Anti-emetics HR

Question 1

How can chemotherapy bring about a feeling of motion sickness?

Answer 1

Cisplatin:

1. Binds gastric enterochromaffin cells
2. Free radicals released
3. Subsequent excessive 5HT release
4. activates 5HT3A receptors on fibres to NTS which then goes to vomiting centre. Also activates fibres to CTZ which then go to VC (direct and indirect effects)

Question 2

What is the cause of motion sickness?

Answer 2

Neural mismatch between auditory labyrinth and CNS

Question 3

Recall the communication between the labyrinth and the CNS

Answer 3

1. Signal from labyrinth to vestibular system. (muscarinic receptors on vestibular system)
2. Signal from vestibular system to hypothalamus
3. Hypothalamus releases histamine. Histamine agonises H1 Receptors in the CTZ
4. CTZ communicates with VC, which then causes vomiting.

Note: there are projections from vestibular system and hypothalamus to VC which binds to muscarinic receptors on VC

Question 4

How can gastroparesis bring about the feeling of motion sickness?

Answer 4

More contents in stomach due to reduced emptying. This causes increased serotonin (5-HT) in stomach – activates 5-HT3A receptors on:

1. Nerves fibres from stomach to vomiting centre (VC) which releases dopamine and acts on D2 receptors in the VC
2. Nerve fibres to chemoreceptor trigger zone (CTZ)

Question 5

Recall the 4 main classes of anti-emetic and their principle uses

Answer 5

Antagonists of:

1. 5HT3ARs - Chemotherapy induced N and V
2. H1Rs - motion sickness
3. D2Rs - gastroparesis induced N and V
4. mAChRs - motion sickness (used with H1R antagonist)

Question 6

What sort of drug is used to treat chemotherapy-induced nausea and why?

Answer 6

5HT3AR antagonists. They reduce the nerve impulses to the CTZ, VC and NTS

Question 7

Give an example of a specific 5HT3AR antagonist

Answer 7

Ondasteron

Question 8

What is coadministered with ondasteron and why?

Answer 8

To increase efficacy coadminister with:

• Glucocorticoid (reduces free radical production because they are anti-inflammatory)
• Aprepitant (neurokinin 1 receptor antagonist)

Question 9

Give an example of a specific H1 receptor antagonist?

Answer 9

Promethazine

Question 10

Give an example of a muscarinic antagonist and recall its selectivity

Answer 10

Hyoscine

Will antagonise all types of mAChR at different concentrations

Question 11

What class of anti-emetic is used to treat gatroparesis-induced nausea and what are its ‘extra actions’ other than its main function?

Answer 11

D2 receptor antagonist
other actions:
1. Inhibits D2Rs in vomiting centre
2. Stimulates gastric emptying (prokinetic drug: increases motility of GIT)
3. Nb it also has partial 5HT3AR antagonist activity and so can also reduce the communication to CTZ from the stomach.

Question 12

Give an example of a D2R antagonists

Answer 12

Metoclopramide

Question 13

Describe the general side effects of anti-emetic drugs

Answer 13

Very non-specific in general

Often cause drowsiness

Question 14

Side effects of 5 HT3A receptor antagonists like ondansetron?

Answer 14

really ‘general’ side effects: constipation, headaches

Question 15

side effects of H1R antagonists and muscarinic receptor antagonists?

Answer 15

Histamine H1 receptor antagonists: drowsiness
Muscarinic receptor antagonists: drowsiness, dry mouth, constipation
note that they both cause drowsiness. They are often given together for motion sickness which is even worse.

Question 16

Side effect of D2R antagonists:

Answer 16

extrapyramidal side effects (blocks dopamine receptors on extrapyramidal motor pathways) and galactorrhea (dopamine normally inhibits prolactin release)