Pharmacologic and Natural Therapeutics in Glaucoma Management

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. As diseased population continues to grow, it is important to review both the well-established and recently developed therapeutics available today to best treat this ocular condition. This chapter will discuss the pharmacologic therapies most commonly used to lower intraocular pressure (IOP) in primary open angle glaucoma patients. It will also examine both natural agents and lifestyle modifications that have been shown to have an effect on intraocular pressure. The prostaglandin analog latanoprost, continues to be the most widely accepted first line medication used to treat glaucoma. However, the efficacious, recently developed, Rho-kinase inhibitor Netarsudil, and fixed dose combination of Netarsudil-Latanoprost should continue to increase in utilization. Multiple mechanisms are often used together to treat glaucoma. Fixed dose combination drug therapy has the potential to decrease patient burden, increase compliance, and improve clinical outcomes.

1. Introduction

Glaucoma is a term used to describe a group of diseases characterized by damage to the optic nerve and retinal nerve fiber layer. It is a chronic progressive optic neuropathy that causes peripheral and occasionally central vision loss. It is the leading cause of irreversible blindness worldwide [1]. The number of people affected by glaucoma is anticipated to continue to rise. It is estimated that approximately 3 million people in the US currently have glaucoma, and this number is expected to grow to 6.3 million by 2050 [2]. Globally, it is estimated that 76 million people suffer from glaucoma with a projected growth to 112 million by 2040 [2]. With such stark projections, it is clear that developments in therapeutics will need to progress in order to optimize patient care and clinical outcomes. Additionally, glaucoma disproportionately affects Black populations in the US. It is the most common cause of blindness in Black persons with a prevalence of 6.1% [2]. The prevalence in Latino communities is second highest at 4.1%, followed by Asian Americans at 3.5% and non-Hispanic White persons at 2.8% [2]. These statistics point to a need to increase the screening and access to care for persons from historically medically underserved communities.

There is no cure for glaucoma. Intraocular pressure (IOP) is the only known modifiable risk factor and therefore of the utmost importance in controlling disease progression. However, in many patients intraocular pressure is only slightly elevated or still within the normal range [1].

The rise in pressure associated with glaucoma can be painless and is often unnoticeable to the patient until subsequent symptoms are present. Early detection is extremely important because any visual field loss noticed by the patient is irreversible. Other general risk factors include older age, race and ethnicity, and family history of glaucoma.

All pharmacologic therapeutics used to treat glaucoma work by lowering intraocular pressure. The common goal is to decrease the loss of ganglion cells, thinning of the retinal nerve fiber layer, and cupping of the optic disc to slow progression. There are a variety of medications used today that work through several different mechanisms. These include cholinergic agents, alpha adrenergic agonists, beta blockers, carbonic anhydrase inhibitors, nitric oxides, prostaglandin analogs, and rho-kinase inhibitors. Additionally, there is a very limited amount of data from studies focusing on natural treatment modalities, therefore the emergence of a potential natural therapy or substance that has the ability to reduce IOP in order to slow glaucomatous progression would be extremely valuable.

2. Treatment

Despite current knowledge of risk factors, genetics, and pathophysiology, the only medical form of treatment for primary open angle glaucoma (POAG) today remains to be intraocular pressure lowering medications. In particular cases, surgical procedures are recommended. However, as the focus of this chapter is pharmacologic and naturopathic therapy, they will only be covered briefly. At this time, there is no way to cure POAG or OHT. The goals of treatment are to delay the progression of visual field loss for the duration of the patient’s lifetime.

IOP lowering medications have been established as the cornerstone of glaucoma treatment for decades. The Ocular Hypertension Treatment Study established that topical ocular hypotensive medication is effective in delaying or preventing the onset of POAG in individuals with elevated IOP [3]. In the study, participants with no evidence of glaucomatous damage were randomized into 2 groups. They were placed in either a treatment with a topical ocular hypertensive medication group or an observation group. The goals of the treatment were a 20% reduction in intraocular pressure and an intraocular pressure of less than or equal to 24 mm Hg. During the course of the study, the mean ± standard deviation of the reduction of IOP in the medication group was 22.5 ± 9.9%. In the observation group, IOP declined by 4.4 ± 11.6% [3]. Additionally, at 60 months, the cumulative probability of developing POAG was 4.4% in the medication group and 9.5% in the observation group. The protective effect of treatment was statistically significant for both optic disc and visual field changes [3]. Furthermore, this study, along with the Early Manifest Glaucoma Trial and the United Kingdom Glaucoma Treatment Study indicated that the degree of reduction of pressure influences disease progression [4, 5]. The Early Manifest Glaucoma Trial estimated that each 1 mm Hg reduction in intraocular pressure reduced the risk of glaucoma progression by about 10% [6]. It can be concluded that reducing IOP through topical ocular hypotensive medications is an extremely effective treatment for delaying disease progression and improving clinical outcomes.

There are numerous forms of medication used to reduce intraocular pressure in POAG patients. These include nitric oxides, cholinergic agents, alpha adrenergic agonists, beta blockers, carbonic anhydrase inhibitors, prostaglandin analogs, and rho kinase inhibitors. It is important to address that personalized treatment promotes better patient outcomes in POAG management. A common strategy is to recommend lowering IOP to a specific target pressure. At this particular pressure, the rate of disease progression should be slowed enough to prevent further damage. Generally, target IOP aims to be a reduction of 20–50% from baseline IOP [7]. This number is established from factors including pre-treatment baseline IOP, severity of visual field loss, risk of progression, life expectancy, and potential for adverse effects [7].

