Antihistamine Toxicoses in Animals
Antihistamines are H1-receptor antagonists that provide relief of allergy signs caused by histamine release, including pruritus and anaphylactic reactions. They are also used as sedatives and antiemetics. Antihistamines belong to different classes and are categorized as first-generation or second-generation (also called nonsedating) antihistamines.
First-generation antihistamines can have adverse effects because of their cholinergic activity and ability to cross the blood-brain barrier. Typical clinical signs of toxicoses due to first-generation antihistamines include lethargy, sedation, agitation, tachycardia, vomiting, hypotension, mydriasis, tremors, and, potentially, seizures. See the table First-Generation Antihistamines.
First-Generation Antihistamines
Name | Classification | Dosage Notes | Toxicokinetics | Onset of Clinical Signs |
|---|---|---|---|---|
Chlorpheniramine | Propylamine-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 2–4 h of ingestion |
Clemastine | Ethanolamine-derivative antihistamine | 1.35 mg clemastine fumarate is equivalent to 1 mg clemastine. Therapeutic dose:
Toxic dose:
|
| Within 30–60 min of ingestion |
Dimenhydrinate and diphenhydramine | Ethanolamine-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 30–60 min of ingestion |
Doxylamine succinate | Ethanolamine-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 30–60 min of ingestion |
Hydroxyzine | Piperazine-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 2 h of ingestion |
Meclizine | Piperazine-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 9 h of ingestion |
Promethazine | Phenothiazine-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 30 min of ingestion, CNS depression is more common than agitation. |
Second-generation antihistamines are more lipophobic than first-generation antihistamines, and they are thought to lack CNS and cholinergic effects at therapeutic doses. With overdoses, CNS signs are possible. Typical clinical signs of toxicoses due to second-generation antihistamines include lethargy, GI upset, and hyperactivity. See the table Second-Generation Antihistamines.
Second-Generation Antihistamines
Name | Classification | Dosage Notes | Toxicokinetics | Onset of Clinical Signs |
|---|---|---|---|---|
Cetirizine | Piperazine-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 5 h of ingestion |
Fexofenadine | Butyrophenone-derivative antihistamine | Therapeutic dose:
Toxic dose:
|
| Within 60 min of ingestion |
Loratadine | Tricyclic, long-acting histamine with selective peripheral histamine H1-receptor antagonist activity | Therapeutic dose:
Toxic dose:
|
| Within 1–4 h of ingestion |
Antihistamines are often found in combination with other ingredients (eg, decongestants, analgesics like acetaminophen or NSAIDs) in many over-the-counter (OTC) cold, sinus, and allergy medications.
Treatment of Antihistamine Toxicoses
Treatment of antihistamine toxicosis is primarily supportive. The induction of emesis should be considered only in patients not yet exhibiting clinical signs; because the onset of clinical signs is rapid, emesis induction is not appropriate for most animals that have ingested first-generation antihistamines. Administration of activated charcoal can be useful for ingestion within 1–2 hours in clinically normal patients.
Clinically affected patients should be watched for anticholinergic clinical signs (agitation, mydriasis, tachycardia, or decreased intestinal motility) and treated as needed. Cardiovascular functions (heart rate and blood pressure) and body temperature should be closely monitored.
Propranolol (0.02–0.06 mg/kg, IV) can be helpful to treat consistent tachycardia in normotensive patients. Hypotension can be treated with dopamine (2–2.5 mcg/kg per minute, IV, to effect) or norepinephrine (0.05–0.1 mcg/kg per minute, IV, to effect).
A short-acting anticonvulsant such as a benzodiazepine or levetiracetam can be administered to control seizures or seizure-type activity. Physostigmine is recommended to counteract the CNS anticholinergic effects of antihistamine overdoses in humans; however, the risk of seizures associated with this drug might limit its use.
IV fluids should be given as needed.
