Animals possess an arsenal of special abilities for survival, many of which are used for food consumption. Ingestion of food can expose internal organs to possible food-related disorders, including viral and bacterial infection, toxins, and allergens. Smell and taste are not always effective means of determining the quality of food, so nausea, vomiting, and diarrhea are additional mechanisms of defense of the GI system.
Humorally mediated emesis results from emetogenic substances in the systemic circulation that activate the chemoreceptor trigger zone (CRTZ) in the area postrema. The CRTZ lies outside the blood-brain barrier. Neurally mediated emesis results from activation of an afferent neural pathway typically coming from the abdominal viscera and synapsing at one or more nuclei in the emetic center. Most pharmacological interventions focus on the humoral pathway of emesis, based on neurotransmitter interactions at the CRTZ. The neural pathway has received less emphasis, even though it is a much more important pathway.
Nausea is an aversive experience that often accompanies emesis; it is a distinct perception different from pain or stress. Despite excellent control of drug-induced emesis in cancer chemotherapy, human patients still experience nausea. This fact suggests that nausea and vomiting are separate physiologic processes.
Motion-induced emesis appears to have an early evolutionary origin, considering that it is present in most animal models of emesis. Motion sickness is thought to result from sensory conflict regarding the body’s position in space, yet no theory satisfactorily explains why humans and animals have this mechanism in the first place.
Nausea and vomiting, as defense systems of the GI tract, by necessity must have a low threshold for activation. Chronic vomiting in cats may indicate underlying thyroid, liver, or kidney dysfunction and should be investigated. Dogs also vomit often (frequently after eating grass) and often eat their own vomit.
Neurotransmitters Involved in Emesis in Monogastric Animals
Acetylcholine (via muscarinic acetylcholine [M1] receptors) and substance P (via neurokinin-1 [NK-1] receptors) act on the emetic center. The CRTZ is stimulated by dopamine (via D2 receptors), alpha-2 adrenergic receptor agonists (via NE receptors), serotonin (via 5-HT3 receptors), acetylcholine (via M1 receptors), enkephalins, and histamine (via H1 and H2 receptors).
Alpha-adrenergic receptors in the CRTZ are important for inducing emesis in cats. Alpha-2 adrenergic receptor agonists (eg, xylazine) are more potent emetics in cats than in dogs.
5-HT1A receptor antagonists (eg, buspirone) and alpha-2 adrenergic receptor antagonists (eg, acepromazine, yohimbine, mirtazapine) suppress vomiting in cats.
D2 receptors in the CRTZ are not as important in mediating humoral emesis in cats as they are in dogs. Apomorphine, a D2 receptor agonist, is a more reliable emetic in dogs than in cats, and D2 receptor antagonists (eg, metoclopramide) are not very effective antiemetic drugs in cats.
H1 and H2 receptors are found in the CRTZ of dogs but not cats. Histamine is a potent emetic in dogs but not cats, and H1 receptor antagonists (eg, diphenhydramine) are ineffective for motion sickness in cats.
M1 receptors are found in the vestibular apparatus of cats. Mixed M1/M2 receptor antagonists (eg, atropine) inhibit motion sickness in cats.
Substance P binds to NK-1 receptors, which are found in the gut and the emetic center of the CNS. Substance P induces emesis, and selective substance P antagonists (eg, maropitant) are potent antiemetics in both dogs and cats, with a broad spectrum of activity against a variety of emetic stimuli.
Afferent Pathways for Emesis
The afferent pathways to the apparent emetic center include the following:
Gastrointestinal: Stimulation of visceral afferent nerves from the stomach and intestines due to irritation, inflammation, or distention. Vagal efferent and myenteric neurons initiate the complex excitation and inhibition of visceral smooth muscle (eg, retrograde duodenal and gastric contractions, relaxation of the caudal esophageal sphincter, gastroesophageal reflux, opening of the proximal esophageal sphincter, and evacuation of GI contents) that culminate in emesis. A number of receptors on myenteric neurons and GI smooth muscle cells regulate gastric emptying or intestinal transit, including 5-HT4 serotonergic, D2 dopaminergic, M2 cholinergic (smooth muscle), and motilin (smooth muscle in dogs only) receptors.
Pharyngeal: Direct stimulation of the pharynx, via the ninth cranial nerve.
Intracranial stimuli: Head trauma, intracranial pressure, or intrapsychic stimuli.
