Just as the tight junctions of the corneal epithelium and endothelium limit anterior access to the interior of the eye, similar barriers limit access through vascular channels. The vascular endothelium of the retina, like that of the brain, is nonfenestrated and knitted together by tight junctions. Although both the choroid and the ciliary body have fenestrated vascular endothelia, the choroid is effectively sequestered by the retinal pigment epithelium (tight junctions); and the ciliary body, by its nonpigmented epithelium (tight junctions).
Compared with medications with lower lipid solubility, drugs with higher lipid solubility more readily penetrate the blood–ocular barrier. Thus, chloramphenicol, which is highly lipid-soluble, penetrates 20 times better than does penicillin, which has poor lipid solubility.
The ability of systemically administered drugs to gain access to the eye is also influenced by the degree to which they are bound to plasma proteins. Only the unbound form can cross the blood–ocular barrier. Sulfonamides are lipid-soluble but penetrate poorly because, at therapeutic levels, more than 90% of the medication is bound to plasma proteins. Similarly, compared with methicillin, oxacillin has reduced penetration because of its increased binding of plasma protein. Because bolus administration of a drug exceeds the binding capacity of plasma proteins and leads to higher intraocular drug levels than can be achieved by a slow intravenous drip, this approach is used for the administration of antibiotics in order to attain high peak intraocular levels.
Sustained-release oral preparations
The practical value of sustained-release preparations is substantial. For example, a single dose of acetazolamide will reduce intraocular pressure for up to 10 hours, whereas a single dose of sustained-release acetazolamide will produce a comparable effect that lasts 20 hours. A sustained-release medication offers a steadier blood level of the drug, avoiding marked peak concentrations and low concentrations, and reduces the frequency of administration.
Intravenously injected agents can be administered for diagnostic effect. Sodium fluorescein and indocyanine green are 2 agents used for retinal angiography to aid in the diagnosis of retinal and choroidal diseases.
Intravenous agents are also used therapeutically in ophthalmology. Although intravitreal injections have replaced intravenous therapy for postoperative endophthalmitis, continuous intravenous administration of an antibiotic is an effective way of maintaining therapeutic intraocular levels in endogenous infection (see BCSC Section 12, Retina and Vitreous).
The barriers and reservoir effects of the eye affect the pharmacodynamics of antibiotics such as ampicillin, chloramphenicol, and erythromycin. When given as a single intravenous bolus, each of these drugs penetrate the eye with a higher initial intraocular level than when given by continuous infusion and maintain comparable bioavailability for 4 hours. The intraocular penetration of a drug may be better in the inflamed eye than in the healthy eye because of the disruption of the blood–aqueous and blood–retina barriers that occurs with inflammation. This disruption is demonstrated by the leakage of fluorescein from inflamed retinal vessels into the vitreous during angiography.
Studies in rabbit eyes found that the bioavailability of intravenous ampicillin, tetracycline, and dexamethasone differed in various structures of the rabbit eye, with the highest levels of these medications found in the sclera and conjunctiva, followed by the iris and ciliary body, and finally the cornea, aqueous humor, choroid, and retina. Very low levels appeared in the lens and vitreous. No marked differences in vascular distribution of the drugs was shown, however. The tissue bioavailability is determined by the vascularity of the tissue and the barriers existing between the blood and that tissue.
In ophthalmology, intramuscular injection of drugs is used less frequently than topical, oral, or intravenous administration of medications. Notable exceptions include intramuscular injection of prostigmine in the diagnosis of myasthenia gravis and botulinum toxin, given for local effect, in facial dystonias and in some cases of strabismus.
Cholkar K, Patel SP, Vadlapudi AW, Mitra AK. Novel strategies for anterior ocular drug delivery. J Ocular Pharmacol Ther. 2013;29(2):106–123.
Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3): 348–360.
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.