23. Anti-emetics

Question 1

Why can chemotherapy cause CINV (chemotherapy induced nausea and vomiting)?

Answer 1

• Toxic to lining of the stomach
• Cisplatin affects and destroys enterochromaffin cells
• Causes release of free radials => destruction of cells and excessive 5-HT release from the stomach
• 5-HT acts on receptors located on nerve fibres to:
-nucleus tractus solitarius (NTS) (in medulla near vomiting centre)
- vomiting centre
- chemoreceptor trigger zone (CTZ)
• Results in increase fibres

Question 2

Is the chemoreceptor trigger zone inside the BBB and is it associated with the vomiting centre?

Answer 2

• No, it’s outside the BBB
• Associated with the VC but not part of it
• Detects things in the blood and sends signals to the VC

Question 3

What is the most effective strategy to prevent CINV?

Answer 3

Blocking 5-HT receptors

Question 4

What medication is usually used to prevent CINV?

Answer 4

• Ondansetron - selective 5-HT3A receptor antagonist (MAIN)
• Glucocorticoids - reduces free radical production
• Aprepitant - neurokinin-1 receptor antagonists

Question 5

What Aprepitant?

Answer 5

CINV treatment - blocks neurokinin 1 (decreases signals to vomiting centre)

Question 6

Where are neurokinin 1 receptor located, and what does inhibition cause?

Answer 6

• Located in the connection between the solitary tract and vomiting centre
• Substance P normally acts on them
• Inhibiting these receptors inhibits vomiting

Question 7

In motion sickness, there is a neural mismatch between…

Answer 7

the auditory labyrinth and CNS

Question 8

Which receptor mediate a signal from the auditory labyrinth?

Answer 8

Muscarinic receptors

Question 9

Through what receptors does the vestibular system communicate with the hypothalamus?

Answer 9

Direct - muscarinic receptors

Indirect - H1 receptors

Question 10

Outline the pathophysiology of motion sickness

Answer 10

• Neural mismatch via muscarinic receptors
• Increase hypothalamic histamine release
• Activates H1 receptors in CTZ
• Vestibular system and hypothalamus may also activate the VC through the cholinergic system

Question 11

How do H1 receptor antagonists (e.g. promethazine) treat motion sickness?

Answer 11

• Block H1 receptors
• May be pre- or post-synaptic
• They are involved in signalling from the hypothalamus to the CTZ
• Reduced likeliness of vomiting being triggered

Question 12

How do non-selective muscarinic receptor antagonists (e.g. hyoscine) treat motion sickness?

Answer 12

Most effect strategy
• Blocks all 5 muscarinic receptors
• Role of cholinergic system in vomiting is not clear
• Treatment is most likely to be blocking signalling from labyrinth => vestibular

Question 13

People with a history of T2DM are most likely to suffer from gastroparesis. What is this?

Answer 13

• Delayed emptying of the stomach (cannot contract properly)

1) Direct recognition from stomach to VC
• lack of emptying is recognised due to release of dopamine from pre-synaptic neurones
• D2 receptors

2) 5-HT release - activation of 5-HT receptors on nerve fibres to VC and CTZ

Question 14

Is the nucleus tractus solitarius relevant in terms of the pathophysiology for gastroparesis?

Answer 14

No

Question 15

Describe the action of the first line treatment for gastroparesis

Answer 15

Dopamine D2 receptor antagonist (e.g. metoclopramide)
• Prokinetic - stimulates contractility for gastric emptying
• Inhibits D2 receptors in the VC
• Metoclopramide is also a 5-HT receptor antagonist