Drugs to Control or Stimulate Vomiting (Monogastric)
Animals possess an arsenal of special abilities for survival, many of which are used for food consumption. Ingesting food can lead to exposure of internal organs to possible food-related disorders, including viral and bacterial infection, toxins, and allergens. Smell and taste are not always effective in 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 pharmacologic 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. Nausea is more difficult to treat than emesis using antiemetic drugs. This became apparent with the excellent control of drug-induced emesis from cancer chemotherapy, but human patients still experience nausea. This suggests that nausea and vomiting are separate physiologic processes.
Motion-induced emesis appears to have a very early evolutionary origin, because 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 there is no satisfactory theory as to why people 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. Cats are well known for their tendency to vomit, particularly when attempting to dislodge hairballs from the throat or upper GI tract. 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.
Acetylcholine (muscarinic receptors) and substance P (NK-1 receptors) act on the emetic center. The CRTZ is stimulated by dopamine (D2 receptors), α2-adrenergic drugs (NE receptors), serotonin (5-HT3 receptors), acetylcholine (M1 receptors), enkephalins, and histamine (H1 and H2 receptors).
α-Adrenergic receptors in the CRTZ are important in inducing emesis in cats. α2-Adrenergic agonists (eg, xylazine) are more potent emetics in cats than in dogs.
5-HT1A antagonists (eg, buspirone) and α2-adrenergic antagonists (eg, acepromazine, yohimbine, mirtazapine) suppress vomiting in cats.
CRTZ D2 dopamine receptors are not as important in mediating humoral emesis in cats as they are in dogs. Apomorphine, a D2 dopamine receptor agonist is a more reliable emetic in dogs than cats, and D2 dopamine receptor antagonists (eg, metoclopramide) are not very effective antiemetic drugs in cats.
Histamine 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 antagonists (eg, diphenhydramine) are ineffective for motion sickness in cats.
Muscarinic M1 receptors are found in the vestibular apparatus of cats. Mixed M1/M2 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.
Emetic drugs are usually administered in emergency situations after ingestion of a toxin (see Emetic Drugs). They generally remove <80% of the stomach contents. The most reliable emetic drugs act centrally to stimulate the vomiting center, either directly or via the CRTZ.
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 min. 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 is an α2-adrenergic agonist used primarily for its sedative and analgesic action. It is a reliable emetic, particularly in cats, in which it stimulates the CRTZ. Because xylazine can produce profound sedation and hypotension, animals should be closely monitored after administration.
Hydrogen peroxide (3%) applied to the back of the pharynx stimulates vomiting via the ninth cranial nerve. Small doses (5–10 mL) of hydrogen peroxide can be administered via oral syringe until emesis occurs. It should be administered cautiously, especially in cats, because aspiration of hydrogen peroxide foam causes severe aspiration pneumonia. When small amounts are administered, 3% hydrogen peroxide is relatively nontoxic. Stronger concentrations (eg, hair dye peroxide) are more toxic.
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 people 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 (salt) and powdered mustard should not be used. Mustard is rarely effective and can be inhaled and cause lung damage, whereas salt toxicity can easily occur if overdosed and can result in fatal cerebral edema.
Protracted vomiting is physically exhausting and can cause dehydration, acid-base and electrolyte disturbances, and aspiration pneumonia. Antiemetic drugs are used to control excessive vomiting once an etiologic diagnosis has been made, to prevent motion sickness and psychogenic vomiting, and to control emesis from radiation and chemotherapy (see Antiemetic Drugs). Antiemetics may act peripherally to reduce 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.
The phenothiazine tranquilizers are α2-adrenergic antagonists and antagonize the CNS stimulatory effects of dopamine and decrease vomiting from a variety of causes, including motion sickness in cats. These drugs also have antihistaminic and weak anticholinergic action. Phenothiazine tranquilizers used as antiemetics include acepromazine, chlorpromazine, and prochlorperazine. Potential adverse effects include hypotension due to α-adrenergic blockade, excessive sedation, extrapyramidal signs, and a lowering of the seizure threshold in animals with epilepsy. Extrapyramidal signs can be counteracted with an antihistamine (eg, diphenhydramine).
The 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 USA as an injectable formulation and oral tablets. It should be more efficacious in the treatment of motion sickness in cats than in dogs, because muscarinic M1 receptors are found in the vestibular apparatus of cats. Aminopentamide has low efficacy for other causes of vomiting.
The antihistamines can block both cholinergic and histaminic nerve transmission responsible for transmission of the vestibular stimulus to the vomiting center of dogs. The commonly used histamine (H1) blocking drugs are diphenhydramine and dimenhydrinate (diphenhydramine plus 8-chlorotheophylline). They may cause mild sedation, especially diphenhydramine, but paradoxical CNS stimulation may also occur, presumably from anticholinergic effects.
Metoclopramide exerts its antiemetic effects via three mechanisms. At low doses, it inhibits dopaminergic transmission in the CNS, whereas at high doses, it inhibits serotonin receptors in the CRTZ. Peripherally, metoclopramide increases gastric and upper duodenal emptying. Metoclopramide is a useful antiemetic for dogs. Because CRTZ D2 dopamine receptors are not very important in mediating humoral emesis in cats, metoclopramide is less effective in cats than in dogs. It 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 a significant first-pass effect. At high doses or with rapid IV administration, metoclopramide causes CNS excitement by dopamine antagonism (similar to the phenothiazine tranquilizers). Extrapyramidal signs can be counteracted with an antihistamine such as diphenhydramine. Metoclopramide should not be administered if a GI obstruction or perforation is suspected.
The serotonin antagonists ondansetron, granisetron, and dolasetron are specific inhibitors of serotonin subtype 3 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 release of serotonin. These are the most effective antiemetics used in people undergoing radiation and chemotherapy, and they have been used in cats and dogs receiving chemotherapy. Although very effective at controlling vomiting associated with chemotherapy and drug-induced vomiting, these drugs do not prevent or relieve nausea, which may be more debilitating than vomiting. They are not effective for emesis caused by motion sickness. All serotonin subtype 3 antagonists have been associated with prolongation of the QT interval in people. Adverse effects of dolasetron include ECG changes (PR and QT prolongation, QRS widening) caused by dolasetron metabolites that block sodium channels.
Butorphanol is an effective antiemetic for dogs receiving cisplatin chemotherapy. It causes 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 apomorphine, cisplatin, and syrup of ipecac–induced vomiting in dogs, which suggests that activation of the nucleus of the solitary tract is a final common step in the initiation of emesis. Despite being very effective antiemetics in people, NK-1 receptor antagonists have little effect on chemotherapy-associated nausea in people or hydromorphone-induced nausea in dogs.
Maropitant injectable is approved for vomiting in cats ≥16 wk old and acute vomiting in dogs ≥8 wk old at 1 mg/kg/day. Maropitant tablets are approved for acute vomiting in dogs ≥8 wk old (2 mg/kg), and to prevent vomiting due to motion sickness in dogs ≥16 wk older (8 mg/kg). Dogs should not be fed for 1 hr before giving maropitant. The best time to give maropitant is 2 hr before travelling, with a small amount of food. The tablets should not be wrapped tightly in fatty food such as cheese or meat, because this may keep the tablets from dissolving and delay the effect of maropitant.
Adverse effects are rare with maropitant, but the most common ones are excessive drooling, lethargy, lack of appetite, and diarrhea. Maropitant injections may also cause a stinging sensation; this can be minimized by keeping the injectable solution refrigerated and, once the drug is drawn up, injecting right away at the refrigerated temperature. A few dogs may vomit after treatment. Giving maropitant with a small amount of food will help avoid this.