David C. Twedt, DVM, DACVIM
Nausea and vomiting are common clinical complaints and anti-emetics may play an important part in the management of many of these cases. However, the primary objective should always be first to identify the underlying etiology and if possible treat that primary disorder. Antiemetics are indicated when vomiting is severe resulting in dehydration, electrolyte loss and acid base disturbances and for the prevention of motion sickness. Additionally, antiemetics should be used for prevention of aspiration pneumonia, vomiting associated with radiation or chemotherapy, management of nausea resulting in inadequate nutritional intake and to enhance patient comfort.
Antiemetics work either peripherally, centrally or in both areas.1 Understanding the basic receptors involved in vomiting provides the rational for selection of an appropriate antiemetic drug. Vomiting is simply best described as a reflex act that is initiated by stimulation of the conceptualized "vomiting center" located in the medulla oblongata of the brain. Activation of the vomiting center occurs either through a humoral pathway initiated via blood-borne substances or by activation through various peripheral neural pathways leading to the vomiting center. Neural stimulation of the vomiting center arises through either afferent vagal, sympathetic, vestibular and cerebrocortical pathways. Activation of peripheral receptors found throughout the body can stimulate these neural pathways. Particularly important are receptors that are located throughout the abdominal viscera. Central nervous system (CNS) disease may directly stimulate the vomiting center such as direct extension of inflammatory stimuli, hydrocephalus or space occupying lesions. The vomiting center is stimulated indirectly via a humoral pathway by activating the chemoreceptor trigger zone (CRTZ) located in the area postrema at the base of the fourth ventricle an area devoid of a blood brain barrier that allows exposure to chemical stimuli found in the circulation. Blood-borne substances stimulating the CRTZ include certain drugs, uremic toxins, electrolyte, osmolar and acid-base disorders as well as a number of metabolic derangements. There is also evidence in the dog that vestibular stimulation passes through the CRTZ before activating the vomiting center. Motion sickness, inflammation of the labyrinth or lesions in the cerebellum result in vomiting via this pathway.
Dopamine (D2) receptors are abundant in the area postrema of the brain (CRTZ) and act as excitatory transmitter on neurons. Dopamine receptors have been implicated in chemotherapy induced emesis.1 Histamine H1 and muscarinic cholinergicreceptors have been identified in the nucleus tractus solitarii located in the medulla oblongata.Antagonists of histamine and acetylcholine have proved usefulin treating emesis associated with motion sickness. Cholinergic receptors are also thought to be associated with the CRTZ. Three types of serotonin receptors(5-hydroxytryptamine, or 5HT) have been identified. One ofthese, the type 3 (5HT3) receptor, appears to have a pivotalrole in the process of vomiting. 5HT3 receptors are abundanton vagal afferent neurons and other neurons and smooth muscle in the gastrointestinaltract and have also been identified in the area postrema (emetic center),in the nucleus tractus solitarii, and presynaptically on vagalafferent terminals in the medulla.1 Neurokinin 1 (NK1) receptors are a new class of receptors found in high concentration in the emetic center and in peripheral afferent nerves. NK1 receptors also are found in the area postrema (CRTZ) and are involved with pathways associated with motion sickness. The neurotransmitter substance P binds to NK1 receptors initiating the stimulus.
Phenothiazine tranquilizers antagonize the stimulatory effects of dopamine (D2). These drugs are also reported to have weak anticholinergic and antihistaminic action. The potential side effects are hypotension from peripheral alpha-adrenergic blockade. Other effects include sedation and possibly seizures by lowering the seizure threshold. Chlorpromazine (ThorazineTM 0.5 mg/kg TID to QID given IV, IM, SC) is the most common antiemetic from this class.
Antihistaminic drugs block both cholinergic and histamine receptor mediated transmission to the vomiting center arising from the vestibular system. These drugs are generally used for management of motion sickness or vestibular disease but will also cause some sedation. A common H1 antihistamine used for this purpose is diphenhydramine (2-4 mg/kg TID given PO).
Anticholinergic drugs block cholinergic afferent pathways peripherally and pathways from the vestibular system leading to the emetic center. Drugs in this class tend to be poor antiemetics and have the negative effect of altering gastrointestinal motility. Common drugs used in small animals include isopropamide (0.2-1.0 mg/kg BID given PO) and propantheline (0.25 mg/kg TID given PO).