Laser or incisional surgeries are indicated when medical treatment is unable to reduce IOP to target pressure or a patient is unable to tolerate pharmacotherapy. In severe cases and when a patient does not adhere to medical recommendations, surgery can be preferred as a first line therapy [8]. Laser trabeculoplasty is a common form of treatment in which a laser induces biological changes in the trabecular meshwork. This is able to increase aqueous outflow and reduce IOP. Trabeculectomy is the most commonly performed incisional surgery used to lower intraocular pressure [8]. It consists of the excision of a small portion of the trabecular meshwork and or adjacent corneoscleral tissue. This provides a drainage route for aqueous humor from within the eye to underneath the conjunctiva where it is absorbed [8]. Additionally, MIGS procedures, or microinvasive glaucoma surgeries are a relatively new treatment option. Most MIGS work by dilating, cleaving open, or bypassing tissue that is obstructing aqueous outflow, or by inserting a device into an outflow structure to increase drainage [2]. Each procedure comes with its own set of risks. Often, a combination of surgery and pharmacologic therapeutic treatments can improve patient outcomes. In this chapter we will be focusing on pharmacologic and non-pharmacologic therapies.

3. Cholinergic agents

Cholinergic agents, also known as parasympathomimetics, are a useful tool in treating primary open angle glaucoma. The miotic effects of cholinergic agents were first reported by Thomas Fraser in 1862 after studying the active ingredient of a potentially lethal poison used in West Africa derived from the Calabar bean – physostigmine [9]. Pilocarpine was discovered to be less toxic and became the first known pharmacotherapy used to treat glaucoma in 1877 [9]. Pilocarpine and carbachol are two prominent examples, however pilocarpine is the best known of this class of IOP lowering drugs. Pilocarpine works by inducing smooth muscle contraction of the cells in the ciliary body. This leads to an increase in aqueous humor outflow through the trabecular meshwork pathway by widening the trabecular meshwork and Schlemm’s canal [10]. This can lead to an IOP reduction of 20–25% [10]. Unfortunately, cholinergic agents are known to produce a wide range of systemic side effects and are not well tolerated by patients. They are even contraindicated in patients under 40 years of age [10]. This is likely due to overstimulation of muscarinic acetylcholine receptors, inducing bradycardia, negative cardiac inotropy, salivation, sweating, and gastrointestinal stimulation [9]. Ocular adverse effects include retinal detachment, ciliary cramps, increased pupillary block, and blurred vision due to induced myopia [7, 10]. This array of side effects typically restricts the use of pilocarpine to short term and very limited situations.

4. Alpha adrenergic agonists

Brimonidine, which is sold under the brand name Alphagan, and apraclonidine, are the most common alpha adrenergic agonists used to treat primary open angle glaucoma. Alpha adrenergic agonists operate by stimulating alpha receptors to release norepinephrine [10]. Norepinephrine is the main neurotransmitter of the adrenergic system. As an alpha-2 agonist, brimonidine is useful in causing vasoconstriction in the ciliary body. This will result in a decrease in aqueous humor production and consequential lowering of intraocular pressure [10]. However, after chronic use, the mechanism of action shifts to the uveoscleral pathway. This mechanism contracts the ciliary body and increases outflow [11]. Brimonidine can cause a 20–25% reduction in intraocular pressure, making it a useful IOP lowering agent [7]. Although generally more well received than other alpha adrenergic receptor agonists, brimonidine is associated with several adverse effects. These include contact dermatitis, ocular irritation, allergic conjunctivitis, anterior uveitis, hyperemia, fatigue, dizziness, and hypotension [7, 10]. Of particular importance in glaucoma treatment is the potential for neuroprotective properties. As there are alpha-2 receptors present in retinal ganglion cells, Brimonidine also has the potential to reduce retinal ganglion cell loss in glaucoma. There have been several studies involving rat models to examine this hypothesis, with one concluding that Brimonidine was in fact useful in significantly reducing retinal ganglion cell loss [10]. With the potential for significant IOP reduction and neuroprotection, but with occasional adverse effects, Brimonidine is often considered a second line glaucoma treatment. It is also frequently used in combination with other topical therapies.

5. Beta adrenergic antagonists

Beta receptor antagonists, or beta blockers as they are commonly known, are a significant and effective form of treatment for primary open angle glaucoma. Beta receptors are located throughout the eye and their antagonists operate through a mechanism of reducing aqueous humor production in the ciliary body. This is achieved through decreasing cAMP production [10]. Like other effective IOP lowering medications, beta blockers are able to reduce intraocular pressure 20–25% of their initial values [7]. Timolol, brand name Timoptic and Betaxolol, brand name Kerlone, are some of the more frequently prescribed options. Timolol was the first nonselective beta blocker used to treat glaucoma on the market and was the most used anti glaucoma drug for many years [10]. As with all pharmacologic therapies, there are potential adverse effects associated with beta blockers. Some severe pulmonary and cardiovascular systemic side effects can present with the use of non-specific beta receptor antagonists. This contraindicates their prescription for patients who suffer from COPD, asthma, decompensated chronic heart failure, symptomatic bradycardia or heart block, and a history of syncope without diagnosis [10]. There is also concern about the systemic hypotensive effect of beta blockers. They have the potential to reduce blood flow to the optic nerve, which could result in exacerbating glaucomatous progression [9]. Betaxolol was developed with the hope of less adverse effects and as a selective beta-1 adrenergic blocker, and it may have less of a tendency to induce bronchospasm [9]. In addition, beta blockers may also have some neuroprotective effects. One study concluded that Timolol was able to reduce IOP and protect retinal ganglion cells in an experimental rat model through upregulation of brain derived neurotrophic factor [12]. The dangerous side effects that can occur with beta blocker use require them to be prescribed with caution. However, their IOP lowering effects and potential for neuroprotection make them a valuable instrument in the treatment of primary open angle glaucoma, either alone or in combination with other agents.

