L24 - Pharm of GIT motility

Question 1

Drugs affecting motility of the GI tract

Answer 1

1) Antiemetic drugs

• H₁ receptor antagonists
• Muscarinic receptor antagonists
• 5HT₃ receptor antagonists
• Dopamine D₂ receptor antagonists

2) Motility stimulants

• 5HT₄ receptor agonists
• Dopamine D₂ receptor antagonists

3) Laxatives

• Bulk laxatives
• Osmotic laxatives
• Faecal softeners
• Stimulant laxatives

4) Antidiarrhoeal agents

• Oral rehydration therapy
• Opioid receptor agonists
• Adsorbents

5) Antispasmodic agents

• Muscarinic receptor antagonists

6) Drugs for Irritable bowel syndrome

• Depends on symptoms:
• spasm: antispasmodic agents
• • pain, nausea*: 5HT₃ receptor antagonists
• constipation: bulk & osmotic laxatives
• diarrhoea: opioid receptor agonists

Question 2

Stimuli of vomiting

Answer 2

1) Pain, repulsive sights & smells, emotional factors
2) Motion sickness
3) Endogenous toxins, drugs (e.g. chemotherapy, surgery anaesthetics, food poisoning)
4) Stimulus in pharynx or stomach (e.g. finger in throat, eating too much)

Question 3

Mechanism of vomit due to Pain, repulsion & emotion

Answer 3

1) Stimuli: Pain, repulsive sights & smells, emotional factors
2) Input: these feelings transmitted via sensory afferents
3) Integration: Signals processed in the higher centers of CNS, then directed to the vomiting center
4) Output: Vomiting center send signals via nerves to somatic & visceral receptors, leading to vomiting

Question 4

Mechanism of vomit due to motion sickness

Answer 4

1) Stimuli: motion information perceived in the labyrinth of the ear (and the contradicting inactivity information perceived by the visual receptors)

2) Input: the above stimuli are perceived by the labyrinth

3) Integration: Cerebellum (H1 & mACh receptors) receive and process the contradictory information; and signals will be sent to vomiting center

4) Output: Vomiting center send signals via nerves to somatic & visceral receptors, leading to vomiting

[note: motion sickness is greater when eyes closed or vehicle does not have a window to allow view of movement]

Question 5

Mechanism of vomit due to endogenous toxins and drugs

Answer 5

1) Stimuli: endogenous toxins & drugs (e.g. high level of alcohol, chemtherapy drugs, surgery anaesthetics, food poisoning, etc.)

2) Input:

i) endogenous toxins & drugs may directly travel through blood to the chemoreceptor trigger zone (CTZ)
ii) endogenous toxins & drugs may stimulate the release of emetogenic agents (5HT, prostanoids, free radicals). These emetogenic agents may enters CTZ directly
iii) endogenous toxins & drugs may stimulate the release of emetogenic agents (5HT, prostanoids, free radicals). These emetogenic agents may stimulate the Extrinsic primary afferent nerves (EPAT; contains 5HT₃ receptors), which will send signals to the CTZ & nucleus of solitary tract in brain stem

3) Integration:

i) Chemreceptor Trigger Zone (CTZ; contains D₂ & 5HT₃ receptors) will be stimulated by:
- endogenous toxins & drugs in blood
- emetogenic agents
- signals from EPAT

and send signals to the vomiting center

ii) Nucleus in solitary tract (contains H₁, mACh, D₂ & 5HT₃ receptors) will be stimulated by signals from EPAT, and send signals to the vomiting center

4) Output: Vomiting center send signals via nerves to somatic & visceral receptors, leading to vomiting

Question 6

Mechanism of vomit due to stimulus in pharynx and stomach

Answer 6

1) Stimuli: stimulus in pharynx and stomach (e.g. finger in throat, stomach distension due to eating too much)

2) Input: the sensory signals will stimulate the Extrinsic primary afferent nerves (EPAT; contains 5HT3 receptors), which will send signals to the Chemoreceptor Trigger Zone & nucleus of solitary tract in brain stem

