pharmacologists’ perspective on colon physiology
TRANSCRIPT
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PHARMACOLOGISTS’ PERSPECTIVE ON COLON
PHYSIOLOGY
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vv
Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
①Nodose
CNS
③SMP
AChv
DAEnk
v
GC-C CFTR Crypt Cell
CIC2
SSt
Enkv②MP
VIP/NOv ACh
ACh
v=
PHARMACOLOGICALLY RELEVANTCIRCUITS ONLY!
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
GC-C CFTR Crypt Cell
CIC2
VIP/NO
ACh
v
MOTILITY and WATER SECRETION/ABSORPTIONare physiologically linked;
MANY DRUGS AFFECT BOTH PROCESSES
MOTILITY
SECRETION
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
GC-C CFTR Crypt Cell
CIC2
VIP/NO
ACh
v
Modulation of secretion is controlled similarly to motility; Enk, SSt and ACh interneurons have been omitted from the submucosal plexus to save space
MOTILITY
SECRETION
Don’t forget hormone actions esp. motilin,
somatostatin!
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PERISTALTIC REFLEX(MOSTLY)
DRUGS THAT PRIMARILY AFFECT MOTILITY
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
VIP/NO
PERISTALTIC REFLEX
PROXIMALCONTRACTION
DISTALRELAXATION
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
v
③SMP
v v②MP
①Nodose
CNS
=
3 MAJOR TYPES OF AFFERENTS CARRY INFORMATION FROM THE MUCOSA
EC CELL FUNCTIONS AS A SENSORY RECEPTOR
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
①Nodose
CNS
=
5HT FROM THE EC CELLS STIMULATES 5HT3 RECEPTORS RESPONSIBLE FOR
NAUSEA AND VOMITING
5HT3
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
①Nodose
CNS
=
MOST 5HT3 ANTAGONISTSARE USED AS ANTIEMETICS
(also act centrally)
5HT3
DOLASETRONGRANISETRON
ONDANSETRONPALONOSETRON
MORE ON THIS IN THE NEXT LECTURE
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
v
③SMP
v v②MP
EC CELL STIMULATION ALSO ACTIVATES AFFERENT NEURONS IN THE MYENTERIC AND SUBMUCOSAL PLEXUSES
5HT1 5HT3
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v
Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
AChv
Enk
v
SSt
Enkv②MP
VIP/NOv ACh
ENTERIC INTERNEURONS CONNECT THE SENSORY AFFERENTS TO THE CHOLINERGIC
AND VIP/NO MOTONEURONS
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v
Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
AChv
v
SSt
v②MP
VIP/NOv ACh
SENSORY NEURON ACTIVATION 1) INCREASES EXCITATORY INPUT TO CHOLINERGIC AND
SOMATOSTATIN NEURONS ↑ PERISTALSIS
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
AChv
Enk Enk②MP
VIP/NO
SENSORY NEURON ACTIVATION 2) INHIBITS INHIBITORY ENKEPHALIN INTERNEURONS
↑ PERISTALSIS
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
VIP/NO
COORDINATION AND TIMING ARE CRITICAL
PROXIMALCONTRACTION
DISTALRELAXATION
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SEROTONIN AGONISTS AND ANTAGONISTSDRUGS AFFECTING AFFERENT FUNCTION
DRUGS THAT PRIMARILY AFFECT MOTILITY
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
v v②MP
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) MAY INCREASE AFFERENT STIMULATION
INCREASED PERISTALSIS
FLUOXETINEPAROXETINESERTALINE
↑ [5HT]
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
v v②MP
ONE 5HT3 ANTAGONIST WORKS LOCALLY IN THE GUTTO DECREASE PERISTALSIS
5HT1 5HT3 ALOSETRON
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
v v②MP
BULK LAXATIVES AND CONTACT CATHARTICS WORK BY STIMULATING ENTERIC SENSORY NEURONS
TO EVOKE THE PERISTALTIC REFLEX
BULK LAXATIVES ↑STRETCHCONTACT CATHARTICS ↑ STIMULATION
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
v v②MP
5HT4 AGONISTS ACT PRESYNAPTICALLY TO INCREASE NEUROTRANSMITTER RELEASE FROM ENTERIC SENSORY
NEURONS INCREASED PERISTALSIS
5HT4
CISAPRIDETEGASEROD
↑ [5HT]
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ENKEPHALIN AGONISTS AND ANTAGONISTS
DRUGS THAT PRIMARILY AFFECT MOTILITY
