Medical Therapy of Glaucoma

Medical Therapy of Glaucoma
Simon K. Law
Joseph Caprioli
The definition of glaucoma has changed considerably over the past several decades. The disease is no longer defined as elevated intraocular pressure (IOP) but rather a disorder consisting of characteristic optic nerve head and visual field abnormalities.1 Major risk factors for the development of glaucomatous optic nerve damage include the level of IOP,2,3,4,5 increasing age,6 black race,7 positive finding for the condition in the family history,8 and thin central corneal thickness9 IOP remains the only risk factor readily amenable to therapy; therefore, almost all currently used strategies for the treatment of glaucoma are aimed at lowering or preventing a rise in IOP.
The ultimate goal of most treatments in medicine is to improve quality of life while minimizing associated side effects and costs. The goal of glaucoma treatment is to improve quality of life through the preservation of visual function. Medical treatment of glaucoma has associated side effects, complications, and costs. This chapter will review medications that reduce IOP in chronic glaucoma. In addition, medications that are useful in treating acutely elevated IOP are reviewed, and newer, non–pressure-related neuroprotective strategies are surveyed.
AQUEOUS HUMOR DYNAMICS
Aqueous humor is actively secreted by the ciliary epithelial bilayer into the posterior chamber by an energy-dependent active process. The net fluid secreted is an osmotic consequence of Na+, K+-adenosine triphosphate ATP-ase driven sodium movement10,11 and HCO3 generation.12 Formation of bicarbonate within the ciliary epithelium involves the reaction of H2O and CO2 enzymatically promoted by carbonic anhydrase. In addition, amino acids and ascorbate are actively transported into the posterior chamber. In normal human eyes, the rate of aqueous humor formation averages 2.5 to 2.8 μL/min, which is enough to replace the entire anterior chamber volume once every 100 minutes. The rate of aqueous formation is independent of IOP, with the exception of extremely high pressures, which can compromise ciliary circulation.12
Aqueous flows from the posterior chamber through the pupil into the anterior chamber and is drained from the eye by structures within the iridocorneal chamber angle. In the normal human eye, 80% to 90% of aqueous outflow is through the trabecular meshwork into Schlemm’s canal and enters the systemic circulation by way of intrascleral and episcleral veins. This outflow is commonly termed conventional outflow and is characterized by IOP dependency. Rate of conventional outflow is thus a function of both the hydrostatic pressure gradient and the resistance (R) across the trabecular meshwork. About 10% to 20% of aqueous humor in normal human eyes traverses the ciliary muscle to reach the suprachoroidal space and leaves the eye through the sclera or blood vessels.13 This second type of outflow is called uveoscleral outflow and is IOP independent.14,15 Mathematical formulas that attempt to describe aqueous humor dynamics have been derived.16
Under steady-state conditions, aqueous inflow must equal total outflow. Thus,
where Fin equals inflow of aqueous into the posterior chamber, Ftrab equals conventional outflow, and Fu equals uveoscleral outflow. A direct relationship between pressure and flow generally holds true for conventional outflow, in which the pressure gradient is that between the IOP and the episcleral venous pressure (Pv), at least throughout the normal range of IOP. Uveoscleral outflow, however, when measured experimentally in monkeys, appears largely independent of pressure, averaging 0.5 μL throughout normal IOP ranges. (Total outflow is higher through the uveoscleral route in monkeys [up to 40%]17 than it is in humans [10%]).18 Thus, Eq. 1 can be written as follows:
or
Conductivity, the inverse of resistance, is used by convention and is termed outflow facility (C). Thus, R = 1/C. Substitution yields what is often termed the modified Goldmann equation:
Methods have evolved to measure most components in Eq. 3. IOP is measured directly with tonometry. Fin is estimated by fluorophotometry and averages 2.5 to 2.8 μL/min. Outflow facility is usually estimated with tonography, whereby corneal indentation is used to cause elevated IOP. The rate of recovery of IOP to baseline is inversely proportional to conventional outflow resistance. Pv, episcleral venous pressure, is normally around 10 mm Hg and can be measured directly with a special manometer. Uveoscleral outflow (Fu) can be calculated only in normal human eyes but has been estimated with invasive techniques in experimental animals. The microscopic pathways of uveoscleral outflow are not entirely understood.
Elevated IOP is usually the result of a reduced outflow facility (C), rarely the result of elevated episcleral venous pressure (Pv), and essentially never the result of increased aqueous production (Fin).
Medical strategies to lower IOP manipulate three components of Eq. 3: aqueous inflow, conventional outflow, and uveoscleral outflow (Table 1). These three variables ([FinFu]/C) together can be termed outflow pressure. This is easily estimated, as outflow pressure = IOP – Pv. The fourth variable, episcleral venous pressure, cannot be altered pharmacologically and presents a theoretic limit for the amount of pressure lowering attainable through medical means. If, for example, Fin were almost completely suppressed, IOP would approach Pv. Of course, certain situations do exist in which IOP falls below Pv; however, these are usually pathologically or surgically induced. Pathologic examples include severe inflammation, phthisis bulbi, choroidal separation, and retinal detachment.
TABLE 1. Effect of Ocular Hypotensive Classes on IOP and Aqueous Dynamic Components
Class IntraocularPressure AqueousProduction ConventionalOutflowFacility UveoscleralOutflowFacility EpiscleralVenousPressure
Nonselective β-blocker ↓ 20%-30% ↓35%
β1-Selectiveβ-blocker ↓ 15%-25% ↓25%
Direct miotic ↓ 15%-25% ↑25%
Indirect miotic ↓ 20%-30% ↑35%
Nonselective adrenergic agonist ↓ 15%-25% ?
α2-Agonist ↓ 20%-30% ↓35% ?
Carbonic anhydrase inhibitor ↓ 20%-35% ↓35%
Prostaglandin analogue ↓ 25%-35% ↑100%
The outflow pressure concept is useful for predicting the amount of pressure reduction attained with specific medical strategies. This concept explains why given therapies do not lower IOP by a constant amount or percentage. For example, a strong miotic agent usually decreases outflow pressure by about 40% by increasing outflow facility. If pretreatment IOP was 40 mm Hg and the Pv is 10 mm Hg, the outflow pressure of 30 mm Hg would be reduced by 40% down to 18 mm Hg, and the IOP would be reduced to 28 mm Hg (10 mm Hg + 18 mm Hg). If the pretreatment IOP was 20 mm Hg, the outflow pressure of 10 mm Hg would have been reduced by 40% to 6 mm Hg, for a resultant IOP of 16 mm Hg (10 mm Hg + 6 mm Hg).
Typically, the magnitude of IOP lowering for a given drug is greater when the drug is used singly than when it is used in combination with other pressure-lowering agents. For example, if pretreatment IOP is 40 mm Hg and Pv is 10 mm Hg, a nonselective β-blocker or moderate miotic each can reduce outflow pressure by 40% when used alone. The β-blocker alone reduces the 30-mm Hg outflow pressure by 40% down to 18 mm Hg, for an IOP of 28 mm Hg. Adding the miotic reduces the new 18-mm Hg outflow pressure to 11 mm Hg, for a final IOP of 21 mm Hg. Note that the first drug reduced the IOP by 12 mm Hg, whereas the second drug dropped it only another 7 mm Hg, assuming equal outflow pressure percentage reductions.
The modified Goldmann equation and the outflow pressure concepts predict that it is impossible to lower IOP below Pv if only Fin, C, and Fu are manipulated. In general, it is difficult to reduce IOP below about 10 mm Hg through medical therapy.
RECEPTOR PHYSIOLOGY
Many commonly used glaucoma drugs are thought to act through sympathetic or parasympathetic pathways. A review of current concepts regarding adrenergic and cholinergic signal transduction is germane to understanding drug efficacy, interactions, and side effects. Norepinephrine is the neurotransmitter released at most sympathetic, postganglionic synapses, and the receptors that bind norepinephrine and other catecholamines are termed adrenergic receptors. In contrast, parasympathetic, postganglionic neurons release acetylcholine (ACh), which is bound by cholinergic receptors. Both systems involve interaction of cell-surface receptors with regulatory proteins located within the cytoplasm that activate or inhibit specific cell functions. Agonist drugs activate receptors, whereas antagonists block the function of receptors.
Adrenergic Pathways
Many medical agents used in glaucoma therapy act through adrenergic receptors. Classification of adrenergic receptors has evolved since 1948 when Ahlquist19 proposed a subdivision into α- and β-subgroups on the basis of relative agonist potency. For the β-adrenergic receptor, the division into β1 and β2 was originally based on relative potencies of epinephrine and norepinephrine. The β1-adrenergic receptors, such as those mediating positive inotropic cardiac effects, are equally responsive to epinephrine and norepinephrine; β2-adrenergic receptors, such as those found in bronchial and vascular smooth muscle, are much more responsive to epinephrine. Subsequently, β3-receptors were identified as a distinct third β-adrenoceptor subtype; β3-receptors are distributed in fat cells and involved in the regulation of lipolysis.
The α-receptors are divided into α1– and α2-groups. The α1-receptors, the original postsynaptic α-receptors, are found in vascular smooth muscle, where they mediate the vasoconstrictor effect of sympathetic stimulation. Selective α1-agonists include phenylephrine and methoxamine. The α2-receptors were initially believed to be localized only to presynaptic norepinephrine synapses but have since been found in postsynaptic locations as well. Clonidine is a selective α2-agonist.
Beside the α- and β-receptors, specific dopamine (D) receptors were identified to interact with the endogenous catecholamine dopamine of the adrenergic pathways. These receptors are important in the brain and in the splanchnic and renal vasculature.
Pharmacologic experiments demonstrated that there are distinct subtypes within the α-, β-, and D-receptors. The known subtypes in the α1-family include α1A, α1B, α1D, in the α2-family include α2A, α2B, α2C, in the β-family include β1, β2, β3, and in the D-family include D1, D2, D3, D4, and D5. The importance of these various subtypes is their mediation of receptor responses in a variety of organs and efficacy and adverse effects of their agonists.
Signal transduction refers to a series of specific cellular responses initiated by the binding of a hormone (signal) to its specific receptor binding site. Our understanding of signal transduction has expanded greatly since the discovery of coupling proteins, termed G-proteins, which regulate specific cellular enzymes or ion channels. Each G-protein is a heterotrimer consisting of α-, β-, γ-subunit determines receptor and effector specificity. All G-proteins are capable of binding guanylyl nucleotides and possess guanosine triphosphatase (GTPase) activity. When receptors are activated by agonist binding, they are able to catalyze the transfer of guanosine diphosphate (GDP) bound to the G-protein for cytoplasmic GTP. This transfer causes release of the active α-subunit from the αβ-unit. The activated GTP-bound αsubunit then regulates the activity of its effectors.
