Gastrointestinal Pro Kinetic Therapy-motilin-like Drugs

Vol. 19, No. 3 March 1997

Continuing Education Article

V

N E W ! C O N T I N U I N G E D U C AT I O N S E R I E S

Refereed Peer Review

FOCAL POINT ★The effect of erythromycin on gastrointestinal motility most closely mimics that of the gastrointestinal hormone motilin.

KEY FACTS ■ Microbially effective oral dosages of erythromycin (10 to 20 mg/kg every 8 hours) stimulate retrograde peristalsis and vomiting in dogs. ■ Microbially ineffective oral dosages of erythromycin (0.5 to 1.0 mg/kg every 8 hours) stimulate migrating motility complexes and antegrade peristalsis in dogs. ■ Erythromycin stimulates gastrointestinal motility by means of direct motilin-receptor activation (in cats) and indirect cholinergic and neurokinin activation (in dogs). ■ Erythromycin stimulates motility in the proximal gastrointestinal tract—the lower esophageal sphincter, stomach, and small intestine.

Small Animal Gastroenterology

Successfully complete the quizzes at the end of each CE article in this series, and receive a certificate suitable for framing. This is the second of five articles.

Gastrointestinal Prokinetic Therapy: Motilin-like Drugs Oregon State University

University of Pennsylvania

Jean A. Hall, DVM, PhD

Robert J. Washabau, VMD, PhD

T

he first article in this five-part series on gastrointestinal prokinetic therapy, which appeared in the February 1997 (Vol. 19, No. 2) issue of Compendium, discussed dopaminergic antagonist agents. This article considers motilin-like drugs, focusing on erythromycin. The third part will deal with serotonergic drugs; the fourth will consider acetylcholinesterase inhibitors or parasympathetic potentiating drugs. The final article will discuss the diagnosis and treatment of esophageal, gastric, and colonic motility disorders.

ERYTHROMYCIN The antibiotic properties of erythromycin and other macrolides were discovered in the early 1950s. Since that time, erythromycin has been widely used in treating patients with gram-positive and gram-negative bacterial and mycoplasmal infections. It was noted that erythromycin therapy was accompanied by frequent gastrointestinal side effects (e.g., nausea and vomiting). This occurrence suggested to researchers that erythromycin might have effects on gastrointestinal motility. It was subsequently demonstrated that microbially effective doses of erythromycin stimulated retrograde peristalsis and vomiting in dogs.1–4 More recently, it was demonstrated that much lower, microbially ineffective doses of the agent stimulate migrating motility complexes and antegrade peristalsis similar to that induced by endogenous motilin.5–8 Erythromycin thus might be a useful gastrointestinal prokinetic agent.9 Physicochemical Properties Erythromycin is produced by Streptomyces erythraeus and belongs to the macrolide group of antibiotics. The active base is a white to off-white powder or crystals that are soluble in alcohol, chloroform, and ether but virtually insoluble in water. Erythromycin is available in parenteral form (erythromycin lactobionate, at 100 mg/ml)

Small Animal

The Compendium March 1997

and enteral form (erythromycin stearate and erythromycin ethylsuccinate). The enteral form is available as enteric-coated tablets (250-, 333-, and 500-mg), filmcoated tablets (250- and 500mg), capsules (125- and 250mg), oral drops (100 mg/ml), or oral suspension (25 and 50 mg/ ml).

Clinical Applications of Erythromycin

lower (0.5 to 1.0 mg/kg every 8 hours).1,3,4,16,17

Clinical Applications Lower Esophageal Sphincter Motilin, erythromycin, and erythromycin analogues that lack antimicrobial activity (e.g., LY267108) increase lower esophageal sphincter (LES) pressure in cats 18 (see the box on Clinical Applications of Erythromycin). These motilin-like drugs can be referred to as motilides. Erythromycin also increases LES pressure in cats in which the basal LES pressure has been lowered experimentally by perfusing the distal esophagus with acid (0.1 normal hydrochloric acid for 3 days) or after intravenous isoproterenol (3.0 µg/kg).18–20 The erythromycin-induced increase in LES pressure does not interfere with LES relaxation that occurs after swallowing; the use of erythromycin thus should not be associated with dysphagia.18 These data suggest that eryt h romycin should be useful in treating cats, and perhaps dogs, with gastroesophageal reflux and reflux esophagitis.

