Physiology of Ocular Barriers and Topical Pharmacokinetics

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Kinetics of the Tear Compartment and Systemic Absorption

The normal tear film has a basal volume of approximately 7 - 10 µL. When instilling a conventional commercial eye drop, the volume of which ranges between 30 and 50 µL, the physical capacity of the conjunctival fornix is ​​immediately exceeded. This triggers a blink reflex that expels most of the drug to the outside or drains it via the nasolacrimal route.

💧 Nasolacrimal Drainage Route

Excess volume drains through the puncta to the canaliculus, lacrimal sac, and finally the inferior nasal meatus:

• Absence of first hepatic pass: The highly vascularized nasal mucosa absorbs the drug directly into the systemic bloodstream, bypassing the initial hepatic inactivation.
• Equivalence to intravenous infusion: Beta-blockers such as timolol or adrenergic agonists such as brimonidine reach systemic plasma concentrations capable of inducing serious adverse effects in minutes.

👁️ Transcorneal Diffusion

To reach the aqueous humor of the anterior chamber, the active ingredient must cross the trilaminar barrier of the cornea through amphipathic permeation:

• Corneal Epithelium: Highly lipophilic structure with continuous tight junctions (tight junctions of the occludin type and zonular immunoglobulins). Requires drugs with a non-ionized character.
• Corneal Stroma: Highly hydrophilic collagen matrix that constitutes 90% of the corneal thickness, requiring the molecule to acquire a water-soluble form.
• Corneal Endothelium: Monolayer cell layer of lipophilic character that contacts the aqueous humor.

Fick's Law and Henderson-Hasselbalch Relationship in the Cornea

The transcorneal diffusion rate (J) responds to Fick's first law:

J = -D · K_p · (Δ C)/(Δ x)

Where D is the diffusion coefficient, K_p is the lipid/water partition coefficient of the molecule, Δ C is the transcorneal concentration gradient and Δ x is the corneal thickness. To maximize the permeation of weak acids or bases, the ophthalmic formulation calibrates the pH so that the ionized fraction (that passes through the hydrophilic stroma) and the non-ionized fraction (that passes through the lipophilic epithelium and endothelium) coexist according to the Henderson-Hasselbalch equation:

pH = pK_a + (([Base])/([Acid]))

Intraocular Barriers: Hematoaqueous and Hematoretinal

Even after penetrating the cornea, access to the tissues of the posterior pole is prohibited by physiological barrier systems:

• Blood-aqueous barrier (BHA): Formed by the tight junctions of the non-pigmented epithelium of the ciliary body, the endothelium of the capillaries of the iris and the corneal endothelium itself. It prevents the passage of macromolecules and most systemic drugs into the anterior chamber, maintaining the optical transparency of the aqueous humor.
• Hematoretinal Barrier (BHR): Subdivided into external and internal. The external BHR is made up of the occluding junctions of the Retinal Pigment Epithelium (RPE), which regulates the entry from the choriocapillaris. The internal BHR is formed by the endothelial cells of retinal capillaries, which lack fenestrations and are surrounded by astrocytic podocytes and pericytes. This structure restricts the delivery of drugs administered systemically or topically to the retina and vitreous, forcing the use of the intravitreal route.