G-proteins of particular importance for adrenoceptor function include Gs, the stimulatory G-protein of adenylyl cyclase; Gi, the inhibitory G-protein of adenylyl cyclase; and Gq, the protein coupling αreceptors to phospholipase G.
Stimulation of α1-receptors by agonists leads to the activation of the Gq coupling protein. The α-subunit of this G-protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacyl-glycerol) from phosphatidylinositol 4,5-bisphosphate. IPs stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic calcium. Calcium may then activate calcium-dependent protein kinase, which in turn phosphorylates its substrates. DAG activates protein kinase C, which modulates the activity of many signaling pathways. In addition, α1-receptor activates signal transduction pathways that were originally described for peptide growth factor receptors, which activate tyrosine kinase.
Binding to β-adrenoceptors stimulates adenylyl cyclase by activating the stimulating G-protein, Gs, which leads to the dissociation of its α-subunit charged with GTP. This αs-subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cyclic adenosine monophosphate (cAMP). On the other hand, α2-adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G-protein, Gi, into its subunits; i.e., an αi-subunit charged with GTP and a βγ-unit. cAMP binds to the regulating subunit of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits that phosphorylate specific protein substrates and modify their activity.20
The active α-subunit activity is self-regulated because the inherently contained GTPase activity converts the recently bound GTP back into GDP, causing reassociation with the other subunits and functional inactivity.21
Various opinions exist regarding the relation between cAMP levels and aqueous formation. It is tempting to explain the effect of the β-blockers on reducing aqueous flow by means of an inhibition of β2-receptor activity, a reduction in Gs stimulation of adenylyl cyclase, and a lowering of cAMP levels. Undoubtedly, the mechanism is more complex because agents that increase cAMP, such as cholera toxin and forskolin, lower IOP.22,23
Cholinergic Pathways
ACh is the neurotransmitter released at autonomic preganglionic, parasympathetic postganglionic, and a few sympathetic postganglionic and somatic motor endings. ACh synthesis by choline acetyltransferase is regulated by choline kinase. Acetylcholinesterase, the enzyme that degrades ACh, is located in cholinergic nerves, synapses, and neuroeffectors.
There are two general types of cholinergic receptors: those stimulated by muscarine and those stimulated by nicotine, hence the names muscarinic and nicotinic receptors. Both receptors are found in the central nervous system (CNS) and ganglia. Muscarinic receptors are also found on smooth muscle fibers, and nicotinic receptors are found on striated muscle fibers. In recent years, these two cholinergic subtypes have been further classified. Five muscarinic subtypes and two nicotinic subtypes have been described (M1 through M5, N1 and N2). The muscarinic receptors are similar to those described in the adrenergic section in that their action is coupled to specific G-proteins. M1, M3, and M5 activate phospholipase C through inositol phosphates and diacylglycerol and can stimulate the release of arachidonic acid. Stimulation of M2 and M4 inhibits adenylate cyclase.24
Some published studies suggest that all five muscarinic receptor subtypes are found within the ciliary muscle.25,26 The early hope of dissociating the accommodative and outflow effects of miotic agents has not yet been borne out. It appears that both effects result from stimulation of the M3 receptor subtype.27
Although second-messenger pathways for the adrenergic and cholinergic systems share similarities, it is important to understand that the specific surface receptors may be differentially distributed in various cell types. Levels of specific hormones may also vary because of regional differences in innervation. For example, parasympathetic fibers predominantly innervate the ciliary muscle and iris sphincter, but it is unclear if the ciliary epithelium receives significant sympathetic innervation.
In addition, seemingly identical signal transduction pathways can give rise to different responses in various cell types. For example, the β-receptor agonist isoproterenol, acting by way of cAMP pathways, can cause an increase in contractility in cardiac muscle and relaxation in other smooth-muscle locations.
CLINICAL TRIALS AND RISK FACTORS
That IOP should be lowered in most cases of untreated, chronic glaucoma generates little debate. In fact, elevated IOP is considered to be a major risk factor of glaucoma, and IOP reduction has been proven to have a protective effect. In the Early Manifest Glaucoma Trial (EMGT), patients with newly detected open-angle glaucoma with early glaucomatous visual field defects were randomized to treatment with laser trabeculoplasty plus topical betaxolol hydrochloride or no treatment. After 6 years, it showed that the risk of progression was halved by treatment that reduced the IOP by an average of 25%, or approximately 5 mm Hg. In the progression analysis, the risk of progression increased by 10% for each mm Hg of higher baseline IOP.28 For patients with ocular hypertension without glaucomatous otic neuropathy or visual field defects, the Ocular Hypertension Treatment Study (OHTS) showed that an average of 22.5% decrease in IOP with topical ocular hypotensive medication was effective in reducing the development of primary open-angle glaucoma (POAG) from 9.5% in controls to 4.4% in treated patients at 60 months’ follow-up.29 The Collaborative Normal Tension Glaucoma Study (CNTGS) found that reducing IOP by greater than 30% reduced the rate of visual field progression from 35% to 12%, confirming a clear role of IOP, even in normal-tension gluacoma.30
In the Advanced Glaucoma Intervention Study (AGIS), which compared the clinical outcomes of two treatment outcome sequences for patients with open-angle glaucoma uncontrolled by medical therapy, eyes with 100% of visits with IOP less than 18 mm Hg over 6 years had mean changes from baseline in visual field defect score close to zero during follow-up. The mean IOP over the first 6 years of follow-up is 12.3 mm Hg for these eyes. In addition, it showed a dose-response relationship between IOP and change in visual field defect score.31 In a follow-up analysis to investigate the risk factors associated with visual field progression with pointwise linear regression analysis of serial visual fields, increasing age (each 5-year increment in age) and greater IOP fluctuation (each 1-mm Hg increase in IOP fluctuation) were associated with increasing the odds of visual field progression by 30%.32
However, some patients continue to suffer disease progression despite the reduction in IOP. Clearly, other risk factors exist, both major (age,6,33,34 race,7 family history,8 thin central cornea35) and minor (diabetes,36 hypertension, myopia).37,38 Major clinical trials in the last two decades have identified other risk factors of disease progression, including reduced central corneal thickness, pseudoexfoliation, frequent disc hemorrhage, and migraine headache.35,39,40 The level of importance of these risk factors remains uncertain. The significance of other risk factors such as vasospasm and antoimmunity are being evaluated.
Target Pressure
For cases in which pressure lowering is indicated, how much is enough? Over the past several decades, the emphasis has shifted from normalizing a statistically elevated pressure to lowering a damaging pressure to a safe range.1 This range of pressure deemed unlikely to cause further optic nerve damage in an individual with glaucoma is the target pressure. It should be regarded as an estimate and a means toward a goal of protecting the optic nerve. However, there are some problems in estimating the target pressure range, where there is no priori way of determining the IOP below which optic nerve damage will be slow. The target IOP may vary among individuals and with the course of disease in an individual. Some patients may have a pressure-independent component of damage, and continue to suffer a deterioration of the optic nerve despite aggressive reduction of the IOP. In addition, prospective studies of specific target pressures using medical therapy only are not available. We must thus formulate target pressures based on studies designed for other purposes, such as studies comparing medical versus surgical treatment modalities. One problem with this process is that it neglects other important variables, such as IOP fluctuation and compliance.
Trabeculectomy often lowers IOP to a mean level of about 12 mm Hg, and most surgically successful cases have little diurnal or intervisit fluctuation in IOP. Medical therapy can also be used frequently to lower IOP to similar levels, but often with greater diurnal and intervisit variability. This greater IOP fluctuation may increase the progression of glaucomatous optic neuropathy.32,41,42,43 Another important difference between surgical and medical treatment is the issue of poor patient compliance. Patients who have had successful filtering surgery often do not depend on medication for IOP control and probably have “real life” IOPs similar to those measured in the physician’s office. It is well known that poor compliance with medical therapy often exists, and these poorly compliant patients probably have “real life” IOPs considerably higher than their optimized office levels.
Several important studies have influenced establishment of current target pressures. Chandler,44 in 1960, anecdotally noted that advanced glaucoma could often be stabilized if IOP was lowered to low-normal levels. In 1982, Grant and Burke45 expanded this concept with retrospective studies of patients declared legally blind from glaucoma at the Massachusetts Eye and Ear Infirmary in Boston. They concluded that stage I glaucoma (little visual field damage) could be stabilized with an IOP in the low 20s, stage II glaucoma (visual field loss in one hemifield) could be stabilized with an IOP in the high teens, and stage III glaucoma (visual field loss in both hemifields) could be stabilized with an IOP in the midteens. These observations were made during a time when kinetic perimetry and direct ophthalmoscopy were commonly used to evaluate glaucoma, and normal-tension glaucoma was less likely to be diagnosed. Nevertheless, they support the generally accepted concept that advanced damage requires an IOP lower than that of early damage.
Mao et al.,46 in a retrospective study of early glaucoma (half these patients had normal visual fields), stratified pressure into three levels and found the chance of progression to be 100% if IOP was above 21 mm Hg, 53% if IOP was between 17 and 21 mm Hg, and 0% if IOP was below 17 mm Hg. Odberg,47 in a study of advanced glaucoma, also stratified IOP and found 33% progression if IOP was below 16 mm Hg, 47% progression if IOP was 10 to 20 mm Hg (mostly below 16 mm Hg), 82% progression if IOP was 10 to 20 mm Hg (mostly above 15 mm Hg), 84% progression with some IOPs above 20 mm Hg, and 100% progression with IOP always above 20 mm Hg. Other studies, including those of Kolker48 and Quigley and Maumenee,49 suggest that long-term IOP maintained in the midteens has a generally favorable prognosis.
A comparison of Mao et al.’s and Odberg’s studies suggests that patients with more advanced damage require a lower IOP to stabilize their glaucoma. More current clinical trials tend to favor this concept.
