Vol. 19, No.
3 March 1997 V Small Animal Gastroenterology
Continuing Education Article
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.
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
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 dis-
cuss the diagnosis and treatment of esophageal, gastric, and colonic motility
disorders.
ERYTHROMYCIN
The antibiotic properties of erythromycin and other macrolides were discov-
ered in the early 1950s. Since that time, erythromycin has been widely used in
treating patients with gram-positive and gram-negative bacterial and myco-
plasmal infections. It was noted that erythromycin therapy was accompanied
by frequent gastrointestinal side effects (e.g., nausea and vomiting). This oc-
currence suggested to researchers that erythromycin might have effects on
gastrointestinal motility.
It was subsequently demonstrated that microbially effective doses of eryth-
romycin stimulated retrograde peristalsis and vomiting in dogs.1–4 More recent-
ly, 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 use-
ful 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. Ery-
thromycin is available in parenteral form (erythromycin lactobionate, at 100 mg/ml)
Small Animal The Compendium March 1997

and enteral form (eryth- lower (0.5 to 1.0 mg/kg ev-

romycin stearate and eryth- Clinical Applications of Erythromycin ery 8 hours).1,3,4,16,17
romycin ethylsuccinate). The
enteral form is available as ■ To increase lower esophageal sphincter pressure Clinical Applications
enteric-coated tablets (250-, in cats Lower Esophageal
333-, and 500-mg), film- ■ To accelerate gastric emptying by inducing antral Sphincter
coated tablets (250- and 500- Motilin, erythromycin,
contractions
mg), capsules (125- and 250- and erythromycin ana-
mg), oral drops (100 mg/ml), ■ To facilitate intestinal transit in patients with small logues that lack antimic-
or oral suspension (25 and intestinal motility disorders robial activity (e.g., LY-
50 mg/ ml). 267108) increase lower
esophageal sphincter (LES)
Pharmacokinetics pressure in cats 18 (see the
Interpreting pharmacokinetic data is difficult because box on Clinical Applications of Erythromycin). These
of gastric instability, variable absorption, and variable motilin-like drugs can be referred to as motilides. Ery-
protein binding of erythromycin.10,11 In one study, in- thromycin also increases LES pressure in cats in which
travenously administered erythromycin (10 mg/kg) had the basal LES pressure has been lowered experimentally
an elimination half-life of 103 minutes in beagles.10 To- by perfusing the distal esophagus with acid (0.1 normal
tal clearance of erythromycin was 21 ml/min/kg, and hydrochloric acid for 3 days) or after intravenous iso-
the apparent volume of distribution was 2.7 L/kg.10 proterenol (3.0 µg/kg).18–20 The erythromycin-induced
Erythromycin is widely distributed in tissues, and increase in LES pressure does not interfere with LES
metabolites are excreted in feces (66%) and urine relaxation that occurs after swallowing; the use of
(33%).12 Erythromycin secreted in bile is reabsorbed from erythromycin thus should not be associated with dys-
the intestinal tract and phagia.18 These data
redistributed in vari- suggest that ery-
ous tissues, suggesting t h romycin should
enterohepatic recy- be useful in treating
cling.13 The pharma- cats, and perhaps
cokinetics of orally dogs, with gastro-
administered eryth- esophageal reflux and
romycin acistrate and reflux esophagitis.
stearate have been
studied in dogs that Gastric Emptying
were fasted and in Intravenous eryth-
dogs that were fed.11 romycin accelerates
Reliable therapeutic gastric emptying by
serum concentrations inducing antral con-
were not achieved tractions that are
when any preparation similar, but not iden-
was given with food, tical, to those that
and serum concentra- are associated with
tions were not consis- Figure 1—Diagram of the pharmacologic effects of the gastrointestinal phase III of the mi-
tent when the drug prokinetic agent erythromycin. In dogs, the mechanism of erythromycin grating motility com-
was given without prokinetic response apparently involves cholinergic and noncholinergic plex (MMC). 1,21–23
food.11 neuronal pathways. The scheme of these pathways is based purely on func- Phase III contrac-
The recommended tional studies of the canine stomach; the effect of erythromycin on gan- tions, which usually
antimicrobial dosage glionic 5HT3 serotonergic receptors (5-HT3) has not yet been substantiat- occur only during
of oral erythromycin ed by radioligand binding studies. In cats, erythromycin behaves as a the fasting state, emp-
in dogs and cats is 10 motilin-receptor agonist (SP = substance P; ACh = acetylcholine; NK1 = ty the stomach of
to 20 mg/kg every 8 postsynaptic NK1 neurokinin receptor; M3 = postsynaptic M3 muscarinic indigestible solids.24
hours. 14,15 However, cholinergic receptor; MOT = postsynaptic motilin receptor; and (+) = Erythromycin accel-
the prokinetic dos- stimulation). (Computer graphics created by Dr. Carl Sammarco, School erates gastric empty-
of Veterinary Medicine, University of Pennsylvania)
age is probably much ing 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 emp-
tied into the small intestine.23 Studies have demonstrat-
ed that the stomach empties only 6% of solids as parti-
cles larger than 0.5 mm.25
Because of the small surface area:mass ratio associated
with large chunks of food, the small intestine may in-
adequately digest and absorb these nutrients. Eryth-
romycin 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 in-
testinal 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 com-
pared 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 contrac-
tions in the intestine similar to those of the naturally
occurring interdigestive MMC.1–5,7,8,26 Intravenous eryth-
romycin 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 intra-
venous EM-523 (0.01 to 0.1 mg/kg/hr)5,26 induce con-
tractions that originate in the gastric antrum and mi-
grate to the duodenum, jejunum, and terminal ileum.
Although these contractions are associated with the re-
lease of endogenous motilin,1,3,5 the amount of motilin
released is apparently not sufficient to induce contrac-
tions.9
There is scant information to indicate that eryth-
romycin 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 gastroin-
testinal prokinetic agent in animals with small intesti-
nal motility disorders (particularly those of the proxi-
INTERDIGESTIVE MOTOR PATTERN ■ GASTRIC CONTRACTIONS ■ CHOLINERGIC PATHWAY
Small Animal
mal small intestine) that are refractory to other proki-
netic 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. Eryth-
romycin 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 mecha-
nism of the erythromycin prokinetic response in dogs
has not been completely elucidated but apparently in-
volves cholinergic and noncholinergic neuronal path-
ways.2,4,5,16,21,22
The cholinergic pathway is mediated by activation
of 5-HT3 receptors on postganglionic cholinergic neu-
rons, neuronal depolarization and release of acetyl-
choline, and cholinergic receptor activation on gas-
trointestinal 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 pre-
dominates if erythromycin is given during fasting;
cholinergic and noncholinergic pathways are activated
if erythromycin is administered during or after feed-
ing.21,22
Erythromycin also stimulates motilin release from
endocrine cells in the canine gastrointestinal tract, but
the amount of motilin released is apparently not suffi-
cient to stimulate contraction.22 In dogs, the pharma-
cology of erythromycin contractions is evidently similar
to that of motilin contractions.34–37
The role of motilin in the regulation of feline gas-
trointestinal motility and the role of erythromycin in
the treatment of feline gastrointestinal motility disor-
ders remain to be determined. In dogs and humans, it
has been proposed that motilin is involved in the in-
duction 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-
 BY PRACTICING DERMATOLOGY Small Animal The Compendium March 1997
SPECIALISTS FOR THE BUSY
GENERAL PRACTITIONER grating contractions constitute the normal fasting mo-
tor pattern in the feline small intestine.39,40 The role of
Canine & Feline motilin in the regulation of these contractions is not
yet determined. In vitro experiments have demonstrat-

