2 Ocular drug delivery and toxicology

Part 2

Ocular drug delivery and toxicology

Frederick T. Fraunfelder MD

Drug delivery to the eye is a complex process. The eye is unique in the body in many ways that affect its pharmacology and toxicology. It includes several different cell types, and functions basically as a self-contained system. The rate and efficacy of drug delivery differ in healthy and diseased eyes. Variables affecting delivery include age, genetic ancestry and route of administration. The complexities of delivery, toxicology or both are greatly influenced by patient compliance, especially in the management of glaucoma, which requires multiple topical ocular medications to be given at one sitting each day, often multiple times daily. Each time and method of drug delivery modifies the therapeutic and toxicological response.

Ocular toxicology is dependent on the concentration of the drug, frequency of application, speed of removal, and whether the drug reaches sensitive cells such as the corneal endothelium, lens epithelium or macula in toxic concentrations. Of equal importance is the vehicle for delivery and the pH, buffering systems and preservatives necessary for optimum drug delivery. Each adds its own potentially toxic effect to this complex picture. Originally, much of ocular pharmacology and toxicology was conducted by trial and error, often with local corner pharmacies compounding medications. Today the ocular pharmaceutical industry is acutely aware of potential problems and is continuously researching and producing medications, usually with fewer side effects and delivered by better medications.

Topical Ocular Administration

This is by far the most commonly used method of drug delivery to the eye. Topically administered medications are convenient, easy to reapply and relatively inexpensive. This method concentrates the pharmacological activity of the drug on/in the eye while limiting systemic reactions. Local toxic responses are increased, however, especially with lifelong use as with glaucoma medications. Unlike medication given orally, topical ocular medications reach systemic circulation while avoiding the first-order pass effect through the liver. A drug absorbed through the nasal mucosa or conjunctiva “drains” to the right atrium and ventricle. The blood containing the drug is then pumped to the head before returning to the left atrium and ventricle. The second passage is through the liver, where the primary detoxification occurs before going to the right atrium. When medications are orally administered, the first pass includes absorption from the gut through the liver, where, depending on the drug, up to 90% of the agent is detoxified before going to the right atrium. Thus oral medications are metabolized during the first pass, while ocularly or nasally administered drugs are not metabolized until the second pass. This is the reason why therapeutic blood levels, and accompanying systemic side effects, may occur from topical ocular medications. Other factors include racial differences in metabolism, as with timolol. One percent of people with Japanese or Chinese genetic ancestry, 2.4% of African Americans and 8% of those with European ancestry do not have the p-450 enzyme CYP2D6 that is necessary to metabolize this drug. The lack of this enzyme significantly enhances systemic blood levels of timolol (Edeki et al 1995).

Basic Pharmacology and Toxicology of Topical Medications

Ocular toxicology is based on pharmacokinetics – how the drug is absorbed, including its distribution, metabolism and elimination – as well as pharmacodynamics, the action of the drug on the body. This bioavailability is influenced by age, body weight, sex and eye pigmentation. It is also affected by the disease process, interactions with other drugs and mode of delivery. Only a small percentage of any topically applied drug enters the eye. At best, 1–10% of topical ocular solutions are absorbed by ocular tissues (Schoenwald 1985). This absorption is governed by ocular contact time, drug concentration, tissue permeability and characteristics of the cornea and pericorneal tissue. Nearly all solutions will leave the conjunctival sac, or cul-de-sac, within 15–30 seconds of application (Shell 1982). The average volume of the cul-de-sac is 7 µL, with one additional µL in the precorneal tear film (Mishima et al 1966). The cul-de-sac may hold 25–30 µL of an eye drop; however, blinking will decrease this volume markedly and rapidly, so that at most only 10 µL remain for longer than a few seconds. The drop size of commercial drugs varies from 25 µL to more than 56 µL (Mishima et al 1966). In a healthy eye, one not affected by disease, lid manipulation to instill the drug will double or triple the normal basal tear flow exchange rate of 16% per minute, thereby decreasing ocular contact time via dilution (Mishima et al 1966).

The cornea is the primary site of intraocular drug absorption from topical drug application. This is a complex process that favors small, moderately lipophilic drugs that are partially nonionized under physiologic conditions. While the cornea is a five-layer structure, it has significant barriers to absorption into the eye. It can be visualized as three layers, like a sandwich, with a hydrophilic stroma flanked by lipophilic epithelium and endothelial layers (Mishima et al 1966).

Topically administered drugs are also absorbed via the conjunctiva, sclera and lacrimal system. The total surface area of the conjunctiva is 17 times the corneal surface area (Mishima et al 1966). The conjunctiva allows absorption of lipophilic agents to a lesser degree than the cornea, but it is relatively permeable to hydrophilic drugs. The sclera is porous via nerve and blood vessel tracts, but otherwise fairly resistant to penetration. Hydrophilic agents may pass through it 80 times faster than through the cornea (Mishima et al 1966); however, the lacrimal system can remove the drug 100 times faster than the cornea and conjunctiva can absorb it (Van Ootegham 1987).

Clearly, overflow from every administration of eye drops occurs not only over the eyelid but also in the lacrimal outflow system. Lynch et al (1987) showed that 2.5% phenylephrine topically applied to the eyes of newborn babies in 8 µL or 30 µL aliquots produced no difference in pupillary response. However, neonates who received the 30 µL dosage had double the plasma concentrations of phenylephrine of those who received 8 µL, increasing the potential for systemic complications.

Intraocular Distribution

Once a drug reaches the inside of the eye, anatomical barriers play a major role in where it ends up. Drugs that enter primarily through the cornea seldom penetrate behind the lens. The pattern of aqueous humor flow and the physical barriers of the iris and ciliary body help keep the drug anterior. It is not uncommon for a drug to be more concentrated in the ciliary body than in the aqueous humor due to scleral absorption directly into the ciliary body with less fluid exchange than in the aqueous humor. In addition, pigmented tissue reacts differently to different drugs. For example, lipid-soluble mydriatics that are more slowly absorbed by pigmented cells will dilate dark pupils more slowly, resulting in longer duration but a decrease in maximum dilation (Harris et al 1971).

Drug distribution is markedly affected by eye inflammation. Tissue permeability is increased, allowing greater drug availability. However, as Mikkelson et al (1973) have demonstrated, protein binding may decrease drug availability 75–100% in inflamed eyes. The protein–drug complex decreases bioavailability. Increases in aqueous or tear protein, such as mucus, are also factors in bioavailability, as is the increased tearing that may wash away a drug before it can be absorbed (Mikkelson et al 1973).


Preservatives are important parts of topical ocular medications, not only to prolong shelf life but also to disrupt the corneal and conjunctival epithelium to allow greater drug penetration.

Preservatives such as benzalkonium have been shown to have antibacterial properties almost as great as those of topical ocular antibiotics. Even in exceedingly low concentrations, benzalkonium causes significant cell damage by emulsification of the cell-wall lipids. De Saint Jean et al (1999) report cell-growth arrest and death at concentrations as low as 0.0001%. Short-term use seldom causes clinically significant damage to healthy corneas and conjunctiva other than superficial epithelial changes. However, with long-term use, e.g. in patients with glaucoma and dry eye, preservatives in topical eye medication may cause adverse effects. Hong et al (2006) have shown induction of squamous metaplasia by chronic application of glaucoma medications containing preservatives. This may progress to more severe side effects, as shown in Table 2.1.

Nov 21, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on 2 Ocular drug delivery and toxicology
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