Central Nervous System Depression After Topical Administration of Brimonidine Eye Drops to Induce Vomiting in a Cat

ABSTRACT

Brimonidine stimulates the chemoreceptor trigger zone via alpha‐2 adrenergic receptors in the postrema of the medulla, which triggers vomiting in cats. This case report details the occurrence of central nervous system (CNS) depression following brimonidine administration to induce vomiting in a cat that had ingested a toxic substance. A 12‐year‐old neutered male American Shorthair cat was presented to the hospital after ingesting two leaves of Anthurium polyschistum, which is toxic to cats. 0.15% of brimonidine eye drops intended for ocular administration were accidentally administered onto the upper eyelids, resulting in the administration of four drops in total. Three incidents of projectile vomiting were then observed 30 min after the brimonidine administration. The cat began to show signs of CNS depression, including deep sedation and respiratory depression after vomiting. Brimonidine use was the suspected aetiology of the CNS depression. Atipamezole (200 µg/kg) was administered intramuscularly; after 5 min, the clinical signs of the CNS depression resolved. This case suggests that while brimonidine may serve as an effective emetic agent in feline patients, its systemic effects, particularly CNS depression, warrant careful monitoring. The potential impact of higher concentrations and increased dosing volume remains uncertain, highlighting the need for further research to establish safe and standardized dosing guidelines.

A 12‐year‐old neutered male American Shorthair cat was presented to the hospital after ingesting toxic plants to cats. Brimonidine instillation was performed to induce vomiting. Three incidents of projectile vomiting were then observed 30 min after the brimonidine administration. After that, the cat began to show signs of central nervous system (CNS) depression, including deep sedation and respiratory depression. Atipamezole (200 µg/kg) was administered intramuscularly, and after 5 min, the clinical signs of the CNS depression resolved.

1. Introduction

Brimonidine, an alpha‐2 adrenergic receptor agonist, stimulates the chemoreceptor trigger zone (CRTZ) via alpha‐2 adrenergic receptors in the medullary postrema (Colby et al. 1981; Hikasa et al. 1989), and substance P binding to the neurokinin 1 receptor (NK1R) in the stimulated CRTZ activates the final common emetic pathway (Okafor et al. 2017). Brimonidine, used to treat open‐angle glaucoma and ocular hypertension via eye drops, can elicit systemic effects through absorption via the conjunctival and nasolacrimal mucosa, and the experimental off‐label use of brimonidine to induce vomiting and sedation in healthy cats has been investigated (Ogata et al. 2017; Kanda et al. 2020). However, caution may be necessary with the off‐label use of brimonidine because it is difficult to predict the intensity of systemic effects resulting from the absorption of eye drops. This case report details the development and treatment of severe central nervous system (CNS) depression in a cat with toxic ingestion after inadvertently applying additional eye drops while instilling brimonidine to induce vomiting.

2. Case Summary

A 12‐year‐old neutered male American Shorthair cat was presented to the hospital after ingesting two leaves of Anthurium polyschistum, which is toxic to cats (Severino 2009). The exact time of ingestion could not be determined; however, it was supposedly within 6 h before presentation. At presentation, the cat was alert and had a normal body condition score. Physical examination and blood tests suggested no remarkable findings. The initial vital signs were as follows: heart rate, 180 beats/min; systolic blood pressure, 120 mmHg; and respiratory rate, 36 breaths/min.

Due to concerns about stress associated with injectable emetic agents, brimonidine ophthalmic solution was chosen as a less invasive alternative for inducing emesis. An initial attempt was made to instill a drop of 0.15% brimonidine into each eye; however, the drops landed on the upper eyelids instead. Additional brimonidine was administered, and simultaneously, the drops that had fallen onto the eyelids entered the eye. As a result, a total of four drops were instilled.

Thirty minutes after the administration of the brimonidine drops, three incidents of projectile vomiting were observed. Contents presumed to be plants were not confirmed in the vomit contents. Maropitant (1 mg/kg) was administered subcutaneously to prevent further vomiting. One hour later, another vomiting was observed as the veterinarian attempted to conduct thoracic radiographs of the patient.

