L18 Clinical Pharmacology Gut motility Pharmacology

Overview

This lecture covers why drugs are needed to modulate gut motility and where they act. It sets out the neural control of the bowel (autonomic plus the enteric nervous system and its two plexuses), the key enteric neurotransmitters (acetylcholine, serotonin, dopamine, opioid peptides), and the physiology of gut water handling that determines stool softness. It then works through the drug classes that exploit these targets: laxatives, prokinetics, anti-motility drugs, anti-spasmodics and anti-emetics, the last of which act on targets in the brain as well as the gut.

Therapeutic rationale and healthcare impact

• 50% of patients will have a gastrointestinal (GIT) disorder.
• GIT disturbance is a common side effect of therapeutics.
• Managing vomiting and nausea is necessary for chemotherapy patients.
• GIT drugs are a major area for healthcare expenditure and drug development, with US5 \times 10^9$ per annum spent on them.

Nervous system organisation and neurotransmitters

The nervous system divides into central and peripheral. Peripherally, it branches into autonomic and somatic; the autonomic branches into sympathetic, parasympathetic (which interact with each other) and enteric.

Transmitter arrangement by pathway:

• Somato-motor: CNS motor neurons release acetylcholine (ACh) onto nicotinic receptors on skeletal muscle.
• Parasympathetic: pre-ganglionic neurons release ACh onto nicotinic receptors at the ganglion; post-ganglionic neurons release ACh onto muscarinic receptors on effector organs (glands, eyes, heart, bronchi, vessels, GI tract).
• Sympathetic: pre-ganglionic ACh onto nicotinic receptors at the ganglion; post-ganglionic neurons release noradrenaline onto effector organs. One sympathetic pathway runs ACh/nicotinic directly to the adrenal gland, which releases adrenaline into the circulation.

Functions of the bowel and gut water balance

The bowel provides the body with water, electrolytes and nutrients. Its three processes are movement (peristalsis), secretion and absorption, all regulated by both enteric control and autonomic control.

Gut water level regulates stool softness, and gut water level is set by absorption and secretion.

Daily fluid handling:

• 10 L of fluid enters the small intestine (maximum capacity 15 L).
• 1 L enters the colon (maximum capacity 5 L).
• ~100 mL remains for incorporation into faeces, which are approximately 80% water.

Flow and ion concentrations along the tract (mEq/L; osmolality as given):

• Flow 9.0 L entering the small intestine: Na+ 60, K+ 15, Cl- 60, HCO3- 15, osmolality variable. 6.0 L is then absorbed across the small intestine.
• Flow 3.0 L: Na+ 140, K+ 6, Cl- 100, HCO3- 30, isotonic. 1.5 L absorbed.
• Flow 1.5 L: Na+ 140, K+ 8, Cl- 60, HCO3- 70, isotonic. 1.4 L absorbed.
• Flow 0.1 L into faeces: Na+ 40, K+ 90, Cl- 15, HCO3- 30, isotonic.

Pathology and therapeutics can change fluid absorption and gut motility:

• Slow motility / high absorption leads to constipation.
• High motility / low water absorption leads to diarrhoea.

Enteric nervous system and the plexuses

The enteric nervous system is the body’s “second brain”: a nervous system that operates independently of the CNS, uses similar neurotransmitters to the central system, and communicates with it. Enteric function covers control of motility and absorption, and mucus secretion.

Gut wall in cross section, from outside in: serosa, longitudinal muscle, circular muscle (with the myenteric plexus lying between the muscle layers), submucosa containing Meissner’s (submucous) plexus, mucosa with mucosal muscle, mucosal and submucosal glands and epithelial lining, plus the mesentery.

Two nerve networks in the GIT:

• Myenteric plexus: controls GI tract motility. Communicates with the CNS through the vagal nerve and synapses to parasympathetic and sympathetic inputs.
• Submucous plexus: controls absorption and mucus secretion. Synapses to parasympathetic inputs.

Warning

The gut-wall schematic used in the lecture carries eight numbered points, but only three are ever identified: ACh at point 1 (a myenteric plexus neuron cell body), dopamine at an interneuron near the myenteric plexus, and 5HT at a release site at the mucosal crypt/lumen boundary. Points 2, 3, 4, 5 and 7 are left unlabelled and the slides do not state what they represent.

