Pharmacologic Control of Vomiting
Todd R. Tams, DVM, Dipl. ACVIM
Pharmacologic Control of Acute Vomiting
Initial nonspecific management of vomiting includes NPO (in minor cases a 6-12 hour period of nothing per os may be all that is required), fluid support, and antiemetics. Drugs used to control vomiting will be discussed here.
The most effective antiemetics are those that act at both the vomiting center and the chemoreceptor trigger zone. Vomiting is a protective reflex and when it occurs only occasionally treatment is not generally required. However, patients that continue to vomit should be given antiemetics to help reduce fluid loss, pain and discomfort.
I strongly favor chlorpromazine (Thorazine), a phenothiazine drug, as the first choice for pharmacologic control of vomiting in most cases. Phenothiazine antiemetics have a broad spectrum effect and are effective in controlling vomiting due to a variety of causes. Chlorpromazine acts on the emetic center, chemoreceptor trigger zone, and on peripheral receptors. It is also thought to function as a calcium channel antagonist. This effect decreases cyclic AMP concentrations in intestinal epithelial cells which leads to decreased intestinal epithelial cell secretion. Further, chlorpromazine has minimal anticholinergic effects. The recommended dose is 0.1 to 0.25 mg/lb IM or SC SID - TID as needed to control vomiting. At this dose there is a minimal sedative effect. Any sedation resulting from use of chlorpromazine, unless pronounced, is not considered a deleterious side effect. patient comfort should always be a priority. Chlorpromazine is an excellent choice for control of nausea.
A potential side effect of phenothiazine drugs is hypotension which can result from an alpha-adrenergic blocking action, causing arteriolar vasodilation. This is a minor problem and it is readily controlled with intravenous fluid support.
If chlorpromazine is ineffective as an antiemetic, metoclopramide (Reglan), a gastric promotility drug that also has central antiemetic effect, can be used. Metoclopramide increases gastric and proximal small intestinal motility and emptying without causing acid secretion and provides inhibition of the chemoreceptor trigger zone. Parvovirus can cause gastric hypomotility and therefore the promotility effects of metoclopramide may prove beneficial. The recommended injectable dose is 0.1 to 0.2 mg/lb IM or SC given TID to QID as needed. Metoclopramide can also be given IV as a constant rate infusion (0.5 - 1.0 mg/lb over 24 hours). Chlorpromazine and metoclopramide are occasionally used together in dogs in which neither drug is effective in significantly reducing the frequency of vomiting when used alone. It is possible, however, that the combination may potentiate side effects that may result from use of either drug individually. Animals that are treated with a combination of chlorpromazine and metoclopramide are observed carefully for nervous-type behavior or significant depression. My preference at this time, if both chlorpromazine and metoclopramide are ineffective when given individually, or if there is severe vomiting that does not respond to whichever of these drugs is used first, is to institute ondansetron (Zofran) therapy (see later discussion).
Metoclopramide - Clinical Applications for Chronic Vomiting
Several clinical applications for use of metoclopramide in dogs with chronic vomiting have been identified. These include gastric motility disorders, gastroesophageal reflux disease (GERD), primary or adjunctive therapy for antral and pyloric mucosal hypertrophy, and as treatment for nausea and vomiting caused by various other disorders.
Gastric motility disorders are being recognized with increased frequency in veterinary medicine. Gastric stasis, characterized by abdominal discomfort, periodic bloating, borborhygmus, nausea and vomiting may be associated with a number of clinical states that include inflammatory disorders (e.g., chronic gastritis), gastric ulcers, gastroesophageal reflux, infiltrative lesions (e.g., neoplasia), and chronic gastric dilatation. Metabolic disturbances that may cause gastric stasis include hypokalemia, hypercalcemia, acidosis, anemia, and hepatic encephalopathy. Short-term continued vomiting that is observed in some cases after apparent recovery from viral enteritis may be due to abnormal gastric motility. Transient (3 to 14 days) gastric hypomotility may also occur after gastric or abdominal surgery. Motility disorders with no organic cause may be best classified as idiopathic. For any of the disorders listed, the primary cause should be treated, and metoclopramide may be a valuable short-term adjunct to therapy in these cases. Metoclopramide alternatively may be used as the primary treatment on a long-term basis for idiopathic hypomotility disorders. Metoclopramide has also been useful in treatment of dogs that have chronic vomiting characterized by episodes occurring routinely in the early morning and containing bilious fluid. In addition, metoclopramide's antiemetic action has proven quite effective in management of chemotherapy induced vomiting.
In general, patients less than 10 pounds receive 2.5 mg per dose, 11-40 pounds 5 mg per dose, and greater than 40 pounds 10 mg per dose. Metoclopramide is given 30 to 45 minutes before meals and again at bedtime. Animals that require chronic medication may need only 1 to 2 doses daily. Because of its short half-life, the drug is not effective when given by intravenous or intramuscular bolus injection for purposes other than when only one treatment would be administered (i.e., to aid in evacuating the stomach if an anesthetic procedure in a non-fasted patient becomes necessary, pre-radiologic contrast study). Subcutaneous administration into fat may be of benefit when oral therapy is contraindicated and an intravenous line is not available.
Metoclopramide is supplied as 5 and 10 mg tablets and as a cherry flavored liquid containing 5 mg/ml. Injectable metoclopramide is available in 2 ml single dose vials and in 10 ml multiple dose vials (5 mg/ml).
