Term
peristalsis is a series of reflex responses to a bolus in the lumen of a given segment of the intestine
the ascending excitatory reflex results in contraction of the CIRCULAR muscle on the oral side of the bolus, while the descending inhibitory reflex results in relaxation caudally.
the net pressure gradient moves the food bolus
1) enterochromaffin cells lines the mucosa of the gut and release serotonin in response to chemical and mechanical stimulation
2) the serotonin binds to serotonin receptors on the primary afferent neuron
3) binding of serotonin excites the primary afferent neuron of the myenteric plexus
4) the primary afferent then communicates with interneurons (through release of neurotransmitters) to the motor neuron (motor output)
5) the motor neuron is part of the efferent component of the peristaltic response and translates sensory information into mechanical force
2 types of motor neurons:
excitatory motor neurons - release ACh to produce contraction of circular muscle on the oral side
inhibitory motor neurons - release NO on the anal side to produce relaxation of circular muscle |
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Definition
| neural network and the peristaltic response |
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Term
1) excite the primary afferent
2) increase ACh release from the excitatory motor neuron
use agonists of receptors that increase ACh release from the excitatory motor neuron
OR
use antagonists of receptors that decrease ACh release from the excitatory motor neurons
3) having direct actions on receptors present on smooth muscle (M3 coupled with Gq), which results in increases in intracellular Ca, eventually leading to smooth muscle contraction |
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Definition
| 3 strategies used by prokinetic drugs to increase GI motility |
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Term
excites the primary afferent:
primary afferents express 5-HT4 receptors which are coupled to Gs
binding to 5-HT4 receptors excites the primary afferent, which will then communicate to interneurons
lead eventually to excitatory motor neurons releasing ACh which then binds to M3 receptors on smooth muscle
teaserod is a 5-HT4 partial agonist
increases ACh release of excitatory motor neurons -> increased peristaltic activitiy when ACh binds to M3 receptors on GI smooth muscle
5-HT4 receptors are also present on the nerve terminals of the excitatory motor neuron, so tegaserod can act on 5-HT4 receptors on the nerve terminal to also increase ACh release
tegaserod is no longer on the market due to increases in heart attack and stroke |
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Definition
| MOA and ADRs of tegaserod |
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Term
excites the primary afferent:
primary afferents express 5-HT4 receptors which are coupled to Gs
binding to 5-HT4 receptors excites the primary afferent, which will then communicate to interneurons
lead eventually to excitatory motor neurons releasing ACh which then binds to M3 receptors on smooth muscle
cisapride is a 5-HT4 full agonist
cisapride is no longer on the market due to increases in arrhythmias |
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Definition
| MOA and ADRs of cisapride |
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Term
excites the primary afferent:
primary afferents express 5-HT4 receptors which are coupled to Gs
binding to 5-HT4 receptors excites the primary afferent, which will then communicate to interneurons
lead eventually to excitatory motor neurons releasing ACh which then binds to M3 receptors on smooth muscle
even though it's thought more as a D2 receptor antagonist, metoclopramide also displays 5-HT4 agonism to where part of it's mechanism of action for stimulating peristalsis, through this effect |
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Definition
| MOA of metoclopramide as a prokinetic agent |
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Term
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Definition
excitatory motor neurons have receptors which can either stimulate or inhibit release of ACh
receptors that increase ACh release include: |
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Term
mu opioid receptors (Gi)
D2 receptors (Gi) |
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Definition
excitatory motor neurons have receptors which can either stimulate or inhibit release of ACh
receptors that decrease ACh release include: |
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Term
increases ACh release of excitatory motor neurons -> increased peristaltic activitiy when ACh binds to M3 receptors on GI smooth muscle
bethanechold is an AGONIST of receptors that enhance ACh release from the excitatory motor neuron
bethanechol is a non-selective muscarinic receptor agonist
bethanechol can act on M1 receptors present on excitatory motor neurons to enhance ACh release from excitatory motor neurons
ADRs:
bethanechol is non-selective for muscarinic receptors and produces many parasympathetic ADRs |
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Definition
| MOA and ADRs of bethanechol |
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Term
