Question 3

Describe the neural integration of vomiting. (60% of marks)

Describe the pharmacology of ondansetron. (40% of marks)

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College Answer

Candidates who failed the question did not answer the actual question. They did not discuss  the neural integration but instead listed various inputs into the CTZ and vomiting centre. It was expected candidates could detail the pathways involved (afferent and efferent limbs) and describe the relationship with the coordinating centres. For example, afferent pathways to the vomiting centre include stretch and chemoreceptors located throughout the GIT via vagal  and sympathetic nerves, pharyngeal touch receptors via glossopharyngeal nerves etc. Again structuring pharmacology answers was often poor.

Discussion

Neurology of nausea and vomiting:

  • Stimuli: toxinaemia, sensory stimuli, visceral afferents, psychological
  • 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
  • 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
  • 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)

Pharmacology of ondansetron:

Class 5-HT3 receptor antagonist
Chemistry Carbazole
Routes of administration Oral, IV, IM, s/c, sublingual
Absorption Rapidly and completely absorbed, bioavailability ~ 60%
Solubility pKa 7.4, sparingly soluble in water
Distribution VOD= 2.5L/kg, 70-76% protein bound
Target receptor 5-HT3 serotonin receptor antagonist - which are ligand-gated cation channels and which mainly conduct depolarising sodium and potassium currents
Metabolism 95% of the dose is cleared by hepatic oxidative metabolism
Elimination Clearance is almost completely hepatic; only some minimal amount is eliminated by the kidneys
Time course of action Half life is about 3.8 hours; duration of effect is about 4-8 hours
Mechanism of action Main mechanism of antiemetic activity is the antagonism of 5-HT3 ligand-gated cation channels at the chemoreceptor trigger zone. No anticholinergic or antidopaminergic effects, and therefore no effects on gastric motility or nausea related to vertigo
Clinical effects - Antiemetic effects
- constipation
- QT prolongation
- Headache, potentiation of migraine
Single best reference for further information Naylor et al, 1992

References

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

Markham, Anthony, and Eugene M. Sorkin. "Ondansetron." Drugs 45.6 (1993): 931-952.