Some adverse effects may occur if metoclopramide is given in the usual therapeutic doses. Clients should be apprised of these before the medication is prescribed. These effects are uncommon.
Motor restlessness and hyperactivity may occur; and when observed, these signs usually begin 20 to 30 minutes after a dose and last 4 to 5 hours. Alternatively, drowsiness and depression occasionally occur. Side effects are infrequent in cats, but clients have reported disorientation, frenzied behavior, and hiding tendencies associated with the medication. These side effects are reversible (Benadryl 1 mg/lb IV or discontinuing the drug) but generally do not subside when lower doses are given. Unless side effects are infrequent, the use of metoclopramide should be discontinued if adverse reactions are seen.
In general, metoclopramide should not be given to epileptic patients. Other contraindications include evidence of significant mechanical obstruction, simultaneous use of anticholinergic agents (antagonism of metoclopramide's effects), and pheochromocytoma.
Ondansetron - Clinical Applications for Acute Vomiting
Ondansetron (Zofran, Glaxo Pharmaceuticals) is a potent new antiemetic drug that holds tremendous promise for use in both human and veterinary medicine. It has been used in human cancer patients undergoing cisplatin therapy, a drug that frequently causes nausea and severe vomiting, with dramatic results. Ondansetron acts as a selective antagonist of serotonin S3 receptors (a principal mediator of the emetic reflex). S3 receptors are found in both the gut in response to a variety of insults (e.g., chemotherapeutic agents, inflammation) from enterochromaffin cells to stimulate receptors in vagal and splanchnic afferent nerves that lead to the emetic center. The chemoreceptor trigger zone may be stimulated as well. High concentrations of serotonin S3 receptors have also been demonstrated in the area-postrema-nucleus tractus solitarii region of the medulla. The principal site of action of ondansetron is in the area postrema, but it also has some peripheral gastric prokinetic activity.
In my experience to date, ondansetron has produced dramatic results in either controlling or at least significantly decreasing the frequency of vomiting in dogs with severe parvovirus enteritis. The recommended dose is 0.05 to 0.08 mg/lb IV given as a slow push every 6 to 12 hours (based on patient response). Frequently dogs that appear quite distressed due to nausea and vomiting look much more relaxed and comfortable within 15 minutes of receiving ondansetron. There are no reports of any significant side effects such as diarrhea, sedation, or extrapyramidal signs in human and animal trials. Ondansetron is expensive (currently approximately $180.00 per 20ml multiple dose vial, concentration 2 mg/ml) and so it is not practical for frequent use in animal patients. However, its use should be considered in any patient with intractable vomiting.
Cisapride - The Newest GI Promotility Drug
Cisapride (Propulsid) is the newest GI prokinetic drug. A great deal of excitement has been generated about this drug because it has broader promotility effects than metoclopramide (e.g., cisapride has demonstrated excellent efficacy in management of colonic inertia). Cisapride is unique among prokinetic agents in that it does not have antidopaminergic properties. Whereas metoclopramide antagonizes the inhibitory effects of dopamine and can cross the blood-brain barrier, cisapride has no effect on the central nervous system. Cisapride is a benzamide derivative that promotes GI motility by increasing the physiologic release of acetylcholine from post ganglionic nerve endings of the myenteric plexus, leading to improved motor activity of the esophagus, stomach, small bowel, and large bowel. In contrast to metoclopramide, which has central effect a the CRTZ in addition to its peripheral effects, cisapride has no known direct antiemetic properties. The onset of pharmacologic action of cisapride is approximately 30 to 60 minutes after oral administration.
Cisapride increases lower esophageal pressure and lower esophageal peristalsis compared to placebo and/or metoclopramide. It significantly accelerates gastric emptying of liquids and solids. Small intestinal and colonic motor activity are also significantly enhanced. Cisapride has been approved for treating gastroesophageal reflux disease in humans, but it has also been shown to be effective in treating a variety of other conditions (e.g., gastroparesis, bile reflux gastritis, nonulcer dyspepsia, intestinal manifestations of systemic disorders, postoperative ileus, constipation, irritable bowel syndrome, and in diagnostic studies [radiographic studies, aid in duodenal intubation of motility and suction catheters]).
The most relevant uses of cisapride in animal patients include treatment of gastroparesis, especially in patients that experience significant side effects from metoclopramide (e.g., hyperactivity and other dystonic reactions), idiopathic constipation, gastroesophageal reflux disease (if H2-receptor antagonists and dietary management alone are not effective), and postoperative ileus.
In my experience to date, cisapride is extremely well tolerated by animal patients. I have used cisapride in dogs and cats that have experienced neurologic side effects from metoclopramide. I have observed no adverse reactions to cisapride in any of these patients, even in those whose side effects to metoclopramide included very bizarre behavior changes.
The suggested dose of cisapride is similar to what has been recommended for metoclopramide (0.1 - 0.25 mg/lb orally SID-TID depending on the clinical situation). In general, animals weighing 10 pounds or less receive 2.5 mg per dose, 11-14 pounds 5 mg per dose, and those over 40 pounds 10 mg per dose. The dose can be gradually increased if necessary. As is recommended for metoclopramide, cisapride should be administered no closer than 30 minutes before feeding. Injectable and oral suspension forms are not yet available in the United States.