For instance, the Advanced Glaucoma Intervention Study (AGIS) showed a dose-response relationship between IOP and change in visual field defect score. Eyes with 100% of visits with IOP less than 18 mm Hg over 6 years had mean changes from baseline in visual field defect score close to zero during follow-up. The mean IOP over the first 6 years of follow-up is 12.3 mm Hg for these eyes.31
A second reason to favor the philosophy of more aggressive IOP lowering to treat more advanced glaucomatous damage is based on “room for error.” Patients with advanced field loss but good central acuity may have less room to progress without dire visual consequences compared with those with earlier disease.
The studies on “high-tension” glaucoma patients (with their emphasis on absolute level of IOP achieved with treatment) are of less value to the patient who is discovered to have progressive cupping or visual field loss despite lower IOPs (below 22 mm Hg). These “low-tension” glaucoma patients often exhibit more advanced damage in the eye with the higher IOP50,51 and have been shown in an early report to benefit from pressure lowering.52 The Collaborative Normal Tension Glaucoma Study (CNTGS) confirmed a clear role of IOP reduction by showing that reducing IOP by greater than 30% reduced the rate of visual field progression from 35% to 12%.30 However, there were a significant number of patients who continued to experience disease progression despite a reduction of IOP. It is possible that in this population in particular, the target pressure should be set lower, though additional IOP independent risk factors of disease progression may be present.
Several different strategies to define target IOPs have been described. One simple goal (simple to define but not necessarily to achieve) is to target all high-tension glaucoma (IOP consistently above 25 mm Hg before treatment) to an IOP in the high teens if the damage is mild, the midteens if the damage is moderate, and the low teens or lower if the damage is severe. Another proposed target is a 30% to 50% reduction in the highest untreated pressure at which the patient suffers progressive damage.
The Collaborative Initial Glaucoma Treatment Study, a multicenter trial attempting to define the best treatment for newly discovered glaucoma, uses the following equation:
where the reference pressure represents the baseline pretreatment IOP and the visual field score is based on the Advanced Glaucoma Intervention Study technique for scoring visual field damage.53 These visual field scores range from 0 (no damage) to 20 (all sites deeply depressed). One problem with this technique is its requirement for reliable perimetry to provide the visual field score. In addition, the scoring process itself is somewhat complex and time-consuming. A useful alternative technique uses the following equation:
where D is a constant based on the level of glaucomatous damage (perhaps modified by other risk factors). We recommend approximate D values of –6 for no evidence of damage, 0 for mild damage, 3 for moderate damage, and 6 for severe damage. These D values produce a pressure threshold in the high 20s for initiating therapy in an eye without evidence of damage (normal visual field and optic nerve head) (Table 2). In a patient with a reproducible pattern of visual field loss, the level of damage is probably best determined by perimetry (Table 3).54 In patients unable to provide reliable, repeatable quantitative perimetric data, emphasis should be placed on the status of the optic nerve head and nerve fiber layer combined with assessments of confrontation visual field testing and central acuity to determine the level of damage.
TABLE 2. Target IOP (mmHg)a
Initial Iop(mm Hg) Level of Damage
None Mild Moderate Severe
15 18-18b 12-13 9-10 6-7
20 22b 16 13 10
25 24-25b 18-19 15-16 12-13
30 27 21 18 15
40 30 24 21 18
aBased on target IOP = initial IOP[(100 – initial IOP)/100] -D, where D = -6 for nodamage, 0 for mild damage, +3 for moderate damage, and +6 for severe damage.bTarget > initial; no treatment needed.
TABLE 3. Criteria for Assessing Level of Damage Based on Humphrey Visual Field
Mild
Damage should be neither extensive nor near fixation. The following three conditions shouldbe met:
The mean deviation (MD) plot is less than -6 dB.On the pattern deviation plot, fewer than 25% of the points (18 points) are depressed below the5% level, and fewer than 10 points are depressed below the 1% level.
No point in the central 5° has a sensitivity of <15 dB.
Moderate
Damage may be significant, but there should not be profound central field damage, and thereshould not be significant central field damage in both hemifields. The following four conditionsshould be met:
The MD is less than -12 dB.
On the pattern deviation plot, fewer than 50% of the points (37 points) are depressed below the5% level, and fewer than 20 points are depressed below the 1% level.
No point in the central 5 has a sensitivity of 0 dB.
Only one hemifield may have a point with a sensitivity of <15 dB within 5° of fixation.
Severe
Any of the following findings indicate severe field loss:The MD is greater than -12 dB.On the pattern deviation plot, more than 50% (37) of the points are depressed below the 5%level, or more than 20 points are depressed below the 1% level.Any point in the central 5 has a sensitivity of 0 dB.
There are points within the central degrees with a sensitivity of <15 dB in both hemifields
Data from Hodapp E, Parrish RK, Anderson DR: The asymptomatic patient with elevated pressure. In Clinical Decisions in Glaucoma. St Louis: CV Mosby, 1993:53.
Since there is no evidence for a variable reduction of IOP for patients at different stages of glaucomatous optic neuropathy, one approach is to apply a single target IOP range of low teens (10 to 12 mm Hg) with little fluctuation (standard deviation less than 3 mm Hg) to most POAG patients based on the results of the Advanced Glaucoma Intervention Study.31,32 Although there is a better chance to slow the progression of glaucoma at this level, it may be more difficult to achieve therapeutically with increase risk of associated adverse reaction from medication or surgery.
Although recommended for virtually all chronic glaucomas, establishment of an appropriate target pressure is probably of greatest importance in the patient with advanced disease with visual field loss impinging on central visual function. In these cases, any progression could cause significant functional compromise. In contrast, the patient with early disease can suffer subtle progression without a significant change in visual function.
Establishing a Baseline
The derivation of a target pressure in a specific patient is multifactorial, individualized, and based on the current level of damage, pretreatment IOP range, the patient’s expected life span, and specific risk factors. The goal of the process is to predict the IOP that will slow the disease enough to maintain acceptable visual function for the remainder of the individual’s life. By definition, it is a prospective process (i.e., an educated guess) and will almost certainly be inadequate in selected patients in the sense of being either overly aggressive with unnecessary costs and side effects or relatively ineffective with an undesired rate of continued progression toward visual compromise.
Diurnal IOP measurements can be valuable in establishing a baseline IOP level, especially in patients without elevation of IOP who demonstrate severe optic neuropathy. However, it is usually impractical to obtain 24-hour IOP measurements. Serial IOPs are usually obtained during regular office hours and limited to 8 to 10 hours in the daytime, and IOP fluctuation at other hours are not measured. One practical alternative is to obtain a baseline range of IOP from several visits with IOP checked at different times of the day. Such a range of IOP control after treatment has been initiated can also be used to assess the stability of the visual field and optic neuropathy. Since individual central corneal thickness that deviates from average can artefactually affect IOP measurements, central corneal thickness should also be measured before setting a target IOP.
It is important to continuously reassess the appropriateness of the target pressure in each patient. This process should include a constant search for ocular and systemic side effects, some of which can be extremely subtle. In addition, evidence of disease worsening should be explored. In general, detection of glaucoma progression involves repeatedly assessing the visual field status and optic nerve head and nerve fiber layer appearance. Perimetry, despite recent computerized advances, remains a subjective technique with sizable long-term fluctuations, particularly in moderately damaged portions of the visual field. The detection of subtle progression is best aided by performing several baseline visual field tests, especially in a perimetrically naive patient, to neutralize the learning effect and establish the patient’s inherent variability. Subtle progression should, in general, be confirmed with additional follow-up studies to minimize regression to the mean and false-positives. Establishing a baseline level of optic disc damage typically involves obtaining high-quality stereoscopic optic disc photographs for future comparisons. Quantitative image analysis techniques can be helpful in the establishment of a basline for follow-up and have been determined to be as good as serial photographs to detect early damage and change. If disc photography is impractical and not available, a careful disc drawing should be substituted, but this is almost certainly of lesser value for longitudinal comparison purposes.
Despite recent advances in the medical lowering of IOP, the practitioner is often faced with the situation of failing to achieve the target IOP despite maximum tolerated medical therapy. This should prompt a reassessment of the appropriateness of the target pressure, with consideration of laser or incisional surgery. If indications are firm for lowering IOP below the level obtained with maximum tolerated medical therapy (IOP unacceptably elevated), then surgery is appropriate. For other patients in whom the target IOP is more nebulous and the treatment strategy has provided equivocal pressure control (IOP borderline), it may be appropriate to observe the patient closely for evidence of further damage. Because target pressures are based on analysis of populations, individual patients who meet or exceed their target pressure reductions (IOP acceptable or optimal, respectively) with medical therapy can still suffer progressive optic nerve damage and demonstrate significant side effects. Therefore, it is important, even in these well-controlled patients, to assess the level of damage and constantly search for untoward adverse drug effects periodically.
COMPLIANCE
Compliance with medical therapy is critical if the therapy is to succeed. Several studies have suggested that poor compliance with glaucoma medication is a common problem. A study of patient compliance with systemic carbonic anhydrase inhibitors (CAIs) that involved monitoring serum bicarbonate levels suggested that 35% of patients were not taking the drug at all and another 22% were using the medication infrequently.55 A study of glaucoma patients who were supposedly using pilocarpine drops four times daily noted that of 99% of patients who claimed at interview to have instilled at least 75% of their drops, only 66% were actually this compliant, with 15% instilling the drops less than 50% of the time and 25% missing all four daily doses at least once a month.56,57
Several general principles can be applied to compliance with medical therapy of chronic glaucoma.
  • The more often a medication must be used, the greater the risk of noncompliance.
  • Patients usually comply with morning doses better than evening doses.
  • In general, patients are less compliant than they claim.
  • Agents with side effects easily recognized by the patient, such as burning on instillation, dimming of vision, headache, and tingling fingers, are less likely to be used compliantly.
  • Multidrug regimens that require waiting a specified time between drops are less likely to be adhered to.
  • Patients who frequently miss appointments or show a poor understanding of their disease are often noncompliant.
  • Elderly patients may be particularly at risk for poor compliance because of poor hearing, slowed cognition, and a desire to reduce side effects.
Compliance is difficult to evaluate. It is a good idea to consider noncompliance in any case of progression despite seemingly good pressure control in the office. At times, it may be helpful to contact a family member to inquire about the use of medications.
Specific efforts to improve compliance include the following:
  • Limit dosing to once or twice daily if possible.
  • Advise use of medications that limit side effects. Nasolacrimal occlusion, prodrugs, and high-viscosity preparations limit systemic absorption.
