Gastrointestinal Tract Function and ENS

Gastrointestinal Tract (GI Tract) Function

• The GI tract is continuously contractile, absorptive, and secretory.
• Control of this state is complex involving several factors.
• Muscle and epithelium play a role.
• The enteric nervous system (ENS) is involved.
• The autonomic nervous system (ANS) contributes.
• Circulating hormones also contribute.

Enteric Nervous System (ENS)

• The ENS is the most important regulator of physiological gut function.
• A network of nerves within the wall of the GI tract.
• The ENS consists of two interconnected networks of neurons and nerve fibers:
  • Myenteric (Auerbach's) plexus: located between the circular and longitudinal muscle layers; largely responsible for motor control.
  • Submucosal (Meissner's) plexus: located in the submucosa; regulates secretion, fluid transport, and blood flow.
• Separated from the central nervous system (CNS), it's capable of independent function.
• Essential for largely autonomous nature of GI activity.

Neurotransmitters

• Acetylcholine (ACh) is the primary excitatory neurotransmitter of the excitatory motor neurons.
• Nitric oxide (NO) is the principal inhibitory neurotransmitter in inhibitory motor neurons, with supplementary contributions from ATP and other substances like vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP).
• Enterochromaffin cells (scattered throughout the epithelium of the intestine) release serotonin (5-HT) to initiate many gut reflexes.

Functional and Motility Disorders of the Bowel

• GI motility disorders are a complex group of syndromes.
• Included are:
  • Achalasia of the esophagus: impaired relaxation of the lower esophageal sphincter resulting in dysphagia and regurgitation.
  • Gastroparesis: delayed gastric emptying.
  • Myopathic and neuropathic forms of intestinal dysmotility.
  • Irritable bowel syndrome (IBS).

Pharmacotherapy

• Prokinetic agents and other stimulants of GI contractility:
  • Enhance coordinated GI motility and transit of material in the GI tract.
  • Types include:
    • Dopamine receptor antagonists (e.g., metoclopramide, domperidone)
    • Serotonin receptor agonists (e.g., prucalopride)
    • Motilides (e.g., erythromycin)

Metoclopramide: Pharmacokinetics

• Absorbed rapidly after oral ingestion.
• Undergoes sulfation and glucuronide conjugation by the liver.
• Excreted principally in the urine (T1/2 = 4-6 hours).
• Peak concentrations occur within 1 hour after a single oral dose.
• Duration of action is1-2 hours.

Metoclopramide: Therapeutic Use

• Used in patients with gastroesophageal reflux disease to relieve symptoms of reflux disease, not to heal.
• Indicated more often for symptomatic patients with gastroparesis, to improve gastric emptying.
• Used as an adjunctive measure in medical or diagnostic procedures such as intestinal intubation and contrast radiography of the GI tract.
• Useful for ameliorating nausea and vomiting often associated with GI dysmotility syndromes.
• Used in the treatment of persistent hiccups, although efficacy is questionable in this situation.
• Usual initial oral dose is 10 mg, 30 minutes before a meal and at bedtime.

Domperidone: D2 Receptor Antagonists

• Predominantly antagonizes the D2 receptor without significantly affecting other receptors.
• Has modest prokinetic activity in doses of 10-20 mg, three times per day.
• Does not readily cross the blood-brain barrier, therefore avoiding extrapyramidal side effects.

Serotonin Receptor Agonists

• 5-hydroxytryptamine (5-HT) plays an important role in normal gut motor and secretory function.
• Over 90% of body 5-HT is found in the GI tract.
• Enterochromaffin cells in the gut epithelium produce most of this 5-HT.
• 5-HT triggers the peristaltic reflex by stimulating intrinsic sensory neurons and extrinsic vagal and spinal sensory neurons.
• Prucalopride is an example and acts throughout the length of the intestine increasing oral-cecal and colonic transit without affecting healthy volunteers' gastric emptying.

Motilides

• Motilin, a 22-aminoacid peptide hormone, found in the GI M cells and some enterochromaffin cells of the upper small bowel (a potent contractile agent), is found in response to factors such as food intake and fasting.
• Motilin levels fluctuate with the migrating motor complex, and appear responsible for its amplification.
• Motilin receptors are in smooth muscle cells and enteric nerves, which regulate phase III activity.

Erythromycin

• Mimics the motilin effect.
• Motilin-like activity is increased at higher doses (250-500 mg).
• Best established use is in diabetic patients to improve short-term gastric emptying.
• May intensely stimulate gastric contractions resulting in dumping of relatively undigested food into the small bowel.
• Induces phase III migrating motor complex activity in dogs and increases smooth muscle contractility.

Mitemcinal (GM-611)

• Macrolide non-antibiotic, shows potential for gastroparesis treatment.

Laxatives, Cathartics, and Therapy for Constipation

• Constipation is characterized by decreased stool frequency and difficulty passing stools.
• Causes are lack of dietary fiber; certain medications; hormonal and neurogenic disorders, and systemic illnesses.
• Chronic constipation has no known cause in 60% of cases.
• Laxatives generally act in one of three ways:
  • Enhancing intraluminal fluid retention through hydrophilic or osmotic mechanisms.
  • Decreasing net fluid absorption in the small and large bowel.
  • Modifying motor activity (either inhibiting segmenting or stimulating propulsive contractions).
  • Types include: bulk-forming agents, osmotic agents, stool-wetting/emollients, stimulants, prokinetics.
• The appendix to the chapter provides further classifications and detail.

Anti-diarrheal Agents

• Diarrhea is characterized as excessive fluid weight. 200 grams per day is the upper limit for healthy adults.
• Most cases of diarrhea are caused by disorders in intestinal water and electrolyte transport.
• Treatment options include several types of agents including bulk-forming agents, bile acid sequestrants, and anti-motility agents (e.g., opioids).

Anti-motility and Anti-secretory Agents: Opioids

• Loperamide: a piperidine butyramide derivative with μ-receptor activity; orally active anti-diarrheal agent.
• Diphenoxylate and difenoxin are structurally related to meperidine and more potent than morphine.
• Octreotide and somatostatin: octapeptide analogs that effectively inhibit severe secretory diarrhea caused by hormone-secreting tumors in the pancreas and GI tract. Mechanisms involve inhibition of 5-HT and other GI peptides including gastrin, vasoactive intestinal peptide (VIP), insulin, secretin, etc.

Test your knowledge on the functions of the gastrointestinal tract and the role of the enteric nervous system. This quiz covers key aspects such as muscle and epithelium involvement, the ENS structure, and its importance in gut regulation. Perfect for those studying human physiology or gastrointestinal health.