■ To increase lower esophageal sphincter pressure in cats ■ To accelerate gastric emptying by inducing antral contractions ■ To facilitate intestinal transit in patients with small intestinal motility disorders

Pharmacokinetics Interpreting pharmacokinetic data is difficult because of gastric instability, variable absorption, and variable protein binding of erythromycin.10,11 In one study, intravenously administered erythromycin (10 mg/kg) had an elimination half-life of 103 minutes in beagles.10 Total clearance of erythromycin was 21 ml/min/kg, and the apparent volume of distribution was 2.7 L/kg.10 Erythromycin is widely distributed in tissues, and metabolites are excreted in feces (66%) and urine (33%).12 Erythromycin secreted in bile is reabsorbed from the intestinal tract and redistributed in various tissues, suggesting enterohepatic recycling.13 The pharmacokinetics of orally administered erythromycin acistrate and stearate have been studied in dogs that were fasted and in dogs that were fed.11 Reliable therapeutic serum concentrations were not achieved when any preparation was given with food, and serum concentrations were not consis- Figure 1—Diagram of the pharmacologic effects of the gastrointestinal tent when the drug prokinetic agent erythromycin. In dogs, the mechanism of erythromycin was given without prokinetic response apparently involves cholinergic and noncholinergic food.11 neuronal pathways. The scheme of these pathways is based purely on funcThe recommended tional studies of the canine stomach; the effect of erythromycin on ganantimicrobial dosage glionic 5HT3 serotonergic receptors (5-HT3) has not yet been substantiatof oral erythromycin ed by radioligand binding studies. In cats, erythromycin behaves as a in dogs and cats is 10 motilin-receptor agonist (SP = substance P; ACh = acetylcholine; NK1 = to 20 mg/kg every 8 postsynaptic NK1 neurokinin receptor; M3 = postsynaptic M3 muscarinic hours. 14,15 However, cholinergic receptor; MOT = postsynaptic motilin receptor; and (+) = the prokinetic dos- stimulation). (Computer graphics created by Dr. Carl Sammarco, School of Veterinary Medicine, University of Pennsylvania) age is probably much

Gastric Emptying Intravenous erythromycin accelerates gastric emptying by inducing antral contractions that are similar, but not identical, to those that are associated with phase III of the migrating motility complex (MMC). 1,21–23 Phase III contractions, which usually occur only during the fasting state, empty the stomach of indigestible solids.24 Erythromycin accelerates gastric emptying of solids during

PHARMACOKINETIC DATA ■ THERAPEUTIC SERUM CONCENTRATIONS ■ MOTILIDES

The Compendium March 1997

the fed state such that food is inadequately triturated (i.e., food particles are larger than 0.5 mm) and emptied into the small intestine.23 Studies have demonstrated that the stomach empties only 6% of solids as particles larger than 0.5 mm.25 Because of the small surface area:mass ratio associated with large chunks of food, the small intestine may inadequately digest and absorb these nutrients. Erythromycin thus should be used as a gastric prokinetic agent with the understanding that (1) it is inducing an interdigestive motor pattern and not restoring a normal fed pattern of gastric motility and (2) food will not be expelled as normally digestible particles of small size.23 If large particles of food in the small bowel cause intestinal distress, use of this prokinetic drug may not lead to improvement and may increase signs despite more-rapid gastric emptying. The prokinetic effect of erythromycin has been compared with that of other gastrointestinal prokinetic agents.5 Cisapride and metoclopramide administered intravenously at a dose of 1 mg/kg induce relatively strong and long-lasting contractions in the stomach in the digestive state, but the amplitude of the gastric contractions is less than that of phase III of the MMC (the peak increase is less than twofold). 5 Antral contractions induced by erythromycin (50 to 100 µg/kg/hr) are greater in amplitude and frequency than those induced by cisapride and metoclopramide or those that occur during phase III of the natural MMC.1

