Toxicology Brief: Phenylephrine ingestion in dogs: What's the harm?

Phenylephrine is a sympathomimetic amine used orally in human medicine mainly as a decongestant. It is found in several over-the-counter cold remedies. Veterinary practitioners should be aware of its toxic potential in dogs since its use has likely increased as restrictions are placed on the sale of another common over-the-counter decongestant, pseudoephedrine, because of pseudoephedrine's involvement with methamphetamine production.

EXPOSURE RISKS FOR DOGS

As a decongestant, phenylephrine is available in nasal (0.25% to 1%) and oral formulations (5- to 10-mg tablets). The oral formulations are often combined with antihistamines, analgesics, expectorants, or antitussives. In an overdose, other ingredients present in the formulation such as acetaminophen or ibuprofen are often more concerning than the phenylephrine.

Parenteral formulations of phenylephrine are used to treat hypotension in animals and people. Phenylephrine is also used as an adjunct in spinal and local anesthesia.

Ocular preparations produce mydriasis and vasoconstriction. These formulations are used for intraocular examination and surgery and to differentiate conjunctival vascular injection from deep-episcleral injection. Ocular phenylephrine is also used in the diagnosis and treatment of glaucoma, treatment and prevention of synechiae, and diagnosis and classification of Horner's syndrome.1,2

Hemorrhoid creams, ointments, and suppositories also contain phenylephrine.

TOXICOKINETICS

Phenylephrine acts directly on alpha1-adrenergic receptors. The stimulation of these receptors results in peripheral vasoconstriction and increased systolic and diastolic blood pressures. At high dosages, the stimulation of cardiac beta-adrenergic receptors may occur.3 This can lead to cardiac stimulation.

After oral exposure, phenylephrine is extensively metabolized in the gastrointestinal tract and liver.1,4 This high metabolization accounts for the low oral bioavailability of phenylephrine (38% in people).1 It is primarily excreted in the kidneys in people.1 Phenylephrine reaches a peak plasma concentration in 30 minutes.5 The half-life is two to three hours. Adverse signs typically have a rapid onset and relatively short duration.3

TOXICITY

The oral LD50 of phenylephrine in rats and mice is 350 mg/kg and 120 mg/kg, respectively.6 Because of low oral bioavailability, the acute oral toxicity is lower for phenylephrine than with other sympathomimetics such as pseudoephedrine, and parenteral administration is more likely to result in marked clinical signs of toxicosis compared with oral exposure. An oral therapeutic dosage in dogs could not be located.

Clinical signs after overdose may include2,3:

• Gastrointestinal upset

• Hypertension

• Reflex bradycardia

• Central nervous system stimulation

• Lethargy

• Nervousness

• Agitation

• Tremors

• Seizures

• Cerebral hemorrhage

• Ventricular arrhythmias.

APCC DATA

The ASPCA Animal Poison Control Center (APCC) toxicology database was searched for oral phenylephrine exposures in dogs. Cases involving combinations of phenylephrine with other medications (e.g. analgesics, antihistamines, antitussives) and multiple agent exposures were excluded. Between January 1, 2007, and December 31, 2011, 178 dogs with clinical signs were identified. These dogs were considered to have a medium or high likelihood of suffering from phenylephrine toxicosis based on history of exposure and the clinical signs present. Of the 178 exposures, 89 were due to ingestion of hemorrhoid medications (creams, ointments, or suppositories), 80 were from ingesting tablets or capsules, and nine were due to ingestion of nasal drops and sprays.7

After ingestion of hemorrhoid preparations in 89 dogs, the most common signs were vomiting (75 dogs; 84%), lethargy (8 dogs; 9%), diarrhea (5 dogs; 6%), bradycardia (4 dogs; 4%), tachycardia (4 dogs; 4%), and trembling (4 dogs; 4%). In most cases, the dosages were unknown, so a range could not be determined. Hypertension was reported in two cases (2%). A systolic blood pressure of 170 mm Hg was reported at 11.9 mg/kg and a systolic blood pressure of 210 mm Hg was reported after an estimated dosage of 7 mg/kg.

