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Responding to accidental atomoxetine ingestion

Article

At fairly low dosages, atomoxetine-a drug in people to treat ADHD-can be toxic in dogs and cats.

Atomoxetine, a selective norepinephrine reuptake inhibitor with minimal affinity for other noradrenergic receptors, is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults.1 It is available by prescription under the brand name Strattera (Eli Lilly) in 10-, 18-, 25-, 40-, 60-, 80-, and 100-mg capsules.

This drug is not used in veterinary medicine. However, you should be aware of its toxic potential because of its availability in households that have pets or animal visitors. Since the release of atomoxetine in 2003, the American Society for the Prevention of Cruelty to Animals (ASPCA) Animal Poison Control Center (APCC) has received more than 700 calls involving a possible exposure to atomoxetine (ASPCA APCC Database, Urbana, Ill: Unpublished data, 2003-2011).

MECHANISM OF ACTION AND PHARMACOKINETICS

The 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

TOXICITY

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.

ASPCA APCC DATA

Of the more than 700 calls received from 2003 to 2010, 59 were single-agent exposures that had been assessed as having clinical signs and exposure histories that were highly consistent with an atomoxetine exposure. Of these cases, 38 were canine exposures and 21 were feline exposures (ASPCA APCC Database, Urbana, Ill: Unpublished data, 2003-2011).

The most common clinical signs seen in dogs are listed in Table 1. Of the 38 canine cases, three (1.32 mg/kg dose exposure, 7.6 mg/kg dose exposure, one with unknown dose) had reported outcomes. Two of these dogs required treatment at a veterinary hospital, but all three made a full recovery.

Clinical signs reported in dogs ingesting atomoxetine*

Common clinical signs noted with feline exposures are listed in Table 2. There were two cases (22 mg/kg and 66.13 mg/kg dose exposures) with reported outcomes; both cats made a full recovery with medical treatment.

Clinical signs reported in cats ingesting atomoxetine*

In both dogs and cats in the ASPCA APCC cases, mild clinical signs (lethargy, hypersalivation, vomiting) were noted at doses as low as 1 or 2 mg/kg. In many of the cases, hypersalivation and vomiting occurred within 15 minutes after the exposure, potentially indicating a taste reaction.

In dogs, more significant clinical signs (hyperactivity, agitation, tachycardia) were seen at doses > 2 mg/kg and generally developed one to three hours after exposure. Tremors occurred in a dog at 22 mg/kg. Doses ranged from 1.32 to 63 mg/kg in the canine cases. The duration of clinical signs ranged from minutes (vomiting) to several hours (six to 33.6 hours). Clinical signs would likely resolve within 24 to 48 hours with high-dose cases, but most of the cases reviewed did not report the outcome, and the durations of clinical signs were not available. No deaths were noted.

In the feline cases, doses ranged from 1.3 to 85.7 mg/kg. Significant clinical signs (tachycardia) were noted in cats at slightly lower doses (1.5 mg/kg) than were noted in dogs, but the onset of clinical signs was similar to that of dogs. In cats, tremors were noted at lower doses than were noted in dogs. Hindlimb tremors occurred in a cat at a dose of 9.7 mg/kg. Eighty percent of the cats with potential doses > 9.7 mg/kg developed trembling or tremors. The durations of clinical signs in the two cases that had outcomes were between 20 and 22.5 hours. No deaths were reported (ASPCA APCC Database, Urbana, Ill: Unpublished data, 2003-2011).

DECONTAMINATION

Induce emesis in animals that have been recently exposed (< 30 minutes) and are exhibiting no clinical signs. In cats, give xylazine (0.44 mg/kg intramuscularly) to induce emesis,7 and in dogs, give apomorphine (0.03 mg/kg intravenously; 0.04 mg/kg intramuscularly).7 If apomorphine is only available in tablet form, it may be administered into the conjunctival sac. When using the ocular method, a quarter of a 6-mg tablet (in any sized dog) should be crushed, diluted with a few drops of saline solution, and administered into the conjunctival sac. After emesis has occurred, gently rinse the conjunctival sac with saline solution to reduce the risk for ocular irritation.

Alternatively in dogs, 3% active hydrogen peroxide can be orally administered at a dose of 1 to 2 ml/kg (generally not exceeding 45 ml as a total dose). This dose may be repeated just once since multiple doses of hydrogen peroxide may result in gastritis.8 Hydrogen peroxide is generally not recommended for cats because of their increased risk for gastritis.9

For dose exposures > 2 mg/kg in dogs and cats, a single dose of activated charcoal with a cathartic can be administered to hinder absorption (1 g/kg of activated charcoal diluted in water to achieve a 1 g/10 ml concentration or 10 ml/kg of a 10% activated charcoal suspension) may be warranted.7 Collect baseline electrolyte values at presentation, and monitor them for four hours after activated charcoal administration to assess for changes to the patient's sodium concentration.

