Question 14

College Answer

The examiners commented that a well-drawn and labelled diagram was a very useful adjunct to answering this question. Consideration of stimulus, sensors, integrators/processors, and effectors was also useful to ensure that all components of the question were covered by a candidate’s answer. Incorrect facts or a lack of detail about the various receptors and their locations was a common theme in answers that scored poorly. Classes of antiemetics, with specific drugs given as examples, were expected to gain marks.

Discussion

Neurology of nausea and vomiting:

• Stimuli:
  • Bloodstream toxins
  • Sensory stimuli (any of the senses!)
  • Gut distension or noxious chemical content
  • Psychological stimuli
• Sensors: Chemoreceptor trigger zone, sense organs (eg. visual, olfactory and gustatory), vestibular labyrinth, mechanoreceptors in the GIT.
• Afferents: vagus, sensory tracts, vestibulocochlear nerve, central descending
  • Main receptors involved are 5-HT₃, D2, H1 and muscarinic.
• Central processors: Nucleus of the solitary tract and chemoreceptor trigger zone both feed into the "central pattern generator" which coordinates the mechanical act of vomiting
  • Neurotransmission in these centres is mediated by:
    • Muscarinic acetylcholine receptors
    • Dopamine receptors
    • 5-HT₃ serotonin receptors
• Efferents: Vagus (to stomach and small intestine), lower cranial nerves (to face and oropharynx), somatic motor fibres (to chest/abdominal muscles), sympathetic nervous system (tachycardia, vasoconstriction, sweating)

Antiemetic classes acting on these receptors:

• Dopamine (D2) antagonists:
  • Phenothiazines (promethazine), which also have potent activity against muscarinic, H1, 5-HT₃ and dopamine receptors
  • Butyrophenones (droperidol), which have slightly less potent anticholinergic and antihistamine effects 
  • Benzamides (metoclopramide), which have a prokinetic effect related to indirect cholinergic activity
• Anticholinergic (antimuscarinic): 
  • Hyoscine, atropine (purely antimuscarinic)
  • Phenothiazines and butyrophenones also have strong antimuscarinic effect
• 5-HT₃ antagonists: 
  • ondansetron and granisetron are pure, high-affinity 5-HT₃ antagonists
  • Phenothiazines and butyrophenones also have strong 5-HT₃ antagonist effects
• Antihistamines: 
  • Cyclizine and prochlorperazine have mainly anti-H1 effects
  • Most centrally acting H1 antagonists also have potent antimuscarinic activity
• NK-1 antagonists: 
  • aprepitant 

Lyons, Samantha, and Ben Ballisat. "Antiemetic drugs: pharmacology and an
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Flake, Zachary A., Robert Scalley, and Austin G. Bailey. "Practical selection of antiemetics." American family physician 69.5 (2004): 1169-1174.

Sanger, Gareth J., and Paul LR Andrews. "A history of drug discovery for treatment of nausea and vomiting and the implications for future research." Frontiers in pharmacology 9 (2018): 913.

Horn, Charles C. "The physiology of vomiting." Nausea and Vomiting. Springer, Cham, 2017. 15-25.

Parkes J.D. (1986) A Neurologist’s View of Nausea and Vomiting. In: Davis C.J., Lake-Bakaar G.V., Grahame-Smith D.G. (eds) Nausea and Vomiting: Mechanisms and Treatment. Advances in Applied Neurological Sciences, vol 3. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-70479-6_12

Singh, Prashant, Sonia S. Yoon, and Braden Kuo. "Nausea: a review of pathophysiology and therapeutics." Therapeutic advances in gastroenterology 9.1 (2016): 98-112.