Lecture 60 – Gastrointestinal Therapeutics

Question 1

Enteric nervous system

Answer 1

o Nervous system of the digestive tract
o Contains 100s of millions of neurones
o Autonomous
o Can act independently of autonomic nervous system but is influenced by ANS – intrinsic and extrinsic control

Question 2

Autonomic innervation of the GI tract

Answer 2

o Parasympathetic innervation
 Stimulatory
 Craniosacral (Vagus and pelvic nerves)
o Sympathetic innervation
 Inhibitory
 Thoracolumbar (prevertebral ganglia)

Question 3

Causes of vomiting

Answer 3

o Unpleasant smells, slights
o Emotional stress
o Pain, headache/migraine
o Abnormal motion
o Toxins
o Hormone changes

Question 4

Vomiting reflex

Answer 4

o Involves several different neurotransmitters and their receptors
o Understanding the cause of vomiting can help in the choice of appropriate anti-emetic

Question 5

Vomiting Anatomical Sites:

Answer 5

1. Vestibular System: Located in the inner ear, this system plays a role in detecting motion and spatial orientation. Motion sickness can trigger nausea and vomiting due to conflicting sensory inputs (e.g., when you feel motion but do not see it).
2. Chemoreceptor Trigger Zone (CTZ): Located near the floor of the fourth ventricle in the brain, the CTZ is outside the blood-brain barrier and can be stimulated by various substances in the blood, such as toxins and drugs.
3. Vomiting Centre: Located in the medulla oblongata in the brainstem, the vomiting centre receives signals from the CTZ and other areas, then coordinates the motor response for vomiting.

Question 6

Vomiting Physiological Pathways:

Answer 6

1. Gastrointestinal Distension: When the stomach or intestines become overly distended, stretch receptors are activated, leading to signals that can trigger nausea and vomiting. This can occur, for example, in cases of gastric obstruction.
2. Irritation and Inflammation: Inflammatory or irritant substances in the gastrointestinal tract can activate sensory neurons, which transmit signals to the brain to induce nausea and vomiting. This can happen in conditions like gastritis.
3. Vestibular Pathway: Motion or balance-related inputs from the vestibular system can lead to conflicting sensory information, causing nausea and vomiting. For example, when motion signals disagree with visual input (e.g., car sickness).
4. Chemoreceptor Pathway: The CTZ can detect various substances in the blood that signal emetic responses. These substances include toxins, drugs, and chemotherapy agents.
5. Psychological Factors: Stress, anxiety, or emotional distress can activate the brain’s limbic system, which can, in turn, affect the vomiting center and lead to nausea and vomiting.

Question 7

Vomiting Signaling Molecules and Receptors:

Answer 7

1. Serotonin (5-HT): Serotonin receptors, particularly 5-HT3 receptors, are found in the gastrointestinal tract and CTZ. Activation of these receptors can trigger nausea and vomiting. Medications like ondansetron target 5-HT3 receptors to prevent nausea and vomiting.
2. Dopamine: Dopamine receptors, specifically D2 receptors, are found in the CTZ and the vomiting center. Overstimulation of these receptors can lead to nausea and vomiting. Medications like metoclopramide work by blocking D2 receptors.
3. Acetylcholine (ACh): Acetylcholine receptors, particularly muscarinic receptors, play a role in nausea and vomiting. Medications like scopolamine, which is an anticholinergic, can be used to prevent motion sickness-induced nausea and vomiting.
4. Histamine: Histamine receptors, specifically H1 and H2 receptors, can contribute to nausea and vomiting when overstimulated. Medications like diphenhydramine (H1 receptor antagonist) and ranitidine (H2 receptor antagonist) can help alleviate symptoms.
5. Neurokinin 1 (NK1) Receptor: Substance P, acting through NK1 receptors, plays a role in the emetic reflex. Medications like prepatent target NK1 receptors to prevent chemotherapy-induced nausea and vomiting.
6. Opioid Receptors: Activation of opioid receptors, especially mu receptors, can lead to nausea and vomiting. Opioid-induced nausea and vomiting can be managed with opioid receptor antagonists.

