Year: 2015
Type: review
Abstract: Clinical Observations.Glaucoma is defined as a group of disorders that result in death of ganglion cells due to axonal damage at the level of the lamina cribrosa of the optic nerve.In essence, glaucoma is a diagnosis of exclusion in instances in which the cause of the optic nerve damage is unknown.While primary open-angle glaucoma (POAG) is the most common form of glaucoma, there could be 20 to 30 subtypes of the disease, as the panel was told by the late David Epstein, MD (Duke University, Durham, NC, USA), who provided his thoughts on treating glaucoma for nearly four decades.Such diversity in the disease most likely explains why it is so difficult to find a single responsible gene for POAG and why patients with glaucoma have differential responses to medical therapy.For example, 10% to 15% of patients do not respond to latanoprost, one of the most commonly used drugs for treatment of glaucoma.5 Studying these nonresponders may provide clues for recognizing the multitude of subtypes within glaucoma.While IOP continues to be the most relied-upon parameter for diagnosis and treatment, it is not always elevated in glaucoma.For example, 90% of Asian populations suffering from POAG have IOP in the normal range in comparison to Caucasians, whose numbers range from 30% to 50%.6 In any case, effectively lowering IOP is neuroprotective, slowing or stopping vision loss in glaucoma patients, even if they do not have elevated IOP.Moreover, IOP has been shown to be causative, since experimentally induced IOP elevation will result in neuronal glaucomatous damage.Intraocular pressure is variable, fluctuating widely between visits or between readings obtained at different times of the day.Therefore, it is often difficult to get a true picture of a patient's IOP particularly when it is measured only two or three times every year.Despite this, clinical management of glaucoma is focused on setting a target pressure for each patient and reaching that target through medications, surgery, or both.For patients with advanced glaucoma and considerable damage to the optic neuronal tissues, an even lower target pressure is warranted.Conventional Drugs Present and Future.At present, the only proven treatment for glaucoma is to lower IOP either by increasing outflow or by reducing AH production.There are currently five classes of drugs commonly used for treating glaucoma-b-blockers, prostaglandin analogues, adrenergic agonists, carbonic anhydrase inhibitor, and cholinergic agents.Of these, only the prostaglandin analogues and cholinergic agents have direct effects on the two outflow pathways and hence will be discussed in more detail.In studies on monkeys and humans, prostaglandin analogues have been shown to lower IOP, primarily by increasing flow via the uveoscleral pathway.7 However, several studies have shown a secondary effect of prostaglandin analogues on the conventional outflow pathway.Bahler et al. 8 have shown that latanoprost can lower pressure in human anterior segment perfusion culture.Likewise, Stamer et al. 9 and Wan et al. 10 showed that treatment with bimatoprost increased outflow facility in human anterior segment culture, and this effect was blocked with AGN 211334, a prostamide antagonist.Tafluprost, approved as an ocular hypotensive drug in 2012, has also been shown to affect the conventional outflow pathway.11,12 Cholinergic agents (e.g., pilocarpine, carbachol) increase conventional outflow by constricting the longitudinal portion of the ciliary muscle, pulling on the elastic net that extends into the inner wall of SC, expanding the TM tissues and preventing collapse of the SC lumen.13,14 The cholinergic agents are generally used only acutely by glaucoma clinicians due to unfortunate side effects (e.g., miosis, induced myopia, brow ache secondary to ciliary spasm, and even retinal detachment).Side effects are often more pronounced in younger patients.A novel and emerging way of decreasing resistance in the conventional outflow pathway is through disruption of actin polymerization.Inhibition of the Rho kinase pathway by Rho Kinase (ROCK) inhibitors results in cellular relaxation, increasing the separation distance in the juxtacanalicular region, increasing access of AH to inner wall and improved AH outflow.[15][16][17][18][19][20][21] Similarly, latrunculin A and B cause extensive extracellular remodeling through microfilament disruption that
Institutions: Mayo Clinic, Duke University
Language: English
Subfield: Ophthalmology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $1,850
OpenAlex ID: W2206998273