Anti-emetics

Question 1

What is the physiological control of nausea/vomiting? Where do these structures receive their inputs from?

Answer 1

Vomiting centre (area postrema): innervated by the nucleus of the tractus solitarius (which receives nerve fibres from stomach)
Vomiting centre also receives direct input from the stomach, as well as from the hypothalamus and vestibular system.

Chemoreceptor Trigger Zone: communicates with the vomiting centre and it receives input from hypothalamus and stomach.

Question 2

What are mechanistic triggers of nausea/vomiting?

Answer 2

Cytotoxic drugs (e.g. cisplatin)
Motion sickness
Gastrointestinal problems (e.g. delayed gastric emptying in diabetics)

Question 3

What are the main classes of anti-emetic drugs?

Answer 3

5-HT3A (serotonin) receptor antagonists (Ondansetron)
Histamine H1 receptor antagonists (Promethazine)
Muscarinic receptor antagonists (Hyoscine)
Dopamine D2 receptor antagonists (Metoclopramide)

Question 4

Which class of drug is used for which cause of vomiting?

Answer 4

5-HT3A (serotonin) receptor antagonists = chemo induced vomiting

Histamine H1 receptor antagonists = motion sickness

Muscarinic receptor antagonists = motion sickness

Dopamine D2 receptor antagonists = gastroparesis

Question 5

Outline how chemotherapy induces vomiting

Answer 5

Cisplatin is toxic to enterochromaffin (EC) cells and causes the release of free radicals => free radicals and apoptosis cause excessive 5-HT release => activation of 5-HT3A receptors (ligand gated ion channels) => firing of nerve fibres to nucleus of tractus solitarius which then fire to the vomiting centre; from stomach straight to vomiting centre; to chemoreceptor trigger zone

Question 6

How to treat chemotherapy induced vomiting?

Answer 6

Ondansetron = 5-HT3A receptor antagonist => block signals to NTS, VC, and CTZ
Corticosteroids => reduction of free radical formation
Areprepritant = neurokinin-1 receptor antagonist => reduces activation of neurokinin-1 receptor so reduced firing from NTC to VC

Question 7

What is the pathophysiology of motion sickness?

Answer 7

Auditory labyrinth neural mismatch is detected by vestibular system via muscarinic receptors =>

1. hypothalamus releases increased histamine which activate H1 receptors in CTZ
2. Vestibular system and hypothalamus activate VC via muscarinic receptors

Question 8

How to treat motion sickness?

Answer 8

Promethazine = H1 receptor antagonist => CTZ does not get activated by hypothalamus
Hyoscine (scopolamine) = non-selective muscarinic receptor antagonist

Question 9

What is the pathophysiology of gastroparesis?

Answer 9

Gastroparesis = delayed gastric emptying
Delayed gastric emtpying triggers nausea:
Reduced contractions by stomach => Signal from stomach to vomiting centre via 5-HT3A receptors (also to CTZ via 5-HT3A) or by releasing dopamine in VC and activating D2 receptors

Question 10

How to treat gastroparesis?

Answer 10

Metoclopramide = dopamine D2 antagonist => Block activation of D2 receptors on VC (which are activated by dopamine release from stomach as a result of reduced contractions)
Metoclopramide is also a prokinetic agent = enhances gastric motility and so stimulates gastric emptying
It also has partial 5-HT3A receptor antagonistic activity as well so reduces signals sent by stomach to VC and CTZ.

Question 11

What are the side effects of muscarinic receptor antagonists?

Answer 11

Drowsiness

Dry mouth

Question 12

What are the side effects of histamine H1 receptor antagonists?

Answer 12

Drowsiness

Question 13

What are the side effects of dopamine D2 receptor antagonists?

Answer 13

Galactorrhoea

Extra-pyramidal effects

Question 14

What are the side effects of 5-HT3A receptor antagonists?

Answer 14

Constipation

Headaches