GIS24 Drugs Affecting Motility Of GI Tract

Question 1

6 drugs

Answer 1

1. Antiemetic
2. Motility stimulants (prokinetics)
3. Laxatives
4. Antidiarrhoeal agents
5. Antispasmodic agents
6. Drugs for IBS

Question 2

Mechanism of vomiting

Answer 2

1. Pain, repulsive sights and smells, emotional factors
   —> Sensory afferents
   —> ***Higher centres
   —> Vomiting centre —> nerves to somatic and visceral receptors
2. Motion sickness
   —> Labyrinth (complex structure in inner ear)
   —> Cerebellum (H1 + mACh receptor)
   —> Vomiting centre —> nerves to somatic and visceral receptors
3. Endogenous toxins, drugs (e.g. chemotherapy)
   —> 1. Blood
   ——> Chemoreceptor trigger zone (CTZ) (D2 + 5HT3 receptor)
   ——> Vomiting centre —> nerves to somatic and visceral receptors
   —> 2. Release of emetogenic agents (5HT, prostanoids, free radicals)
   ——> Visceral afferents / CTZ
4. Stimulus from pharynx and stomach
   —> Visceral afferents (5HT3)
   —> Nucleus of the solitary tract (5HT3, D2, mACh, H1 receptor) / CTZ
   —> Vomiting centre —> nerves to somatic and visceral receptors

Question 3

Antiemetic

Answer 3

1. H1 receptor antagonist e.g. **Dimenhydrinate
   SE:
   - dizziness, sedation, confusion
   - **inhibit muscarinic receptors as well (cause dry mouth, blurred vision, urinary retention, constipation)
2. Muscarinic receptor antagonist e.g. ***Hyoscine
   SE:
   - drowsiness, dry mouth, blurred vision, urinary retention, constipation, tachycardia
3. 5HT3 receptor antagonist e.g. ***Ondansetron
   SE:
   - headache, dizziness, constipation
4. Dopamine receptor antagonist e.g. **Metoclopramide / **Domperidone
   SE:
   - headache, dizziness
   - Metoclopramide blocks dopamine receptors elsewhere in CNS —> ***extrapyramidal symptoms (parkinsonian features, dystonias, tardive dyskinesia)
   - Domperidone does not penetrate BBB (CTZ on blood side of barrier) —> less central SE

Question 4

Control of GI motility

Answer 4

Pressure / other stimuli —> ***Enterochromaffin cells (=/ ECL (EC-like)cells!!!!!) —> 5HT

Intrinsic primary afferent nerves (IPAN):
- 5HT1p receptor —> **5HT4 receptor —> ACh, CGRP (calcitonin gene-related peptide) —> ENS neurone —> ACh —> GI muscle wall
- Increase LES tone, stimulation of **gastric emptying and peristalsis

Extrinsic primary afferent nerves (EPAN):
- **5HT3 receptor —> dorsal root / cranial nerve afferent —> CNS
- **Nausea, vomiting and abdominal pain
—> Ondansetron (5HT3 antagonist) —> relieve IBS symptoms

Question 5

Motility stimulants (prokinetics)

Answer 5

Works via IPAN pathway

1. 5HT4 receptor agonists e.g. ***Cisapride
   - ↑ release of ACh and CGRP
   —> ↑ LES tone, ↑ gastric emptying and gut motility
   SE:
   - diarrhoea
   - abdominal cramp
   - long QT syndrome —> predisposes to arrhythmia (withdrawn in many countries)
2. Dopamine D2 receptor antagonists e.g. **Domperidone, Metoclopramide
   - Dopamine an inhibitory neurotransmitter in IPAN
   - **↑ release of ACh from postganglionic cholinergic neurones in GI tract
   —> ↑ LES tone, ↑ gastric emptying and gut motility

Question 6

Motility stimulants (prokinetics) indication

Answer 6

1. Esophageal reflux
   - **incompetence of LES
   - transient LES relaxation
   - **delay in gastric emptying
2. **Gastroparesis (delayed gastric emptying)
   - occurs when **vagal nerves are damaged and muscles of stomach and intestines do not work normally

Treatment: Prokinetics (+ gastric acid inhibitor for esophageal reflux)

