Understand neurotransmitter receptor interactions to treat vomiting in dogs

Q: Please provide a quick review about various treatments available for the management and control of vomiting in dogs.

A: Initially, dietary restriction by withholding food for 24 hours is all that is needed for most acute vomiting situations in dogs of all ages. Depending on the severity of the clinical signs such as dehydration and continuous vomiting, the dog may need intravenous crystalloid solutions such as lactated Ringer's solution but no oral water.

Since most dogs with persistent vomiting are hypokalemic, potassium chloride needs to be supplemented based on measured serum potassium concentration - generally potassium chloride 20-40 mEq per liter of fluids administered. A bland commercially prepared or home-cooked diet given in small amounts multiple times during the day is indicated. The regular food can then be slowly reintroduced when vomiting has ceased.

In some dogs, symptomatic treatment with antiemetics is needed. Because medical approaches to antiemetic therapy are based on neurotransmitter-receptor interactions, it is important to understand these mechanisms.

Chemoreceptor trigger zone

In the chemoreceptor trigger zone (CRTZ), several neurotransmitters and (receptors) are present: dopamine (D2-dopaminergic), norepinephrine (a2-adrenergic), 5-hydroxytryptamine (5-HT3-serotonergic), acetylcholine (M1-cholinergic), histamine (H1-histaminergic and H2-histaminergic) and enkephalins (ENKd-enkephalinergic). In the emetic center, the only receptors identified so far are 5-hydroxytryptamine1A and a2-adrenergic receptors. The a2-adrenergic receptors in the emetic center and in the CRTZ may be antagonized by pure a2-adrenergic antagonists (e.g. yohimbine and atipamezole) or by mixed a1-/a2-adrenergic antagonists (e.g. prochlorperazine and chlorpromazine).

In the vestibular apparatus, muscarinic M1-cholinergic receptors and acetylcholine are present and, therefore, mixed M1/M2-cholinergic antagonists (e.g. atropine and scopolamine) and pure M1-cholinergic antagonists such as pirenzepine may inhibit a dog's motion sickness.

Many different types of receptors are found in the gastrointestinal tract, but the 5-HT3-serotonergic receptors are likely to play an important role in the initiation of the vomiting.

Cytotoxic agents used in cancer therapy cause the release of 5-hydroxytryptamine from enterochromaffin cells in the gastrointestinal tract, which then activates the 5-HT3-serotonergic receptors on afferent vagal fibers. Treating the dog with a 5-HT3-serotonergic antagonist, such as ondansetron, granisetron or tropisetron, may abolish this vomiting induced by 5-HT3-serotonergic receptor activation. Another 5-HT3-serotonergic antagonist is metoclopramide but only in high concentrations.

Classification

Several antiemetic drugs have been formulated based on the neurotransmitter-receptor system just mentioned (see Table 1). These antagonists are classified as: a2-adrenergic, D2-dopaminergic, H1-histaminergic, H2-histaminergic, M1-muscarinic cholinergic, 5-HT3-serotonergic, and 5-HT4-serotonergic.

Table 1: Antiemetic medication classification and dosages

The phenothiazines (e.g. prochlorperazine and chlorpromazine) are antagonists of a1-adrenergic, a2-adrenergic, D2-dopaminergic, H1- histaminergic, H2-histaminergic, and muscarinergic cholinergic receptors. phenothiazines are very potent but should be avoided in dehydrated and/or hypotensive dogs without previously administered fluid support, and they are contraindicated in dogs with a known history of seizures.

Metoclopramide blocks receptors in the CRTZ, increases the threshold in the emetic center, and has multiple effects on the viscera (increased lower esophageal sphincter tone, decreased pyloric sphincter tone, and increased gastric and duodenal amplitude and contraction). This makes metoclopramide useful in controlling vomiting caused by nonspecific gastritis or gastric motility disorder.

There are three serotonin antagonists on the market - Zofran (ondansetron)/Glaxo Wellcome; Kytril (granisetron)/SmithKline Beecham; and Anzemet (dolasetron)/Aventis.

Although there are slight differences in pharmacokinetics, bioavailability and potency, these serotonin antagonists all share the same mechanism of action and act on the same 5-HT3-serotonergic receptor site. At equivalent doses, these serotonin antagonists are considered therapeutically equivalent antiemetics and are the most expensive. Intravenous 5-HT3-serotonergic antagonists are roughly four times as expensive as the nearest comparative parenteral drug. For those dogs that are in the perioperative period - that is either prior to, during or immediately following surgery but are still in a critical situation - ondansetron may be used for the refractory nausea and vomiting situations. In addition, when metoclopramide is not effective in controlling the vomiting, then ondansetron may be the next most effective and safest drug to be administered.