Metoclopramide has antiemetic effects through several mechanisms. At low doses it inhibits dopamine (D2) receptors and at higher doses inhibits serotonin (5HT3) receptors in the CRTZ. Cats are reported to have few CNS dopamine receptors and consequently metoclopramide may be a poor antiemetic choice. Metoclopramide is rapidly metabolized through the liver and the best results are observed when given at continuous rate infusion (ReglanTM 0.01 to 0.02 mg/kg every hour or 1 to 2 mg/kg every 24 hours). At high doses it causes CNS excitement from dopamine antagonism. It also has effects on GI motility (see prokinetic agents). Metoclopramide should be avoided in epileptics or in animals receiving other drugs that are likely to cause extrapyramidal reactions and should not be used with phenothiazine tranquilizers that can cause an additive effect.
Serotonin antagonists are effective at blocking 5HT3 receptors found peripherally, in the CRTZ and vomiting center. They are not very effective in relieving motion sickness.1 Common drugs used include ondansetron (ZofranTM 0.1-1.0 mg/kg SID-BID given PO) and dolasetron (AnzemetTM 0.6 mg/kg given IV q 24 hours). They also are used for prevention of chemotherapy induced vomiting. Another serotonin antagonist sometimes used in cats is mirtazepine (RemaronTM 1.25-2.5 mg per cat PO once every 3 days). This drug is not only a 5HT3 antagonist but also has a 5HT1 agonist effect that functions as an appetite stimulate.
Maropitant (CereniaTM 1 mg/kg Q 24 hours given SQ or 2 mg/kg Q 24 hours given PO) is a neurokinin 1 antagonist that blocks receptors found in the emetic center, CRTZ and in peripheral afferent nerves. Maropitant appears to be a good broad-spectrum antiemetic that is approved for use in the dog.2 At higher doses (8 mg/kg given orally up to two consecutive days) it is also prevents motion sickness.3 Our experience finds it very effective in preventing vomiting and nausea associated with chemotherapy, in management of parvovirus, pancreatitis as well as many other causes of vomiting.4 It is not yet approved for use in cats, however some have used it in cats as well. Maropitant does not appear to effect GI motility and because of the drugs hepatic metabolism it should be used with caution in patients that have significant hepatic dysfunction.
Abnormal gastrointestinal motility in small animals is generally associated with megaesophagus, gastroesophageal reflux, gastric hypomotility and chronic constipation. Dogs with megaesophagus do not respond to prokinetic agents because the esophagus in the dog is predominately skeletal muscle and does not respond to agents that effect visceral smooth muscle. However, gastric prokinetic agents are used to prevent gastroesophageal reflux. This section will deal with prokinetic agents as they relate to the management of gastric hypomotility and chronic constipation. Prior to prokinetic therapy for a gastric motility disorder, attempts should be directed at identifying and correcting any possible underlying etiology that may be present. Frequently animals with motility disorders can be managed with diets alone. High fiber diets and laxatives are used for management of constipation while diets of a liquid or semi-liquid consistency, low in fiber, fat and osmolarity fed in small amounts frequently improve gastric emptying.5
Metoclopramide was the first prokinetic to come on the market for treating gastric hypomotility.6 Metoclopramide acts on both dopaminergic (D2) and serotoninergic (5HT3 and 5HT4) receptors. The prokinetic effects are through cholinergic stimulation of the upper gastrointestinal tract mediated by antagonism at the D2 and 5HT3 receptors and activation of the 5HT4 receptors that are located both in neural and non-neural tissues of the GI tract. Metoclopramide increases the tone and amplitude of gastric contractions, relaxes the pyloric sphincter and increases peristalsis of the duodenum and proximal jejunum resulting in accelerated gastric emptying and intestinal transit.7 It also increases the resting tone of the lower esophageal sphincter. It however has little, if any, effect on the motility of the colon or gallbladder. It is given orally at a dosage of 0.2-0.4 mg/kg one-half hour before meals three or four times a day. This drug is contraindicated in gastric outflow obstructions, with concurrent phenothiazine or narcotic therapy or if the patient has epilepsy. Side effects with metoclopramide are common and include central nervous system abnormalities associated with hyperexcitability or depression. If side effects occur the drug should be discontinued for 48 hours and then given at a lower dosage. This drug also has an antiemetic effect attributed to its central antidopaminergic activity through actions at the CRTZ (see antiemetics).
