Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
Table 10.2 Selective toxicity (continued)
Mechanism Parasite receptor Susceptible
parasite group
G proteincoupled
receptor
Nuclear
receptor
Voltage-gated Na +
channel
Latrophilin receptor
(GPCR)
Octopamine receptor
(GPCR)
Juvenile hormone (JH)
receptor
Arthropod
Helminth
(nematode)
Antiparasitic
agents
Pyrethrins,
pyrethroids
(permethrin,
cypermethrin,
deltamethrin,
flumethrin),
metaflumizone
Emodepside
Antiparasitic action
Agonist
Act at binding site 7
(pyrethrins) or
possibly 9
(metaflumizone) to
slow opening and
closing of Na +
channels, blocking
fast inactivation,
causing membrane
depolarization and
repetitive
after-discharges
Agonist
Inhibition of
pharyngeal
pumping and
somatic muscle cell
paralysis
Arthropod (acarine) Amitraz Agonist
Stimulates
octopaminergic
neurotransmission
via GPCR
Arthropod (insect)
Tubulin β-tubulin Helminth (various
nematode,
cestode,
trematode spp),
protozoa (Giardia)
α-tubulin
Protozoa
(apicomplexa and
trypanosomatid)
DNA Kinetoplast DNA (kDNA) Protozoa
(trypanosomatid)
S-methoprene,
pyriproxyfen
Benzimidazoles and
prodrugs:
albendazole,
febantel,
fenbendazole
Trifluralin (herbicide
with possible
application as
antiparasitic drug)
Aromatic diamidines
Agonist
JH mimics, maintain
high JH activity
and inhibit
metamorphosis
Antagonist
Inhibits tubulin
polymerization in
susceptible
helminths and
protozoa
Antagonist
Inhibits tubulin
polymerization
in plants,
apicomplexa and
trypanosomatids
Antagonist
Interact
electrostatically
with RNA and
kDNA leading to
structural
disorganization and
unwinding
Giardia DNA Protozoa (Giardia) Quinacrine Antagonist
Intercalation of
giardial DNA
inhibiting nucleic
acid function
Comments on
selective toxicity*
PK: dermal barrier;
metabolic inactivation
PD: (pyrethins/oids) less
sensitive receptors,
temperature
dependence.
Combined PK + PD
selectivity ratio of
>2000. Do block
mammalian GABA A
and other receptors
PK: little selectivity;
high dermal
bioavailability in cats
PD: receptor differences
assumed
PK: dermal barrier
PD: absence of
octopaminergic
pathways in
mammals. α 2 -agonist
and MAOI in
mammals
PK: dermal barrier,
rapid metabolism
PD: JH not present in
mammals
PK: low oral
bioavailability
PD: less avid binding to
mammalian β-
tubulin. Receptor
selectivity ratio of
25–400
PK: low oral
bioavailability
PD: less avid binding to
mammalian
α-tubulin
PK: absorption and
distribution impacted
by cationic form
PD: kDNA unprotected
by histones and more
sensitive. Off-target
effects include
increased cholinergic
activity
PK: absorbed rapidly
and widely distributed
with extended
elimination
PD: reduced uptake by
mammalian cells
* PK pharmacokinetic factors; PD pharmacodynamic factors.
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