3) Integration:

i) Chemreceptor Trigger Zone (CTZ; contains D2 & 5HT3 receptors) will be stimulated by signals from EPAT and send signals to the vomiting center
ii) Nucleus in solitary tract (contains H1, mACh, D2 & 5HT3 receptors) will be stimulated by signals from EPAT, and send signals to the vomiting center

4) Output: Vomiting center send signals via nerves to somatic & visceral receptors, leading to vomiting

Question 7

Types of Antiemetics

Answer 7

1) histamine H₁ receptor antagonist
2) muscarinic receptor antagonist
3) 5HT₃ receptor antagonist
4) Dopamine D₂ receptor antagonist

Question 8

histamine H₁ receptor antagonists

Answer 8

Antiemetics

Example: Dimenhydrinate

Mechanism:

• blocking the histamine H₁ receptors found in cerebellum & the nucleus of the solitary tract, thus preventing signals to vomiting center from these two sites
• effective against vomiting caused by motion sickness (exclusively integrated by cellubellum)
• not as effective against vomiting caused by endogenous toxins & drugs and pharngeal- gastric stimuli as CTZ is not blocked

ADR:

• Dizziness, sedation, confusion (conterindicative of machine operation)
• Not very specific, thus can inhibit muscarinic receptors as well (i.e. causing dry mouth, blurred vision, urinary retention, constipation, tachycardia)

Question 9

Muscarinic receptor antagonist (antiemetics)

Answer 9

Antiemetics, antispasmodic agents

Example: Hyoscine

Mechanism:

• blocking the muscarinic mACh receptors in cerebellum & nucleus of the solitary tract, thus preventing signals to vomiting center from these two sites
• effective against vomiting caused by motion sickness (exclusively integrated by cellubellum)
• not as effective against vomiting caused by endogenous toxins & drugs and pharngeal- gastric stimuli as CTZ is not blocked

ADR:

• Drowsiness
• dry mouth
• blurred vision
• urinary retention
• constipation
• tachycardia

Question 10

5HT₃ receptor antagonist (antiemetics)

Answer 10

Antiemetics, drugs for IBS

Example: Ondansetron

Mechanism:

• blocking the 5HT₃ receptors found in CTZ, Nucleus of solitary tract, & EPAN, thus preventing stimulation of vomiting centers from these sites
• effective against vomiting caused by endogenous toxins & drugs (e.g. chemo, surgery, food poison) and pharngeal- gastric stimuli as CTZ, nucleus of solitary tract & EPAN are blocked
• not effective against vomiting caused by motion sickness (as cerebellum is not blocked)

ADR:

• Headache, dizziness, and constipation

Question 11

Dopamine D₂ receptor antagonist (antiemetics)

Answer 11

Antiemetics, prokinetics

Example:

• Metoclopamide
• Domperidone

Mechanism:

• blocking the dopamine D₂ receptors found in CTZ & Nucleus of solitary tract, thus preventing stimulation of vomiting centers from these sites
• effective against vomiting caused by endogenous toxins & drugs (e.g. chemo, surgery, food poison) and pharngeal- gastric stimuli as CTZ & nucleus of solitary tract are blocked
• not effective against vomiting caused by motion sickness (as cerebellum is not blocked)

ADR:

• Headache, dizziness

**Metoclopamide can pass through BBB, thus blocks dopamine receptors elsewhere in the CNS; resulting in extrapyrimidal symptoms (e.g. parkinsonian features, dystonias and tardive dyskinesia)

** Domperidone does not penetrate BBB, thus less side effects

Question 12

CTZ location

Answer 12

On the blood side of blood-brain barrier

Question 13

Extrinsic primary afferent nerves

Answer 13

Receptor: 5HT₃ receptors

Transmission:

• to CNS (i.e. Chemoreceptor trigger zone, nucleus of the solitary tract)

Output: nausea, vomiting and abdominal pain

Question 14

Intrinsic primary afferent nerves

Answer 14

Receptor:

• 5HT_1P receptor at dendrite
• 5HT₄ receptor at axon

Transmission:

