Prokinetic drugs increase the movement of ingested material through the GI tract (see the table Prokinetic Drugs). They are useful in the management of motility disorders in humans and animals by inducing coordinated motility patterns. Unfortunately, some prokinetic drugs may produce serious adverse effects that complicate their use.
The enteric nervous system can function independently of the CNS to control bowel function. Because no nerve fibers 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 produced in the GI tract, and > 90% is stored in the enterochromaffin cells scattered in the enteric epithelium from the stomach to the colon.
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, but 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 receptor antagonists, such as ondansetron and granisetron, are effective for treatment of vomiting that accompanies 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 receptor agonists, such as cisapride, enhance neurotransmission and depend on natural stimuli to evoke peristaltic and secretory reflexes. These drugs are well tolerated and do not induce perpetual or excessive motility. These drugs are not effective if enteric nerves have degenerated or become nonfunctional (as in cats with end-stage megacolon).
Prokinetic Drugs
Drug | Dosage |
|---|---|
Metoclopramide | Dogs, cats: 0.2–0.5 mg/kg, PO or SC, q 8 h; 0.01–0.02 mg/kg/h, IV infusion |
Horses: 0.125–0.25 mg/kg, diluted in 500 mL of polyionic solution and administered IV over 60 min or as a CRI of 0.04 mg/kg/h | |
Domperidone | Dogs, cats: 0.1–0.5 mg/kg, IM; 0.5–1 mg/kg, PO |
Cisapride | Dogs: 0.1–0.5 mg/kg, PO, q 8–12 h; doses up to 1 mg/kg have been used in some dogs |
Cats: 2.5 mg/cat for cats < 5 kg, and 5 mg/cat for cats > 5 kg, PO, q 8 h | |
Erythromycin | Dogs, 0.5–1 mg/kg, PO, q 8–12 h |
Horses: 1 mg of erythromycin lactobionate/kg, IV | |
Ranitidine | Dogs, cats: 1–2 mg/kg, PO, q 12 h |
Nizatidine | Dogs, cats: 2.5–5 mg/kg, PO, q 12 h |
Lidocaine | Horses: 1.3 mg/kg, IV, as a bolus, followed by a CRI of 0.05 mg/kg/min |
Abbreviations: CRI, constant-rate infusion. |
Metoclopramide is a central dopaminergic receptor 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; however, it 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, so it is not useful in cats with megacolon. It is occasionally used to treat postoperative ileus in horses.
Metoclopramide is indicated primarily 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 treatment with metoclopramide is initiated.
The prokinetic action of metoclopramide 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 decreased absorption. Bioavailability may be increased for drugs absorbed in the small intestine. Because of accelerated food absorption, metoclopramide treatment may increase the insulin dose required in patients with diabetes.
Metoclopramide readily crosses the blood-brain barrier. Dopaminergic receptor antagonism at the chemoreceptor trigger zone (CRTZ) produces an antiemetic effect. However, dopaminergic receptor antagonism in the striatum has 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 restoration of an appropriate dopamine-acetylcholine balance with the anticholinergic action of an antihistamine, such as diphenhydramine hydrochloride (1 mg/kg, IV).
Domperidone is a peripheral dopaminergic receptor antagonist that has been marketed outside the US for human use since 1978. It is available in Canada as a 10-mg tablet. In the US, it is available as 1% oral domperidone gel to treat mares for agalactia 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 little physiologic effect in the colon. It has antiemetic activity from dopaminergic blockade in the CRTZ. Because little domperidone crosses the blood-brain barrier, reports of extrapyramidal reactions are rare; if a reaction does occur, extrapyramidal signs can be reversed by restoration of an appropriate dopamine-acetylcholine balance with the anticholinergic action of an antihistamine, such as diphenhydramine hydrochloride (1 mg/kg, IV).
In one study, domperidone failed to enhance gastric emptying in healthy dogs.(1) In other studies, domperidone was superior to metoclopramide in stimulating antral contractions in dogs but not cats. It also improved antroduodenal coordination in dogs.
Given its favorable safety profile, domperidone appears to be an attractive alternative to metoclopramide.