increases ACh release of excitatory motor neurons -> increased peristaltic activitiy when ACh binds to M3 receptors on GI smooth muscle
alvimopan is an antagonist of receptors that decrease ACh release from excitatory motor neurons
alvimopan is a newer drug approved to treat opioid induced bowel dysfunction
PERIPHERAL MU RECEPTOR ANTAGONIST
mu opioid receptor is present in cell bodies of excitatory motor neurons of smooth muscle
agonism of mu opioid receptors can cause analgesia and constipation
analgesia is mediated through central mu opioid receptors; constipation is mediated through peripheral mu opioid receptors
morphine can cause constipation by decreasing ACh from excitatory neurons through agonism of mu receptors in the GI tract
alvimopan cannot cross the BBB, so it cannot exert central antagonistic acitvity (does not antagonize the analgesia produced by morphine) |
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Definition
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Term
increases ACh release of excitatory motor neurons -> increased peristaltic activitiy when ACh binds to M3 receptors on GI smooth muscle
metoclopramide antagonizes receptors that decrease ACh release from the excitatory motor neurons
agonism of dopamine receptors in the GI tract suppress ACh release from myenteric motor neurons, mediated throug the D2 receptor
antagonism of the D2 receptor by metoclopramide increases ACh release from myenteric motor neurons and is an effective prokinetic drug |
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Definition
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Term
inhibit the breakdown of ACh
side effects are a huge problem as ACh esterase inhibitors are non-selective as ACh can bind to both nicotinic and muscarinic receptors |
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Definition
| MOA and ADRs of ACh esterase inhibitors as prokinetic drugs |
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Term
erythromycin is a macrolide antibiotic shown to possess "short lived" motilin receptor activity
smooth muscle contains motilin receptors
motilin is ahormone released from endocrine cells and duodenal mucosal cells which increases motility during the interdigestive period
motilin receptors are coupled with Gq
tolerance develops to erythromycin quickly |
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Definition
| MOA of erythromycin as a prokinetic drug |
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Term
fluid is absorbed by the epithelial cells lining the villi
2 mechanism by which absorption occurs:
paracellular route - substances are transported BETWEEN the cells
transcellular route - substances are transported ACROSS the cell
ions can be actively transported across the cell using ATP to move the ions against their gradients
ions can be co-transported (symporters) across the cell
or ions may use transporters which exchange one ion for another in opposite directions (antiporters)
in general, solute is absorbed first with water following passively
the absorbate is always isosmotic meaning that solute and water absorption occur in proportion to one another
the permeability (to ions and water) of tight junctions varies along the GI tract
in the small intestines there is low transepithelial resistance (tight junctions are leaky) - freer movement of water and ions between epithelial cells
int he colon, there is high transepithelial resistance - significantly restricts the movement of water and ions by the paracellular route
the colon has a reduced absorptive capacity compared to the small intestine |
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Definition
| intestinal fluid absorption |
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Term
absorption of electrolytes varies along the GI tract
majority of eletrolyte and water absorption in the small intestines occurs in the jejunum and ileum (major sites of Na absorption)
jejunum: net absorption of NaHCO3
ileum: net absorption of NaCl
the colon displays mechanisms similar to the collecting duct of the distal tubule of the kidney
K is effluxed and Na can be absorbed
aldosterone can increase Na absorption and increase K excretion
with diarrhea, the K efflux can become significant to where disturbances in electrolytes is a concern |
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Definition
| intestinal electrolyte transport in the jejunum, ileum, and colon |
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Term
[image]
glucose and amino acid transport are Na dependent
one Na molecule is transported across the lumen with each glucose or amino acid molecule
the Na/K/ATPase on the basolateral membrane extrudes Na that entered the cell from the lumen, thereby maintaining a low intracellular Na
as these organic solutes are absorbed, water follows osmotically |
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Definition
| jejunum electrolyte transport: absorption |
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Term
[image]
the ileum contains the same transport mechanisms as the jejunum, but also possesses a Cl/HCO3 exchange mechanism in the apical membrane and a Cl-transporter
