PHARMACOLOGISTS’ PERSPECTIVE ON COLON PHYSIOLOGY

v v Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell ① Nodose CNS ③ SMP ACh v DA Enk v GC-C  CFTR Crypt Cell CIC2 SSt Enk v ② MP VIP/NO v ACh v = PHARMACOLOGICALLY RELEVANT CIRCUITS ONLY!

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v GC-C  CFTR Crypt Cell CIC2 VIP/NO ACh v MOTILITY and WATER SECRETION/ABSORPTION are physiologically linked; MANY DRUGS AFFECT BOTH PROCESSES

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v 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 Don’t forget hormone actions esp. motilin, somatostatin!

PERISTALTIC REFLEX (MOSTLY) DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v VIP/NO PERISTALTIC REFLEX

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell v ③ SMP v v ② MP ① Nodose 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 5HT Enterochromaffin Cell ① Nodose CNS = 5HT FROM THE EC CELLS STIMULATES 5HT 3 RECEPTORS RESPONSIBLE FOR NAUSEA AND VOMITING 5HT 3

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell ① Nodose CNS = MOST 5HT 3 ANTAGONISTS ARE USED AS ANTIEMETICS (also act centrally) 5HT 3 DOLASETRON GRANISETRON ONDANSETRON PALONOSETRON MORE ON THIS IN THE NEXT LECTURE

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell v ③ SMP v v ② MP EC CELL STIMULATION ALSO ACTIVATES AFFERENT NEURONS IN THE MYENTERIC AND SUBMUCOSAL PLEXUSES 5HT 1 5HT 3

v Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell ACh v Enk v SSt Enk v ② MP VIP/NO v ACh ENTERIC INTERNEURONS CONNECT THE SENSORY AFFERENTS TO THE CHOLINERGIC AND VIP/NO MOTONEURONS

v Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell ACh v v SSt v ② MP VIP/NO v ACh SENSORY NEURON ACTIVATION 1) INCREASES EXCITATORY INPUT TO CHOLINERGIC AND SOMATOSTATIN NEURONS  ↑ PERISTALSIS

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell ACh v Enk ② MP VIP/NO SENSORY NEURON ACTIVATION 2) INHIBITS INHIBITORY ENKEPHALIN INTERNEURONS  ↑ PERISTALSIS

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v VIP/NO COORDINATION AND TIMING ARE CRITICAL

SEROTONIN AGONISTS AND ANTAGONISTS DRUGS AFFECTING AFFERENT FUNCTION DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell v v ② MP SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) MAY INCREASE AFFERENT STIMULATION  INCREASED PERISTALSIS FLUOXETINE PAROXETINE SERTALINE ↑ [5HT]

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell v v ② MP ONE 5HT 3 ANTAGONIST WORKS LOCALLY IN THE GUT TO DECREASE PERISTALSIS 5HT 1 5HT 3 ALOSETRON

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell v v ② MP BULK LAXATIVES AND CONTACT CATHARTICS WORK BY STIMULATING ENTERIC SENSORY NEURONS TO EVOKE THE PERISTALTIC REFLEX BULK LAXATIVES ↑STRETCH CONTACT CATHARTICS ↑ STIMULATION

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell v v ② MP 5HT 4 AGONISTS ACT PRESYNAPTICALLY TO INCREASE NEUROTRANSMITTER RELEASE FROM ENTERIC SENSORY NEURONS  INCREASED PERISTALSIS 5HT 4 CISAPRIDE TEGASEROD ↑ [5HT]

ENKEPHALIN AGONISTS AND ANTAGONISTS DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa Submucosal plexus Circular muscle Myenteric plexus 5HT Enterochromaffin Cell ACh v Enk ② MP VIP/NO SENSORY NEURON ACTIVATION 2) INHIBITS INHIBITORY ENKEPHALIN INTERNEURONS  ↑ PERISTALSIS

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v Enk VIP/NO OPIATES CAUSE CONSTIPATION THROUGH INHIBITORY ACTIONS MEDIATED BY µ RECEPTORS µ DIPHENOXYLATE LOPERAMIDE µ

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v Enk VIP/NO µ RECEPTOR ANTAGONISTS ACT PERIPHERALLY TO OVERCOME ENKEPHALIN/OPIATE-INDUCED DECREASES IN MOTILITY µ ALVIMOPAN METHYLNALTROXONE µ

Mucosa Submucosal plexus Enk SINCE SIMILAR CIRCUITS EXIST IN THE SUBMUCOSAL PLEXUS, OPIATES ALSO DECREASE WATER SECRETION GC-C  CFTR Crypt Cell CIC2 ACh v ③ SMP DIPHENOXYLATE LOPERAMIDE

DOPAMINE ANTAGONISTS DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v DA D 2 RECEPTOR ANTAGONISTS INHIBIT INHIBITION  INCREASED MOTILITY D2D2 METOCLOPRAMIDE DOMPERIDONE

ANTICHOLINERGIC AGENTS DRUGS THAT PRIMARILY AFFECT MOTILITY

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v TCAs PRODUCE CONSTIPATION THROUGH TWO “ANTICHOLINERGIC” ACTIONS: 1) Increase in synaptic [NE]  presynaptic α 2 -mediated decrease in ACh release 2) Increase in synaptic DA  Increase in D 2 inhibition Postganglionic Sympathetic α2α2 DA AMITRIPTYLINE DESIPRAMINE

Mucosa Submucosal plexus Circular muscle Myenteric plexus ACh v 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 plexus Enk SINCE SIMILAR CIRCUITS EXIST IN THE SUBMUCOSAL PLEXUS, DRUGS THAT AFFECT ENTERIC NEURONS AFFECT SECRETION GC-C  CFTR Crypt Cell CIC2 ACh v ③ SMP v v ACh

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 LINACLOTIDE LUBIPROSTONE

Mucosa Submucosal plexus BLOCKING CFTR REDUCES Cl - SECRETION GC-C  CFTR Crypt Cell CIC2 CROFELEMER

Mucosa Submucosal plexus SOMATOSTATIN DECREASES Cl - AND HCO 3 - SECRETION BY AFFECTING MULTIPLE UPSTREAM PATHWAYS GC-C  CFTR Crypt Cell CIC2 OCTREOTIDE

Mucosa Submucosal plexus SALICYLATE DECREASES Cl - SECRETION IN THE COLON VIA AN UNKNOWN MECHANISM GC-C  CFTR Crypt Cell CIC2 BISMUTH SUBSALICYLATE

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 TRACT VIA 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 MOVEMENT INTO THE LUMEN OF THE GI TRACT CHOLESTYRAMINE COLESTIPOL Bile acids LUMEN OF GI TRACT