Vestibular: Stimulation of the vestibular apparatus with motion sickness or vestibulitis. Three neurotransmitters play important roles in the neural processes of motion sickness: histamine, acetylcholine, and norepinephrine.
Histaminic neurons and the CRTZ are involved in motion sickness in dogs. Therefore, antihistamines are useful for motion sickness in dogs.
M1 receptors and acetylcholine in the vestibular system and alpha-adrenergic receptors in the CRTZ are involved in motion sickness in the cat. Therefore, anticholinergic drugs are useful for motion sickness in cats.
Uremia: Emesis associated with uremia is due to stimulation of D2 receptors in the CRTZ by circulating uremic toxins and by uremic gastritis.
The humoral component of uremic vomiting is best treated by a D2 receptor antagonist (eg, metoclopramide).
The uremic gastritis is best treated with drugs that decrease gastric acid secretion (eg, H2 receptor antagonists or proton pump inhibitors).
Intoxication: Toxins or other drugs (eg, digoxin, chemotherapy drugs, and toxins) can directly stimulate the CRTZ because it is not protected by a complete blood-brain barrier.
Chemotherapy-induced emesis is mediated by activation of 5-HT3 receptors in the CRTZ of cats.
Chemotherapy appears to stimulate visceral and vagal 5-HT3 receptors in dogs.
5-HT3 receptor antagonists (eg, ondansetron) are effective at alleviating chemotherapy-induced emesis in dogs and cats; however, they do not completely eliminate nausea. Metoclopramide has some 5-HT3 receptor antagonist activity, but it is not as effective as the more selective drugs.
Emetic Drugs Used in Monogastric Animals
Emetic drugs are usually administered in emergency situations after ingestion of a toxin (see the table Emetic Drugs). They generally remove < 80% of the gastric contents. The most reliable emetic drugs act centrally to stimulate the vomiting center, either directly or via the CRTZ.
Emetic Drugs
Drug | Dosage |
|---|---|
Apomorphine | Dogs: 4 mg/kg, PO; 0.02 mg/kg, IV; 0.3 mg/kg, SC; 0.25 mg in the conjunctival sac |
Xylazine | Cats: 0.4–0.5 mg/kg, IV or IM |
Dexmedetomidine | Cats: 6–18 mcg/kg, IV or IM |
Hydrogen peroxide | Dogs: 5–10 mL, PO Cats: NOT RECOMMENDED |
Syrup of ipecac | NOT RECOMMENDED |
Sodium chloride (table salt) | NOT RECOMMENDED |
Powdered mustard | NOT RECOMMENDED |
Apomorphine is an opioid drug that acts as a potent central dopamine agonist to directly stimulate the CRTZ. Therefore, it is less effective in cats than in dogs. It can be administered PO, IV, or SC; the IM route is not as effective. It can also be applied directly to conjunctival and gingival membranes, using the tablet formulation, which can easily be removed once emesis is initiated. Vomiting usually occurs in 5–10 minutes.
Although apomorphine directly stimulates the CRTZ, it has a depressant effect on the emetic center. Therefore, if the first dose does not induce emesis, additional doses are not helpful. Because the vestibular apparatus may also be involved in apomorphine-induced vomiting, sedate and motionless animals will not vomit as readily as active animals. Excitement that results from apomorphine in cats can be treated with the opioid antagonist naloxone.
Xylazine and dexmedetomidine are alpha-2 adrenergic receptor agonists used primarily for their sedative and analgesic action. They are fairly reliable emetics in cats (~50% will vomit), where they stimulate the CRTZ. Emesis should occur in 5–10 minutes.
Because ablation of the CRTZ in cats eliminates emesis after xylazine administration, the emetic action in cats is known to require the CRTZ. Emesis induced by xylazine or dexmedetomidine can be blocked by administration of the alpha-2-adrenergic receptor antagonist yohimbine. Xylazine and dexmedetomidine can produce profound sedation and hypotension in small animals, and treated patients should be monitored.
Hydrogen peroxide (3%) applied to the back of the pharynx stimulates vomiting via the ninth cranial nerve. In dogs, small doses (5–10 mL) can be administered via oral syringe until emesis occurs. It should be administered cautiously, because aspiration of hydrogen peroxide foam results in severe aspiration pneumonia.
When small amounts are administered, 3% hydrogen peroxide is relatively safe; however, esophageal and gastric mucosal irritation may occur. Stronger concentrations (eg, hair dye peroxide) are more toxic.
