Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 10 ANTIPARASITIC DRUGS
levamisole for 2–4 weeks has shown some success in the
treatment of infection with Spirocera lupi and Oslerus
(Filaroides) osleri. In cats, levamisole has also been
found to be effective for the treatment of Aelurostrongylus
abstrusus infection. In dogs, levamisole HCl
(2.5 mg/kg daily for 14 days, followed by 5.0 mg/kg for
14 days and then a final 14 days at 10.0 mg/kg) was
widely used in the past as a microfilaricide for Dirofilaria
immitis after adult worms (macrofilaria) had been
removed. Levamisole administered at 5 mg/kg for 5–10
days to dogs with Dipetalonema repens microfilaremia
led to sustained amicrofilaremia, first apparent at 3
days. It appeared that levamisole may not only be
microfilaricidal but adulticidal as well.
Pharmacokinetics
Levamisole is rapidly absorbed from all routes of administration,
with peak blood levels occurring within an
hour followed by rapid metabolism and depletion principally
via urinary excretion, with an elimination halflife
of approximately 4 h.
Adverse effects
Adverse effects associated with the use of levamisole
include:
● vomiting (sometimes in as many as 20% of dogs
and prevented by pretreatment with atropine)
● nervous signs (panting, apprehensiveness and
shaking)
● supraventricular premature contractions
● less frequently, hemolytic anemia (after protracted
use), bleeding and thrombocytopenia.
Known drug interactions
Although levamisole is cholinomimetic and it has been
suggested that concurrent use of cholinesterase inhibitors
such as the organophosphates should be avoided,
there is no evidence of any adverse interaction with
concurrent use of these antiparasitic agents.
MACROCYCLIC LACTONE PARASITICIDES
Endectocides (avermectin-milbemycin
class)
The avermectins were first isolated in 1976 from the
actinomycete Streptomyces avermitilis, cultured from a
soil sample collected near a golf course in Japan. The
avermectins were quickly characterized as extremely
potent anthelmintics with unexpected activity against
arthropods (insects, mites and ticks). Although the
milbemycins had already been described in 1973 and
activity against agriculturally important mites defined,
their activity against nematodes was only investigated
after the anthelmintic properties of the avermectins were
published. It soon became apparent that both avermectins
and milbemycins were important members of a
single class with a common mode of action. Structurally,
they all share a 16-membered macrocyclic ring,
giving rise to the class name. The avermectins are disaccharides
(ivermectin, doramectin) or monosaccharides
(selamectin), while the milbemycins (milbemycin oxime
and moxidectin) have no sugar substituents.
The macrocyclic lactones (MLs) have become an
important class of parasiticide in agriculture, animal
health and human health. In the latter case, ivermectin
has been used extensively and safely for the treatment
of onchocerciasis, the cause of ‘river blindness’ in large
areas of Africa.
Mechanism of action
In both arthropods and nematodes, exposure to MLs
results in lethal paralysis following opening of chloride
ion channels in cell membranes of peripheral nerve
tissues, leading to hyperpolarization. The target site has
been well characterized as a glutamate-gated Cl − channel
that is present in both neuronal and muscle membranes
of many invertebrates but which is not present in
mammals. Actions on nematode muscle include the
paralysis of the pharyngeal pump, necessary for food
intake, resulting in starvation. A combination of neural
and muscular effects is probably involved in the biological
activity of the MLs. An absence of binding sites in
cestodes and trematodes renders these parasites insensitive
to the action of the MLs. The reason why adult
filarial parasites (for example, Dirofilaria immitis) are
not susceptible to the lethal effects of the MLs is unclear
but may be associated with adult-specific expression
and distribution of less susceptible chloride channel
subunits.
The MLs are also agonists of GABA-gated Cl − channels
of invertebrates and vertebrates where they are
located in the CNS. In part, the selectivity of action of
the MLs is due to the protection of the mammalian CNS
from exposure by the blood–brain barrier conferred by
the transmembrane transport pump, P-glycoprotein
(responsible for drug efflux) expressed within brain capillary
endothelial cells. Animals with increased sensitivity
to ivermectin (for example, collies) have been shown
to be deficient in P-glycoprotein in both the CNS and
intestinal epithelium.
Adverse effects
● Generally the MLs are particularly safe even at elevated
doses. However, a toxicosis syndrome has
been described, especially in particularly sensitive
animals, notably collies and related breeds and in
kittens. Likelihood of toxicity is related to the selected
drug, the dose rate and the recipient animal’s
predisposition.
210