  • Avoid confusing regimens. Carbachol three times daily, acetazolamide four times daily, and a β-blocker twice daily is a confusing regimen. Echothiophate iodide, sustained-release acetazolamide, and a β-blocker, all twice daily, is much easier to remember.
  • Use medication instruction sheets with dosing times clearly displayed.
  • Consider combination therapy with multiple drugs in a single bottle.
  • Avoid drug interactions that can aggravate side effects.
  • Educate patients about and engage them in their disease. Tell them their IOP and target pressure, show them their visual field printouts, and discuss the optic disc findings.
Generally, topical agents such as prostaglandin analogs and long-acting β-blockers that allow effective IOP reduction with once-daily dosing will produce better compliance. In fact, the increased effectiveness of contemporary medical regimens has achieved better IOP reduction and a reduction in number of glaucoma operations performed.58,59,60
DRUG DELIVERY
The eye affords us the ability to prescribe topical medicines. However, topical therapy does not eliminate systemic absorption and side effects, particularly from β-blockers. The capacity of the human conjunctival cul-de-sac is about 10 μL. The design of an eye drop bottle tip that delivers a small enough drop to saturate but not overflow the tear film creates essentially a micropipet, the shape of which presents a significant hazard to the cornea if accidental contact occurs. A “safe” tip design delivers 25 to 50 μL; this overflows the tear film into the lacrimal drainage system or onto the cheek. Of the 20% to 40% of the medication initially present in the cul-de-sac, about 15% per minute exits the tear film by new tear formation, blinking, and lacrimal drainage. Although the total dose of medications reaching the nasal mucosa may seem trivial compared with typical oral doses, medication absorbed by way of the nasal mucosa is not subjected to first-pass hepatic metabolism. Clinically significant blood levels can be achieved at target tissues, producing undesired adverse reactions. Efforts to maximize ocular penetration and minimize systemic absorption by way of the nasal mucosa generally limit lacrimal drainage. These efforts include increasing drop viscosity and using nasolacrimal occlusion or eyelid closure for several minutes after instillation. If the ocular contact time can be increased with these techniques, it should be possible to lower the medication concentration, thus reducing costs and additional systemic side effects. Another powerful strategy to reduce systemic absorption is the use of prodrugs that enhance ocular penetration and reduce the total dose requirement. To maximize ocular absorption, a second topical agent should not be given for at least 10 minutes after the first.
One-Eyed Therapeutic Trials
Use of one-eyed therapeutic trials helps to define peak individual dose-response relations, minimizing overdosage with its attendant costs. Each ocular hypotensive agent is not uniformly efficacious in every patient because of multiple factors, including iris pigmentation, reflex tearing, circulating catecholamine levels, and adrenergic tone. High diurnal and intervisit fluctuations in IOP have been commonly noted in glaucoma and ocular hypertensive patients, which confounds the ability to assess drug response with bilateral administration. A useful technique to judge individual therapeutic efficacy is the one-eyed therapeutic trial whereby medication is instilled in one eye and the contralateral eye is used as an untreated control. Pretreatment IOP need not be bilaterally identical to use one-eyed trials; however, the difference in IOP must be fairly consistent. In addition, certain medications, such as the topical β-blockers, do show a mild contralateral reduction in IOP with unilateral use that is believed to be secondary to systemic absorption.61
Examples of the results of one-eyed trials include the following:
  • Pretreatment IOP right eye (RE) 28, left eye (LE) 28. RE only treated with miotic → RE 24, LE 30 = IOP reduction of 6 mm Hg
  • Pretreatment IOP RE 30, LE 25 (consistent 5-mm Hg difference). RE only treated with dipivefrin → RE 27, LE 27 = net IOP reduction of 5 mm Hg
  • Pretreatment IOP RE 25, LE 23, RE treated with β-blocker → RE 22, LE 20 = net IOP reduction probably minimal
There are, of course, potential problems with this approach. A retrospective review reported that the apparent response to a therapeutic trial in one eye did not adequately predict the response in the fellow eye, and suggested that one should not assume that magnitudes of response would be equal in both eyes.62,63 The difficulties in applying the one-eye therapeutic trial include the potentially large and asymmetric diurnal variability of the two eyes and contralateral effect of some uniocularly administered topical agents. Diurnal measurements of pretreatment IOP or measurements on different visits at different times of day may allow a better understanding of an individual patient’s IOP variability before initiation of a one-eye therapeutic trial and would allow more accurate interpretation of the results.
Treatment Algorithm
Introduction of new medications over the past decade has dramatically altered typical glaucoma treatment algorithms. In the 1980s, standard therapy was to start with a topical β-blocker or epinephrine and then, as second line, add a miotic. If more aggressive treatment was required, either a systemic carbonic anhydrase inhibitor or laser trabeculoplasty was used.
The more recent introduction of three new classes of topical medications–the selective α2-agonists, topical CAIs, and prostaglandin (PG) analogues–has more than doubled the possibilities of topical antiglaucoma therapy. Most such classes are additive when used in combination, which provides the treating ophthalmologist with many therapeutic options. These medications together with β-blockers have become the mainstay of medical therapy. Miotic agents and nonselective adrenergic agonists are now used much less frequently.
Currently, the two most commonly used first-line drugs are topical β-blockers and PG analogues. The β-blockers represent the historical first-line drug because of their excellent efficacy, local tolerability, and in most cases ability to be dosed once a day. Serious side effects related to systemic β-blockade are uncommon, although cautious review of many patients reveals subtle changes such as a reduced pulse and exercise tolerance, mild wheezing, increased cholesterol levels, and CNS reactions including depression, fatigue, and impotence.
Concern over the systemic side effects of the β-blockers has led to the increasing popularity of topical PGs as first-line therapy. PGs are statistically slightly more effective at lowering IOP than β-blockers, are available for once daily dosing, and have minimal if any risk of systemic reactions. The ocular side effects, such as conjunctival hyperemia, permanent iris color changes, periocular pigmentation, and rare aggravation of cystoid macular edema (CME) and uveitis must be considered. The Food and Drug Administration (FDA) of the United States has approved latanoprost to be used as a first-line agent for glaucoma, while the European Commission has approved bimatoprost as a first-line agent.
The α2-agonists are typically equally effective to β-blockers, with fewer cardiopulmonary side effects, and have been promoted as first-line drugs. Factors limiting their use as such include a need for twice daily or three times daily dosing, a high rate of ocular allergy, frequent dry mouth, and occasionally significant CNS depression. This class may be more effective than topical β-blockers in patients already treated with a systemic β-blocker.64 The ocular allergy may develop at any time during its use, and thus the ocular allergy rate is almost certainly higher than 5%, as reported in a short period of use in clinical trials.
Topical CAIs have been shown to be less effective than β-blockers and require twice daily or three times daily dosing. These drugs are still sometimes useful as first-line treatment because of their good local and systemic tolerability. Oral CAIs are rarely used for chronic treatment because of their high incidence of systemic side effects. This class is occasionally helpful in patients allergic to multiple different eyedrops or unable to instill drops.
Nonselective adrenergic agonists such as epinephrine and dipivefrin are uncommonly used because of their high rate of local intolerance, systemic side effects, need for twice daily dosing, and poor additivity to β-blockers.
The parasympathomimetics such as pilocarpine remain an important class for glaucoma treatment. Factors leading to their unpopularity in many phakic open-angle glaucoma patients include common local tolerability problems such as induced myopia and miosis as well as a short duration of action that requires three times daily or four times daily dosing. Nevertheless, in patients with pseudophakia and relatively older patients less likely to be plagued by induced myopia, the miotics can be very effective (and inexpensive) drugs. There may also be a specific role for this medication class in preventing pigment liberation in pigment dispersion or pseudoexfoliative glaucoma or in pulling the angle open in plateau iris syndrome and primary angle closure glaucoma when the angle is not closed by peripheral anterior synechae.
According to a recent meta-analysis of 28 randomized clinical trials to estimate the IOP reduction achieved by the most frequently prescribed topical glaucoma drugs, bimatoprost, travaprost, latanoprost, and timolol are the most effective IOP-reducing agents in POAG and ocular hypertensive patients.65 Among the different prostaglandins, bimatoprost appears to have a small but statistically significant greater IOP reduction than the other prostaglandin analogs; the clinical significance of this difference, if any, remains to be determined. It cannot be overemphasized that the response to medical treatment is very individualized. Differences in response may be related to variations in absorption, receptor distribution, or pigmentation of ocular structures.
Our typical treatment algorithm for most open-angle glaucoma patients is a β-blocker or PG as the first-line drug, with the other drug added as the second line. If a patient is concerned about iris color change, a β-blocker is used, and either an α2-agonist or topical CAI is added second line. Patients with contraindications to β-blocker use should be considered for first-line treatment with a PG compound and either an α2-agonist or topical CAI added next. Pseudophakic patients and the previously mentioned secondary glaucomas may be considered for miotic therapy.
It is important to allow enough time and also ensure correct use of drops before determination of the response or comparison of the response of one drop versus another. For most of the drops, four weeks of use is required to achieve a steady state IOP response. Some drops may have an initially lower IOP level but higher level after a few weeks of use. On the other hand, some drops may have a less than desirable IOP response before the steady state. Generally, if the IOP reduction is less than 5% from baseline, the response should be considered inadequate, and switching to another medication should be considered instead of adding another medication. In switching medication, one would generally consider medication from another class of agents that has a different mechanism of action. Maximal tolerated medical therapy is not a fixed number of medications, but is individualized. Certain patients may tolerate more medication, but compliance usually decreases with increased numbers of medications, and additional medications achieve less IOP reduction.
Results of the Glaucoma Laser Trial demonstrated a favorable efficacy to complication ratio of argon laser trabeculoplasty (ALT) compared with medical therapy. Over the past decade many ophthalmologists treating glaucoma have escalated ALT’s role from third or fourth line to first or second. ALT’s relatively short lasting effect of 2 to 5 years must be discussed with the patient, and laser remains a particularly helpful option in older patients where this length of control can be significant. The newly available selective laser trabeculoplasty (SLT) uses a Q-switched, frequency-doubled 532-nm Nd:YAG laser to deliver a short pulse duration of 3 nanoseconds of energy to perform the trabeculoplasty. Histologic studies in human cadaver eyes after SLT reveal no evidence of coagulative damage or disruption of the corneoscleral or uveal trabecular beam structure.66 SLT and ALT appear to offer equivalent IOP reduction. Laser therapy is often useful in noncompliant patients, patients with high rates of medication allergy, or patients unable to afford medications.
