Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 19 GASTROINTESTINAL DRUGS
is unfortunate given that, in most cases, the patients
had pre-existing risk factors and/or were receiving other
medications known to inhibit the hepatic CYP3A4
enzyme system and metabolism of cisapride. However,
despite this, cisapride has recently been withdrawn from
the market in many countries, including the USA and
UK. Given that the drug is no longer widely available,
its use can no longer be considered. Further, related
novel compounds developed as alternatives to cisapride
(e.g. prucalopride) have failed to gain approval for
similar reasons.
Tegaserod (Zelmac®) is an aminoguanidine indole
derivative of serotonin, which has recently become
available in North America. It acts as a selective partial
agonist highly selective for 5-HT 4 receptors; various
studies have demonstrated prokinetic effects including
stimulation of peristaltic activity in vitro, increased
canine intestinal and colonic motility and transit,
reduced visceral afferent firing or sensation in response
to distension in animals, accelerated gastric, small
bowel and colonic transit in healthy patients and
increased small bowel transit in human patients with
constipation-predominant irritable bowel syndrome.
Thus, in time it may prove to be a suitable alternative
to cisapride. However, the authors are not aware of any
clinical trials of this drug in companion animals and
more work is required before its use can be recommended
in veterinary patients.
Erythromycin
Clinical applications
Erythromycin has antibacterial activities (not discussed
further here) but at subantimicrobial doses can also be
used as a prokinetic. It is used most commonly to
improve the rate of gastric emptying, but may also be
beneficial in the treatment of esophageal reflux.
Mechanism of action
Erythromycin is a macrolide antibiotic which, at doses
below the level required for antimicrobial activity, has
prokinetic activities. In many species (e.g. cats, rabbits
and humans), the effect is due to the drug acting on
motilin and 5-hydroxytryptophan (5-HT 3 ) receptors,
thus stimulating migrating motility complexes and antegrade
peristalsis. However, the mechanism of action in
dogs is less well understood, but it is most likely via
action on 5-HT 3 receptors. Gastric emptying is enhanced
by stimulating antral contractions, whilst lower esophageal
pressure is also increased. However, given that
erythromycin has most effect in stimulating interdigestive
activity, beneficial effects on gastric emptying during
the digestive phase are less clear.
Formulations and dose rates
Erythromycin is available in numerous preparations as different
esters, including erythromycin estolate, erythromycin ethylsuccinate,
erythromycin lactobionate and erythromycin gluceptate. Erythromycin
is also available as the base form. Oral preparations (tablets, capsule
and suspension) are used most commonly for the prokinetic effects.
Tablets and capsules usually contain erythromycin as base, stearate
ester or ethylsuccinate ester; the suspension usually contains erythromycin
ethylsuccinate. It is likely that pharmokinetics and toxicity
vary depending upon the exact ester used.
DOGS AND CATS
• 0.5–1.0 mg/kg PO q.8 h
Pharmacokinetics
Erythromycin is absorbed after oral administration in
the upper small intestine and a number of factors may
influence bioavailability. These include the form of the
drug, acidity of the gastrointestinal tract, presence of
food and gastric emptying time. Given that the base is
acid labile, it should be administered on an empty
stomach. Erythromycin is partly metabolized in the liver
to inactive metabolites, although most is excreted
unchanged through the biliary route. Some active
erythromycin is reabsorbed after biliary excretion,
potentially prolonging the activity of each dose. The
elimination half-life in cats and dogs is estimated to be
60–90 min.
Adverse effects
● The main side effect of erythromycin is vomiting,
although this is less common when administered at
the doses used for prokinetic effect, and entericcoated
products may further reduce the frequency of
vomiting. Other gastrointestinal signs can also be
seen, including anorexia and diarrhea.
● When used for its prokinetic effects, clinical signs
may deteriorate rather than improve because the
drug can stimulate the emptying of larger than
normal food particles from the stomach.
● In humans, erythromycin estolate is occasionally
associated with cholestatic hepatitis, although such
an adverse effect has not been reported in a veterinary
species. Nevertheless, as a precaution, this drug
should not be given to patients with pre-existing
hepatic dysfunction.
● Erythromycin should not be used in patients who are
hypersensitive to it.
Known drug interactions
● Erythromycin may increase gastrointestinal absorption
of digoxin, potentially leading to digoxin
toxicity.
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