6. Carbonic anhydrase inhibitors

Carbonic anhydrase inhibitors are a staple of primary open angle glaucoma treatment. Carbonic anhydrase is important for the production of aqueous humor and through its inhibition, a reduction in aqueous humor can cause a decrease in intraocular pressure. Through restricting the amount of sodium and bicarbonate ions available, less water will be able to enter ciliary epithelial cells [10]. The second generation carbonic anhydrase inhibitors include Dorzolamide, brand name Trusopt, and Brinzolamide, brand name Azopt. These are topical therapeutics and are able to reduce intraocular pressure 15–20% from initial value [10]. Common side effects to second generation carbonic anhydrase inhibitors include allergic reaction, ocular burning, ocular stinging, bitter taste, superficial punctate keratitis, blurred vision, headache, and dizziness [10]. Additionally, there is evidence that topical carbonic anhydrase inhibitors enhance ocular blood flow in the retina and optic nerve with a potentially favorable response on retinal ganglion cells [9]. Dorzolamide and Brinzolamide are effective IOP lowering agents and should be used as second line treatments and in combination with other glaucoma medications.

6.1 Nitric oxides

Although some may consider Latanoprostene bunod to be a subcategory of prostaglandin analogs, it should have its own category as it employs a different mechanism of action. This recently developed medication is commonly known by its brand name Vyzulta. It is essentially a modified prostaglandin analog that acts by dual mechanism. It is applied to the eye topically and is first hydrolyzed by endogenous esterases into Latanoprost acid, which is the active component of Latanoprost. What makes Latanoprostene bunod unique is that it also breaks down into butanediol mononitrate, which is further broken down into nitric oxide and inactive 1,4 butanediol [7]. The Latanoprost acid component increases aqueous outflow through the uveoscleral pathway, while the nitric oxide component induces relaxation within the trabecular meshwork. It works to increase aqueous outflow through the trabecular meshwork pathway and Schlemm’s canal [7]. There have been several studies completed to examine safety and efficacy of latanoprostene Bunod. The Apollo Study concluded that latanoprostene bunod demonstrated significantly greater intraocular pressure lowering than Timolol, another commonly used IOP lowering agent. The study shows that latanoprostene bunod was effective and safe in adults with primary open angle glaucoma and ocular hypertension over 3 months of treatment [13]. Another study compared the efficacy of Latanoprostene Bunod to Latanoprost. They were able to conclude that Latanoprostene Bunod was significantly more effective than Latanoprost at lowering IOP with similar side effects [14]. This is a significant study because Latanoprost is widely accepted as the clinical benchmark of glaucoma treatment to which other drugs should be compared.

6.2 Prostaglandin analogs

Prostaglandin analogs are the most widely used pharmacologic treatment for primary open angle glaucoma and for good reason. They have been the clinical gold standard of IOP lowering agents since the 1990s. They are extremely efficacious, present very little risk, and are easy to use with a dosage schedule of once a day before bed. It is important to review the physiology of prostaglandins to understand their mechanism of action. Prostaglandins are proinflammatory molecules produced when arachidonic acid is metabolized by cyclooxygenase enzymes, COX-1 and COX-2 [15]. Basal levels are produced by COX-1, and further increased by COX-2 [15]. The 5 classes of prostaglandins are E2, F2 (PGF2), I2, D2, and Thromboxane A [16]. Each of these molecules is able to elicit different responses when interacting with their corresponding G-protein coupled receptor (GPCR). FP receptor proteins in humans have been detected throughout the anatomy of the eye. They are located in the corneal epithelium, ciliary epithelium, the circular portion of the ciliary muscle, and iris stromal and smooth muscle cells [15]. FP receptors activate metabolism through G-coupled proteins, resulting in the increase of intracellular calcium concentrations and modulation of various signaling cascades [15]. Prostaglandin analog mechanism of action works through decreasing IOP by increasing uveoscleral outflow. They activate prostaglandin receptors in ciliary muscle, iris root, and sclera to effectively induce relaxation of ciliary muscle and alter cytoskeletal remodeling of the extracellular matrix of the uveoscleral pathway. They also may enhance aqueous outflow via FP receptors present in the trabecular meshwork by lowering resistance [15]. Binding to prostaglandin receptors in the ciliary muscle allows for widening and decompression of the fluid filled spaces along the ciliary muscle bundles [10]. Simply put, prostaglandin F2 analogs bind to prostaglandin receptors to promote muscle relaxation and extracellular matrix remodeling in the ciliary muscle and trabecular meshwork, increasing aqueous humor outflow. These mechanisms provide prostaglandin F2 receptor agonists like Latanoprost, Bimatoprost, and Travoprost with the ability to be very effective IOP reducing agents.

Prostaglandin analogs are the most effective known pharmacologic treatment in terms of IOP reduction for primary open angle glaucoma [7]. They are able to reduce IOP by as much as 25–33% [17]. They rose to prominence after FDA approval in the 1990s when their IOP lowering success and lack of serious adverse effects became widely known. They were able to rapidly replace beta blockers as the gold standard of glaucoma pharmacologic therapy. The brand name version of Latanoprost, Xalatan became the first drug to exceed 1 billion US dollars in annual sales [9]. Although valued for their lack of serious side effects, some adverse reactions are noted. These include conjunctival hyperemia, burning, stinging, eyelash growth and hyperpigmentation, increased periocular skin pigmentation, increased iris pigmentation and loss of periorbital fat. Additionally, some cases of cystoid macular edema as well as reactivation of herpes keratitis and anterior uveitis have been documented [7, 10]. The incidence of increased iris pigmentation was found to be higher than expected. One observational cohort study concluded that 69.7% of patients developed iridial anisochromia after chronic Latanoprost use [18]. Therefore, it is suggested to use Latanoprost bilaterally in order to avoid hyperpigmentation on one side of the face. However, a lack of serious systemic side effects keeps Latanoprost as the first line glaucoma medication.

