Antiemetic therapy in dogs and cats: new versus old (Proceedings)

The vomiting reflex is a complex mechanism that can be initiated peripherally from the GI tract, pharynx, chemoreceptor trigger zone (CRTZ), and vestibular systems or centrally at the emetic center in the brain. Direct stimulation of the pharynx can result in vomiting, although this is a relatively infrequent cause in animals. Vomiting can be initiated from the GIT due to irritation, inflammation, or distention of the stomach or intestines and is typically mediated by serotonin (5HT3) receptors which than progress through the CRTZ or the solitary tract nucleus in the brain. The solitary tract nucleus contains enkephalin, histamine (H1), muscarinic (M1), substance P (neurokinin NK-1), and 5HT3 receptors. The chemoreceptor trigger zone can also initiate the vomiting reflex due to blood borne drugs or toxins (i.e. morphine induced vomiting in dogs) which is mediated by opiate, 5HT3, dopamine (D2) and M1, NK1, and norepinephrine (α-2) receptors. Motion sickness or vestibular disease can stimulate the vomiting reflex primarily through histamine (H1) and muscarinic receptors. The emetic center coordinates the vomiting reflex and contains high concentrations of 5HT1 and α-2 receptors. The complex nature and multiple pathways that can stimulate the vomiting reflex can be confusing but offer many targets for symptomatic treatment of vomiting, but no one treatment is expected to be highly efficacious for all causes of vomiting. Is is also important to reiterate that antiemetics are treating a symptom and not a disease process, therefore every effort should be made to make a primary diagnosis as some underlying disease can prove fatal if not treated.

Antihistamines

Antihistamines are commonly used for vomiting associated with vestibular stimulation such as motion sickness or vestibular disease. Most antihistamines have weak anticholinergic effects as well, which is the reason they are typically contraindicated in glaucoma and cardiovascular disease. Diphenhydramine (Benadryl), dimenhydrinate (Dramamine), and hydroxyzine have all been used for the treatment of vestibular vomiting. The efficacy of antihistamines to treat vestibular vomiting in cats is less than that in dogs and may not be an optimal choice in cats.

Anticholinergics

Aminopentamide (Centrine) is the representative antimuscarinic agent used for vomiting in veterinary medicine. The efficacy of aminopentamide is essentially limited to vestibular induced vomiting. Aminopentamide has low efficacy for other causes of vomiting. The adverse effects of anticholinergics (decreased stomach emptying, ileus) are often contraindicated for many causes of vomiting. Other adverse effects include xerostomia, urine retention, increased intraocular pressure, constipation, and excitement in cats. The clinical usefulness of this drug class as antiemetics is minimal.

Phenothiazines

Phenothiazines are effective antiemetics due to their activity as D2 antagonists. However most phenothiazines have weak antihistaminic and anticholinergic effects that may contribute to their efficacy. Phenothiazines are also α-1 antagonists which results in vasodilation and their hypotensive effects. As a result phenothiazines are typically contraindicated in hypotensive or severely dehydrated animals. A common adverse effect of phenothiazines is sedation which is used as an indication for acepromazine. Although it is widely reported that phenothiazines are contraindicated in epileptic, there is minimal data supporting this statement. Chronic administration of phenothiazines can result in dyskinesia (Parkinsonian like signs) due to their effects as D2 antagonists. Phenothiazines are primarily eliminated by hepatic metabolism. Phenothiazines are typically considered effective for vestibular, gastrointestinal, CRTZ induced vomiting. Phenothiazines have lower efficacy in the prevention and treatment of chemotherapy induced vomiting than maropitant or ondansetron.

Chlorpromazine

Chlorpromazine (0.5 mg/kg SC q 6-8 h) is probably the most commonly used phenothiazine as an antiemetic. Acepromazine is also an effective antiemetic, but produces more profound sedation than chlorpromazine. Promethazine (Phenergan) has marked effects as an antihistamine in addition to its D2 antagonist effects (less than chlorpromazine) and has less sedative effects than the other phenothiazines. Promethazine can be administered PO to dogs 0.2-0.5 mg/kg q 6-8 as an antiemetic and is generally used for the prevention of motion sickness.

Metoclopramide

Metoclopramide is a broad spectrum antiemetic which elicits is effect as a D2 antagonist and through prokinetic effects. High doses of metoclopramide also produce 5HT3 antagonist effects, but adverse effects such as excitement and abdominal cramping / colic are more likely. Metoclopramide also increases the release of aldosterone and prolactin. Peripheral edema has been reported as an adverse effect in humans and has anecdotally occurred in animals, which is likely due to its effects on aldosterone release. Increased aldosterone release may exacerbate underlying or pre-existing cardiovascular disease and potentially result in pulmonary edema. Chronic administration may also produce lactation or gynecomastia through increased release of prolactin. Due to its potential for CNS excitement, the use of metoclopramide in patients susceptible to seizures (i.e. epileptics) is generally contraindicated. Due to metoclopramide's prokinetic effects, it should not be administered to animals with a GIT obstruction or foreign body.

