Page 237 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

204 SECTION | II Organ Toxicity

VetBooks.ir which may be the earliest indication of toxicosis in the GABA
horse, the most sensitive species (Coleman, 1998).
GABA serves as the predominant inhibitory neurotrans-
Contracture of facial muscles may result in abnormal
wrinkles in the skin, erect ears or an abnormal expression, mitter in the brains of mammals and is synthesized from
glutamic acid. Two main receptor subtypes, GABA A and
sometimes referred to as a sardonic grin. Progression of
GABA B , exist. GABA A has at least seven subunits which
the disease results in an inability to rise and possible sei-
combine with a chloride channel to form a receptor/iono-
zures. Severe muscular contraction or seizures may be
phore complex. The complex contains binding sites not
induced by external stimuli. Death is due to an inability
only for GABA but also for drugs such as the anticonvul-
of the muscles of respiration to relax and subsequent hyp-
sant benzodiazepines and barbiturates. Stimulation of
oxia (Roder, 2004b).
these receptors results in CNS depression, somnolence,
Diagnosis of tetanus is based on characteristic clini-
fatigue, lethargy, ataxia, and muscular incoordination.
cal signs, history of a wound in which the organism
Paradoxical hyperactivity, excitement or aggression can
could have proliferated, and the anaerobic culture of an
also occur. In overdoses, CNS and respiratory depression
infected wound. Vaccination with tetanus toxoid is
may be extreme, leading to hypotension, hypoxia, hypo-
recommended to prevent the disease in horses. Animals
thermia and death (Spencer, 2000; Rudolph et al., 2001).
with wounds should be treated with penicillin, and the
A discussion of GABA warrants mentioning drugs of
wound should be cleaned routinely to prevent prolifera-
the avermectin class, commonly used in veterinary medi-
tion of the bacteria. A tetanus antitoxin exists but is
cine for the prevention of heartworm disease (Dirofilaria)
ineffective for a toxin that is already bound and will not
in dogs and cats, the treatment of endoparasitism (stron-
reverse existing clinical signs. It can help to prevent pro-
gyles, ascarids, bots, threadworms, lungworms, stomach
gression of the disease, though. The dose for horses and
worms and summer sores (Habronema, Draschia spe-
cattle is 10,000 50,000 units SC or IM and
cies)), and ectoparasitism (Sarcoptes, Demodex).
3000 15,000 units for sheep and swine and can be
Examples of avermectins include ivermectin (Heartgard),
repeated in 7 10 days (Roder, 2004b). Contrary to pop-
selamectin (Revolution), milbemycin (Interceptor), moxi-
ular belief, the antitoxin may be extremely cost effec-
dectin, and abamectin. Various mechanisms of action on
tive. At the time of this writing, the Colorado Serum
target species, which lead to parasite paralysis and even-
Company (Denver, CO) sells 15,000 units for $28.00
tual death, have been proposed including enhanced
(US) (www.colorado-serum.com). Muscle spasms and
release of GABA at presynaptic neurons (Plumb, 2015)
seizure activity can be managed by minimization of
and effects on glutamate-gated chloride channels in the
external stimuli as well as with tranquilizers and muscle
CNS (Mealey, 2006). Such channels are not present in the
relaxants such as acepromazine, diazepam, barbiturates
mammalian brain, allowing for a wide margin of safety of
and methocarbamol (Coleman, 1998). The prognosis for
these drugs in the host animal (Mealey, 2006).
severely affected individuals is poor.
Furthermore, in genetically healthy animals, p-glycopro-
Another antagonist of glycine is the neurotoxic bait
tein, part of the blood brain barrier, is present in the api-
strychnine, an alkaloid derived from the Strychnos nux
cal membrane of brain capillary epithelial cells, and
vomica and Strychnos ignatii trees. It binds with high
serves as an efflux pump to remove avermectins from the
affinity to the glycine receptor and blocks its effects as a
brain (Mealey, 2006).
result (Patocka, 2009). Extreme muscle rigidity occurs as
Significant clinical signs can be seen, though, in an
in the tetanus-intoxicated patient and can rapidly progress
acute or chronic avermectin overdose, particularly with
to intermittent or continuous seizures within 10 120 min
a dog that has a p-glycoprotein defect or MDR1 muta-
of strychnine ingestion. Anxiety, apprehension, nervous-
tion. They include ataxia, CNS depression (potentially
ness and tachypnea also may be part of the clinical pre-
to the point of coma), recumbency, disorientation,
sentation because of this rapid progression. Death occurs
mydriasis/apparent blindness, muscle tremors, seizures,
because of hypoxia as a result of contracture of the dia-
respiratory depression, hypothermia, bradycardia, hyp-
phragm and abdominal and intercostal muscles. The oral
oxia and death. The onset of signs is expected to be
LD 50 is 0.5 1.2 mg/kg for dogs; 0.5 mg/kg for horses
more rapid and the severity of the clinical picture more
and cows; 2 mg/kg for cats; and 0.5 1 mg/kg for pigs
extreme in the p-glycoprotein deficient dog. Signs may
(Talcott, 2013). In the exposed but asymptomatic patient,
persist for weeks, but the duration of effect is often diffi-
aggressive decontamination is warranted. Treatment of
cult to predict based on the severity of signs. Extreme
the symptomatic patient is limited to symptomatic and
supportive care is indicated for the comatose patient.
supportive care. The agents used to treat muscle spasms,
Assisted ventilation may be necessary. Repeated doses
seizures and anxiety in the tetanic patient may also be
of activated charcoal can be of significant benefit due to
used in the strychnine-intoxicated patient. The prognosis
the enterohepatic recirculation of avermectin drugs. In
for symptomatic patients is grave.