Metoclopramide has antiemetic effects via three mechanisms: (i) metoclopramide (at low doses) inhibits dopaminergic (DA₂) transmission in the CNS, similar to phenothiazines; (ii) metoclopramide has peripheral effects on the GI tract that increase emptying of the stomach and upper duodenum; (iii) metoclopramide (at high doses) inhibits serotonin (5-HT₃) receptors. 5-HT₃ stimulates vomiting in dogs and cats either in the CRTZ or vagal afferent neurons. Metoclopramide is a broad-spectrum antiemetic that has been popular in small animal medicine, particularly for animals that vomit because of drug therapy (e.g., cancer drugs) or gastrointestinal disease. However, for control of vomiting caused by cancer drugs the results have often been disappointing (Fukui et al., 1992). This drug is also discussed later in the section on prokinetic agents.

The pharmacology of serotonin and the antagonists are covered in more detail in Chapter 19. Specific serotonin antagonists include ondansetron (Zofran), granisetron (Kytril), palonosetron (Aloxi), and dolasetron (Anzemet). New drugs in development include tropisetron and azasetron. Of these, ondansetron (Zofran^®) is the best known to veterinarians of the specific serotonin (5-HT₃) inhibitors.

Ondansetron has been used to treat vomiting associated with cancer chemotherapy as well as nausea and vomiting caused by gastroenteritis, pancreatitis, and inflammatory bowel disease. In cats, the oral absorption was 32% from oral administration and 75% from subcutaneous administration. The half-life in cats was 1.8 hours from IV administration, 1.2 hours from oral administration, and more prolonged (3.2 hours) from subcutaneous administration. In dogs, it is much less bioavailable (<10%) after oral administration and shorter half-life of 30 minutes, raising questions about the clinical effectiveness of ondansetron in dogs.

The doses used for ondansetron are 0.5–1.0 mg/kg, IV or oral 30 minutes prior to administration of cancer drugs. For other diseases it has been administered at a dose of 0.1–0.2 mg/kg to dogs and cats and increased to 0.5 mg/kg if necessary, and given as often as every 12 hours. Because of concerns regarding oral absorption in dogs to obtain full effects, it should be administered intravenously. Other serotonin antagonists used for antiemetic therapy include granisetron, ondansetron, dolasetron, azasetron, and tropisetron.

As discussed in Section Metoclopramide (Reglan^®), metoclopramide at high doses of 1–3 mg/kg can act as a serotonin antagonist and have been used as an IV infusion during cancer chemotherapy to decrease vomiting; but adverse effects are more likely at these high doses.

Glucocorticoids such as dexamethasone have antiemetic properties, possibly by inhibiting prostaglandin synthesis. These drugs are used sometimes in addition to other drugs for decreasing vomiting, particularly when it is caused by cancer chemotherapy. Glucocorticoids are covered in more detail in Chapter 29.

Cannabinoids have been used in people who have not responded to any other antiemetic drugs (e.g., patients that are receiving anticancer drugs). The availability of medical marijuana and prescription forms of cannabinoids have increase the interest in the use in veterinary medicine. They have also been used to increase the appetite in human patients with terminal disease, cancer, and AIDS. Except for anecdotal accounts, the use has not been reported in veterinary patients. These agents have been used occasionally by some veterinarians to increase the appetite in cats, but these effects have been untested in clinical studies.

There are approximately 100 cannabinoids in the cannabis plant, but delta-9 tetrahydrocannabinol (Δ⁹-THC) is believed to be the most pharmacologically active. There are two important cannabinoid receptors: CB1 and CB2. The CB2 receptor is almost entirely peripheral and responsible for antiinflammatory and antinociceptive effects. The CB1 receptor is located centrally and is responsible for antinausea, psychoactive effects, appetite stimulation, and other central nervous system properties (Vemuri and Makriyannis, 2015). The effect on nausea and vomiting may occur from binding to the CB1 cannabinoid receptor in the emetic center.

