Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
Lufenuron
(R,S) - 1 - [2,5 - dichloro - 4 - (1, 1, 2, 3, 3, 3 - hexafluoropropoxy)phenyl]-3-(2,6-difluorobenzoyl)urea.
Mechanism of action
The precise mechanism of action of lufenuron, a member
of the benzoylphenylurea (BPU) class, is not known.
However, while it does not directly inhibit chitin synthase,
there is evidence that it inhibits the γ-S-GTP
stimulated uptake of Ca 2+ by chitin microfibercontaining
excretory vesicles, disrupting vesicle fusion
with the outer cell membrane and cuticle formation in
exposed insects. Lufenuron is both ovicidal and larvicidal.
The ovicidal action is most notable with higher
concentrations of lufenuron. As concentrations deplete,
eggs will hatch; however, the larvae are reduced in size
and further development to pupae is inhibited. Excretion
of lufenuron in flea feces provides a source of
exposure to flea larvae, whose continued development
is then impaired. In vitro studies of adult fleas have
shown that sustained lufenuron exposure can be adulticidal.
This activity is not encountered in vivo, as the
concentrations of lufenuron in host blood are inadequate
to disrupt adult flea chitin synthesis.
Although chitin occurs in most invertebrate phyla
(the chitin content of the cuticle of larval insects is 30–
60% while the weight of chitin in the cuticle of ticks is
around 3%), it is absent among vertebrates, accounting
for the high margin of mammalian safety associated
with lufenuron.
Pharmacokinetics
The absorption of lufenuron following oral administration
is improved in both rate and extent by the presence
of food, with maximum concentrations achieved in
around 6 h. Systemic bioavailability, at least in cats,
may not be high, in view of an oral dose of 30 mg/kg
providing efficacy for 1 month in comparison with parenteral
administration of 10 mg/kg providing greater
than 90% effect on flea development for 6 months.
Lufenuron is highly lipophilic and accumulates in
adipose tissue, forming a depot from where it slowly
dissipates, extending the period of flea exposure following
a single dose. Lufenuron is excreted unchanged in
bile.
Formulations and dose rates
Applications and use rates are summarized in Table 10.5.
Pyriproxyfen
4-phenoxyphenyl (R,S)-2-(2-pyridyloxy)propyl ether.
Mechanism of action
Although a carbamate, pyriproxyfen has no cholinesterase
activity but is a potent insect juvenile hormone
mimetic. It is ovicidal and larvicidal when applied either
directly to ova, via ingestion of fecal blood excreted by
treated fleas, or indirectly via exposure of adults (both
male and female fleas). It is photostable with extended
residual activity in the environment. When young pupae
are exposed pyriproxyfen diffuses across the pupal case,
resulting in accelerated emergence and increased mortality
of emerging adults, although the fecundity of surviving
females is unaffected.
Pharmacokinetics
Pyriproxyfen is photostable and is available in a variety
of formulations that permit persistence in the coats of
treated dogs and cats. An analytical study of pyriproxyfen
administered orally to cats at doses up to 50 mg/kg
was unable to detect any drug in samples of hair.
However, dogs and cats treated topically on the dorsal
midline of the neck with 0.04 and 0.1 mg/kg as a 1%
solution of pyriproxyfen had sustained levels of pyriproxyfen
in their hair at concentrations above 0.02 mg/
kg for more than 48 d. Not unexpectedly, there was a
clear concentration gradient from the site of application
to the hair of the hindquarters and considerable interanimal
variation in hair concentration. The minimum
concentration causing inhibition of development of flea
eggs has been shown to be 0.0001 mg/kg in hair.
MISCELLANEOUS EXTERNAL
PARASITICIDES
Benzyl benzoate
Benzoic acid phenylmethyl ester.
Clinical applications
Benzyl benzoate is used as a pediculicide and scabicide
in dogs, although its principal use in humans is as a
repellent of ticks, chiggers and mosquitoes. It is generally
applied as a spot treatment.
Pharmacokinetics
Benzyl benzoate is rapidly absorbed and is hydrolyzed
to benzoic acid and benzyl alcohol, conjugated with
glycine or glucuronide and eliminated in urine.
Adverse effects
● While generally considered of low toxicity, cats are
about 10 times more sensitive than dogs (acute oral
LD 50 in cats is 2240 and in dogs 22,440 mg/kg) and
its use in this species is contraindicated in some
countries.
226