19
Gastrointestinal drugs
Alexander J. German, Jill E. Maddison and Grant Guilford
ANTIEMETIC DRUGS
Vomiting may occur as a sequel to primary or secondary
(nonenteric) gastrointestinal disease. Antiemetic therapy
should only be considered as symptomatic therapy.
The clinician’s attention should primarily be directed
at determining and resolving the underlying disease
process. A great variety of drugs have been found to be
useful in treating vomiting due to different causes.
However, no single drug is effective for all types of
emesis.
Given that they are a symptomatic therapy, antiemet-
ics are often used in combination with other drugs and
clinicians should be aware of potential drug interactions
that may arise. For example, metoclopramide may affect
the absorption of other drugs and have an impact on
efficacy (see below). Therefore, these drugs must be used
with due care.
Clinical applications
Antiemetics are indicated to:
● control vomiting, especially when profuse and pro-
tracted vomiting may lead to fluid, electrolyte or
acid–base disturbances or is causing distress to the
patient or owner
● prevent vomiting predicted to occur with use of
emetic drugs, e.g. cisplatin, amphotericin.
Use of antiemetics is not necessary if vomiting is
intermittent, the patient is not distressed and correction
of fluid and electrolyte imbalances can easily be
achieved.
Inappropriate use of antiemetics
Use of antiemetics in the following situations is
inappropriate:
● gastrointestinal obstruction – antiemetics may delay
diagnosis
● gastrointestinal toxicity – antiemetics may prevent
the patient from eliminating the toxin
● systemic hypotension – the phenothiazines and
α2-adrenergic antagonists, when used in high doses,
can intensify hypotension.
Ch019-S2858.indd 469
Relevant pathophysiology
Antiemetic drugs may have central or peripheral actions
(Fig. 19.1).
Initiation of vomiting
Vomiting is initiated by either humoral or neural path-
ways. The humoral pathway involves stimulation of the
chemoreceptor trigger zone (CTZ) by blood-borne sub-
stances, while the neural pathway is through activation
of the vomiting center.
Vomiting center
All animal species that vomit have a brainstem ‘vomit-
ing center’ – a group of several nuclei that act in concert
to co-ordinate the somatomotor events involved in
expelling gastric contents. Nonvomiting species (such as
rodents and rabbits) also have the brainstem nuclei and
motor systems necessary for emesis but lack the complex
synaptic interaction among nuclei and viscera required
for a co-ordinated reflex.
The concept of a discrete vomiting center within the
reticular formation of the medulla oblongata has been
challenged. However, whether it is a discrete anatomical
center or represents sequential activation of a series of
effector nuclei, the important concept is that the medulla
has a central co-ordinating role in emesis.
The vomiting center receives input from vagal and
sympathetic neurones, the CTZ in the area postrema,
the vestibular apparatus and the cerebral cortex. It may
also be stimulated directly by blood-borne toxins that
can cross the blood–brain barrier.
The receptors that have been identified as important
in the vomiting center are 5-hydroxytryptamine (5-
HT)1A, α2-adrenergic receptors and neurokinin-1 (NK1)
receptors which are receptors for substance P. Drugs
such as buspirone act as antiemetics by acting as antago-
nists at 5-HT1A receptors. Antiemetics such as prochlor-
perazine block α-adrenergic receptors. Maropitant
(Cerenia®) acts at NK1 receptors.
Central stimulation
Central stimulation of the vomiting center occurs via
higher centers in the central nervous system. Stimuli
include nervousness, unpleasant odors, pain and psy-
chogenic factors. Opioids and benzodiazepine receptors
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 CHAPTER 19 GASTROINTESTINAL DRUGS

histaminergic and NK1 receptors must be involved in

Cerebral cortex Nucleus tractus solitarius
Opioid H1, NK1, M1
Phenothiazines
Vestibular
Antihistamines H1, M1
Vomiting centre
α2, 5HT1A, NK1
CRTZ
D2, M1, H1 and H2 Anticholinergics
5HT3, NK1 Opioid
NK1 antagonists
Peripheral receptors
5HT3 antagonists
M2, 5HT3, 5HT4, Motilin,
NK1, D2
Metoclopramide,
dromperidone
Fig. 19.1 Diagrammatic representation of receptors
involved in emesis and sites of action of antiemetics.
have been implicated in centrally initiated vomiting but
have not been well characterized pharmacologically.
The role of opioid receptors in emesis is confusing.
Various studies have demonstrated that opioids have an
emetic action in dogs and cats. However, opioids have
been used in humans and animals to reduce nausea and
vomiting associated with cancer chemotherapy. This
apparent paradox is caused by a differential effect of
opioids on the CTZ and the vomiting center. If an
opioid penetrates the vomiting center it may strongly
block the vomiting reflex. However, if an opioid pene-
trates the CTZ first it will initially cause vomiting before
blocking the vomiting center. Morphine has been dem-
onstrated to have this dual effect (although it may also
cause vomiting because of histamine release).
Centrally induced vomiting may also occur as a result
of direct stimulation of the vomiting center by increased
cerebrospinal fluid pressure, encephalitis or CNS
neoplasia.
Vestibular apparatus
Labyrinthine impulses associated with motion sickness
and middle-ear infection also stimulate the vomiting
center via neural pathways arising from the vestibular
system. The CTZ is involved in this pathway in the dog
but not in the cat.
The neuronal pathways for motion sickness have not
been completely characterized. M1-cholinergic, H1-
the dog because antagonists at these receptors are very
effective antiemetic agents. D2-dopaminergic, α2-
adrenergic and 5-HT3 receptors are not involved.
Chemoreceptor trigger zone (CTZ)
The CTZ is located in the area postrema in the floor of
the fourth ventricle. It has no blood–brain barrier, thus
allowing access to toxins and chemicals normally
excluded from the CNS by the blood–brain barrier. The
CTZ is stimulated by endogenous toxic substances pro-
duced in acute infectious diseases or metabolic disorders
such as uremia and diabetic ketoacidosis and by drugs
and other exogenous toxins.
A variety of neurotransmitters and their receptors are
important in the CTZ, including dopamine, adrenaline
(epinephrine), 5-HT, acetylcholine, histamine, encepha-
lins and substance P. Species differ in the relative impor-
tance of some neurotransmitter–receptor systems. For
example, apomorphine, a D2-dopamine receptor agonist,
is a potent emetic in dogs and humans but not in the
cat, monkey, pig, horse or domestic fowl. This suggests
that D2-dopamine receptor antagonists such as metoclo-
pramide might not be very useful as antiemetics in
the cat.
In contrast, xylazine, an α2-adrenergic agonist, is a
more potent emetic in the cat than the dog. Cytotoxic
drug-induced emesis has been shown to be mediated
directly by 5-HT3 receptors in the CTZ of the cat, in
contrast to the dog, in which peripheral visceral and
vagal afferent 5-HT3 receptors are activated.
Histamine receptors have not been demonstrated in
the CTZ of the cat. Studies based on eliminating the
emetic response to parenterally administered compounds
by lesioning the CTZ suggest that the CTZ may be less
sensitive to emetic compounds in the cat than in the dog.
Alternatively, other sites for the origin of emesis may be
more important in the cat than the dog.
Peripheral receptors
Peripheral receptors are located mainly in the gastroin-
testinal tract, particularly the duodenum but also in the
biliary tract, peritoneum and urinary organs. The recep-
tors may be stimulated by distension, irritation, inflam-
mation or changes in osmolarity.
Afferent receptors
Of the many afferent receptors found in the gut, 5-HT3
receptors play an important role in initiation of vomit-
ing by cytotoxic drugs. Cytotoxic drugs cause 5-HT
release from enterochromaffin cells that activates 5-HT3
receptors on vagal afferent fibers. 5-HT3 receptor antag-
onists are very effective antiemetics for cytotoxic drug-
induced vomiting. However, the role of 5-HT3 receptors
in other disorders of the gut has yet to be ascertained.

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Efferent receptors
Vagal efferent receptors and myenteric neurones initiate
the complex excitation and inhibition of visceral smooth
muscle that culminates in emesis. Receptors involved
include D2-dopaminergic, 5-HT4 serotonergic, M2-
cholinergic, NK1 and motilin receptors.
CLASSES OF ANTIEMETICS
Phenothiazines
EXAMPLES
Prochlorperazine (e.g. Stemetil®, Compazine®,
Darbazine®), chlorpromazine (e.g. Thorazine®)
Clinical applications
Phenothiazines are broad-spectrum antiemetics that
have efficacy against vomiting initiated by central and
peripheral stimuli.
Mechanism of action
Phenothiazines antagonize α1- and α2-adrenergic
receptors, D2-dopaminergic receptors, H1- and H2-
histaminergic receptors and muscarinic cholinergic
receptors (weakly). They therefore have antiemetic
activity (see Fig. 19.1) at the CTZ (D2-receptors, H1-
and H2-receptors and muscarinic cholinergic receptors)
and at high doses at the vomiting center (α2-
receptors).
Prochlorperazine is a piperazine phenothiazine with
less sedative action than other phenothiazines such
as acepromazine and chlorpromazine. In contrast to
acepromazine, chlorpromazine has antiemetic efficacy
at doses low enough to avoid sedation.
Formulations and dose rates
In most countries, prochlorperazine is only available in human-
approved formulations (e.g. Stemetil®, Compazine®) such as pro-
chlorperazine edisylate (injectable or oral syrup), prochlorperazine
maleate (tablets) or prochlorperazine base (rectal suppositories).
There are few, if any, countries where chlorpromazine is available as
a veterinary-approved product.
DOGS AND CATS
Prochlorperazine
• 0.1–0.5 mg/kg IV, IM, SC q.6-8 h
• 0.5–1.0 mg/kg PO q.8-12 h
NB: Intramuscular injection may be painful but not to a degree that
precludes administration by this route in most patients if necessary.
Chlorpromazine
• 0.1–0.5 mg/kg IM, SC q.8 h
Ch019-S2858.indd 471
CLASSES OF ANTIEMETICS
Pharmacokinetics
Little information is available regarding the pharmaco-
kinetics of prochlorperazine in animals, although it is
believed to follow the general pattern of metabolism
and elimination of other phenothiazine agents, i.e.
metabolism in the liver with both conjugated and
unconjugated metabolites eliminated in the urine.
Although chlorpromazine is absorbed well from the
gastrointestinal tract, it has a high first-pass metabo-
lism. In the circulation, chlorpromazine is highly bound
to plasma proteins – in humans the half-life is 36 h.
Adverse effects
● Phenothiazines may cause hypotension because of
central effects and an α-adrenergic receptor-blocking
action resulting in arteriolar vasodilation. Therefore,
they should not be included at high doses in a thera-
peutic regime until dehydration is corrected by intra-
venous fluid therapy. They should not be given as an
undiluted intravenous bolus.
● Sedation may occur at high doses.
● Similarly to other phenothiazines, it is believed that
prochlorperazine may lower the seizure threshold.
There is anecdotal evidence in the literature that this
occasionally occurs.
● Extrapyramidal reactions such as rigidity, tremors,
weakness and restlessness may occur at high doses.
Known drug interactions
● It has been stated that phenothiazines should not be
given within 1 month of worming with an organo-
phosphate agent as the effect of either drug may
be potentiated. Whether this is a realistic clinical
problem is debatable.
● Other CNS-active drugs such as barbiturates, narcot-
ics and anesthetic agents may cause additive CNS
depression.
● Quinidine given with phenothiazines may cause
additive cardiac depression.
● Antidiarrheal mixtures containing kaolin and pectin
and antacids may cause reduced absorption of orally
administered phenothiazines.
● Increased blood concentrations of both drugs
may occur if propranolol is administered with
phenothiazines.
● As phenothiazines block α-adrenergic receptors, if
adrenaline (epinephrine) is administered concur-
rently, unopposed β-adrenergic effects will occur,
causing vasodilation and tachycardia.
● Phenytoin metabolism may be decreased if given con-
currently with phenothiazines.
● The following drugs that might conceivably be used
concurrently with prochlorperazine or chlorproma-
zine (other drugs may also be incompatible) are
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 CHAPTER 19 GASTROINTESTINAL DRUGS
reported to be incompatible in solution: amphoteri-
cin B, ampicillin sodium, chloramphenicol sodium
succinate, dimenhydrinate, hydrocortisone sodium
succinate, penicillin G sodium, phenobarbital
sodium. Chlorothiazide sodium and methicillin are
also incompatible with chlorpromazine. In addition,
do not mix with other drugs or diluents containing
parabens as preservatives.
Metoclopramide
Clinical applications
Metoclopramide is indicated for control of vomiting
associated with:
● various emesis-inducing disorders involving either
stimulation of the CTZ or depressed
gastrointestinal motility
● cancer chemotherapy
● gastroesophageal reflux
● decreased gastric emptying associated with:
– inflammatory gastrointestinal disorders
– gastric ulcers
– gastric neoplasia
– autonomic neuropathy (diabetes mellitus)
– postoperative gastric dilation and volvulus
surgery/intervention
– abnormal gastric motility.
Although metoclopramide is sometimes recommended
for endoscopic procedures to facilitate passage of the
endoscope through the pylorus, this effect was not con-
firmed in a well-controlled study of the effect of phar-
macological agents on the ease of endoscopic intubation
in dogs. In fact, increased antral motility caused by
metoclopramide makes endoscopic intubation more
difficult.
Mechanism of action
Centrally, metoclopramide antagonizes D2-dopaminergic
receptors and 5-HT3 serotonergic receptors and has a
peripheral cholinergic effect. The antiemetic properties of
metoclopramide may be related to 5-HT3 receptor antag-
onism rather than D2-receptor antagonism, even though
it has been classified for many years as an antidopaminer-
gic drug. The evidence supporting reassessment of its
mode of action includes the observation that analogs of
metoclopramide have been developed that are effective
antiemetics but show little or no dopamine antagonism.
They are very specific 5-HT3 antagonists and it is there-
fore believed that the serotonin-antagonist effects of
metoclopramide account for a large part of its antiemetic
effects. However, antidopaminergic mechanisms are
still believed to play a role in the antiemetic action of
metoclopramide.
Metoclopramide is commonly believed to cause
increased gastric emptying, primarily through antago-
472
Ch019-S2858.indd 472
nism of peripheral D2-receptors, although enhanced
cholinergic activity may also be involved. However,
there is evidence from some animal studies that the
gastrointestinal effects of metoclopramide may be disas-
sociated from its dopamine receptor-blocking action.
Intact vagal innervation is not necessary for enhanced
motility but anticholinergic drugs will negate its effects.
Metoclopramide has also been demonstrated to have
anticholinesterase effects and there are suggestions that
this drug sensitizes gastrointestinal smooth muscle to
the effects of acetylcholine.
Gastrointestinal effects include increased tone and
amplitude of gastric contractions, relaxation of the
pyloric sphincter and increased duodenal and jejunal
peristalsis. Gastric emptying and intestinal transit times
can be significantly reduced. There is little or no effect
on colonic motility.
A beneficial effect of metoclopramide could not be
demonstrated in dogs with gastric dilation and volvulus
and delayed gastric emptying treated with metoclo-
pramide postsurgically. However, as the study involved
use of liquids rather than solids, it might have been dif-
ficult to demonstrate an effect even if gastric motility
was enhanced.
Metoclopramide will also increase lower esophageal
pressure and reduce gastroesophageal reflux. This effect
is abolished by diphenhydramine. The increased lower
esophageal pressure induced by metoclopramide is not
sufficient to prevent gastric reflux in anesthetized dogs,
although it does lower the risk.
Studies have indicated that metoclopramide has a
biphasic effect on ureteral motility, increasing motility
at low doses and inhibiting it at high doses. Semen
volume is reported to be reduced in dogs treated with
metoclopramide but sperm number was not significantly
affected.
Formulations and dose rates
Metoclopramide is available as a veterinary preparation in tablet and
injectable formulations in some countries (e.g. Australia) but only as
a human preparation in others (e.g. USA, UK). Metoclopramide is
photosensitive and should be stored in light-resistant containers at
room temperature.
DOGS AND CATS
• 0.2–0.5 mg/kg IM, SC, PO q.6–8 h
• 1–2 mg/kg IV infusion over 24 h
The efficacy of metoclopramide is believed to be enhanced by admin-
istering 1–2 mg/kg/d by a constant-rate infusion instead of intermit-
tent boluses.
When used to treat disorders of gastric motility and esophageal
reflux, metoclopramide should be administered at a dose of 0.2–
0.5 mg/kg PO 30 min before meals.
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Pharmacokinetics
Metoclopramide is well absorbed from the gastrointes-
tinal tract in humans and dogs. In humans, bio-
availability can be reduced by up to 30% in some
patients as a result of first-pass metabolism; this effect
is quite variable among individuals. One study sug-
gested that similarly, in dogs, the liver plays an active
role in reducing the systemic availability of metoclo-
pramide after oral administration. In a study of two
greyhounds, bioavailability of metoclopramide after
oral administration was about 48%. Bioavailability
after intramuscular injection in humans is 74–96%.
The plasma half-life of metoclopramide in the dog is
approximately 90 min. In contrast to humans, in whom
glucuronidation and sulfate conjugation are the major
metabolic pathways, N-demethylation is more impor-
tant for metoclopramide metabolism in dogs.
Adverse effects
Side effects are uncommon but occur more often in cats
than in dogs.
● Metoclopramide may cause (infrequently) mental
changes ranging from hyperactivity to depression.
● Cats will infrequently show disorientated or
frenzied behavior.
● Metoclopramide should not be used when
gastrointestinal hemorrhage, obstruction or
perforation is suspected.
● This drug is relatively contraindicated in patients
with seizure disorders.
● Use with caution in patients with renal
insufficiency because some reports suggest that
metoclopramide reduces renal blood flow and may
exacerbate pre-existing disease.
Known drug interactions
● Excellent synergy (as a result of their different modes
of action) can be obtained in the management of
persistent vomition using metoclopramide and phe-
nothiazines concurrently. However, because of the
potential for enhanced CNS effects, metoclopramide
should be used with care with phenothiazines,
butyrophenones and opioid analgesics.
● Anticholinergic drugs (e.g. atropine) and narcotic
analgesics may negate the effects of metoclopramide
on gastrointestinal tract motility.
● The gastrointestinal stimulatory effects of metoclo-
pramide may affect absorption of many drugs. Drug
products that disintegrate, dissolve or are absorbed
in the stomach, such as digoxin, may be absorbed
less, although the increased vigor of antral contrac-
tions can also hasten disintegration.
● Metoclopramide may enhance the absorption of
drugs that are absorbed primarily in the small
Ch019-S2858.indd 473
CLASSES OF ANTIEMETICS
intestine, e.g. cimetidine, aspirin, tetracyclines,
diazepam.
● Given that metoclopramide can accelerate the absorp-
tion of nutrients, insulin requirements may be influ-
enced in diabetic animals.
● Metoclopramide antagonizes the antiprolactinemic
effects of cabergoline.
Domperidone
Clinical applications
Domperidone is a dopamine antagonist at D2-receptors
which has similar actions to metoclopramide. It does
not appear to cross as readily into the CNS as metoclo-
pramide and therefore is believed not to have the same
CNS effects as that drug. However, extrapyramidal
adverse effects have been observed in some human
patients.
Mechanism of action
Domperidone is a dopamine antagonist in the CTZ and
GI tract. It also is an α2- and β2-adrenergic antagonist
in the stomach.
Formulations and dose rates
Domperidone is not available as a veterinary preparation in any
market but is available as a human preparation (Motilium®) and used
quite extensively in some European countries. It is available as 10 mg
tablets and a 1 mg/mL suspension and in some markets as supposi-
tories and an oral suspension.
DOGS AND CATS
• 2–5 mg per animal q.8 h
Pharmacokinetics
Domperidone is absorbed from the GI tract but has an
oral bioavailability of only 20% in the dog. This is
presumably due to a high first-pass effect. The drug is
highly protein bound (93%). Peak levels occur about
2 h after dosing. Metabolites are excreted in urine and
feces.
Adverse effects
● There is little information on the use of domperidone
in veterinary medicine.
● It may cause gastroparesis.
● Because domperidone is a potential substrate of P-
glycoprotein, it should be used with caution in
herding breeds such as collies which may have the
gene mutation that causes a nonfunctional protein.
● The drug is teratogenic at high doses in mice, rats
and rabbits.
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 CHAPTER 19 GASTROINTESTINAL DRUGS
● Because dopamine is involved in prolactin produc-
tion, domperidone may increase prolactin levels
resulting in galactorrhea or gynecomastia.
● There may be an impact on fertility as a result of
domperidone’s effect on prolactin levels.
● Injectable formulations have been associated with
cardiac arrhythmias in human patients with cardiac
disease or hypokalemia.
● Rarely, somnolence or dystonic reactions have
occurred in people.
Known drug interactions
Domperidone should not be used with dopaminergic
drugs such as dopamine or dobutamine.
NK1 receptor antagonists
EXAMPLE
Maropitant (Cerenia®)
Clinical applications
Maropitant is the first drug of its class registered (in
some markets) for veterinary use. It is indicated for the
prevention and treatment of general emesis in the dog
and the prevention of motion sickness in the dog.
In laboratory studies, the drug was highly effective in
preventing and treating vomiting induced by apomor-
phine (centrally acting purely at the CTZ), cisplatin
(central and peripheral emetic stimulus) and ipecac
(peripheral emetic stimulus) at a dose of 1 mg/kg SC or
2 mg/kg PO.
Efficacy has also been demonstrated in field studies.
Maropitant was significantly more effective in reducing
emetic events in dogs treated for acute vomiting than
metoclopramide; the proportion of dogs not vomiting
within 24 h was 92% for maropitant and 50% for
metoclopramide, a difference that was statistically sig-
nificant. In relation to prevention of cisplatin-induced
emesis, only two of 39 dogs treated with maropitant 1 h
prior to cisplatin treatment vomited compared with 39
of 41 dogs who vomited when treated with saline alone
prior to cisplatin treatment. Maropitant was also suc-
cessful in treating cisplatin-induced vomiting, i.e. when
the drug was given after cisplatin-induced vomiting
commenced.
Maropitant also has efficacy in preventing motion
sickness but a higher dose is required. In a small field
study, motion sickness was prevented in the majority of
(but not all) dogs with recurrent and persistent motion
sickness only at a dose of 8 mg/kg PO. The higher dose
of maropitant required to prevent emesis associated
with motion sickness is likely to be related to the differ-
474
Ch019-S2858.indd 474
ent input to the vomiting center (vestibular system),
compared with the neural and humoral inputs associ-
ated with general emesis.
Mechanism of action
Maropitant is a selective antagonist of substance P at
the NK1 receptor. Some studies would suggest the antag-
onism is competitive. However, other studies suggest
the inhibition is nonsurmountable. It inhibits the final
common pathway involved in activating the vomiting
reflex in the CNS and is effective against emesis induced
by both peripheral and central stimuli.
Formulations and dose rates
DOGS
Prevention or treatment of emesis due to central or
peripheral stimuli
• 2 mg/kg PO, once daily for up to 5 d
• 1 mg/kg SC, once daily for up to 5 d
Prevention of motion sickness
• 8 mg/kg PO, once daily for a maximum of two consecutive days
Pharmacokinetics
Oral bioavailability is 23.7% at a 2 mg/kg dose rate and
37% at 8 mg/kg. The difference suggests that first-pass
metabolism is proportionally greater at the 8 mg/kg
dose, possibly due to saturation of a high-affinity, low-
capacity enzyme system (or efflux pump system) limiting
access of the drug to the systemic circulation at the
2 mg/kg dose. Feeding does not affect oral bio-
availability at the 2 mg/kg dose rate. Bioavailability
when given subcutaneously is 90.7%.
Maropitant is metabolized by first-order kinetics in
the liver by two enzyme systems: CYP2D15 (high affin-
ity, responsible for >90% of clearance) and CYP3A12
(low affinity, high capacity). Hepatic clearance is the
major route of excretion; there is no evidence of excre-
tion of active drug or its major metabolite.
Adverse effects
Post-dosing emesis occurs in approximately 8% of dogs
treated at the 8 mg/kg dose rate for the prevention of
motion sickness. This is believed to be due to a local
effect of the drug on the GI tract and can be reduced by
dosing after consumption of a small amount of food.
Known drug interactions
● In laboratory and field studies significant drug inter-
actions are unlikely to occur due to its margin of
safety and well-characterized pharmacokinetics.
● Significant hepatic dysfunction could interfere with
metabolism and elimination of maropitant but the
11/19/2007 2:28:57 PM

wide margin of safety for the drug suggests that this
may not have clinically relevant adverse effects.
5-HT3 antagonists
EXAMPLES
Ondansetron (Zofran®), granisetron (Kytril®), dolasetron
(Carpuject®, Anzemet®, Anemet®, Zamanon®) and
tropisetron
Clinical applications
The 5-HT3 receptor antagonists are extremely potent
(and expensive) antiemetics used in the management of
cancer therapy-induced emesis in humans. Their clinical
efficacy is orders of magnitude better than metoclo-
pramide (e.g. 100 times better in the ferret) and they are
often used in cases when ‘first-line’ antiemetics (e.g.
metoclopramide or chlorpromazine) are ineffective. In
this regard, these drugs can often control vomiting in
puppies with parvoviral gastroenteritis. They have been
used occasionally in dogs to control cisplatin-induced
emesis but cost is prohibitive for most veterinary clinical
situations.
Mechanism of action
5-HT3 receptors are located in the CTZ and, peripher-
ally, on vagal nerve terminals and on enteric neurones
in the gastrointestinal tract. Although initially 5-HT3
antagonists were thought to have a central action on the
CTZ, recent work suggests that their main effect is
through antagonism of peripheral 5-HT3 receptors in
the gut. This is supported by work demonstrating that
chemotherapy-induced vomiting is caused by serotonin
release from small intestinal enterochromaffin cells.
Formulations and dose rates
Most veterinary experience has been with ondansetron; most of the
other drugs have not had extensive use at the current time. No
veterinary formulations of any of these drugs are available.
ONDANSETRON
Ondansetron is available both as injectable and as tablet
formulations.
DOGS
Prevention of cisplatin-induced vomiting
• 0.5 mg/kg IV as a loading dose and then 0.5 mg/kg/h as an
infusion for 6 h
• 0.1 mg/kg PO q.12–24 h or at 30 min prior to and 90 min after
cisplatin infusion
Ch019-S2858.indd 475
CLASSES OF ANTIEMETICS
For intractable vomiting, when first-line drugs are ineffective
• 0.1–0.176 mg/kg q.6–12 h as a slow intravenous push
• 0.5–1.0 mg/kg PO once or twice daily
CATS
The use of ondansetron in cats is controversial and many pharmacolo-
gists do not recommend its use in this species.
OTHER 5-HT3 ANTAGONISTS
Dolasetron is also available as both injectable (0.625 mL ampoules)
and tablet (50 mg and 100 mg strength) formulations. The size of
tablets is inconvenient for most cats and dogs, such that oral ondan-
setron preparations are preferred.
• 0.5–0.6 mg/kg IV, SC or PO q.24 h
Adverse effects
● Experimental studies suggest that 5-HT3 antagonists
are very safe in animals, showing minimal toxicity at
doses up to 30 times greater than those needed to
abolish vomiting.
● Given that ondansetron, and related products, are
potent antiemetics, their use may mask signs of ileus
or gastrointestinal distension. These drugs should be
used with caution in cases where gastrointestinal
obstruction cannot be excluded because appropriate
therapy may be delayed.
● In humans, constipation, headaches, occasional
alterations in liver enzymes and rarely hypersensitiv-
ity reactions have been reported.
● Dolasetron has also been associated with ECG inter-
val prolongation (of the P-R, Q-T and J-T segments),
whilst arrhythmias and hypotension have also been
reported for ondansetron.
● Safety of this drug group during gestation has not
been clearly established, so the drug should be used
with caution in pregnant animals.
● Ondansetron is a potential substrate of P-glycopro-
tein. Given that some rough collies have a mutation
causing a nonfunctional protein, these dogs and
associated breeds may be more sensitive to the effects
of 5-HT3 antagonists.
Anticholinergics
EXAMPLES
Atropine, butylscopolamine (hyoscine), propantheline,
isopropamide
Clinical applications
Anticholinergics are mainly used for their antispasmodic
and antisecretory actions for some types of diarrhea.
Given that their use is contradicted in many
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 CHAPTER 19 GASTROINTESTINAL DRUGS
circumstances, they should be used with caution. These
drugs have also been used frequently in the past as
antiemetics but usually inappropriately. They are usually
not effective unless vomiting is initiated by smooth
muscle spasm (an extremely uncommon occurrence).
They do not stop vomiting caused by stimulation of
peripheral receptors by other means such as inflamma-
tion. Those anticholinergic drugs that can cross the
blood–brain barrier (e.g. hyoscine) are effective for
motion sickness through antagonism of M1-receptors in
the vestibular apparatus.
Anticholinergics have been used in the management
of pancreatitis on the basis that they may reduce pan-
creatic secretion. However, no appreciable benefit has
been demonstrated experimentally or clinically from
this treatment. In fact, some clinicians consider that
their use is contraindicated in pancreatitis because they
cause thickening of pancreatic secretions.
Mechanism of action
Anticholinergics act as antagonists at central and periph-
eral muscarinic receptors (M1 and M2). Quaternary
ammonium antimuscarinics, such as butylscopolamine
and propantheline, do not cross the blood–brain barrier,
so have a predominantly peripheral action, and CNS
side effects are minimal.
Formulations and dose rates
Atropine sulfate is available as an injectable preparation. No veteri-
nary-approved preparations of propantheline are available, but generic
human tablet formulations can be used (7.5 mg, 15 mg). In some
countries, butylscopalamine is available, as both injectable and oral
preparations (Buscopan®) and also in an injectable formulation in
combination with metamizole (dipyrone) (Buscopan Compositum®;
4 mg/mL butylscopalamine, 500 mg/mL metamizole); the latter is a
pyrazoline drug with anti-inflammatory, analgesic and antipyretic
properties.
Atropine
• The standard dose rate is 0.02–0.04 mg/kg, IM or SC
Propantheline
• The dose for both dogs and cats is 0.25 mg/kg PO q.8 h
Butylscopalamine
• In dogs, the primary indication is as a long-acting antispas-
modic at a dose of 0.5 mg/kg IM or PO q.12 h (sole prepara-
tions) or 0.1 mg/kg IV or IM (in combination with metamizole)
Adverse effects
● The major problem with anticholinergics is that they
also affect M2-receptors, potentially causing delayed
gastric emptying and ileus. This may potentiate vom-
iting and exacerbate gastric hypomotility, which
occurs in many disorders causing vomiting. These
476
Ch019-S2858.indd 476
drugs should also be avoided in cases suspected to
have gastrointestinal obstruction.
● Overuse can result in gastric atony and intestinal
ileus, which may predispose to absorption of endo-
toxins through damaged mucosa.
● Antimuscarinic agents should be used with caution
in cases with known or suspected enteric infections,
because the reduction in motility may prolong the
retention of the causative agent.
● Antimuscarinic agents should also be used with
caution in animals with hepatic or renal disease,
hyperthyroidism, congestive heart failure, hyperten-
sion, concurrent myasthenia gravis, prostatic hyper-
trophy and in geriatric or pediatric patients.
● Side effects are those expected for antimuscarinics,
e.g. xerostomia, dry eyes, hesitant urination, tachy-
cardia and constipation. CNS side effects include
stimulation, drowsiness, ataxia, seizures and respira-
tory depression; however, these effects are unlikely
with the quaternary ammonium antimuscarinics.
Ocular side effects of this group include mydriasis,
cycloplegia and photophobia; again, these side
effects are less likely with quaternary ammonium
antimuscarinics.
Known drug interactions
● Antimuscarinics can enhance the actions of thiazide
diuretics and sympathomimetics and antagonize the
effects of metoclopramide.
● Antihistamines, procainamide, quinidine, meperi-
dine, benzodiazepines and phenothiazines can all
potentiate the effects of anticholinergics.
● Adverse effects can be exacerbated by corticoste-
roids, primidone, nitrates and disopyramide.
Antihistamines
EXAMPLES
Diphenhydramine (Benadryl®), dimenhydrinate
(Dramamine®)
Clinical applications
Antihistamines are primarily indicated for treatment
and prevention of motion sickness in the dog.
Mechanism of action
Antihistamines block histamine receptors in the CTZ
and vestibular pathways. Histamine receptors in CTZ
are involved in motion sickness in the dog but not in
the cat.
In addition to its antihistaminergic effects, diphen-
hydramine has substantial sedative, anticholinergic,
11/19/2007 2:28:57 PM

antitussive effects and local anesthetic effects. The anti-
cholinergic action may in fact be the main mechanism
by which it is effective in motion sickness, as there are
muscarinic receptors in the vestibular system.
Formulations and dose rates
DOGS AND CATS
Diphenhydramine
• 2–4 mg/kg PO, IM q.8-12 h
Dimenhydrinate
• 4–8 mg/kg PO, IM q.8 h
Pharmacokinetics
The pharmacokinetics of these drugs have not been
studied in domestic species. In humans diphenhydr-
amine is well absorbed after oral administration but
systemic bioavailability is only 40–60% because of first-
pass metabolism. Diphenhydramine and dimenhydri-
nate are metabolized in the liver and largely excreted as
metabolites in urine.
Adverse effects
● CNS depression (e.g. lethargy, somnolence,
paradoxical excitement – cats). The sedative effects
may diminish with time.
● Anticholinergic effects (e.g. dry mouth, urinary
retention).
● Gastrointestinal side effects (e.g. vomiting and
diarrhea) are uncommon, but have been reported.
● These drugs should be used with caution if pyloric
or proximal intestinal obstruction is suspected.
● Use with caution in patients with hyperthyroidism,
seizure disorders, cardiovascular disease,
hypertension and closed-angle glaucoma; signs of
ototoxicity may also be masked by these drugs.
Known drug interactions
Increased sedation can occur if antihistamines are com-
bined with other CNS-depressant drugs. Antihistamines
may counteract the anticoagulatory effects of heparin
or warfarin. Diphenhydramine may exacerbate the
effects of adrenaline (epinephrine).
ANTIULCER DRUGS
Clinical applications
Antiulcer drugs are useful in the specific management of
gastrointestinal ulceration and reflux esophagitis. They
are not usually needed for treatment of simple acute
gastritis.
Ch019-S2858.indd 477
ANTIULCER DRUGS
Relevant pathophysiology
The protective barrier that prevents gastric mucosa from
being damaged by gastric acid includes the following
factors.
● Mucus, with bicarbonate incorporated into the
mucosal gel layer.
● High epithelial turnover (thus a high metabolic rate
and oxygen requirement).
● Tight junctions and lipoprotein layer of epithelial
cells.
● A rich vascular supply.
● Prostaglandins – PGE series and PGI2 are
protective:
– inhibit gastric acid secretion
– maintain mucosal blood flow
– involved in secretion and composition of healthy
mucus
– may be intercellular messengers for stimulus of
mucosal cell turnover and migration.
Gastrointestinal ulceration may be associated with a
number of events.
● Drugs (aspirin, phenylbutazone, corticosteroids)
● Uremia (toxins, increased gastrin)
● Liver disease (cause not known)
● Stress
● Increased production of HCl (mast cell tumor at
any site, gastrin-producing tumor of the pancreas
(Zollinger–Ellison syndrome))
● Hypotension, e.g. during surgery,
hypoadrenocorticism
● Spinal cord disease
Interruption of the gastric mucosal barrier allows back-
diffusion of gastric acid into the submucosa, which
causes mast cell degranulation, resulting in histamine
release and subsequent further stimulation of acid
production by gastric parietal cells, which enhances
inflammation and edema in the submucosa. The aim of
antiulcer therapy is to repair the mucosal barrier directly,
reduce the amount of gastric acid produced or neutral-
ize its effect and hence stop the vicious cycle of gut
damage.
A number of classes of antiulcer drugs are available
and numerous agents are available within each class.
There are differences in mechanism of action amongst
groups and in potency amongst individual agents.
However, there is little information as to whether the
reported differences in potency relate to real differences
in clinical efficacy. An example is a recent study in
healthy laboratory dogs, which examined changes in
luminal pH after administration of four acid-blocking
drugs: ranitidine, famotidine, omeprazole and panto-
prazole. Famotidine, pantoprazole and omeprazole sig-
nificantly suppressed gastric acid secretion, compared
477
11/19/2007 2:28:57 PM
 CHAPTER 19 GASTROINTESTINAL DRUGS
with saline solution, as determined by median 24-h pH,
and percentages of time pH was ≥3 or ≥4. However,
ranitidine did not. Of the four agents examined, twice-
daily omeprazole was most effective in suppressing
gastric acid secretion. Although this suggests that proton
pump inhibitors are the agents of choice, the study
involved healthy laboratory animals and it is not clear
whether the criteria used in the study (luminal pH) were
those which were most important in determining clini-
cal efficacy.
CLASSES OF ANTIULCER DRUGS
Histamine-receptor antagonists
EXAMPLES
Cimetidine (Zitac®, Tagamet®), ranitidine (Zantac®),
famotidine (Pepcid®), nizatidine (Axid®)
Clinical applications
The histamine-receptor antagonists have efficacy in
treating gastric ulceration caused by a variety of disor-
ders, including nonsteroidal anti-inflammatory drugs
(NSAIDs) and uremia. However, they do not appear to
be effective in preventing NSAID-induced ulcers. Raniti-
dine and nizatidine are also used as prokinetic agents
(see below).
Mechanism of action
These drugs act as competitive inhibitors at the hista-
mine (H2) receptors on gastric parietal cells. H2-
receptors, when occupied by histamine and in the
presence of acetylcholine and gastrin, stimulate maximal
acid secretion. The H2-receptor is the dominant receptor
for stimulation of acid secretion. H2-receptor antago-
nists cause a 70–90% decrease in gastric acid produc-
tion. Ranitidine is reported to suppress gastric acid
production to a greater extent than cimetidine (90%
versus 75%); similarly, famotidine is more effective at
suppressing acid secretion than is ranitidine. However,
this does not appear to result in improved clinical effi-
cacy in dogs. By decreasing the amount of gastric acid
produced, H2-antagonists also proportionally decrease
pepsin secretion.
Cimetidine and famotidine have no effect on lower
esophageal pressure or gastric emptying time and none
of these agents affects pancreatic secretion or biliary
secretion. However, ranitidine and nizatidine increase
lower esophageal sphincter pressure and have anti-
cholinesterase activity which significantly enhances
gastrointestinal motility (by increasing the amount of
478
Ch019-S2858.indd 478
acetylcholine supplied to muscarinic receptors). Nizati-
dine may also have direct agonist effects on M3-
muscarinic receptors. In fact, nizatidine is more
commonly used primarily for its prokinetic activity than
as an acid-blocking drug.
Cimetidine has an apparent immunomodulatory
effect as it has been demonstrated to reverse suppressor
T cell-mediated immune suppression by blocking H2-
receptors on suppressor T lymphocytes. It also increases
lymphocyte response to mitogen stimulation. This effect
has been used clinically in the treatment of malignant
melanomas in people and gray horses. Cimetidine also
possesses weak antiandrogenic activity.
Formulations and dose rates
DOGS AND CATS
Cimetidine
• 5–10 mg/kg PO, IV q.6–8 h
Ranitidine
• 1–2 mg/kg PO, SC, IV q.8-12 h
Famotidine
• 0.5–1.0 mg/kg PO, IV q.12–24 h
Nizatidine
• 2.5–5.0 mg/kg PO, IV q.12–24 h
Pharmacokinetics
Cimetidine
Oral bioavailability of cimetidine is reported to be
95% and serum half-life 1.3 h. Inhibition of gastric acid
secretion peaks at 75% within 1.5 h and 50% inhibition
lasts about 2 h after an oral dose. The effects of the drug
are gone after 5 h. Concurrent administration with food
delays drug absorption.
Cimetidine decreases hepatic blood flow and inhibits
hepatic microsomal enzymes. This can affect the metab-
olism of other drugs, although the clinical significance
of this is uncertain. In humans, cimetidine is both
excreted unchanged by the kidneys and metabolized in
the liver. More drug is excreted by the kidneys when
administered parenterally than when given orally.
Ranitidine
In dogs, the oral bioavailability of ranitidine is approxi-
mately 80% and serum half-life is 2.2 h. Food does not
affect absorption. Inhibition of gastric acid production
peaks at 90% and 50% inhibition lasts about 4 h.
Ranitidine does not inhibit hepatic microsomal
enzymes to the same extent as cimetidine. In humans,
ranitidine is both excreted in the urine via glomerular
filtration and tubular secretion and metabolized in the
liver to inactive metabolites.
11/19/2007 2:28:57 PM

Famotidine
Famotidine is not completely absorbed after oral admin-
istration but hepatic first-pass metabolism is minimal.
In humans, the oral bioavailability is approximately
40–50%.
Nizatidine
In dogs, oral absorption is rapid and almost complete
and there is minimal hepatic first-pass metabolism.
Although food improves oral bioavailability, the differ-
ence is not thought to be clinically relevant. Nizatidine
is metabolized in the liver to a number of metabolites
and at least one of these may have activity.
Adverse effects
● In animals, adverse effects appear rare at the doses
commonly used.
● In humans, side effects of cimetidine such as gyneco-
mastia and antiandrogenic activity and CNS signs
(mental confusion, lethargy and seizures) have been
reported.
● Occasionally, agranulocytosis may occur.
● Transient cardiac arrhythmias may occur if cimeti-
dine, ranitidine or famotidine are given
intravenously.
● Long-term used of H2-antagonists could cause hypo-
acidity and bacterial overgrowth in the stomach but
there is no clinical evidence that this is a serious
concern. There is no evidence that rebound hyperse-
cretion occurs after stopping therapy with cimetidine
or ranitidine.
● Cimetidine has been reported to cause a cutaneous
drug eruption in a cat.
● The dose of the H2-antagonists should be reduced by
50% in patients with impaired renal function.
Known drug interactions
● Cimetidine can decrease hepatic microsomal enzyme
systems and thus theoretically can decrease hepatic
metabolism of various drugs, including benzodiaze-
pines, barbiturates, propranolol, calcium channel
blockers, metronidazole, phenytoin, quinidine, the-
ophylline and warfarin. This has been demonstrated
in the dog in a study of the pharmacokinetics of
verapamil when cimetidine was administered concur-
rently. The clinical significance of this effect has
not been established, although there are anecdotal
reports of cimetidine therapy adversely affecting
dogs receiving phenobarbital. Ranitidine inhibits micro-
somal enzyme systems to a much lesser (5–10-fold)
degree.
● Cimetidine and ranitidine may decrease the renal
excretion of procainamide.
Ch019-S2858.indd 479
CLASSES OF ANTIULCER DRUGS
● Famotidine may exacerbate leukopenias if given
concurrently with other bone marrow-suppressing
agents.
● Nizatidine may increase salicylate levels in patients
taking high doses of aspirin.
● Anticholinergic agents (e.g. atropine and propanthe-
line) may negate the prokinetic effects of ranitidine
and nizatidine.
● The increased intragastric pH associated with H2-
antagonist administration may reduce the absorption
of drugs that require an acid medium for dissolution
and absorption, such as ketoconazole.
● It is recommended that at least 2 h elapses between
dosing with cimetidine and giving antacids, metoclo-
pramide, digoxin or ketoconazole.
Sucralfate
Clinical applications
Sucralfate is indicated for the symptomatic treatment
of gastric ulceration from various causes. In humans,
sucralfate is as effective as antacids or H2-receptor
antagonists in healing ulcers. It does not appear to be
successful, however, in preventing corticosteroid-induced
ulceration in dogs subjected to spinal surgery. Its effi-
cacy in preventing NSAID-induced ulcers is unproven
in the dog. Sucralfate has also been used to treat oral
and esophageal ulcers and esophagitis.
Mechanism of action
Sucralfate is composed of sucrose octasulfate and alu-
minum hydroxide, which dissociate in the acid environ-
ment of the stomach. Minimal systemic absorption
of either compound occurs. Sucralfate is structurally
related to heparin but does not possess any appreciable
anticoagulant activity. It is also structurally related to
sucrose but is not used as a sugar by the body.
When given orally, sucrose octasulfate reacts with
hydrochloric acid and is polymerized to a viscous sticky
substance that binds to the proteinaceous exudate
usually found at ulcer sites. Because of electrostatic
charges, sucralfate preferentially adheres to ulcerated
tissues. It protects the ulcer against hydrogen ion back-
diffusion, pepsin and bile and therefore promotes ulcer
healing. The aluminum hydroxide theoretically neutral-
izes gastric acid but this antacid activity is not believed
to be clinically important.
It was believed that the formation of a physical pro-
tective barrier was the major mechanism by which
sucralfate assisted ulcer healing. However, it is now
believed that the major drug actions of sucralfate are
related to stimulation of mucosal defense and reparative
mechanisms, possibly related to stimulation of local
PGE2 and PGI2 production. Sucralfate also inactivates
pepsin, adsorbs bile acids and is believed to be
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11/19/2007 2:28:57 PM
 CHAPTER 19 GASTROINTESTINAL DRUGS
cytoprotective by stimulating prostaglandin synthesis. It
does not significantly affect gastric acid output but may
slow gastric emptying appreciably.
Formulations and dose rates
LARGE DOGS
• 1 g PO q.8 h
SMALL DOGS
• 0.5 g PO q.8 h
CATS
• 0.25–0.5 g PO q.8–12 h
It is preferable to administer sucralfate at least 60 min prior to
feeding.
Pharmacokinetics
Only 3–5% of an oral dose of sucralfate is absorbed
and this is excreted unchanged in urine within 48 h. The
remainder of the drug is excreted in feces within 48 h.
Sucralfate binds to the ulcer site for up to 6 h after oral
dosing.
Adverse effects
● Because very little drug is absorbed systemically, no
systemic toxicities have been reported.
● The only reported side effect in humans is
constipation.
Known drug interactions
● Recommendations vary concerning whether con-
current administration of H2-antagonists decreases
sucralfate dissolution. Although it was believed that
sucralfate required an acid environment for dissolu-
tion, a study in rats indicated that sucralfate pre-
vented mucosal injury in both acidic and neutral
environments. However, as there are no definitive
studies in dogs and cats, it is probably prudent where
practical to administer sucralfate 30 min before an
H2-antagonist if both drugs are used.
● Sucralfate may have the ability to bind other drugs
but no clinically important drug interactions have
been reported. However, it is recommended that
drugs such as tetracyclines, digoxin, fluoroquino-
lones and aminophylline should not be given within
2 h of administering sucralfate.
● Sucralfate can bind to and interfere with the absorp-
tion of fat-soluble vitamins (e.g. A, D, E and K).
Therefore, avoid giving this medication concurrently
with enteral feeding preparations.
480
Ch019-S2858.indd 480
Misoprostol
Clinical applications
Misoprostol (Cytotec®) is a synthetic prostaglandin
(PGE1). In human medicine, there are conflicting data
about whether misoprostol is as effective as H2-
antagonists in healing ulcers. It is, however, most useful
for prevention of NSAID-induced ulceration and its effi-
cacy in this regard has been demonstrated in dogs. This
contrasts with the lack of prophylactic efficacy of other
antiulcer drugs. However, some studies suggest that it
may not be effective in preventing gastric ulceration
caused by high-dose glucocorticoid therapy (e.g.
methylprednisolone).
Other less common uses include intravaginal admin-
istration in conjunction with PGF2 for pregnancy termi-
nation in dogs (mid to late gestation). It has also been
reported to be effective in reducing ciclosporin-induced
toxicity and one study suggested some efficacy in treat-
ment of atopic dermatitis in dogs.
Mechanism of action
Misoprostol has gastric antisecretory and mucosal pro-
tective effects as it acts as a synthetic replacement for
PGE1. PGE1 inhibits hydrochloric acid through a direct
action on gastric parietal cells, by suppressing the acti-
vation of histamine-sensitive adenylate cyclase. It also
inhibits gastrin secretion and increases gastric mucus
formation. It increases blood flow to the mucosa, which
increases the oxygen and nutrient supply to the healing
mucosa, ultimately enhancing epithelialization.
Formulations and dose rates
Misoprostol is not currently approved for veterinary use in any country.
Although the most common recommendation is for q.8 h dosing, a
recent study examining effects on aspirin-induced gastric ulceration
suggested that q.12 h dosing was as effective.
DOGS
• 2–5 µg/kg PO q.8–12 h
Pharmacokinetics
Misoprostol pharmacokinetics are similar in dogs and
humans. It is absorbed extensively after oral admin-
istration in dogs, although there is significant first-pass
metabolism. It undergoes rapid esterification to its free
acid, which is the active form. It is further metabolized
in several tissues (biotransformed via oxidation to inac-
tive metabolites) and is excreted mainly in urine. Both
misoprostol and its acid are relatively highly protein
bound. In humans the serum half-life of misoprostol is
about 30 min and its duration of pharmacological effect
3–6 h.
11/19/2007 2:28:57 PM

Adverse effects
● Misoprostol can induce parturition or abortion as a
result of luteolysis and myometrial contractions and
is therefore contraindicated in pregnant animals
unless intended as an abortifacient.
● Diarrhea, abdominal pain, flatulence and vomiting
are relatively frequent side effects, although they are
often transient and resolve over several days. They
can be minimized by dosage adjustment and giving
the dose with food.
● Life-threatening diarrhea has been reported in
humans with inflammatory bowel disease, so it
would be prudent to avoid or use the drug with
caution in dogs with this disorder.
● Misoprostol should not be used in patients with
known hypersensitivity to prostaglandins or prosta-
glandin analogs.
● Some prostaglandins and prostaglandin analogs
(although not misoprostol to date) have precipitated
seizures in epileptic humans.
Known drug interactions
● The presence of food decreases the rate but not
extent of drug absorption.
● Bioavailability is reduced by concomitant use of
antacids but this may not be clinically significant.
● Magnesium-containing antacids may exacerbate
diarrhea induced by misoprostol.
Special considerations
Pregnant women should handle the drug with caution
(check label warning).
Proton pump inhibitors
EXAMPLES
The main agent used in veterinary medicine is omeprazole
(Prilosec®, Losec®). Other drugs in this group are now
used in humans (e.g. lansoprazole, pantoprazole) but there
is limited information about their use in companion animals.
Clinical applications
Omeprazole has slightly greater efficacy in promoting
ulcer healing in humans than H2-antagonists but is
more expensive. Its use in veterinary medicine is usually
restricted to refractory ulcers or ulcers associated with
gastrinomas or mastocytosis. However, some veterinary
gastroenterologists use omeprazole as their first-choice
antiulcer drug. Such an approach is supported by the
study previously referred to assessing efficacy and dura-
tion of gastric acid suppression, by measuring luminal
pH, in healthy research dogs; omeprazole and panto-
Ch019-S2858.indd 481
CLASSES OF ANTIULCER DRUGS
prazole were more effective than either famotidine or
ranitidine. Nevertheless, given that the study was in
healthy dogs, it is not clear whether the differences
noted relate to clinical efficacy.
Excellent long-term clinical outcomes have been
reported in humans and dogs with nonresectable gastri-
nomas treated with omeprazole. Omeprazole has been
reported to be useful in dogs in management of severe
erosive esophagitis, gastritis or gastric ulcer disease
refractory to therapy with H2-receptor antagonists and
sucralfate. It has been used successfully to treat severe
erosive esophagitis in one cat but had no effect in two
similarly affected cats.
One recent study demonstrated that omeprazole has
some efficacy in preventing exercise-induced gastritis in
racing Alaskan sled dogs. In another study, omeprazole
did not reduce mechanically induced gastric ulceration
or prevent aspirin-induced gastritis in dogs, although
there was a trend that suggested that omeprazole was
more effective than cimetidine in this regard. However,
a further study demonstrated limited efficacy, in both
treating and preventing gastric mucosal lesions, in dogs
with acute degenerative disc disease treated with
corticosteroids.
Mechanism of action
Omeprazole, a substituted benzimidazole, is a proton
pump inhibitor that binds to and irreversibly blocks
H+/K+-ATPase, thereby blocking gastric acid secretion.
Omeprazole inhibits gastric acid secretion stimulated by
any secretagogue, in contrast to H2-receptor antago-
nists, which only suppress gastric acid production
stimulated by histamine. Because it is a weak base,
omeprazole accumulates in the acid compartment of the
parietal cell; therefore its effect persists after the drug is
no longer detectable in blood. Omeprazole is inactive at
physiological pH and so does not affect ATPase else-
where in the body.
Omeprazole has a longer duration of action than the
H2-antagonists and most recommendations are for
once-daily dosing. However, a recent study reported
that twice-daily omeprazole maintained gastric lumen
pH > 3 throughout a 24-h period, whereas q.24 h dosing
did not. Whether it is necessary to maintain pH > 3 to
achieve effective ulcer healing is not clear. Given the cost
and convenience of once-daily dosing, this protocol is
likely to remain the most common approach, with more
frequent dosing used for refractory cases only.
The antisecretory effects increase with each dose
until the drug attains a steady-state inhibition. In
dogs, gastric acid output is reduced by about 30% in
the first 24 h after an oral dose of 0.7 mg/kg and after
five doses gastric acid production is almost completely
inhibited.
481
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 CHAPTER 19 GASTROINTESTINAL DRUGS

Formulations and dose rates Known drug interactions

Omeprazole is labeled for equine use in some countries but not, to
the authors’ knowledge, for small animal use. The drug is rapidly
degraded by acid, so is formulated as 20 mg enteric-coated granules
in a gelatin capsule. For dogs less than 20 kg, the enteric-coated
granules must be repackaged in a gelatin capsule.
DOGS
• 0.5–1.0 mg/kg PO q.24 h (for ulcer management). Consider
q.12 h dosing in refractory cases. A pragmatic dosing schedule
has been recommended as follows:
one 20 mg capsule daily for dogs weighing more than 20 kg
0.5 × 20 mg capsule daily for dogs weighing less than 20 kg
0.25 × 20 mg capsule daily for dogs weighing less than 5 kg
• 0.7–2.0 mg/kg PO q.12–24 h (for esophagitis)
CATS
• 0.7 mg/kg PO q.24 h (for ulcer management).
● Inhibition of P450 hepatic enzymes may decrease
hepatic clearance of some drugs such as diazepam,
phenytoin and warfarin.
● Drugs that require a low pH for optimal absorption
(e.g. ketoconazole, ampicillin) may have reduced
absorption, as omeprazole increases gastric pH.
● In humans, omeprazole can occasionally cause bone
marrow suppression, which may be exacerbated if
used with other drugs that also suppress
hematopoiesis.
Nonsystemic antacids
EXAMPLES
Nonsystemic antacids include a variety of oral preparations
that contain aluminum hydroxide, calcium carbonate and
magnesium compounds.

Pharmacokinetics
Omeprazole is rapidly absorbed from the gut and dis-
Clinical applications
Nonsystemic antacids are probably most frequently
tributed widely but primarily in gastric parietal cells. It
used in the management of uremia, as aluminum
is metabolized extensively in the liver to at least six dif-
hydroxide binds phosphate, thus reducing hyperphos-
ferent metabolites, which are excreted principally in the
phatemia as well as having an antacid effect.
urine and also via bile into feces. Significant hepatic
dysfunction can reduce the first-pass effect of the drug,
increasing the systemically available drug and prolong-
Mechanism of action
Nonsystemic antacids act to neutralize hydrochloric
ing its duration of action. Omeprazole inhibits hepatic
acid, bind bile acids, decrease pepsin activity and pos-
microsomal enzymes to a similar degree to cimetidine.
sibly stimulate local prostaglandin (PGE1) production.
Preparations are usually a combination of aluminum
Adverse effects
hydroxide and magnesium hydroxide to maximize the
● There is limited information on veterinary use of
buffering capabilities of each compound. Magnesium
omeprazole but anecdotal reports suggest that it is
causes increased bowel motility and aluminum causes
well tolerated in dogs and cats.
decreased motility, which is another reason why the two
● The main potential side effects include gastrointesti-
are usually combined. Both magnesium hydroxide and
nal signs (anorexia, nausea, vomiting, flatulence,
calcium carbonate have a short, rapid effect; aluminum
diarrhea), hematological abnormalities, urinary tract
hydroxide has a slow, persistent effect.
infections, proteinuria and CNS disturbances.
Administration of antacid medications poses difficul-
● Long-term therapy has been reported to cause revers-
ties in veterinary patients because of the high volume
ible gastric hypertrophy in dogs because of the
and frequency of treatment required to prevent rebound
trophic effect of gastrin. Gastric hypertrophy has not
acid secretion. Nevertheless, the clinical efficacy of
been detected in dogs treated for 20 d.
antacid tablets was recently shown to be similar to
● In rats, long-term therapy is reported to cause gastric
higher doses of antacid liquids or cimetidine in
hypertrophy and carcinoids. Similar changes have
humans.
been found with long-term ranitidine therapy. There
is a concern that similar changes may develop after
long-term therapy in other species. However, given
that similar changes have not been detected in
Formulations and dose rates
humans, the relevance of this side effect is not clear. Although inexpensive, nonsystemic antacids must be administered
Nevertheless, as in humans, most clinicians do not orally (which may be difficult in a vomiting patient) and frequently,
recommend extending therapy beyond 8 weeks, which results in poor owner compliance.
unless the benefits outweigh potential risks.

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• Dosages are empirical as no specific dosages have been
defined for animals
Tablets (e.g. aluminum hydroxide 500 mg) can be administered at
10–30 mg/kg PO q.8 h
For liquid preparations (e.g. aluminum hydroxide gel 4% w/v), usual
doses are generally in the order of 5–10 mL PO q.8 h
To be effective, antacids must be administered at least every 4 h
Adverse effects
● Calcium-containing antacids tend to promote consti-
pation; magnesium promotes looser feces and alumi-
num reduces gastric motility and delays gastric
emptying.
● If antacids are administered infrequently they may
actually result in increased gastric acid production.
● Administration of excessive calcium-containing ant-
acids may predispose to renal calculi.
● Hypophosphatemia and accumulation of aluminum
are potential sequelae with long-term use of alumi-
num-containing antacids.
Known drug interactions
Antacids will interfere with gastric absorption of con-
currently administered drugs such as digoxin, tetracy-
clines and fluoroquinolones.
THERAPY FOR ERADICATION OF
HELICOBACTER SPP
Helicobacter pylori is the major cause of pyloric ulcer
disease in humans. A number of Helicobacter species
have been shown to colonize the gastric mucosa of cats
and dogs, including H. felis and H. heilmanii, and
gastric spiral organisms are often identified during his-
topathological inspection of gastric mucosal biopsy
specimens procured from both symptomatic and asymp-
tomatic companion animals. Therefore, it remains con-
troversial as to whether or not Helicobacter species are
a significant cause of disease in small animals. Certainly,
disease is not the result of simple infection and disease
pathogenesis is likely more complicated. Instead, it is
thought that these organisms are normal commensal
bacteria and that most dogs and cats can tolerate their
presence. Current theories on the pathogenesis of
Helicobacter-associated gastritis center on the hypothe-
sis that disease manifests after a breakdown in mucosal
tolerance to Helicobacter species. As a consequence,
many clinicians choose to eradicate Helicobacter species
in patients with chronic vomiting and biopsy-proven
gastric inflammation.
Treatment usually involves administering a combina-
tion of antibacterial and acid-blocking drugs. Numer-
Ch019-S2858.indd 483
PROKINETIC DRUGS
ous combinations have been suggested, but those which
have been critically evaluated include the following.
● Amoxicillin (20 mg/kg PO q.12 h for 14 d), metro-
nidazole (20 mg/kg PO q.12 h for 14 d) and famoti-
dine (0.5 mg/kg PO q.12 h for 14 d) in dogs.
● Clarithromycin (30 mg PO q.12 h for 4 d), metroni-
dazole (30 mg PO q.12 h for 4 d), ranitidine (10 mg
PO q.12 h for 4 d) and bismuth subsalicylate (40 mg
PO q.24 h for 4 d) in H. heilmanii-infected cats.
● Azithromycin (30 mg PO q.24 h for 4 d), tinidazole
(100 mg PO q.24 h for 4 d), ranitidine (20 mg PO
q.24 h for 4 d) and bismuth subsalicylate (20 mg PO
q.12 h for 4 d) in H. heilmanii-infected cats.
● Amoxicillin (20 mg/kg PO q.8 h for 21 d), metroni-
dazole (20 mg/kg PO q.8 h for 21 d) and omeprazole
(0.7 mg PO q.24 h for 21 d) in H. pylori-infected
cats.
● Amoxicillin (20 mg/kg PO q.12 h for 14 d), clar-
ithromycin (7.5 mg/kg PO q.12 h for 14 d) and
metronidazole (10 mg/kg PO q.12 h for 14 d) in H.
pylori-infected cats.
Thus if a decision is made to eradicate Helicobacter
species, use of one of the above protocols is
recommended.
DRUG COMBINATIONS
Hyoscine and dipyrone
Spasmogesic®, Buscopan® and other trade names
describe drug combinations containing the anticholiner-
gic hyoscine and the NSAID dipyrone. Although this
combination is relatively commonly used in small
animals, its value in the management of gastrointestinal
disease is questionable.
The potential concerns with anticholinergic usage in
the management of vomiting or diarrhea are discussed
elsewhere in this chapter. The potential adverse effects
from dipyrone are discussed in Chapter 13 on
NSAIDs.
PROKINETIC DRUGS
Treatment of certain conditions such as delayed gastric
emptying and suboptimal colonic motility is facilitated
by the use of prokinetic drugs. These include meto-
clopramide (discussed previously), ranitidine (again
described previously), erythromycin and cisapride.
Cisapride was previously the prokinetic of choice in
small animals. However, this drug was recently impli-
cated in causing adverse cardiac events in people. This
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 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-HT4 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 recom-
mended 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-HT3) receptors,
thus stimulating migrating motility complexes and ante-
grade peristalsis. However, the mechanism of action in
dogs is less well understood, but it is most likely via
action on 5-HT3 receptors. Gastric emptying is enhanced
by stimulating antral contractions, whilst lower esopha-
geal pressure is also increased. However, given that
erythromycin has most effect in stimulating interdiges-
tive activity, beneficial effects on gastric emptying during
the digestive phase are less clear.
484
Ch019-S2858.indd 484
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 eryth-
romycin 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 enteric-
coated 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 veteri-
nary 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 absorp-
tion of digoxin, potentially leading to digoxin
toxicity.
11/19/2007 2:28:58 PM

● Erythromycin may increase serum concentrations of
theophylline and terfenadine. In humans, this effect
is particularly important because this combination
has been associated with the development of fatal
arrhythmias.
● The metabolism of methylprednisolone may be
inhibited and the clearance of theophylline may be
increased by concurrent erythromycin administra-
tion. The significance of the former interaction is not
clear, whilst the interaction with theophylline may
lead to theophylline toxicity and close pharmacologi-
cal monitoring is recommended.
● Erythromycin may prolong prothrombin times and
lead to bleeding when given to a patient previously
stabilized on warfarin.
● Other reported human drug interactions of erythro-
mycin include ciclosporin, carbemazepine and tri-
azolam. However, the significance of such interactions
for veterinary species is less well established.
● Administration of erythromycin may falsely elevate
serum concentrations of ALT and AST if colorimetric
assays are used and urinary catecholamine measure-
ments may be altered in a similar manner.
LAXATIVES, ENEMAS AND
BOWEL CLEANSERS
These drugs are commonly used to evacuate the large
bowel and the main pathological indications are consti-
pation and obstipation.
LAXATIVE THERAPY
A number of groups of laxative drugs exist, including
bulk-forming laxatives, emollient laxatives, lubricant
laxatives, hyperosmotic laxatives and stimulant
laxatives.
Bulk-forming laxatives
Most of the available agents in this group are dietary
fiber supplements which contain poorly digestible poly-
saccharides and celluloses. These are mainly derived
from cereal grains, wheat bran and psyllium. This group
of agents can either be given in a purpose-formulated
‘prescription’ diet or as a preparation added to the exist-
ing diet. Examples include psyllium (Vetasyl®, Metamu-
cil®, Genifiber®, etc.) and sterculia (Peridale®). Dietary
fiber supplements are usually well tolerated, more effec-
tive and more physiological than the other groups of
laxatives.
Ch019-S2858.indd 485
LAXATIVE THERAPY
Psyllium
• DOGS: 5 mL (1 teaspoonful) to 30 mL (2 tablespoonfuls) PO
q.12–24 h
• CATS: 5–20 mL (1–4 teaspoonfuls) PO with each meal
Sterculia
DOGS and CATS
• <5 kg: 1.5 g PO q.24 h
• 5–15 kg: 3 g PO q.12–24 h
• >15 kg: 4 g PO q.12–24 h
Emollient laxatives
Emollient laxatives are anionic detergents that reduce
surface tension, thus increasing the miscibility of water
and lipid digesta. This thereby increases lipid absorption
and impairs the absorption of water. There is some evi-
dence that docusate sodium (dioctyl sodium sulfosucci-
nate), the main agent used in this group, also increases
colonic mucosal cell cAMP concentration and thus
increases both ion secretion and fluid permeability.
Most of the effect of this drug is local, although some
drug is absorbed from the small intestine and then
excreted into bile.
Docusate is present as the sole agent in enemas (e.g.
Fletcher’s enemette, Dioctynate®, Enema-DSS®, Docu-
soft®, Ther-evac®) and some oral preparations (tablets,
capsules and syrups of various strengths) or in combina-
tion products with dantron, a fecal softener (e.g. ‘con-
danthrusate’, Docusol®; 50 mg dantron and 60 mg
docusate/5 mL). The enema preparations are all veteri-
nary-licensed products, but the oral preparations are
not.
Clinical efficacy has not been established definitively.
Nevertheless, they are safe agents when used in healthy
well-hydrated individuals. However, these preparations
should be avoided in patients with pre-existing electro-
lyte or fluid deficits. These drugs have few reported side
effects when used at recommended doses; cramping,
diarrhea and intestinal mucosal damage have been
reported, whilst liquid oral preparations can sometimes
cause pharyngeal irritation. Concurrent administration
of mineral oil is not recommended, because enhanced
absorption of the oil may occur. If overdose occurs, it
is advisable to monitor hydration and systemic electro-
lyte status. If concurrent administration is essential, it
is advisable to stagger dosing by at least 2 h.
Docusate sodium (dioctyl sodium sulfosuccinate)
• DOGS: 50–300 mg PO q.12–24 h; 10–15 mL of a 5% solution
mixed with 100 mL of water and instilled per rectum
• CATS: 50 mg PO q.12–24 h; 2 mL of a 5% solution mixed with
50 mL of water and instilled per rectum
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 CHAPTER 19 GASTROINTESTINAL DRUGS
Lubricant laxatives
As their name suggests, these agents have lubricating
properties. They impede colonic water absorption and
make it easier for feces to be passed. Some reports have
suggested that up to 60% of these preparations may be
absorbed, although most reports dispute these findings.
Examples include paraffin (mineral oil) and white soft
paraffin (white petrolatum). These agents have only
moderate effects and are only likely to be of use in mild
cases of constipation. Preparations of paraffin include
generic preparations (e.g. liquid paraffin) and white soft
paraffin (Katalax®).
In humans, use of these drugs is contraindicated in
young or old patients, debilitated patients and pregnant
patients. In addition, these agents should be avoided in
patients with pre-existing dysphagia, regurgitation or
vomiting. The main side effect is lipoid pneumonia sec-
ondary to inhalation (paraffin is tasteless and may not
elicit normal swallowing when syringed). When signifi-
cant quantities of mineral oil are absorbed, granuloma-
tous reactions may develop in the liver, spleen and
mesenteric lymph nodes. Long-term use is not recom-
mended since it may predispose to malabsorption of
fat-soluble vitamins (vitamins A, D, E and K), although
the significance of this has not been determined
clinically. Docusate sodium should not be administered
concurrently with mineral oil, because it may enhance
absorption.
DOGS
• Use liquid paraffin (mineral oil) 15–30 mL (1–2 tablespoonfuls)
PO per meal, as required
CATS
• Adult cats: 1 inch of white soft paraffin paste PO q.12–24 h
• Kittens: 0.5 inch of white soft paraffin paste PO q.12–24 h
Hyperosmotic laxatives
Hyperosmotic laxatives consist of agents which are
poorly absorbed in the gastrointestinal tract but osmoti-
cally active. Lactulose is a nondigestible carbohydrate
used for both treatment of constipation and manage-
ment of hepatic encephalopathy (see below). Polyethyl-
ene glycol 3350 (PEG) also acts as an osmotic agent and
is commonly included in bowel-cleansing solutions used
prior to lower bowel colonoscopy. Most preparations
used for this purpose also contain sodium sulfate, which
minimizes sodium absorption and other electrolytes
(e.g. bicarbonate, potassium and chloride) to maintain
isotonicity and prevent any net gain or loss in the secre-
tion of water or electrolytes in the intestine.
A variety of preparations of PEG are available, e.g.
Golytely®, Klean Prep®, Colyte® and Nulytely®. PEG
486
Ch019-S2858.indd 486
should not be administered to animals with gastric
retention, suspected gastrointestinal obstruction, bowel
perforation, megacolon or in patients with reduced
swallowing function (which may predispose to inhala-
tion pneumonia). Occasional vomiting may be seen,
especially if the maximal dose has been administered.
Otherwise, this drug preparation is very well tolerated.
Given that gastrointestinal motility is affected, the
absorption of other drugs may be affected by adminis-
tration of bowel cleansers.
DOGS
• Withhold food for 18–24 h prior to colonoscopy. Give 2–3 doses
of 20–30 mL/kg, 4–6 h apart, by orogastric intubation. Prior to
the procedure, a warm water enema should be administered
CATS
• Withhold food for 18–24 h prior to colonoscopy. Give 2 doses of
30 mL/kg, 4–6 h apart, by orogastric intubation. Prior to the
procedure, a warm water enema should be administered
Stimulant laxatives
This group stimulates propulsive motility and the
main agent used in companion animals is bisacodyl
(Ducolax®). The exact mechanism of action is unclear;
the two putative mechanisms are promoting peristalsis
through direct stimulation of intramural neural plexuses
and increasing fluid and ion accumulation in the large
intestine and thus increasing catharsis. This drug can
be given as sole therapy, or in combination with other
laxative preparations such as fiber supplements. The
drug is reported to be minimally absorbed after oral
administration and onset of action is 6–10 h. Relatively
few side effects have been reported but include cramp-
ing, nausea and diarrhea. Stimulant laxatives are con-
traindicated in cases of intestinal obstruction not caused
by constipation, when rectal bleeding is present or if
intestinal perforation is suspected. Bisacodyl should not
be given concurrently with milk or antacids as both can
cause premature disintegration of the enteric coating.
Further, this drug should not be administered concur-
rently with other oral medications (e.g. not ≤2 h),
because its effect on gastrointestinal motility may affect
absorption. Daily administration is inadvisable because
of potential injury to myenteric neurones when used
chronically.
DOGS
• 5–20 mg PO q.24 h
CATS
• 2–5 mg PO q.24 h
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ANTIDIARRHEAL DRUGS
For most cases of acute diarrhea, the mainstay of therapy
is to replace fluid losses, modify the diet and treat the
specific cause (infectious, immune-mediated, etc.) where
possible. Treatment of diarrhea does not often require
use of drugs but they may be considered when relief of
discomfort will benefit the patient, provided that their
use does not risk exacerbating the diarrhea or causing
systemic effects.
MOTILITY-MODIFYING DRUGS
Intestinal transit time is predominantly determined by
the balance between peristalsis, which moves ingesta in
an aboral direction, and segmental contractions, which
narrow the bowel lumen and increase the resistance to
flow. Peristalsis is influenced by the cholinergic system
and gut hormones such as motilin. Segmental contrac-
tions are cholinergic dependent.
Although it is theoretically possible to reduce diar-
rhea by either decreasing peristalsis or increasing
segmental contractions, reducing peristalsis is of little
clinical benefit and is generally contraindicated. This is
because, in most cases of diarrhea, the gut is hypomo-
tile, not hypermotile, and peristalsis and segmental con-
tractions are already reduced.
Gastrointestinal motility may be modified by two
groups of agents: opioids, which increase segmental
contractions, and anticholinergic drugs, which decrease
both segmental contractions and peristalsis.
Opioids
EXAMPLES
Diphenoxylate (Lomotil®), loperamide (Imodium®),
paregoric
Clinical applications
These drugs may be effective for the symptomatic treat-
ment of diarrhea as they increase segmental contrac-
tions, thus delaying gut transit time. They may relieve
abdominal pain and tenesmus and reduce the frequency
of defecation, although convincing clinical efficacy has
not been observed in many veterinary patients.
They are rarely required, however, in management
of diarrhea in small animals. Acute diarrhea is usually
self-limiting with appropriate treatment and chronic
diarrhea does not usually respond to such therapy and
requires a definitive diagnosis to be established to allow
specific treatment to be instituted.
The use of motility modifiers is not without risk as
the diarrhea may be beneficial in removing toxins and
Ch019-S2858.indd 487
MOTILITY-MODIFYING DRUGS
slowing transit may be counterproductive. Reduced
motility may allow enterotoxin-producing organisms to
remain in the small intestine, resulting in increased fluid
loss. In addition, in cases of diarrhea caused by invasive
bacteria, diarrhea probably has a protective function in
hastening elimination of organisms. Slowing transit
time may prolong the time bacteria are resident in the
bowel, resulting in a greater opportunity for prolifera-
tion, invasion of the mucosa and absorption of toxic
products. However, loperamide appears to be antisecre-
tory and therefore may have value in treating animals
with secretory diarrhea due to Escherichia coli. Anec-
dotally, opioids appear to be useful in the management
of fecal incontinence in some patients.
Mechanism of action
Opioids increase the amplitude of rhythmic contraction
and decrease propulsive contractions. They directly affect
intestinal smooth muscle, producing both tonic and
phasic contractions of the circular muscle. They also act
centrally and on synapses to augment segmentation.
They either have no effect on longitudinal muscle or they
relax it. The net effect of these actions is to inhibit flow
of intestinal contents, delay gastric emptying and increase
the tone of the ileocolic valve and anal sphincter.
Some opioids, such as loperamide and to a lesser
extent diphenoxylate, also increase fluid and water
absorption, possibly by a calcium-blocking effect or by
inhibition of calmodulin, the intrinsic calcium-binding
protein. Loperamide and diphenoxylate also inhibit the
activity of secretagogues such as E. coli enterotoxin,
vasoactive intestinal peptide, bile acids and PGE2.
Finally, opiates may also enhance mucosal absorption
in the gastrointestinal tract.
Lomotil® contains atropine as well as diphenoxylate.
This is to discourage abuse of the drug by people. At
therapeutic doses of Lomotil® the atropine has no clini-
cal effect.
Formulations and dose rates
There are no currently approved veterinary formulations of these
drugs. Human formulations are available; paregoric is available as a
liquid. Diphenoxylate and loperamide are available in tablet and liquid
forms. Use of diphenoxylate in cats is not recommended.
DOGS AND CATS
Paregoric
• 0.05–0.06 mg/kg PO q.8 h
Loperamide
• 0.1–0.2 mg/kg PO q.8 h
DOGS ONLY
Diphenoxylate
• 0.1 mg/kg PO q.8 h
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 CHAPTER 19 GASTROINTESTINAL DRUGS
Pharmacokinetics
There are few data on the pharmacokinetics of the
opioid agents in small animals. The morphine in parego-
ric is absorbed in a variable fashion from the gastro-
intestinal tract and rapidly metabolized in the liver,
resulting in serum concentrations that are much lower
than those produced by morphine administered
parenterally.
In humans diphenoxylate is rapidly absorbed. Onset
of action occurs about 45 min after dosing and lasts for
3–4 h. In dogs, it has been stated that loperamide has a
faster onset and longer duration of action than diphenox-
ylate, although published clinical studies confirming this
appear to be lacking.
Adverse effects
● In dogs, the most common side effects of opiates
are constipation, sedation and bloating. Overdosage
with these medications can lead to significantly
reduced gastrointestinal motility (i.e. ileus) and
delayed absorption.
● Signs of systemic opioid intoxication may occur
with use of the opioid antidiarrheals, particularly in
cats.
● Neurological disturbances such as ataxia, hyperex-
citability, circling, head pressing, vocalization and
prostration may occur with overdosage. In dogs
there has been a suggestion that collies may be more
sensitive to the toxic effects of loperamide.
● Treatment of side effects or overdosage involves use
of the opioid antagonist naloxone and recovery is
usually uneventful.
● Massive overdoses with the diphenoxylate/atropine
preparations may also lead to atropine toxicity.
Known drug interactions
● Other CNS depressants such as anesthetic agents,
antihistamines, phenothiazines, barbiturates and
tranquilizers may cause increased CNS or respiratory
depression when used with opiate antidiarrheal
agents.
● Opiate antidiarrheal agents are contraindicated in
patients receiving monoamine oxidase inhibitors,
e.g. l-deprenyl (selegiline), within at least 14 d.
However, the significance of this interaction in vet-
erinary species is not clear given that this drug group
is rarely used.
● Plasma amylase and lipase concentrations may be
increased for up to 24 h after the administration of
opiates.
488
Ch019-S2858.indd 488
Anticholinergic drugs
Anticholinergics have little use in the management of
diarrhea in small animals, although they are frequently
prescribed, usually in combination products. As dis-
cussed previously, most diarrheal disorders in small
animals are associated with a hypomotile rather than a
hypermotile gut and the risk with anticholinergics is
that they will produce a dynamic ileus, especially if
electrolyte imbalances such as hypokalemia are also
present. Anticholinergics reduce but do not abolish peri-
stalsis and substantially decrease segmental contrac-
tions. As long as some peristaltic activity is present, no
matter how weak, it can propel liquid ingesta along the
flaccid intestine and diarrhea will occur.
Although anticholinergics reduce gastric secretions,
including protein exudation induced by histamine, they
have little effect on intestinal secretions.
They may be justified in the short term for relief of
pain and tenesmus associated with large bowel inflam-
matory disease. They also may be indicated in stress-
induced colitis where cholinergic mechanisms might be
involved.
Adsorbents and protectants
Kaolin and pectin
Kaolin and pectin are in many preparations that are
widely used for the management of diarrhea in small
and large animals. They are purported to soothe irri-
tated gastrointestinal mucosa and bind toxins and
pathogenic bacteria. However, their clinical efficacy is
unproven. There is no evidence that kaolin and pectin
reduce gastrointestinal fluid or electrolyte loss and
kaolin may in fact increase fecal sodium loss.
Many preparations contain combinations of kaolin
and pectin and/or antibacterials and/or anticholinergics.
As discussed previously, the value of the latter two types
of compound in the treatment of diarrhea is limited in
small animals and may be detrimental.
Montmorillonite
Montmorillonite (Diarsanyl®) is an intestinal adsor-
bent/protectant, which is used in the symptomatic
treatment of companion animals with diarrhea. It is a
trilamellar smectite clay, with a similar mechanism of
action to that of kaolin. However, it is reported to have
superior adsorbent properties. Most preparations of
montmorillonite also contain simple sugars and electro-
lytes. No adverse affects are known, but are likely to
be similar to that of kaolin preparations. Overdosage
would be expected to cause constipation. The main
formulation (Diarsanyl®) is a paste in 10 mL, 24 mL
and 60 mL multidose syringes. Each 10 mL of paste
contains 4.5 g of montmorillonite and the recommended
dose rate is as follows.
11/19/2007 2:28:58 PM

DOGS
• <7 kg: 1 mL PO q.12 h
• 7–17 kg: 2 mL PO q.12 h
• 18–30 kg: 4 mL PO q.12 h
• 31–60 kg: 10 mL PO q.12 h
CATS
• 1 mL PO q.12 h
Activated charcoal
Activated charcoal has been used for many years in the
treatment of toxicosis. The drug is not absorbed from
the gastrointestinal tract and is thought to have a local
effect, by adsorbing toxic substances and binding bacte-
rial toxins. However, it is not reported to be effective
for mineral acids or alkalis and, in fact, there is limited
work supporting its efficacy. Recommended dosages are
in the range of 2–8 g/kg as an aqueous suspension per
os. For example, administering 10 mL/kg of a 20%
slurry provides a dose equivalent to 2 g/kg. Given the
volumes involved, this drug is usually given by oro- or
nasogastric intubation.
Very rapid administration may induce emesis and
charcoal can cause effects on fecal characteristics (e.g.
diarrhea, constipation, black feces). Aside from these,
there are no reported systemic adverse effects. Finally,
activated charcoal can permanently stain objects with
which it comes into contact and the powder has a ten-
dency to float over wide areas. Therefore, care is advised
during preparation.
Bismuth subsalicylate
Bismuth subsalicylate is reported to be an effective agent
for treatment and prevention of enterotoxigenic diar-
rhea. Nausea, abdominal pain and diarrhea are reduced
in humans with infective diarrhea treated with bismuth-
containing products. Bismuth subsalicylate has modest
antibacterial effects against enteropathogens such as E.
coli, Salmonella spp and Campylobacter jejuni. However,
it is sometimes used in combination protocols for
the eradication of Helicobacter species. The salicylate
moiety is believed to decrease intestinal secretion by
inhibiting prostaglandin production and inhibiting gen-
eration of cAMP by the enterotoxin.
Preparations which contain bismuth subsalicylate
(Pepto-Bismol®, Peptosyl®) can be clinically useful in
the management of acute diarrhea. However, such
conditions usually resolve with appropriate nondrug
therapy.
Reported side effects in humans include nausea and
vomiting. Long-term use of bismuth-containing prod-
Ch019-S2858.indd 489
MOTILITY-MODIFYING DRUGS
ucts is not recommended as the drug can be neurotoxic
and is contraindicated in patients with renal impair-
ment. Further, given that bismuth is radio-opaque, it
may interfere with radiographic studies of the gastroin-
testinal tract. Overdosage can result in salicylate toxic-
ity, especially in cats. A safe dose in dogs and cats is
0.25 mL/kg q.4–6 h. Dosages greater than 0.7 mL/kg
could result in toxicity. Aside from this, changes in fecal
characteristics can be seen, i.e. color change to black or
green-black.
Sulfasalazine
Clinical applications
Sulfasalazine is indicated in the treatment of chronic
colitides (e.g. inflammatory bowel disease) in dogs and
(less commonly) cats. Although well-controlled studies
have not been performed in small animals, uncontrolled
studies and widespread clinical use indicate that the
drug has convincing clinical benefit in patients with
chronic colitis. It is not a panacea, however, and a
number of animals do not respond or relapse during or
after therapy.
Preparations containing only 5-aminosalicylic acid
(5-ASA) (mesalazine, mesalamine) are now used in
human and veterinary medicine in the treatment of
ulcerative colitis. 5-ASA appears to retain the effective-
ness of sulfasalazine but reduces (but does not eliminate
altogether) the incidence of side effects by dispensing
with the sulfonamide entity. The drug is administered
as a suppository or as an enteric-coated tablet to ensure
that the majority of drug reaches the colon. Other drugs
used in human colitis include olsalazine, which is two
molecules of 5-ASA linked by an azo bond. The clinical
value of this drug in veterinary medicine has yet to be
established.
Mechanism of action
Sulfasalazine is a combination of sulfapyridine and 5-
ASA, which is cleaved by colonic bacteria, resulting in
sulfapyridine being absorbed and ASA excreted in feces.
Given that the colonic concentrations of both sulfapyri-
dine and 5-ASA are higher than when given orally as
individual agents, it is not entirely established which is
responsible for the clinical effects. However, 5-ASA is
probably the active ingredient, as a result of antiprosta-
glandin and antileukotriene activity. In addition, this
agent is thought to have oxygen free radical-scavenging
actions, to interfere with phagocytic chemotaxis and
function and to inhibit cytokine and immunoglobulin
production. NSAIDs such as aspirin that inhibit prosta-
glandin but not leukotriene synthesis are ineffective in
treating colonic inflammation and may actually worsen
inflammatory bowel disease.
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 CHAPTER 19 GASTROINTESTINAL DRUGS
Formulations and dose rates
Sulfasalazine is available as tablets or liquid. Various dosage regimens
have been successfully used.
DOGS
• Some clinicians recommend a dose of 10–15 mg/kg PO q.8–
12 h for 2 weeks, then tapered to the lowest effective dose
• Other reports suggest that higher doses are required, e.g. 20–
50 mg/kg (up to a maximum of 1 g) PO q.8 h; from 2–4 weeks,
attempts can be made to taper the dose gradually (e.g. by
reducing 25–50% of the dose every 2–4 weeks) to the lowest
effective dose
• Therefore, it is usually recommended to start at a low dose
(e.g. 12.5 mg/kg PO q.8 h) and increase this after 4 weeks if it
has been ineffective
• Olsalazine is used in dogs that cannot tolerate sulfasalazine.
The recommended dose is 10–20 mg/kg PO q.8 h
CATS
• 10–20 mg/kg PO q.24 h. The reduced dosing interval is used in
light of increased sensitivity to salicylates in this species
Pharmacokinetics
After oral administration approximately 20–30% of the
drug is absorbed in the small intestine. Some of this
absorbed drug is believed to be excreted unchanged into
the bile. Unabsorbed and biliary excreted drug is cleaved
in the colon by bacterial flora. Because the colonic
microflora is required to cleave the drug, sulfasalazine
is not effective against small bowel inflammation. The
sulfapyridine component is rapidly absorbed but only a
small percentage of the 5-ASA is absorbed; both are
metabolized in the liver and excreted in the urine.
Olsalazine is poorly absorbed and that which is absorbed
is rapidly eliminated. Approximately 98% of an oral
dose is thought to reach the colon.
Adverse effects
● The major adverse effect, although uncommon, is
keratoconjunctivitis sicca. Should decreased tear
production be recorded, this can be resolved by
reducing the dose or discontinuing the drug
altogether.
● Other occasional adverse effects include vomiting,
allergic dermatitis, cholestatic jaundice, hemolytic
anemia and leukopenia.
● Drug hypersensitivity manifested as lethargy, pyrexia,
arthralgia and cutaneous drug eruption can occur
with sulfonamide drugs and has been reported with
the use of sulfasalazine.
Known drug interactions
● Sulfasalazine may displace other highly protein-
bound drugs such as methotrexate, warfarin,
490
Ch019-S2858.indd 490
phenylbutazone, thiazide diuretics, salicylates and
phenytoin. The clinical significance of these interac-
tions has not been established.
● Sulfasalazine may decrease the bioavailability of
folic acid or digoxin. Antacids may decrease the
oral bioavailability of sulfasalzine if administered
concurrently.
● Antacids may decrease the oral bioavailability of
sulfasalazine if administered concurrently.
● As with other sulfonamides, sulfasalazine may affect
blood thyroid concentrations, e.g. decreased total
and free T4, increased cTSH.
● Olsalazine may causes increases in plasma concentra-
tions of ALT and AST.
APPETITE STIMULANTS
The main appetite stimulants used in companion animals
are the H1-receptor antagonists cyproheptadine and
diazepam. In both drugs, the appetite stimulation is
effectively a ‘side effect’ of the indication for which they
were predominantly designed.
Cyproheptadine also has serotonin antagonist and
calcium channel-blocking properties. It is indicated for
short-term use as an appetite stimulant in cats; pro-
found anorexia or chronic nutritional disorders are
better managed with more intensive nutritional support,
i.e. tube feeding. The drug is well absorbed, almost
completely metabolized in the liver and metabolites are
excreted in the urine. The main side effects are sedation
and anticholinergic effects (dry mucous membranes,
mydriasis); occasional reports of hemolytic anemia have
been described.
Diazepam is used mainly for its anticonvulsant, anx-
iolytic and skeletal muscle relaxant properties. However,
when used IV, it can be an effective appetite stimulant
in cats. Again, only short-term (and preferably single)
use is recommended. The IV preparation should be
injected slowly, since rapid administration may cause
marked excitation. Thrombophlebitis has also been
reported. The drug should be used with caution in
patients with pre-existing or suspected renal or hepatic
insufficiency. The main side effects include muscle fas-
ciculations, weakness, ataxia, behavior changes and
excessive sedation. Fulminant hepatic necrosis has also
been described in cats after oral administration (usually
for >5 d). Given that the IV preparation is used for
appetite stimulation, the significance of this finding is
unclear. Nevertheless, cautious use is recommended.
CATS
Cyproheptadine
• 1–4 mg per cat PO q.12–24 h
11/19/2007 2:28:58 PM

Diazepam
• 0.05–0.4 mg/kg IV. Eating may begin shortly after administra-
tion so have a food supply ready
Oxazepam
• 2 mg per cat PO q.12 h
DRUGS USED FOR MANAGEMENT OF
HEPATIC DISEASE
URSODEOXYCHOLIC ACID (URSODIOL)
Clinical applications
Ursodeoxycholic acid (ursodiol) is a naturally occurring
bile acid found in the bile of the Chinese black bear.
Black bear bile has been used for many years by practi-
tioners of Eastern medicine and has been commercially
synthesized and available for use as a hepatoprotective
agent in Japan since the 1930s. Since the 1970s ursode-
oxycholic acid has been used in Western human medi-
cine for dissolution of gallstones. More recently, it has
been used in the management of chronic hepatic diseases
in humans such as primary biliary cirrhosis, biliary
disease secondary to cystic fibrosis, nonalcoholic steato-
hepatitis, idiopathic chronic hepatitis, autoimmune
hepatitis, primary sclerosing cholangitis and alcoholic
hepatitis. However, its therapeutic efficacy in some of
these disorders has not been firmly established.
In veterinary medicine, ursodeoxycholic acid has been
used in the management of dogs with chronic hepatitis
and cats with lymphocytic plasmacytic cholangitis. It is
believed to be most beneficial in disorders where bile
toxicity plays an important role in the ongoing pathol-
ogy. The efficacy of ursodeoxycholic acid in veterinary
patients has not been definitely established, although
anecdotal reports suggest it may have some benefit in
patients with chronic inflammatory hepatobiliary
disease. It may be of some benefit in slowing disease
progression, especially if used at an early stage of the
disease. Some authors recommend ursodeoxycholic acid
treatment for all cats with cholangiohepatitis where
extrahepatic biliary obstruction has been eliminated.
Mechanism of action
Ursodeoxycholic acid decreases intestinal absorption
and suppresses hepatic synthesis and storage of choles-
terol. This is believed to reduce cholesterol saturation
of bile, thereby allowing solubilization of cholesterol-
containing gallstones. It has little effect on calcified
gallstones or on radiolucent bile pigment stones and
therapy is only successful in patients with a functioning
gallbladder.
Ursodeoxycholic acid, a relatively hydrophilic bile
acid, is also believed to protect the liver from the damag-
Ch019-S2858.indd 491
URSODEOXYCHOLIC ACID (URSODIOL)
ing effects of hydrophobic bile acids, which are retained
in cholestatic disorders. Hydrophobic bile acids can be
cytotoxic through detergent-like and nondetergent-like
actions. The mechanisms responsible for this hepato-
protective effect in humans have not been fully eluci-
dated and are controversial but they are believed to
involve replacement of the more hydrophobic bile acids,
increased bile flow (choleresis) and immunomodulation.
Ursodeoxycholic acid may also inhibit ileal uptake of
toxic secondary bile acids formed by bacterial modifica-
tion of primary bile acids in the gut lumen. The hepa-
toprotective effect may, however, be less in cats and dogs
than in humans as the major circulating bile acid in dogs
and cats is taurocholate. This is more hydrophilic and
less hepatotoxic than the major circulating bile acids in
humans.
Choleresis results from protonation of unconjugated
ursodeoxycholic acid when it is secreted into bile, result-
ing in the generation of a bicarbonate ion. Protonated
ursodeoxycholic acid is passively absorbed by biliary
epithelial cells, resulting in the net secretion of one
bicarbonate ion, which then serves as an osmotic draw
for biliary water secretion. Induced choleresis may
protect the hepatocytes from potentially toxic sub-
stances normally secreted into bile such as copper,
leukotrienes, cholesterol and bilirubin.
The immunomodulatory effects of ursodeoxycholic
acid are believed to involve decreased immunoglobulin
production by B lymphocytes, decreased interleukin-1
and -2 production by T lymphocytes, decreased expres-
sion of hepatocyte cell surface membrane HLA class I
molecules and possibly stimulation of the hepatocyte
glucocorticoid receptor.
Formulations and dose rates
Currently, no veterinary preparations are available but a variety of
human products exist, including both tablet (250 mg; e.g. Destolit®,
Urso®) and capsule formulations (300 mg; e.g. Ursofalk®, Acti-
gall®). The exact choice of product depends upon the size of patient
and ease of dosing with a particular type of preparation.
DOGS AND CATS
• 10–15 mg/kg q.24 h or divided and given q.12 h
It is recommended that ursodeoxycholic acid be administered for 3–4
months, after which the patient should be reassessed for improve-
ment in biochemical markers of hepatocellular pathology. If there has
been improvement treatment is continued but if there has been no
improvement or progression, either treatment should be terminated
or additional therapies such as glucocorticoids or colchicine added.
Pharmacokinetics
Ursodeoxycholic acid is well absorbed from the small
intestine in humans, with over 90% of the administered
dose being absorbed. It is extracted from the portal
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11/19/2007 2:28:58 PM
 CHAPTER 19 GASTROINTESTINAL DRUGS
circulation and conjugated with either taurine or glycine
and excreted into bile. Only very small amounts enter
the systemic circulation and minimal amounts are
detected in urine. It undergoes enterohepatic circula-
tion; at each cycle some of the free and conjugated drug
is degraded by gut bacteria, oxidized or reduced to less
soluble compounds and eliminated in the feces.
Adverse effects
● Ursodeoxycholic acid appears to be well tolerated by
dogs and cats; vomiting and diarrhea are reported
rarely.
● There is some concern in human patients that taurine
depletion may be potentiated by chronic treatment
with ursodeoxycholic acid. This may be important
in cats, who are obligate taurine conjugators. This
potential for taurine depletion may be exacerbated
in some cats with hepatobiliary disease, who have
increased urinary excretion of taurine-conjugated
bile acids. Dogs are less likely to become taurine
depleted by this mechanism as they can shift to
glycine conjugation.
● Ursodeoxycholic acid should not be used in patients
with extrahepatic biliary obstruction, biliary fistulas,
cholecystitis or pancreatitis.
Known drug interactions
Aluminum-containing antacids or colestyramine resin
may bind to ursodeoxycholic acid, thus reducing its
efficacy. Ursodeoxycholic acid dissolves more rapidly in
bile and pancreatic juice; therefore, administration with
food may improve absorption and is recommended.
Colchicine
Clinical applications
Colchicine is used in the management of gout in humans,
providing acute relief of symptoms as well as prophy-
laxis. It has also been used for the treatment of fibrosing
liver diseases such as primary biliary cirrhosis, alcoholic
liver disease, cryptogenic liver fibrosis and liver cirrho-
sis. However, two recent meta-analyses have demon-
strated limited efficacy of this drug, but more adverse
events. Thus, this drug is likely to fall from favor in
human hepatology. In veterinary medicine it has been
used in the management of amyloidosis and chronic
hepatic fibrosis. There is anecdotal evidence from a few
case studies that colchicine may improve liver function
and slow the progression of hepatic fibrosis. However,
controlled clinical trials are lacking and, given recent
findings in human studies, it should therefore be used
cautiously or avoided altogether.
Mechanism of action
Collagen secretion from lipocytes requires microtubules,
the assembly of which is inhibited by colchicine, thereby
492
Ch019-S2858.indd 492
interfering with the transcellular movement of collagen.
The drug increases collagenase activity and may there-
fore promote degradation of existing collagen, although
collagen already cross-linked cannot usually be degraded.
It has anti-inflammatory effects by inhibiting leukocyte
migration, which may suppress fibrogenesis. It may also
have a direct hepatoprotective effect by stabilizing hepa-
tocyte membranes. Colchicine is also reported to block
synthesis of serum amyloid A by hepatocytes, thus
preventing amyloid formation. The mechanism of its
apparent efficacy in gout is poorly understood.
Formulations and dose rates
Various colchicine preparations are available in tablet form, usually in
either 0.5 mg or 0.6 mg sizes (dependent upon manufacturer). Inject-
able formulations may be available, but most experience in veterinary
species is with oral dosing. Doses in dogs have been extrapolated
from the human literature. Its use in the cat has not been reported.
Colchicine is marketed in combination with probenecid in some
countries – this combination should be avoided as probenecid can
cause nausea, vomiting and lethargy.
DOGS
• 0.025–0.03 mg/kg/d
Pharmacokinetics
No information is available on the pharmacokinetics of
colchicine in dogs and cats. Data derived from humans
and laboratory animals indicate that the drug undergoes
first-pass metabolism after absorption from the gut, the
metabolites, as well as unchanged drug, being resecreted
into the gut in bile and then reabsorbed. Colchicine is
concentrated in leukocytes. Its plasma half-life is about
20 min; leukocyte half-life is 60 h.
Colchicine is deacetylated in the liver as well as being
metabolized in other tissues. Most of the dose is excreted
in the feces, with a small amount excreted in urine,
particularly in patients with hepatic disease.
Adverse effects
● Because of the limited veterinary experience with
colchicine, little is known about its potential toxicity
in dogs and cats.
● In humans, the therapeutic window for colchicine is
quite narrow, with toxic effects occurring after only
small overdoses.
● Nausea, vomiting and diarrhea have been reported
in dogs.
● Bone marrow suppression has occurred in humans
after prolonged use.
● Myopathy and peripheral neuropathy have been
reported rarely in humans.
11/19/2007 2:28:58 PM

● Severe local irritation occurs if the drug is inadver-
tently administered perivascularly. Thrombophlebitis
has also been reported.
● Colchicine is contraindicated in patients with serious
renal, gastrointestinal or cardiac disease and should
be used with caution in patients with less severe
disease of these organs.
● Colchicine is teratogenic in mice and hamsters; there-
fore it should not be used in pregnant patients unless
the benefits outweigh the risks.
● Colchicine may decrease spermatogenesis.
● Safety for nursing neonates is unknown as it is not
known whether it is excreted in milk.
Known drug interactions
● NSAIDs, especially phenylbutazone, increase the risk
of thrombocytopenia, leukopenia or bone marrow
suppression when used concurrently with
colchicine.
● Many antineoplastic and other potentially marrow-
suppressing drugs may cause additive myelosuppres-
sion when used concurrently with colchicine.
● Colchicine may enhance the activity of sympathomi-
metic drugs and CNS depressants, although the clini-
cal significance of this interaction is not known
● Colchicine may cause false-positive results for eryth-
rocytes on urine dipsticks and may elevate serum
ALP concentrations.
Penicillamine
Penicillamine is a degradation product of penicillin but
has no antimicrobial activity. It was first isolated in
1953 from the urine of a patient with liver disease who
was receiving penicillin.
Clinical applications
Penicillamine is a monothiol chelating agent which is
used in veterinary medicine in the treatment of copper
storage hepatopathy (e.g. Bedlington terriers), lead tox-
icity and cystine urolithiasis. It has also been used in the
management of rheumatoid arthritis in humans.
Mechanism of action
Penicillamine chelates several metals, including copper,
lead, iron and mercury, forming stable water-soluble
complexes that are excreted by the renal route. It also
combines chemically with cystine to form a stable,
soluble, readily excreted complex.
Although it usually takes months to years for hepatic
copper levels to decrease, clinical improvement is often
seen in Bedlington terriers after only a few weeks,
suggesting that the drug has beneficial effects other
than copper depletion. Penicillamine induces hepatic
Ch019-S2858.indd 493
URSODEOXYCHOLIC ACID (URSODIOL)
metallothionein, which may bind and sequester copper
in a nontoxic form. It may also have antifibrotic effects
as it inhibits lysyl oxidase, an enzyme necessary for col-
lagen synthesis, and directly binds to collagen fibrils,
preventing cross-linking into stable collagen fibers.
However, its efficacy as an antifibrotic agent in humans
is doubtful and it has not been evaluated in veterinary
medicine.
Penicillamine may have immunomodulatory effects
and has been demonstrated to reduce IgM rheumatoid
factor in humans with rheumatoid arthritis. However,
its mechanism of action in this disease remains
uncertain.
Formulations and dose rates
Penicillamine is available as tablets and capsules.
DOGS AND CATS
Copper-associated hepatopathy
• 10–15 mg/kg PO q.12 h on an empty stomach. However, if
gastrointestinal adverse effects are experienced, these may be
reduced if it is given with food, although absorption may be
reduced. Alternatively, reduce dose and gradually build up to
full dose
Cystine urolithiasis
• 15 mg/kg PO q.12 h (same comments as above if toxicity
experienced)
Lead toxicity
• 110 mg/kg/day divided q.6–8 h. Reduce dose to 33 mg/kg/d if
gastrointestinal adverse effects occur
Adverse effects
● Gastrointestinal tract adverse effects are common,
resulting in nausea and vomiting. Smaller doses on
a more frequent basis may alleviate adverse effects.
Alternatively, the drug can be given with food,
although this will reduce absorption.
● Other adverse effects observed infrequently or
rarely include:
– fever
– lymphadenopathy
– skin hypersensitivity reactions
– immune-complex glomerulonephropathy.
● Leukopenia, aplastic anemia and agranulocytosis
have been reported in humans.
Known drug interactions
Administration of penicillamine with gold compounds,
cytotoxic or immunosuppressant drugs or phenylbuta-
zone may increase the risk of hematological and/or
renal adverse effects. Zinc (or other cationic minerals)
may decrease the efficacy of penicillamine when given
concurrently.
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 CHAPTER 19 GASTROINTESTINAL DRUGS
Zinc
Zinc is a nutritional metal agent that is used to reduce
copper toxicity in breeds with copper-associated hepa-
topathies, e.g. Bedlington terrier. It is also reported to
have antifibrotic functions. The effect of copper toxicosis
relates to the ability of zinc to inhibit the absorption of
copper in the gastrointestinal tract. For liver disease, zinc
supplementation is often provided as part of a purpose-
formulated prescription diet. However, oral and inject-
able forms are also available and usually include either
zinc acetate or zinc sulfate. Zinc acetate is the prepara-
tion most commonly used for hepatic disorders.
Large doses of zinc can cause gastrointestinal signs,
including vomiting, whilst hemolysis can occur after
administration of large doses or if serum concentrations
exceed 1000 µg/dL. Penicillamine and ursodeoxycholic
acid can decrease zinc absorption, whilst zinc salts can
reduce the absorption of tetracycline and fluoroquino-
lones (e.g. enrofloxacin). It is recommended to stagger
dosing by at least 2 h.
Formulations and dose rates
DOGS
Copper-associated hepatopathy
• 5–10 mg/kg (of elemental zinc) PO q.12 h. Start at the higher
end of the dose range for the first 3 months, then reduce dose
to 50 mg PO q.12 h for maintenance. Separate the dose from
feeding by 1–2 h. Monitor plasma zinc concentrations every
2–3 months and aim for plasma zinc concentrations of
200–400 µg/dL
Hepatic fibrosis
• 10 mg/kg (of elemental zinc) q.24 h PO, aiming for plasma zinc
concentrations between 200–300 µg/dL
S-adenosyl methionine (SAMe)
S-adenosyl methionine (SAMe) is an endogenous mole-
cule which is synthesized, from methionine, by many
cells in the body. However, the enzyme SAMe synthetase
is found in the liver and is the rate-limiting step for
SAMe synthesis in the face of hepatic compromise.
SAMe is an essential factor in three major biochemical
pathways (most important in the liver), namely trans-
methylation, transsulfuration and aminopropylation.
SAMe functions as a donor of methyl groups and is thus
essential for the activation or elimination of many
substances. For transsulfuration, SAMe generates
sulfur-containing compounds, which are important for
conjugation reactions and for synthesis of glutathione
(GSH). The latter is also essential for numerous meta-
bolic processes and detoxification reactions; conversion
of SAMe to GSH requires folate, cyanocobalamin and
pyroxidine. Ample SAMe is usually synthesized but,
494
Ch019-S2858.indd 494
with hepatic disease or if toxic substances are present,
conversion to GSH may be reduced. Administration of
exogenous SAMe increases hepatic and red blood cell
GSH concentrations, whilst this compound also inhibits
apoptosis secondary to the presence of alcohol or bile
acids in hepatocytes. Other effects include anti-
depressant activity, possibly due to increased serotonin
turnover, and increased dopamine or noradrenaline
(norepinephrine) release.
Oral bioavailability is reported to be 1% and the
amount absorbed can be reduced further in the presence
of food. Once absorbed, SAMe enters the portal circula-
tion and is metabolized in the liver.
Clinical applications
SAMe is most frequently used as adjunctive therapy for
a variety of hepatic disorders (canine chronic hepatitis,
hepatic lipidosis, cholangiohepatitis, etc.). It may also
be beneficial in the treatment of certain hepatotoxic
disorders, most notably paracetamol (acetaminophen).
Formulations and dose rates
No pharmaceutical preparations exist; SAMe is considered to be a
nutritional supplement. Therefore, potency, purity, safety and efficacy
may vary across the various preparations. Specific animal products
exist, e.g. Denosyl®, Zentonil® and Hepatosyl®.
DOGS AND CATS
• Calculate daily dose based upon 17–20 mg/kg PO q.24 h (or
divided twice daily), rounded to the closest tablet size. The
product should be administered on an empty stomach, ≥1 h
before feeding
• Or, dose according to the following regimen: 5.5 kg, 90 mg PO
q.24 h; 5.5–11 kg, 180 mg PO q.24 h; 11–16 kg, 225 mg PO
q.24 h; 16–29.5 kg, 450 mg PO q.24 h; 29.5–41 kg, 675 mg
PO q.24 h; 41 kg+, 900 mg PO q.24 h
Adverse effects
SAMe appears relatively safe for use in small animals
and adverse effects are minimal. In humans, oral dosing
may cause anorexia, nausea, vomiting, diarrhea, flatu-
lence, constipation, dry mouth, insomnia, headache,
sweating and dizziness.
Known drug interactions
Concurrent use of pethidine (meperidine), monoamine
oxidase inhibitors (e.g. selegiline), serotonin reuptake
inhibitors (e.g. fluoxetine) and other antidepressants
(e.g. amitryptiline, clomipramine) could cause additive
serotonergic effects.
Silymarin
Milk thistle, Silybum marianum, is a flower used for
thousands of years for medical purposes. Three bio-
11/19/2007 2:28:59 PM