Several clinical studies have examined the efficacy of prostaglandin analogs against other members of this class as well as against other intraocular pressure reducing agents. When comparing the IOP reducing effectiveness of prostaglandin analogs, Bimatoprost, brand name.

Lumigan, consistently ranks the highest. This is usually followed by Latanoprost and Travoprost.

One meta-analysis of 17 different clinical studies suggests that Bimatoprost is the most effective of these three commonly used prostaglandin analogs following long term treatment, but also appears to have the most adverse effects and lower ocular tolerability [19]. Reviews suggest similar findings, with the efficacy of Bimatoprost to be about 1 mm Hg reduction superior to Latanoprost, yet Bimatoprost having the least appealing adverse effect profile [9]. Although clearly deserving of medical use, Bimatoprost’s risk of lower ocular tolerability compared to Latanoprost puts Latanoprost ahead in terms of optimal clinical efficiency. Numerous additional studies prove prostaglandin analogs to be the most potent intraocular pressure reducing agents. One analysis displays the results of 50 studies with over 9000 patients included. Classes of IOP reduction used in the comparison includes beta blockers, alpha adrenergic agonists, and carbonic anhydrase inhibitors. It indicates that of all monotherapies examined, prostaglandin monotherapy showed the largest IOP reducing effect [20]. Another study examined the mean reductions in IOP after 3 months of usage. Bimatoprost averaged 5.61, Latanoprost 4.85, Travoprost 4.83, Timolol 3.70, Brimonidine 3.59, and Dorzolamide 2.59 mm Hg among others [21]. Prostaglandin analogs and specifically Latanoprost with its higher degree of ocular tolerability are well studied, potent, IOP reducing agents for glaucoma treatment. As the primary option for clinical use since the 1990s, new glaucoma therapies should continue to be compared against them.

7. Rho-kinase inhibitors

Rho-kinase inhibitors, also known as ROCK inhibitors are a relatively new class of antiglaucoma therapeutics. Netarsudil, brand name Rhopressa, was approved by the US Food and Drug Administration to be used for the treatment of glaucoma in 2017 [9]. Netarsudil is a an effective new therapy and is notable for its IOP lowering effects through a variety of different mechanisms. ROCK inhibitors work to decrease intraocular pressure (IOP) by inhibiting ROCK, a ubiquitous downstream effector protein that regulates the cell cytoskeleton [22]. ROCK consist of an amino-terminal serine-threonine kinase domain that is followed by a coiled-coilforming region and other functional motifs at a carboxyl terminus [22]. The carboxyl terminal domain forms an autoinhibitory loop that folds back onto the kinase domain and inhibits its activity [22]. The natural function of ROCK is to promote the assembly of actin stress fibers and focal adhesions within the trabecular meshwork [23]. As a potent rho-kinase inhibitor and amino.

Isoquinaline amide, Netarsudil also inhibits norepinephrine transporter (NET) [23]. There have been many animal studies that examine the effects of rho-kinase inhibitors. One study concluded that 2 ROCK inhibitors were able to relax ciliary arteries in rabbits to improve blood flow and suggested that they may have the potential to increase optic nerve blood flow to treat glaucoma [24]. Netarsudil is unique in that it has three proven mechanisms of action by which it reduces intraocular pressure in humans. It relaxes the trabecular meshwork, Schlemm’s canal, and ciliary muscle to increase aqueous humor outflow through the conventional trabecular pathway [22, 23]. It acts by decreasing actomyosin-driven cellular contraction and reducing production of fibrogenic extracellular matrix proteins [25]. It also reduces IOP by decreasing the production of aqueous humor as well as lowering episcleral venous pressure [23]. These different mechanisms make Netarsudil an effective pharmacologic glaucoma treatment, however more research is needed to further study its additional effects on animals in human trials.

Several clinical studies have occurred to examine the safety and efficacy of chronic Netarsudil use. In a 12 month long clinical trial of 756 eligible patients, the ROCKET-2 study group showed that the most frequently reported adverse effects associated with once daily Netarsudil use were ocular. The most common effect was hyperemia, followed by corneal verticillata and conjunctival hemorrhage [25]. All of these effects were reported as mild and there was no clinically meaningful impact of corneal verticillata on visual function upon observational follow up [25]. Other reported adverse effects of Netarsudil include instillation site pain, blurred vision, increased lacrimation, eye pruritus, and erythema of the eyelid [17]. Phase 3 clinical trials ROCKET-1 and ROCKET-2 reported that the Netarsudil was able to elicit statistically significant reductions from baseline intraocular pressure and was evaluated to be noninferior to the IOP reducing effects of Timolol on open angle glaucoma and ocular hypertension patients [26]. The mean decrease from baseline IOP for once daily Netarsudil ranged from 3.3–4.6 mm Hg while those for Timolol ranged from 3.7–5.1 mm Hg [26]. This provided a 16–21% decrease in intraocular pressure for Netarsudil and a 18–23% decrease in IOP with Timolol [26].