based on these differences, there is a net absorption in the ileum of NaCl instead of NaHCO3 |
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Definition
| ileum electrolyte transport: absorption |
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Term
[image]
in the colon there are luminal membranes containing Na channels
absorption of water by the colon is secondary to active transport of Na as the tight junctions of the colon have high transepithelial resistance, which decreases paracellular movement of water and ions
aldosteron can increase Na channel expression and increase K efflux |
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Definition
| electrolyte transport in the colon: absorption |
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Term
[image]
fluid secretion is mediated by epithelial cells lining the crypts of the small intestine and colon
the electrolytes and fluids secreted by the crypt cells are normally absorbed by intestinal villar cells
the Cl channels on the luminal side are closed in the resting secretory cell
however, substances that increse cAMP (through activation of Gs) can induce Cl channel opening
with Cl channel opening, Cl is secreted into the lumen generating an electrochemical gradient which serves as a driving force for Na secretion through the paracellular pathway
thus Cl flow into the lumen, Na follows passively along with water |
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Definition
| INTESTINAL FLUID SECRETION |
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Term
with cholera, there is maximum induction of adenylyl cyclase, leading to maximal stimulation of cAMP and Cl channel opening, Na follows due to the electrochemical gradient and water follows the Na
the absorptive mechanism of the villi cells is overwhelmed leading to diarrhea
rationale for oral rehydration therapy:
glucose can still be absorbed normally; Na and water is absorbed in this process to where the fluid losses can be replaced by the glucose-electrolyte solutions |
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Definition
| cholera and oral rehydration therapy |
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Term
osmotic
secretory
exudative
abnormal intestinal transit |
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Definition
| 4 types of chronic diarrhea |
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Term
| chronic diarrhea: osmotic |
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Definition
solute molecules generate osmotic forces that retard the normal absorption of water or even act to draw water from the circulation into the intestinal lumen
i.e. phosphate, sulfate, and Mg
disaccharides
sugar alcohols
due to ingestion, maldigestion, or malabsorption
treatment involves removing/avoiding offending agent |
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Term
| chronic diarrhea: secretory |
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Definition
imbalance in secretion or absorption
increased secretion of anions or decreased absorption of sodium
impact on electrolytes
can be caused by: infection, neurotransmitters |
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Term
| chronic diarrhea: exudative |
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Definition
structural disruption of the intestinal wall leads to additional serum debris (mucus, serum, blood) into the lumen of the colon
ulcerative colitis, Crohn's disease
treatment of the inflammation is of the utmost importance |
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Term
| chronic diarrhea: abnormal intestinal transit |
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Definition
| relates to a combination of bacterial overgrowth, bile salt wastage, and disorders of motility |
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Term
opioids are anti-diarrheal as they slow intestinal transit, reduce secretion, and stimulate absorption
opioids act on the mu receptor -> coupled with Gi -> decrease ACh release -> constipation
by decreasing intestinal motility, there is increased contact time for increased fluid absorption by the intestine
this results in reduced fecal volume, increased bulk density, and viscosity of the feces, and decreased loss of fluid and electrolytes from the body
opioid receptors are coupled with Gi and have inhibitory actions on cAMP
cAMP stimulates secretion by the epithelial crypt cells
inhibition of cAMP causes decreased fluid secretion by the epithelial cells |
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Definition
| mechanism of opioids as a treatment of diarrhea |
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Term
mu receptor agonist that penetrates the CNS very poorly (acts peripherally)
loperamide produces the constipatory effects without the abuse liability
loperamide decreases peristalsis, increases anal sphincter tone, and has antisecretory activity against cholera and E. coli |
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Definition
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Term
the active metabolite of diphenoxylate is difenoxin
mu receptora agonist that can be used to treat diarrhea
the anti-diarrehal effects of difenoxin are less effective than loperamide in treating diarrhea
