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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