Cisapride is a promotility agent that is more potent than metoclopramide.6 The drug binds to 5HT4 receptors on enteric postganglionic cholinergic neurons and stimulates contraction of gastrointestinal smooth muscle. Cisapride also has serotonin (5HT1/5HT3) antagonistic effects on enteric cholinergic neurons as well as some non-5HT effects on canine antral cholinergic neurons. Cisapride increases lower esophageal sphincter pressure, improves gastric emptying and promotes increased motility of both the small and large intestine. In cats cisapride increases distal esophageal motility and has become an important prokinetic agent for management of feline megacolon. Cisapride was marketed as PropulsidTM but was taken off the market because of induced cardiac arrhythmias referred to as "torsades de pointes" that resulted in sudden death in some people. Cisapride caused QT interval prolongation and slowing of cardiac repolarization as an explanation for the fatal arrhythmia. This abnormality has not been observed in dogs or cats. Cisapride is now only available through compounding pharmacies. A recommended dose is 0.1 to 0.5 mg/kg BID to TID given 30 minutes before meals. Higher doses of 1 mg/kg may be required in some cases. Cats appear to tolerate 2.5 mg dose without problems. Side effects include vomiting, diarrhea and abdominal discomfort. Cisapride should not be used with anticholinergic drugs as they will counteract cisapride's effect on motility. Cisapride may affect absorption of some drugs through increased GI motility. It has little if any effects as an antiemetic.
Erythromycin is a novel prokinetic. This antibiotic is associated with frequent gastrointestinal side effects, including nausea and vomiting. Resulting research as to the cause of erythromycin induced vomiting found the gastrointestinal effects occur from the drugs binding to motilin receptors in both cholinergic nerves and smooth muscle. In the dog antral contractions are due to a cholinergic (5HT3) mechanism and in cats it is a smooth muscle motilin agonist.7 Erythromycin when given at very low sub-microbiological doses stimulates migrating motor complexes in the stomach. This motility occurs during the fasting state with an empty stomach but studies have also shown if given during feeding it accelerates gastric emptying of food.8 It also increases lower esophageal sphincter pressure and may be useful in management of gastroesophageal reflux. Erythromycin will increase colonic activity in the dog but not the cat. In dogs a dose of 0.5 to 1 mg/kg given TID is the recommended prokinetic dose. Erythromycin also appears to be a better prokinetic than metoclopramide.
H2 receptor antagonists ranitidine (ZantacTM) and nizatidine (AxidTM) stimulate gastrointestinal motility in addition to their ability to inhibit gastric acid secretion. They function by inhibiting acetylcholinesterase activity and increasing the amount of acetylcholine available to smooth muscle muscarinic-cholinergic receptors in the gastrointestinal tract.9 When given at the normal antisecretory doses (see antacids below) they also stimulate gastric contractions and accelerates gastric emptying. These drugs could be useful in the management of gastric ulceration with concurrent gastric hypomotility. The relative potency of these antacids as a prokinetic compared to those drugs discussed above is unknown but believed to be weaker.
Domperidone is both an antiemetic and prokinetic agent not yet available in the United States. Domperidone is a peripheral and CRTZ dopamine (D2) receptor antagonist. It appears to be a better antiemetic than prokinetic agent having weak effects on GI motility.7 It has little effect on sustaining lower esophageal sphincter pressure and gastric motility does not appear to be significantly enhanced during the fed state.
The stomach is resistant to the physiochemical effects of such things as food, acid, pepsin and abrasive substances. This unique characteristic is referred to as the gastric mucosal barrier. The pre-epithelial component consists of mucus and the bicarbonate secreted by the epithelial cells. The adherent layer of mucus gel protects and lubricates the epithelium. Bicarbonate, also secreted by the epithelial cells, is incorporated in the mucus gel and functions in neutralizing the effects of gastric acid. Adequate mucosal blood supply is also an important component in the barrier. The epithelial cells are held together by strong intracellular tight junctions with the apical portion of the cell being specialized to resist diffusion of acid back through the barrier. Rapid epithelial cell turnover rate called restitution allows for rapid healing. The local tissue prostaglandins have also been shown to exert certain "cytoprotective" properties. While damage to the gastric mucosa results in the production of various prostanoids, the prostaglandins of the E-type (PGE) found locally in the gastric mucosa are known to have a protective role.10 It is the back diffusion of gastric acid into the disrupted gastric mucosa that perpetuates mucosal damage and highlights the importance of mucosal protection and blockade of acid in the treatment success.
Oral antacids neutralize gastric acid to water and a neutral salt. Common antacids are bases of aluminum, magnesium or calcium. In addition to their acid-neutralizing ability, antacids decrease pepsin activity, bind to bile acids in the stomach and stimulate local prostaglandin (PGE1) production. Antacids are effective as long as they remain within the stomach and consequently must be given frequently. Antacids may interfere with the GI absorption of concurrently administered drugs and often cause constipation. Many OTC antacids are available such as MaaloxTM, MylantaTM and DiGelTM.