The indications and timing of incisional surgical treatment (e.g., trabeculectomy) vary widely. Factors involved in such decisions include the patient’s understanding of surgery, the surgeon’s skill and experience, the likelihood of surgical versus medical success, and medical compliance and tolerability issues. The advent of wound healing modulation with 5-fluorouracil and mitomycin C as well as postoperative argon laser suture lysis and releasable suture techniques have improved surgical success, although late-onset bleb-related infections and hypotony remain concerns. Another concern of surgical intervention for glaucoma is the acceleration of cataract development. The Advanced Glaucoma Intervention Study (AGIS) showed that trabeculectomy increases the relative risk of cataract formation by 78%.67 In many clinical trials, the increase of cataract masked the beneficial preservative effect of IOP reduction by trabeculectomy on the visual field.
There is increasing evidence that chronic treatment with glaucoma topical agents can activate the subconjunctival fibroblast population, compromising surgical success. Some ophthalmologists have thus advocated earlier or even initial surgery. The Collaborative Initial Glaucoma Treatment Study (CIGTS) is a multicenter, randomized trial of surgical versus medical treatment of newly diagnosed glaucoma using current surgical technique and medications. It showed that initial medical and initial surgical therapy resulted in similar visual field outcomes after 5 years of follow-up. The overall rate of progression was lower than in many clinical trials, potentially the result of more aggressive IOP reduction. Over the course of follow-up, IOP in the medical group averaged 17 to 18 mm Hg, whereas that in the surgery group averaged 14 to 15 mm Hg.68 In this study, the choices of medications were broader and a 30% of IOP reduction was achievable, which is greater than in previous trials. Although there is no significant difference between the two groups in visual field scores, the possible visual field preservation effect with lower IOP achieved by trabeculectomy may have been masked by the cataract formation after the surgical intervention, and 5 years of follow-up in a chronic disease may not be adequate to draw treatment conclusions. The complication rate associated with trabeculectomy was not high in this trial. However, bleb-related late-onset complications such as leaky bleb, blebitis, or endophthalmitis may not yet be evident in 5 years.
β-ADRENERGIC BLOCKING AGENTS
The initial study of the effects of the sympathetic nervous system on IOP and aqueous flow was made in rabbits by Linnér and Prijot in 1955.69 They observed that excision of the superior cervical ganglion had a marked IOP-lowering effect that lasted 24 hours. Because outflow resistance was similar to that in contralateral control eyes, it was concluded that aqueous secretion was reduced.
In 1958, Powell and Slater70 discovered the selective β-adrenergic antagonist dichloroisoproterenol (DCI). Sears and Bárány71 in 1960 reported that DCIs reduced IOP in ganglionectomized and control rabbits, providing the first evidence that this class of medications could act as an ocular hypotensive agent. Unfortunately, DCI had little effect on IOP in humans (M. L. Sears, personal communication, 1980).
β-Adrenergic blocking agents were first reported to lower IOP in humans in 1967 when Phillips et al.72 described the ocular hypotensive effect of intravenous propranolol. In 1971, topical propranolol was also reported to reduce IOP.73 Unfortunately, the drug also produced corneal anesthesia, limiting its clinical usefulness. During the early 1970s, a search for a nonanesthetizing β-blocker ultimately led to the introduction of timolol in 1978.
β-Adrenergic antagonists reduce IOP by inhibiting aqueous humor formation by the ciliary epithelium.74,75,76 These drugs have a minimal effect on outflow facility.77 Topical β-blockers reduce aqueous formation by 24% to 48% in awake humans.78 Since timolol maleate was introduced for topical therapy in the late 1970s, this class of drug has become the standard first-line medication to lower IOP.79,80,81,82 The popularity of these drugs is no doubt due to the agents’ long duration of action, efficacy, favorable local side effect profile, and relatively infrequent systemic adverse reactions when used appropriately.
Pharmacology
The ocular hypotensive effect of β-blockers seems to be largely mediated by the β2-receptor.83 Unlike other aqueous suppressants, such as CAIs or α2-agonists, the β-blockers are ineffective during sleep,84 presumably because of reduced humoral or neural adrenergic tone (aqueous production normally falls by 45% during sleep).85
Most β-blockers are derivatives of the prototype β-adrenergic agonist isoproterenol and contain a benzene ring nucleus coupled to an ethylamine chain. A multitude of β-blockers are available for systemic use, and five are available for topical use (Table 4). These drugs differ in β-receptor selectivity, potency, intrinsic sympathomimetic activity (ISA), and membrane-stabilizing effects. The prototype nonselective β-blocker used systemically is propranolol (Inderal; Wyeth-Ayerst, Philadelphia, Pennsylvania), whereas metoprolol was one of the first “cardioselective” (β1-selective) agents. ISA refers to low-level stimulation of the adrenergic receptor as blocking occurs. Membrane stabilization prevents cellular depolarization, and some of these agents (such as propranolol) have local anesthetic properties, limiting topical ophthalmic use.
TABLE 4. Currently Available Topical β-Blockers
Agent Selectivity IntrinsicSympathomimeticActivity MembraneStabilization Viscositya(CP) Drop Sizea(μL/yr) Costa,b(dollars/yr) Other
Timoptic(0.5%)       3.1 33 112 (10 mL)  
Betagan(0.5%)       3.5 47-67c 75 (10 mL) Longer half-life thanTimoptic
OptiPranolol(0.3%)       6.5 37 66 (10 mL) Rare uveitisd
Ocupress(1.0%) +         ? Less adverselipid changes  
Betoptic S(0.25%)   + Mild 100 34 114 (10 mL) Reduced IOPlowering;reducedadversesystemiceffects
aData from Ball: Arch Ophthalmol 110:654***AU: Please supply full publication information for Ball.****** Ball SF,Schneider E. Cost of beta-adrenergic receptor blocking agents for ocular hypertension. Arch Ophthalmol 110;654, 1992.***bAssumes 4 drops per day for 365 days.cBottle angle and temperature dependent.dPredominantly reported with 0.6% concentration in Europe. In U.S.A., with 0.3%, only three cases reported.
In patients using systemic β-blockers, topical β-blockers may have a smaller IOP reduction effect. Studies also suggested that β-blocker eyedrops may aggravate noctural arterial hypotension and reduce the heart rate, and may be a potential risk factor in vulnerable individuals with glaucomatous optic neuropathy or ischemic optic neuropathy.86 In addition, since the β-blockers are ineffective during sleep, it is advisable to use β-blocker eyedrops in the morning and avoid the use of the second dose, if twice daily dosage is required, at bedtime.
β-blockers were also reported to have a neuroprotective effect by blunting the effect of ischemia in animal studies,87,88,89,90 despite the fact that that retinal neurons appear to lack b-adrenoceptors. One cause of ganglion cell death is an overactivation of glutamate receptors and a subsequent rise in intracellular levels of sodium and calcium ions as well as a generation of reactive oxygen species. In contrast, optic nerve death in ischemia is caused by an influx of sodium and reversal of the sodium/calcium exchanger, which leads to a rise in intracellular calcium. β-blockers, having both calcium and sodium channel blocking activity with betaxolol being the most efficacious of those analyzed, were suggested to have protective effect on the ganglion cell axon and cell body. Metipranolol was also found to have powerful antioxidant properties.91 However, for neuroprotection in glaucoma to become a reality, it is still necessary to devise a method of drug delivery to the optic nerve head. It is generally agreed that very little of topically applied substances reach the retina, either directly or indirectly through the systemic circulation.
Clinically Available Agents
Timolol.
In 1976, timolol was reported to lower IOP in glaucomatous rabbits92 and normal human study subjects93 without significant ocular irritation. In 1977, the drug was noted to markedly reduce IOP in glaucoma patients.94
Timolol is nonselective, inhibiting both β1– and β2-adrenergic receptor activity. The commercial preparations consist of the L-isomer. Timolol has minimal ISA and membrane-stabilizing effects and is about five times more potent than propranolol.95,96,97
Efficacy.
Timolol significantly lowers IOP in most patients not undergoing other β-blocker treatment, including normal volunteers,98 ocular hypertensive patients,99,100,101 and chronic glaucoma patients.16,102,103,104 The percentage or absolute pressure reduction obtained with topical timolol varies from study to study because of differences in study populations (including pretreatment IOP and iris pigmentation) and study methodology. Nevertheless, most studies demonstrate a 20% to 28% reduction in IOP with topical timolol used as a single hypotensive agent. The additional IOP-lowering effect is usually reduced in patients already receiving systemic, nonselective β-blocker treatment.105
The initial dose of timolol usually produces the greatest reduction in IOP, and over several weeks there is a partial loss of effect.106,107 This “short-term escape” may be caused by an increase in the number of β-adrenergic receptors within days of initiating therapy.108 Because of this short-term escape, the chronic IOP-lowering effect of timolol should not be concluded until the completion of 2 to 4 weeks of use. A “long-term drift” has also been described. This is a timolol-induced reduction in aqueous flow that is lower after 1 year of treatment than it is after 1 week.109 Clinically, many patients with an acceptable IOP response after several initial weeks of therapy gradually lose pressure control after months to years of treatment.110 Whether this drift is due to further long-term adaptation of β-receptors, gradually declining outflow facility, or other factors is unknown. Long-term drift is not unique to the β-blockers but is seen with most medical modalities that lower IOP.
Timolol is usually more effective at lowering IOP than other topical β-blockers, nonselective α-agonists111,112, selective α2-agonists, topical CAIs,65 and pilocarpine113; and it is this efficacy, combined with a favorable local side effect profile and a long duration of action, that accounts for its popularity as a first-line agent. Drugs such as oral CAIs and strong miotics have an efficacy approximately equivalent to that of timolol but more often produce adverse local or systemic side effects. As a first-line drug, the topical CAIs require three-times-daily dosing for optimal effect and are slightly less effective than topical timolol.114 Initial clinical experience with the chronic IOP-lowering effect of the α2-adrenergic agonists, when used as single agents, appears to equal that of 0.5% timolol.115 Unfortunately, a majority of apraclonidine-treated eyes develop local ocular allergies. Brimonidine is less allergenic; however, it must be dosed twice or three times daily. Topical PG analogues have been shown to be at least as effective as timolol and can be dosed once daily. They have minimal systemic side effects; however, local tolerance issues such as hyperemia and iris color change are often a concern. Latanoprost has become a commonly used first-line alternative to timolol.116,117,118
Even with efforts to limit systemic absorption, some blood levels of timolol usually occur. It is not uncommon to note a mild contralateral IOP-lowering effect with unilateral use (crossover effect).61,119 This effect should be considered when using one-eyed therapeutic trials to evaluate β-blocker efficacy.
