Biophasic availability of ophthalmic carbachol. I. Mechanisms of cationic polymer- and surfactant-promoted miotic activity.

Abstract: The influence of the topical application of cationic benzalkonium chloride and diethylaminoethyl dextran (mol. wt. ≃ 10 8 ) adjuvants on the time variation of the miotic response intensity elicited by intraconjunctivally and intraaqueously administered carbachol was studied. The inclusion of either adjuvant in a 0.1 % carbachol ophthalmic solution topically administered in the eye was observed to augment the miotic response activity attributable to direct transcorneal absorption into the biophase of the treated eye; the effect was nearly comparable to that achieved with similar dosing of a 2.0% solution containing carbachol alone. Simultaneous miotic activity in untreated control eyes of the rabbits, as well as other cholinergic side effects observed with the 2.0% carbachol solutions, did not occur with the 0.1 % adjuvant-containing solutions, indicating that the enhanced local effects were not accompanied by a concomitantly promoted undesirable systemic absorption. The topical application of the adjuvants to the cornea following injection of the carbachol into the anterior chamber of the eye also appreciably promoted the miotic activity of the drug when it was administered by this mode. The principal mechanism of the observed adjuvant effects on carbachol biophasic availability is postulated as attributable to a promoted tissue permeability and release of the drug from corneal tissue binding sites; these occurrences result from an inductively implemented diminution of carbachol tissue binding affinities. The inductive effects originate and are propagated from fixed anionic corneal sites which interact with the cationic adjuvants. The impermeability of the cornea prevents the penetration of the adjuvant molecules to the deeper tissue layers where they could more directly influence carbachol tissue interactions.