Sucralfate (CarafateTM) is a nonabsorbable compound containing aluminum hydroxide and sucrose octasulfate. When given orally sucralfate forms a gel that has local effects on the gastrointestinal tract. Sucralfate has a high affinity for ulcerated tissue and will selectively bind with connective tissue in the ulcer exerting a local protective role. It will inactivate pepsin, absorbs bile acids, and the aluminum hydroxide portion has an acid neutralizing effect. Studies have also shown that this compound has a cytoprotective role thought to be caused by stimulating local tissue prostaglandins. A dose of 1/4 to 1 gram 3 to 4 times a day is suggested depending on animal size. The timing of administration when given with other drugs has been a topic of debate suggesting gastric acid is needed to dissolve the tablet and antacids should be given following sucralfate. That has not been proven in vivo and is probably of little significance however more important is the fact that sucralfate can bind to other drugs and inhibit their absorption. There are no studies showing the benefit of combination therapy (sucralfate and acid blocker) over single therapy. Sucralfate is also effective in treating esophagitis when given as a liquid.
H2-receptor antagonists such as cimetidine, ranitidine, famotidine and nizatidine are effective in reducing acid production by blocking the histamine receptor of the parietal cell. However, blocking only one of the three receptors on the parietal cell does not maximally inhibit all acid secretion. Cimetidine is the first generation of H2-receptor antagonists but the newer agents are more potent and require less frequent administration. Some studies also suggest the H2-receptor antagonists may have benefits related to stimulation of local prostaglandin synthesis and thus a cytoprotective function. The prophylactic value of H2-receptor antagonists to prevent gastric ulceration is at this time questionable but they have been shown to be effective in healing ulceration. Cimetidine is given at 5-10 mg/kg QID given IV, IM or PO. Ranitidine is more potent, has a longer half-life and is administered at 2 mg/kg TID and famotidine is dosed at 0.5 mg/kg BID or once daily. Cimetidine will also alter hepatic biotransformation of certain drugs and should be used with care in dogs with liver disease.
Proton pump inhibitors (PPIs) block all acid production by the parietal cell through irreversibly binding the proton-transporting enzyme (sodium/potassium ATPase) at the luminal surface of the cell. There is a delayed onset of action but the duration of action is prolonged (24 hours or more) until new enzyme is produced.10 It is a potent acid blocker effectively blocking all stimuli causing acid secretion (histamine, gastrin and acetylcholine). Omeprazole (ProlosecTM) is given at a dose of 0.7 mg/kg PO once a day. This drug is safe, with minimal side effects but may compete with hepatic metabolism of some drugs. It is more effective in healing aspirin induced ulcers than the H2 antagonists and may also have some gastroprotective effects preventing gastric ulcer formation.11,12 Omeprazole is recommended in patients with severe ulceration or those that fail to respond to traditional ulcer therapy such as dogs with mastocytosis, gastrinomas or other causes of hypergastrinemias. PPIs are my choice when treating reflux esophagitis because the esophagus is easily damaged by gastric acid and PPIs block all gastric acid formation.
Prostaglandin E has potent anti-secretory effects as well as cytoprotective effects. The synthetic PGE misoprostol (CytotecTM) is given at a dose of 2-5 mcg/kg QID. Misoprostol suppresses gastric acid secretion by inhibiting the activation of histamine-sensitive adenylate cyclase.10 The cytoprotective effects arise from stimulation of bicarbonate and mucus secretion, increased mucosal blood flow, decreased vascular permeability and increased epithelial cell renewal.13 The main indication for misoprostol use is the prevention or treatment of gastric ulceration from NSAIDs. It is uncertain if misoprostol will improve healing of established gastric ulcers and apparently does not have distinct advantages over other antacids in treating ulcers not associated with NSAIDs. High doses cause diarrhea and abdominal cramping and should not be used in pregnant animals as it can cause abortion.
1. Olyer IN. Intern Med J 2005; 35(8):478,
2. Benchaoui HA, et al. J Vet Pharmacol Ther 2007; 30(4):336,
3. Benchaoui HA, et al. Vet Rec. 2007; 29;161(13):444,
4. de la Puente-Redondo VA, et al. Am J Vet Res 2007; 68(1):48,
5. Hall JA, et al. Vet Clin North Am Small Anim Pract. 1999; 29(2):377,
6. Burger DM, et al. J Vet Med A Physiol Pathol Clin Med 2006; 53(2):97,
7. Washabau RJ, Vet Clin North Am Small Anim Pract 2003; 33(5):1007,
8. Boivin MA, et al. Pharmacotherapy 2003; 23(1):5,
9. Ohira Y, et al. J Smooth Muscle Res 1993; 29(4):131,
10. Papich MG, Vet Clin North Am Small Anim Pract 1993;23(3):497,
11. Davis MS, et al. J Vet Intern Med 2003; 17(2):163,
12. Jenkins CC, et al. Am J Vet Res. 1991; 52(5):658,
13. Johnson SA, et al. J Vet Intern Med 1995; 9(1):32.