Take-home message: Rho kinase inhibitors are intriguing in that they work directly on the pathogenic mechanism of abnormally elevated IOP, increased resistance to trabecular outflow.
It is a sad irony that not a single glaucoma medication in use today primarily targets the pathogenic cause of increased IOP: impaired function of the conventional trabecular outflow pathway.
As Kopczynski and Epstein noted in an editorial last year: “The trabecular outflow pathway is the primary draining tissue for the aqueous humor in the eye. It consists of 3 structures, the trabecular meshwork, juxtacanalicular tissue, and Schlemm’s canal. In a healthy eye, IOP is maintained within a narrow range through dynamic regulation of trabecular outflow resistance. In a glaucomatous eye, elevated IOP is due to an abnormally high resistance to outflow in the trabecular outflow pathway. The causes of increased outflow resistance are not fully understood, but it has been hypothesized to involve an increase in the contractile tone and stiffness of the trabecular meshwork and changes in extracellular matrix composition and/or a change in the conductance of Schlemm’s canal.”1
The most commonly prescribed class of ocular hypotensive drugs—the prostaglandin analogues—reduces IOP by increasing uveoscleral outflow. While this pharmacologic activity remains relatively consistent over time, IOP still tends to increase, and patients tend to require additional adjunctive medications, because the outflow resistance of the trabecular meshwork continues to increase as the disease progresses.
Similarly, drugs that decrease aqueous production—such as carbonic anhydrase inhibitors, alpha agonists, and beta-blockers—may actually serve to reduce trabecular outflow in a counterproductive fashion by increasing trabecular resistance indirectly through feedback mechanisms that attempt to regulate IOP.
In fact, the addition of second and third medications to the regimen of patients with glaucoma yields progressively less satisfactory results in terms of IOP reduction.2
However, in a recent fortunate development, a novel class of glaucoma medications, the rho kinase inhibitors, have been found to actually increase trabecular outflow by acting directly on the contractile tone of the trabecular meshwork.3
Increasing outflow facility
Rho kinase is a serine/threonine kinase whose activity increases actomyosin contraction in smooth muscle cells, including the smooth muscle-like cells of the trabecular meshwork. Bacharach et al. have recently published results of a phase II clinical trial of AR-13324 (Rhopressa, Aerie Pharmaceuticals), the first of a new class of ocular hypotensive compounds that inhibits both rho kinase and the norepinephrine transporter.