Nitric Oxide Donors
Nitric oxide (NO) is a ubiquitous, versatile, endogenous signaling molecule with diverse biological effects. As a gaseous molecule, NO is highly lipophilic and volatile, able to readily diffuse across cell membranes and function as a paracrine messenger that induces changes in adjacent cells. NO is also a highly reactive free radical. Excessive NO, particularly during ischemia, can result in tissue damage.
Endogenous NO is derived from the amino acid l-arginine by the action of NO synthase (NOS). The enzyme has 3 isoforms: endothelial NOS (eNOS or NOS-3), found mainly in endothelial cells; neuronal NOS (nNOS or NOS-1), expressed in central and peripheral neurons; and inducible NOS (iNOS or NOS-2), expressed primarily in macrophages but potentially in any cell type and induced by inflammatory cytokines or bacterial endotoxins.
In physiologic conditions, eNOS is present in the endothelium of ciliary and retinal vessels, ciliary muscle, and Schlemm canal cells, whereas nNOS is found in the nonpigmented ciliary epithelium and optic nerve head. Under stimulated conditions, iNOS can be detected in the iris, ciliary body, vessels, and optic nerve head. NO generated in the trabecular meshwork (TM) is most likely mediated by iNOS.
Significant clinical and experimental evidence indicates that an endogenous insufficiency of NO bioavailability is linked to POAG, although the exact relationship between the two is unclear. NO is thought to lower IOP by increasing trabecular outflow. Evidence suggests that NO affects trabecular outflow by relaxing the juxtacanalicular TM, altering contractility and cell volume of the TM and Schlemm canal cells. NO may be involved in aqueous secretion through regulation of blood flow, uveoscleral outflow via relaxation of the smooth muscle fibers, and autoregulation of optic nerve head circulation during changes in IOP. Exogenous NO delivered to the anterior eye can facilitate outflow and lower IOP.
Latanoprostene bunod (LBN) ophthalmic solution, 0.024%, is a NO-donating PG analogue that chemically combines an NO-donating moiety with latanoprost. The molecular structure of LBN is nearly identical to that of latanoprost. However, LBN is distinguished by the integration of an NO-donating moiety (a terminal butyl nitrate ester functional group) in lieu of an isopropyl ester. Upon topical administration, LBN is hydrolyzed by endogenous corneal esterases into latanoprost acid and butanediol mononitrate, which is further metabolized to NO and the inactive 1,4-butanediol. The molecule is thought to exert pharmacologic effects, with latanoprost increasing uveoscleral outflow and NO enhancing trabecular outflow.
LBN is dosed once daily at bedtime and has an adverse effect profile similar to that of other PGs in clinical settings. In phase 3 clinical trials, LBN produced a mean IOP reduction of 7.5–9.1 mm Hg and was superior to twice-daily timolol 0.5%; in addition, the IOP-lowering efficacy lasted for 12 months. Notably, in the phase 2 study, reduction in IOP was 1.2 mm Hg greater with LBN treatment for 28 days than with latanoprost.
NO-donating moieties combined with other ocular hypotensive agents are under development. They include introduction of NO-donating moieties to bimatoprost (another PG analogue), to a nonselective β-blocker, and to the CAIs dorzolamide and brinzolamide.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.