The active ingredient in many cannabinoid products is Δ⁹-THC. Δ⁹⁻THC is a partial agonist for CB1 and CB2. Synthetic marijuana (THC) is available as a prescription drug (dronabinol) for antiemetic therapy; it is marketed as Marinol^®. Cannabinoids are relatively well tolerated in people, but side effects include drowsiness, dizziness, ataxia, and disorientation. Withdrawal signs may occur after abrupt discontinuation following repeated doses. For dronabinol, the oral absorption is good, but bioavailability is low due to high first-pass effects. The volume of distribution is very high.

Suggested doses for dronabinol (Marinol^®) in animals (but untested in clinical trials) are 5 mg/m², and increased as needed up to 15 mg/m² for antiemetic administration prior to chemotherapy. For appetite stimulation in animals, doses start at 2.5 mg before meals. It is available as 2.5, 5, and 10-mg capsules.

The neurotransmitter neurokinin-1 (NK-1, also known as substance P) has several functions that include regulating vascular tone and permeability, mucus production and bronchial tone in the respiratory tract, heart rate, and some activity in the central nervous system. The effects on the emetic center led to the development of a new class of antiemetics to antagonize this receptor. The first one approved for use in people for cancer chemotherapy-induced vomiting was aprepitant (Emend^®), which was the first substance P/neurokinin-1 (NK-1) receptor antagonist (Dando and Perry, 2004). The use of NK-1 receptor antagonists such as aprepitant in dogs was primarily experimental until the approval of a specific veterinary drug, maropitant citrate (Cerenia^®) (Wu et al., 2004; Watson et al., 1995; Huskey et al., 2004; Fukuda et al., 1999; de la Puente-Redondo et al., 2007a; Vail et al., 2007). This agent was approved for use in dogs in 2007, and later approved for cats in 2012. It is available as a 10 mg/ml injection to be administered 1 mg/kg once daily SC for up to 5 days, or a tablet 16, 24, 60, or 160 mg to be administered at a dose of 2 mg/kg per day, PO, for up to 5 days. The tablet can also be used to prevent vomiting caused by motion sickness (vestibulitis) at a dose of 8 mg/kg for up to 2 days. The dosing interval can also be extended to 14 days without significant accumulation as described below in Section Pharmacokinetic. The original approval for dogs and cats restricted injection of maropitant to the SC route. However, some patients may have a painful reaction to SC injection (discussed in Section Adverse Effects). Subsequently, the sponsor obtained FDA approval for intravenous route of administration in dogs and cats to prevent vomiting associated with anesthesia and medical procedures.

The efficacy of maropitant is attributed to its central site of action. It blocks neurokinin-1 (NK-1) receptors in the area of the brain called the nucleus tractus solitarius – the site known as the emetic center. Input into the emetic center may come from different sources: gastrointestinal tract, higher brain centers, CRTZ, and vestibular apparatus (motion sickness). These inputs also utilize a variety of neurotransmitters: dopamine, histamine, acetylcholine, and serotonin. Traditionally, to block emesis from these stimuli, multiple drugs may be needed: antihistamines, antidopamine drugs (e.g., metoclopramide), dopamine antagonists (e.g., phenothiazines), and serotonin antagonists (e.g., ondansetron). Because NK-1 inhibitors – such as maropitant – block input from multiple sources regardless of the input they are considered broad spectrum in action.

Mirtazapine is used more often as an appetite stimulant – especially in cats – but it also has antiemetic properties and is briefly discussed here and also included in Chapter 18, along with other appetite-stimulating drugs for cats. Mirtazapine is used as an antidepressant medication in people and is used to treat mood disorders. Its mechanism of action is unknown but it may enhance central noradrenergic and serotonergic activity. In animals it has appetite-stimulating and antinausea properties. These effects are attributed to the 5-HT₃ antagonist properties; therefore, it may share similar effects as antiserotonin medications discussed in Section Serotonin Antagonists.