Question 8

Classes of anti-emetics that target particular receptors

Answer 8

o Histamine receptor antagonist
o Muscarinic receptor antagonist
o Dopamine D2 receptor antagonists %HT3 receptor antagonists
o Neurokinin-1/substance P receptor antagonist

Question 9

Histamine receptor antagonist

Answer 9

o Promethazine, meclizine
o Competitive antagonist at H1 histamine receptors (primarily)
o Also muscarinic M1 receptors (moderate) and dopamine D2 receptors (weak)
o Treatment of motion sickness
o Side effects = sedation and drowsiness

Question 10

Muscarinic receptor antagonist

Answer 10

o Hyoscine hydrobromide “Kwells”
o Competitive antagonist for Ach at M1 muscarinic receptors
o Treatment of motion sickness
o Side effects = anti-cholinergic effects = drowsiness, constipation, dry mouth, blurred vision, tachycardia

Question 11

Dopamine D2 receptor antagonists

Answer 11

o Phenothiazines
o Phenothiazines used as anti-psychotic drugs
o Prochlorperazine; trade name “stemetil”
o D2 dopamine receptor antagonist
o Acts at CTZ (and VC)
o Side effects – extrapyramidal effects (movement disorders) and anti-cholinergic effects (constipation, dry mouth)

Question 12

Metoclopramide

Answer 12

o Trade name maxolon
o Antagonist of dopamine D2 receptors at CTZ
o Crosses BBB to act centrally and peripherally
o EPSE

Question 13

Comperidone

Answer 13

o Trade name motillum
o Antagonist of dopamine D2 receptors at CTZ
o Only has peripheral effects
o EPSE are rare
o Side effects = increased gastric emptying, restlessness, anxiety, drowsiness

Question 14

5HT3 receptor antagonists

Answer 14

o The ‘setrons’
o E.g. Zofran, dolasetron, palonosetron
o Activity at CTZ, VC and GIT
o Used for nausea and vomiting associated with cancer radiotherapy and chemotherapy
o Side effects = few, may cause constipation
o No sedation (antihistamines), no extrapyramidal/anti-cholinergic effects

Question 15

Neurokinin-1/substance P receptor antagonists

Answer 15

o Newest class of anti-emetic drugs the ‘pitants’.
o aprepitant “Emend”- oral
o fosaprepitant (pro-drug converted to aprepitant) - IV
o Block neurokinin type 1 receptors in the central and peripheral nervous system – selectively and with high affinity Little to no affinity for serotonin (5HT3) or dopamine (D2) receptors
o Activity at CTZ and particularly at the vomiting centre
o Used for prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy (cisplatin), and pain
o Often used as adjunctive therapy with 5HT3 receptor antagonists and corticosteroids (dexamethasone)
o Side effects: Few (fatigue, dizziness, GI disturbance), reduce effectiveness of hormonal contraceptives Inhibits CYP3A4 in a dose dependent fashion, so can result in elevated plasma concentrations of other drugs – particularly cisapride

Question 16

The parietal cell

Answer 16

o Expresses
 H2 histamine receptors, M3 muscarinic receptors, CCK8 gastrin receptors
 SSTR2 somatostatin receptor
 EP3 prostaglandin receptor
 When acetylcholine, gastrin or histamine bind to these receptors the parietal cell is stimulated to produce HCL
 When somatostatin or prostaglandins bind the production of HCl is inhibited

Question 17

G-cell

Answer 17

o Releases gastrin
o Stimulated by gastric releasing peptide binding to BB2
o Releases gastrin that binds to CCK2 on parietal cell
o The gastrin also binds to CCK2 on ECL cell to stimulate it to release histamine

Question 17

Enterochromaffin like cell (ECL)

Answer 17

o Releases histamine
o Acetylcholine binds to its M1 receptor to stimulate
o Somatostatin binds to its SSTR2 receptor to inhibit
o Gastrin binds to its CCK2 to stimulate

Question 18

D-cell

Answer 18

o Releases somatostatin
 When binds to G-cell, parietal cell and ECL cell to stop release of their molecules
 Acetylcholine binds to M2 to stop D-cells release of somatostatin

Question 19

Drugs that can cause oesophagitis and dyspepsia

Answer 19

o Directly irritate lining of oesophagus, cause structures and/or affect acid production
o E.g. aspirin, antibiotics, iron supplements

Question 20

antacids

Answer 20

o act to neutralise HCl, bind bile acids and decrease pepsin activity
o Provide symptomatic relief
o Usually cause production of CO2 so can cause bloating and gas
o Need to use magnesium, calcium and aluminium together to increase bowel motility (M) and decrease bowel activity (C/A)

Question 21

H2 histamine receptor antagonists

Answer 21

o The “tidiness”
o Cimetidine, famotidine, ranitidine
o Competitive receptor blockage
o Generally well tolerated
o Bind to the H2 histamine receptor blocking the binding of histamine on gastric parietal cells thereby reducing acid secretion (competitive)
o Treatment of peptic ulcer disease, GORD, dyspepsia Important drug - drug interactions involving cytochrome p450 enzyme
o Cimetidine decreases activity of cytochrome P450 enzyme (is only member of family to do this).