Albuterol Toxicosis in Animals
Albuterol is a synthetic sympathomimetic amine with primarily beta-2 adrenergic receptor agonist properties at therapeutic doses. With overdoses, it can exert agonist effects on beta-1 adrenergic receptors as well.
Albuterol is used primarily as a bronchodilator or to treat bronchospasm or cough. It is available by prescription as an aerosol or powder for inhalation, solution for nebulization, or liquid or tablet for oral administration.
Albuterol is rapidly absorbed: peak plasma concentrations in humans are reached within 10 minutes to 5 hours. It is extensively metabolized in the liver to inactive metabolites.
At therapeutic doses, the effect can persist for 3–12 hours, depending on the route of administration; in cases of overdose, effects can last up to 3 days.
Clinical Findings of Albuterol Toxicosis
Overdose with albuterol can result in sinus tachycardia, arrhythmias (especially premature ventricular contractions), tachypnea, hypertension or hypotension, weakness, shaking, lethargy or agitation, and, rarely, pulmonary edema.
Clinical laboratory findings frequently include hypokalemia, hypophosphatemia, and, potentially, hyperglycemia. These clinical signs usually appear within 1–4 hours of ingestion, but arrhythmias often are delayed.
Treatment of Albuterol Toxicosis
For most cases of albuterol ingestion, decontamination is not recommended. Emesis can be induced if multiple tablets were ingested, the ingestion happened within 1 hour, and the pet is clinically normal. Heart rate, heart rhythm, and blood pressure should be assessed and monitored and an ECG obtained if needed.
Tachycardia can be controlled with a beta blocker such as propranolol (0.02–0.06 mg/kg, IV, to effect, repeated if needed); or with esmolol (0.2–0.5 mg/kg, administered slowly IV or as a CRI at 25–200 mcg/kg per minute, to effect). IV fluids should be given.
Diazepam (0.25–0.5 mg/kg, IV, to effect) can be administered if CNS signs (eg, apprehension, shaking) are present.
Serum electrolytes (ie, potassium and phosphorus) and blood glucose should be assessed and corrected as needed. Hypokalemia secondary to albuterol exposure might require treatment with potassium supplementation. Hypokalemic patients receiving potassium after albuterol exposure have been reported to develop hyperkalemia, even when potassium was supplemented at appropriate dosages; therefore, electrolyte levels must be monitored closely in these patients.
Dextromethorphan Toxicosis in Animals
Dextromethorphan is a nonsedating, nonaddictive, centrally acting opioid cough suppressant. It is available in many OTC cold and cough medications. At the recommended dosage, it enhances the threshold for coughing.
Dextromethorphan is rapidly absorbed orally and converts to the active metabolite dextrorphan in the liver. Cough suppressant activity can last 3–12 hours, depending on the formulation.
Dextromethorphan overdoses can cause CNS and GI effects such as lethargy, ataxia, agitation, hallucination, nervousness, mydriasis, shaking, vomiting, or diarrhea. Hypersensitivity reactions with facial edema or urticaria are possible as well. Some clinical signs are similar to those of serotonin syndrome (agitation, disorientation, hyperthermia, nervousness, shaking).
Treatment is mainly supportive care. Diphenhydramine (1–2 mg/kg, PO, IM, or SC, to desired effect) can be administered for hypersensitivity reactions. Diazepam can be administered to control some of the CNS effects.
Phenothiazine tranquilizers (acepromazine or chlorpromazine) or cyproheptadine (for dogs: 1.1 mg/kg, PO or per rectum; for cats: 2–4 mg/cat, PO or per rectum; for both dogs and cats: repeat once in 6–8 hours if needed) can be administered for serotonin syndrome.
Imidazoline Decongestant Toxicoses in Animals
The imidazoline derivatives oxymetazoline, xylometazoline, tetrahydrozoline, and naphazoline are found in OTC topical ophthalmic and nasal decongestants. They are generally used as topical vasoconstrictors in the nose and eyes for temporary relief of nasal congestion due to colds, hay fever or other upper respiratory allergies, or sinusitis.