• releases acetylcholine (ACh) & calcitonin gene-related peptide (CGRP), which stimulates neurons of Enteric Nervous System, which will release ACh to stimulate GIT muscle walls

Output:

• Increase the tone of lower oesophageal sphincter
• stimulation of gastric emptying
• stimulation of peristalsis

Question 15

Stimulation of EPAN & IPAN

Answer 15

when stimulated, enterochromaffin cells will release 5HT that stimulates the 5HT receptors on EPAN & IPAN

Question 16

Oesophageal reflux mechanism

Answer 16

• Incompetence of the lower esophageal sphincter (LES)
• Transient LES relaxation
• Delay in gastric emptying

Medication:

• prokinetics
• Gastric acid inhibitor for oesophageal reflux (e.g. proton pump Inhibitors, H2 antagonists)

Question 17

Gastroparesis

Answer 17

Disorder of gastric emptying

Mechanism: Occurs when vagal nerves are damaged and the muscles of the stomach and intestines do not work normally

Medication: prokinetics

Question 18

Diseases that require prokinetics

Answer 18

• Oesophageal reflux
• Gastroparesis

Question 19

Types of prokinetics

Answer 19

1) 5HT₄ receptor agonist
2) Dopamine D₂ receptor antagonist

Question 20

5HT₄ receptor antagonist

Answer 20

Prokinetics

Example: cisapride

Mechanism:

• Stimulation of 5HT₄ receptors on axon of IPAN
• increase the release of acetylcholine and calcitonin gene-related peptide (CGRP), thus stimulating ENS neurons, which in turn stimulate GIT muscle walls
• increases tone of lower oesophageal sphincter, gastric emptying and gut motility

ADR:

• Diarrhoea, abdominal cramp

** long QT syndrome, which predisposes to arrhythmias (therefore in US & HK cisapride withdrawn; had its indications limited as an alternative when dopamine receptor antagonist failed)

Question 21

Dopamine D₂ antagonist (prokinetics)

Answer 21

Antiemetics, prokinetics

Example:

• Domperidone
• Metoclopamide

Mechanism:

• Normally, dopamine will act on dopamine D₂ receptors on ENS neurons to inhibit ACh release
• D₂ receptor antagonist can block these receptors, thus Increase the release of acetylcholine from postganglionic cholinergic ENS neurons, which stimulates GIT muscle walls

ADR:

• Headache, dizziness

**Metoclopamide can pass through BBB, thus blocks dopamine receptors elsewhere in the CNS; resulting in extrapyrimidal symptoms (e.g. parkinsonian features, dystonias and tardive dyskinesia)

** Domperidone does not penetrate BBB, thus less side effects

Question 22

Constipation durgs

Answer 22

Laxatives

Question 23

Types of laxatives

Answer 23

1) Bulk laxatives
2) Osmotic laxatives
3) Faecal softeners
4) Stimulant laxatives

Question 24

Bulk laxatives

Answer 24

Laxative

Examples: Methylcellulose

Mechanism:

• They increase faecal mass which stimulates peristalsis (cannot be digested by humans)
• Drink plenty of water so that the bulk laxatives can work efficiently (by absorbing water and forming bulk)

ADR:

• Flatulence (bacteria may digest methyl cellulose and release gases)
• abdominal distension

Question 25

Osmotic laxatives

Answer 25

Laxative **Example**: Lactulose **Mechanism**: They increase the amount of water in the large bowel, either by drawing fluid from the body into the bowel or by retaining the fluid they were administered with **ADR**: Flatulence, abdominal distension

Question 26

Faecal softeners

Answer 26

Laxative **Examples**: - Docusate sodium (ingested) - Glycerol (applied in anus) - Liquid paraffin (applied in anus) **Mechanism**: They soften stool materials by acting as a detergent, which permits water and lipids to penetrate Docusate sodium and glycerol are also weak stimulant laxatives that encourage peristalsis **ADR:** - Paraffin may lead to seepage as it is liquid - Anal irritation after prolong use (glycerol & paraffin)

