Application of Prokinetic Therapies in Small Animals

Application of Prokinetic Therapies in Small Animals

Gastrointestinal (GI) prokinetic drugs stimulate smooth muscle contractions to enhance gastric emptying and transit of the small and large intestines. They are useful in the treatment of motility disorders in humans and animals because they induce coordinated motility patterns.

In human medicine, prokinetic drugs are used for the pharmacological treatment of several GI motility disorders such as gastroesophageal reflux disease, diabetic gastroparesis, delayed gastric emptying in critically ill patients, functional dyspepsia, constipation-dependent irritable bowel syndrome, idiopathic chronic constipation and postoperative ileus. In recent years however, withdrawal from the US market of two new prokinetic drugs has created a therapeutic challenge for the practitioner since it is increasingly recognized that the presently available “traditional” prokinetic drugs have major limitations.

In veterinary medicine, there is presently no prokinetic drug labeled for use in companion animals. Hence, the availability of these promotility drugs for use in veterinary patients is entirely dependent on the approval of their usage in human medicine. The most common GI motility disorders identified in companion animals are delayed transit disorders involving the esophagus (hypomotility, megaesophagus), stomach (delayed gastric emptying), small intestine (postoperative ileus) and colon (constipation and megacolon). These pathophysiological conditions of the GIT may benefit from the administration of prokinetic agents. However, it is important to remember that even though these medical conditions are commonly diagnosed (for which pharmacological treatment is warranted), adequate double-blinded, controlled, randomized, prospective studies have not been conducted in dogs or cats for any of the available prokinetic drugs.

In order to understand the specific mechanisms of action of the different prokinetic drugs, it is important to briefly review the physiology of the GIT. Roles of the GIT include immunologic interactions, digestive processes, modulation of sensation, and coordination of motility and secretion. The pathophysiology of functional GI disorders is thought to arise mainly from disturbances in sensation, motility and/or secretion. Receptors modulating these functions are prime pharmacological targets for the development of agonist or antagonist agents of prokinetic activity.

