Gastric Motility Disorders & Prokinetic Therapies in Small Animals
ACVIM 2008
Jean A. Hall, DVM, PhD, DACVIM
Corvallis, OR, USA

Gastric Motility Disorders1,2

There are three general types of gastric motility disorders: accelerated gastric emptying (usually iatrogenic causes), retrograde transit (e.g., enterogastric and gastroesophageal reflux), and delayed gastric emptying (mechanical and functional obstruction). Gastric motility disorders alter normal gastric functions (i.e., storage of injesta, mixing and dispersion of food particles, and timely emptying of gastric contents into the duodenum). In general, anatomical lesions causing mechanical obstruction (e.g., pyloric stenosis or chronic hypertrophic pyloric gastropathy, neoplasias such as adenocarcinomas in dogs or lymphosarcomas in cats, adenomatous polyps, chronic hypertrophic gastritis, severe eosinophilic gastritis, gastric phycomycosis, foreign bodies, hepatic or pancreatic abscesses, and intra-abdominal neoplasia causing pyloric obstruction) are straightforward in diagnosis (involves survey and contrast radiography, ultrasonography or gastroscopy) and management. Gastrointestinal prokinetic agents are contraindicated in treating patients with mechanical obstruction.

Conversely, disorders of defective propulsion cause delayed gastric emptying because of abnormalities in myenteric neuronal or gastric smooth muscle function, or because of abnormalities in antropyloroduodenal coordination. Functional obstruction is usually diagnosed after mechanical obstruction has been ruled out. A number of primary conditions have been associated with functional obstruction and delayed gastric emptying. Recovery from gastric dilatation/volvulus is almost always associated with significant myoelectrical and motor abnormalities in the dog.3 In GDV, electrophysiological abnormalities in gastric smooth muscle cells are associated with delayed gastric emptying. It is still unclear whether delayed gastric emptying in affected dogs after surgical treatment and recovery is the result or the cause of GDV. Other primary conditions that have been associated with functional obstruction and delayed gastric emptying include infectious (canine parvovirus, Physaloptera, ascarid infestation in puppies) or inflammatory disease (inflammatory gastritis or infiltrative lesions), ulcers (they reduce antral motility and disrupt the MMC), and postsurgical gastroparesis. Delayed gastric emptying has also been associated with a number of secondary conditions including electrolyte disturbances (e.g., hypokalemia alters membrane potentials and neuromuscular function), metabolic disorders (e.g., hypoadrenocorticism, diabetes mellitus, hypergastrinemia, and uremia), concurrent drug use (cholinergic antagonists, adrenergic agonists, and opioid agonists), acute stress (e.g., sympathetic stimulation, spinal cord injury), and acute abdominal inflammation. More commonly, an underlying condition is not identified, and the condition is referred to as idiopathic delayed gastric emptying or gastroparesis.

Regulation and integration of gastrointestinal motility is mediated by the action of chemicals on receptors of target cells, including chemicals delivered by nerves (neurocrines), chemicals delivered by the blood (hormones), and chemicals delivered by diffusion through the interstitial fluid (paracrines). In addition, the enteric nervous system and parasympathetic and sympathetic innervations control activity of the GI tract. Any drug or disease that alters these normal control mechanisms can alter gastric motility. Diagnosis and management of functional disorders causing delayed gastric emptying is not straightforward.

Gastric Prokinetic Agents1,2,4

Delayed gastric emptying is a significant cause of upper gastrointestinal tract signs in dogs and cats. Dietary management and gastric prokinetic agents are used to treat delayed gastric emptying disorders, as surgical procedures are often unsuccessful. Dietary management is attempted initially. Dietary choices are made based on the knowledge that liquids are expelled from the stomach faster than solids, carbohydrates are expelled faster than protein, and protein is expelled faster than fats. Small amounts of a semiliquid, low-protein, and low-fat diet should be fed at frequent intervals. Cooked pasta or boiled rice can be added to the diet. Drug therapy with gastric prokinetic agents should be considered in animals that fail to respond to dietary management alone. Some gastrointestinal prokinetic agents have effects throughout the gastrointestinal tract, whereas others exert action on the proximal or distal gastrointestinal tract. Gastrointestinal prokinetic agents work by many different mechanisms of action. Mechanisms, sites of activity, and indications for their use are summarized in Table 1.4 Cisapride is the drug of choice for treating delayed gastric emptying, followed by erythromycin and ranitidine or nizatidine.

New Prokinetic Agents

The prokinetic effects of mitemcinal, an erythromycin derived orally active motilin-receptor agonist, have been recently studied in conscious normal dogs and conscious dogs with experimentally-induced delayed gastric emptying.5 This drug accelerated gastric emptying in both groups of dogs in a dose-dependent manner much more robustly than cisapride. Although clinical trials are needed, these results suggest that mitemcinal may be able to replace the withdrawn drug, cisapride, as the drug of choice for treating delayed gastric emptying.

