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o As you increase pressure in rectum (distend it), two things happen:
 The Internal Anal Sphincter relaxes to accommodate the fecal matter
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 Pooping is voluntary (usually)
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A large constituent of fiber is cellulose which human can't digest
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MIGRATING MOTOR COMPLEX (MMC): Housekeeping function throughout the small intestine, to sweep
bacteria aborally
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o MMC is caused by Motilin and Acetylcholine -- it is blocked by atropine
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The following receptors feed into the vomiting center
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 Apomorphine is a drug that stimulates the chemical trigger zone
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o Touch Receptors in throat (as in gagging reflex)
o Mechanoreceptors and Chemoreceptors in stomach and duodenum
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OUTPUT: The vomiting act
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o Four groups of muscles are stimulated: this is the process of retching, which is reverse peristalsis
accompanied by relaxation of esophageal sphincters
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 Abdominal Muscles ------> positive intraabdominal pressure to facilitate upchucking
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 Esophageal sphincter (LES and UES) must relax for vomiting to occur
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combined sympathetic / parasympathetic on salivary
glands causes hypersalivation

SECRETIONS and ABSORPTION
SALIVARY SECRETIONS: Average about 1500 mL a day
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o Salivary Amylase: Secreted primarily by Parotid gland
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However,
if it is inside a bolus of food and protected on all sides then it can still be active even in stomach
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 FNXN: Lubrication of food and it serves as a buffer
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It thereby serves as an antibacterial
role
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 It can serve a backup function in case pancreatic lipase is lacking
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o Lysozymes: Antibacterial secretions
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It can lead to caries (cavities) because the anti-bacterial salivary secretions are
lacking
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HYPOTONICITY: Salivary secretions are hypotonic and concentrated in HCO3- and K+, due to exchangers in the
salivary ducts
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o Low in Na+ and higher in K+, as a result of a Na+/K+-ATPase exchanger in salivary ducts
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Nervous Stimulation of Salivation: Both sympathetic and parasympathetic cause salivation, but parasympathetic is
the primary one
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o Parasympathetic: Two pathways
 Cholinergic Pathway causes vasodilation via two mediators: It causes production of kallikrein (a
vasodilator) and it causes conversion of Plasma Kininogen ------> Bradykinin (another
vasodilator)
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GASTRIC SECRETIONS:
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GASTRIC EPITHELIAL CELL TYPES:
o Parietal Cells: Produce HCl
o G-Cells: Produce Gastrin
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o Stem Cells in crypt
PARIETAL (OXYNTIC) CELLS: Produce gastric acid
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o Carbonic Anhydrase: Parietal cell creates carbonic acid via this enzyme: CO2 + H2O <====> H2CO3
<====> HCO3- + H+
 The H+ is then secreted into the lumen
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Transport occurs by a HCO3-/Cl- antiport
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o PARIETAL CELL STIMULATION: Three things stimulate parietal cells in synergy -- the effects are
additive, but the effect of all of them together is greater than the sum of the individual effects
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 H2-Blockers block the histamine receptor
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 Acetylcholine: Muscarinic receptor that acts by the alpha-adrenergic pathway (IP3)
 Atropine blocks the ACh receptor, duh??
