Approach to Vomiting

Vomiting is a complex reflex act that can result from a number of conditions. Depending on the underlying cause of vomiting, anti-emetic drugs may be indicated. Understanding the vomiting reflex and mechanism of action of various drugs will allow the clinician to select the appropriate drug. Vomiting must be distinguished from regurgitation and gastrooesophageal reflux. The best way to determine this is to imitate the two acts for the client, emphasising the repetitive abdominal contractions seen in the vomiting patient. The timing of the event with respect to eating, the volume of material brought up, or contents (unless it contains bile, suggesting true vomiting) do not reliably distinguish vomiting from regurgitation. Vomiting is a reflex act that includes abdominal contractions and prodromal signs, including behavioural changes, salivation and repeated swallowing attempts. It must be emphasised that these signs are variable. Complications of vomiting include aspiration pneumonia, malnutrition, electrolyte imbalances, acid-base disturbances and dehydration. In most cases it is helpful to establish a definitive diagnosis, but this is not always necessary or possible.

Vomiting Reflex

The vomiting reflex begins with afferent receptors located in visceral organs (including gastrointestinal tract, pancreas, heart, liver, genitourinary tract and peritoneum) and pharynx. Afferent impulses travel through the vagus and sympathetic nerves to the vomiting centre located in the medulla. Vomiting can also be initiated by stimulation of the chemoreceptor trigger zone (CRTZ) located in the area postrema. The CRTZ is sensitive to blood-borne substances. The vomiting reflex can also be initiated by input from the cerebral cortex (rare in animals vs. humans) and from the vestibular apparatus (i.e., motion sickness). Thus, vomiting can be initiated through a 'humoral' pathway, caused by blood-borne substances stimulating the CRTZ, or a 'neural' pathway, caused by stimulation of the vomiting centre from vagosympathetic, CRTZ, vestibular or cerebral neurons. Examples of vomiting caused by activation of the humoral pathway include chemotherapy drugs, digitalis, uraemic toxins and apomorphine. Examples of vomiting caused by activation of the neural pathway include gastroenteritis, pancreatitis, peritonitis, motion sickness and emotions (cerebral input). Several neurotransmitters and their respective receptors stimulate the CRTZ. Figure 1 gives a list of the neurotransmitters and their respective receptors.

Figure 1. Neurotransmitters and their respective receptors.

In the dog, dopamine, substance P and histamine are significant neurotransmitters in the CRTZ, whereas these are much less important in the cat (though less is known about substance P). Therefore metoclopramide (a D₂-dopaminergic antagonist) is less effective in the cat for control of vomiting, and apomorphine (a D₂-dopaminergic agonist) is less emetogenic in the cat. On the other hand, α₂-adrenergic and 5-HT₃-serotonergic receptors are more important in the CRTZ in the cat versus the dog. Therefore xylazine (an α₂-adrenergic agonist) is emetogenic in the cat versus the dog, and ondansetron (a 5-HT₃-serotonergic antagonist) helps prevent vomiting mediated through the CRTZ in the cat (whereas this agent works peripherally in the dog).

In the emetic centre, α₂-adrenergic receptors are the most clinically important. Therefore, pure α₂-receptor antagonists (such as yohimbine) and mixed α₁-and α₂-receptor antagonists (such as prochlorperazine) are effective anti-emetics. It is likely that much of the anti-emetic effects of phenothiazine drugs act through inhibiting α-receptors in the CRTZ.

The most important peripheral receptor mediating vomiting in the dog is the 5-HT₃-serotonergic receptor. Activation of this receptor can occur through inflammation of the gut, luminal distention, toxins, chemotherapy agents, etc. Antagonists of the 5-HT₃-serotonergic receptor (such as ondansetron) help abolish vomiting by this mechanism. Motility modification through peripheral receptor effects can also control vomiting. Antagonism of D₂-dopaminergic receptors with metoclopramide will increase gastric emptying and proximal intestinal motility in the dog and cat. Activation of 5-HT₄-serotonergic receptors with cisapride will increase propulsive gastrointestinal motility from the lower oesophageal sphincter to the colon. Activation of motilin receptors will also improve gastric emptying during the fasting state. This can be accomplished with low dose erythromycin (0.5-1.0 mg/kg orally or i.v. q8h).

Control of Vomiting

Control of vomiting can be accomplished with so called broad-spectrum drugs (i.e., acting at the level of the vomiting centre or at several sites in the vomiting reflex) or narrow-spectrum drugs (acting at a specific site in the vomiting reflex). For example, phenothiazines are effective drugs through inhibition of the vomiting centre and CRTZ. Antihistamines inhibit the CRTZ and the vestibular apparatus. Maropitant, a new NK-1 receptor antagonist, is effective in both the vomiting centre and CRTZ. An excellent review of antiemetic therapy written by Robert Washabau and Marc Elie outlined a classification of antiemetic drugs. An excerpt of this classification is below:

Α₂-Adrenergic Antagonists

 Prochlorperazine (Compazine®) 0.5 mg/kg q8h, s.c., i.m., rectal suppository

 Chlorpromazine (Thorazine®) 0.2-0.4 mg/kg q8h s.c., i.m.

 Yohimbine (Yobine®) 0.25-0.5 mg/kg q12h s.c., i.m.

NK-1 Receptor Antagonists

 Maropitant (Cerenia®) 1 mg/kg q24h s.c., orally

D₂-Dopaminergic Antagonists

 Metoclopramide (Reglan®) 0.2-1 mg/kg q6h orally, s.c., i.m.; CRI @ 2-4 mg/kg/day

 Domperidone (Motilium®) 0.1-0.3 mg/kg q12h i.m., i.v.