To truly evaluate the potential of Netarsudil to become a popular clinical treatment, it is important to compare it against the efficacy of Latanoprost. One clinical trial comparing Netarsudil to Latanoprost concluded that Netarsudil was approximately 1 mm Hg less effective than Latanoprost in patients with unmedicated intraocular pressures between 22 and 35 mm Hg [27].

Interestingly, they also remarked that the adverse effect of ocular hyperemia was more prominent in both tested concentrations of Netarsudil than they were for Latanoprost [27]. Additionally, many large scale literature reviews and meta-analyses have been conducted comparing the older but remarkably effective Latanoprost to the newly approved formulation of netarsudil. Results are generally consistent in suggesting that Netarsudil is inferior to Latanoprost in reducing intraocular pressure in primary open angle glaucoma and ocular hypertension patients. They also conclude that Netarsudil has the potential for more ocular adverse effects [28, 29]. Although consistently proving slightly inferior to Latanoprost and similar in efficacy to Timolol, netarsudil usage should continue to grow as a secondary line of defense against glaucoma. The unique 3 part mechanism by which it reduces intraocular pressure could be useful in treating secondary glaucoma or in patients who do not respond well to more established IOP reducing agents. With further research, clinical trials, and investigation into combination therapy, Netarsudil has the potential to become a frequently utilized pharmacologic glaucoma treatment.

8. Combination therapy

Fixed dose combinations (FDCs) are an extremely useful tool in treating primary open angle glaucoma. The use of multiple pharmacologic agents to treat glaucoma via different mechanistic pathways has long been common clinical practice. However, the development and subsequent use of fixed dose combinations often presents an increased efficacy to the components of the combination when used alone. Additionally, FDC’s have the potential to facilitate greater adherence to medical recommendations. Reducing the number and cost of topical drops for a patient will lead to easier instructions, happier patients, and better clinical outcomes. This is especially true in medically underserved communities. As discussed previously, glaucoma disproportionately affects Black and Latino populations, and these populations have been shown to be affected by higher rates of inconsistent follow up visits [30]. With better access to, and more efficacious fixed dose combinations, pharmacologic glaucoma therapy has the potential to increase its efficiency and improve patient outcomes.

Modern fixed dose combinations frequently used in the United States today include Dorzolamide-Timolol (Cosopt), Brimonidine-Timolol (Combigan), and Brinzolamide-Brimonidine (Simbrinza). These combinations are all efficacious in their IOP lowering potential. In one study comparing combination therapies, those with a prostaglandin analog demonstrated more powerful IOP lowering efficacy [20]. Consequently, the recently FDA approved fixed dose combination of Netarsudil-Latanoprost (Rocklatan), has been shown to be a potent anti-glaucoma medication. This is significant in that it combines the widely accepted prostaglandin analog that is known as the most efficacious IOP lowering agent, with a new drug with a unique and effective mechanism. In a phase 3 clinical trial comparing the safety and efficacy of Netarsudil Latanoprost with its individual components, it consistently outperformed both Netarsudil and Latanoprost monotherapy [31]. Netarsudil-Latanoprost FDC was superior to its individual components at each time point measured in the study. It lowered IOP by an additional 1.8–3.0 mm Hg vs. Netarsudil and 1.3–2.5 mm Hg vs. Latanoprost [31]. After 3 months of treatment, the proportion of patients achieving a mean diurnal IOP of less than or equal to 15 mm Hg was 43.5% for the FDC, 22.7% for Netarsudil, and 24.7% for Latanoprost [31]. Conjunctival hyperemia was the highest reported adverse effect and the range of effects was comparable to Netarsudil monotherapy. The FDC did however produce a higher percentage of conjunctival hyperemia with 53.4% patients compared to 41% with Netarsudil and 14% with Latanoprost [31].

Severity of effects however was reported as mild and it was concluded that the FDC of Netarsudil-Latanoprost was safe and effective for use. Pooled data by the researchers of the different phase 3 clinical trials confirms prior results concluding that once daily Netarsudil Latanoprost FDC produced statistically significant and clinically relevant reductions in mean IOP when compared to its individual components [32]. Additionally, a systematic review of clinical trials comparing Netarsudil-Latanoprost FDC to each component yielded similar results. It concluded that the FDC was superior in IOP lowering effectiveness, but with some concern over the higher incidence of adverse effects when compared with Latanoprost specifically [33]. With significant efficacy and the ease of once daily dosing, Netarsudil-Latanoprost has the potential to become a staple of combination glaucoma treatment.

9. Oral

The first generation of carbonic anhydrase inhibitors includes Acetazolamide, brand name Diamox. It is a potent IOP reducing agent with a 25–30% reduction possible [17]. Acetazolamide is different from other glaucoma medications in that it is often used in a pill form. It has been used as a systemic therapeutic to treat glaucoma for over 50 years, but presents significant adverse effects due to its inhibition of carbonic anhydrase in tissues other than the eye [17]. Therefore it is not recommended for chronic use and is best utilized as a temporary IOP reducing measure in instances of severe elevation. Medication in pregnancy is usually the second treatment option. The FDA classifies medication into pregnancy risk categories. Category A (no risk) to Category E (the highest risk). There are no class A glaucoma drugs on the market. Class B includes alpha adrenergic agonists (Brimonidine, Apraclonidine) and nonselective alpha and beta agonist (epinephrine). Class C drugs include beta blockers, carbonic anhydrase inhibitors and prostaglandin analogs. Netarsudil and Latanaprostene Bunod have yet to be classified. A great alternative is SLT therapy. Medication in children is usually safe, however caution should be taken to avoid the alpha adrenergic agonist brimonidine as it can lead to respiratory and CNS depression (lower level of consciousness and hypotonic). Medication in the elderly is safe as long as a thorough history is taken and all comorbidities are taken into consideration when prescribing any medication. As there are increased risks of underlying medical problems such as heart, lung, and kidney disease, any prescription given should be prescribed cautiously. Generic medications are usually safe and many insurance companies will only prescribe them. They have the same active ingredients and effect as brand name medications, but may be a different, size, color, or shape. They are usually less expensive than brand name medications. Many drug companies may make versions of the same medication. The FDA requires that the same active ingredients in brand name drugs are in generic drugs.