Key enteric neurotransmitters

Acetylcholine

• Released by interneurons.
• Acts on GIT muscarinic receptors.
• Causes muscle contraction (important for motility) and mucus secretion.
• Degraded by acetylcholine esterase.
• Because so many autonomic drugs act on this system, constipation and diarrhoea are common side effects.

Serotonin (5HT)

• 5-Hydroxytryptamine; 14 5HT receptor subtypes discovered.
• In the gut it is released by enterochromaffin cells, the body’s major source of 5HT, to regulate smooth muscle.
• Enterochromaffin cells release 5HT in response to mechanical stress from food.
• 5HT triggers peristalsis by stimulating intrinsic sensory neurons in the myenteric plexus, via 5HT1 and 5HT4 receptors.

Dopamine

• Dopamine receptors are G protein coupled.
• D2 receptor activation inhibits ACh release from the myenteric plexus.

Opioid neuropeptides (enkephalins, endorphins, dynorphins)

• Opioid receptors are G protein coupled, with 3 major types: μ (MOR), δ (DOR) and κ (KOR).
• In the GI tract, receptors are expressed in smooth muscle cells and neurons.
• μ receptors regulate motility; δ receptors regulate mucus secretion.
• Enkephalins: [Leu5]enkephalin (Y-G-G-F-L) and [Met5]enkephalin (Y-G-G-F-M) act on DOR to inhibit mucus secretion.
• Endomorphins: endomorphin-1 (Y-P-W-F) and endomorphin-2 (Y-P-F-F) act on MOR to inhibit motility, relaxing smooth muscle by inhibiting ACh release.
• Dynorphins: dynorphin A (Y-G-G-F-L-R-R-I-R-P-L-W-D-N-Q) and α-neomorphin (Y-G-G-F-L-R-K-Y-P-K) act on KOR to inhibit neurotransmitter release.
• They have short half-lives and are not major modulators of GI tract function under standard physiological conditions, but become important under pathological conditions (tissue damage or infection).
• They matter greatly in pharmacology because of drug side effects: opioid receptors in the CNS are key therapeutic targets for pain relief.

Laxatives

Bulk laxatives

• Generally polysaccharide polymers, that is non-absorbable solids from the plant cell wall.
• Examples: dietary fibre content, bran, methylcellulose, agar.
• Take time to work; take with water; no serious side effects.

Osmotic laxatives

• Aid water retention.
• Magnesium, sodium or potassium salts: magnesium sulfate (Epsom salt, MgSO4), magnesium hydroxide (Milk of Magnesia, Mg(OH)2).
• Lactulose is a sugar metabolised by colonic bacteria; its metabolites (acetic and lactic acids) aid water retention.
• Bacterial metabolism of lactulose can cause cramps and flatulence.

Stimulant laxatives

• Stimulate accumulation of water and electrolytes.
• Potential mechanisms: interactions with the enteric plexus inducing contractions, and inhibition of intestinal Na+/K+ ATPase.
• Examples: senna (a dihydroxy-anthraquinone, Senokot) and bisacodyl (a bis-(acetoxyphenyl)-pyridylmethane, Dulcolax).

Prokinetics

Dopamine inhibits release of ACh from the myenteric plexus via D2 dopaminergic receptors. Dopamine antagonists therefore increase ACh release at the nerve-muscle junction without interfering with the rhythm of motility, so they systemically enhance GIT motility.

This makes them superior to muscarinic agonists or acetylcholine esterase inhibitors, which cause contraction but no propulsion because they do not act in rhythm.

Dopamine D2 receptor antagonists such as Metoclopramide accelerate gastric emptying and are useful in gastric hypomobility: indigestion, heartburn and gastroesophageal reflux disease.

Anti-motility drugs

Opioids

• Agonists at μ receptors on the myenteric plexus.
• Inhibit ACh release.
• Reduce bowel motility by disrupting peristalsis.
• Used as anti-diarrhoeals.
• Loperamide is beneficial for localised gut actions, with low CNS effects.

Anti-cholinergics and indirect cholinergic modulation

• Cholinergic agonists and antagonists are not usually used to treat bowel motility disorders because of systemic side effects.
• Muscarinic antagonists have limited applications in treating diarrhoea.
• Indirect modulation of cholinergic neurotransmission: tricyclic antidepressants (amitriptyline) block noradrenaline uptake and boost sympathetic action, opposing the effects of acetylcholine. Used as a treatment for diarrhoea.

Anti-spasmodics

Irritable bowel syndrome presents as abdominal pain accompanied by diarrhoea or constipation, and is linked to mental state: stress, anxiety and depression.