Concentration and Dose.
Timolol is available in two salt forms, maleate and hemihydrate. Timolol hemihydrate is marketed as Betimol (Santen, Napa Valley, California) and is not considered a generic substitution for timolol maleate. Timolol maleate is available as Timoptic (Merck & Co., Inc., West Point, Pennsylvania) and Istalol (ISTA Pharmaceuticals, Inc., Irvine, California) and is also available as a generic from various sources. Most available timolol solutions contain benzalkonium chloride 0.01% as a preservative, except Istalol (timolol maleate 0.5%), which uses 0.005% benzalkonium chloride. Preservative-free timolol dropperettes are available from Merck & Co. Timolol maleate is also available in a gel-forming solution as Timoptic XE (Merck & Co., Inc.) as gellen gum gel-forming solution, or Timolol GFS (Alcon Laboratories, Inc., Forth Worth, Texas) as xantham gum gel-forming solution. The gellen gum gel-forming solution uses an anionic polysaccharide vehicle derived from gellan gum, which reacts with tear film cations to produce a high-viscosity gel, prolonging ocular contact time.120 Xanthan gum is a purified high molecular weight polysaccharide gum produced from the fermentation by bacterium Xathomonas campestris. An aqueous solution of xanthan gum, in the presence of tear protein (lysozyme), forms a gel that is subsequently removed by the flow of tears. The gel-forming formulations of timolol use benzododecinium bromide as preservative. The 0.5% concentration timolol is at the top of the dose-response curve, and the 0.25% solution is often equally efficacious.121 Little difference in effectiveness was observed between the 0.25% and 0.5% solutions after 1 year of therapy in a population of open-angle glaucoma patients.122 Both concentrations decrease IOP maximally 2 hours after instillation and maintain a significant reduction for at least 24 hours.123 The 0.25% concentration may have similar efficacy, particularly in less pigmented eyes.124 Although twice daily use of timolol solution is recommended, once-daily administration is often clinically effective, also cutting the cost in half.125 In fact, for timolol maleate solution, the labeling information indicates that if the IOP is controlled at a satisfactory level, dosing can be changed to once daily. Istalol is approved for once daily use. It may be worth using a lower concentration and less frequent use of timolol such as 0.25% and using it once daily and titrating the dose upward according to the response of IOP reduction, while decreasing the potential for adverse effects. If the medication is used every morning, a trough IOP measurement can be obtained by withholding drops on the day of an early morning pressure measurement.
The gel-forming formulation of timolol used once daily appears as effective as the same concentration of solution used bid; therefore, it is recommended for once daily use. Timoptic XE 0.5% once daily and Timoptic 0.5% solution once daily were compared in a small, 1-week, double-masked, parallel-group study that showed greater IOP reduction with the XE preparation. Longer trials involving more patients are needed before it can be concluded that Timoptic XE provides better once-daily IOP control. Because the cost of Timoptic solution when used once a day is approximately half that of Timoptic XE, it may be worth evaluating the response of the less expensive therapy in individual patients, particularly after encouraging nasolacrimal occlusion. Although gel-forming formulations of timolol used once daily are claimed to result in lower systemic plasma concentrations than Timoptic 0.5% used twice daily, differences in other systemic effects, such as pulse rate, blood lipids, and pulmonary function, have not yet been reported.126 There is some evidence that timolol is less effective in dark irides, possibly because of pigment binding.127 One study used home tonometry to compare (five times during the day) the mean IOP reductions of 0.5% timolol administered once daily in the morning or in the evening and 0.25% timolol administered in the morning; no significant difference was found among the three groups.121
Timolol is also available as the hemihydrate salt (Betimol; Santen) is available in both 0.5% and 0.25% concentrations. Timolol hemihydrate solution when used once a day was similar in efficacy to timolol gel used once a day.128 Despite what should be higher plasma levels compared with the gel vehicle, the solution had similar effects on maximal pulse rate when exercising.129
Discontinuing or “washing out” timolol does not restore aqueous flow to normal levels for 2 to 6 weeks, and IOP requires at least 2 weeks to return to baseline levels.130 This is particularly important when stopping β-blockers before filtering surgery in an effort to reduce early postoperative hypotony.
Combination Therapy.
In many patients, timolol therapy alone does not achieve target IOP lowering. Most of the other classes of ocular hypotensive agents, including the CAIs,131,132 miotics,133,134 a2-adrenergic agonists,135,136,137 and PG analogues138,139 produce an additive effect. One apparent exception is the nonselective β-agonist class (epinephrine and dipivefrin), which typically provides little additional IOP-lowering effect (approximately 2 mm Hg).140,141,142,143 Nevertheless, wide patient variability is seen, and occasionally patients show more impressive additive effects, often best demonstrated in one-eyed therapeutic trials.
A fixed combination of 2% dorzolamide hydrochloride and 0.5% timolol maleate (Cosopt; Merck & Co., Inc.) is commercially available. Another two fixed combinations of timolol and latanoprost (Pharmacia Co., Kalamazoo, Michigan) and timolol and travaprost (Alcon Laboratories) are not approved in the United States but either are available or under process of approval in other countries. Generally, the IOP-lowering effect of the fixed combination products is comparable to that of concurrent therapy with the two agents. Single bottle combinations may have the advantages of enhanced patient compliance and less preservative exposure.
Systemic Adverse Reactions.
A 30-μL Drop of 0.5% timolol maleate contains about 0.2 mg of the drug, considerably less than the 30-mg maximum recommended oral dose for cardiovascular timolol use. Topical timolol is generally well tolerated. It must be remembered, however, that oral drugs are susceptible to first-pass hepatic metabolism, whereas nasal mucosal–absorbed medications travel to the pulmonary, cardiovascular, and CNS circulations more directly. Thus, seemingly minimal doses of topical ocular timolol can cause significant adverse effects in susceptible individuals. Following two drops of timolol 0.5%, plasma concentrations ranged from 5 to 9.6 ng/mL, which is close to the 10 ng/mL of therapeutic plasma level when timolol is administered intravenously at 0.25mg/kg.144,145,146
Physicians in general and ophthalmologists in particular must be familiar with the potential systemic reactions of topical β-blockers. The effects are usually subtle and include fatigue, lethargy, mood changes, impotence, reduced exercise tolerance, shortness of breath, headache, and ankle edema. Elderly patients often use a host of other medications, which makes it difficult to identify significant timolol-related side effects. In addition, these reactions are commonly ascribed to aging or coexisting disease.147
Timolol can affect the cardiovascular, pulmonary, and central nervous systems. Cardiovascular (β1) effects of topical β-blockers can lead to reductions in pulse rate, cardiac contractility, and blood pressure. Timolol often reduces the resting pulse and blunts the exercise-induced increase in heart rate.148 Severe bradycardia, cardiac arrhythmias, heart block, congestive heart failure (CHF), and death are possible but are rare.149 Most β-blockers also alter plasma lipid profiles. Topical timolol 0.5% given twice daily to volunteers increased plasma triglycerides by 12% and decreased high-density lipoprotein cholesterol by 9%. This change in plasma lipids presents a theoretically significant risk factor for the development of coronary artery disease, although use of systemic timolol after myocardial infarction (MI) has been shown to reduce the frequency of subsequent MIs and mortality.150
Antagonism of β2-receptors in bronchi and bronchioles contracts smooth muscle, which can cause increased airway resistance, especially in patients with reactive forms of asthma or chronic obstructive pulmonary disease (COPD).151 Respiratory failure has been documented with timolol therapy, and the drug should not be used in patients with severe respiratory disease.152,153 Topical timolol therapy may adversely affect respiratory function in elderly patients without a history of known airway disease. In a study of 80 such patients older than age 60, topical timolol was replaced with either the β1-selective β-blocker betaxolol or the adrenergic agonist dipivefrin. There was a 13% increase and an 8% increase in mean peak flow rate and forced expiratory volume in 1 second (FEV1), respectively, when betaxolol was used, and a 14% increase and an 11% increase when dipivefrin was used. There was also improved exercise tolerance with both agents, although this was within the range of learning effect.154 An epidemiologic study of a largely white, inner-city population in the north of England found a 37% prevalence of airway obstruction in the over-65 age group.155
The CNS side effects of timolol are related to the drug’s lipophilic structure and low protein binding, which enable it to cross the blood-brain barrier. These effects include fatigue, depression, anxiety, confusion, formed hallucinations, memory loss, psychosis, and disorientation.156,157 Timolol can decrease libido and cause impotence.158 Depression is more common in glaucoma patients than in those with ocular diseases of similar chronicity,159 with prevalences ranging from 15% to 80%.160,161 One study concluded that the greatest single risk factor for falls in elderly glaucoma patients is the use of topical β-blockers.162
β-Blockers may blunt the responses to hypoglycemia-induced endogenous epinephrine release.163 Because these responses normally produce hyperglycemia, sweating, and tremor, β-blocked hypoglycemic diabetic patients may have more pronounced hypoglycemia and be less aware of it.164 Timolol treatment has been reported to worsen myasthenia gravis165,166 and can mask the symptoms of hyperthyroidism.
Adverse local side effects with timolol are infrequent. In susceptible individuals, an allergic blepharoconjunctivitis can occur. This is occasionally secondary to preservatives and can be alleviated by use of the nonpreserved single-use vials. Local irritation of the corneal epithelium with blurring of acuity, conjunctival hyperemia, superficial punctate keratitis, and dry eye has been reported. Basal tear turnover has been reported to increase after a change to the nonpreserved preparation.167 Corneal anesthesia may also occur.168,169 Use of timolol as a sole agent in general has no effect on pupil size, but in combination with an adrenergic agonist it increases mydriasis.
Patients undergoing chronic timolol treatment show a decrease in goblet cell density170 and may develop subconjunctival fibroblast activation, altering the success of filtering surgery. In a cultured human Tenon’s capsule fibroblast model, timolol, betaxolol, and levobunolol inhibited fibroblast proliferation. Some of this inhibition may be related to the benzalkonium chloride preservative.171
The influence of topical timolol on various components of ocular blood flow remains unclear, and there are conflicting reports in the literature.172,173,174,175,176,177 β-Blockers can cause vasoconstriction, and there have been reports of Raynaud syndrome induced by timolol.178 If similar β-blocker–induced vasoconstriction occurs in the blood vessels supplying the optic nerve head, this class of medication, despite its IOP-lowering ability, may be relatively contraindicated in glaucomas associated with poor optic nerve head perfusion.
