Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 19 GASTROINTESTINAL DRUGS
● Because dopamine is involved in prolactin production,
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.
NK 1 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 apomorphine
(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 significant.
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 successful
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-
ent input to the vomiting center (vestibular system),
compared with the neural and humoral inputs associated
with general emesis.
Mechanism of action
Maropitant is a selective antagonist of substance P at
the NK 1 receptor. Some studies would suggest the antagonism
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, lowcapacity
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 bioavailability
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 affinity,
responsible for >90% of clearance) and CYP3A12
(low affinity, high capacity). Hepatic clearance is the
major route of excretion; there is no evidence of excretion
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 interactions
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
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