Small Intestinal Transit Erythromycin, like motilin, induces strong contractions in the intestine similar to those of the naturally occurring interdigestive MMC.1–5,7,8,26 Intravenous erythromycin lactobionate (0.05 to 50 mg/kg/hr),1–4,8 oral erythromycin ethylsuccinate (250 or 500 mg),3 oral erythromycin stearate (30 to 500 mg),2,3,7 and intravenous EM-523 (0.01 to 0.1 mg/kg/hr)5,26 induce contractions that originate in the gastric antrum and migrate to the duodenum, jejunum, and terminal ileum. Although these contractions are associated with the release of endogenous motilin,1,3,5 the amount of motilin released is apparently not sufficient to induce contractions.9 There is scant information to indicate that erythromycin will be useful in treating pseudoobstruction and ileus, but two preliminary reports suggest that it may be of use in treating postoperative ileus in dogs.26,27 Based on the available information, it seems reasonable to recommend the use of erythromycin as a gastrointestinal prokinetic agent in animals with small intestinal motility disorders (particularly those of the proxi-

Small Animal

mal small intestine) that are refractory to other prokinetic agents.

Colonic Motility Erythromycin-induced contractions propagate from the stomach to the terminal ileum and proximal colon, but erythromycin contractions in the colon apparently do not stimulate propulsive motility.26,28 The agent thus will probably not prove to be useful in treating patients with colonic motility disorders.29 Pharmacologic Effects In cats, rabbits, and humans, erythromycin behaves as a motilin-receptor agonist6,9,30–32 (Figure 1). In these species, the contractile response of erythromycin results entirely from the binding of erythromycin to motilin receptors on gastrointestinal smooth muscle cells. Erythromycin does not behave as a motilin agonist in all species; for example, the drug has no direct effect on canine gastrointestinal smooth muscle.33 The mechanism of the erythromycin prokinetic response in dogs has not been completely elucidated but apparently involves cholinergic and noncholinergic neuronal pathways.2,4,5,16,21,22 The cholinergic pathway is mediated by activation of 5-HT3 receptors on postganglionic cholinergic neurons, neuronal depolarization and release of acetylcholine, and cholinergic receptor activation on gastrointestinal smooth muscle cells. The noncholinergic pathway is mediated by activation of 5-HT3 receptors on postganglionic substance P–containing neurons, neuronal depolarization and release of substance P, and neurokinin-1 receptor activation on gastrointestinal smooth muscle cells.21,22 The cholinergic pathway predominates if erythromycin is given during fasting; cholinergic and noncholinergic pathways are activated if erythromycin is administered during or after feeding.21,22 Erythromycin also stimulates motilin release from endocrine cells in the canine gastrointestinal tract, but the amount of motilin released is apparently not sufficient to stimulate contraction.22 In dogs, the pharmacology of erythromycin contractions is evidently similar to that of motilin contractions.34–37 The role of motilin in the regulation of feline gastrointestinal motility and the role of erythromycin in the treatment of feline gastrointestinal motility disorders remain to be determined. In dogs and humans, it has been proposed that motilin is involved in the induction of phase III of the MMC.24 This cannot be the physiologic role of motilin in cats, however, because they are the only known mammalian species that does not exhibit MMCs in the fasting state.30,38 Giant mi-

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The Compendium March 1997

grating contractions constitute the normal fasting motor pattern in the feline small intestine.39,40 The role of motilin in the regulation of these contractions is not yet determined. In vitro experiments have demonstrated that erythromycin binds motilin receptors in the feline intestine and stimulates intestinal smooth muscle contraction.30

Adverse Reactions The side effects of oral erythromycin therapy are dose-dependent and primarily related to the gastrointestinal tract. Side effects include nausea, vomiting, abdominal pain, diarrhea, and anorexia. 3 Hepatic dysfunction and/or abnormal liver function tests may occur. Allergic reactions range from urticaria and mild skin eruptions to anaphylaxis. The emergence of resistant bacterial strains during chronic therapy is theoretically possible but has not been documented clinically. All parenteral preparations may produce irritation at the site of injection. Drug Interactions Several drug interactions have been identified in treated humans. 41 Kaolin, pectin, and bismuth decrease gastrointestinal absorption of erythromycin. Erythromycin binds serum proteins competitively with chloramphenicol, lincomycin, and clindamycin. At low doses, erythromycin may antagonize the antimicrobial action of the penicillins. Increased serum erythromycin concentrations may develop in patients that are receiving theophylline; an increased digitalis effect may occur in humans that receive the drugs concurrently. Erythromycin may cause prolonged bleeding in patients that are receiving warfarin therapy. Methylprednisolone metabolism may be inhibited by erythromycin. Concurrent use of erythromycin with terfenadine may predispose patients to severe cardiac arrhythmia. No serious drug interactions have been reported in veterinary species. OTHER MACROLIDES The 14-membered macrolides (e.g., erythromycin, clarithromycin, oleandomycin, and roxithromycin) have gastrointestinal prokinetic activity. 2,7–9 These compounds are currently being investigated for comparative efficacies and side effects. The 16-membered macrolides (e.g., tylosin, leukomycin, and acetylspiramycin) have no effect on gastrointestinal motility.2,7–9 Other macrolides (e.g., EM-523, EM-574, and LY267108) have gastrointestinal prokinetic effects without the antibacterial properties.9,26 This group of drugs may be particularly useful if resistant strains of bacteria begin to emerge during chronic therapy.