Clinical Indications.
Timolol is FDA approved for use as a first-line agent in the treatment of patients with chronic open-angle glaucoma and patients with increased IOP who are thought to be at risk for the development of optic nerve damage or visual field loss. It is effective in reducing IOP in congenital glaucoma, although apnea and cardiovascular side effects have been reported in timolol-treated neonates. Timolol is contraindicated in patients with asthma, CHF, COPD, and myasthenia gravis. It is often administered during pregnancy, although its teratogenic effects have not been thoroughly studied. β-Blockers have been associated with arrhythmias and bradycardia in the fetus due to transplacental transfer, although case reports have also described the use of these drops throughout pregnancy without adverse effects. A further consideration in treatment during the later stages of pregnancy is the evidence that topical medications, especially β-blockers, can be actively secreted into breast milk and cause potential adverse effects in infants who are breast-fed.179
Levobunolol.
Levobunolol hydrochloride, the L-isomer of bunolol, is a nonselective β-adrenergic antagonist. It demonstrates neither ISA nor membrane-stabilizing properties and has been shown to significantly reduce IOP in normal subjects, ocular hypertensive patients,180 and glaucoma patients.181,182,183,184
Efficacy.
In general, levobunolol is similar to timolol,185,186,187,188 although it possesses a slightly longer half-life.189 A double-masked study of 391 glaucoma and ocular hypertensive patients found a sustained mean reduction in IOP of 27% over 2 years, similar to the efficacy found in a timolol control group.190 This study found minimal long-term drift with levobunolol.
Concentration and Dose.
Levobunolol is commercially available as Betagan (Allergan, Irvine, California) and as generic preparations in concentrations of 0.25% and 0.5%. Maximum IOP reduction occurs within 2 to 6 hours, with measurable effects noted at 24 hours.191 The 0.5% concentration appears to be at the top of the dose-response curve, and several studies demonstrate equal efficacy for the 0.25% and 0.5% concentrations,192,193 even with once daily dosing.194,195 A small contralateral pressure reduction has been noted, similar to that seen with timolol.
Combination Therapy.
Combination of levobunolol with other classes of ocular hypotensive agents has not been as well studied as timolol combination therapy, but it appears to have a similar additive effect. There is little additive effect when levobunolol is combined with dipivefrin.196
Adverse Reactions.
Levobunolol does not differ significantly from timolol in terms of adverse reactions, and it is generally well tolerated by most patients.197 Vigilance for subtle side effects and cautious use in patients with reactive airway disease, bradycardia, CHF, and myasthenia gravis are recommended.
Clinical Indications.
In general, indications for levobunolol use are similar to those for timolol.
Metipranolol.
Metipranolol is a nonselective β-adrenergic antagonist that lacks ISA and membrane-stabilizing ability. The drug is available in the United States as OptiPranolol (Bausch & Lomb, Tampa, Florida), a 0.3% preparation. It is available in Europe as a 0.6% preparation.
Efficacy.
The 0.3% concentration of metipranolol decreased IOP by 21%, and the 0.6% concentration decreased IOP by 31%.198 It is generally given twice daily, although once-daily use may be effective. Metipranolol is typically as effective as the other nonselective topical β-blockers in reducing IOP.
Concentration and Dose.
In a double-masked crossover study, reducing the metipranolol concentration from 0.6% to 0.3% caused no difference in IOP reduction.199
Adverse Reactions.
In general, systemic adverse reactions are similar to those of the other nonselective topical β-blockers. Metipranolol 0.3% may have fewer cardiovascular effects than 0.5% timolol.200 An unusual local reaction unique to metipranolol is granulomatous uveitis, which has been reported in patients in Europe, particularly with the 0.6% concentration.201 In the United States, three patients to date have been reported to have developed granulomatous uveitis after topical use of 0.3% metipranolol.202,203 The uveitis recurred when one patient was rechallenged with the drug.
Clinical Indications.
In general, indications for metipranolol use are similar to those for the other nonselective β-antagonists.
Carteolol.
Carteolol is a nonselective β-blocker similar to the previously mentioned agents in its lack of membrane stabilization. Unlike these other drugs, however, carteolol demonstrates weak ISA, causing an early transient agonist response.204 This ISA theoretically reduces bronchoconstriction and bradycardia, improves blood flow, and produces less alteration of the serum lipid profile,205 although these effects have not been clinically demonstrated.206
Efficacy.
Two trials comparing carteolol and timolol found equivalent IOP reductions.207,208 No difference in effect was found between 1% and 2% concentrations.209 Carteolol 1% reduced IOP 11% to 14% versus placebo.210,211 This reduction is less than that usually reported for timolol; however, this was not a controlled study.
Concentration and Dose.
Carteolol 1% was previously marketed as Ocupress (Novartis, Duluth, Georgia). It is currently marketed as carteolol (Bausch and Lomb). The half-life of an active metabolite, 8-hydroxy carteolol, is two to three times that of the parent compound.182 It is approved for twice daily use.
Adverse Reactions.
No evidence to date is available that substantiates a reduction in systemic side effects compared with timolol as predicted by ISA. A preliminary report suggests a reduction in adverse lipid profiles compared with timolol, although this effect was seen only in the initial portion of a crossover study and disappeared in the second half of the study.212 Similar effects of both drugs on pulse and blood pressure were seen in a double-masked, randomized comparison of carteolol and timolol.213
Clinical Indications.
In general, carteolol use is indicated for situations that are similar to those for which the other nonselective β-blockers are used. If the recently claimed lipid profile advantages are substantiated, the drug may be preferred in patients with coexisting hypercholesterolemia or coronary artery disease. The contraindications listed for the other nonselective β-blockers apply to carteolol as well.
Betaxolol.
Betaxolol is the only selective β-adrenergic antagonist available for topical ophthalmic use. It is often termed cardioselective because of its relative affinity for the β1 (cardiac) over the β2 (pulmonary) adrenergic receptor. The reduction in aqueous production by β-blockade is thought to involve primarily the β2-receptors that predominate in the ciliary nonpigmented epithelium.214,215 Although relatively β1-selective, betaxolol in the high ocular concentration achieved with topical use probably possesses enough β2-antagonist activity to reduce aqueous production. Alternatively, there may be a low level of β1-receptors in the nonpigmented epithelium, which accounts for the ocular hypertensive effect. Betaxolol must decrease aqueous flow because it has no effect on conventional or uveoscleral outflow facility.216
Efficacy.
Topical betaxolol lowers IOP in normal and elevated states.217,218,219,220 When it is compared with timolol, most studies have shown betaxolol to be slightly less effective in reducing aqueous flow221 and decreasing IOP.222,223,224 A multicenter, randomized trial found equivalent efficacy between betaxolol and dipivefrin, with both agents decreasing IOP by 14% to 17%.225 When patients are changed from timolol to betaxolol or randomized to one versus the other, IOP is often about 2 mm Hg higher in the betaxolol-treated eyes. One report suggests that despite a smaller reduction in IOP with betaxolol compared with timolol, betaxolol may better prevent visual field worsening in POAG patients. This report used mean sensitivity as the sole basis for following the visual fields and requires substantiation in larger cohorts of patients with more sophisticated visual field analysis.226 Other reports suggest that betaxolol may have beneficial ocular hemodynamic effects compared with timolol, particularly in low-tension glaucoma.227
Betaxolol appears to have both calcium and sodium channel blocking activity that may attenuate ischemic injury to ganglion cells in laboratory studies. This effect does not appear to be related to β-blockade. However, the clinical significance of this property is uncertain.228
Concentration and Dose.
Betaxolol was previously available commercially in a 0.5% solution as Betoptic (Alcon Laboratories) and a 0.25% suspension (Betoptic S), which suspends the drug in microscopic polymeric resin beads. The 0.5% betaxolol solution has been discontinued. The suspension effectively increases the ocular contact time and reduces stinging considerably. Both preparations have similar IOP-lowering ability.229 Maximum drug effect is 2 hours after instillation and lasts at least 12 hours. There may be less systemic absorption with betaxolol compared with timolol.230 It is approved for twice daily use. However, the increase of contact time with the use of suspension may allow it to be effective once daily in some patients.
Combination Therapy.
Betaxolol appears similar to timolol in its additive effect with CAIs, miotics, α2-agonists, and prostaglandin analogues. The additivity of betaxolol to epinephrine-type drugs appears to be significantly greater than that of timolol, making this combination potentially clinically useful.222,225
Systemic Adverse Reactions.
Systemic cardioselectivity makes betaxolol theoretically a better drug than the nonselective b-blockers in patients with mild pulmonary disease, although it certainly can provoke bronchospasm.231,232 Several studies suggest that betaxolol is better tolerated than nonselective β-blockers in patients with pulmonary disease.233,234,235,236
In theory, there should be similar cardiac side effects when β1-selective agents are used compared with nonspecific β-blockers; betaxolol has been reported to result in bradycardia, sinus arrest,237 and CHF.238 Despite these potential problems, betaxolol does not appear to affect exercise-induced pulse rate increases in normal volunteers, perhaps because of decreased systemic absorption.230 Betaxolol binds well to plasma protein and may have a reduced propensity to cross the blood-brain barrier, producing fewer CNS side effects compared with those associated with timolol.80,239
Local Adverse Reactions.
The betaxolol 0.5% solution therapy has reportedly caused more ocular discomfort (stinging) than other topical β-blockers. This problem has been reduced with the Betoptic S preparation. Betaxolol 0.25% suspension seems to cause less irritation then the discontinued Betaxolol 0.5% solution.240
Indications.
Betaxolol is indicated to reduce IOP in patients with ocular hypertension or glaucoma who are at risk for progressive optic nerve head damage. Its use may be preferred over the nonselective β-blockers in patients with mild cardiovascular, pulmonary, or CNS compromise. Significant systemic adverse reactions can still occur in these patients, and its use is strongly contraindicated in patients with more compromised cardiopulmonary systems.
NONSELECTIVE α-ADRENERGIC AGONISTS
Clinically Available Agents
Epinephrine.
