Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors (CAIs) continue to be the only systemic agents used for the long-term treatment of glaucoma, if only occasionally. A topical version introduced more than 40 years after the introduction of the systemic agent moved the oral agents quite far down on the list of practical options for the chronic treatment of glaucoma. These drugs are all derivatives of sulfonamides and were introduced into clinical practice as diuretics. Even with chronic use, their diuretic action is only effective for 1–2 weeks. CAIs reduce intraocular pressure (IOP) by decreasing aqueous humor formation. As such they are useful in essentially all forms of glaucoma, even when the anterior chamber angle is sealed or the outflow facility is very low.

Acetazolamide was introduced into clinical practice as an antiglaucoma drug in 1954 and remains the prototype for this class of drugs.1 Other members of this group include the oral agents, methazolamide, ethoxzolamide, and dichlorphenamide, as well as the topical agents, dorzolamide and brinzolamide.

Carbonic anhydrase inhibitors have also been important tools for the study of aqueous humor dynamics.Their ability to alter aqueous humor formation has been useful in understanding the chemical composition, the turnover of substances, and the rate of aqueous humor formation.

Mechanism of action

The enzyme carbonic anhydrase (CA) catalyzes the following reaction:

This enzyme is found in many tissues in the body, including the renal cortex, gastric mucosa, red blood cells (RBCs), lung, pancreas, and central nervous system (CNS). It is also found in many tissues in the eye, including the corneal endothelium, non-pigmented iris epithelium, pigmented and non-pigmented epithelium of the ciliary processes, Müller cells, and retinal pigment epithelium.2 Carbonic anhydrase exists in multiple forms. Although type I and II CAs are both present in the corneal endothelium and lens, the type II isoenzyme (type C in another classification system) appears to be the only one of the two forms present in any quantity in human ciliary epithelium.3,4 Recent animal studies have placed both types III and IV CA in the non-pigmented ciliary epithelium of both rabbits and humans and have implicated it as having a role in aqueous production.5–8

The notion that CAIs reduce aqueous humor formation is amply supported by a number of experimental and clinical studies

involving tonography,1,9 fluorophotometry,10 fluorescein appearance time in the anterior chamber,11 photogrammetry,12 changes in the steady-state concentration of endogenous ions (e.g., ascorbate, phosphate) in the anterior and posterior chambers,13 turnover of systemically administered substances (e.g., ascorbate, p-amino- hippuric acid, urea, iodide, iodopyracet) in the anterior and posterior chambers,14–16 and dilution techniques measuring the loss of substances infused into the anterior or posterior chambers (e.g., inulin or isotopically labeled protein).17,18 Although all of these techniques have underlying assumptions and shortcomings, there is general agreement that CAIs in full doses reduce aqueous humor formation by about 40%. This means that at least 60% of aqueous humor formation is independent of the enzyme CA. This limits not only the efficacy of the inhibitors but also their potential ocular side effects. More than 99% of the enzyme activity must be inhibited before aqueous production is reduced.19,20

There has been considerable debate about the mechanism by which CAIs decrease aqueous humor formation. This debate reflects our imperfect understanding of aqueous humor formation and the contradictory results of studies performed in different animal species. Among the issues under discussion are whether CAIs play a direct or indirect role in reducing aqueous humor formation and whether the effect is primarily ocular or systemic. With the advent of a successful topical CAI that does not change systemic parameters, that aspect of the debate is largely settled.

Direct effect on aqueous humor formation

The bulk of evidence strongly suggests that CAIs reduce aqueous humor formation by a direct effect on ciliary epithelial CA:

1    Carbonic anhydrase is found in the non-pigmented epithelium of the ciliary processes.2–4 This metabolically active tissue is thought to be responsible for the secretion of aqueous humor.

2    Acetazolamide inhibits aqueous humor secretion by isolated rabbit ciliary processes.21

3    Intravenous injection of acetazolamide, 125 mg, does not lower IOP in patients with a congenital deficiency of CA II.22

4    Small doses of CAIs can reduce IOP while producing minimal or no systemic acidosis or electrolyte imbalance.20,23

5   The CAIs are capable of reducing IOP in nephrectomized rabbits.24,25 Friedman and co-workers found that intravenous injection of acetazolamide, 5 mg/kg, to nephrectomized rabbits lowered IOP without an effect on arterial pH, partial arterial pressure of carbon dioxide bicarbonate, or base excess.25 Furthermore, acetazolamide lowers IOP in elasmobranches that lack renal CA.