Gastric Electrical Stimulation

A novel two-channel implantable gastric pacemaker has been shown to improve drug-induced delayed gastric emptying and gastric dysrhythmia in dogs via gastric electrical stimulation (GES).6 GES induces gastric antral contractions in the fasting state, enhances glucagon-induced antral hypomotility in the fed state, and accelerates glucagon-induced delayed gastric emptying. The effect on antral contractions is mediated via the cholinergic pathway. Manipulation of gastric motility by GES has been suggested as a minimally invasive alternative treatment of gastric motility disorders. Stimulation parameters can be reprogrammed after implantation.7

Table 1. Mechanisms, sites of activity, indications, and dose for gastrointestinal prokinetic agents.

Drug/classification

Mechanisms of action

Sites of activity

Indications

Dose

Dopaminergic (D2) antagonists

--Metoclopramide

D2 dopaminergic antagonist

GES, stomach, intestine, CRTZ

Vomiting disorders, gastroesophageal reflux, delayed gastric emptying, ileus, intestinal pseudo-obstruction

0.2-0.5 mg/kg PO, IV TID; 0.01-0.02 mg/kg/h infusion

α2-adrenergic antagonist

Stomach

β2-adrenergic antagonist

Stomach

5-HT4 agonist

GES, stomach, intestine

5-HT3 antagonist

Stomach, intestine

--Domperidone

D2 dopaminergic antagonist

Stomach, CRTZ

Vomiting disorders, gastroesophageal reflux (?)

0.05-0.10 mg/kg PO BID

α2-adrenergic antagonist

Stomach

β2-adrenergic antagonist

Stomach

Serotonergic 5-HT4 agonists

--Cisapride

5-HT4 agonist

GES, stomach, intestine

Gastroesophageal reflux, delayed gastric emptying, ileus, intestinal pseudo-obstruction, constipation, chemotherapy-induced emesis

0.1-0.5 mg/kg PO TID (doses as high as 0.5-1.0 mg/kg have been used in some dogs)

5-HT1 antagonist

Stomach, intestine, emetic center

5-HT3 antagonist

Stomach, intestine, CRTZ

5-HT2 agonist

Colon

Nonserotonergic mechanism

Canine antrum

--Tegaserod

5-HT4 agonist

Intestine, colon

Constipation, ileus, intestinal pseudo-obstruction

0.05-0.10 mg/kg PO, IV BID

--Prucalopride

5-HT4 agonist

Stomach, colon

Delayed gastric emptying, constipation

Not yet approved

Motilin-like drugs

--Erythromycin

Motilin agonist (cat)

GES, stomach, intestine

Gastroesophageal reflux, delayed gastric emptying, constipation (dogs)

0.5-1.0 mg/kg PO, IV TID

5-HT3 antagonist (dog)

Stomach, intestine

Acetylcholinesterase inhibitors

--Ranitidine & Nizatidine

Acetylcholinesterase inhibitor

Stomach, intestine, colon

Delayed gastric emptying, intestinal pseudo-obstruction, constipation

Ranitidine: 1.0-2.0 mg/kg PO BID-TID

Nizatidine: 2.5--5.0 mg/kg PO SID

M3 muscarinic cholinergic agonist (?)

Stomach

Growth hormone secretagogues

--Ghrelin

Ghrelin receptor agonist

Stomach, afferent vagus nerve

Delayed gastric emptying

Not yet approved

5-HT, 5-hydroxytryptamine; M, muscarinic; CRTZ, chemoreceptor trigger zone; GES, gastroesophageal sphincter.

References

1.  Hall JA, Washabau RJ. Diagnosis and treatment of gastric motility disorders. Vet Clin North Am Small Anim Pract. 1999;29(2):377.

2.  Washabau RJ. Gastrointestinal motility disorders and gastrointestinal prokinetic therapy. Vet Clin North Am Small Anim Pract 2003;33:1007.

3.  Hall JA, Solie TN, Seim HB, Twedt DC. Gastric myoelectric and motor activity in dogs with gastric dilatation-volvulus. Am J Physiol 1993;265:G646.

4.  Hall JA, Washabau RJ. Gastric prokinetic agents. In Bonagura JD, ed. Kirk's Current Veterinary Therapy XIII. Philadelphia: WB Saunders Co, 2000; 614.

5.  Onoma M, et al. Oral mitemcinal (GM-611), an erythromycin-derived prokinetic, accelerates normal and experimentally delayed gastric emptying in conscious dogs. Clin Exp Pharmacol Physiol 2008;35(1):35.

6.  Xu J, et al. Two-channel gastric pacing with a novel implantable gastric pacemaker accelerates glucagon-induced delayed gastric emptying in dogs. Am J Surg 2008;195(1):122.

7.  Jalilian E, et al. Implantable neural electrical stimulator for external control of gastrointestinal motility. Med Eng Phys 2007;29(2):238.

Speaker Information
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Jean Hall, DVM, PhD, DACVIM
Corvallis, OR


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