BOOKS

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SYS T E M S

ANAPHYLAXIS ■ THEOPHYLLINE

The Compendium March 1997

About the Authors Dr. Hall is affiliated with the College of Veterinary Medicine, Oregon State University, Corvallis, Oregon. Dr. Washabau is affiliated with the Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Drs. Hall and Washabau are Diplomates of the American College of Veterinary Internal Medicine.

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REFERENCES 1. Itoh Z, Nakaya M, Suzuki T, et al: Erythromycin mimics exogenous motilin in gastrointestinal contractile activity in the dog. Am J Physiol 247:G688–G694, 1984. 2. Itoh Z, Suzuki T, Nakaya M, et al: Gastrointestinal motorstimulating activity of macrolide antibiotics and analysis of their side effects on the canine gut. Antimicrob Agents Chemother 26(6):863–869, 1984. 3. Otterson MF, Sarna SK: Gastrointestinal motor effects of erythromycin. Am J Physiol 259:G355–G363, 1990. 4. Holle GE, Steinbach E, Forth W: Effects of erythromycin in the dog upper gastrointestinal tract. Am J Physiol 263: G52–G59, 1992. 5. Inatomi N, Satoh H, Maki Y, et al: An erythromycin derivative, EM-523, induces motilin-like gastrointestinal motility in dogs. J Pharmacol Exp Ther 251(2):707–712, 1989. 6. Peeters T, Matthijs G, Depoortere I, et al: Erythromycin is a motilin receptor agonist. Am J Physiol 257:G470–G474, 1989. 7. Nakayoshi T, Izumi M, Tatsuta K: Effects of macrolide antibiotics on gastrointestinal motility in fasting and digestive states. Drugs Exp Clin Res 18:103–109, 1992. 8. Itoh Z, Suzuki T, Nakaya M, et al: Structure–activity relation among macrolide antibiotics in initiation of interdigestive migrating contractions in the canine gastrointestinal tract. Am J Physiol 248:G320–G325, 1985. 9. Peeters TL: Erythromycin and other macrolides as prokinetic agents. Gastroenterology 105:1886–1899, 1993. 10. Duthu GS: Interspecies correlation of the pharmacokinetics of erythromycin, oleandomycin, and tylosin. J Pharmaceut Sci 74(9):943–946, 1985. 11. Eriksson A, Rauramaa V, Happonen I, Mero M: Feeding reduced the absorption of erythromycin in the dog. Acta Vet Scand 31(4):497–499, 1990. 12. Lee CC, Anderson RC, Chen KK: The biliary and urinary excretion of erythromycin in dogs. Antibiot Annu:485–492, 1953. 13. Lee CC, Anderson RC, Bird HL, Chen KK: Reabsorption of erythromycin and a microbiologically active metabolite in the bile of dogs and rats. Antibiot Annu:493–495, 1953. 14. Allen D: Handbook of Veterinary Drugs. Philadelphia, JB Lippincott Co, 1993, p 15. 15. Brown SA: Appropriate use of antimicrobial agents, in August JR (ed): Consultations in Feline Internal Medicine. Philadelphia, WB Saunders Co, 1991, pp 583–596. 16. Carlson RG, Hocking MP, Sninsky CA, Vogel SB: Erythromycin acts through a cholinergic pathway to improve

