C. When a drop is instilled into the conjunctival sac
1. Absorption of an ocular medication from the cul-de-sac begins with mixing of the drug with tears to give some unknown dilution that is exposed to the entire conjunctival and corneal surface.
2. Tear volume (in canine) is 8–12 μL; conjunctival sac is about 3–6 μL; delivery volume is about 50 μL; at most 20 μL can be retained.
3. Excess spills over the lid margin or goes down the nasolacrimal duct.
4. Tear turnover rate is 0.5–1.0 μL/min, so the t½ of the initial drug concentration is 3–6 minutes.
5. Slower elimination is achieved with ointments.
6. Washout times are shortened with increased lacrimation due to irritation/discomfort or increased drainage induced by blinking. (Restraint of the dog increases the blink rate.)
7. The spillover or drained portion may be absorbed by the mucous membranes in the nose or digestive tract and can lead to systemic side effects.
The principal route into the eye is through the cornea.
a. Epithelial and endothelial cell membrane and intercellular tight junctions limit penetration to the lipophilic agents; the stroma is hydrophilic and water-soluble agents diffuse most readily.
b. Ideally, one should couple lipophilic component to a more hydrophilic drug that would cleave or dissociate after passage through the cornea.
9. Drug binding to protein in tears or to conjunctival pigment may reduce bioavailability. Degradation by enzymes within the cornea may destroy the drug enroute, and binding to protein in aqueous humor may inactivate and hasten elimination from the anterior chamber.
10. Drug molecules
pass between compartments by diffusion and active transport processes.
a. Diffusion follows concentration gradient. Related inversely to molecular size and directly to temperature.
b. Related to chemical structure and stearic configuration.
c. Active transport is affected by competition of other substrates for the transport system.
11. Binding, diffusion, and transport processes are quite variable between individuals and species, and are affected by pathologic conditions such as inflammation.
12. Penetration into the eye through the conjunctiva is generally not relevant. Conjunctival epithelium is similar to corneal epithelium. The subconjunctiva, episclera, sclera, and choroid are not significant barriers to diffusion.
13. Drugs crossing the conjunctiva and sclera are eliminated by the blood circulation in the choroid.
14. Once through the cornea, drugs diffuse in the aqueous humor and are taken up in the iris, base of the ciliary body and the lens. There is little to no flow into the posterior segment. Posterior segment diseases cannot be treated effectively with topical medications.
15. Cornea and lens can absorb drugs, then retain and release them over a prolonged time, such as corticosteroids in the lens.
16. Drugs are eliminated from the eye in the aqueous humor outflow into the aqueous veins or by diffusion through the uveal tissues, and washout by the venous blood circulation. (There are no lymphatics in the eye.)
17. Breakdown and metabolism of drugs applied to the eye may begin in the tears and the conjunctival and corneal epithelium as well as other ocular tissues, although these processes in the eye are somewhat limited. Enzymes for oxidizing, reducing, and conjugating are present in ocular tissues (esterases, oxidases, reductases, lysosomal enzymes, peptidases, transferases, catechol-O-methyl transferase, monoamine oxidase, corticosteroid hydroxylase).
18. Many of the topically applied drugs, particularly antibiotics and corticosteroids, are not broken down in the eye, but leave the eye unchanged and enter the general circulation.
19. Eyelids and orbital tissue are best treated with systemically administered drugs as ophthalmic preparations applied to the surface of the eye do not reach these areas.