title: A comparison between the effect of topical and systemic carbonic anhydrase inhibitors on aqueous humor secretion.
abstract: We have assessed the onset and duration of decreased intraocular pressure and aqueous humor flow contrasting systemic and topical administration of carbonic anhydrase inhibitors. The relationship between physiological effects and fractional activity of carbonic anhydrase isoenzymes in the eye was also investigated. Experiments were performed in normotensive New Zealand white rabbits. Intraocular pressure was determined manometrically or tonometrically and aqueous humor flow by sulfacetamide clearance. We studied methazolamide (25 mg kg-1), ethoxzolamide (4 mg kg-1), and MK-927 (2% in 0.5% hydroxyethylcellulose, topical, pH 4.8). There is an immediate reduction in intraocular pressure (1.2 and 1.8 mmHg by 2 min) and aqueous flow (33% and 40% by 5 min) following intravenous dosing with either methazolamide or ethoxzolamide. This correlates with rapid appearance of drug in the anterior uvea and very low fractional activity of ocular carbonic anhydrase isoenzymes II (cytosolic) and IV (membrane bound). Peak intraocular pressure reduction averaged 4.2 +/- 0.68 mmHg and 4.5 +/- 0.8 mmHg for methazolamide and ethoxzolamide at 60 and 45 min, respectively. Peak flow reduction was 38% for methazolamide and 40% for ethoxzolamide, at 5 min. Aqueous flow and intraocular pressure returned to baseline at 7 and 4 hr following methazolamide and ethoxzolamide, respectively. This corresponds to decay of drug from ocular tissues and significant increases in fractional activity of carbonic anhydrase isoenzymes. Topical MK-927 resulted in a 1.2 mmHg decrease in pressure by 5 min. This correlated with the early appearance of drug in the anterior uvea prior to its appearance in aqueous humor and very low fractional activity of carbonic anhydrase isoenzymes. Intraocular pressure decreased 3.6 +/- 0.35 mmHg at 1 hr and returned to baseline by 6 hr. Aqueous flow was reduced 12% by 5 min and 35% at 1 hr. The appearance of MK-927 in the anterior uvea prior to detection in aqueous suggests a significant non-corneal route of absorption following topical administration. Topical MK-927 results in a more gradual reduction in intraocular pressure and flow, although peak effects are not statistically different from systemic carbonic anhydrase inhibitors. The time of pressure return to baseline is also comparable to systemic carbonic anhydrase inhibitors. Because the relations between carbonic anhydrase II and carbonic anhydrase IV in the ciliary process are not yet clear and since the drugs have different affinities for the isozymes, the precise degree of fractional inhibition necessary for pharmacological effect is not certain, but based on drug concentration in the anterior uvea, may take 98% inhibition for full intraocular pressure reduction.
authors.affiliation: University of Florida Health Science Center, College of Medicine, Department of Pharmacology and Therapeutics, Gainesville 32610-0267.
authors.forename: W F
authors.initials: WF
authors.lastname: Brechue
authors.forename: T H
authors.initials: TH
authors.lastname: Maren
mesh_terms: D000287:Administration, Topical; D000818:Animals; D001082:Aqueous Humor / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage*; D002256:Carbonic Anhydrases / Q000378:metabolism; D005016:Ethoxzolamide / Q000494:pharmacology; D007275:Injections, Intravenous; D007429:Intraocular Pressure / Q000187:drug effects; D008297:Male; D008704:Methazolamide / Q000494:pharmacology; D011817:Rabbits; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D014602:Uvea / Q000378:metabolism
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D002256:Carbonic Anhydrases; C057921:sezolamide; D008704:Methazolamide; D005016:Ethoxzolamide