Imidazoline decongestants are sympathomimetic agents, with primary effects on alpha-adrenergic receptors and little, if any, effect on beta-adrenergic receptors. Oxymetazoline is readily absorbed orally.
Effects on alpha receptors from systemically absorbed oxymetazoline hydrochloride can persist for up to 7 hours after a single dose. The elimination half-life in humans is 5–8 hours.
Oxymetazoline is excreted unchanged both in urine (30%) and in feces (10%) (1).
Clinical Findings of Imidazoline Decongestant Toxicosis
In dogs, clinical signs of imidazoline decongestant toxicosis include vomiting, bradycardia, cardiac arrhythmias, poor capillary refill time, hypotension or hypertension, panting, increased upper respiratory sounds, depression, weakness, collapse, nervousness, hyperactivity, or shaking. These clinical signs usually appear within 30 minutes to 4 hours after ingestion.
In general, ingestion of imidazoline decongestants can affect the GI, cardiopulmonary, and nervous systems.
Treatment of Imidazoline Decongestant Toxicosis
Decontamination (induction of emesis and administration of activated charcoal) might not be practical to treat imidazoline decongestant toxicosis, because of the rapid absorption and onset of clinical signs.
Heart rate, heart rhythm, and blood pressure should be assessed and an ECG obtained if needed. IV fluids should be given, along with atropine (0.02 mg/kg, IV), if bradycardia is present.
A benzodiazepine (midazolam [0.25–0.5 mg/kg, IV] or diazepam [0.25–0.5 mg/kg, IV]) can be administered if CNS signs (eg, apprehension, shaking) are present. Serum electrolytes (ie, potassium, sodium, chloride) should be assessed and corrected as needed.
Atipamezole, a specific alpha-2 adrenergic antagonist, can be administered for treatment of bradycardia and/or CNS depression at a dosage of 50 mcg/kg, one-fourth IV and the rest IM; it can be repeated in 30–60 minutes if there is no improvement.
Phenylephrine Toxicosis in Animals
Phenylephrine is a sympathomimetic amine with mainly an alpha-1 adrenergic receptor agonist effect, available OTC as a decongestant in oral formulations (5- to 10-mg tablets), nasal sprays, or eye drops (0.25–1%). It has poor oral bioavailability (38%) in humans because of an appreciable first-pass effect and extensive metabolism by monoamine oxidases in the GI tract and liver.
The oral LD50 of phenylephrine in rats is 350 mg/kg, and in mice, 120 mg/kg. Mild clinical signs have been observed at < 10 mg/kg in dogs. The half-life is 2–3 hours.
Vomiting is the most common clinical sign of phenylephrine toxicosis. CNS stimulation, agitation, nervousness, and hypertension are possible; however, these signs are less common with phenylephrine than with pseudoephedrine.
Treatment is mainly supportive care and is similar to that for pseudoephedrine toxicosis.
Pseudoephedrine and Ephedrine Toxicoses in Animals
Pseudoephedrine is a sympathomimetic drug found naturally in plants of the genus Ephedra. Several states in the US limit the availability and use of pseudoephedrine as an OTC decongestant because of its use as a precursor in illegal amphetamine synthesis. It is being replaced with other decongestants, such as phenylephrine.
Pseudoephedrine is a stereoisomer of ephedrine and is available as the hydrochloride or sulfate salt. Both ephedrine and pseudoephedrine have alpha- and beta-adrenergic agonist effects. The pharmacological effects of the drugs are due to the direct stimulation of adrenergic receptors and the release of norepinephrine.
In humans, pseudoephedrine is rapidly absorbed orally. The onset of action is 15–30 minutes, and its effects peak within 30–60 minutes. With extended-release preparations (12–24 hours), onset of clinical signs can be delayed (2–8 hours), and clinical signs can last longer than with regular preparations.
