Spotlight Commentary: Examining Safety Profiles of Topical Ocular MedicationLorena Karla Šklebar1,2, Robert Likić2,3, Sonja Jandroković1,21 Department of ophthalmology, University Hospital Centre Zagreb, Zagreb, Croatia2 University of Zagreb, School of medicine, Zagreb, Croatia3 Division for clinical pharmacology and therapeutics, Department of internal medicine, University Hospital Centre Zagreb, Zagreb, CroatiaKeywords: eye drops; systemic side effect; ocular side effect; safety profile; topical ocular medicationWord count: 1085Table count: 1Figure count: 0Topical medications are frequently used in treating a wide range of ocular diseases due to their efficiency in delivery directly to the afflicted area. However, localized administration cannot prevent side effects, both local and systemic, which can sometimes be overlooked or underestimated. The aim of this spotlight commentary is to provide a review of safety profiles of topical ocular medications, analysing their effect on the ocular structures as well as their systemic and environmental impacts. 1Although topical ocular medications are designed for localized treatment and are administered directly on the surface of the eye, there is a significant systemic absorption of these drugs through several pathways. The first of two major pathways 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 easily be circumvented by manually providing pressure to the medial canthus or by closing the eyes for 5 minutes after the instillation of each drop, which will cause compression on the nasolacrimal duct. The other major pathway for systemic absorption is through the conjunctiva and conjunctival blood vessels. Minor pathways of systemic drug delivery are through the pharynx, gastrointestinal tract, skin of the cheeks and the eyelids, aqueous humour, and inner ocular tissues. Special care must be taken when treating the paediatric patients who have a much higher risk of developing systemic side effects, due to inadequate dosage and increased systemic permeability of the drugs. 2Localised adverse effects of topical ocular medications commonly arise due to preservatives, which are used in eye drops and ointments in order to prolong their shelf life and guard against microbiological contamination. Benzalkonium chloride (BAC) is the most used preservative in ophthalmic medications. Clinical studies have extensively examined the toxic effects of BAC, revealing that its prolonged use causes time- and dose-dependent cytotoxicity on the ocular surface, leading to tear film instability and the development of ocular surface disease, dry eye, and Meibomian gland dysfunction 3,4. Therefore, the European Medicine Agency recommends avoiding preservatives in patients who have pre-existing ocular surface disease or who develop dry eye or ocular irritation over time. 3Among eye drops, the most commonly discussed side effects, both local (as stated in Table 1) and systemic, in certain groups of topical ocular medications, pertain to antiglaucoma eyedrops, such as β receptor blockers, α receptor agonists and pilocarpine. Due to their chronic usage, physicians must take special care in choosing the right therapy for their patients as well as monitor for potential adverse events. β receptor blockers have a major limitation in their usage due to their frequent systemic side effects, although they are a potent antiglaucoma medications. Targeting β1-receptor causes reduced cardiac contractility and heart rate, bradycardia, and a blood pressure decrease and β2-receptor targeting leads to exacerbated 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 therefore causes fewer side effects to the respiratory system. 5 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.6Excessive use of pilocarpine can also have numerous adverse effects due to its parasympathomimetic action which includes excessive sweating, drooling, bronchospasm, vomiting, diarrhea, stomach-ache, bradycardia, a drop in blood pressure, hallucinations and depression.Special caution also must be taken when prescribing topical ocular or systemic steroid medication. Because of their potential to change the microstructure of the trabecular meshwork, they can induce a rise in intraocular pressure by decreasing aqueous humour outflow and potentially causing the development of 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.Another group of eye drops which can have substantial systemic effects are mydriatics, such as phenylephrine and atropine. Phenylephrine, a selective α1-receptor, is applied in the form of eye drops for dilating the pupils during ophthalmological examinations. Due to its sympathomimetic effect it can cause major cardiovascular side effects, especially when administered in patients with pre-existing hypertension conditions.7 Atropine is a muscarinic receptor antagonist often used in ophthalmology in the form of eye drops for its mydriatic and cycloplegic effect. When systemically absorbed, it can potentially cause side effects like mouth and eye dryness, flushed skin and face, fever, tachycardia, delirium or restlessness, urinary retention, and constipation. If used in higher doses or over a longer period, in severe cases, central anticholinergic syndrome may occur, which is 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. This necessitates careful monitoring of patients on long-term topical therapies for any alterations in choroidal structure because of their potential effect on visual function.9Other eyedrops, such as antiallergics, can also be sometimes used in treating eye conditions. Topical H1-receptor blockers and mast cell stabilizers in the form of antiallergic eye drops 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.7The environmental effect is another part of pharmaceutical safety profiles which 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 Other than the drug itself, its packaging can also cause substantial waste, as is the case with monodose eye drops. These eyedrops are stored in small single-use containers, in order to prevent microbial growth which can occur in standard eye drop bottles after opening. However, their disposal creates a lot of waste. 11 Pharmaceutical companies should provide education and raise awareness among healthcare providers and patients about how to properly manage pharmaceutical waste.In conclusion, although topical ocular medication is the foundation of ophthalmic treatment, before prescribing physicians must be aware of their safety profiles. Although they are generally considered safe, their potential adverse effects on ocular and systemic health highlights challenges in the management of ocular diseases. Healthcare practitioners should choose preservative-free formulations where possible, monitor for both local and systemic side effects, and act responsibly while taking into consideration the environmental implications of pharmaceutical use. These safety concerns should be further investigated in future studies with the goal of improving therapeutic outcomes for patients while minimizing risks.
