Spotlight commentary: Safety and sustainability of eye drops—More than meets the eye

Abstract

Topical medications are frequently used in treating a wide range of ocular diseases due to their efficiency in delivering treatment directly to the affected area. With modern advancements in the pharmaceutical industry, eye drops have become indispensable, safe and effective tools in day-to-day practice for treating a broad variety of ocular conditions. However, because of their extensive and frequent use, clinicians can sometimes overlook or underestimate that localized administration cannot entirely prevent side effects, both local and systemic. The aim of this spotlight commentary is to review the safety profiles of eye drops, analysing their effect on ocular structures as well as their systemic and environmental impacts by drawing together content recently published in the journal and placing this in the context of contemporaneous work in other journals.¹

Although topical ocular medications are designed for localized treatment and are administered directly to the surface of the eye, significant systemic absorption of these drugs can occur through two major pathways. The first is from the lacrimal sac through the nasolacrimal duct into the nasopharynx, where drugs can be systemically absorbed through the nasal mucosa. This pathway can be easily circumvented by manually applying pressure to the medial canthus or by closing the eyes for 5 min after instillation, which will compress the nasolacrimal duct. The second major pathway is through the conjunctiva and conjunctival blood vessels. Special care must be taken when treating paediatric patients, as they have a much higher risk of developing systemic side effects, due to inadequate dosage and increased systemic permeability of the drugs.²

Localized adverse effects of topical ocular medications commonly arise due to preservatives used in eye drops and ointments to prolong their shelf life and prevent microbiological contamination. Benzalkonium chloride (BAC) is the most commonly used preservative in ophthalmic medications. Clinical studies have revealed that prolonged use causes time- and dose-dependent cytotoxicity on the ocular surface, leading to tear film instability and development of ocular surface disease, dry eye and Meibomian gland dysfunction.^{3, 4} Therefore, the European Medicine Agency recommends avoiding preservatives in patients with pre-existing ocular surface disease or those who develop dry eye or ocular irritation over time.³

Among eye drops, the most commonly discussed side effects, both local (as discussed in Table 1) and systemic, pertain to antiglaucoma eye drops, which are used to treat glaucoma. Due to their chronic use, physicians must take special care in choosing the right therapy for their patients and monitor for potential adverse events. Β-receptor blockers are potent antiglaucoma medications, but they have significant limitations due to their frequent systemic side effects. Targeting β₁-receptors reduces cardiac contractility and heart rate, leading to bradycardia, and a decrease in blood pressure while targeting β₂-receptors exacerbates asthma and chronic obstructive pulmonary disease symptoms. Additionally, central nervous system symptoms such as headaches, depression and confusion may occur. Betaxolol is a selective β₁-receptor antagonist, which causes fewer side effects on the respiratory system.⁶ When α₂ adrenergic agonists are applied, systemic side effects such as dry mouth, dizziness, fatigue and drowsiness may occur, particularly in patients predisposed to bradycardia.⁵ Excessive use of pilocarpine can also result in numerous adverse effects due to its parasympathomimetic action including excessive sweating, drooling, bronchospasm, vomiting, diarrhoea, stomachache, bradycardia, hypotension, hallucinations and depression.

Special caution must also be taken when prescribing topical ocular or systemic steroid medication for patients with uveitis or any other type of inflammatory ocular disorders. Due to their potential to alter the microstructure of the trabecular meshwork, steroids can induce a rise in intraocular pressure by decreasing aqueous humour outflow, potentially leading to steroid induced glaucoma. Prolonged use of topical corticosteroids can also induce cataract formation and increase susceptibility to infection. If used in eyes with epithelial defects, they can inhibit growth factors and delay wound healing. These side effects can develop within weeks, months or years of steroid therapy.

Another group of eye drops with substantial systemic effects is mydriatics, such as phenylephrine and atropine. Phenylephrine, a selective α₁-receptor agonist, is applied in the form of eye drops to dilate pupils during ophthalmological examinations. Due to its sympathomimetic effects, it can cause significant cardiovascular side effects, especially in patients with pre-existing hypertension.⁷ Atropine, a muscarinic receptor antagonist, is often used in ophthalmology in the form of eye drops for its mydriatic and cycloplegic effects. When systemically absorbed, it can cause side effects such as dry mouth and eye, flushed skin, fever, tachycardia, delirium, restlessness, urinary retention and constipation. In higher doses or with prolonged use, severe cases of central anticholinergic syndrome may occur, characterized by confusion, agitation and hallucinations.⁸ Mydriatics also affect inner ocular structures: Phenylephrine is linked with a decrease in choroidal thickness, while atropine eye drops are associated with an increase in choroidal thickness.⁹ The mentioned side effects necessitate careful monitoring of patients on long-term topical mydriatic therapies, initially on a weekly basis and later monthly, due to their potential effects on visual function and systemic health. Other eye drops, such as antiallergics (topical H1-receptor blockers and mast cell stabilizers) infrequently cause systemic side effects following ocular use. When they do occur, these side effects are usually mild, presenting as dry mouth, nausea, headache or drowsiness.⁷ Antibiotic ocular medications are mainly prescribed for short-term use, and side effects are rare, with the most common being allergic reactions to antibiotic or toxic reactions to preservatives. However, prescribers should keep in mind that topical ocular administration of chloramphenicol can lead to severe hepatic and hematologic disorders as well as atrophy of the maculopapular bundle.

The environmental impact is another part of pharmaceutical safety profiles that cannot be disregarded. Inappropriate disposal of drugs, including eye medications, poses a significant risk to public health and environmental sustainability by contaminating water supplies and disrupting ecosystems.¹⁰ Beyond the drug itself, its packaging can also cause substantial waste, as seen with monodose eye drops. These eye drops are stored in small single-use containers, to prevent microbial growth, which can occur in standard eye drop bottles after opening. However, their disposal creates a considerable amount of waste.¹¹ Pharmaceutical companies should provide education and raise awareness among healthcare providers and patients about the proper management of pharmaceutical waste.

In conclusion, although topical ocular medication is the foundation of ophthalmic treatment, physicians must be aware of their safety profiles before prescribing. While generally considered safe, the potential adverse effects on ocular and systemic health present challenges in the management of ocular diseases. Prescribers should consult the European Medicines Agency's summaries of product characteristics (SmPC) for detailed information on using medicines safely and effectively. Special care must be taken when prescribing long-term therapy for patients with chronic ocular conditions, such as glaucoma or uveitis. Healthcare practitioners should choose preservative-free formulations where possible, monitor for both local and systemic side effects and act responsibly by considering the environmental implications of pharmaceutical use. These safety concerns should be further investigated in future studies to improve therapeutic outcomes for patients while minimizing risks.