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Dorzolamide is a powerful inhibitor of carbonic anhydrase (CA) II that penetrates the sclera and cornea to reach the ciliary process and lowers formation of HCO3 and aqueous humor. The usual dose applied to the eye in treatment of glaucoma is 1 drop (30 microL of 2% solution) every 8 hr to each eye, or a total daily dose of 4 mg. On this regime, the red cells accumulated drug over a period of 8 days, reaching a value of 20-25 microM, which corresponds to the concentration of CA II in human red cells. This drug concentration persisted throughout the 18 months of application. The plasma concentration was 0.034 microM, or 1/700 that of the red cells. This plasma concentration corresponds to that calculated from the dilution of administered drug into body water. The data are well fitted into the equilibrium expression for KI of dorzolamide against CA II at 37 degrees C, as 8 x 10(-9) M. The red cells also contain a small amount (5 microM) of the N-des-ethyl metabolite, probably reflecting its modest binding to CA I. In the initial 8-day drug period, virtually none appeared in the urine since CA II sites were being filled. At steady state, renal excretion was 1.3 mg/day and the renal clearance 90 ml/min. These excretion numbers include the small (20%) amount of the des-ethyl metabolite of dorzolamide. The relation of these data to lowering of intraocular pressure is clear. By the systemic route, an inhibitor such as acetazolamide is effective when free drug concentration in plasma is 2.5 microM. In the case of topical drugs, as shown here, the plasma concentration is some 100 x lower, but the concentration in ciliary process is 2-10 microM, comparable to that following systemic drugs (1). In conclusion, the concentration in plasma (reflecting free drug) of dorzolamide is about 1/200 of that needed for systemic effects as seen following acetazolamide or methazolamide. Thus, there is a clear pharmacological basis for the lack of any physiological effects of ocular dorzolamide, except on the eye itself.

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The effect of ketamine on intraocular pressure (IOP) was studied in 10 children. Control IOP values were determined prior to induction of anesthesia, following premedication with atropine alone or in combination with pentobarbital and meperidine. After the IM injection of 8 mg/kg of ketamine, the IOP was determined at 5, 10, 15, and 20 minutes. Mean (+/- SD) IOP values before and after ketamine were 22.2 +/- 4.8 and 16.7 +/- 3.3 torr (p less than 0.001), respectively. The authors believe that the reduction in IOP was not due to ketamine, per se, but rather to lack of patient relaxation and cooperation during control measurements. At the end of 20 minutes, a second dose of ketamine, this time 1 mg/kg IV, was given and measurements were repeated at the same intervals. In 5 patients, the effects on IOP of d-tubocurarine, endotracheal intubation, and N2O inhalation also was evaluated. A significant increase (6.7 torr) in IOP was observed only after endotracheal intubation. The authors conclude that ketamine does not raise IOP in the healthy pediatric patient and, therefore, can be used for ophthalmic procedures requiring sedation or anesthesia.