10. Natural therapies

Glaucoma management focuses on reducing intraocular pressure to halt visual field loss. Ophthalmologists are often required to invest massive amounts of time and energy when managing glaucoma cases by working to maintain IOP in a homeostatic range in order to preserve the anatomical integrity of the optic nerve [34]. In order to prevent this neuropathy from being expressed, vigorous medical interventions are required, and the treatment modalities should be personalized given the fact that no two individual cases of glaucoma are identical to each other [34]. Data indicates that by lowering IOP, there can be a beneficial impact on the slowing of glaucomatous progression [35]. The following natural substances have been identified in our review process as potential treatments to help reduce IOP in glaucoma patients while having limited to no adverse effects.

10.1 Persimmon leaves

Persimmon (Diospyros kaki) is native to Eastern Asia, including Korea, China and Japan [36]. It is plentiful in carotenoids (e.g., lutein and zeaxanthin), which can protect eyes from detrimental optic disorders, such as glaucoma, cataracts, and macular degeneration [36]. Just like its fruit counterpart, the persimmon leaves house copious amounts of biologically active compounds, including organic acids, polyphenols, flavonoids, and vitamins, most of which are known to exert beneficial treatment properties, such as aggressive radical-scavenging, antioxidant properties, and immune-enhancing traits [36]. In one particular study, Ahn et al. efficaciously created a microbeads-induced ocular hypertension glaucoma model and compared the results with those of DBA/2 mice, as both animal models develop age- dependent glaucoma phenotype. Furthermore, both animal models can effectively raise and sustain IOP, which is optimal for validating the pharmacologic efficacy of the persimmon leave extract. Undeniably, IOP in both the DBA/2 and microbeads-induced ocular hypertension mouse models was raised to a level substantially higher than that of the control group mice. Persimmon leave extract distribution via ocular eye drop absorption produced IOP values akin to those recorded from treatment with prostaglandin analogs (i.e., Xalatan), which is the most commonly used pharmacologic agent used in glaucoma management [37].

10.2 Omega-3-fatty acids

One specific dietary factor that has piqued the interest of researchers has been whether or not omega-3 essential fatty acids can prevent and/or support therapies for a host of prevalent health conditions, including glaucoma [38]. As omega-3 and omega-6 fatty acids compete in vivo for enzymes regulating their metabolism, the ratio of consumed omega-3 to omega-6 essential fatty acids regulates the inflammatory condition of the body, with omega-3’s amplifying prostaglandin metabolism which subsequently promotes the production of anti-inflammatory eicosanoids [38]. This chain reaction helps keep inflammation in the body to a minimum [38]. Data indicates that individuals who ingest high amounts of omega-3 essential fatty acids in their diet tend to express a reduced risk of heart disease mortality, abated age-related neurological decline, and a decreased risk of age-related macular degeneration. Additionally, an absence of omega-3 essential fatty acids may expose individuals to optic diseases in the elderly stages of life [38]. It serves that the possible perk of omega-3 fatty acid supplementation has undergone assessment in clinical trials for ocular diseases that show an increased prevalence with age, particularly age-related macular degeneration and glaucoma [39]. Data from the cross-sectional National Health and Nutrition Examination Survey indicated that elevated amounts of daily consumption of the long-chain, polyunsaturated omega-3 fatty acids, eicosapentaenoic acid, and docosahexaenoic acid, was associated with a lesser prevalence of glaucomatous optic neuropathy [39]. Moreover, in that same cross-sectional study, it was shown that the likelihood of an individual having glaucoma was nearly three times as high in individuals whose daily dietary total long-chain omega-3 consumption level was in the second and third quartiles, compared to those in the first quartile [39].

10.3 Ginseng

Ginseng, (i.e., the roots of Panax ginseng, P. notoginseng, and P. quinquefolius), has been broadly utilized as a panacea for a wide spectrum of medical conditions for many years and is currently being scientifically analyzed for its efficacy in the treatment of certain ocular diseases, such as glaucoma [40]. Numerous studies have shown the effects of ginseng extract or ginsenoside on all four of the major eye conditions previously listed in this review, including glaucoma [41]. The ability to unearth natural treatments that would replace more toxic and expensive pharmaceutical agents to prevent or prolong glaucomatous progression and subsequent blindness would sustain a higher quality of life while also simultaneously easing the financial burden associated with managing this condition. Investigations have been initiated to reveal the preventative and therapeutic effects of ginseng and ginsenosides on a multitude of ocular diseases. There have been some strong indicators that suggest the biochemical mechanisms of antiinflammation, antioxidation, elimination of waste products, and inhibition of vascular endothelial growth factor are thought to be involved in the therapeutic outcomes for this natural substance [41].

10.4 Curcumin

Curcumin (diferuloylmethane) is a compound derived from the rhizome of the Indian spice turmeric (Curcuma longa) and belongs to the class of micronutrients known as the polyphenols [42]. Curcumin has been observed to play a role in slowing, and in some cases, even reversing age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, proliferative vitreoretinopathy, and retinal cancers [43]. This makes curcumin a particularly interesting agent when examining natural treatment modalities for the treatment of retinal disorders and glaucoma.

