Topical brinzolamide and metabolic acidosis

Treatment of ophthalmic disease largely involves the administration of topical medication in doses that would appear small relative to those used systemically. With a few exceptions (such as β receptor antagonists) the systemic side effects of topical ocular medication, though recognised, are often ignored in clinical practice. We report a case that highlights the need for constant vigilance in the context of such ophthalmic therapy.

Case report

A 66 year old white man, on treatment with topical latanoprost for primary open angle glaucoma, required further reduction of intraocular pressure, in the pursuit of which topical brinzolamide was added to one eye only.

At review 3 months later, the patient reported having stopped brinzolamide on his own initiative because of lethargy and a bad taste in the mouth. The subject had worn a silver chain around his neck for many years; interestingly, this chain had turned black within 2 days of starting topical brinzolamide. The chain was professionally cleaned and then re‐worn, immediately upon which it turned black once again (fig 1).

Figure 1 The blackened silver medallion.

Adequate control of intraocular pressure was subsequently established with a combination of topical travoprost, timolol, and pilocarpine.

Comment

The clinical history strongly indicates the development of metabolic acidosis in response to topical brinzolamide, a recognised consequence of therapy with carbonic anhydrase inhibitors. The blackening of the silver chain was caused by oxidation of the silver, most likely as a result of exposure to acidic sweat, a homeostatic mechanism to normalise the pH of the extracellular fluid. Incontrovertible objective verification of such disturbance of the acid‐base balance would necessitate re‐challenging the patient with the drug along with arterial blood gas analysis, a measure that was deemed excessive and inappropriate on the grounds of patient safety.

It would appear remarkable that such acidosis developed in response to an apparently small dose of medication, the drug having been instilled twice daily in only one eye—until the pharmacodynamics of topical ocular medications are studied. It is well recognised that topically administered drugs are rapidly absorbed into the systemic circulation.¹ Manual lacrimal sac compression has been advocated as a means of reducing systemic absorption, on the basis that drugs are absorbed more effectively from the ciliated columnar (respiratory) epithelium of the nasal passages—the effects of such lacrimal compression are, however, variable.²,³ Lacrimal compression also does not affect drug absorption across the vascular conjunctiva, which has been estimated at being 10 times faster than the transcorneal route. Transconjunctival absorption also competitively reduces absorption across the cornea, thus depotentiating any ocular therapeutic effect.

It has been estimated that less than 5% of an instilled dose of a topical drug is absorbed intraocularly.⁴ The achievement of a desired ocular therapeutic effect therefore often necessitates higher concentrations and frequent instillations of a drug, with the attendant increased risk of systemic effects. In this context it is also clinically significant that topical eye drops, when absorbed, do not undergo first pass metabolism, bypassing as they do the liver and gaining direct entry into the systemic circulation.

We submit that the common tendency to consider eye drops as representing miniscule and systemically insignificant doses of therapeutic agents is therefore ill founded—the prescription of eye drops merits comparable weight and consideration as that of systemic medication.