Question 27

Stimulant laxatives

Answer 27

laxative **Example**: - Bisacodyl - Senna **Mechanism:** Bisacodyl acts by stimulating sensory nerve endings in gut directly, leading to enhanced peristalsis Anthraquinones are released from senna after hydrolysis by bacteria. Anthraquinones then stimulate the myenteric plexus, leading to enhanced peristalsis **ADR**: Diarrhea, abdominal clamp

Question 28

Treatment of diarrhoea

Answer 28

1) Oral rehydration solution 2) Antidiarrhoeal agents - Opioid agonists - Adsorbents [Note: Usually only ORT os prescribed but not antidiarrhoeal agents, as diarrhoeaa will eliminate toxins and pathogens and is protective. Drugs are given when diarrhoea must be controlled for convenience e.g. work]

Question 29

Oral rehydration therapy

Answer 29

Treatment of diarrhoea **Components**: - Sodium - Potassium - Chloride - Citrate: as a basic salt that can reduce effect of acidosis caused by diarrhoea - Glucose: help to enhance sodium absorption via glucose-sodium co-transporter * \*\* Formula must be slightly **_hypo-osmolar_** to prevent the possible induction of osmotic diarrhoea* * \*\* Bicarbonate not used because not stable - will decompose to water & CO2 naturally* **Mechanism**: - Replace the electrolyte deficit adequately - Enhance the absorption of water and electrolytes **Clinical considerations:** - The amount of rehydration that is needed depends on the size of the individual and the degree of dehydration. - Rehydration is generally adequate when the person no longer feels thirsty and has a normal urine output. **Home-made ORT:** + 1 level teaspoon of salt + 8 level teaspoons of sugar + 1 litre of clean drinking water

Question 30

Opioid receptor agonists

Answer 30

Antidiarrhoeal agent **Examples:** - Codeine - Loperamide - Diphenoxylate **Mechanism:** - They stimulate opioid receptors in ENS neurons, which will inhibit the release of ACh from ENS neurons - that in turn decrease peristalsis of gut, thus increasing colonic transit time - increase faecal water absorption will decrease diarrheoa - Codeine and loperamide have antisecretory actions as well. **ADR:** - Drowsiness, dizziness - constipation, paralytic ileus can also occur.

Question 31

Adsorbents

Answer 31

Antidiarrhoeal agent **Examples**: - Kaolin - Pectin **Mechanism: ** - claim to bind toxins and bacteria - But there is no good evidence to show their effectiveness **Notes**: - no side effects - very cheap

Question 32

Intestinal pain & spasm treatment

Answer 32

Antispasmodic drugs e.g. muscarinic receptor antagonist

Question 33

Muscarinic receptor antagonist (antispasmodic agent)

Answer 33

Antiemetics, antispasmodic agent **Example**: Hyoscine **Mechanism:** - Normally, both neurons from ANS (parasympathetic) & ENS will release ACh that act on muscarinic receptors of GIT smooth muscle cells for contraction - By blocking muscarinic receptors in intestinal smooth muscle cells, intestinal smooth muscle will relax, thus decreasing peristasis and basal tone, hence reducing spasm **ADR:** - Drowsiness - dry mouth - blurred vision - urinary retention - constipation - tachycardia

Question 34

irritable bowel syndrome

Answer 34

- An idiopathic chronic disorder **Clinical presentation:** - Abdominal discomfort (pain, bloating, distension, nausea) - Alteration in bowel habits (diarrhoea, constipation, or cycle of both)

Question 35

Therapies for IBS

Answer 35

Therapies for irritable bowel syndrome are directed at relieving abdominal pain and discomfort - For patients with predominant diarrhoea, **opioid agonists** (e.g. loperamide) are used. - For patients with predominant constipation, **bulk laxatives** or **osmotic laxatives** are used. - For intestinal spasm, **antispasmodic agents** (i.e. muscarinic receptor antagonist) are used - \*\*For unpleasant visceral sensation (e.g. nausea, bloating and pain), **5HT₃ receptor antagonists** will be used by blocking the 5HT₃ receptors of EPAN, preventing sensory signalling to CNS