The cat began to show signs of CNS depression, which progressively worsened after the incidence of vomiting. Originally, the cat did not wear a neck collar and disliked being touched; however, the patient showed less mobility and was unresponsive to constant stimulation after vomiting. Approximately 80 min after the instillation of brimonidine, the cat showed severe CNS depression and respiratory depression (Figure 1). At this time, the vital signs were markedly altered, with a heart rate of 90 beats/min, systolic blood pressure of 200 mmHg, and a respiratory rate of 15 breaths/min. Since the brimonidine use was the suspected aetiology for CNS depression, atipamezole (200 µg/kg), an α‐2 adrenergic antagonist, was administered. The antagonist was administered 90 min after brimonidine instillation. Five minutes after atipamezole administration, the cat fully recovered from CNS depression and could enter the cage by itself. The patient was discharged from the hospital as it had recovered and was in good condition.

FIGURE 1.

Cat with severe central nervous system depression after brimonidine instillation.

The cat ingested leaves of a plant belonging to the Aroid family, which can cause irritation of the oral mucosa, vomiting, regurgitation, difficulty in breathing, gastrointestinal disorders and neurological symptoms (Pedaci et al. 1999; Dip et al. 2004). Therefore, close monitoring for 2–3 days was required. Oral N‐acetylcysteine (20 mg/kg), chlorpheniramine (1 mg/cat), metronidazole (15 mg/kg) and famotidine 0.5 mg/kg were prescribed twice a day for 3 days. Maropitant (2 mg/kg) was prescribed once daily for 3 days. The cat visited the hospital 3 days and 2 weeks later, respectively, during which the patient's appetite, urination, bowel movements, vitality or blood and oral examination results were unremarkable. Mild gastroenteritis was confirmed on abdominal ultrasonography, oral medication was prescribed for an additional 3 days, and treatment was completed.

3. Discussion

Brimonidine, an ophthalmic alpha‐2 adrenergic receptor agonist, is primarily used for managing open‐angle glaucoma and ocular hypertension in human medicine (Cantor 2006; Bakheit et al. 2023). While it is occasionally used in veterinary medicine, its off‐label application as an emetic in cats remains poorly documented, with limited studies exploring its safety and efficacy (Ogata et al. 2017; Kanda et al. 2020; Lee and Odunayo 2022). In the present case, a 12‐year‐old neutered male American Shorthair cat was presented after ingesting a toxic plant (Anthurium polyschistum). Due to concerns about inducing emesis with injectable agents, brimonidine eye drops were chosen as an alternative. However, an accidental administration of four drops of 0.15% brimonidine resulted in three episodes of projectile vomiting within 30 min, followed by progressive CNS depression requiring intervention with atipamezole. This case highlights both the potential efficacy of brimonidine in inducing emesis and the risk of severe systemic effects, reinforcing the need for cautious use and further research into its safety profile.

Conventional emetic agents, including morphine, hydromorphone, dexmedetomidine and xylazine, have demonstrated variable efficacy in cats, ranging from 51% to 81%, with administration routes such as oral transmucosal and intramuscular injections often inducing significant stress (Thawley and Drobatz 2015; Willey et al. 2016; Nystrom et al. 2019; Lee and Odunayo 2022). Given these limitations, brimonidine has been proposed as a less stressful alternative. Previous studies have reported high emetic efficacy (80%–100%) when one to two drops of 0.1% brimonidine ophthalmic solution (58.6 ± 3.3 µg per drop) were administered to both eyes (Ogata et al. 2017; Kanda et al. 2020). Despite these findings, brimonidine is neither an approved nor a standard emetic agent in feline medicine, and the literature regarding its safety and efficacy in this setting remains minimal.

A major concern associated with brimonidine administration is systemic absorption leading to adverse effects. Although its primary mechanism involves reducing intraocular pressure, systemic absorption can occur via the conjunctiva and nasolacrimal mucosa, leading to side effects such as hypertension, hypotension, bradycardia, vomiting, sedation, and CNS depression (Gould and McLellan 2014; Ogata et al. 2017; Plumb 2018b). In the present case, sedation and respiratory depression developed approximately 80 min post‐administration, necessitating the use of atipamezole for reversal.