Hydrogen peroxide is not recommended for emesis in cats due to the risk of severe hemorrhagic esophagitis and gastritis.
Other products have been used but are not recommended to induce emesis in dogs and cats. Syrup of ipecac is no longer recommended for home use in humans or animals. The active ingredient is emetine, a toxic alkaloid, which produces vomiting by acting as a stomach irritant. If repeated use fails to induce emesis, then gastric lavage is necessary to remove the emetine to prevent additional toxicosis. Although sometimes suggested, sodium chloride (table salt) and powdered mustard should not be used. Mustard is rarely effective and can be inhaled and result in lung damage, and salt toxicosis can easily occur in cases of overdose and can result in fatal cerebral edema.
Antiemetic Drugs Used in Monogastric Animals
Protracted vomiting is physically exhausting and can result in dehydration, acid-base and electrolyte disturbances, and aspiration pneumonia. Antiemetic drugs are used to control excessive vomiting after an etiologic diagnosis has been made, to prevent motion sickness and psychogenic vomiting, and to control emesis from radiation and chemotherapy (see the table Antiemetic Drugs). Antiemetics may act peripherally to decrease afferent input from receptors or to inhibit efferent components of the vomiting reflex response. They may also act centrally to block stimulation of the CRTZ and emetic center.
Antiemetic Drugs
Drug | Dosage |
|---|---|
Acepromazine | 0.025–0.2 mg/kg, IV, IM, or SC, as needed up to 3 mg; 1–3 mg/kg, PO, as needed |
Chlorpromazine | 0.5 mg/kg, IV, IM, or SC, q 6–8 h |
Prochlorperazine | 0.1 mg/kg, IM, q 6–8 h; 1 mg/kg, PO, q 12 h |
Aminopentamide | 0.022 mg/kg, PO, SC, or IM, q 8–12 h |
Dimenhydrinate | 4–8 mg/kg, PO, q 6–8 h |
Diphenhydramine | 2–4 mg/kg, PO, q 6–8 h |
Butorphanol* | 0.2–0.4 mg/kg, IM, q 12–24 h |
Metoclopramide | 0.1–0.5 mg/kg, IM, SC, or PO, q 6–8 h; 0.01–0.02 mg/kg/h, IV infusion |
Ondansetron | 0.1–0.2 mg/kg, PO, q 12–24 h; 0.1–0.15 mg/kg, IV, q 8–12 h |
Granisetron | 0.5–1 mg/kg, PO, q 12 h; 0.1–0.15 mg/kg, IV, q 8–12 h |
Dolasetron | 0.6–1 mg/kg, IV, q 24 h |
Maropitant | For acute vomiting: 2 mg/kg, PO, or 1 mg/kg, SC, q 24 h (acute vomiting); 8 mg/kg/day, PO, for up to 2 days (motion sickness) For motion sickness: 8 mg/kg, PO, q 24 h for up to 2 d |
*Dogs with ABCB1 polymorphism may be predisposed to adverse events |
Phenothiazine tranquilizers are alpha-1-adrenergic receptor antagonists that antagonize the CNS stimulatory effects of dopamine and decrease vomiting due to a variety of causes, including opioid administration and motion sickness in cats. Phenothiazines also have antihistaminic and weak anticholinergic action. Phenothiazine tranquilizers used as antiemetics include acepromazine, chlorpromazine, and prochlorperazine. Acepromazine is ineffective as an antiemetic or for motion sickness in cats.
Potential adverse effects include hypotension due to alpha-adrenergic blockade, excessive sedation, and extrapyramidal signs. Extrapyramidal signs can be counteracted with an antihistamine (eg, diphenhydramine).
Pearls & Pitfalls
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Anticholinergic drugs block cholinergic afferent pathways from the GI tract and the vestibular system to the vomiting center. Alone, they are less effective than the other emetics. Aminopentamide is approved for use in dogs and cats in the US as an injectable formulation and as oral tablets. Given that M1 receptors are found in the vestibular apparatus of cats, it should be more efficacious in the treatment of motion sickness in cats than in dogs. Aminopentamide has low efficacy for other causes of vomiting.
