Toxicities from Over-the-Counter Drugs

Toxicities from Over-the-Counter Drugs

Human drugs or nutritional supplements available without a prescription are known as over-the-counter (OTC) medications. Exposures to OTC drugs in pets can be accidental or intentional. A valid client-patient-veterinarian relationship must exist for veterinarians to recommend extra-label use of these drugs to their clients. Safety of most OTC drugs has not been determined in animals, as most are not approved for veterinary use by the FDA. Veterinarians should understand the potential risks of using OTC medications and communicate them to their clients.

COLD AND COUGH MEDICATIONS (TOXICITY)

ANTIHISTAMINES

Antihistamines are H1-receptor antagonists that provide symptomatic relief of allergic 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- or second-generation (also called non-sedating) antihistamines. First-generation antihistamines may cause adverse effects because of their cholinergic activity and ability to cross the blood-brain barrier. Second-generation antihistamines are more lipophobic than first-generation antihistamines and are thought to lack CNS and cholinergic effects at therapeutic doses. Antihistamines are often found in combination with other ingredients in many OTC cold, sinus, and allergy medications.

Chlorpheniramine is a first-generation propylamine-derivative antihistamine. Oral absorption of chlorpheniramine in dogs is rapid and complete, reaching peak plasma concentrations in 30–60 min. Chlorpheniramine maleate undergoes substantial first-pass effect. Chlorpheniramine and its metabolites are primarily excreted in urine. The recommended dose in cats and dogs is 1–2 mg and 2–8 mg respectively, PO, bid-tid. Mild clinical signs such as depression and GI upset have been reported for dosages <1 mg/kg. Significant clinical signs such as ataxia, tremors, depression or hyperactivity, hyperthermia, and seizures may be seen within 6 hr of ingestion of large amounts.

Dimenhydrinate and diphenhydramine are first-generation ethanolamine-derivative antihistamines. Dimenhydrinate is used for its antiemetic effects and for prevention of motion sickness in dogs and cats. Diphenhydramine is well absorbed orally in people, but undergoes first-pass metabolism in the liver with only 40–60% of the drug reaching the systemic circulation. Peak plasma concentrations of ethanolamine-derivative antihistamines occur within 1–5 hr; elimination half-lives vary from 2.4–10 hr. A recommended dose for dimenhydrinate and diphenhydramine in cats and dogs is 4–8 mg/kg and 2–4 mg/kg, respectively. Hyperactivity or depression, hypersalivation, tachypnea, and tachycardia are the most common adverse signs reported with these antihistamines, generally within 1 hr of exposure.

Promethazine hydrochloride is an ethylamino derivative of phenothiazine and first-generation antihistamine used for the management of motion sickness. Promethazine is widely distributed in body tissues and readily crosses the placenta. Overdoses may result in CNS depression or excitation. CNS depression was reported in a dog 30 min after ingesting 1 mg/kg of promethazine.

Meclizine is a first-generation piperazine-derivative antihistamine commonly used as an antiemetic. Peak plasma concentrations occur within 2–3 hr of oral administration. Meclizine is primarily excreted as metabolites in urine, with a reported serum half-life of 6 hr. In cases involving <33 mg/kg of meclizine in dogs, only mild hyperactivity or depression has been reported.

Loratadine is a tricyclic long-acting antihistamine with selective peripheral histamine H1-receptor antagonist activity. In humans, loratadine is well absorbed orally and extensively metabolized to an active metabolite. Most of the parent drug is excreted unchanged in the urine. The mean elimination half-life in humans is 8.4 hr. Loratadine appears to have a large margin of safety in laboratory animals. No deaths were reported at oral doses up to 5 g/kg in rats and mice. In rats, mice, and monkeys, no clinical signs were observed at 10 times the maximum recommended human daily oral dose.

Cetirizine, a major metabolite of hydroxyzine, is a piperazine derivative nonsedating antihistamine now available OTC. It selectively inhibits peripheral H1 receptors and does not have significant anticholinergic or antiserotonergic effects when used at the recommended dosage. The recommended dosage for histamine-mediated pruritic conditions in dogs is 1 mg/kg, PO, sid-bid and 5 mg, PO, bid for cats. The drug appears to be well tolerated in dogs and cats. The minimum lethal dosage is 237 mg/kg in mice and 562 mg/kg in rats. Adverse reactions include vomiting, hypersalivation, sedation, drowsiness, and occasionally hyperactivity.

Treatment

Treatment of antihistamine toxicosis is primarily symptomatic and supportive. Emesis should only be considered in asymptomatic patients. Activated charcoal may be useful for recent ingestion. Cardiovascular function and body temperature should be closely monitored. Diazepam can be used to control seizures or seizure-type activity. Physostigmine is recommended to counteract the CNS anticholinergic effects of antihistamine overdoses in people, although the risk of seizures associated with this drug may limit its use. IV fluids should be given as needed.

DEXTROMETHORPHAN

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. It is rapidly absorbed orally and converts to the active metabolite dextrorphan in the liver. Cough suppressant activity can last 3–12 hr, depending on the formulation. Overdoses can cause CNS and GI effects such as agitation, hallucination, nervousness, mydriasis, shaking, vomiting, or diarrhea. Some clinical signs may be similar to serotonin syndrome (agitation, nervousness, shaking). Treatment is mainly supportive care. Diazepam can be used to control some of the CNS effects. Phenothiazine tranquilizers (acepromazine or chlorpromazine) or cyproheptadine can be given for serotonin syndrome.