Prokinetic drugs increase the movement of ingested material through the GI tract. They are useful in the treatment of motility disorders in humans and other animals because they induce coordinated motility patterns. Unfortunately, some prokinetic drugs may produce a number of serious side effects that complicate their use. Metoclopramide is a dopaminergic antagonist and peripheral serotonin receptor antagonist with GI and CNS effects. In the upper GI tract, metoclopramide increases both acetylcholine release from neurons and cholinergic receptor sensitivity to acetylcholine. Metoclopramide stimulates and coordinates esophageal, gastric, pyloric, and duodenal motor activity. It increases lower esophageal sphincter tone and stimulates gastric contractions; while relaxing the pylorus and duodenum. Inadequate cholinergic activity is incriminated in many GI motility disorders; therefore, metoclopramide should be most effective in diseases where normal motility is diminished or impaired. Metoclopramide speeds gastric emptying of liquids, but may slow the emptying of solids. It is effective in treating postoperative ileus in dogs, which is characterized by decreased GI myoelectric activity and motility. Metoclopramide has little or no effect on colonic motility. Metoclopramide is primarily indicated for the relief of nausea and vomiting associated with chemotherapy and as an antiemetic for dogs with parvoviral enteritis and for the treatment of gastroesophageal reflux and postoperative ileus. GI obstruction, such as intussusception in puppies with parvoviral enteritis, must be excluded prior to initiating metoclopramide therapy. Its prokinetic action is negated by narcotic analgesics and anticholinergic drugs, such as atropine. Drugs that dissolve or are absorbed in the stomach, such as digoxin, may have reduced absorption. Bioavailability may be increased for drugs that are absorbed in the small intestine. Due to accelerated food absorption, metoclopramide therapy may increase the insulin dose required in diabetics. Concurrent use of phenothiazine and butyrophenone tranquilizers should be avoided because they also have central antidopaminergic activity, so they increase the potential for extrapyramidal reactions. Metoclopramide readily crosses the blood-brain barrier, where dopamine antagonism at the CTZ produces an antiemetic effect. However, dopamine antagonism in the striatum causes adverse effects known collectively as extrapyramidal signs, which include involuntary muscle spasms, motor restlessness, and inappropriate aggression. If recognized in time, the extrapyramidal signs can be reversed by restoring an appropriate dopamine:acetylcholine balance with the anticholinergic action of an antihistamine, such as diphenhydramine hydrochloride given IV at a dosage of 1.0 mg/kg. Cisapride is chemically related to metoclopramide, but unlike metoclopramide, it does not cross the blood-brain barrier or have antidopaminergic effects. Therefore, it does not have antiemetic action or cause extrapyramidal effects (extreme CNS stimulation). Cisapride enhances the release of acetylcholine from postganglionic nerve endings of the myenteric plexus and antagonizes the inhibitory action of serotonin on the myenteric plexus, resulting in increased GI motility and heart rate. Cisapride is more potent and has broader prokinetic activity than metoclopramide, increasing the motility of the colon, as well as that of the esophagus, stomach, and small intestine. Although availability is now restricted (see below), cisapride was especially useful in animals that experienced neurologic side effects from metoclopramide. It was also useful in managing gastric stasis, idiopathic constipation, gastroesophageal reflux, and postoperative ileus in dogs and cats. Cisapride was especially useful in managing chronic constipation in cats with megacolon; in many cases, it alleviated or delayed the need for subtotal colectomy. Cisapride was also useful in managing cats with hairball problems and dogs with idiopathic megaesophagus that continued to regurgitate frequently despite a carefully managed, elevated feeding program. In horses, cisapride increases motility of the left dorsal colon and improves coordination of the ileocecal- colonic junction. There is some evidence that cisapride is useful in preventing postoperative ileus, but clinical use has so far been limited. In comparative studies of GI motility in humans and animals, cisapride was clearly superior to other treatments. Initially, the only adverse effects reported in humans were increased defecation, headache, abdominal pain, and cramping and flatulence; cisapride appeared to be well tolerated in animals. As cisapride became widely used in the management of gastroesophageal reflux in humans, cases of heart rhythm disorders and deaths were reported to the FDA. These cardiac problems in humans were highly associated with concurrent drug therapy or specific underlying conditions. In veterinary medicine, adverse reactions to clinical use of cisapride have not been reported. But because of the cardiovascular side effects in humans, the manufacturer of cisapride voluntarily placed it under a limited-access program. Cisapride for animals can still be obtained through compounding veterinary pharmacies. Domperidone is a peripheral dopamine receptor antagonist that has been marketed outside the USA since 1978. It is available in Canada as a 10-mg tablet. Currently, it is available in the USA only as an investigational new drug (as a 1% oral domperidone gel) for the treatment of agalactia in mares due to fescue toxicosis. Domperidone regulates the motility of gastric and small-intestinal smooth muscle and has some effect on esophageal motility. Domperidone appears to have very little physiologic effect in the colon. It has antiemetic activity from dopaminergic blockade in the CTZ. But because very little domperidone crosses the blood-brain barrier, reports of extrapyramidal reactions are rare, and treatment is the same as for metoclopramide. Domperidone failed to enhance gastric emptying in healthy dogs in one study. In other studies, however, domperidone was superior to metoclopramide in stimulating antral contractions in dogs but not cats and improved antroduodenal coordination in dogs. Because of its favorable safety profile, domperidone appears to be an attractive alternative to metoclopramide. Macrolide antibiotics, including erythromycin and clarithromycin, are motilin receptor agonists. They also appear to stimulate cholinergic and noncholinergic neuronal pathways to stimulate motility. At microbially ineffective doses, some macrolide antibiotics stimulate migrating motility complexes and antegrade peristalsis in the proximal GI tract. Erythromycin therapy has been effective in the treatment of gastroparesis in human patients in whom metoclopramide or domperidone was ineffective. Erythromycin increases gastric emptying rate in healthy dogs, but large food chunks may enter the small intestine and be inadequately digested. Erythromycin induces contractions from the stomach to the terminal ileum and proximal colon, but the colon contractions do not appear to result in propulsive motility. Therefore, erythromycin is unlikely to benefit patients with colonic motility disorders. Human pharmacokinetic studies indicate that erythromycin suspension is the ideal dosage form for administration of erythromycin as a prokinetic agent. Other macrolide antibiotics have prokinetic activity with fewer side effects than erythromycin and may be suitable for use in small animals. While causing less GI distress than erythromycin, clarithromycin (250 mg, IV) increased gastroduodenal motility in patients being treated for functional dyspepsia and Helicobacter pylori gastritis. Both erythromycin and clarithromycin are metabolized by the hepatic cytochrome P450 enzyme system and inhibit the hepatic metabolism of other drugs including theophylline, cyclosporine, and cisapride. Nonantibiotic derivatives of erythromycin are being developed as prokinetic agents. Ranitidine and nizatidine are 2 histamine H2-receptor antagonists that are prokinetics in addition to inhibiting gastric acid secretion in dogs and rats. Their prokinetic activity is due to acetylcholinesterase inhibition, with the greatest activity in the proximal GI tract. Cimetidine and famotidine are not acetylcholinesterase inhibitors and do not have prokinetic effects. Ranitidine and nizatidine stimulate GI motility by increasing the amount of acetylcholinesterase available to bind smooth muscle muscarinic cholinergic receptors. They also stimulate colonic smooth muscle contraction in cats through a cholinergic mechanism. Ranitidine is available as tablets (75, 150, and 300 mg), a syrup (15 mg/mL), and an injectable solution (25 mg/mL). An oral dose of 1-2 mg/kg, bid, inhibits gastric acid secretion and stimulates gastric emptying. Nizatidine is available as capsules (75, 150, and 300 mg). Like ranitidine, at gastric antisecretory dosages of 2.5-5 mg/kg, nizatidine also has prokinetic effects. Ranitidine causes less interference with cytochrome P450 metabolism of other drugs than does cimetidine, and nizatidine does not affect hepatic microsomal enzyme activity, so both drugs have a wide margin of safety. Neostigmine inactivates acetycholinesterase and, therefore, prolongs the action of acetylcholine. It may also directly stimulate cholinergic receptors. It is recommended for use in large animals for treatment of paralytic ileus; however, it is short acting (15-30 min). It may cause increased secretion into the GI tract, so it is contraindicated in small-intestinal disease. In horses, it may actually decrease small-intestinal propulsive contractions and delay gastric emptying. IV lidocaine is used in the treatment of postoperative ileus in humans, and has recently been shown to be useful in treating ileus and proximal duodenitis- jejunitis in horses. It is thought to suppress the firing of primary afferent neurons, as well as to have anti-inflammatory properties and direct stimulatory effects on smooth muscle. The dosage is 1.3 mg/kg as a bolus, followed by a continuous infusion of 0.05 mg/kg/min. Most horses respond within 12 hr of starting the infusion.

