Indications
Brinzolamide is approved by the FDA for managing elevated intraocular pressure in patients who have either ocular hypertension or open-angle glaucoma. It can be administered as a single agent or in conjunction with brimonidine. Additionally, in Europe, brinzolamide is approved for use in combination with timolol for treating these same conditions.
Pharmacodynamics
Brinzolamide functions by inhibiting carbonic anhydrase II (CA-II) located in the eye's ciliary process, which slows down the formation of bicarbonate. This process reduces fluid flow within the eye, thereby lowering intraocular pressure (IOP). Studies involving brinzolamide as an adjunctive treatment to the prostaglandin analog travoprost have demonstrated its efficacy. In these studies, patients who had an IOP of 19 mmHg or higher were randomized to receive either brinzolamide or timolol. Both groups experienced a reduction in mean diurnal IOP, with decreases ranging from 3.2 to 3.4 mmHg in the brinzolamide group and 3.2 to 4.2 mmHg in the timolol group. Although there was a higher incidence of mild local irritation in the brinzolamide/travoprost group, it did not significantly impact the study's discontinuation rates. Further clinical trials involving 32 pediatric patients, both treatment-naive and those previously on IOP-lowering therapies, showed that brinzolamide produced IOP reductions comparable to those seen in adult patients.
Absorption
Upon topical ocular administration, brinzolamide is absorbed through the cornea. It also enters the systemic circulation, where it binds strongly to carbonic anhydrase in red blood cells. Despite this, plasma concentrations remain very low.
Metabolism
Brinzolamide undergoes metabolism predominantly via hepatic cytochrome P450 isozymes, specifically CYP3A4, CYP2A6, CYP2B6, CYP2C8, and CYP2C9. The primary metabolite formed is N-desethylbrinzolamide, followed by several other metabolites including N-desmethoxypropyl, O-desmethyl, and an N-propionic acid analog. It is noteworthy that brinzolamide and N-desethylbrinzolamide do not inhibit cytochrome P450 isozymes at concentrations that exceed systemic levels by at least a hundredfold.
Mechanism of Action
Brinzolamide operates as a highly selective, reversible, non-competitive inhibitor of carbonic anhydrases (CA), which are enzymes responsible for catalyzing the reversible conversion of water and carbon dioxide into bicarbonate ions. Among the seven CA isoforms present in human tissues, brinzolamide exhibits the greatest affinity for CA II. Significantly, neither brinzolamide nor its active metabolites have been observed to displace known ligands from their receptors or interact with other enzymes frequently associated with side effects or secondary pharmacological actions, thereby contributing to its exceptional safety profile.