IMIDAZOLINE DECONGESTANTS

The imidazoline derivatives, oxymetazoline, xylometazoline, tetrahydrozoline, and naphazoline are found in topical ophthalmic and nasal decongestants available OTC. 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.

Imidazolines are sympathomimetic agents, with primary effects on α-adrenergic receptors and little if any effect on β-adrenergic receptors. Oxymetazoline is readily absorbed orally. Effects on α-receptors from systemically absorbed oxymetazoline hydrochloride may persist for up to 7 hr after a single dose. The elimination half-life in humans is 5–8 hr. It is excreted unchanged both by the kidneys (30%) and in feces (10%).

Clinical Findings

In dogs, signs of intoxication may include vomiting, bradycardia, cardiac arrhythmias, poor capillary refill time, hypotension or hypertension, panting, increased upper respiratory sounds, depression, weakness, nervousness, hyperactivity, or shaking. These signs appear within 30 min to 4 hr postexposure. In general, imidazoline decongestant exposure may affect the GI, cardiopulmonary, and nervous systems.

Treatment

Decontamination may not be practical due to the rapid absorption and onset of clinical signs. Heart rate and rhythm and blood pressure should be assessed, and an ECG obtained if needed. IV fluids should be given, along with atropine at 0.02 mg/kg, IV, if bradycardia is present. Diazepam (0.25–0.5 mg/kg, IV) can be given if CNS signs (eg, apprehension, shaking) are present. Serum electrolytes (ie, potassium, sodium, chloride) should be assessed and corrected as needed. Yohimbine, which is a specific α2-adrenergic antagonist, can also be used at 0.1 mg/kg, IV, and repeated in 2–3 hr if needed. If yohimbine is not available, atipamezole can be used at 50 μg/kg, 1/4th IV and the rest IM; it can be repeated in 30–60 min if there is no improvement.

PHENYLEPHRINE

Phenylephrine is an α1-adrenergic receptor agonist available OTC as a decongestant in oral formulations, nasal sprays, or eye drops. It has poor oral bioavailability due to a significant first-pass effect and extensive metabolism by monoamine oxidases in the GI tract and liver. The half-life is 2–3 hr. CNS stimulation, agitation, nervousness, and hypertension are possible but are less frequent with phenylephrine than with pseudoephedrine. Treatment is mainly symptomatic care and is similar to that for pseudoephedrine toxicosis .

PSEUDOEPHEDRINE AND EPHEDRINE

Pseudoephedrine is a sympathomimetic drug, which occurs naturally in plants of the genus Ephedra. Several states in the USA have limited the availability and use of pseudoephedrine as an OTC decongestant due to 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 α- and β-adrenergic agonist effects. The pharmacologic effects of the drugs are due to direct stimulation of adrenergic receptors and the release of norepinephrine.

In humans, pseudoephedrine is rapidly absorbed orally. The onset of action is 15–30 min, with peak effects within 30–60 min. It 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 2–21 hr, depending on urinary pH.

Clinical Findings

Pseudoephedrine and ephedrine overdose can result in mainly sympathomimetic effects including agitation, hyperactivity, mydriasis, tachycardia, hypertension, sinus arrhythmias, anxiety, tremors, head bobbing, hiding, and vomiting. Clinical signs can be seen at 5–6 mg/kg and death may occur at 10–12 mg/kg.

Treatment

Treatment of pseudoephedrine toxicosis consists of decontamination, controlling the CNS and cardiovascular effects, and supportive care. Vomiting should be induced, followed by administration of activated charcoal with a cathartic. If the animal's condition contraindicates induction of emesis, a gastric lavage with a cuffed endotracheal tube should be performed. Hyperactivity, nervousness, or seizures can be controlled with acepromazine (0.05–1.0 mg/kg, IM, IV, or SC), chlorpromazine (0.5–1.0 mg/kg, IV), phenobarbital (3–4 mg/kg, IV), or pentobarbital to effect. Diazepam should be avoided as it can exaggerate hyperactivity. Phenothiazines should be used with caution as they can lower the seizure threshold, lower blood pressure, and cause bizarre behavioral changes. Tachycardia can be controlled with propranolol at 0.02–0.04 mg/kg, IV, repeated if needed, or with esmolol at 0.2–0.5 mg/kg, given slowly IV or as a constant-rate infusion at 25–200 μg/kg/min. IV fluids should be given. Acidifying the urine with ammonium chloride (50 mg/kg, PO, qid) or ascorbic acid (20–30 mg/kg, IM or IV, tid) may enhance urinary excretion of pseudoephedrine. Acid-base status should be monitored if ammonium chloride or ascorbic acid is given. Electrolytes, heart rate and rhythm, and blood pressure should be monitored. Excessive trembling or shaking can cause myoglobinuria; if this occurs, kidney function should be monitored. Clinical signs of toxicosis can last 1–4 days. The presence of pseudoephedrine in urine can support the diagnosis.