Toxicity refers to the adverse effects of either medications or environmental chemicals, including poisoning. Toxicity may be influenced by pharmacokinetics and/or pharmacodynamics (the biochemical and physiological effects of a drug/agent). For example, topically applied ophthalmic medications are readily absorbed through the mucous membranes of the eye and nasopharynx, as well as through the iris and ciliary body. Topical absorption avoids the first-pass metabolism of the liver and increases systemic bioavailability. Therefore, the systemic toxicity of these medications may be greater than expected relative to the total topical dose.
The importance of pharmacokinetics and its influence on potential toxicity can be illustrated by the pediatric population. Drug metabolism and excretion are less developed in neonates and infants than in adults. For example, in early neonatal life, the drug-metabolizing activities of the cytochrome P450–dependent, mixed-function oxidases and the conjugating enzymes are approximately 50%–70% of those in adults. A second example is the formation of glucuronide, which does not reach adult levels until the third or fourth year of life. Similarly, the glomerular filtration rate is low in young infants, reaching the adult value by 6–12 months of life. Therefore, drug doses and dosing schedules must be adjusted appropriately in pediatric populations to avoid toxicity.
Local toxicity of topical drugs is more common than systemic toxicity. Local toxicity may be a type I immunoglobulin E (IgE)–mediated hypersensitivity reaction, or it may represent a delayed hypersensitivity reaction to either the medication itself or its associated preservatives.
Preservatives and toxicity
Preservatives commonly used in ophthalmic preparations include quaternary cationic surfactants such as benzalkonium chloride and benzododecinium bromide; mercurial agents such as thimerosal, chlorobutanol, and parahydroxybenzoates; and aromatic alcohols. The preservatives used in ophthalmic solutions can be toxic to the ocular surface following topical administration; they can also enhance the corneal permeability of various drugs.
Preservatives have been developed that use different methods to reduce the toxic effect on the ocular surface. One method allows the preservative to dissipate upon exposure to light or to the ions in the tear film. Two examples of preservatives using this method are stabilized oxychloro complex, which breaks down to sodium chloride and water, and sodium perborate, which breaks down to hydrogen peroxide before becoming oxygen and hydrogen. Theoretically, these “disappearing preservatives” should have no toxic effect on the corneal surface.
Other preservative systems may be less toxic to the ocular surface than quaternary cationic surfactants such as benzalkonium chloride. One such system is an ionic buffer containing borate, sorbitol, propylene glycol, and zinc that breaks down into innate elements upon encountering the cations in the tear film. Polyquaternium-1, another preservative system, is a cationic polymer of quaternary ammonium structures that lacks a hydrophobic region. Although polyquaternium-1 is a detergent, human corneal epithelial cells tend to repel the compound.
To completely eliminate toxicity from preservatives, some topical ophthalmic products are available preservative-free, in single-use containers.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.