10.5 Baicalein

Baicalein is categorized as a flavonoid glycoside. After it loses a water molecule via hydrolysis, it converts into a closely related aglycone known as Baicalein [44]. Baicalein is commonly found in the plants of the genus Scutellaria (Lamiaceae) as a major component of leaves, root bark, and fruit while Baicalin is found in bountiful amounts in stem bark and leaves [44]. There have been multiple investigations that have concluded that both these molecules have a tremendous capacity to function as powerful anti-inflammatory mediators [44]. One of the chief anti-inflammatory mechanisms that these molecules use is reducing oxidative stress in the cellular environment, which in turn improves the antioxidant status of the host cell [45]. Additionally, we encountered data demonstrating that baicalein suppresses the net chloride-transport and fluid movement across the excised ciliary epithelium, potentially reducing the aqueous humor formation and IOP [46].

10.6 Saffron

Saffron (Crocus sativus L.) is one of the oldest cultural and culinary spices used. Saffron ingestion has been shown to catalyze significant radical scavenging, anti-inflammatory, and anti-apoptotic activities in multiple investigations [47]. Biochemical pathways are activated from the diverse collection of bioactive agents housed in the spice. In one study, a total of 34 randomized subjects including 17 patients (7 female and 10 male individuals) were selected to be in the experimental saffron group and 17 other patients (6 female and 11 male individuals) were slotted to be in the placebo group [48]. The average baseline IOP measured 12.9 ± 3.7 versus 14.0 ± 2.5 mmHg in the saffron and control groups, respectively (p = 0.31) [48]. After 21 days of treatment, IOP was significantly decreased to 10.9 ± 3.3 mmHg in the saffron group as compared to 13.5 ± 2.3 mmHg in the control group (p = 0.013) [48]. Collectively, this set of data points strongly suggests that oral aqueous saffron extract seems to exert an ocular hypotensive effect in primary open-angle glaucoma patients.

10.7 Dietary nitrates

There is a consensus that dietary nitrates are fundamentally inert and are only activated biochemically after reduction to nitrite [49]. Nitrate serves as a source, via successive reduction, to produce nitrite and nitric oxide as well as a host of other metabolic compounds. In one specific study, the authors set out to find evidence that supports the association between dietary nitrate intake, derived from green leafy vegetables, and the onset of glaucoma. The key finding that arose from the data was that compared with the lowest quintile of dietary nitrate intake (80 mg/d), the highest quintile (240 mg/d) was associated with a 21% lower risk of all glaucoma and 44% lower risk of glaucoma with early paracentral visual field loss [50]. This key finding could have a significant impact on the future direction of treatment modalities for glaucoma if the association of higher dietary nitrate consumption is correlated with a lower glaucoma risk and this relationship is confirmed via observational or interventional studies [50].

10.8 Ginkgo Biloba

In modern times, Ginkgo biloba is one of the most prescribed and used herbal medicines in the United States with market sales of over $150 million in 2015 [51]. As far as a potential therapeutic agent for the management of glaucoma, there are three main properties of this herbal extract that make it appealing to researchers and ophthalmologists: (1) ability to increase vascular flow and reduce blood viscosity; (2) antioxidative inducing effects; and (3) neuroprotective enhancing properties [52].

10.9 Green tea

Green tea is an ancient Chinese drink derived from the Camellia sinensis plant. Green tea has been studied intensely for its possible protective effects against heart disease and cancer and this discussion is designed to probe its possible role in the treatment and management of glaucoma. We encountered a significant study which set out to show the therapeutic effect of green tea extract on ischemia-induced retinal ganglion cell degeneration in an animal model of rats. There were six fundamental takeaways that were reported to be significant out of this animal model study and they are as follows: (1) oral administration of 275 mg/kg of green tea extract was safe and no toxic or detrimental effects were observed in the retinas of the observed rats; (2) ischemic reperfusion induced retinal ganglion cell degeneration in rats; (3) ischemia injury induces a pathological cocktail of inflammation, oxidative stress, and cell apoptosis in the retina; (4) green tea extract treatment effectively ameliorates ischemia-induced retinal ganglion cell degeneration; (5) green tea extract treatment inhibited the pupillary light reflex and retinal ganglion cell impairment in rats Naturak Medication Options after induced ischemic injury; and (6) green tea extract treatment reduced cell apoptosis, oxidative stress, and inflammation and increased survival signal in the retina [53]. Together, these revelations highlight a significant protective effect of green tea extract on retinal ganglion cell degeneration caused by ischemia and suggest a beneficial therapeutic application of green tea extract for the management of glaucoma.

10.10 Hesperidin

Hesperidin is a major flavonoid found in almost all citrus fruit and various polyherbal formulations and is one of the chief nutrients of the vitamin P class [54]. Virtually all observed therapeutic mechanisms are associated with hesperidin’s ability to promote antioxidant defense mechanisms while concurrently suppressing the synthesis of pro inflammatory cytokines [55]. Flavonoids such as hesperidin, present a strong case for use as a therapeutic agent for glaucoma management due to their lower toxicity at higher doses and prolonged period of treatment duration that has been shown in animal model studies [56]. In one study, Lu et al. selected hesperidin due to its strong antioxidant potential. Kara et al. have reported the therapeutic effect of hesperetin against apoptosis in ischemia-induced retinal injury model of rats [56]. Moreover, Maekawa et al. have described the neuroprotective effect of hesperidin in N-methyl-D-aspartate -induced retinal injury [56]. There have been multiple experiments that have highlighted the therapeutic potential of bioflavonoids against ocular disorders. Estruel-Amades et al. have noted the therapeutic potential of hesperidin against oxidative stress in rats [56]. This data indicates that hesperidin supplementation was effective against glaucoma in experimental rat models.

