Page 424 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxicity of Drugs of Abuse Chapter | 22 391

VetBooks.ir 125 mg/kg. The margin of safety for barbiturates is low; Barbiturates also act to inhibit glutamate receptors and
decrease norepinephrine (NE) release (Volmer, 2005).
the therapeutic dose may be 50% 70% of the LD 50
(Kisseberth and Trammel, 1990; Branson, 2001).
Actions on the PNS include inhibition of acetylcholine
sensitive nerve depolarization at postsynaptic junctions
Toxicokinetics and motor end plates. Respiratory depression is caused by
chemoreceptor suppression by barbiturates. This effect is
Gastrointestinal absorption of barbiturates is variable,
more marked in cats where the reticular formation gov-
with rapid absorption of short-acting compounds and
erns medullary control of respiration. Control of respira-
slower absorption of long-acting barbiturates. Barbiturates
tory activity is believed to be more complex in other
are rapidly distributed throughout the body and readily
species.
cross the blood brain barrier (Kisseberth and Trammel,
Barbiturates can cause hypotension and secondary
1990; Branson, 2001; Volmer, 2005). Short-acting thio-
anuria (Branson, 2001; Volmer, 2005). Increased heart
barbiturates are highly lipid soluble and enter the brain
rate is believed to be governed by arterial pressorecep-
rapidly, resulting in rapid onset of CNS depression. This
tors. The effects of barbiturates on concentrations of
is followed by rapid redistribution to tissues with less per-
sodium, potassium, and calcium in cardiac myocytes
fusion and thus rapid clinical recovery. Longer-acting bar-
produce a change in cardiac contractility. Hypothermic
biturates are less lipophilic; therefore, they enter and
animals are predisposed to ventricular fibrillation with
leave the brain more slowly and have a more gradual
barbiturates. Fibrillation is reported in 100% of hypo-
onset and longer duration of action. Barbiturates cross the
thermic animals given pentobarbital and 50% of those
placenta and fetal concentrations equilibrate with those of
given thiopental.
the dam within minutes.
There is significant variation in barbiturate metabo-
lism and excretion based on the barbituric acid derivative, Clinical Signs
the species of animal, and the individual. Barbiturates are
Onset of clinical signs depends on the route of exposure,
metabolized by microsomal P450 enzymes in the liver.
the barbiturate involved, and the presence or absence of
Barbiturates interfere with metabolism of other com-
food in the stomach. Animals that have ingested short-
pounds either through competitive inhibition of the P450
acting barbiturates usually have clinical signs within
enzymes or, in chronic exposures, by inducing P450
30 min. If long-acting barbiturates were ingested, the first
enzymes and thus increasing the rate of metabolism of
effects might not be observed for an hour (Kisseberth and
xenobiotics and endogenous substances, including steroids
Trammel, 1990). The time to onset of clinical anesthesia
(Volmer, 2005). Some barbiturates, in particular the
is doubled if phenobarbital is given to an animal with
short-acting thiobarbiturates, undergo significant oxida-
food in its stomach versus an empty stomach or if con-
tion in the tissue. Phenobarbital is metabolized very
taminated carrion is ingested. Duration of effects is also
rapidly in ruminants and horses, relatively rapidly in
variable, as alluded to previously, and dependent on the
dogs, more slowly in humans, and slower still in cats
agent involved, species of animal, nutritional status, age,
(Branson, 2001).
sex, and weight. The duration of a given barbiturate is
Barbiturates are excreted as both parent compound and
expected to be prolonged in greyhounds, which have less
metabolites in the urine. Excretion of some barbiturates is
adipose tissue for the drug deposition.
dependent on urine pH and is increased 5 10 times in
The predominant symptoms of barbiturate intoxication
alkaline urine through ion trapping. Ion trapping is less
are profound CNS depression and anesthesia (Humphreys
effective with short-acting barbiturates, which are highly
et al., 1980; Kisseberth and Trammel, 1990; Volmer,
metabolized, highly protein bound drugs, and have high
2005). Animals usually present with severe ataxia, weak-
pK a s(Kisseberth and Trammel, 1990; Volmer, 2005).
ness, disorientation, and loss of deep tendon reflexes.
Barbital is excreted very slowly in birds (Branson, 2001).
Hypothermia is common and is associated with cardiac
dysrhythmia in humans and dogs as noted previously.
Mechanism of Action Rapid, weak pulse and severe respiratory depression can
Barbiturates bind to the γ-aminobutyric acid (GABA) lead to cyanosis and death.
receptor complex and decrease the rate of GABA dissoci- Certain preexisting conditions enhance the effects of
ation (Branson, 2001). These actions increase permeabil- barbiturates, such as renal failure, uremia, and decreased
ity of the postsynaptic membrane to chloride, causing rate of excretion. Barbiturates can accelerate liver damage
membrane hyperpolarization and reduced excitability. in an individual with preexisting liver disease. Allergic
GABA receptors are found in motor and sensory areas of and idiosyncratic reactions to barbiturates have been
the cerebral cortex and possibly in the thalamus, where reported, including necrolytic dermatitis and Stevens-
barbiturates act to control seizures and induce anesthesia. Johnson syndrome (Cornelis et al., 2016).