Question 22

Proton pump inhibitors

Answer 22

o the “prazoles” omeprazole, lansoprazole, esomeprazole (Nexium), pantoprazole
o Prodrugs that require activation in the acidic environment of the parietal cell canaliculus
o Converted in acidic environment to a permanent cation
o Irreversible inhibition of the parietal cell H+/K+ ATPase proton pump to block active transport of H+ ions
o Used for ulcerative oesophagitis or unresponsive gastric ulcer
o Advantage is that will reduce acid secretion independently of how secretions stimulated

Question 23

Cyto-protective drugs

Answer 23

o Rarely used
o Prostaglandin analogues
o Misoprostol
o Treatment of ulcers
o Prevention in use with NSAIDs
o Decreased acid secretion, increased mucus secretion

Question 24

Sucralfate

Answer 24

o Sulphated sucrose and aluminium hydroxide
 In presence of acid  dissociates  sticky adherent gel + neutralising agent  protective and acid resistant

Question 25

Drugs for ulcers caused by H. pylori

Answer 25

o Eradication of H. pylori is considered a first line treatment
o Monotherapy ineffective, so combinations developed
o Triple therapy (many variants)
 proton pump inhibitor
 antibiotics (clarithromycin, amoxycillin, metronidazole)
o Success dependent on adherence to treatment
o Short term treatments < 7 days with low adverse events have greatest adherence

Question 26

Motility disorders – constipation

Answer 26

o Difficult faecal evacuation as a result of hardness or infrequent movements
o Can be due to
 Lifestyle/dietary related causes
 Medically related causes
 Often adverse effect of many commonly used drugs

Question 27

Motility stimulant drugs (prokinetics)

Answer 27

o Dopamine Receptor Antagonists Domperidone (Motillum) and metoclopramide (Maxolon)
o Increase gastrointestinal motility via antagonism of the dopamine D2 receptors.
 Dopamine signaling inhibits ACh mediated smooth muscle activity.
o Antagonism of dopamine receptors increases motility by increasing parasympathetic smooth muscle activity.
o Promote motility without purgation (diarrhoea).
o Metoclopramide is also an agonist at 5HT4 and antagonist at 5HT3 serotonin receptors
o 5HT4 agonism stimulates parasympathetic activity whereas 5HT3 inhibits parasympathetic activity

Question 28

Motility disorders (diarrhoea)

Answer 28

o Too much motility
o Increased passage of semi-liquid or liquid stools
o Numerous causes
o Acute and chronic

Question 29

Anti-motility drugs

Answer 29

o Opioids
o codeine, morphine, loperamide “Imodium”, diphenoxylate
o Bind to μ-opioid receptors in gut wall (myenteric plexus)
o Reduces secretions and propulsive movements of smooth muscle, prolonging transit of intestinal contents and absorption of water
o Short term use only – do not use in children
o Oral administration
o Increasing misuse of loperamide in US > high doses for euphoria or self-management of opioid withdrawal > some cases of misuse leading to cardiac failure and respiratory depression > death (40 mg–300 mg daily)

Question 30

Methylnaltrexone (relistor)

Answer 30

o Approved in 2008 by FDA
o Selective and competitive antagonist of u-opioid receptors
o Does not cross BBB (peripherally acting)
o Reverses peripheral effect of opioids such as constipation, without interfering with central analgesic effects
o Indicated for opioid induced constipation

Question 31

Anti-spasmodic (spasmolytics)

Answer 31

o Hyoscine BUTYL bromide “Buscopan” Also known as scopolamine butyl bromide
o Anti-cholinergic – muscarinic receptor antagonist (high affinity)
o Does not cross BBB – acts peripherally
o Smooth muscle relaxant, reduces GI motility and spasm
o Used for symptomatic relief in pathological conditions in which there is gastrointestinal spasm
o Oral, IV/IM administration
o Well tolerated

Question 32

Drugs affecting the GI system

Answer 32

o Anti-emetics = motion H1, M1 and stressors DF2, 5HT3, NK1
o Acid/peptide diseases = antacids, acid suppressants (H2, proton-pump inhibitors), helicobacter eradication, mucosal protectants
o Motility disorders (constipation, anti-diarrhoea, spasmolytics)