Responding to accidental atomoxetine ingestion
MECHANISM OF ACTION AND PHARMACOKINETICSThe mechanism of action by which this medication improves clinical signs associated with ADHD is not yet known, but it is thought to be due to the selective inhibition of the presynaptic norepinephrine transporter.1
In people, atomoxetine is well-absorbed orally with a peak plasma concentration occurring one or two hours after administration.2 It is highly protein bound in both dogs (97%) and people (98%).3 In people, atomoxetine is metabolized primarily through the cytochrome P-450 enzymatic pathway CYP2D6 to an oxidative metabolite (4-hydroxyatomoxetine). There is a genetic polymorphism of CYP2D6 in people. Those that metabolize CYP2D6 poorly experience plasma concentrations that are five times greater than the concentrations that extensive metabolizers experience. About 7% of Caucasian populations are poor metabolizers. The reported elimination half-life in people is 5.3 hours in extensive metabolizers and 24 hours in poor metabolizers.2
Dogs do not express CYP2D6; they metabolize the drug by aromatic ring hydroxylation and N-demethylation, but atomoxetine is ultimately metabolized to the same primary oxidative metabolite as in humans, 4-hydroxyatomoxetine.3 In dogs, 48% of the drug is excreted through the kidneys and 42% in the feces. The terminal half-life in dogs after oral administration of atomoxetine at a dose of 2 mg/kg is about 3.7 (+/- 0.5) hours.3
Clinical research involving acute atomoxetine toxicosis in dogs and cats is minimal, and there is no LD50 established for either species. Because atomoxetine selectively inhibits the presynaptic norepinephrine transporter while having minimal affinity and effect on other neurotransmitter receptors, it may cause an increase in autonomic tone.4
As with the body's natural fight-or-flight response, a pharmacologically induced increase in norepinephrine may result in clinical signs that are consistent with cardiovascular stimulation: vasoconstriction, hypertension, or tachycardia followed by possible reflex bradycardia. Other noradrenergic effects such as urinary sphincter contractions, transient hyperglycemia, and mydriasis may also be seen with excessive accumulation of norepinephrine.5
Additionally, since the drug's release, there have been some documented cases of severe hepatic injury in people receiving this medication.2 This has not been noted in any ASPCA APCC cases.
In a study involving 8-week-old beagle puppies receiving oral doses of atomoxetine at 4, 8, or 16 mg/kg/day for four weeks, dose-related clinical signs of vomiting, retching, tremors, mydriasis, and decreased pupillary light reflex were noted. With the exception of repetitive head movements reported at 16 mg/kg/day, the abstract (the full study was not published) does not provide doses at which specific clinical signs were seen.6
A rodent study showed that when 25 mg/kg of atomoxetine was fed to female rats for two weeks before conception and continued throughout lactation, decreased pup survival rates were observed.2 A decrease in pup survival was also noted when male rats were fed the same dose starting 10 weeks before mating.