MONITORING

Closely monitor heart rate and blood pressure in exposed patients. Baseline electrolyte values should be obtained and monitored for changes as marked gastrointestinal effects develop or hydration becomes a concern. In cases in which activated charcoal has been administered, monitor electrolyte values for at least four hours (see "Decontamination" above).

Marked tremor activity may result in hyperthermia and rhabdomyolysis with subsequent hyperkalemia and renal damage; thus, in patients exhibiting serious clinical signs, also monitor renal indices.

Monitor patients that are asymptomatic after ingestion for six hours before their release.

TREATMENT OF TOXICOSIS

If a patient has developed agitation or hyperactivity and is normotensive or hypertensive, acepromazine at a dosage of 0.02 mg/kg intravenously or intramuscularly may be administered for sedation. Tremors may be controlled with methocarbamol (50 to 220 mg/kg intravenously slowly to effect, not to exceed 330 mg/kg/day). Seizure activity can be treated with diazepam (0.5 to 2 mg/kg intravenously in dogs, 0.25 to 1 mg/kg intravenously in cats starting at lower doses and given to effect), but administer this drug with caution; occasionally patients may develop paradoxical excitation after administration. Alternatively, a barbiturate such as phenobarbital (2 to 5 mg/kg intravenously to effect, may be repeated at 20-minute intervals up to two times), gas anesthesia, or propofol (5 to 6 mg/kg intravenously) may be given to control seizures.7

Tachycardia and hypertension may resolve after sedation. If tachycardia persists and the patient is normotensive, propranolol (0.02 to 0.06 mg/kg intravenously slowly to effect), a nonselective beta-adrenergic antagonist, may be administered to obtain the desired heart rate.7 A nitroprusside continuous-rate infusion may be given to manage hypertension (> 200 mm Hg systolic arterial blood pressure). Administer an initial a dose of 1 or 2 µg/kg/min in dogs (0.5 µg/kg/min in cats), and then increase the dose incrementally every three to five minutes until the target blood pressure is attained. The blood pressure should be reduced by 25% over four hours to allow the cerebral vessels to readapt.7

If tremor activity occurs, fluid therapy (balanced, isotonic crystalloid) is indicated to aid in thermoregulation and provide renal support. Fluids should be administered intravenously starting at the maintenance rate of 45 to 60 ml/kg/day, adjusting for ongoing needs and blood pressure and hydration changes. If fluids are administered, the patient should be monitored closely for hypertension and potential fluid overload.

CONCLUSION

Fairly low doses of atomoxetine can result in clinical signs in dogs and cats. However, these developments are not expected to be life-threatening with appropriate medical management.

Adrienne Coleman, DVM

ASPCA Animal Poison Control Center

1717 S. Philo Road

Suite 36 Urbana, IL 61802

REFERENCES

1. McEvoy GK. Atomoxetine hydrochloride. In: American Hospital Formulary Service Drug Information. Bethesda, Md: American Society of Health System Pharmacists 2009;2704-2706.

2. Eli Lilly. Strattera prescribing information. Available at: http://pi.lilly.com/us/strattera-pi.pdf. Accessed Feb. 16, 2013.

3. Mattiuz EL, Ponsler GD, Barbuch RJ, et al. Disposition and metabolic fate of atomoxetine hydrochloride: pharmacokinetics, metabolism, and excretion in the Fischer 344 rat and beagle dog. Drug Metab Dispos 2003;31(1):88-97.

4. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 2001;108(5):E83.

5. Porterfield SP. Endocrine physiology. St. Louis, Mo: Mosby-Year Book, 1997;130-133.

6. Clarke DO, Connelly CS, Hall RL, et al. Nonclinical pediatric testing of tomoxetine: toxicity study in young beagle dogs (abst). Neurotoxicol Teratol 2001;23(3):294-295.

7. Plumb DC. Veterinary drug handbook. 6th ed. Stokholm, Wis: PharmaVet, 2005; 4, 91, 235, 368, 794, 886, 962, 1044-1047, 1048, 1253.

8. Plumlee KH. Clinical veterinary toxicology. St. Louis, Mo: Mosby, 2004;15.

9. American Society for the Prevention of Cruelty to Animals Animal Poison Control Center. Unpublished Data 2013. 1717 S. Philo Rd, Ste 36, Urbana, IL 61802.

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