Page 241 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

208 SECTION | II Organ Toxicity

VetBooks.ir Chloride Channels complex. Additionally, clinicians should be aware of met-
abolic
neurotoxicoses.
exacerbate
can
that
factors
As opposed to sodium and potassium channel neurotoxi-
Examples of these factors include acidosis, hypoglycemia,
cants, relatively few toxicants have been identified that
and hepatic encephalopathy. Increased carbon dioxide,
affect the chloride channel. Chloride ions can diffuse pas-
which readily diffuses across the blood brain barrier, can
sively down their concentration gradient out of the neu-
cause narcosis by affecting neurotransmitters as well as
ron. Chloride ion channels regulate the entrance of
increasing intracranial pressure. Compensation for hyper-
chloride into the neuron and affect the membrane poten-
capnea with hyperventilation is the reason that metabolic
tial as a result. Normal resting membrane potential is
acidosis is less likely to contribute to encephalopathy than
270 mV. Threshold potential, the potential at which an
respiratory acidosis (Dewey, 2008). Monitoring of acid
action potential is propagated, is roughly 250 mV.
base status, volume restoration, correction of metabolic
Membranes can be hyperpolarized by allowing entrance
acidosis with sodium bicarbonate as needed (Plumb,
of negative chloride into the neuron and making it more
2015), and assisted ventilation when necessary are means
difficult to reach threshold potential. Both benzodiaze-
by which these potential complications can be minimized.
pines and barbiturates mediate their effects via GABA A
Hypoglycemia can be a primary effect of neurotoxi-
receptors which are chloride ionophore complexes
coses as with sulfonylurea medication overdoses or xylitol
(Crystal and Schaumburg, 2000). Minute details regarding
ingestion in dogs (Meadows, 2011) or a secondary effect
binding sites, duration, and frequency of chloride channel
with increased glucose utilization in the patient with
opening affected by barbiturates and benzodiazepines
refractory seizures. Signs of neuroglycopenia occur when
have been extensively studied (Hobbs et al., 1996; Crystal
blood glucose goes below 45 mg/dL and include weak-
and Schaumburg, 2000; Maytal and Shinnar, 2000), yet
ness, ataxia, collapse, restlessness, tremors, seizures,
the exact mechanism remains unclear. Ultimately, the two
blindness, and potential changes in behavior (Podell,
classes of drugs inhibit excitatory neurotransmission by
2000; Nelson, 2009). Hypoglycemia can be corrected
increasing chloride conductance into the neuron.
with administration of IV dextrose to effect (Meadows,
The use of potassium bromide for chronic manage-
2011).
ment of idiopathic epilepsy in veterinary patients is based
Finally, hepatic encephalopathy can result in neurotox-
on the competition of the bromide ion with chloride ions
icity because of the inability of the liver to clear the body
for transport across cell membranes. The therapeutic
of toxins, namely ammonia, and the brain’s sensitivity to
action relies on hyperpolarization of the neuronal mem-
it. Alterations of serotonin, GABA and glutamine, and
brane and a decrease in the propagation of epileptic dis-
stimulation of NMDA and benzodiazepine receptors,
charges. Bromide blood levels should be monitored
ensue and are responsible for potential disorientation, gait
routinely in treated animals and particularly in those ani-
disorders, behavioral changes, and/or seizures (Watson
mals exhibiting signs of bromide toxicity. Neurologic
and Bunch, 2009). Treatment with lactulose to lower
signs consistent with a bromide toxicosis include ataxia,
blood ammonia, appropriate antibiotics, supportive care,
tremors and sedation to the point of stupor in veterinary
and management of seizure activity are indicated
species (Plumb, 2015). Headache, mood alterations,
(Webster, 2011).
hallucinations, speech abnormalities and visual distur-
bances have also been reported with human bromism
(Spencer, 2000). Because bromide has a longer half-life
CONCLUDING REMARKS AND FUTURE
than chloride, the latter is preferentially excreted by the
kidney. In animals with a deficiency of dietary salt, the DIRECTIONS
half-life of bromide is prolonged, enhancing the chances
The health of the nervous system, and largely that of the
of neurotoxicity. Conversely, the epileptic patient with a
individual, relies on the system’s structural and functional
high dietary salt intake may have seizure activity that is
integrity. From specialized nerve cells and anatomic
poorly managed with potassium bromide treatment
structures to axonal transport, myelination, neurotransmit-
(Plumb, 2015).
ter synthesis, storage, release, binding and degradation as
well as the regulation of action potentials, maintenance of
OTHER MECHANISMS OF nervous system integrity is a complex task requiring
significant energy expenditure. This functional complex-
NEUROTOXICITY
ity and structural specialization provide a plethora of
Knowledge of the nervous system is continually expand- targets for neurotoxicant action. The scope of this chapter
ing. Whereas the mechanisms of action of neurotoxicants precludes a detailed discussion of every known neurotoxi-
discussed thus far have been simplified to affect one neu- cant. Many more mechanisms exist by which neurotoxi-
rotransmitter or ion channel, the reality is likely far more cants exert their effects. Table 12.3 provides a