Metoclopramide has multiple actions. It is a dopamine (DA₂) antagonist, serotonin (5-HT₄) agonist and serotonin (5-HT₃) antagonist. Among the proposed mechanisms of metoclopramide is an increase in the release of acetylcholine in the GI tract, possibly via a prejunctional mechanism. It also may increase motility of gastric smooth muscle by increasing sensitivity of the cholinergic response. Since it also is a dopamine antagonist, it may antagonize dopamine’s (DA₂) inhibitory action on GI motility.

Metoclopramide increases gastric emptying, increases the tone of the esophageal sphincter, and stimulates motility of the duodenum. It has less effect on distal segments of the intestine. Metoclopramide acts centrally to inhibit DA₂, which produces the antiemetic effects discussed in Section Antiemetic Drugs. In people, metoclopramide also has been used to treat hiccups and lactation deficiency.

Adverse effects from metoclopramide can include excitement (seen in horses, for example), anxiety, and involuntary muscle movements. There are also endocrine effects: There is a transient increase in prolactin and aldosterone. Since some breast cancers are prolactin-dependent, there has been some concern about the carcinogenicity of this drug in women.

Domperidone is a dopamine-2 receptor (DA₂) antagonist. It may also have α₁-receptor antagonist and serotonin (5-HT₂) antagonist effects. It has been available as a 10-mg tablet outside the USA as a human prokinetic drug but not allowed for human use in the USA because of cardiac toxicity. Its mechanism of action and GI prokinetic effects are similar to metoclopramide, but its efficacy has not been very impressive in animals and thus a clinical use has not been recommended (Whitehead et al., 2016). A difference between metoclopramide and domperidone is that the latter does not cross the blood–brain barrier. Therefore, adverse CNS effects are not as much of a problem compared to metoclopramide in horses. It may have antiemetic properties, but only if the stimulus for vomiting affects the CRTZ. It is capable of reaching the area postrema of the brain because this area is not protected by the blood–brain barrier. An additional effect is to stimulate lactation (see Section Use in Horses).

In July 2000, cisapride (formerly called Propulsid^®) was removed from the market because of serious cardiac adverse events, and some deaths in people, secondary to cardiac arrhythmias. The drug sponsor has no plans to market this drug to veterinarians, but there is continued interest among veterinarians and it is still available via compounding pharmacists. Until other new replacement drugs become available, such as prucalopride or mosapride, veterinarians will rely on compounded formulations or consider alternative drugs.

The reviews on cisapride by Washabau and Hall (1995) and Van Nueten and Schuurkes (1992) describe the details of its mechanism of action and clinical effects. Cisapride has greater prokinetic effects in comparison to the other drugs discussed thus far. Its mechanism is believed to be as an agonist for the 5-hydroxytryptamine (5-HT₄) receptor on myenteric neurons (5-HT₄ ordinarily stimulates cholinergic transmission in the myenteric neurons). (Serotonin and antagonists/agonists are covered in more detail in Chapter 19.) Cisapride may also be an antagonist for the 5-HT₃ receptor. Via these mechanisms – or independently – cisapride may enhance release of acetylcholine at the myenteric plexus. There is evidence that, in cats, cisapride directly stimulates smooth muscle motility via an unknown noncholinergic mechanism (Washabau and Summarco, 1996). Cisapride increases the motility of the stomach, increases stomach emptying, and increases motility of the small intestine and colon. It accelerates the transit of contents in the bowel and intestines. Because of the 5-HT₃ antagonist properties, it also has some antiemetic effects. Other drugs with a similar mechanism of action have been investigated, but are not in clinical use. One such drug is mosapride. Like cisapride, mosapride is also a 5-HT₄ agonist and has been approved in some countries for treating upper gastrointestinal motility disorders in dogs (Chae et al., 2015). It has been studied in experimental horses and demonstrated to increase motility of the small intestine and cecum at a dose of 1.5–2 mg/kg PO (Sasaki et al., 2005).