Pseudoephedrine is incompletely metabolized in the liver. Approximately 90% of the drug is eliminated through the kidneys. Renal excretion is accelerated in acidic urine. Elimination half-life varies between 2 and 21 hours, depending on urinary pH.
Clinical Findings of Pseudoephedrine and Ephedrine Toxicoses
Pseudoephedrine and ephedrine overdoses can result in mainly sympathomimetic effects, including agitation, hyperactivity, mydriasis, tachycardia, hypertension, sinus arrhythmias, anxiety, tremors, hyperthermia, head bobbing, hiding, and vomiting.
Clinical signs appear at doses of 5–6 mg/kg. Death can occur at 10–12 mg/kg.
Treatment of Pseudoephedrine and Ephedrine Toxicoses
Treatment of pseudoephedrine toxicosis consists of decontamination, control of the CNS and cardiovascular effects, and supportive care. Emesis should be induced only in clinically normal patients, followed by administration of activated charcoal with a cathartic.
Hyperactivity, nervousness, or seizures can be controlled with acepromazine (0.05–1 mg/kg, IM, IV, or SC), chlorpromazine (0.5–1 mg/kg, IV), phenobarbital (3–4 mg/kg, IV), or pentobarbital to effect.
Diazepam should not be administered, because it can exaggerate hyperactivity. Phenothiazines should be administered with caution because they can lower the seizure threshold, lower blood pressure, and cause bizarre behavioral changes.
Tachycardia can be controlled with propranolol (0.02–0.06 mg/kg, IV, repeated if needed), or with esmolol (0.2–0.5 mg/kg, administered slowly IV or as a CRI at 25–200 mcg/kg per minute). IV fluids should be given.
Acidifying the urine with ammonium chloride (50 mg/kg, PO, every 6 hours) or ascorbic acid (20–30 mg/kg, IM or IV, every 8 hours) can enhance urinary excretion of pseudoephedrine; however, this treatment should be administered with caution, because many of these patients could be acidotic already.
Acid-base status should be monitored if ammonium chloride or ascorbic acid is administered. Electrolytes, heart rate, heart rhythm, and blood pressure should be monitored. Excessive trembling or shaking can cause myoglobinuria; if this occurs, kidney function should be monitored.
Appreciable and persistent hyperthermia due to severe hyperactivity and CNS excitation could result in DIC. Clinical signs of toxicosis can last 1–4 days. The presence of pseudoephedrine in urine can support the diagnosis.
For More Information
ASPCApro: Dextromethorphan Ingestion in Pets.
ASPCApro: Dangers & Veterinary Treatment Options for Cold & Flu Medications in Pets.
Bischoff K. Cold, cough and allergy medications. In: Gupta RC, ed. Veterinary Toxicology Basic and Clinical Principles. 3rd ed. Academic Press; 2018:373-378.
Waratuke K. Decongestants (imidazolines). In: Hovda LR, Brutlag AG, Poppenga RH, Epstein SE, eds. Blackwell's Five-Minute Veterinary Consult Clinical Companion Small Animal Toxicology. 3rd ed. Wiley Blackwell; 2024:303-307.
Gwaltney-Brant S. (2024) Decongestants (pseudoephedrine, phenylephrine). In: Hovda LR, Brutlag AG, Poppenga RH, Epstein SE, eds. Blackwell's Five-Minute Veterinary Consult Clinical Companion Small Animal Toxicology. 3rd ed. Wiley Blackwell; 2024:308-313.
Romelhardt T. Dextromethorphan. In: Hovda LR, Brutlag AG, Poppenga RH, Epstein SE, eds. Blackwell's Five-Minute Veterinary Consult Clinical Companion Small Animal Toxicology. 3rd ed. Wiley Blackwell; 2024:314-318.
Also see pet owner content regarding poisoning from over-the-counter human drugs.
References
Dollery C. Therapeutic Drugs. Churchill Livingstone; 1991.