Muscarinic antagonists used: atropine, hyoscine (scopolamine).

Nausea, vomiting and anti-emetics

The enteric system and CNS communicate via the vagal nerve in response to sensory inputs. Information is collated by the brain (vomiting centre), and the vomiting reflex is actioned by the enteric system.

Stimuli: abnormal motion (vestibular inputs), pathologies, food toxins and drugs.

The reflex loop, in order:

1. A stimulus in the gut acts on 5HT3 receptors on the vagal afferent.
2. The vagal afferent carries the signal to the brain, reaching the chemoreceptor trigger zone (CTZ), which carries dopamine D2 receptors, and the vomiting centre, which carries histamine H1 receptors.
3. The vagal efferent carries the vomiting reflex signal back to the gut, completing the loop.

Each of these three receptors is a drug target:

5HT3 receptor antagonists

• Excessive 5HT release in the intestine initiates a vomiting reflex via 5HT3 receptors on the vagus afferent nerve.
• Antagonists such as ondansetron block the 5HT3 receptor.

Dopamine D2 receptor antagonists

• Block dopamine receptor activation in the CTZ (for example metoclopramide).
• Used to treat nausea and vomiting, widely used in conjunction with cancer therapy, and can treat postoperative nausea and vomiting.

Anti-histamines

• Block histamine receptor activation in the vomiting zone (for example cyclizine).
• Used to treat nausea and vomiting, widely used in conjunction with cancer therapy, and can treat postoperative nausea and vomiting.

Important

The three anti-emetic classes map onto three different sites in the same reflex arc: 5HT3 antagonists at the gut/vagal afferent, D2 antagonists at the CTZ, and H1 antagonists at the vomiting centre.

Self-test

1. Outline the therapeutic rationale for drugs that modulate gut motility, with the figures given for disease burden and expenditure.
2. Describe the transmitter and receptor sequence from CNS to effector organ for the parasympathetic and the sympathetic pathways.
3. State the daily fluid volumes entering the small intestine and colon, their maximum capacities, and the volume remaining for faeces.
4. Explain how gut motility and water absorption determine whether a patient develops constipation or diarrhoea.
5. Distinguish the myenteric plexus from the submucous plexus by function and by autonomic input.
6. Describe the actions of acetylcholine in the enteric nervous system and how it is terminated.
7. Describe the steps by which food in the gut triggers peristalsis via serotonin, naming the cell type and receptors involved.
8. What happens to acetylcholine release from the myenteric plexus when dopamine D2 receptors are activated, and what does this predict for a D2 antagonist?
9. List the three major opioid receptor types and state which GI function each of enkephalins, endomorphins and dynorphins regulates through them.
10. Explain why opioid neuropeptides are described as unimportant physiologically but very important pharmacologically.
11. List the three classes of laxative, with one distinguishing mechanism and one example of each.
12. Explain why lactulose can cause cramps and flatulence.
13. Explain why dopamine antagonists are superior prokinetics to muscarinic agonists or acetylcholine esterase inhibitors.
14. Describe the mechanism by which loperamide reduces diarrhoea, and state why it is preferred over other opioids for this purpose.
15. Explain how amitriptyline is used to treat diarrhoea, given that it is not a muscarinic antagonist.
16. Describe irritable bowel syndrome as presented in this lecture and name the anti-spasmodic drugs used.
17. Describe the vomiting reflex loop in order, naming the receptor at each of the three drug-targetable sites.
18. A chemotherapy patient develops nausea and vomiting. Name three anti-emetic drug classes that could be used and state where in the reflex each acts.
19. Integrative: acetylcholine release from the myenteric plexus is the common node for several drug classes in this lecture. Explain how dopamine antagonists, opioid agonists and serotonin acting on the myenteric plexus each change motility through this node.