difenoxin can penetrate the CNS and at high doses can be subject to abuse
for that reason, it is formualted with a sub-therapeutic dose of atropine |
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Definition
| MOA of diphenoxylate/difenoxin |
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Term
multiple MOAs:
anti diarrheal
anti-inflammatory effects
antimicrobial
anti-secretory
it is possible that bismuth subsalicylate may produce its anti-diarrheal effects through inhibition of PG synthesis (diarrhea can be worsened by PGs)
bismuth as antimicrobial actions that can prevent the attachment of microorganisms to the intestinal mucosa
bismuth inactiates enterotoxins such as those produced by vibrio cholerae |
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Definition
| MOA of bismuth subsalicylate for diarrhea |
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Term
octreotide is a somatostatin receptor agonist (SSTR2)
somatostatin receptors are coupled with Gi and have inhibitory actions on the release of many hormones including:
gastrin
vasoactive intestinal polypeptide
insulin
secretin
growth hormone
in addition, b/c it is a Gi it has inhibitory actions on intestinal fluid secretion, helping with diarrhea
octreotide can inhibit severe secretory diarrhea produced by hormone secreting tumors of the pancreas and GI tract
b/c octreotide is a peptide, it is only available parenterally |
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Definition
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Term
endocrine disorders
diseases of the nervous system
diseases of the large intestine
drug-induced |
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Definition
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Term
dietary fiber
2 types of fiber: soluble and insoluble
soluble fiber:
found in fruits and vegetables
soften stool, will less effect on transit time
insoluble fiber:
found in grains and cereals
increase stool bulk and shortens intestinal transit time
MOA:
can bind water and ions in colonic lumen (softens feces)
supports growth of colonic bacteria (increases fecal mass)
some dietary components may be digested to metabolites which contribute to the osmotic activity of the luminal fluid |
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Definition
| non-pharmacological treatments for constipation |
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Term
many different types: wheat bran and other whole grains, psyllium husk, semi-synthetic celluloses, and polycarbophil
MOA:
absorb and retain water in the intestinal lumen and therby "bulking up" the mass of the intesteinal material
result is mechanical distention of the intestinal wall and stimulation of peristalsis |
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Definition
| MOA of bulk formint laxative |
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Term
several different types:
unabsorbed carbohydrates (lactulose and sorbitol)
polyethylene glycol electrolyte solutions
saline laxative (Mg salts and Na phosphate)
MOA:
produce an osmotic effect which attracts and retains water in the intestinal lumen
this increases intraluminal pressure, stimulating peristalsis |
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Definition
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Term
ARE PRODRUGS
3 classes of stimulant laxative:
1)diphenylmethane derivatives
bisacodyl and sodium picrosulfate
active component is BHPM
2) anthraquinone derivatives
senna and cascara
active component is rhein antrone
3) caster oil
active component is ricolineic acid
the griglyceride of riconoleic acid is hydrolyzed by lipase in the small intestine to ricinoleic acid which inhibits intestinal water absorption and stimulates prokinetic activity by damaging mucosal cells and releasing neurotransmitters (5-HT)
stimulant laxatives are dose dependent
low doses prevent absorption of water and Na
high doses stimulate secretion of Na, with water following, into the colon
MOA:
stimulates peristaltic movement by local mucosal irritation
promotes evaculation of the colon by alering intestinal fluid and electrolyte absorption - may inhibit intestinal N/K/ATPase, increase cAMP) |
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Definition
| MOA of stimulant laxatives |
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Term
prolonged use of stimulant laxatives may result in cathartic colone
meaning, it may result in physical dependence on the stimulant laxatives for bowel movements
senna:
may cause abnormal colloring of the urine (red) - pH dependent
pseudomelanosis coli - occurs with extended use (or abuse)
melanosis is darkening of the colonic mucosa
it is reversible if senna is discontinued
may lead to colon cancer possibly |
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Definition
| important considerations for stimulant laxatives |
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Term
Cl channela activator increasing intestinal fluid secretion without altering serum electrolyte concentrations
softens stool, increases motility
does not produce tolerance
well tolerated |
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Definition
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