11. Lifestyle modification

As with most chronic conditions, the expression of different glaucoma prevalence rates within different subsets of our populations is due to a delicate balance of both genetic and environmental factors being co-expressed simultaneously. Therefore, no review on natural treatments for the management of glaucoma would be complete without addressing the fundamental areas of key lifestyle modifications that can be implemented to improve upon the prevention and treatment regrading desirable health outcomes of glaucoma cases. There have been a multitude of active chemical compounds identified in tobacco smoke that have been found to have toxic ocular effects via oxidative pathways or ischemic mechanisms [57]. We identified a recent study derived from a population sample drawn from the United States National Health and Nutrition Examination Survey that identified the correlation that high volume smoking (i.e., multiple packs of cigarettes per day) was associated with greater risk of the onset of glaucoma with a specific odds ratio being calculated at 1.7 [58].

One of the most studied lifestyle modifications is exercise. It has been demonstrated that aerobic inducing exercises can lead to decreased IOP, while activities such as yoga and strength training (i.e., isometric exercise) can have the inverse effect of raising IOP levels by increasing intrathoracic pressure [59]. When specifically examining the association between glaucoma prevalence rates and exercise participation, there was an influential population-based study that highlighted a U-shaped association for male participants in the study [60]. This nonlinear data showcased the association of high and low levels of exercise intensity with higher prevalence rates of glaucoma when evaluated against data produced from moderate intensity exercise sessions [60]. Therefore, it seems reasonable to state that exercise, when performed ideally at a rate of three times a week can be suggested to improve a patient’s general health and decrease risk of glaucoma.

12. Racial and ethnic disparities in glaucoma

Disparities in healthcare exist across a wide range of diseases and medical conditions. It is important to acknowledge racial and ethnic disparities when reviewing a specific disease in order to promote awareness and improve patient outcomes. Members of minority groups in the.

United States and the world often have less access to and receive lower quality medical care than White individuals. They also have lower rates of representation in clinical studies than White Americans. This presents a significant problem in the treatment of glaucoma. The standard treatment for primary open angle glaucoma is reducing intraocular pressure. Therefore, it is critically important to adhere to medical and surgical appointments and to follow therapeutic regiments in order to increase clinical outcomes. Black and Latino racial and ethnic patient status has been shown to be an independent risk factor for inconsistent follow up visits at appointments and lower rates of glaucoma testing. Cost, health literacy, and access to screening are some of the greatest obstacles that Black and Latino patients face with respect to glaucoma [30, 61]. Another factor that could add to this disparity is that less than 2% of ophthalmologists in the United States identify as Black or Latino [30]. This has the potential to negatively affect patient interactions, trust, communication, and satisfaction.

13. Disparities in care: clinical trials and beyond

Globally, it is estimated that 76 million people suffer from glaucoma with a projected jump to 112 million by 2040 [2]. This number indicates the importance of studying this disease and continuing to search for therapeutics that can improve patient outcomes. This involves improving racial and ethnic diversity in study participants. Glaucoma has been shown to affect Black and Latino populations at a significantly higher rate than White populations in the United States. It is reported that this disease is 7 times more likely to cause blindness in Black individuals when compared with White individuals, and 15 times more likely to cause visual impairment in Black individuals than White individuals [62]. As mentioned previously, primary open angle glaucoma (POAG) is the most common form of glaucoma. Additional statistics indicate that Black individuals had a higher prevalence rate of POAG than White individuals in the United States. Black persons had the highest rate at 3.4% while White persons had a rate of 1.7% [62]. Additionally, increasing the diversity of clinical study participants will help with understanding how to better improve clinical outcomes for Black and Latino populations. Allison et al. reported that between 1994 and 2019, White participants made up 70.7% of study populations, while Black participants made up only 16.8% and Latino individuals only 3.4% [62]. It has been theorized that there could be genetic variants associated with the increased rate of glaucoma in Black populations. However, previous observational studies have proven to be inconclusive [62]. It is commonly agreed upon that further research is needed to study the genetic mechanisms of primary open angle glaucoma.

Although more genetic studies into POAG disparities in race and ethnicity need to be performed, it is clear that that socioeconomic status plays a central role in these epidemiologic differences. Socioeconomic status is a social determinant of health and it is commonly understood that racial and ethnic minority groups in the United States experience more socioeconomic disadvantages when compared to White individuals [62]. As socioeconomic disadvantages increase, the use of eye care services for age related diseases decreases [63]. Minority populations in the United States are underserved and over-affected by POAG.

14. Conclusion

Glaucoma is the leading cause of irreversible blindness worldwide. With a population of patients expected to grow to 112 million people globally by 2040 [2], it is important to continue to develop new pharmacologic therapies to control intraocular pressure. While the prostaglandin analog latanoprost continues to be the widely accepted first line IOP reducing agent used today, the recently developed Rho-kinase inhibitor netarsudil, and fixed dose combination of netarsudil-latanoprost should continue to increase in utilization as both second line and combination therapy drugs. In addition to once daily dosing and complementary mechanisms of action, future directions of glaucoma treatment should work to increase clinical outcomes through more research on natural therapeutics, sustained release mechanisms, and achieving longer acting effects. Prioritizing patient care by decreasing medication burden will lead to increased compliance, improved satisfaction, and better patient outcomes.