chemicals of interest have been isolated from the milk
thistle: silychristine, silydianin and silybin. The mixture
of these three substances is called ‘silymarin’. Silymarin
has been traditionally used in the treatment of liver
disease but while it has recently been advocated for use
in pets, all scientific information available concerns
human use. The biological mechanism of action is yet
unknown but several theories exist. Silymarin may:
● control hepatic cell membrane permeability and
thus prevent toxin penetration
● inhibit the cytotoxic, inflammatory and apoptotic
effects of tumor necrosis factor
● inhibit lipid peroxidase and β-glucoronidase and
act as a free radical scavenger and antioxidant
● reduce hepatic collagen formation
● increase hepatic glutathione content.
Clinical applications
Controlled studies demonstrating the efficacy of silyma-
rin are lacking and formulations are not standardized.
However, it is used commonly in the treatment of human
and companion animal hepatic disorders. It is most
commonly utilized in the treatment of chronic hepa-
topathies, although it may also be suitable for acute
hepatic disease and as a hepatoprotective agent against
a variety of hepatotoxic substances (such as Amanita
phalloides).
Formulations and dose rates
No pharmaceutical preparations exist and, as with SAMe, silymarin is
considered to be a nutritional supplement. Therefore, potency, purity,
safety and efficacy may vary across the various preparations. A variety
of preparations exist, including tablets and capsules in various
strengths, e.g. from 150 mg to 1000 mg.
DOGS AND CATS
• 20–50 mg/kg PO q.24 h
Adverse effects
● There are no reported absolute contraindications for
silymarin and this drug is well tolerated by the oral
route.
● Overdoses rarely cause significant morbidity. The
main signs seen in these situations are
gastrointestinal.
Known drug interactions
● Silymarin may inhibit the cytochrome P450 enzyme
2C9, such that drugs with narrow therapeutic ranges
should be used with caution, e.g. warfarin, amitrip-
tyline and verapamil.
● Silymarin may also inhibit cytochrome P3A4, but
this interaction has not yet been found to be
significant.
Ch019-S2858.indd 495
URSODEOXYCHOLIC ACID (URSODIOL)
● Finally, silymarin may increase the clearance of drugs
which undergo hepatic glucuronidation, e.g.
paracetamol (acetaminophen), diazepam and
morphine.
Lactulose
Lactulose is a synthetic derivative of lactose, consisting
of one molecule of galactose and one molecule of fruc-
tose. This disaccharide cannot be digested by enzymes
of the mammalian digestive tract, allowing the colonic
microflora to convert it to low molecular weight acids
(lactic, formic and acetic acid). These acids both increase
osmotic pressure (thus drawing water into the intestine
and having a laxative effect) and cause an acidifying
effect. By acidifying the colonic contents, ammonia
(NH3) is trapped as ammonium (NH4+) and, in this
form, cannot be absorbed across the intestinal wall. Less
than 3% of this drug is absorbed, the drug is not metab-
olized and is excreted unchanged in the urine within
24 h.
Clinical applications
The main use of lactulose is to reduce blood ammonia
concentrations in the treatment of hepatic encephalopa-
thy. It can also be used as an osmotic laxative for the
treatment of constipation.
Formulations and dose rates
The commercially available preparations are viscous sweet liquids
and have an adjusted pH of 3–7.
DOGS
• 5–30 mL PO q.6–8 h initially, then adjust the dose to achieve
2–3 soft stools per day
• For encephalopathic coma, first empty and clean the lower
bowel with repeated warm water enemas, then use 18–20 mL/
kg of a solution containing 3 parts lactulose and 7 parts warm
water, as a retention enema. Replace every 4–8 h
CATS
• For hepatic encephalopathy: 0.25–5mL PO q.8–12 h. Again,
modify the dose to achieve soft stools
• For encephalopathic coma, first empty and clean the lower
bowel with repeated warm water enemas, then use 18–20 mL/
kg of a solution containing 3 parts lactulose and 7 parts warm
water, as a retention enema. Replace every 4–8 h
• For constipation, 0.5 mL/kg q.8–12h PO
Adverse effects
● The main adverse effects are gastrointestinal, e.g.
flatulence, gastric distension and cramping.
● The main side effect of overdose is diarrhea.
● Use cautiously in patients with pre-existing fluid
and electrolyte imbalances.
495
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 CHAPTER 19 GASTROINTESTINAL DRUGS
● Cats do not like the taste of lactulose and it can be
difficult to administer this drug to some patients.
Known drug interactions
● Do not use lactulose and other laxatives
concurrently.
● In theory, the use of some antibacterials (e.g. neomy-
cin) could eliminate the bacteria that convert lactu-
lose to low molecular weight acids that exert an
osmotic effect. However, this has not appeared
to be a clinical concern since synergy has been
reported when lactulose and antibiotics are used
concurrently.
● Nonabsorbable oral antacids may reduce colonic
acidification and might reduce the efficacy of
lactulose.
EMETIC AGENTS
In some circumstances, most notably after recent inges-
tion of toxic compounds, drugs are required to induce
vomiting. A number of household products have been
used for the purpose, most notably strong salt (sodium
chloride) solutions, hydrogen peroxide and washing
soda crystals. In addition, the sedative drug xylazine
may be effective for this purpose in cats. However, the
most commonly used pharmaceutical agents are syrup
of ipecacuanha (ipecac) and apomorphine.
Emetic agents rarely eliminate more than 80% of the
ingested material and more commonly only 40–60%.
Therefore, it is advisable to use other symptomatic
therapies in conjunction with emetic agents.
Ipecac syrup
Clinical applications
Ipecac syrup is derived from the roots and rhizomes of
certain plants; it contains two active alkaloid agents:
emetine and cephaeline. The main indication of this
agent is to induce vomiting, after the ingestion of toxic
compounds or after a drugs overdose.
Mechanism of action
The major alkaloids of ipecac (emetine and cephaeline)
are thought to be the pharmacologically active agents
and have both local and central activity. Locally, they
produce an irritant effect on the gastric mucosa, whilst
centrally they stimulate the chemoreceptor trigger zone.
The medullary regions must be responsive for vomiting
to be elicited. When vomiting occurs, contents from
both the stomach and small intestine are evacuated.
Vomiting usually occurs with 10–30 min of administra-
tion in both dogs and cats.
496
Ch019-S2858.indd 496
Formulations and dose rates
There are no veterinary-approved formulations, but a variety of human
preparations are available (e.g. Ipeca®, Ipecacuanha tincture®,
Ipecavom®, Ipetitrin®, etc.) containing various concentrations, e.g.
1.5%, 1.75% and 2%.
DOGS
• 1.0–2.5 mL/kg PO (to a maximum of 15 mL) as a single dose.
Repeat after 20 min if no response. If the stomach is empty,
give 5 mL/kg of water immediately afterwards. If vomiting does
not occur after the second dose, subsequently perform gastric
lavage to retrieve the ipecac
CATS
• 1.0–3.3 mL/kg PO as an initial dose. It may be prudent to dilute
the dose 50:50 with water, to minimize the adverse effect of
the taste. Repeat with a second dose 20 min after the first if
vomiting does not occur; subsequently perform gastric lavage to
retrieve the ipecac
Pharmacokinetics
There are few data available on the pharmacokinetics
of ipecac syrup. Apparently, there is great interindivid-
ual variability in the proportion absorbed amongst
patients.
Adverse effects
● Emetics are contraindicated in patients that are
hypoxic, dyspneic, unable to swallow, hypovolemic
or comatose.
● Emetics should not be given to animals which have
ingested strong acids or alkalis because the contents
of the vomitus may cause further damage to esopha-
geal, pharyngeal or oral tissues.
● Given the risk of aspiration, emetics should not be
given after ingestion of petrolatum or related com-
pounds because the risk of subsequent aspiration
outweighs the potential toxicity.
● The syrup is clear, with a mild odor. It has an unpleas-
ant taste and, as a consequence, may be difficult to
administer successfully to cats.
● Although side effects are uncommon, occasional side
effects include salivation, lacrimation, protracted
vomiting, diarrhea and lethargy.
● Overdosage of ipecac has been known to lead to
cardiotoxicity (e.g. arrhythmias, hypotension and
fatal myocarditis).
Known drug interactions
● Use of emetics in the face of strychnine intoxication,
or with other CNS stimulants, may precipitate
seizures.
● Activated charcoal may adsorb ipecac syrup and, as
a result, these drugs should not be administered con-
11/19/2007 2:28:59 PM

currently. Instead, ipecac syrup should be given first
and activated charcoal only administered once vom-
iting has occurred.
● The efficacy of ipecac may be decreased by dairy
products and carbonated beverages.
Apomorphine
Clinical applications
Apomorphine is used as an emetic agent in dogs, where
it is considered to be the drug of choice for this purpose.
Its use is controversial in cats.
Mechanism of action
Apomorphine stimulates dopamine receptors in the che-
moreceptor trigger zone and thereby induces vomiting.
Although it may have both stimulatory and inhibitory
effects within the CNS, stimulatory effects predominate.
However, depression of medullary centers may lead to
respiratory depression.
Formulations and dose rates
No veterinary licensed products are available, but there are a number
of human preparations.
DOGS
• 0.03–4 mg/kg IV or 0.04–0.08 mg/kg IM or SC, as a single
dose
CATS
• 0.04 mg/kg IV, or 0.08 mg/kg IM or SC as a single dose.
However, use in this species is controversial and many do not
recommend it
• If vomiting does not occur after administration, it is inadvisable
to administer repeated doses as they are unlikely to be effective
and signs of toxicity may occur
Pharmacokinetics
Apomorphine is slowly absorbed after oral administra-
tion and efficacy is unpredictable by this route. As a
FURTHER READING
Hall JA, Washabau RJ 2000 Gastric prokinetic agents. In: Bonagura J
(ed.) Current veterinary therapy XIII. WB Saunders, Philadelphia, PA,
pp 614-617
Leveille-Webster C 2000 Ursodeoxycholic acid therapy. In: Bonagura J
(ed.) Current veterinary therapy XIII. WB Saunders, Philadelphia, PA,
pp 691-693
Ch019-S2858.indd 497
FURTHER READING
result, parenteral (or subconjunctival) administration is
preferred. Emesis usually occurs rapidly after intrave-
nous administration, whilst therefore may be a delay of
5 min after intramuscular injection. Although conjunc-
tival administration is effective, response is less predict-
able and injected routes are preferred.
Adverse effects
● Emetics are contraindicated in patients that are
hypoxic, dyspneic, unable to swallow, hypovolemic
or comatose.
● Emetics should not be given to animals which have
ingested strong acids or alkalis because the contents
of the vomitus may cause further damage to esopha-
geal, pharyngeal or oral tissues.
● Given the risk of aspiration, emetics should not be
given after ingestion of petrolatum or related com-
pounds because the risk of subsequent aspiration
outweighs the potential toxicity.
● The principal adverse effect is protracted vomiting.
Excitement, restlessness, CNS excitement/depression
and cardiorespiratory depression may occur if an
overdose is administered. The CNS adverse effects
can be reversed by naloxone, although this drug
cannot usually block the vomiting.
● Apomorphine should not be used in cases of oral
opiate or other CNS depressant (e.g. barbiturate)
toxicity.
● Apomorphine is contraindicated in patients hyper-
sensitive to morphine.
● The use of this drug is controversial in cats and many
clinicians believe that xylazine and ipecac syrup are
both more effective.
Known drug interactions
● Drugs with antidopaminergic effects may antagonize
the effect of apomorphine, e.g. phenothiazines.
● Additive CNS, cardiac and respiratory adverse
effects may develop if apomorphine is administered
concurrently with opiates.
Plumb DA 2005 Plumb’s veterinary drug handbook, 5th edn. Blackwell
Publishing, Ames, IA
Washabau RJ, Elie MS 1995 Antemetic therapy. In: Bonagura J (ed.)
Current veterinary therapy XIII. WB Saunders, Philadelphia, PA,
pp 679-684
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