Pathophysiology

Vomiting, a reflex act in dogs and cats, requires the coordination of the gastrointestinal, musculoskeletal and nervous systems (Figure 1). Activation of the emetic centre, which lies within the reticular formation of the medulla oblongata, can happen by various stimuli. The neurons can be activated by certain blood-borne toxins or drugs through activation of the chemoreceptor trigger zone (CRTZ) that is located within the area postrema on the floor of the fourth ventricle. This stimulus is called the humoral pathway. Furthermore, vagal and sympathetic neurons stimulated by receptors in the abdominal viscera and many other sites throughout the body can produce a vomiting reflex in the emetic centre, which is called the neural pathway. Receptor activation can occur as a result of inflammation, irritation, distensions or hypertonicity, among other factors. Activation of the CRTZ is induced by a variety of humoral emetogenic substances (e.g., uraemic toxins, apomorphin, cardiac glycosides, cytotoxic agents). The reflex arch needs to be intact in order for animals to vomit as ablation of the area postrema abolishes emesis. Finally, impulses from the vestibular centre (inner ear) during motion sickness are thought to travel through the CRTZ to the vomiting centre.

Electrolyte And Acid-Base Disturbances

Vomiting may result in many adverse problems for the animal, such as dehydration, acid-base disturbances or aspiration pneumonia. Potassium depletion, which is a frequent complication of profuse vomiting, may impair renal tubular concentrating ability and worsen dehydration. Prerenal azotaemia may develop, and in patients with preexisting borderline renal failure this may lead to a decompensation of the renal concentrating ability. Acid-base disturbances and electrolyte changes are difficult to predict in both magnitude and direction. Sodium, chloride and potassium loss are likely, but plasma concentrations depend not only on the amount lost relative to plasma water, but also on concurrent diseases (e.g., hypoadrenocorticism, pyloric stenosis, etc.). While pyloric outflow obstruction or high duodenal closure with loss of gastric juice were thought to result mainly in loss of hydrochloric acid, a recent study was unable to confirm this.

Therapy

With acute vomiting the animal should be kept in a quiet place, food withheld for 12 to 24 hours and water given in small portions over the day. Starving over long periods is no longer advocated and feeding should start as soon as the animal can tolerate oral feeding. Re-feeding should start with highly digestible diet, three to four times daily in the first few days, with the original diet being gradually reintroduced. If the animal is anorectic, tube feeding (naso-oesophageal intubation) might be necessary. If dehydration is present, parenteral fluid is necessary supplemented with potassium chloride (10–30 mEq/l).

Antiemetics

Since most medical approaches to antiemetic therapy are based upon the neurotransmitter-receptor interactions, it is important to understand these mechanisms.

Figure 1

In the chemoreceptor trigger zone (CRTZ), several neurotransmitters and receptors have been found, including dopamine (D₂-dopaminergic), neurokinin₁ (NK₁), norepinephrine (α₂-adrenergic), 5-hydroxytryptamine (5-HT₃-serotonergic), acetylcholine (M₁-cholinergic), histamine (H₁ and H₂-histaminergic), and enkephalins (ENKδ-enkephalinergic). In the emetic center, the only receptors shown to be present so far are NK₁, 5-hydroxytryptamine_1A and α₂-adrenergic. The α₂-adrenergic receptors in the emetic center and in the CRTZ may be antagonized by α₂-antagonists (e.g., yohimbine, atipamezole) or by mixed α₁/α₂-antagonists (e.g., prochlorperazine, chlorpromazine). In the vestibular apparatus, muscarinic M₁- receptors and acetylcholine have been demonstrated, and therefore mixed M₁/M₂-antagonists (e.g., atropine, scopolamine) and pure M₁-antagonists, such as pirenzepine may inhibit motion sickness in dogs and cats. Many receptors are found in the gastrointestinal tract, but the NK₁, 5-HT₃ receptors are likely to play the most important role in the initiation of vomiting. Cytotoxic agents cause the release of 5-HT₃ from enterochromaffin cells in the gastrointestinal tract, which then activate the 5-HT₃ receptors on afferent vagal fibers. Thus, vomiting induced by 5-HT₃-receptor activation can be completely abolished by treating the patient with a 5-HT₃-antagonist, such as dolasetron, ondansetron, granisetron, or tropisetron. Another antagonist of 5-HT₃ is metoclopramide, but only in high concentrations. Recently, substance P has been found to result in emesis by binding to the NK₁-receptor. NK₁-receptor antagonists block central and peripheral vomiting both in dogs and ferrets. Several antiemetic drugs have been formulated based on the neurotransmitter-receptor system just mentioned (Table 1). These antagonists are classified as α₂-adrenergic, D₂-dopaminergic, NK₁, H₁-histaminergic, H₂-histaminergic, M₁-muscarinic cholinergic, 5-HT₃-serotonergic, and 5-HT₄-serotonergic. Some of these drugs have several mechanisms of action as antiemetics. For example, the phenothiazines (e.g., prochlorperazine, chlorpromazine) are antagonists of α₁- and α₂-adrenergic, D₂-dopaminergic, H₁- and H₂-histaminergic, and muscarinergic cholinergic receptors. They are very potent but should be avoided in dehydrated or hypotensive animals without previous fluid support. Also, these drugs are contraindicated in animals with a known seizure history. Metoclopramide blocks receptors in the CRTZ, increases the threshold in the emetic center, and also has an effect on the viscera. Metoclopramide increases the lower esophageal sphincter tone, decreases pyloric sphincter tone, and increases gastric and duodenal amplitude and contraction. This makes metoclopramide useful in controlling vomiting that is due to nonspecific gastritis or gastric motility disorders. The prokinetic activity of metoclopramide seems to be limited to the liquid phase of gastric emptying, as a study showed no effect on gastric emptying rate of digestible solids. Metoclopramide can be given orally, intravenously, or as a constant rate infusion.

A new NK₁ receptor antagonist, maropitant, has recently been licensed for dogs in many countries. In various studies, maropitant has been highly effective in abolishing vomiting induced through peripheral emetogenic stimuli (e.g., cisplatin) or central emetogenic stimuli (e.g., apomorphine). Furthermore, even travel-sickness-induced vomiting was successfully suppressed by maropitant.

Table 1. Antiemetic medications for dogs and cats

CTRZ= chemoreceptor trigger zone; PO = oral; SC = subcutaneous; IM = intramuscular; IV = intravenous