Brimonidine binds to alpha‐2 adrenergic receptors more selectively than other drugs, such as apraclonidine and clonidine. Furthermore, its affinity to the alpha‐2 adrenergic receptor is 1000‐fold higher than that to alpha‐1 adrenergic receptors (Plumb 2018b). After ocular administration of a 0.1%, 0.15% or 0.2% brimonidine solution, the plasma concentrations peak within 0.5–2.5 h, and the systemic half‐life decreases for approximately 2 h (Plumb 2018b). Brimonidine eye drops are absorbed through the conjunctiva, cornea and mucosa of the nasal cavity and reach the systemic circulation. Systemically delivered brimonidine stimulates CRTZ via alpha‐2 adrenergic receptors in the postrema of the medulla (Colby et al. 1981; Hikasa et al. 1989). The binding of substance P to NK1R in the stimulated CRTZ induces vomiting in cats by activating the final common emetic pathway (Okafor et al. 2017). In addition, systemically absorbed brimonidine passes through the blood‐brain barrier (BBB) and affects the CNS via α2‐adrenergic receptors, producing sedative effects (Ogata et al. 2017). The important point is that because CRTZ exists outside the BBB, vomiting occurs before CNS effects, and CNS effects that appear after crossing the BBB may appear relatively later than vomiting. Ogata et al. (2017) reported on the sedative and physiological effects of 0.1% brimonidine in healthy cats showed that two drops of intraocular brimonidine caused vomiting in five of six cats between 9 and 38 min after administration, and all cats showed remarkable sedation between 60 and 120 min (Ogata et al. 2017). In this case, vomiting occurred 30 min after the instillation of brimonidine, and CNS depression occurred approximately 80 min after the instillation of brimonidine.

The present case exhibited profound sedation and respiratory depression following brimonidine administration, prompting investigation into the potential contributing factors. One plausible explanation is the unintentional administration of four drops instead of two, leading to an increased systemic burden. However, previous pharmacokinetic studies indicate that simultaneous administration of multiple drops does not necessarily result in a proportional increase in systemic absorption, as the dilution effect of tears limits further absorption (Sebbag et al. 2019). Another possible explanation is the higher concentration (0.15%) used in this case compared to the 0.1% brimonidine solution employed in previous studies, suggesting dose‐dependent systemic effects (Ogata et al. 2017). At the time of administration, the authors did not anticipate that this difference in concentration would have a clinically significant impact on systemic effects. However, given the observed progression of CNS depression in this case, it is possible that the higher concentration contributed to increased systemic absorption or prolonged effects.

Brimonidine‐induced adverse effects, including bradycardia, hypertension, sedation, and CNS depression, necessitate prompt recognition and intervention. If CNS effects occur following vomiting, delays in treatment could lead to severe complications. In this case, atipamezole, an alpha‐2 adrenergic antagonist, was successfully administered to reverse the CNS depression. Atipamezole functions by competitively inhibiting alpha‐2 adrenergic receptors and is commonly used as a reversal agent for alpha‐2 adrenergic agonists such as medetomidine, dexmedetomidine, xylazine, clonidine, and brimonidine (Plumb 2018a). The present case demonstrated effective reversal of CNS depression with intramuscular administration of 200 µg/kg atipamezole, suggesting that this approach may be considered in similar scenarios.

Brimonidine eye drops may be a viable alternative for inducing emesis in feline patients, but their use requires careful consideration due to challenges in dose regulation and the potential for systemic toxicity. This case demonstrated successful emesis induction with brimonidine but also highlighted the risk of significant CNS depression, suggesting that close monitoring is essential when using this agent. Given the limited literature on its safety and efficacy in cats, further studies are needed to assess its clinical applicability, optimal dosing parameters, and risk‐benefit profile. Until more data become available, brimonidine should be considered with caution and only when conventional emetic agents are deemed unsuitable.

Author Contributions

Dalhae Kim: investigation, writing – original draft. Jaehan Jun: investigation, writing – review and editing. Eunbin Park: investigation, review and editing. Joohyun Jung: investigation, writing – review and editing. Won‐gyun Son: supervision, writing – review and editing.

Ethics Statement

The authors confirm that they have complied with the journal's ethics policy as stated on the journal's Author Guidelines page. This review article does not require ethical approval as it is a case review without original research data.

Conflicts of Interest

The authors declare no conflicts of interest.

Peer Review

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1002/vms3.70282.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.