Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
increase the transdermal flux of concurrently administered
products.
Adverse effects
● DEET is usually well tolerated by dogs and cats,
although repeated applications of concentrated products
have been associated with vomiting, tremors
and hyperactivity.
● Treatment is directed at reducing exposure and
symptoms and is usually successful.
● A rare syndrome of toxic encephalopathy described
in children does not appear to have a counterpart in
dogs and cats.
Di-N-propylisocinchomeronate (MGK 326)
Dipropyl 2,5-pyridinedicarboxylate.
MGK 326 is widely used as a component of companion
animal external parasiticides. It is considered very
safe, with an acute oral LD 50 in the rat of more than
5200 mg/kg. There is little published material describing
objective assessments of efficacy. A recent review of the
efficacy of MGK 326 by the Pest Management Regulatory
Agency in Canada concluded that there was insufficient
evidence in support of a repellent effect.
SYNERGISTS
The discovery in 1940 that sesame oil potentiates the
insecticidal activity of pyrethrins stimulated a search for
synergistic compounds and resulted in the characterization
of the methylene-dioxyphenyls. The synergists most
widely incorporated into veterinary insecticides include
piperonyl butoxide and MGK 264, described below.
These products act as competitive inhibitors of mixedfunction
oxidases in both insects and mammals. Selectivity
for insects is assured by poor absorption in
mammals and rapid metabolism. However, exposure of
mammals to sustained high concentrations has been
associated with hepatic enzyme induction and increased
liver weight. By inhibiting insect detoxification pathways,
synergists increase the available concentration of
insecticide, increasing effectiveness. Synergists thus
allow a reduction in the content of the insecticide with
retention of efficacy.
It should be noted that the use of inhibitors of mixedfunction
oxidases will not invariably lead to synergy.
For those compounds that are activated by oxidative
pathways, a reduction in insecticidal activity will be
observed. This is the case with fipronil and the
phosphoro(di)thioates (see Organophosphates), which
require oxidative desulfuration for activation. Another
consideration is the effect of temperature on synergy. In
a study of the interaction of imidacloprid and piperonyl
butoxide, it was observed that 16-fold synergy was
observed against adult fleas at 26°C but no effect at a
temperature (35°C) likely to be encountered in the coat
of dogs and cats. It should be emphasized that synergy
will not be present if resistance is due to target site
insensitivity and synergy will be reduced or absent if
resistance arises because of accelerated drug efflux.
Piperonyl butoxide
5-[2-(2-butoxyethoxy)ethoxymethyl]-6-propyl-1,3-
benzodioxole.
Piperonyl butoxide (PBO) was first developed in 1947
and is still widely used. It is usually combined with
pyrethrin or rotenone preparations in ratios of 5–20:1
by weight. PBO appears very safe in companion animals,
with an acute oral LD 50 in the cat and dog of more than
7500 mg/kg. Rarely, cats have been reported to develop
central nervous system signs. PBO is poorly absorbed
from the gastrointestinal tract of dogs, with more than
80% recovered in feces. The absorbed fraction is rapidly
excreted in urine.
N-octyl bicycloheptene dicarboximide
(MGK 264)
2-(ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1
H-isoindole-1,3(2H)-dione.
MGK 264 is widely used as a component of products
for cats and dogs containing pyrethrins and synthetic
pyrethroids. The acute oral LD 50 in rats is reported to
be 4980 mg/kg. Although there are no reports of inefficacy
or adverse effects, there is little objective assessment
of its efficacy and safety in the literature. A recent
review of the efficacy of MGK 264 by the Pest Management
Regulatory Agency in Canada concluded that
there was insufficient evidence in support of any
synergism.
ANTICHOLINESTERASE PARASITICIDES
Organophosphates
Examples of available organophosphate preparations
are presented in Table 10.5.
Pharmacokinetics
All commercially available organophosphate (OP) pesticides
are very lipid soluble, with rapid absorption
expected from most routes of exposure. In healthy
animals, the OPs are metabolized by a variety of oxidative
processes both in tissues and blood (especially by
esterases) and in the liver, and conjugated with glucuronide,
sulfate and glycine. Excretion is mainly in the
urine. Many OPs may form slow-release depots in fat.
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