Many of the formulations of bethanechol have been discontinued and are no longer marketed. Some generic forms may still remain and veterinarians have also obtained it through compounding pharmacies. This drug is a cholinergic agonist that has been used to nonspecifically stimulate smooth muscle. It binds to muscarinic receptors and initiates GI smooth muscle contractions, but its actions are nonspecific. In contrast to cisapride or metoclopramide, bethanechol has a more pronounced effect on motility of the ileocecocolic region in cattle (0.7 mg/kg). In horses, bethanechol increases gastric emptying at a dose of 0.025 mg/kg IV (Ringger et al., 1996). One of its other uses has been to stimulate contraction of bladder smooth muscle in animals that have a failure to completely empty their urinary bladder when voiding. Adverse effects are common and include diarrhea and other consequences of cholinergic stimulation.

Neostigmine inactivates the enzyme acetylcholinesterase, which results in inhibition of degradation of acetylcholine at the synapse. It prolongs the action of acetylcholine and may directly stimulate cholinergic receptors. It is short acting. In horses, its use is discouraged because it may actually decrease intestinal propulsive contractions, delay gastric emptying, and cause abdominal discomfort.

One of the other uses of neostigmine in animals is for the treatment of neuromuscular diseases such as myasthenia gravis. Its adverse effects are significant, and include diarrhea, salivation, respiratory difficulty, vomiting, and muscle twitching. (Usually, another anticholinesterase drug, pyridostigmine, is preferred for treating myasthenia gravis because it has fewer side effects.)

H₂-receptor blockers such as ranitidine and nizatidine have prokinetic effects on intestinal smooth muscle in animals. These drugs are discussed later in Section Drugs for Treatment of Gastrointestinal Ulcers in Animals.

Erythromycin is a macrolide antibiotic ordinarily used to treat bacterial infections. Pharmacology of macrolides is discussed in Chapter 36. It has long been associated with vomiting and regurgitation in small animals as an adverse consequence of treatment. This effect is caused by stomach contraction and expulsion at high doses. However, at low doses it can produce a beneficial stimulation of GI motility. Not all macrolide antibiotics exhibit this property because it requires a unique chemical structure that not all drugs in this class possess. (Erythromycin has a 14 carbon structure, but other macrolides that are less effective – tylosin and tilmicosin – have a 16 carbon structure.)

Erythromycin stimulates GI motility via activation of motilin receptors, via release of endogenous motilin, or via cholinergic mechanisms in the upper GI tract (Hall and Washabau, 1997; Lester et al., 1998; Hawkyard and Koerner, 2007). Motilin is a 22 amino acid peptide released from endocrine cells of duodenal mucosa. It increases the motor contractions, the housekeeper wave, during the interdigestive period. Motility is stimulated specifically in the pyloric antrum or the smooth muscle cells of the proximal small intestine (Nouri and Constable, 2007; Nouri et al., 2008). Because most of the motilin receptors are on the stomach and proximal small intestine, there is a weak response to erythromycin in the distal GI tract. In people, erythromycin has been used to promote gastric motility and increase stomach emptying in patients with diabetic gastroparesis and used in conjunction with enteral feeding in critical care patients (Hawkyard and Koerner, 2007).

The effective dose is 1 mg/kg or less – much lower than the antibacterial dose. It was effective for stimulating motility in experimental horses (Ringger et al., 1996), but clinical responses to erythromycin in horses have been somewhat disappointing. One study showed that responses to erythromycin in horses that had undergone surgery were not as effective as the effects in healthy horses (Roussel et al., 2000). A dose of 8.8 mg/kg IM increased abomasal and rumen motility in calves (Nouri and Constable, 2007; Nouri et al., 2008; Wittek and Constable, 2005). The dose in small animals is also in the range of 0.5–1 mg/kg, but has not been tested for clinical efficacy (Whitehead et al., 2016). There is a concern that erythromycin may cause diarrhea in some horses through the effect on the normal bacterial flora of the intestine. An additional concern is that routine use may promote antibacterial resistance.

