Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 19 GASTROINTESTINAL DRUGS
Cerebral cortex
Opioid
Antihistamines
CRTZ
D 2 , M 1 , H 1 and H 2
5HT 3 , NK 1 Opioid
Phenothiazines
Vomiting centre
α 2 , 5HT 1A , NK 1
5HT 3 antagonists
Metoclopramide,
dromperidone
NK 1 antagonists
Nucleus tractus solitarius
H 1 , NK 1 , M 1
Vestibular
H 1 , M 1
Anticholinergics
Peripheral receptors
M 2 , 5HT 3 , 5HT 4 , Motilin,
NK 1 , D 2
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 penetrates
the CTZ first it will initially cause vomiting before
blocking the vomiting center. Morphine has been demonstrated
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. M 1 -cholinergic, H 1 -
histaminergic and NK 1 receptors must be involved in
the dog because antagonists at these receptors are very
effective antiemetic agents. D 2 -dopaminergic, α 2 -
adrenergic and 5-HT 3 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 produced
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, encephalins
and substance P. Species differ in the relative importance
of some neurotransmitter–receptor systems. For
example, apomorphine, a D 2 -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 D 2 -dopamine receptor antagonists such as metoclopramide
might not be very useful as antiemetics in
the cat.
In contrast, xylazine, an α 2 -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-HT 3 receptors in the CTZ of the cat, in
contrast to the dog, in which peripheral visceral and
vagal afferent 5-HT 3 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 gastrointestinal
tract, particularly the duodenum but also in the
biliary tract, peritoneum and urinary organs. The receptors
may be stimulated by distension, irritation, inflammation
or changes in osmolarity.
Afferent receptors
Of the many afferent receptors found in the gut, 5-HT 3
receptors play an important role in initiation of vomiting
by cytotoxic drugs. Cytotoxic drugs cause 5-HT
release from enterochromaffin cells that activates 5-HT 3
receptors on vagal afferent fibers. 5-HT 3 receptor antagonists
are very effective antiemetics for cytotoxic druginduced
vomiting. However, the role of 5-HT 3 receptors
in other disorders of the gut has yet to be ascertained.
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