 Gastrin: Gastrin also acts by the alpha-Adrenergic pathway (IP3)
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 CCK will block the gastrin receptor
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K+ gradient is maintained by the traditional Na+/K+ATPase
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Good drug for antacid
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o CEPHALIC PHASE: 30% of secretion, occurs when food is seen, smelled, or tasted
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 Vagus Nerves releases Acetylcholine during this phase
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Gastric Releasing Peptide is also released in stomach
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It also stimulates release of Gastrin
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o INTESTINAL PHASE: Post-gastric-emptying
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o Acid stimulates the release of Somatostatin, which turns off Parietal Cells and G-Cells
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o Treatment: Use acid-reducers like H2-Blockers
o VICIOUS CYCLE: The excess acid can cause conversion of pepsinogen to pepsin which will stimulate
further acid release
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HELICOBACTER PYLORI: Those little critters in the stomach that have been recently proven to cause ulcers
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o ULCER treatment should include antibiotics to fight these bacteria, but H
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INTRINSIC FACTOR (IF): Produces by parietal cells in stomach, it is necessary for Vit-B12 absorption
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o Stomach: Secretes intrinsic factor into bolus
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Without the IF, only 20% of B12
is absorbed
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ACHLORHYDIA is an overgrowth of bacteria in stomach resulting in low HCl secretion which will cause high
Gastrin levels
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Acid converts the proenzyme to pepsin
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o Pepsin can continue to activate itself once active
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 Acetylcholine
 H+
 Secretin
 CCK
o Pepsinogen I found in Chief Cells
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ZOLLINGER-ELLISON SYNDROME:
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ETIOLOGY: Pancreatic tumor ------> Under secretion of Pancreatic Enzymes ------> Over secretion of GASTRIN
due to no CCK
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o Diarrhea from hypergastrinemia
o Steatorrhea (fat in stool):
 Denaturation of pancreatic lipase due to acidic environment in the duodenum
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o GERD

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PANCREATIC SECRETIONS:
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General Properties:
o They are basic (pH = 8
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Higher HCO3- at increased flow levels until it plateaus
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o H+ ------> stimulates S-Cells to secrete Secretin ------> stimulates pancreatic enzymes
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o BOTH CCK and Secretin are required for maximal (or near maximal) pancreatic secretion
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ACID TIDE: Pancreatic Ductal Cells counter the alkaline tide with an acid tide
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o Carbonic Anhydrase can then make lots of HCO3-, which it secretes into the lumen
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o NaCl is pulled out of gall-bladder cells, and H2O follows, so that bile becomes superconcentrated
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o CHOLERETIC: Any substance that increases the flow of bile down the bile duct, but does not affect bile
synthesis
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o HYDROCHOLERETIC: Any compound that promotes the secretion (synthesis) of bile in the liver, such
as Secretin
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It is tonically contracted when no food is in the duodenum
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MICELLES: Bile Salts + Cholesterol + Lecithin
o LECITHIN (PHOSPHATIDYLCHOLINE): MICELLES require lecithin to function at maximum
efficiency
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SYNTHESIS / STRUCTURE OF BILE ACIDS: Bile acids are synthesized from cholesterol in the liver, stored in the gall
bladder, and secreted through the common bile duct
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This hydroxylation destines the product to become a bile-acid
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It has three OH-groups in the rings, and a carboxylic acid at the end of
the side chain
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o DEOXYCHOLATE: The minor bile acid
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They inhibit 7alphaHydroxylase
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Bile Salts are even more
polar than their corresponding acids
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o Taurocholate: Cholate with Taurine added as an amide function
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o Glycochenodeoxycholate and Taurochenodeoxycholate are the minor bile salts
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ENTEROHEPATIC CIRCULATION: The circulation of bile between the intestine and liver
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This is mixed in with bile acids that
are recirculated
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This
occurs in the liver
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o Deconjugation: Deconjugation and reduction of bile salts often occurs in the intestine, aided by intestinal
bacteria
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 Reabsorption sends the acids through the portal circulation and ultimately back to the liver
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This is one way to get rid of cholesterol
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This makes cholesterol precipitate out
of the bile solution and form stones
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Women
taking BIRTH CONTROL are at even higher risk, relatively, for same reason
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It is carried by Albumin in the blood stream, where it goes to
liver
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Bilirubin Glucuronide is then secreted in bile to intestine
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UROBILINOGEN FATE:
