PHARMACOLOGISTS’ PERSPECTIVE ON COLON

PHYSIOLOGY

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!

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

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!

PERISTALTIC REFLEX(MOSTLY)

DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

AChv

VIP/NO

PERISTALTIC REFLEX

PROXIMALCONTRACTION

DISTALRELAXATION

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

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

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

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

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

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

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

5HTEnterochromaffin

Cell

AChv

Enk Enk②MP

VIP/NO

SENSORY NEURON ACTIVATION 2) INHIBITS INHIBITORY ENKEPHALIN INTERNEURONS

↑ PERISTALSIS

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

AChv

VIP/NO

COORDINATION AND TIMING ARE CRITICAL

PROXIMALCONTRACTION

DISTALRELAXATION

SEROTONIN AGONISTS AND ANTAGONISTSDRUGS AFFECTING AFFERENT FUNCTION

DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

5HTEnterochromaffin

Cell

v v②MP

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) MAY INCREASE AFFERENT STIMULATION

INCREASED PERISTALSIS

FLUOXETINEPAROXETINESERTALINE

↑ [5HT]

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

5HTEnterochromaffin

Cell

v v②MP

ONE 5HT3 ANTAGONIST WORKS LOCALLY IN THE GUTTO DECREASE PERISTALSIS

5HT1 5HT3 ALOSETRON

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

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]

ENKEPHALIN AGONISTS AND ANTAGONISTS

DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

5HTEnterochromaffin

Cell

AChv

Enk Enk②MP

VIP/NO

SENSORY NEURON ACTIVATION 2) INHIBITS INHIBITORY ENKEPHALIN INTERNEURONS

↑ PERISTALSIS

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

AChv

Enk Enk

VIP/NO

OPIATES CAUSE CONSTIPATIONTHROUGH INHIBITORY ACTIONS MEDIATED BY µ RECEPTORS

µDIPHENOXYLATE

LOPERAMIDE µ

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

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

DOPAMINE ANTAGONISTS

DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

AChv

DA

D2 RECEPTOR ANTAGONISTS INHIBIT INHIBITION INCREASED MOTILITY

D2

METOCLOPRAMIDEDOMPERIDONE

ANTICHOLINERGIC AGENTS

DRUGS THAT PRIMARILY AFFECT MOTILITY

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

Mucosa

Submucosal plexus

Circular muscle

Myenteric plexus

AChv

ANTIMUSCARINIC DRUGS BLOCK RECEPTORS ON THE CIRCULAR MUSCLE CELLS

M ATROPINE

MOTILIN AGONISTS

DRUGS THAT PRIMARILY AFFECT MOTILITY

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

DRUGS THAT PRIMARILY AFFECT SECRETION

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

CHLORIDE SECRETION

DRUGS THAT PRIMARILY AFFECT SECRETION

Mucosa

Submucosal plexus

DRUGS THAT ACTIVATE CIC2 AND GUANYLYL CYCLASE C ( CFTR) INCREASE Cl- SECRETION

GC-C CFTR Crypt Cell

CIC2

LINACLOTIDELUBIPROSTONE

Mucosa

Submucosal plexus

BLOCKING CFTR REDUCES Cl- SECRETION

GC-C CFTR Crypt Cell

CIC2CROFELEMER

Mucosa

Submucosal plexus

SOMATOSTATIN DECREASES Cl- AND HCO3- SECRETION

BY AFFECTING MULTIPLE UPSTREAM PATHWAYS

GC-C CFTR Crypt Cell

CIC2OCTREOTIDE

Mucosa

Submucosal plexus

SALICYLATE DECREASES Cl- SECRETION IN THE COLONVIA AN UNKNOWN MECHANISM

GC-C CFTR Crypt Cell

CIC2

BISMUTHSUBSALICYLATE

DRUGS THAT ALTER OSMOTIC BALANCE

DRUGS THAT PRIMARILY AFFECT SECRETION

LUMEN OF GI TRACT

Mucosa

SOME DRUGS PULL WATER INTO THE LUMEN OF THE GI TRACTVIA OSMOSIS

OSMOTIC CATHARTICS

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