Lidocaine is a well-known local anesthetic. (Local anesthetics are covered in more detail in Chapter 15, and with antiarrhythmics in Chapter 22.) It is used for local infiltration for minor surgical procedures and to treat cardiac arrhythmias. Intravenous infusions of lidocaine also improve intestinal motility in horses. Lidocaine has been used in horses postsurgically to reduce postoperative ileus. Postoperative ileus in horses is a widespread clinical problem that may be caused by (i) sympathetic stimulation, (ii) pain, or (iii) inflammation. These effects inhibit smooth muscle motility in the intestine and lidocaine may work by suppressing this transmission. Another view on the mechanism is that lidocaine does not have a direct prokinetic effect, but rather restores motility via other mechanisms (Cook and Bilkslager, 2008). These authors presented evidence that in horses lidocaine restores motility by inhibiting intestinal inflammation and reperfusion injury.

In one study (Malone et al., 2006), lidocaine administration to horses produced less reflux and shorter time of hospitalization. Infusions of lidocaine have decreased postoperative ileus either through a direct effect, or via suppression of painful stimuli. Doses in horses are 1.3 mg/kg loading dose (bolus), followed by 0.05 mg/kg/min IV infusion.

Opiates and their antagonists are discussed in Chapter 13. Activation of opiate µ receptors in the intestinal smooth muscle decreases propulsive motility. Expression of µ-opiate receptors have been found in the submucosal plexus, myenteric plexus, and longitudinal muscle of the ileum. Activating these receptors has been used to treat some forms of diarrhea (e.g., loperamide). Administration of opiate analgesics postoperatively (Boscan et al., 2006; Sojka et al., 1988) or increased levels of endogenous opioids (endorphins), stimulate these receptors to inhibit intestinal motility causing postoperative ileus (DeHaven-Hudkins et al., 2008). Therefore, postoperative ileus may be treated by blocking intestinal opiate receptors (µ receptors) (Hicks et al., 2004).

Selective peripheral opiate antagonists act as peripheral opioid antagonists, rather than central opioid antagonists. They do not produce a central effect because they are unable to cross the blood–brain barrier. Naloxone should not be used for this indication because it will cross the blood–brain barrier to diminish the analgesic effect of opioids. Such agents include alvimopan, methylnaltrexone, and naloxegol.

Alvimopan (Entereg^®) has advantages over methylnaltrexone with respect to potency and duration of activity (DeHaven-Hudkins et al., 2008; Taguchi et al., 2001). It is administered orally with low bioavailability (6%) and produces a local effect on the intestine to promote motility, without diminishing analgesic effect of opioids. It is a zwitterionic molecule and the high polarity restricts its diffusion across the blood–brain barrier. A dose of 3 mg orally to people, three times daily completely reversed the GI effects of morphine, without affecting analgesia. The typical dose is 12 mg (one capsule) administered orally prior to surgery, and continuing after surgery twice daily.

Methylnaltrexone (Relistor^®) is available as a SC injection (0.15 mg/kg) administered once every 48 hours for postoperative ileus. Like alvimopan, it does not have systemic effects and will not interfere with analgesia. There has been limited use of methylnaltrexone in horses. At a dose of 0.75 mg/kg IV q 12 h for four days to horses inhibited morphine-induced intestinal effects (Boscan et al., 2006).

Naloxegol (Movantik^®), in 12.5 and 25-mg tablets, is a pegylated opioid antagonist. It is used for oral treatment of opioid-induced constipation. It acts peripherally because pegylation of the molecule reduces the ability of naloxegol to cross the blood–brain barrier and makes it a substrate for the efflux transporter P-glycoprotein.

The common antacids are bases of either aluminum, magnesium, or calcium. Examples include aluminum hydroxide (Al(OH)₃), magnesium hydroxide (Mg(OH)₂), and calcium carbonate (CaCO₃, e.g., Tums^®). These drugs neutralize stomach acid through a simple reaction to form water and a neutral salt. They have no systemic effects. In addition to their acid-neutralizing ability, antacids may benefit patients by decreasing pepsin activity, binding to bile acids in the stomach, and stimulating local prostaglandin (e.g., PGE₂) synthesis.