Pathogenesis: Humoral and Neural Pathways

Our current understanding of the physiology of emesis is dominated by concepts elaborated in the early 1950's by Borison and Wang. In their two-component model, vomiting is believed to occur through activation of a humoral or neural pathway. In this model, vomiting occurs through activation of the CRTZ by blood-borne substances (humoral pathway), or through activation of the emetic center by vago-sympathetic, CRTZ, vestibular, or cerebrocortical neurons (neural pathway). Thus, activation of the CRTZ by circulating emetogenic substances (e.g., uremic toxins, cardiac glycosides, ammonia and other hepatoencephalopathic toxins, endotoxins, and apomorphine) is abolished by CRTZ antagonism, but not by vagotomy, sympathectomy, or emetic center antagonism. In contrast, neural activation of the emetic center by gastrointestinal disease (e.g., inflammation, infection, etc.) is abolished by vagotomy, sympathectomy, and emetic center antagonism, but not by CRTZ antagonism. Many experimental data have been readily explained by this two-component model. The Borison-Wang model is not without challenge, however and it has been suggested that there are parallel mechanisms for the initiation of emesis in response to any stimulus, and it is the sum of these inputs that drives the emetic response.

Many of the spontaneous vomiting disorders of cats and dogs, particularly those of the primary gastrointestinal tract, are believed to result from activation of the neural pathway. Vomiting associated with primary gastrointestinal tract disease (e.g., inflammation, infection, malignancy, toxicity) results from activation of visceral receptors, afferent neurons, and the emetic center. Efferent information transmitted back to the gastrointestinal tract stimulates the motor correlates of vomiting (retrograde duodenal and gastric contractions, relaxation of the caudal esophageal sphincter, gastroesophageal reflux, opening of the proximal esophageal sphincter, and evacuation of gastrointestinal contents). A neural pathway can also be involved in vomiting associated with motion sickness. Motion within the semicircular canals is transduced to vestibulo-cochlear neurons that ultimately synapse in the CRTZ or emetic center. Cats and dogs experience motion sickness, although the neuroanatomy and pharmacology appear to be somewhat different between the two species. Histaminergic neurons and the CRTZ are involved in motion sickness in the dog, whereas neither are involved in motion sickness in the cat. A neural pathway involving cerebrocortical neurons may be involved in vomiting disorders associated with anxiety or anticipation, but these are probably more important in human beings.

The essential component of the humoral pathway is the chemoreceptor trigger zone (CRTZ) located within the area postrema that is sensitive to blood-borne substances. Receptors within the CRTZ may be activated by many endogenous (e.g., uremic-, hepatoencephalopoathic-, or endotoxins) and exogenous (e.g., digitalis glycosides, apomorphine) blood-borne substances. Most pharmacological approaches to anti-emetic therapy have been based on neurotransmitter-receptor interactions at the CRTZ, emphasizing the humoral pathway of emesis. The neural pathway has received much less emphasis even though it is a much more important pathway in many spontaneous vomiting disorders.

Anti-Emetic Classification

A number of anti-emetic drugs have been formulated based on the aforementioned neurotransmitter-receptor systems. These drugs may be classified as: α₂ adrenergic antagonists, D₂ dopaminergic antagonists, H₁ and H₂ histaminergic antagonists, M₁ muscarinic cholinergic antagonists, ENK enkephalinergic mixed agonists/antagonists, and 5-HT₃ serotonergic antagonists. The 5-HT₄ serotonergic agonists are not direct anti-emetic drugs per se, but may have an indirect anti-emetic effect by promoting gastrointestinal motility. The most recent new classification of anti-emetic agents are the neurokinin NK₁ antagonists. This classification of anti-emetic agents has humoral and neural anti-emetic activities.

Rational Use of Anti-Emetic Agents in the Diagnosed Patient

1.  Motion Sickness: Motion sickness is believed to arise from stimulation of labyrinthine structures in the inner ear. The chemoreceptor trigger zone and H₁ histaminergic receptors are involved in this pathway in the dog, but apparently they are less importantly involved in the cat. Motion sickness in the cat is probably best treated with an α-adrenergic antagonist, e.g., chlorpromazine, instead of a pure H₁ histaminergic antagonist.

2.  Uremia: Vomiting associated with uremia has both central and peripheral components. The central component of uremic vomiting is associated with activation of CRTZ D₂ dopaminergic receptors by circulating uremic toxins. The central component is best treated with a D₂ dopaminergic antagonist, e.g., metoclopramide. The peripheral component of uremic vomiting is associated with uremic gastritis and is best treated with acid secretory inhibitors (e.g., ranitidine 1-2 mg/kg q 12 h IV; omeprazole 0.7 mg/kg q 12 h PO) to diminish gastric parietal cell H⁺ ion secretion, and with chemical barrier diffusion barriers (e.g., sucralfate 0.25-0.5 grams q 8-12 h PO) to provide a barrier to H⁺ ion back diffusion.

3.  Cancer Chemotherapy: Certain cancer chemotherapies (e.g., cisplatinum, cyclophosphamide) are associated with a high incidence of vomiting. Chemotherapy-induced emesis is mediated by 5-HT₃ serotonergic receptors, either in the CRTZ or in vagal afferent neurons. Antagonists of the 5-HT₃ serotonergic receptor (e.g., ondansetron, granisetron, tropisetron) abolish the vomiting associated with cisplatinum administration in the cat. Although metoclopramide has some 5-HT₃ antagonistic properties, it has not proved very useful in chemotherapy-induced emesis.

4.  Delayed Gastric Emptying Orders: Disorders of delayed gastric emptying (e.g., gastritis, metabolic derangements, post-operative gastric dilatation and volvulus) may cause an animal to experience nausea and vomiting. Treatment of these disorders with cholinomimetic agents has been associated with untoward side effects. Contemporary therapy consists of 5-HT₃ serotonergic agonists (e.g., cisapride, metoclopramide), cholinesterase inhibitors (e.g., ranitidine or nizatidine), and motilin agonists (e.g., low dose erythromycin--dog only). Cisapride is superior to metoclopramide in the treatment of gastric emptying disorders in cats and dogs. Ranitidine and nizatidine inhibit acetylcholinesterase activity in addition to their effects on histamine H₂ receptors in the gastric mucosa. Both drugs (ranitidine and nizatidine) stimulate gastric emptying in the cat and dog. Erythromycin stimulates phase III migrating myoelectric complex (MMC) activity in the dog, but the migrating spike complex (MSC) activity of the cat is under different physiologic regulation.

Classifications--5-HT₃ antagonists.

Classifications--NK₁ antagonists.

Combination anti-emetic agents.

Alpha-2-Adrenergic Antagonists
5-HT3 Serotonergic Antagonists

D2 Dopaminergic Antagonists
5-HT3 Serotonergic Antagonists

D2 Dopaminergic Antagonists
Alpha-2-Adrenergic Antagonists

Combination anti-emetic and prokinetic therapy.

NK1 Neurokinin Antagonists
5-HT3 Serotonergic Antagonists
lpha-2-Adrenergic Antagonists
+
5-HT4-Agonists--Cisapride or prucalopride
or
Motilin Agonists--Erythromycin (0.5-1.0 mg/kg)
or
Cholinomimetic Agents--Ranitidine or nizatidine