Page 234 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Nervous System Toxicity Chapter | 12 201

VetBooks.ir target neurotransmitter of OP and carbamate insecticides, for life-threatening bradycardia and/or dyspnea caused by
bronchospasm and excess bronchial secretions (Plumb,
which have been marketed since the 1970s and now are
2015; Blodgett, 2006).
widely available commercially for home and agricultural
use (Meerdink, 2004b; Gupta, 2006). Acetylcholinesterase In addition to the chronic OPIDN (discussed under
(AChE) is the enzyme that degrades ACh to choline and “Axonopathy” above) and the acute toxicosis with
acetic acid within the synaptic cleft. OP and carbamate SLUDDE effects, there is an intermediate syndrome that
insecticides bind to AChE—the former by phosphorylat- is most commonly seen with more liphophilic OPs and
ing the enzyme, the latter by carbamylating the enzyme— classically with chlorpyrifos exposure in cats. It is thought
and prevent its degradative action on ACh. This results in to arise from a down-regulation of muscarinic receptors
an excess of ACh in the synaptic cleft and continued with sublethal, prolonged exposures. The clinical signs as
binding to the postsynaptic receptors. Examples of OPs a result are predominantly nicotinic in nature because
include disulfoton, malathion, terbufos, phosmet, chlor- those receptors are not down-regulated. Signs which typi-
pyrifos, tetrachlorvinphos, and parathion. Examples of cally appear within 3 10 days of exposure include gener-
carbamates include carbaryl, carbofuran, aldicarb, metho- alized weakness (including ventroflexion of the neck due
myl, and propoxur. The onset of action and severity of to the cat’s lack of a nuchal ligament), anorexia, muscle
signs vary widely among these agents. OPs with a sulfur tremors, seizures, depression, and/or death (Blodgett,
linkage need to be activated by p450 enzymes in the liver 2006). Because of the reversibility of the bond of AChE
prior to exerting their toxic effects, a process which may with carbamates, the intermediate syndrome is not typi-
take just minutes. Carbamates are active upon absorption cally seen. However, it has been uncommonly reported
but some of them are less likely to cross the blood brain with aldicarb exposures in people (Waseem et al., 2010)
barrier than the more fat-soluble OPs. Cholinergic effects and has also been reported with canine aldicarb exposures
are mediated by both muscarinic and nicotinic receptors. (Arnot et al., 2011).
Classic muscarinic effects include excess salivation, lacri- Another toxicant with muscarinic effects is the myco-
mation, increased urination, diarrhea, dyspnea (due to toxin slaframine, produced from the fungus Rhizoctonia
increased bronchial secretions), and emesis (abbreviated leguminicola and primarily associated with clovers
as the mnemonic SLUDDE or the alternative DUMBELS, (Trifolium species). It is a cholinergic agonist which is
which stands for diarrhea, urination, miosis, broncho- responsible for the clinical picture of profuse salivation or
spasm, emesis, lacrimation, and salivation). Nicotinic “slobbers” in affected animals (Meerdink, 2004a).
effects include tremors, weakness, and paralysis. CNS Clinical signs consistent with muscarinic stimulation are
effects can range from coma and depression to hyperac- also seen with ingestion of mushrooms of the genera
tivity and seizures (Blodgett, 2006). Inocybe and Clitocybe, among others, which contain the
The main distinction between the OPs and carbamates toxic principal muscarine (Turner and Szczawinski,
is the reversibility of the bond between the insecticide 1991). Anatoxin-a(s), a neurotoxin produced by the cya-
and AChE. OPs phosphorylate affects the esteratic site of nobacteria Anabaena sp., Aphanizomenon sp. and
the enzyme. At variable times, depending on the type of Oscillatoria sp., inhibits AChE in the PNS. Like slafra-
OP bound, the carbon groups attached to the phosphorus mine, the toxin does not cross the blood brain barrier
are hydrolyzed and replaced by hydrogen. This process is (Roder, 2004c).
classically referred to as “aging” and represents the point Several examples of neurotoxicants exist that antago-
at which there is no possible functional recovery of that nize muscarinic effects as well. The classic poisonous
enzyme. The use of pralidoxime (2-PAM) as an antidote plant Atropa belladonna, or deadly nightshade, is the
to preferentially bind the OP is useful only before the source of atropine, a racemic mixture of the tropane alka-
aging process has occurred. In contrast, the affinity of car- loids, D- and L-hyoscyamine (Burrows and Tyrl, 2013).
bamates for AChE is much more labile, and aging does Another belladonna alkaloid is scopolamine (L-hyoscine).
not occur with carbamylation of the enzyme. Therefore, Datura sp., commonly known as jimsonweed, thorn apple
the bond between AChE and carbamates is spontaneously or devil’s trumpet, contains scopolamine and hyoscya-
reversible with time (t 1 /2 5 30 40 min) and precludes the mine. Excessive anticholinergic action can result in sinus
use of 2-PAM. Provided the receptor effects are not life- tachycardia, a dry mouth manifesting as increased thirst,
threatening, the prognosis for carbamate toxicoses is gen- dilated pupils, visual disturbances, ileus, urinary retention,
erally good. With potent carbamates such as methomyl, restlessness, muscular twitching, incoordination, delirium
however, the signs may be severe enough and the duration (as a result of crossing the blood brain barrier and enter-
of the effects long enough for the outcome to be fatal. ing the CNS), respiratory paralysis, and, uncommonly,
Competitive inhibition of ACh with intravenous (IV) atro- death (Burrows and Tyrl, 2013; Pickrell et al., 2004).
pine (0.2 0.5 mg/kg, /4 of dose IV to effect then remain- Nicotinic cholinergic receptors alone can be involved
1
der intramuscular (IM) or subcutaneous (SC)) is indicated with neurotoxicoses. Nature has provided several poisonous