Page 238 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Nervous System Toxicity Chapter | 12 205

VetBooks.ir recent years, treatment of moxidectin toxicity with an used in the management of chronic pain. Particularly in
the early course of treatment, stimulatory signs in dogs
emulsion of IV lipids indicates that it may be an effec-
such as agitation may be seen. Seizures, tremors, and psy-
tive way to hasten elimination of fat-soluble toxicants
(Crandell and Weinberg, 2009). If treated aggressively, chosis have been reported in relatively small overdoses in
with or without IV lipids, severely affected dogs can people (Plumb, 2015).
recover without long-term sequelae (Mealey, 2006;
Merola et al., 2009). Histamine
A unique example of neurotoxicity in dogs relates to a
species difference in metabolism. Isoniazid, an antibiotic Histamine is a physiologically active amine that is both a
used in the treatment of tuberculosis, is metabolized by neurotransmitter as well as a mediator of peripheral
acetylation via the enzyme N-acetyltransferase. Dogs are effects relating to allergic reactions and gastric acid secre-
poor acetylators and, therefore, cannot effectively metabo- tion. It is formed from the decarboxylation of L-histidine.
lize the drug. Isoniazid forms a complex with pyridoxine Peripherally, histamine receptors are of two subtypes: H 1
(vitamin B 6 ), creating a pyridoxine deficiency. Synthesis and H 2 . The former mediate allergic reactions in which
of GABA requires the cofactor pyridoxal phosphate. In histamine is released from the granules of mast cells,
the absence of sufficient cofactor, the inhibitory neuro- resulting in dilation and increased permeability of
transmitter is not made and seizures ensue. Emergency capillaries (wheal and flare reaction) and constriction of
treatment involves IV administration of pyridoxine at a bronchial smooth muscle. The H 2 receptor stimulation
dose equivalent to the mg of isoniazid ingested, if known. increases gastric acid secretion (Gwaltney-Brant, 2004b).
Supportive care with fluid therapy is indicated, as may be Antagonists of H 1 receptors are commonly used to
adjunctive diazepam or other anticonvulsants, particularly treat acute and chronic allergic reactions, to prevent mast
if the pyridoxine is not immediately available (Villar cell degranulation during surgical excision as well as to
et al., 1995). minimize motion sickness in veterinary and human medi-
cine. They are divided into first- and second-generation
antagonists. The first-generation antihistamines can both
Glutamate/Aspartate
stimulate and depress the CNS; while the second-
The primary excitatory neurotransmitters of the brain generation antihistamines are considered nonsedating due
are the nonessential amino acids glutamate and aspartate. to their exclusion from the brain at therapeutic dosages.
Their synthesis in the brain from glucose and other mole- At therapeutic doses and with mild overdosages, particu-
cules is tightly regulated. The blood brain barrier larly with the first-generation antihistamines, CNS depres-
excludes excesses of these excitatory neurotransmitters sion and hypotension may be seen. Epinephrine is
except in areas of the hypothalamus (arcuate nucleus) and contraindicated for management of hypotension in these
retina where acute cellular degeneration may occur as a patients. Paradoxical CNS excitation including restless-
result. Three main receptor subtypes exist for glutamate: ness, hyperactivity, tachycardia, tremors, and seizures
AMPA (DL-α-amino-3-hydroxy-5-methyl-4-isoxazole-pro- may also occur, and the potential for it varies largely with
pionic acid), kainate (KA) and NMDA (N-methyl-D-aspar- the individual. Large overdoses of either antihistamine
tate) receptors (Traynelis et al., 2010). As previously class can result in extreme CNS and cardiovascular stimu-
mentioned (see “Neuronopathy,” above), domoic acid is lation to the point of seizure activity, cardiac arrhythmias,
an example of a toxicant that stimulates kainate receptors hypertension, and death. Seizures, tremors, and hyperac-
(Jeffery et al., 2004). tivity may be treated with diazepam or barbiturates
As discussed above, glutamate and aspartate may play (Gwaltney-Brant, 2004b).
a role in the pathogenesis of yellow star thistle intoxica- Common H 2 blockers used in veterinary medicine to
tion in horses (Spencer, 2000). The plant is known to con- decrease gastric acidity include cimetidine, ranitidine, and
tain both excitatory amino acids in addition to several famotidine. Of the H 2 blockers, cimetidine is more likely
unstable guaianolide sesquiterpene lactones that may to cross the blood brain barrier. Adverse effects are rare
degrade to the former to exert their neurotoxic effects in veterinary patients (Plumb, 2015).
(Burrows and Tyrl, 2013).
A limited number of drugs used in veterinary medicine Mixed Neurotransmitter Effects
are NMDA antagonists. Ketamine, a dissociative anes-
thetic used commonly for induction of general anesthesia, Many pharmaceuticals and toxicants exert their effects
blocks the open NMDA ion channel by binding to it. through multiple neurotransmitters. One example group is
Seizures, due to elevation of CSF pressure, are a potential the many ergot alkaloids produced by fungi of the
sequela of ketamine use at therapeutic doses. Amantadine, Claviceps genus. The mycotoxins can be further divided
an antiviral drug that is an NMDA antagonist, is being into ergopeptine and ergoline alkaloids. The alkaloids