Question 7

Drugs for treatment of constipation

Answer 7

1. Bulk laxatives
   - ***Methylcellulose
   - increase faecal mass which stimulates peristalsis
   - drink plenty of water so work more efficiently
   - SE: flatulence (bacteria breakdown methylcellulose to produce gas), abdominal distension
2. Osmotic laxatives
   - ***Lactulose
   - ↑ water in large bowel by drawing fluid from body into bowel / retain fluid administered with
   - SE: flatulence, abdominal distension
3. Faecal softeners
   - **Docusate sodium, **Glycerol (rectal use), **Liquid paraffin (rectal use)
   - soften stool materials by acting as **detergent —> permit water and lipid to penetrate
   - docusate and glycerol also weak stimulant laxative
   - SE: seepage of paraffin, anal irritation after prolonged use
4. Stimulant laxatives
   - **Bisacodyl, **Senna
   - Bisacodyl: stimulating sensory nerve endings in gut directly
   - Senna: ***anthraquinones released from senna after hydrolysis by bacteria —> anthraquinones stimulate myenteric plexus
   - SE: diarrhoea, abdominal cramp

Question 8

Drugs for treatment of diarrhoea

Answer 8

1. Oral rehydration solution
   - replace electrolyte deficit adequately
   - enhance absorption of water and electrolytes
   - slightly ***hypo-osmolar (<285 mOsm/L) to prevent possible induction of osmotic diarrhoea
   - amount of rehydration depend on size of individual and degree of dehydration
   - generally adequate when person no longer feels thirsty and has normal urine output
   - homemade: 1 teaspoon salt, 8 teaspoon sugar, 1L water
2. Opioid receptor agonists (anti-diarrhoeal)
   - **Codeine, **Loperamide, **Diphenoxylate
   - stimulate opioid receptor in enteric neurones —> **↓ gut peristalsis —> ↑ colonic transit time —> ↑ faecal water absorption —> ↓ diarrhoea
   - codeine and loperamide have ***antisecretory actions as well
   - SE: drowsiness, dizziness, constipation, paralytic ileus
3. Kaolin, Pectin (adsorbents)
   - claim to bind toxins and bacteria
   - no good evidence to show effectiveness

Question 9

Drugs for treating bowel spasms (Antispasmodic drugs)

Answer 9

Muscarinic receptor antagonist: **Hyoscine
- inhibit muscarinic receptors in intestinal **smooth muscle cells

1. inhibit ANS (ACh secreted under basal condition, control ***basal tone + peristalsis)
2. inhibit Enteric NS (ACh secreted during ***peristalsis)

Overall:
—> relax intestinal smooth muscle (↓ peristalsis + ↓ basal tone)
—> ↓ spasm

SE: constipation, tachycardia, urinary retention, blurred vision, dry mouth, drowsiness

Question 10

Drugs for irritable bowel syndrome

Answer 10

• IBS: idiopathic chronic disorder
• abdominal discomfort (pain, bloating, distension, nausea)
• alteration in bowel habits (diarrhoea, constipation, cycle of both)
• therapies aim at relieving abdominal pain and discomfort

1. Predominant diarrhoea: opioid agonists (loperamide)
2. Predominant constipation: bulk laxatives (methylcellulose) / osmotic laxatives (lactulose)
3. Muscarinic antagonists (hyoscine)
   **4. 5HT3 antagonists (ondansetron)
   - inhibit EPAN —> inhibit **unpleasant visceral sensation (nausea, bloating, pain)

Question 11

Summary

Answer 11

Antiemetic:
1. H1 receptor antagonist (Dimenhydrinate)
2. mACh receptor antagonist (Hyoscine)
3. 5HT3 receptor antagonist (Ondansetron)
4. Dopamine receptor antagonist (Metoclopramide, Domperidone)

Motility stimulants:
1. 5HT4 receptor agonist (Cisapride)
2. Dopamine receptor antagonist (Domperidone)

Laxatives:
1. Bulk (Methylcellulose)
2. Osmotic (Lactulose)
3. Faecal softener (Docusate sodium, Glycerol, Liquid paraffin)
4. Stimulant (Bisacodyl, Senna)

Antidiarrhoeal:
1. Oral rehydration therapy
2. Opioid receptor agonist (Codeine, Loperamide, Diphenoxylate)
3. Adsorbent (Kaolin, Pectin)

Antispasmodic agents:
1. Muscarinic receptor antagonist (Hyoscine)

Drugs for IBS:
1. 5HT3 receptor antagonist (Ondansetron)