Gastrointestinal Prokinetic Drugs (Monogastric)
Prokinetic drugs increase the movement of ingested material through the GI tract (see Prokinetic Drugs). They are useful in the treatment of motility disorders, because they induce coordinated motility patterns. Unfortunately, some prokinetic drugs may produce a number of serious adverse effects that complicate their use.
The enteric nervous system of the GI tract can function independently of the CNS to control bowel function. Because there are no nerve fibers that actually penetrate the intestinal epithelium, the enteric nervous system uses enteroendocrine cells such as the enterochromaffin cells as sensory transducers. More than 95% of the body’s serotonin is located in the GI tract, and >90% of that store is in the enterochromaffin cells scattered in the enteric epithelium from the stomach to the colon. The remaining serotonin is located in the enteric nervous system, where 5-HT acts as a neurotransmitter. From the enterochromaffin cells, serotonin is secreted into the lamina propria in high concentrations, which overflow into the portal circulation and intestinal lumen. The effect of serotonin on intestinal activity is coordinated by 5-HT receptor subtypes. The 5-HT1P receptor initiates peristaltic and secretory reflexes, and so far no drugs have been developed to target this specific receptor. The 5-HT3 receptor activates extrinsic sensory nerves and is responsible for the sensation of nausea and induction of vomiting from visceral hypersensitivity. Therefore, specific 5-HT3 antagonists such as ondansetron and granisetron are very effective for treatment of vomiting seen with chemotherapy. Stimulation of the 5-HT4 receptor increases the presynaptic release of acetylcholine and calcitonin gene-related peptide, thereby enhancing neurotransmission. This enhancement promotes propulsive peristaltic and secretory reflexes. Specific 5-HT4 agonists such as cisapride enhance neurotransmission and depend on natural stimuli to evoke peristaltic and secretory reflexes. This makes these drugs very well tolerated, because they do not induce perpetual or excessive motility. It is also the reason for the limitations of these drugs, because they are not effective if enteric nerves have degenerated or become nonfunctional (as in cats with end-stage megacolon).
Metoclopramide is a central dopaminergic antagonist and peripheral 5-HT3 receptor antagonist and 5-HT4 receptor agonist 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 in which 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 relief of vomiting associated with chemotherapy in dogs, as an antiemetic for dogs with parvoviral enteritis, and for treatment of gastroesophageal reflux and postoperative ileus. GI obstruction, such as intussusception in puppies with parvoviral enteritis, must be excluded before 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 absorbed in the small intestine. Because of accelerated food absorption, metoclopramide therapy may increase the insulin dose required in animals with diabetes.
Metoclopramide readily crosses the blood-brain barrier, where dopamine antagonism at the CRTZ 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. Concurrent use of phenothiazine and butyrophenone tranquilizers should be avoided, because they also have central antidopaminergic activity, which increases the potential for extrapyramidal reactions. 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 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 is a serotonin 5-HT4 agonist with some 5-HT3 antagonist activity, so it enhances the release of acetylcholine from postganglionic nerve endings of the myenteric plexus and antagonizes the inhibitory action of serotonin (5-HT3) on the myenteric plexus, resulting in increased GI motility and increased 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. Cisapride is especially useful in animals that experience neurologic effects from metoclopramide. Cisapride is very useful in managing gastric stasis, idiopathic constipation, and postoperative ileus in dogs and cats. Cisapride may be especially useful in managing chronic constipation in cats with megacolon; in many cases, it alleviates or delays the need for subtotal colectomy. Cisapride is also useful in managing cats with hairball problems and in dogs with idiopathic megaesophagus that continue to regurgitate frequently despite a carefully managed, elevated feeding program. In comparative studies of GI motility in people and animals, cisapride is clearly superior to other treatments.
Initially, the only adverse effects reported in people were increased defecation, headache, abdominal pain, and cramping and flatulence; cisapride appeared to be well tolerated in animals. As cisapride became widely used in management of gastroesophageal reflux in people, cases of heart rhythm disorders and deaths were reported to the FDA. These cardiac problems in people 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. Cisapride for animals can only 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 (1% oral domperidone gel) to treat 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. It appears to have very little physiologic effect in the colon. It has antiemetic activity from dopaminergic blockade in the CRTZ. But because very little domperidone crosses the blood-brain barrier, reports of extrapyramidal reactions are rare; however, if a reaction occurs, the treatment is the same as for reactions to 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 it 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 has been effective in the treatment of gastroparesis in human patients in whom metoclopramide or domperidone was ineffective. Erythromycin increases the 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 adverse effects than erythromycin and may be suitable for use in small animals. 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 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 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.
IV lidocaine is used in the treatment of postoperative ileus in people and has been shown to be useful in treating ileus and proximal duodenitis-jejunitis in horses. It is thought to suppress firing of primary afferent neurons, as well as to have anti-inflammatory properties and direct stimulatory effects on smooth muscle. It is also thought to suppress the primary afferent neurons from firing, as well as have anti-inflammatory properties and direct stimulatory effects on smooth muscle. Most horses respond within 12 hr of starting an infusion.