Dermatology ed that erythromycin binds motilin receptors in the fe-

line intestine and stimulates intestinal smooth muscle
contraction.30
D i a g n o s i s a n d Tr e a t m e n t Adverse Reactions
The side effects of oral erythromycin therapy are
Gene H. Nesbitt • Lowell J. Ackerman
dose-dependent and primarily related to the gastro-
intestinal tract. Side effects include nausea, vomiting,
abdominal pain, diarrhea, and anorexia. 3 Hepatic
Canine dysfunction and/or abnormal liver function tests may
occur. Allergic reactions range from urticaria and mild
& Feline skin eruptions to anaphylaxis. The emergence of resis-
tant bacterial strains during chronic therapy is theoreti-
Dermatology ff!
cally possible but has not been documented clinically.
All parenteral preparations may produce irritation at

10% o
Nesbitt • Ackerman
the site of injection.

D i a g n o s i s a n d Tr e a t m e n t Drug Interactions

89 $ Several drug interactions have been identified in treat-

ed humans. 41 Kaolin, pectin, and bismuth decrease
gastrointestinal absorption of erythromycin. Eryth-

$99 romycin 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
Replete with handy streamlined tables, highlighted humans that receive the drugs concurrently. Eryth-
romycin may cause prolonged bleeding in patients that
clinical profiles for each condition, and photos of
are receiving warfarin therapy. Methylprednisolone
lesions and other pertinent characteristics. metabolism may be inhibited by erythromycin. Concur-
rent use of erythromycin with terfenadine may predis-
■ Separate canine and feline sections
pose patients to severe cardiac arrhythmia. No serious
■ Nearly 250 color and black-and-white photos drug interactions have been reported in veterinary species.

■ Step-by-step descriptions of all phases of care OTHER MACROLIDES

The 14-membered macrolides (e.g., erythromycin,
■ Comprehensive coverage of 500 pages, coated
clarithromycin, oleandomycin, and roxithromycin)
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have gastrointestinal prokinetic activity. 2,7–9 These
parasitic, endocrine, black & white,
compounds are currently being investigated for com-
neoplastic, and various spring 1998
parative efficacies and side effects. The 16-membered
miscellaneous diseases macrolides (e.g., tylosin, leukomycin, and acetyl-
spiramycin) have no effect on gastrointestinal mo-
■ Superb case studies
tility.2,7–9
■ Color type to highlight and organize Other macrolides (e.g., EM-523, EM-574, and LY-
267108) have gastrointestinal prokinetic effects with-
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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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The Compendium March 1997
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