Page 437 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

404 SECTION | IV Drugs of Use and Abuse

VetBooks.ir ketamine in rodents is 600 mg/kg PO (Gable, 2004). receptors, dopaminergic receptors, nicotinic receptors,
muscarinic receptors, and opioid receptors. Analgesic
Large doses of ketamine do not appear to produce analge-
properties are most likely attributable to the actions of
sia in chickens or pigeons, but a dose of 0.11 mg/kg was
reportedly associated with respiratory failure in pigeons. ketamine on opioid receptors.
A dose of 0.05 0.1 mg/kg produced anesthesia in para- Ketamine is usually sold as a racemic mixture, but the
keets, but 0.5 mg/kg IM was lethal (Branson, 2001). S-enantiomer is the active portion. S-ketamine is being
studied for therapeutic use by physicians treating major
Toxicokinetics depressive disorder and by veterinarians for use in
anesthesia.
Phencyclidine is ionized at gastric pH, thus little is
absorbed in the stomach, but there is significant intestinal
absorption (Kisseberth and Trammel, 1990; Volmer, Clinical Signs
2005). Inhaled phencyclidine is well absorbed. The drug
Dogs dosed with phencyclidine appear depressed at low
is lipophilic, with a wide tissue distribution that includes
doses and stimulated at high doses, with the potential for
the CNS, adipose tissue, and gastric secretions. The latter
convulsive seizures (Branson, 2001). Onset of clinical
leads to recycling and increases the biological half-life.
effects is within 2 min of IV dosing (Ortega, 1967).
Metabolism is variable between species. In the dog,
Symptoms reported in dogs include muscular rigidity,
approximately 68% of a given dose undergoes hepatic
risus sardonicus-like facial expression, increased motor
metabolism to a monohydroxyl form which is then conju-
activity, head weaving, stereotyped sniffing behavior,
gated for excretion. The remaining 32% is excreted
blank staring, incoordination, hypersalivation, nystagmus,
unchanged in the urine. Approximately 88% of a dose of
opisthotonos, ascending loss of motor function, coma,
phencyclidine is excreted unchanged in the urine in cats.
tonic clonic convulsions, and hyperthermia (Ortega,
Peak plasma concentrations in cats occur 10 min after
1967; Kisseberth and Trammel, 1990; Volmer, 2005).
IM injection of ketamine (Branson, 2001; Volmer, 2005).
Cardiovascular effects include tachycardia, hypertension,
Ketamine is about 50% bound to plasma proteins in
and cardiac arrhythmia. Deaths have been attributed to
horses. It is distributed to the brain, adipose tissue, liver,
respiratory failure. Symptoms associated with phencycli-
lung, and other tissues. Ketamine undergoes hepatic
dine in swine include muscle tremors and hypersalivation
metabolism via N-demethylation or hydroxylation and
(Jones, 1972). Behavioral changes have been noted in
glucuronide conjugation to a water soluble metabolite for
neonates that were exposed during gestation (Branson,
excretion in the urine. The elimination half-life is approx-
2001). Reported changes in clinical chemistry parameters
imately 67 min in the cat after parenteral dosing, 60 min
include acidosis, hypoglycemia, electrolyte imbalances,
in the calf, 42 min in the horse after IV dosing, and
and increased creatine phosphokinase and aspartate trans-
2 3 h in the human (Branson, 2001).
aminase. Postmortem lesions associated with phencycli-
dine include epicardial and subendocardial hemorrhage
Mechanism of Action and pulmonary congestion and hemorrhage (Kisseberth
How compounds like phencyclidine and ketamine pro- and Trammel, 1990; Volmer, 2005).
duce their dissociative effects is not entirely understood. Pineal, pedal, photic, corneal, papillary, laryngeal,
It is known that these drugs act on sites in the cerebral pharyngeal, and other reflexes are maintained during keta-
cortex, thalamus, and limbic system (Branson, 2001; Pal mine anesthesia (Branson, 2001; Volmer, 2005). There
et al., 2002; Volmer, 2005). The effects on behavior and are significant species differences in the effects of keta-
cognition in humans can mimic schizophrenia. mine. Ketamine increases muscle tone in cats, sometimes
Phencyclidine and ketamine bind to N-methyl-D-aspartate causing forelimb extensor rigidity or opisthotonos. Other
(NMDA) receptors at a different site than glutamate, the symptoms in cats include mydriasis and fixed staring.
excitatory neurotransmitter, and therefore, act as noncom- Hypersalivation and chops licking are associated with oral
petitive inhibitors. Reuptake of NE, dopamine, and sero- dosing. Most cats can sit upright within 2 h and recover
tonin is decreased through inhibition of the biogenic completely within 10 h. Ketamine causes excitation in
amine reuptake complex. The sympathomimetic effects dogs and can produce tonic clonic seizures. Tonic-clonic
are associated with changes in heart rate, blood pressure, seizures have been described in dogs undergoing an anes-
and cardiac output, and increased myocardial oxygen con- thesia protocol that utilized S-ketamine (Adami et al.,
sumption. Phencyclidine inhibits γ-aminobutyric acid. 2013). Pulmonary edema was reported in a dog 2 days
Cardiovascular effects are more prominent with ketamine after anesthesia with ketamine and xylazine.
than phencyclidine. Hypersalivation, apneustic breathing, and increased pulse
Ketamine induces stage I and stage II anesthesia but are reported in sheep. Goats salivate, struggle, and vocal-
not stage III. Ketamine acts on non-NMDA glutamate ize but usually recover within 20 min of dosing.