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 produce extrapyramidal effects (extreme CNS stimulation).
Cisapride is a 5-HT4 receptor agonist with some 5-HT3 receptor antagonist activity. It enhances the release of acetylcholine from postganglionic nerve endings of the myenteric plexus and antagonizes the inhibitory action of serotonin (via 5-HT3 receptors) on the myenteric plexus, resulting in increased GI motility and increased heart rate.
Cisapride is more potent than metoclopramide and has broader prokinetic activity, increasing the motility of the colon as well as that of the esophagus, stomach, and small intestine.
Cisapride is especially useful in animals that develop neurologic effects from metoclopramide. Cisapride is also useful in managing gastric stasis, idiopathic constipation, and postoperative ileus in dogs and cats. Cisapride may promote more effective gastric emptying in cats. It may be particularly useful in managing cats with chronic constipation or megacolon; in many cases, it alleviates or delays the need for subtotal colectomy. Cisapride is also useful in dogs with idiopathic megaesophagus that continue to regurgitate frequently, despite a carefully managed, elevated feeding program. In comparative studies of GI motility in humans and animals, cisapride has been found to be clearly superior to other treatments.
Initially, the only adverse effects of cisapride reported in humans were increased defecation, headache, abdominal pain, and cramping and flatulence; the drug 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, and cisapride was removed from the human market. These cardiac problems in humans were highly associated with concurrent drug treatment or specific underlying conditions.
In veterinary medicine, adverse reactions to clinical use of cisapride have not been reported. Cisapride for animals can be obtained through compounding veterinary pharmacies from imported active pharmaceutical ingredients.
Macrolide antimicrobials, including erythromycin and clarithromycin, are motilinergic receptor agonists. They also appear to stimulate cholinergic and noncholinergic neuronal pathways to stimulate motility. At microbially ineffective doses, some macrolide antimicrobials 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; however, 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; however, 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 the drug as a prokinetic agent. Other macrolide antimicrobials have prokinetic activity with fewer adverse effects than erythromycin has 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. Nonantimicrobial derivatives of erythromycin are being developed as prokinetic agents.
Ranitidine and nizatidine are H2-receptor antagonists that act as prokinetic agents 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 interferes less 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.
Lidocaine is administered IV in the treatment of postoperative ileus in humans and has been shown to be useful in treating ileus and proximal duodenitis-jejunitis in horses, but the evidence is conflicting. Suppression of inhibitory GI reflexes by the decrease of postoperative peritoneal irritation is suggested as the mechanism of action. Lidocaine is also thought to suppress the primary afferent neurons from firing, as well as to have anti-inflammatory properties and direct stimulatory effects on smooth muscle. Most horses respond within 12 hours of starting an infusion; however, the large volume of lidocaine required is expensive.
Alpha-2 adrenergic receptor antagonists have potential in the treatment of ileus in horses. Alpha-2 adrenergic receptors have a role in regulating gastric tone and acetylcholine release through a presynaptic mechanism in the enteric nervous system. Sympathetic nerve activity and plasma concentrations of catecholamine increase during endotoxemia, contributing to lipopolysaccharide-induced ileus. Adrenergic receptor antagonists, especially alpha-2 receptor antagonists, should prevent the effects of norepinephrine on intrinsic neurons and stimulate smooth muscle.
Yohimbine, although not a very selective alpha-2 receptor antagonist, blocks vomiting in cats and is somewhat effective in the treatment of trauma-induced ileus in horses. In one study, yohimbine was effective in blocking the effects of lipopolysaccharide on gastric emptying in horses and was also effective in blocking the lipopolysaccharide-induced decrease in cecal blood flow in the horse.
Atipamazole, a very selective alpha-2 receptor antagonist, has been successful in treating laparotomy-induced ileus in rats.
Alpha-2 receptor antagonists have the potential to cause excitement and should be administered by slow IV infusion.
References
Orihata M, Sarna SK. Contractile mechanisms of action of gastroprokinetic agents: cisapride, metoclopramide, and domperidone. Am J Physiol. 1994 Apr;266(4 Pt 1):G665-76. doi: 10.1152/ajpgi.1994.266.4.G665. PMID: 8179003.