Answers

Reveal answers

1. 50% of patients will have a GI disorder, GI disturbance is a common side effect of therapeutics, and vomiting/nausea must be managed in chemotherapy patients. GI drugs are a major area of healthcare expenditure and drug development, with US5 \times 10^9$ per annum spent on them.
2. Parasympathetic: pre-ganglionic ACh onto nicotinic receptors at the ganglion, then post-ganglionic ACh onto muscarinic receptors on the effector organ. Sympathetic: pre-ganglionic ACh onto nicotinic receptors at the ganglion, then post-ganglionic noradrenaline onto the effector organ; one pathway goes ACh/nicotinic straight to the adrenal gland, which releases adrenaline into the circulation.
3. 10 L enters the small intestine (max capacity 15 L), 1 L enters the colon (max capacity 5 L), and about 100 mL remains for faeces, which are roughly 80% water.
4. Slow motility with high absorption removes too much water and produces constipation; high motility with low water absorption leaves too much water and produces diarrhoea. Both pathology and therapeutics can shift fluid absorption and motility this way.
5. The myenteric plexus controls motility, communicates with the CNS through the vagal nerve, and synapses to both parasympathetic and sympathetic inputs. The submucous plexus controls absorption and mucus secretion and synapses to parasympathetic inputs only.
6. ACh is released by interneurons and acts on GIT muscarinic receptors, causing muscle contraction (important for motility) and mucus secretion. It is degraded by acetylcholine esterase.
7. Food creates mechanical stress on enterochromaffin cells, the body’s major source of 5HT; they release 5HT, which stimulates intrinsic sensory neurons in the myenteric plexus via 5HT1 and 5HT4 receptors, triggering peristalsis.
8. D2 activation inhibits ACh release from the myenteric plexus. A D2 antagonist therefore increases ACh release at the nerve-muscle junction, without interfering with the rhythm of motility, so motility is systemically enhanced.
9. μ (MOR), δ (DOR) and κ (KOR). Endomorphins act on MOR to inhibit motility by inhibiting ACh release and relaxing smooth muscle; enkephalins act on DOR to inhibit mucus secretion; dynorphins act on KOR to inhibit neurotransmitter release. In general terms μ receptors regulate motility and δ receptors regulate mucus secretion.
10. They have short half-lives and are not major modulators of GI function under standard physiological conditions, becoming important only in pathology such as tissue damage or infection. Pharmacologically they matter because CNS opioid receptors are key analgesic targets, so gut effects appear as drug side effects.
11. Bulk laxatives: non-absorbable polysaccharide polymers from plant cell wall, for example bran or methylcellulose. Osmotic laxatives: aid water retention, for example magnesium sulfate or lactulose. Stimulant laxatives: stimulate accumulation of water and electrolytes, possibly via enteric plexus interactions inducing contractions or inhibition of intestinal Na+/K+ ATPase, for example senna or bisacodyl.
12. Lactulose is a sugar metabolised by colonic bacteria; that bacterial metabolism causes cramps and flatulence, while its metabolites (acetic and lactic acids) aid water retention.
13. Dopamine antagonists increase ACh release without interfering with the rhythm of motility, producing propulsion. Muscarinic agonists and acetylcholine esterase inhibitors cause contraction but no propulsion because they do not act in rhythm.
14. Loperamide is an agonist at μ receptors on the myenteric plexus; it inhibits ACh release and reduces bowel motility by disrupting peristalsis. It is preferred because its actions are localised to the gut with low CNS effects.
15. Amitriptyline, a tricyclic antidepressant, blocks noradrenaline uptake and boosts sympathetic action, which opposes the effects of acetylcholine; this indirect modulation of cholinergic neurotransmission is used to treat diarrhoea.
16. IBS is abdominal pain accompanied by diarrhoea or constipation, linked to mental state (stress, anxiety, depression). The muscarinic antagonists used are atropine and hyoscine (scopolamine).
17. A gut stimulus acts on 5HT3 receptors on the vagal afferent; the afferent carries the signal to the chemoreceptor trigger zone (dopamine D2 receptors) and the vomiting centre (histamine H1 receptors); the vagal efferent then carries the reflex back to the gut.
18. 5HT3 receptor antagonists such as ondansetron, acting on 5HT3 receptors on the vagal afferent in the intestine; dopamine D2 receptor antagonists such as metoclopramide, blocking dopamine receptor activation in the CTZ; and anti-histamines such as cyclizine, blocking histamine receptor activation in the vomiting zone. All three are widely used alongside cancer therapy.
19. ACh released from the myenteric plexus acts on muscarinic receptors to contract smooth muscle and drive motility. Dopamine acting on D2 receptors inhibits that ACh release, so D2 antagonists disinhibit it and enhance motility. Opioid agonists at μ receptors also inhibit ACh release, relaxing smooth muscle and reducing motility, which is the basis of their anti-diarrhoeal use. Serotonin acts upstream, stimulating intrinsic sensory neurons in the myenteric plexus via 5HT1 and 5HT4 receptors to trigger peristalsis.