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
5HTEnterochromaffin
Cell
AChv
Enk Enk②MP
VIP/NO
SENSORY NEURON ACTIVATION 2) INHIBITS INHIBITORY ENKEPHALIN INTERNEURONS
↑ PERISTALSIS
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
Enk Enk
VIP/NO
OPIATES CAUSE CONSTIPATIONTHROUGH INHIBITORY ACTIONS MEDIATED BY µ RECEPTORS
µDIPHENOXYLATE
LOPERAMIDE µ
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
Enk Enk
VIP/NO
µ RECEPTOR ANTAGONISTS ACT PERIPHERALLY TO OVERCOME ENKEPHALIN/OPIATE-INDUCED DECREASES IN MOTILITY
µALVIMOPAN
METHYLNALTROXONE µ
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Mucosa
Submucosal plexusEnk
SINCE SIMILAR CIRCUITS EXIST IN THE SUBMUCOSAL PLEXUS, OPIATES ALSO DECREASE WATER SECRETION
GC-C CFTR Crypt Cell
CIC2
ACh
v
③SMP
DIPHENOXYLATELOPERAMIDE
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DOPAMINE ANTAGONISTS
DRUGS THAT PRIMARILY AFFECT MOTILITY
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
DA
D2 RECEPTOR ANTAGONISTS INHIBIT INHIBITION INCREASED MOTILITY
D2
METOCLOPRAMIDEDOMPERIDONE
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ANTICHOLINERGIC AGENTS
DRUGS THAT PRIMARILY AFFECT MOTILITY
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
TCAs PRODUCE CONSTIPATION THROUGH TWO “ANTICHOLINERGIC” ACTIONS:
1) Increase in synaptic [NE] presynaptic α2-mediated decrease in ACh release
2) Increase in synaptic DA Increase in D2 inhibition
Postganglionic Sympathetic
α2
DA
AMITRIPTYLINEDESIPRAMINE
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
AChv
ANTIMUSCARINIC DRUGS BLOCK RECEPTORS ON THE CIRCULAR MUSCLE CELLS
M ATROPINE
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MOTILIN AGONISTS
DRUGS THAT PRIMARILY AFFECT MOTILITY
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Mucosa
Submucosal plexus
Circular muscle
Myenteric plexus
MOTILIN AGONISTS ACT DIRECTLY ON THE CIRCULAR MUSCLE TO PROMOTE CONTRACTION
(by initiating the migrating motor complex)
Motilin Receptor
MACROLIDE ANTIBIOTICS
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DRUGS THAT PRIMARILY AFFECT SECRETION
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Mucosa
Submucosal plexusEnk
SINCE SIMILAR CIRCUITS EXIST IN THE SUBMUCOSAL PLEXUS, DRUGS THAT AFFECT ENTERIC NEURONS AFFECT SECRETION
GC-C CFTR Crypt Cell
CIC2
ACh
v
③SMP v
vACh
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CHLORIDE SECRETION
DRUGS THAT PRIMARILY AFFECT SECRETION
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Mucosa
Submucosal plexus
DRUGS THAT ACTIVATE CIC2 AND GUANYLYL CYCLASE C ( CFTR) INCREASE Cl- SECRETION
GC-C CFTR Crypt Cell
CIC2
LINACLOTIDELUBIPROSTONE
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Mucosa
Submucosal plexus
BLOCKING CFTR REDUCES Cl- SECRETION
GC-C CFTR Crypt Cell
CIC2CROFELEMER
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Mucosa
Submucosal plexus
SOMATOSTATIN DECREASES Cl- AND HCO3- SECRETION
BY AFFECTING MULTIPLE UPSTREAM PATHWAYS
GC-C CFTR Crypt Cell
CIC2OCTREOTIDE
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Mucosa
Submucosal plexus
SALICYLATE DECREASES Cl- SECRETION IN THE COLONVIA AN UNKNOWN MECHANISM
GC-C CFTR Crypt Cell
CIC2
BISMUTHSUBSALICYLATE
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DRUGS THAT ALTER OSMOTIC BALANCE
DRUGS THAT PRIMARILY AFFECT SECRETION
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LUMEN OF GI TRACT
Mucosa
SOME DRUGS PULL WATER INTO THE LUMEN OF THE GI TRACTVIA OSMOSIS
OSMOTIC CATHARTICS
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Mucosa
NORMALLY REABSORBED, IF BILE ACIDS REMAIN IN THE LUMEN OF THE GI TRACT, THEY CAUSE SECRETORY DIARRHEA;
BILE ACID BINDING RESINS DECREASE WATER MOVEMENTINTO THE LUMEN OF THE GI TRACT
CHOLESTYRAMINECOLESTIPOL
Bile acids
Bile acids LUMEN OF GI TRACT