o 80% of it is them excreted in feces
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 Most of that goes back to liver and is re-secreted
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JAUNDICE: Caused by bilirubin build up, indicating problems with the liver
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OBSTRUCTIVE JAUNDICE: Obstruction of bile-duct, preventing Bilirubin Glucuronide from entering intestine;
it is therefore diverted to kidneys ------> excessive bilirubin in urine + big drop in fecal urobilinogen

INTESTINAL ABSORPTION: Absorption is ultimately dependent on the Na+/K+ Pump to create the gradient
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o Na+/Nutrient Cotransport: (30% )There are several Na+-Cotransporters, for glucose and for individual
amino acids
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PERICELLULAR: Recent evidence says that majority of fluid appears to be absorbed between cells rather than
through cells (transcellular), although both occur
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POTASSIUM: Passively absorbed in small intestine, and secreted in large intestine
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VIPOMA: Cancer causing excess release of VIP ------> excess secretion ------> secretory diarrhea
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o No Solute Gap -- fecal analysis is osmotically normal or hypoosmotic
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o ETIOLOGY:
 CHOLERA TOXIN: It causes increased basal levels of cAMP in enterocytes
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The result is that Cl- channels on luminal membrane are
blocked open ------> perpetual secretion
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 Gastric Tumor ------> Over secretion of Gastrin
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o SOLUTE GAP: Fecal analysis shows a large "solute gap," i
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hyperosmotic feces
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o LAXATIVES cause osmotic diarrhea because their contents (magnesium) are like fiber in that they are not
absorbed ------> higher bolus tonicity
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o Celiac Sprue also causes osmotic diarrhea
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Endopeptidase
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o Mainly splits bonds between Tyr and Phe
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o CLEAVAGE-SPECIFICITY: It cleaves aromatic and non-polar side-chains
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It will cleave any of the following residues: Trp, Phe, Tyr, Met, Leu
ELASTASE: Endopeptidase
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Elastase is activated by Trypsin, too
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CARBOXYPEPTIDASE: These are exopeptidases that cleave at the carboxy-end
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Trypsin is activated by ENTEROKINASE, which is secreted in the intestinal brush-border
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Auto-Catalytic: Activated trypsin acts on trypsinogen to make more of itself
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This is a different mechanism than the
endopeptidases which are serine proteases
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Carboxypeptidase-A: Cleaves neutral and acidic side-chains (on the carboxy end), such as Alanine,
Valine, Isoleucine, Leucine
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This in effect gives us a free amino acid of Lysine or Arginine which can then be absorbed
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o This is secreted by the intestinal mucosa further along the small intestine (jejunum)
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o This cuts, usually on smaller peptides, one acid at a time off the amino end
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PROTEIN ABSORPTION:
o About 70% of proteins are taken in as dipeptides and tripeptides
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o About 30% are taken in as free amino acids, via Na+-Cotransport
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CARBOHYDRATE DIGESTION:
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SALIVARY AMYLASE: Begins breakdown of starch in mouth
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Secreted by
pancreas into lumen of duodenum
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That is not digestible by humans and thus constitutes fiber
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They are broken down by isomaltase
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o MALTASE: Breaks down Maltose ------> Glucose + Glucose
 Located in the intestinal brush-border
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 LACTOSE DEFICIENCY is a very common problem
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o ISOMALTASE: Breaks down alpha-1,6 LIMIT DEXTRANS Branches in starch
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The monosaccharides are then transported as follows:
o Glucose: Enters enterocyte via Na+-Glucose Cotransport, and enters bloodstream via facilitated diffusion
on other side
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So, if both sugars are present then glucose will preferentially bind
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o Glucose-Galactose Malabsorption syndrome: Congenital disorder; mutation in Na+/Glucose
Cotransporters
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FAT DIGESTION:
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GENERAL PROCESS of Digestion and Absorption:
o EMULSIFICATION by micelles
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 There is an unstirred water layer right at the villus border
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o DIGESTION: LIPASE then breaks down the triglyceride ------> monoglyceride + free fatty acids
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o RE-ESTERIFICATION: Fatty acids are re-esterified to triglycerides inside the enterocytes
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o LYMPH: Chylomicrons enter circulation through lacteals ------> lymphatic system
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LINGUAL LIPASE: In the tongue
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It attaches to micelles, with aid of bile salts, to facilitate
Triglyceride ------> 2-Monoglyceride + 2 Fatty Acids
PHOSPHOLIPASE A2:
COLIPASE: Forms a "wedge" in fat globules which facilitates attachment of lipase
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There is great
redundancy in the supply of pancreatic exocrine enzymes
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