Gastrointestinal Prokinetic Drugs:
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.
Gastrointestinal Prokinetic Drugs
Gastrointestinal Prokinetic Drugs: