After topical instillation of a drug, the rate and extent of absorption are determined by the time the drug remains in the cul-de-sac and precorneal tear film, elimination by nasolacrimal drainage, drug binding to tear proteins, drug metabolism by tear and tissue proteins, and diffusion across the cornea and conjunctiva. A drug's residence time may be prolonged by changing its formulation. Residence time also may be extended by blocking the egress of tears from the eye by closing the tear drainage ducts with plugs or cautery. (Figure 63-2.) Nasolacrimal drainage contributes to systemic absorption of topically administered ophthalmic medications. Absorption from the nasal mucosa avoids so-called first-pass metabolism by the liver, and consequently significant systemic side effects may be caused by topical medications, especially when used chronically. Possible absorption pathways of an ophthalmic drug following topical application to the eye are shown schematically in Figure 63-3.
Transcorneal and transconjunctival/scleral absorption are the desired routes for localized ocular drug effects. The time period between drug instillation and its appearance in the aqueous humor is defined as the lag time. The drug concentration gradient between the tear film and the cornea and conjunctival epithelium provides the driving force for passive diffusion across these tissues. Other factors that affect a drug's diffusion capacity are the size of the molecule, chemical structure, and steric configuration. Transcorneal drug penetration is a differential solubility process due to the cornea's trilamellar "fat-water-fat" composition. The epithelium and endothe-lium represent barriers for hydrophilic substances, while the stroma is a barrier for hydrophobic compounds. Hence, a drug with both hydrophilic and lipophilic properties is best suited for transcorneal absorption.
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