In the nine dogs with clinical signs as a result of nasal spray or drop exposure, vomiting (9 dogs; 100%) and trembling (1 dog; 1%) were the only signs reported.7

The most common signs after tablet or capsule ingestion in 80 dogs were vomiting (63 dogs; 79%), hyperactivity (9 dogs; 11%), lethargy (7 dogs; 9%), panting (6 dogs; 8%), and trembling (4 dogs; 5%). Dosages ranged from 0.23 to 30 mg/kg. Hypertension was not reported.7

The ASPCA APCC data are consistent with the expected low oral toxicity of phenylephrine, probably due to phenylephrine's low bioavailability. Based on phenylephrine's physiologic effects, hypertension is expected to be the main serious concern after phenylephrine overdose. However, hypertension was noted in only 2% of cases and only after exposures to hemorrhoid medications. This may possibly be due to oral mucosal absorption of phenylephrine from the creams, ointments, and suppository formulations. One of the hypertensive dogs made a full recovery within five hours. The outcome for the other dog was not known.7

TREATMENT

An exact dosage of concern in dogs after oral exposure is unknown. Because of phenylephrine's low bioavailability, severe signs after oral exposure are unlikely. If needed, emesis with 3% hydrogen peroxide (2.2 ml/kg orally—maximum of 45 ml—repeat once in 15 minutes if not successful) or apomorphine (0.03 mg/kg intravenously or into the conjunctival sac) could be considered if the exposure is recent and the patient is not exhibiting clinical signs.8,9 Consider the risk for aspiration if inducing emesis after ingestion of ointments. Activated charcoal is not typically necessary. Monitor dogs for gastrointestinal upset, hyperactivity, lethargy, and, potentially, hypertension (especially after ingestion of creams, ointments, or suppositories containing phenylephrine).

Acepromazine (0.02 mg/kg intravenously) can be used to control the stimulatory signs and mild hypertension.10 Nitroprusside (1 to 2 µg/kg/minute) may be necessary if marked hypertension persists.11 Intravenous fluids can be used for supportive care. The gastrointestinal signs are often self-limiting but should respond to symptomatic care if necessary.

MONITORING

In dogs exhibiting marked clinical signs, monitor blood pressure, heart rate and rhythm, temperature, and central nervous system status. Also, monitor for gastrointestinal upset. A baseline complete blood count and serum chemistry profile may be performed in patients exhibiting marked central nervous system or cardiovascular effects, although no direct specific laboratory changes are expected.

SUMMARY

Phenylephrine is a sympathomimetic alpha1-adrenergic agonist commonly found alone or in combination as a decongestant and as the active ingredient in hemorrhoid preparations. Because of its low oral bioavailability, phenylephrine has a wider safety margin than does pseudoephedrine (another common sympathomimetic decongestant). Per ASPCA APCC experience, the most common signs in dogs after ingestion are vomiting, hyperactivity, and lethargy. However, there is a risk for more serious sequelae such as hypertension, heart rate changes, and central nervous system stimulation.

Acknowledgements

The author thanks Mary Kay McLean, MS, research associate at the ASPCA Animal Poison Control Center, for her contribution to this article.

Colette Wegenast, DVM

ASPCA Animal Poison Control Center

1717 S. Philo Road, Suite 36

Urbana, IL 61802

REFERENCES

1. Phenylephrine. In: DRUGDEX System [intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc.

2. Plumb DC. Phenylephrine. In: Plumb's veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing, 2008;724-726.

3. AHFS drug information. Bethesda, Md: American Society of Health-System Pharmacists Inc, 2000;1205-1209.

4. Kelley MT. Sympathomimetics. In: Haddad LM, Shannon MW, Winchester JF, eds. Clinical management of poisoning and drug overdose. 3rd ed. Philadelphia, Pa: WB Saunders Company; 1998;1078-1086.

5. Understanding phenylephrine metabolism, pharmacokinetics, bioavailability and activity. Summit NJ: Schering-Plough, 2007. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4335±-01-Schering-Plough.pdf

6. Sciencelab.com. Material Safety Data Sheet Phenylephrine hydrochloride MSDS. Accessed Sept. 7, 2011 at http://www.sciencelab.com/msds.php?msdsId=992650.

7. AnTox Database. Urbana, Ill: ASPCA Animal Poison Control Center, 2003-201+.

8. Richardson JA. Managing toxicoses in dogs and cats, in Proceedings. Atlantic Coast Veterinary Conference, 2009.

9. Plumb DC. Apomorphine. In: Plumb's veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing, 2008;68-69.

10. Tranquilli WJ. College of Veterinary Medicine, University of Illinois, Champaign, Ill: Personal communication with Dr. Judy Holding, 2003.

11. Plumb DC. Nitroprusside. In: Plumb's veterinary drug handbook. 6th ed. Ames, Iowa: Blackwell Publishing, 2008;659-661.