Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ANTICHOLINESTERASE PARASITICIDES
Inhibition of cholinesterase (both pseudocholinesterase
in plasma and acetylcholinesterase) is essentially irreversible
and return of activity necessitates synthesis of
new enzymes. While regeneration can be rapid in nerve
cells and liver, renewed erythrocyte enzyme, given the
absence of a nucleus, requires production of new erythrocytes.
Therefore, the duration of depression of erythrocyte
cholinesterase activity following exposure is
related to the life-span of these cells and may be more
a measure of exposure than of current clinical
condition.
A number of organophosphates must first be oxidized
in order to produce an active form. Examples include
diazinon and malathion, which are desulfurated to
diazoxon and malaoxon respectively, and trichlorphon,
which is activated to dichlorvos.
Adverse effects
● Cats are more sensitive to the toxic effects of
OPs than dogs and only malathion is commonly
used.
● In addition to the classic syndrome of increased
muscarinic and nicotinic activity, certain nonanticholinesterase
effects have been described, the most
infamous of which is organophosphate-induced
delayed neuropathy (OPIDN), a delayed (2–4 weeks
after exposure) sensorimotor polyneuropathy affecting
predominantly the hindlimbs. OPIDN follows
phosphorylation and aging of a protein in neurones
called neuropathy target esterase (NTE). The affinity
of clinically useful OPs for NTE is orders of magnitude
lower than for acetylcholinesterase and consequently
OPIDN has rarely been encountered in dogs
and cats. In those OPs capable of interacting with
NTE (trichlorphon and chlorpyrifos), because of differential
affinities, a significant acute cholinergic syndrome
would be expected to precede the onset of
delayed neuropathy. However, cats appear to be particularly
susceptible to chlorpyrifos toxicity and
delayed neuropathy has been described.
● The effect of chronic exposure to low doses of OPs
has been the subject of much investigation. While
cognitive enhancement has been observed (and led
to the use of specific OPs for the treatment of
Alzheimer’s disease), concerns have been raised
about possible adverse neurobehavioral effects.
Available data, which include a number of epidemiological
surveys, suggest that these concerns may be
unwarranted.
Toxicity of specific organophosphates
● In comparison with other species, cats appear particularly
sensitive to chlorpyrifos. The onset of signs
of intoxication may be delayed for several days following
topical exposure. Usual treatment protocols
are appropriate but, in contrast with dogs, recovery
may take significantly longer.
● Under conditions that may be found in emulsifiable
concentrates (EC) contaminated with trace quantities
of water, diazinon breaks down to highly toxic tetra
ethyl pyrophosphates (TEPPs), especially O,O-TEPP
(monotepp) and O,S-TEPP (sulfotepp), which are
300 and 2500 times more toxic, respectively, than
diazinon. Outdated products and inadequate storage
conditions can increase the likelihood of toxicity.
Deaths of dogs have been recorded in a number of
countries and EC formulations are expected to be
withdrawn.
● Fenthion should not be used on chihuahuas.
● Incorrect storage of malathion (e.g. at 40°C for protracted
periods) can lead to the formation of degradation
products that can increase the toxicity of
malathion preparations. Despite these potential limitations,
malathion remains one of the least toxic
organophosphates for use in both dogs and cats.
Treatment of organophosphate toxicity
Having obtained a history and secured the diagnosis,
the essential principles of treatment of poisoning should
be applied: stabilize vital signs, prevent continued exposure
to or absorption of poison, administer antidotes,
accelerate metabolism and excretion of absorbed
poisons, and provide supportive and symptomatic
therapy. Specific antidotal treatments are described
below.
Oximes
Oximes were developed purposefully and specifically in
the mid-1950s, on the basis of pharmacological theory,
to restore the activity of acetylcholinesterase inhibited
by combination with organophosphates. Organophosphates
interact with the serine hydroxyl group within
the active site of acetylcholinesterase to form a stable
phosphorylated and inactive enzyme. Enzyme activity is
returned very slowly by hydrolysis but, in the face of
significant exposure to organophosphates, natural reactivation
is insufficient to restore function. Oximes accelerate
the reactivation of inhibited enzyme by nucleophilic
attack, leading to dephosphorylation and restitution of
the catalytic site of the enzyme. Simultaneously, the
oxime, with a greater affinity for phosphorus, is sacrificed
by phosphorylation. The phosphorylated oxime is
also a potent anticholinesterase but fortunately is
quickly hydrolyzed and inactivated.
While oximes can lead to dramatic improvements in
clinical recovery if used soon after intoxication, with
time (at a rate and extent dependent on the characteristics
of the organophosphate) the phosphorylated
enzyme is dealkylated, resulting in irreversible phosphorylation,
unavailable to nucleophilic attack and
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