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

canine-delayed gastric emptying following vagotomy and Roux-Y antrectomy. J Surg Res 50:494–498, 1991. Carlson RG, Hocking MP, Courington KR, et al: Erythromycin enhances delayed gastric emptying in dogs after Roux-Y antrectomy. Am J Surg 161:31–34, 1991. Greenwood B, Dieckman D, Kirst HA, et al: Effects of LY267108, an erythromycin analogue derivative, on lower esophageal sphincter function in the cat. Gastroenterology 106:624–628, 1994. Eastwood GL, Castell DO, Higgs RH: Experimental esophagitis in cats impairs lower esophageal sphincter pressure. Gastroenterology 69:146–153, 1975. Biancani P, Barwick K, Selling J, et al: Effects of acute experimental esophagitis in mechanical properties of lower esophageal sphincter function. Gastroenterology 87:8–16, 1984. Ohtawa M, Mizumoto A, Hayashi N, et al: Mechanism of gastroprokinetic effect of EM523, an erythromycin derivative, in dogs. Gastroenterology 104:1320–1327, 1993. Shiba Y, Mizumoto A, Inatomi N, et al: Stimulatory mechanism of EM523-induced contractions in postprandial stomach of conscious dogs. Gastroenterology 109:1513–1521, 1995. Lin HC, Sanders SL, Gu YG, Doty JE: Erythromycin accelerates solid emptying at the expense of gastric sieving. Dig Dis Sci 39(1):124–128, 1994. Hall JA, Burrows CF, Twedt DC: Gastric motility in dogs. Part I. Normal gastric function. Compend Contin Educ Pract Vet 10(11):1282–1293, 1988. Meyer JH, Thomson JB, Cohen MB, et al: Sieving of solid food by the canine stomach and sieving after gastric surgery. Gastroenterology 76:804–813, 1979. Inatomi N, Satoh T, Satoh H, et al: Comparison of the motor-stimulating action of EM523, an erythromycin derivative, and prostaglandin F2α in conscious dogs. Jpn J Pharmacol 63:209–217, 1993. Holle GE, Forth W: Response of prostigmine and erythromycin on gastrointestinal motility after abdominal surgery. Gastroenterology 100:A450, 1991. Zara GP, Thompson HH, Pilot MA, et al: Effects of erythromycin on gastrointestinal tract motility. J Antimicrob Chemother 16:175–179, 1985. Longo WE, Vernava AM: Prokinetic agents for lower gastrointestinal motility disorders. Dis Colon Rectum 36: 696–708, 1993. Depoortere I, Peeters TL, Vantrappen G: Distribution and characterization of motilin receptors in the cat. Peptides 14:1153–1157, 1993. Depoortere I, Peeters TL, Vandermeers A, et al: Purification and amino acid sequence of motilin from cat small intestine. Reg Peptides 49:25–32, 1993. Depoortere I, Peeters TL, Vantrappen G: The erythromycin derivative EM-523 is a potent motilin agonist in man and in rabbit. Peptides 11:515–519, 1990. Fox JET, Daniel EE, Jury J, et al: Sites and mechanisms of action of neuropeptides on canine gastric motility differ in vivo and in vitro. Life Sci 33:817–825, 1983. Mizumoto A, Sano I, Matsunaga Y, et al: Mechanism of motilin-induced contractions in isolated perfused canine stomach. Gastroenterology 105:425–432, 1993.

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35. Itoh Z, Mizumoto A, Iwanaga Y, et al: Involvement of 5-hydroxytryptamine 3 receptors in regulation of interdigestive gastric contractions by motilin in the dog. Gastroenterology 100:901–908, 1991. 36. Haga N, Mizumoto A, Satoh M, et al: Role of endogenous 5-hydroxytryptamine in the regulation of gastric contractions by motilin in dogs. Am J Physiol 270:G20–G28, 1996. 37. Milenov K, Shahbazian A: Cholinergic pathways in the effect of motilin on the canine ileum and gallbladder motility: In vivo and in vitro experiments. Comp Biochem Physiol 112A:403–410, 1995.

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38. Weisbrodt NW, Christensen J: Electrical activity of the cat duodenum in fasting and vomiting. Gastroenterology 63: 1004–1010, 1972. 39. De Vos WC: Migrating spike complex in the small intestine of the fasting cat. Am J Physiol 265:G619–G627, 1993. 40. De Vos WC: Role of the enteric nervous system in the control of migrating spike complexes in the feline small intestine. Am J Physiol 265:G628–G637, 1993. 41. Allen D: Handbook of Veterinary Drugs. Philadelphia, JB Lippincott Co, 1993, pp 143–144.