 Prochlorperazine (Compazine®) 0.5 mg/kg q8h, s.c., i.m., rectal suppository

 Chlorpromazine (Thorazine®) 0.2-0.4 mg/kg q8h s.c., i.m.

H₁-Histaminergic Antagonists

 Diphenhydramine (Benadryl®) 2-4 mg/kg q8h orally, i.m.

 Dimenhydrinate (Dramamine®) 4-8 mg/kg q8h orally

 Prochlorperazine (Compazine®) 0.5 mg/kg q8h, s.c., i.m., rectal suppository

 Chlorpromazine (Thorazine®) 0.2-0.4 mg/kg q8h s.c., i.m.

M₁-Muscarinic Cholinergic Antagonists

 Scopolamine (Hyoscine®) 0.03 mg/kg q6h s.c., i.m.

 Prochlorperazine (Compazine®) 0.5 mg/kg q8h, s.c., i.m., rectal suppository

 Chlorpromazine (Thorazine®) 0.2-0.4 mg/kg q8h s.c., i.m.

5-HT₃-Serotonergic Antagonists

 Ondansetron (Zofran®) 0.5-1 mg/kg q12h orally, or 30 minutes prior to chemotherapy, or 0.1-0.5 mg/kg q12h i.v.

 Dolasetron (Anzemet®) 0.5-1 mg/kg q12h orally, or 30 minutes prior to chemotherapy, or 0.1-0.5 mg/kg q12h i.v.

 Granisetron (Kytril®) No dose available

 Metoclopramide (Reglan®) 0.2-1 mg/kg q6h orally, s.c., i.m.; CRI @ 2-5 mg/kg/day

5-HT₄-Serotonergic Agonists

 Cisapride (Propulq24h®) 0.5-1 mg/kg q8h orally, or 1-1.5 mg/kg q12h orally

 Tegaserod (Zellnorm®) 0.25-0.5 mg/kg q8-12h orally?

Motilin Agonists

 Erythromycin 0.5-1 mg/kg q8h orally, i.v.

Specific Syndromes To Use Anti-Emetics

Motion Sickness

Motion sickness is stimulated by receptors in the inner ear. The CRTZ mediates the pathway in the dog, but not in the cat. The most important receptors mediating vomiting in patients with motion sickness are M₁-cholinergic and H₁-histaminergic receptors. Therefore, treatment should involve antagonists of these two receptors. Antagonists of M₁-cholinergic receptors include scopolamine and prochlorperazine/chlorpromazine (mainly cats). Antagonists of H₁-histaminergic receptors include diphenhydramine and dimenhydrinate. Since histamine is not an important mediator of vomiting in cats, and histamine receptors are not present in the CRTZ of cats, antihistamines are usually ineffective in this species. Rather, chlorpromazine and prochlorperazine are more appropriate drugs. Maropitant is also effective for motion sickness at higher doses.

Uraemia

Vomiting in uraemic patients is initiated through both central and peripheral pathways. Central pathways are mediated through the effect of blood-borne uraemic toxins on the CRTZ. There is primarily stimulation of D₂-dopaminergic receptors (mainly dogs, not cats), and treatment should be with D₂-dopaminergic receptor antagonists such as metoclopramide or chlorpromazine/prochlorperazine. Maropitant is also effective for uraemia-induced vomiting. Peripheral pathways are mediated through the effect of uraemic toxins on the gastrointestinal mucosa, resulting in erosions/ ulcers and uraemic gastritis. Therefore treatment should be directed towards gastroprotective agents such as drugs that inhibit gastric acid production (H₂-histaminergic receptor antagonists and proton pump inhibitors such as omeprazole) and drugs that act locally on the gastric mucosa (such as sucralfate).

Drug-Induced Vomiting

Many drugs can induce vomiting. These include a variety of chemotherapy drugs, digitalis and a variety of antibiotics. These drugs may either stimulate receptors in the CRTZ or peripheral receptors. Chemotherapy drugs in particular stimulate 5-HT₃-serotonergic receptors and NK-1 receptors. Maropitant and 5-HT₃-receptor antagonists seem to be very effective for chemotherapy-induced nausea.

Gastrointestinal Motility Disorders

Vomiting induced by gastrointestinal motility disorders should be treated with prokinetic agents. Non-specific stimulators of motility with cholinergic agents are ineffective. Cisapride is the most effective prokinetic agent, stimulating gastrointestinal motility from the lower oesophageal sphincter to the colon (through stimulation of 5-HT₄-serotonergic receptors). Cisapride has minimal direct anti-emetic effects. Metoclopramide is useful to stimulate motility of the lower oesophageal sphincter, stomach and duodenum (through stimulation of D₂-dopaminergic receptors). It is therefore useful for delayed gastric emptying. Metoclopramide has minimal effect on the remainder of the intestine due to the lack of D₂-dopaminergic receptors beyond the duodenum. Erythromycin may also be useful for delayed gastric emptying due to its effect of stimulating motilin receptors. When used for this purpose, it should be given at low doses (0.5-1 mg/kg q8h), much lower than doses used for antibacterial purposes. At the latter doses, erythromycin can cause vomiting. When any of these drugs are used for delayed gastric emptying, they should be given 30 minutes prior to eating. These drugs are also used to treat dogs that vomit bile in the morning prior to eating ('bilious vomiting syndrome').

References

1.  Washabau RJ, Elie MS. Antiemetic therapy. In: Bonagura, JD; Kirk RW. eds. Kirk's Current Veterinary Therapy XII. Philadelphia: WB Saunders, 1995: 679-684.