Update on the Mechanism of Action of Topical Prostaglandins for Intraocular Pressure Reduction

Abstract

A decade has passed since the first topical prostaglandin analog was prescribed to reduce intraocular pressure (IOP) for the treatment of glaucoma. Now four prostaglandin analogs are available for clinical use around the world and more are in development. The three most efficacious of these drugs are latanoprost, travoprost, and bimatoprost, and their effects on IOP and aqueous humor dynamics are similar. A consistent finding is a substantial increase in uveoscleral outflow and a less consistent finding is an increase in trabecular outflow facility. Aqueous flow appears to be slightly stimulated as well. Prostaglandin receptors and their associated mRNAs have been located in the trabecular meshwork, ciliary muscle, and sclera providing evidence that endogenous prostaglandins have a functional role in aqueous humor drainage. Earlier evidence found that topical PG analogs release endogenous prostaglandins. One well-studied mechanism for the enhancement of outflow by prostaglandins is the regulation of matrix metalloproteinases and remodeling of extracellular matrix. Other proposed mechanisms include widening of the connective tissue-filled spaces and changes in the shape of cells. All of these mechanisms alter the permeability of tissues of the outflow pathways leading to changes in outflow resistance and/or outflow rates. This review summarizes recent (since 2000) animal and clinical studies of the effects of topical prostaglandin analogs on aqueous humor dynamics and recent cellular and molecular studies designed to clarify the outflow effects.

Pressure Lowering Medications

“…Aqueous humour production is not significantly affected by latanoprost but the most consistent finding is a substantial increase in uveoscleral (pressure-insensitive) outflow; a less consistent finding is the role in trabecular (pressure-sensitive) outflow capacity (Toris et al, 2008;Lim et al, 2008;Johnson et al, 2010). …”

“…These include: (1) Remodelling of extracellular matrix of the ciliary muscle and sclera causing permeability changes, (2) widening of the connective tissue-filled spaces among the ciliary muscle bundles, which may be caused by relaxation of the ciliary muscle and (3) changes in the shape of ciliary muscle cells as a result of altered actin and vinculin localization (Toris et al, 2008;Lindsey et al, 1997). The remodelling of extracellular matrix is believed to be responsible for sustaining the long-term pressure-lowering effect (Johnson et al, 2010).…”

Open-angle glaucoma: therapeutically targeting the extracellular matrix of the conventional outflow pathway

“…A recent meta-analysis has confirmed that prostaglandin analogs are the most effective in lowering IOP, a reflection of the fact that these compounds are the most commonly prescribed eye-drop [115]. Significant increases in unconventional outflow [116], and to a lesser extent, conventional outflow [117,118], are observed with such analogs. Prostaglandins are endogenously expressed in many tissues and throughout the anterior chamber [119], such expression being influenced by bioactive molecules, laser treatments, mechanical stress, or glucocorticoids, indicating their importance in homeostasis [120].…”

A refresher relating to open and closed angle glaucoma

“…Cholinergic agents such as pilocarpine influence the papillary block. Prostaglandins modulate glaucoma by increasing the uveoscleral outflow [11]. Patients often become refractory to their medications over time.…”