Metoclopramide is rapidly metabolized by the liver with a short half-life, ~ 2 hours. The oral bioavailability is ~ 50% in dogs. Metoclopramide can be administered IV, IM, PO to dogs and cats, 0.2-0.5 mg/kg q 6-8 hours with the higher end of the dose range administered PO. Metoclopramide can also be administered as a constant rate IV infusion up to 2 mg/kg/d. High dose metoclopramide, 1 mg/kg, used primarily for the prevention of chemotherapy induced vomiting elicits 5HT3 antagonist effects (similar to ondansetron, see below), but with the availability of generic ondansetron the use of high dose metoclopramide has decreased.

Serotonin (5HT3) antagonists

Serotonin (5HT3) antagonists are highly effective antiemetics for gastrointestinal, chemotherapy, postoperative nausea, and nausea and emesis due to pregnancy (in humans). Maropitant (see below) was more effective in controlling vomiting due to ipecac in dogs, but the clinical relevance of this difference is not known. The agents are not effective for motion sickness, whereas maropitant is effective. Ondansetron (0.1-0.2 mg/kg q 6-12 h as a slow IV injection or for chemotherapy 0.5 mg/kg IV) is the prototypical drug in the class and is now a viable choice in veterinary medicine due to the low cost of generics. Granisetron and dolasetron are also in the same drug class but are costly. Ondansetron is primarily eliminated by hepatic metabolism. The elimination half-life is short, but the antiemetic effects outlast the drug concentrations. The duration of antiemetic effects in dogs is between 6 and 12 hours. The oral bioavailability is very poor (<10%) in dogs, therefore it is probably not effective per os. Although the label states it should not be administered subcutaneously due to its low pH (3.5), it has been administered as a SC infusion to people. Until safety, efficacy and pharmacokinetic studies are conducted in dogs, the routine use of subcutaneous ondansetron is discouraged. The adverse effects of ondanstron are limited due to its high receptor specificity, but headaches, dizziness, and constipation and diarrhea are reported in humans. Electrocardigraphic changes have been reported in humans, but cardiovascular disease is not considered a contraindication.

Maropitant

Maropitant is in the newest class of antiemetics – neurokinin (NK-1) antagonists. Substance P is the neurotransmitter associated with NK-1 receptors. Maroptitant is a highly efficacious antiemetic against vomiting caused by gastrointestinal diseases, chemotherapy, and motion sickness. Maropitant has a half-life of about 6 hours, is metabolized by hepatic mechanisms, and has a 30% oral bioavailability. Maropitant has dose dependant metabolism (increasing doses result in increased half-life) and is recommended for short-term administration. Adverse effects included decreased body weight, decreased liver and testes weight, weakness, lethargy, decreased appetite, mild neutropenia, decreased heart rate and prolonged QT intervals in toxicity trials. Maropitant also exhibits effects as a calcium channel blocker (i.e. diltiazem) and as a potassium channel blocker (i.e. sotalol), which explains its cardiac adverse effects. Cardiovascular studies in healthy young Beagles did not result in any cardiotoxicity, but the concurrent use with calcium channel blockers, beta blockers, and potassium channel blockers, should be done cautiously. No studies have examined the safety of maropitant on dogs with cardiovascular disease. Use in animals with underlying cardiovascular or hepatic disease should also be cautious. Maropitant is labeled for use in dogs over 16 weeks of age, therefore use in parvoviral gastroenteritis would be extralabel in most dogs. Maropitant resulted in a greater incidence of bone marrow suppression (compared to placebo) in puppies 11 weeks of age.

The maropitant dose for acute vomiting is 2 mg/kg PO q 24 h for up to 5 days and 8 mg/kg PO q 24h for up to 2 days for motion sickness. Maropitant is also available as an injectable solution, 1 mg/kg SC q 24 hours for up to 5 days. Pain, sedation, ataxia, and bradycardia have been reported as adverse effects.

Maropitant is not labeled for use in cats, but has been administered at a dose of 0.5-1 mg/kg SC to cats. Prelimimary safety studies administered 5 mg/kg SC once daily to HEALTHY cats which produced no adverse effects. However safety studies have not been performed in animals affected by disease. Maropitant should be avoided or used cautiously in cats currently receiving beta blockers (atenolol, propranolol, sotalol, et al), diltiazem, or amlodipine.