Antiemetics, dopamine D2-receptor antagonists

Key examples

• Metoclopramide
• Domperidone

 

Common indications

• Prophylaxis and treatment of nausea and vomiting in a wide range of conditions, but particularly in the context of reduced gut motility.

 

Mechanisms of action

• Nausea and vomiting are triggered by a variety of factors, including gut irritation, drugs, motion and vestibular disorders, as well as higher stimuli (sights, smells, emotions). The various pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone, the solitary tract nucleus (which is innervated by the vagus nerve), the vestibular system and higher neurological centres. Dopamine, acting via D2 receptors, is relevant in two respects. 
• First, the D2 receptor is the main receptor in the chemoreceptor trigger zone (CTZ), which is the area responsible for sensing emetogenic substances in the blood (e.g. drugs). Second, dopamine is an important neurotransmitter in the gut, where it promotes relaxation of the stomach and lower oesophageal sphincter and inhibits gastroduodenal coordination. 
• Drugs that block D2 receptors therefore have a prokinetic effect – promoting gastric emptying – which contributes to their antiemetic action. 
• They are effective in nausea and vomiting due to CTZ stimulation (e.g. due to drugs) and reduced gut motility (e.g. due to opioids or diabetic gastroparesis).

 

Important adverse effects

• Diarrhoea is probably the most common side effect of D2-blocking antiemetics. 
• Metoclopramide can induce extrapyramidal syndromes (movement abnormalities) via the same mechanism as for antipsychotics. 
• In the context of short-term treatment for nausea and vomiting, this is most likely to take the form of an acute dystonic reaction such as an oculogyric crisis. 
• Domperidone tends not to cause extrapyramidal symptoms because it does not cross the blood–brain barrier (note that the chemoreceptor trigger zone is largely outside the blood–brain barrier, so this characteristic does not affect its antiemetic action).

 

Warnings

• Extrapyramidal side effects are more common in children and young adults so its use should be avoided in these groups. 
• As both drugs have prokinetic effects, they are contraindicated in patients with gastrointestinal obstruction and perforation.

 

Important interactions

• The risk of extrapyramidal side effects is increased when metoclopramide is prescribed with antipsychotics. 
• It should not be combined with dopaminergic agents for Parkinson’s disease, as it will antagonise their effects. 
• Domperidone is not subject to these interactions.