Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
products unless more judicious use practices are
instituted.
Mechanisms of resistance that have been described
include drug target site insensitivity, increased drug
efflux and accelerated drug detoxification. Each mechanism
requires a unique management strategy. For
example, unlike the situation with increased drug degradation,
with site insensitivity, increased dose rates
cannot be expected to restore efficacy. Resistance has
appeared in ticks, lice and flies affecting ruminants.
Many of the tick and fly species selected by treatment
of ruminants can potentially infect dogs and cats that
are in close proximity. The response to treatment should
always be closely monitored and lower than expected
efficacy should be investigated.
There are many causes of apparent lack of efficacy,
including misdiagnosis, incorrect dose rate, poor application,
inappropriate retreatment interval and (very
commonly) high and sustained challenge. Resistance is
just one additional possible cause and should be confirmed,
as its presence will require a change in treatment
strategy.
FORMAMIDINES
Amitraz
N′ -(2,4-dimethylphenyl)- N -[[(2,4- dimethylphenyl)
imino]methyl]-N-methylmethanimidamide.
Clinical applications
Amitraz is applied externally and has broad-spectrum
activity against all mites and ticks, with no significant
activity against insect parasites of dogs and cats. Amitraz
collars have been shown experimentally to reduce or
prevent transmission of Borrelia burgdorferi by adult
Ixodes scapularis.
Mechanism of action
Amitraz elicits a variety of behavioral changes in both
argasid and ixodid ticks, often manifested as hyperactivity,
leg waving and detaching behavior. It is thought
that behavioral effects are secondary to the actions of
amitraz on tick octopaminergic G protein-coupled
receptors (GPCR). Indeed, sublethal and behavioral
effects are considered more important in the mode of
action than lethality. Other effects include diminished
fecundity, inhibition of oviposition and reduced egg
hatchability.
Although amitraz inhibits tick monoamine oxidase,
the lethal biochemical lesion appears to be due to inhibition
of mixed function oxidases.
Despite precautions against the use of amitraz with
monoamine oxidase inhibitors (MAOIs) in mammals,
MAOI inhibition by amitraz has only been demonstrated
in vitro and not confirmed in vivo. However,
amitraz has been shown to be an α 2 -agonist and intoxication
of dogs and cats can be controlled by use of α 2 -
antagonists such as yohimbine and atipamezole.
Pharmacokinetics
Orally administered amitraz is rapidly absorbed by
dogs, with a T max at 5 h, followed by hepatic biotransformation,
with cumulative 96 h excretion of 57% in
urine and 24% in feces. The elimination half-life is
approximately 23 h. After dermal treatment with 1 mg
amitraz/cm 2 , peak blood concentrations occurred within
24–72 h and only 25–40% was recovered in urine and
feces over a 10-day collection period, demonstrating the
poor dermal absorption of amitraz. Similarly there was
little absorption after dermal application of a spot-on
formulation of amitraz (in combination with metaflumizone).
However, amitraz distributed throughout the
hair coat, reaching maximum concentration in 7–14
days, and quantifiable levels were present for 56 days.
Formulations and dose rates
General use recommendations are to charge dip washes at 250–
500 mg/L. Effi cacy is most unpredictable against Demodex spp. For
generalized demodicosis, an increasing use rate has been recommended
(extra-label) for increasingly refractory cases, as follows:
250 mg/L Initial use rate for mites and ticks, repeated every 2
weeks
250 mg/L Repeated weekly
500 mg/L Repeated weekly
1000 mg/L Repeated weekly
1250 mg/L Applied to one side of dog on rotating basis daily.
Some cases of demodicosis may be insensitive to amitraz and
alternative approaches (e.g. use of MLs) may be warranted.
In cases of feline demodicosis that failed to respond to repeated
lime sulfur treatments, weekly amitraz at 125 mg/L has been successful.
However, transient sedation, salivation and behavioral
changes were observed initially and use should be avoided in diabetic
cats.
Amitraz is available as a spot-on formulation in combination with
the insecticide metafl umizone with both actives applied to dogs to
provide at least 20 mg/kg bodyweight of each compound.
Adverse effects
● No overt clinical signs of toxicity were observed in
dogs receiving 0.25 mg/kg PO per day. CNS
depression, bradycardia and hypothermia were
present at 1.0 mg/kg PO per day.
● Amitraz may cause a transient sedative effect for
12–24 h after first and subsequent treatments.
● Some dogs may become pruritic after treatment.
● At high exposures (e.g. following accidental
ingestion of an amitraz collar) the following
adverse effects may occur:
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