Antihistamines can block both cholinergic and histaminic nerve transmission of the vestibular stimulus to the vomiting center of dogs. The commonly used H1 receptor antagonists are diphenhydramine and dimenhydrinate (diphenhydramine plus 8-chlorotheophylline). They may produce mild sedation, especially diphenhydramine; however, paradoxical CNS stimulation may also occur, presumably from anticholinergic effects.
Metoclopramide exerts its antiemetic effects via several mechanisms. At low doses, it inhibits dopaminergic transmission in the CNS. At high doses, it inhibits serotonergic receptors in the CRTZ. Peripherally, it increases gastric and upper duodenal emptying.
Metoclopramide is a useful antiemetic for dogs. It is less effective in cats because D2 receptors in the CRTZ are not very important in mediating humoral emesis in cats.
Metoclopramide is used to control emesis induced by chemotherapy, nausea and vomiting associated with delayed gastric emptying, reflux gastritis, and viral enteritis.
There is tremendous individual variability in metoclopramide pharmacokinetics, and oral bioavailability is only ~50% because of an important first-pass effect. At high doses or with rapid IV administration, metoclopramide excites the CNS through dopaminergic receptor antagonism (similar to the action of phenothiazine tranquilizers). Extrapyramidal signs can be counteracted with an antihistamine such as diphenhydramine.
Because of its prokinetic effects, metoclopramide should not be administered if a GI obstruction or perforation is suspected.
The serotonergic receptor antagonists ondansetron, granisetron, and dolasetron are specific inhibitors of 5-HT3 receptors in the CRTZ. These receptors are located peripherally on vagal nerve terminals and centrally in the area postrema of the brain. Cytotoxic drugs and radiation damage the GI mucosa, causing the release of serotonin.
Serotonergic receptor antagonists are the most effective antiemetics used in humans undergoing radiation and chemotherapy, and they have been used in cats and dogs receiving chemotherapy as well. Although effective at controlling vomiting associated with chemotherapy and drug-induced vomiting, serotonergic receptor antagonists do not prevent or relieve nausea, which may be more debilitating than vomiting. They are also not effective for emesis due to motion sickness.
All 5-HT3 receptor antagonists have been associated with prolongation of the Q–T interval in humans. Adverse effects of dolasetron include ECG changes (P–R and Q–T prolongation, QRS widening) due to sodium channel blockade by dolasetron metabolites.
Butorphanol is an effective antiemetic for dogs receiving cisplatin chemotherapy. It produces only mild sedation. It is believed to exert its antiemetic effect directly on the vomiting center.
Maropitant is a neurokinin-1 (NK-1) receptor antagonist approved to treat and prevent emesis in dogs and cats. Substance P is a regulatory peptide that binds to the NK-1 receptors and induces emesis. NK-1 receptor antagonists are believed to provide antiemetic activity by suppressing activity at the nucleus of the solitary tract, where vagal afferents from the GI tract converge with inputs from the CRTZ and other regions of the brain involved in the control and initiation of emesis.
Despite its selectivity for the NK-1 receptor, maropitant blocks vomiting induced by apomorphine, cisplatin, or syrup of ipecac in dogs, suggesting that activation of the nucleus of the solitary tract is a final common step in the initiation of emesis. Despite being effective antiemetics in humans, NK-1 receptor antagonists do not completely alleviate chemotherapy-associated nausea or hydromorphone-induced nausea in dogs.
Injectable maropitant is approved as treatment for vomiting in cats ≥ 16 weeks old and for acute vomiting in dogs ≥ 8 weeks old at 1 mg/kg every 24 hours. Maropitant tablets are approved to treat acute vomiting in dogs ≥ 8 weeks old (2 mg/kg, PO, every 24 hours), and to prevent vomiting due to motion sickness in dogs ≥ 16 weeks old (8 mg/kg, PO, every 24 hours). Dogs should not be fed for 1 hour before maropitant is administered. The best time to give maropitant is 2 hours before traveling, with a small amount of food.
Adverse effects are rare with maropitant; the most common adverse effects are excessive drooling, lethargy, lack of appetite, and diarrhea. Maropitant injections may also produce a stinging sensation, which can be minimized by keeping the injectable solution refrigerated and, once the drug is drawn up, immediately injecting it at the refrigerated temperature.
Some dogs may vomit immediately after being administered maropitant by mouth; administering maropitant with a small amount of food will help lessen this reaction. The tablets should not be wrapped tightly in fatty food (eg, cheese or meat), which may prevent the tablets from dissolving and delay the drug's effect.
