Rho-Kinase (ROCK) Inhibitors Medication for Glaucoma

 

Commonly prescribed:

In December 2017 netarsudil (brand name: Rhopressa) became the first FDA approved medication in this class^[1]. 

Cap color:

White 

How it is taken:

One drop every evening. 

How it works:

This class of medication seems to be the trifecta of glaucoma eye drops as it has not one, but at least three mechanisms of action^[2]:

• It works at the trabecular meshwork to improve outflow of fluid from the eye^[3]
• Like many other glaucoma medications, it also reduces the amount of fluid produced^[4]
• It reduces the episcleral venous pressure which essentially sets the floor on how low the eye pressure can go^[5].

Additionally, there may also be IOP-independent benefits to this class^[6] including:

• Neuroprotection of the optic nerve^[7]
• Improvement of blood flow to the eye^[8]
• Reduction of oxidative damage to the trabecular meshwork^[9]

How well does it work:

Seems to work about as well as either timolol^[10] or latanoprost^[11] in those with baseline IOP lower than 25 mmHg. However, it is not fast-acting as it can take up to six weeks to see the full IOP lowering effect.

Potential for treating Normal Tension Glaucoma

Unlike other glaucoma medications, the IOP-lowering effect of netarsudil does not depend on initial IOP. In other words, the benefit of most glaucoma medications is proportional to the baseline IOP. So the higher the baseline IOP, the greater the benefit of a given medication. This works to the advantage of those with significantly elevated IOP, but to the disadvantage of those with normal tension glaucoma in which the IOP is not significantly elevated.

As netarsudil seems to lower IOP by about 4-6 mmHg regardless of initial IOP, this class of medication could be of particular valuable in those with normal tension glaucoma. Additional studies will need to be performed in order to confirm this assumption.

Potential for treating Steroid-Induced IOP Elevation

Chronic topical steroid use often leads to elevated IOP. This “steroid response” appears to be at least partially induced by Rho-Kinase (ROCK) activation at the trabecular meshwork^[12]. Thus, it makes sense that a ROCK inhibitor such as netarsudil could potentially prevent or limit the steroid-related elevation of IOP^[13].

Side effects^[14]:

Local

• Most common: conjunctival hyperemia (red eye)
  • About half of those on this eye drop will experience this side effect
  • This appears to improve with time
• Conjunctival hemorrhage (small bleed on surface of the eye)
  • About 15% will experience this cosmetic side effect
• Cornea verticillata (fine pigment deposits on corneal surface)
  • Do not appear to affect vision and are generally only visible under the exam microscope
• As well as the usual list encountered with nearly all prescription eye drops:
  • Stinging upon instillation
  • Blurred vision (usually temporary)
  • Eye irritation/discomfort
  • Headache

Systemic

• None reported

How to minimize side effects:

Use at night.

Note on Fixed Combinations:

None available in the USA but the next to be approved ROCK inhibitor will likely be combined with a prostaglandin analog

Cost?

Very expensive if not covered by your insurance. However, the company that manufactures this medication is currently offering discount cards. I’ve found, however, that not all pharmacies either have the knowledge or desire to complete the paperwork for these discount programs. As such, I tend to refer my patients for whom I prescribed Rhopressa to Delta Drugs Pharmacy in Glendale, CA. I have no financial interest in this pharmacy, they just seem to process these discount programs more effectively than most other pharmacies I’ve dealt with. I’ll place their contact information in the notes section below this video. Don’t worry if you don’t live near my office as they will mail the drops to you.

Summary:

This exciting new class of glaucoma medications has many advantages over other classes:

• It works through multiple mechanisms to reduce IOP
• It’s dosed once daily
• It has few side effect (all of which are local; no systemic effects)

Netarsudil, may be preferred in those with normal tension glaucoma or steroid-induced glaucoma.

However, as with all newly FDA-approved medications, insurance coverage is sparse and without coverage one year of this medication would cost thousands of dollars (as much as glaucoma surgery). As such, few patients are likely to benefit from this class for at least a few years.

References:

[1]  Choy M. Pharmaceutical Approval Update. P T. 2018;43(4): 205–227.

[2]  Ren R, Li G, Le TD, Kopczynski C, Stamer WD, Gong H. Netarsudil increases outflow facility in human eyes through multiple mechanisms. Invest Ophthalmol Vis Sci. 2016;57(14):6197–6209.

[3]  Nakajima E, Nakajima T, Minagawa Y, Shearer TR, Azuma M. Contribution of ROCK in contraction of trabecular meshwork: proposed mechanism for regulating aqueous outflow in monkey and human eyes. J Pharm Sci. 2005;94(4):701–708.

[4]  Wang RF, Williamson JE, Kopczynski C, Serle JB. Effect of 0.04% AR-13324, a ROCK, and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J Glaucoma. 2015;24(1):51–54.

[5]  Kiel JW, Kopczynski CC. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther. 2015; 31(3):146–151.

[6]  Honjo M, Tanihara H. Impact of the clinical use of ROCK inhibitor on the pathogenesis and treatment of glaucoma. Jpn J Ophthalmol. 2018;62(2):109–126.

[7]  Kitaoka Y, Kitaoka Y, Kumai T, et al. Involvement of RhoA and possible neuroprotective effect of fasudil, a Rho kinase inhibitor, in NMDA-induced neurotoxicity in the rat retina. Brain Res. 2004;1018(1): 111–118

[8]  Sugiyama T, Shibata M, Kajiura S, et al. Effects of fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest Ophthalmol Vis Sci. 2011;52(1):64–69.

[9]  Fujimoto T, Inoue T, Ohira S, et al. Inhibition of rho kinase induces antioxidative molecules and suppresses reactive oxidative species in trabecular meshwork cells. J Ophthalmol. 2017, Article ID 7598140, 23 pages.

[10]  Serle JB, Katz LJ, McLaurin E, et al. Two phase 3 clinical trials comparing the safety and efficacy of netarsudil to timolol in patients with elevated intraocular pressure: Rho kinase elevated IOP treatment trial 1 and 2 (ROCKET-1 and ROCKET-2). Am J Ophthalmol. 2018;186:116–127.

[11]  Bacharach J, Dubiner HB, Levy B, Kopczynski CC, Novack GD, AR-13324-CS202 Study Group. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated intraocular pressure. Ophthalmology. 2015;122(2):302–307.

[12]  Yuan Y, Call MK, Yuan Y, et al. Dexamethasone induces cross-linked actin networks in trabecular meshwork cells through noncanonical wnt signaling. Invest Ophthalmol Vis Sci. 2013;54(10):6502–6509.

[13]  Fujimoto T, Inoue T, Kameda T, et al. Involvement of RhoA/Rho-associated kinase signal transduction pathway in dexamethasone-induced alterations in aqueous outflow. Invest Ophthalmol Vis Sci. 2012; 53(11):7097–7108.

[14]  Levy B, Ramirez N, Novack GD, Kopczynski C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am J Ophthalmol. 2015;159(5):5.e1. 

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