Objectives

1. Provide the practitioner with a brief review of GI physiology with emphasis on the Enteric Nervous System (ENS) and its important neuromodulating substances.
2. Provide the practitioner with an understanding of the different mechanisms of action underlying prokinetic action of available drugs.
3. Provide the practitioner with pharmacokinetic data that have clinical implications in the use of prokinetic drugs in dogs and cats.
4. Provide the practitioner with specific clinical uses of available prokinetic drugs.
5. Identify the adverse side effects and potential drug interactions associated with the administration of specific prokinetic drugs.
6. Provide the practitioner with an insight on future prokinetic drug development.

Important GI physiological points

1. Gastrointestinal functions are regulated by fine tuned extrinsic (parasympathetic and sympathetic fibers) and intrinsic (ENS) systems that are under complex neurohormonal control.
2. The ENS (also called “mini-brain”) is a large and highly organized collection of neurons located in the walls of the GIT that includes the myenteric plexus (Auerbach’s plexus) and the submucous plexus (Meissner’s plexus).
3. Important identified neuromodulator substances involved in GI motility are either excitatory or inhibitory. Receptors for acetylcholine (ACh), serotonin (5-HT) and peptides (substance P, ghrelin, motilin, guanylate cyclase C, octreotide, CCK) are excitatory whereas NE (norepinephrine), dopamine, nitric oxide (NO), vasoactive intestinal peptide (VIP) and endorphins are inhibitory.

Important GI pathophysiological points

1. The most common GI motility disorders identified in companion animals involving the esophagus are hypomotility, megaesophagus, lower esophageal sphincter disorders.
2. The most common GI motility disorder identified in companion animals involving the stomach is delayed gastric emptying (functional obstruction/gastroparesis).
3. The most common GI motility disorders identified in companion animals involving the small intestine is postoperative ileus.
4. The most common GI motility disorders identified in companion animals involving the colon are chronic constipation and megacolon.
5. Most common etiological factors decreasing GI motility are autoimmune (myasthenia gravis), neuronal (trauma, dysautonomia), hormonal (hypothyroidism, hypoadrenocorticism, diabetes), inflammatory (bacterial, viral), iatrogenic (surgery, drugs), traumatic and congenital.

General mechanisms of action

Current pharmacologic targets for prokinetic action include cholinergic, dopaminergic and serotonergic receptors, motilin, opioid and H2 receptors, and chloride channels (Table 1).

Table 1. Current pharmacological targets for prokinetic action

Important pharmacologic points

1. Most of what we know is derived from in vivo and in vitro studies conducted in rodents and dogs as animal models for humans, as well as several clinical studies (Phase II to IV) conducted in human patients
2. In general, because of their pharmacological action, prokinetic drugs may affect the absorption of other oral medications and they are contraindicated in the presence of GI obstruction.
3. Metoclopramide has a short half-life hence it must be given often and has a variable oral bioavailability.
4. Metoclopramide is contraindicated in epileptic patients (extrapyramidal reactions and frequency/severity of seizure may increase) or with head injury (increase ICP).
5. The substituted benzamides, metoclopramide and cisapride, are mainly metabolized by the liver and may interact with other drugs.
6. Cisapride should not be given concomitantly with antifungal agents or macrolide antibiotics. These combinations may result in potentially fatal ventricular arrhythmias.
7. Erythromycin inhibits CYP450 and PgP transport (great potential for drug interactions).
8. Erythromycin increases gastric emptying rate in dogs, but large chunks may enter the small intestine and be inadequately digested.
9. Erythromycin may have decreased efficacy with long-term use. The combination of erythromycin and metoclopramide has shown to be beneficial and may be associated with less tachyphylaxis.
10. Ranitidine may increase the risk of side effects associated with metoclopramide when administered concomitantly.

Important therapeutic points 

Critically ill/hospitalized veterinary patients are prone to impaired GI motility as they are often administered drugs that decrease GI motility (opioids, anticholinergics, calcium channel blockers, proton pump inhibitors, sedatives, cimetidine), have high levels of circulating catecholamines, may have head trauma or sepsis, have decrease activity or have undergone invasive surgery. These patients may benefit from the administration of prokinetic drugs as they may potentially shorten the hospital stay.

 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 Agents

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.

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

Compiled  & Shared by- Team, LITD (Livestock Institute of Training & Development)

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Reference-On Request.

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