Page 426 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Toxicity of Drugs of Abuse Chapter | 22 393

VetBooks.ir as heroin (Rech et al., 2015). More common in Russia produces 6-o-acetylmorphine and morphine, which appear
in the plasma of dogs within minutes (Garrett and
than the United States, desomorphine, also known as kro-
Gu ¨rkan, 1980).
kodil, is usually injected and has gained notoriety because
of the necrotizing skin lesions caused by contaminants. It Opioids are excreted predominantly as metabolites in
has been estimated that the survival time for krokodil the urine. Metabolites may be detected in horse urine for
users is 2 years. up to 6 days (Branson and Gross, 2001). There is some
Small animal exposure to opioids may be because of biliary excretion and enterohepatic cycling. The biological
accidental ingestion of pharmaceuticals, illegal drugs, or half-life of morphine in cats is about 3 h. The initial
occasionally by oral or parenteral dosing with malicious plasma half-life of heroin in dogs is 8 min, but the termi-
intent (Kisseberth and Trammel, 1990; Volmer, 2005). nal half-life is 80 min due to repartitioning from the tis-
There have been several reports in the US news media of sues (Garrett and Gu ¨rkan, 1980).
small animals that accidentally ingested or were inten-
tionally injected with heroin. Ingestion of therapeutic fen-
tanyl patches has been reported in children, dogs, and Mechanism of Action
monkeys (Deschamps et al., 2012). Major opioid receptors are designated μ, δ, and κ and are
believed to be stimulated by endogenous endorphins
Toxicity (Branson and Gross, 2001; Volmer, 2005). The μ recep-
tors are activated by endogenous enkephalins, and are fur-
With such a wide variety of opioids, there is much varia-
ther differentiated into μ 1 and μ 2 . Activation of the μ 1
tion in toxicity. The lethal parenteral dose of morphine in
receptor induces supraspinal analgesia, and μ 2 receptor
dogs is between 110 and 210 mg/kg (Kisseberth and
activation causes spinal analgesia, suppression of respira-
Trammel, 1990; Branson, 2001; Volmer, 2005). The mini- tion, and inhibition of gastrointestinal motility. The δ
mum lethal dose for subcutaneous (SC) injection of mor- receptors are more selective for enkephalins than the μ
phine in cats is 40 mg/kg. The minimum lethal dose of
opioid receptors and are also involved in spinal analgesia.
heroin for dogs is 25 mg/kg given subcutaneously.
Activation of κ receptors produces spinal and supraspinal
Approximately 0.20 mg/kg heroin causes clinical signs in
analgesia, sedation, and dysphoria. The σ receptor, previ-
dogs, including sedation and respiratory depression;
ously classified as an opioid receptor, does not appear to
whereas, a dose of 0.58 mg/kg causes increased duration
mediate analgesia.
of effects, respiratory difficulty, and aggressive behavior
Opioid receptors are found in the CNS, ANS, gastroin-
with clinical signs lasting up to 8 h (Garrett and Gu ¨rkan,
testinal tract, heart, kidney, pancreas, adrenal glands, vas
1980). The minimum oral lethal dose of heroin for cats is
deferens, lymphocytes, and adipocyte (Volmer, 2005).
20 mg/kg. Meperidine causes clonic convulsions in cats at
Opioid receptors in the CNS are concentrated in the
a dose of 30 mg/kg (Branson and Gross, 2001).
amygdala and frontal cortex in dogs, monkeys, and
humans where stimulation is associated with CNS depres-
Toxicokinetics sion (Branson and Gross, 2001; Kisseberth and Trammel,
Opioids are weakly acidic, and absorption after oral dos- 1990). Activation in cats, swine, goats, sheep, horses, or
ing is predominantly in the small intestine. There is rapid oxen alters dopaminergic or noradrenergic function, lead-
absorption from the subcutis after SC injection (Branson ing to excitation. Activation of opioid centers in the che-
and Gross, 2001). Distribution is variable. Heroin is more moreceptor trigger zone in the fourth ventricle of the
lipophilic than morphine and more readily crosses the brain produces emesis. Opioid receptors are present in the
blood brain barrier (Garrett and Gu ¨rkan, 1980). Opioids brain stem, including the cough centers where they sup-
are also distributed to skeletal muscle, kidney, liver, intes- press the cough reflex, and the respiratory centers, though
tine, lungs, spleen, brain, and placenta (Kisseberth and initial increases in respiration are followed by respiratory
Trammel, 1990). Opioids are readily metabolized in the suppression because of generalized CNS depression.
liver with a significant first pass effect after ingestion. Stimulation of gastrointestinal opioid receptors decrease
Phase I metabolism includes hydrolysis, oxidation, and motility, leading to delayed passage of ingesta, increased
N-dealkylation. Approximately 50% of a dose of mor- water absorption and constipation.
phine is conjugated to glucuronide in most species. Opioid drugs act as agonists, partial agonists, or
A notable exception is cats, accounting in part for the antagonists. Morphine and related drugs are agonists at μ
increased sensitivity of this species. The primary glucuro- receptors. Naloxone is an antagonist with a high affinity
nide conjugate is morphine-3 glucuronide, though the for the μ receptors and a low affinity for δ receptors
metabolically active morphine-6-glucuronide is also pro- (Volmer, 2005). An opioid is classified as a partial ago-
duced. Heroin is metabolized in the liver and other tissues nist if it acts as an agonist at one receptor but an antago-
and is cleared more rapidly than morphine. Deacetylation nist at another.