Epinephrine or adrenaline is a nonselective α- and β-adrenergic agonist. It is a natural hormone released by the adrenal medulla into the systemic circulation during the “fight or flight” response. Norepinephrine is a neurotransmitter released at most sympathetic postganglionic junctions.
Epinephrine was reported to lower IOP in the 1920s,241,242 but early responses to the drug varied, no doubt because of a poor understanding of angle-closure mechanisms and impure preparations. The drug did not achieve widespread use until the 1950s when more stable preparations were available.243
The mechanisms of action of epinephrine in lowering IOP are complex and only partially understood, but they probably result from a balance of α- and β-adrenergic receptor stimulation. One major problem in understanding specific mechanisms underlying epinephrine’s ocular hypotensive effect is the influence of receptor desensitization over time. Because the clinically used doses of epinephrine or epinephrine prodrug produce high ocular concentrations, changes in the normal signal transduction pathways probably occur. Thus, these drugs may lower IOP both acutely and chronically by differing mechanisms. In addition, the role of newer subtypes of adrenoreceptors, such as the β3-class, is not well understood in ocular tissues.
Any α-stimulation in the ciliary processes may cause vasoconstriction. β-Adrenergic receptor stimulation in the ciliary epithelium acutely increases aqueous production,244,245 and in the ciliary muscle it may increase uveoscleral246 and trabecular outflow.247
Epinephrine measurably increases both conventional and uveoscleral outflow.248 Epinephrine increases intracellular cAMP,249 which has been shown to mediate the epinephrine-induced increase in conventional outflow facility. The trabecular outflow effect of epinephrine can be blocked with the nonselective β-blocker timolol, but not with the β1-selective betaxolol, suggesting β2-mediation.222 This may explain why the addition of epinephrine to betaxolol lowers IOP significantly more than the addition of epinephrine to timolol.
Epinephrine is commercially available as bitartrate (Epitrate 2.0%; Ayerst Laboratories, New York, New York), hydrochloride (Epifrin 0.5%, 1%, 2%, Allergan; Glaucon 1%, 2%, Alcon Laboratories), and borate salts (Eppy/N 1%, 2%; Barnes-Hind, Sunnyvale, California). The bitartrate preparation has about half the available epinephrine as equivalent concentrations of the other salts. A dose-response range of 0.12% to 1% is seen with maximum effect after 4 hours.250 Most clinicians use a twice daily dosing schedule.
Efficacy.
The long-term ocular hypotensive effect of epinephrine appears similar or slightly worse than that achieved with timolol, and timolol seems superior in the first year of treatment.251
Combination Therapy.
Epinephrine is additive to CAIs and miotics.252 Its combined effect with β-blockers is less impressive, but it may be greater when epinephrine is added to β1-selective betaxolol compared with nonselective agents.222,253,254,255 The epinephrine prodrug dipivefrin is additive to latanoprost.256 The ocular hypotensive effect of epinephrine is partially inhibited by oral indomethacin.257
Systemic Adverse Reactions.
Systemic reactions are common with epinephrine preparations and include tachycardia, hypertension, and arrhythmias.258 Cardiovascular side effects have been described in 25%259 of patients, and headache or brow ache in 10%. Caution should be exercised in patients using monoamine oxidase inhibitors, tricyclic antidepressants, and antihistamines, and in those with known cardiac problems or hyperthyroidism.
Local Adverse Reactions.
More than 50% of patients started on epinephrine become intolerant to the drug over time, mostly because of local reactions.258 Conjunctival injection, tearing, and irritation are the most common local side effects with epinephrine use.260 After initial instillation, the conjunctiva blanches from vasoconstriction, but rebound hyperemia is often seen. The mydriatic effect may be enhanced by combined therapy with β-blockers,261 and acute angle-closure glaucoma may be precipitated in susceptible patients. Patients often develop local allergic reactions, with chronic topical epinephrine use often manifested as follicular conjunctivitis262 or periocular dermatitis. Epinephrine can be oxidized to adrenochrome, a melanin pigment,263 which may cause black conjunctival deposits in about 20% of patients undergoing chronic therapy. Adrenochrome can also discolor soft contact lenses.264 Corneal pigmentation occurs less frequently and is usually visually insignificant. Nasolacrimal duct obstruction may result from chronic epinephrine use.265 Corneal edema is rarely reported after long-term use.266
Epinephrine can cause blood-aqueous barrier breakdown, which exacerbates anterior uveitis.267 CME, resembling Irvine-Gass syndrome, has been reported in 10% to 20% of aphakic patients using epinephrine.268,269,270 Although this usually resolves on prompt discontinuation, chronic epinephrine-induced CME may be irreversible. The potential for CME in pseudophakic individuals with intact posterior capsules is less established.
Clinical Indications.
Epinephrine is indicated to reduce IOP in patients with chronic open-angle glaucoma and ocular hypertension who are at high risk for subsequent optic nerve damage. Caution should be exercised in prescribing epinephrine for patients with narrow angle glaucoma; those using monoamine oxidase inhibitors, tricyclic antidepressants, or antihistamines; and those with known cardiac disease or hyperthyroidism. Since more selective medications are now available, requiring less frequent dosing and with fewer ocular and systemic side effects, the use of epinephrine for the treatment of glaucoma has markedly declined.
Dipivefrin.
Dipivefrin is a prodrug of epinephrine that enhances local bioavailability and reduces systemic side effects.271 The compound consists of two pivalyl acid chains esterified to epinephrine. This increases lipophilicity, enhancing corneal penetration 17-fold over epinephrine.272 After entry into the corneal stroma, esterases cleave the pivalyl chains, thus releasing free epinephrine into the anterior chamber.273 Because of its enhanced penetration, total concentration can be lowered to 0.1%, reducing systemic absorption and adverse systemic reactions. This enhanced penetration does not dissociate the adverse intraocular reactions from the therapeutic response.
Efficacy.
When used twice daily as a single agent, dipivefrin decreases IOP 20% to 24% compared with baseline, which is similar to the effect of 1% epinephrine.274 A multicenter study found equivalent IOP lowering between betaxolol and dipivefrin when used as single agents.225 A concentration of 0.25% is at the top of the dose-response curve; however 0.1% produces less mydriasis.275
Concentration and Dose.
Dipivefrin hydrochloride 0.1% is commercially available as Propine (Allergan) and is also available in generic form (Alcon Laboratories; Schein Pharmaceutical, Port Washington, New York). The maximal hypotensive effect is at 1 hour, and the drug is usually used twice daily.
Combination Therapy.
In general, the additive effect of dipivefrin with other classes of ocular hypotensive agents resembles that seen with epinephrine. Dipivefrin has been shown to be additive to latanoprost.256
Systemic Adverse Reactions.
Cardiovascular side effects are, for the most part, greatly reduced with dipivefrin compared with epinephrine use.259,276
Local Adverse Reactions.
Dipivefrin may be less likely than epinephrine to produce local allergy, although long-term studies are lacking.277 Adrenochrome deposits are much less likely to occur with dipivefrin use.263,276 The amount of mydriasis is similar between the two drugs, and, in general, dipivefrin should not be used in patients with narrow chamber angles. The incidence of aphakic CME theoretically should be similar to that found with epinephrine, although few studies are available.
Clinical Indications.
In general, dipivefrin indications are similar to those for epinephrine. The drug may be preferred over epinephrine because of reduced systemic reactions. Even so, because of more potent drugs with fewer side effects, its use is significantly declining.
SELECTIVE α2-AGONISTS
Clinically Available Agents
Clonidine.
The prototype α2-agonist is clonidine, which was introduced in 1962 as a nasal decongestant because of its pronounced vasoconstrictive abilities. It was coincidentally noted to have a systemic hypotensive effect,278 mediated largely by the CNS.279 Clonidine’s lipophilicity allows it to readily penetrate the blood-brain barrier and stimulate vasomotor centers of the brain stem. These receptors reduce central sympathetic activity, producing reductions in resting heart rate, stroke volume, and total peripheral resistance.
In 1966, intravenous clonidine was noted to reduce IOP.280 In 1969, the same result was reported with topical application.281 Several investigators have since established the effectiveness of topical 0.25% and 0.5% clonidine in decreasing IOP, and these concentrations are available in Europe for glaucoma therapy.282,283,284 Unfortunately, these concentrations also markedly lower systemic blood pressure.282,283 Because of its intense vasoconstrictive effect, questions have been raised regarding clonidine’s ability to reduce ocular blood flow. Varying effects on ophthalmic artery pressure have been reported.285,286
The α2-adrenergic agonists are potent inhibitors of aqueous production, reducing fluorophotometrically determined flow by 35% to 40% in awake humans.287,288,289 In normotensive subjects, IOP can fall to as low as 10 mm Hg, raising the possibility of outflow effects as well.290,291 Tonographic studies show unaltered conventional outflow by α2-adrenergic agonists. Thus, elevated uveoscleral outflow and reduced episcleral venous pressure have been suggested as additional ocular hypotensive mechanisms.289
Reduction in aqueous flow occurs presumably by way of an α2-adrenergic stimulation in the ciliary epithelium. In epithelial cells, α2-receptors are often negatively coupled, by way of inhibitory G-proteins, to adenylyl cyclase.292 Theoretically, the α2-agonist mediated reduction in aqueous flow could involve a prejunctional or postjunctional process (if the ciliary epithelium in humans receives significant sympathetic innervation) or could involve noninnervated receptors present on ciliary epithelial cells, or some combination of both. Presynaptic effects would be predicted to cause ciliary vasodilation, which has not been observed. In addition, in rabbits, transection of the superior cervical nerve trunk leads to increased ocular responses to apraclonidine293 suggesting postsynaptic supersensitivity. Thus, it appears that the presynaptic mechanisms are minimally involved in apraclonidine’s ocular hypotensive effect.
Apraclonidine.
Apraclonidine hydrochloride is a relatively selective α2-agonist created by adding an amide group to the clonidine benzene ring. This increases the molecule’s ionization, limiting blood-brain barrier penetration, with reduced CNS and cardiovascular side effects.291,294 This ionization also reduces corneal penetration, and one study suggests that apraclonidine reaches the ciliary body primarily by way of transscleral routes.295
Similar to clonidine, apraclonidine decreases IOP by reducing aqueous production.289 A 35% suppression in aqueous flow has been measured after 4 hours.287 Its effect on outflow facility has been controversial. It was previously determined that outflow facility was not altered as measured with tonography.289 However, a more recent study with fluorophotometric techniques demonstrated that after 1 week of unilateral apraclonidine 0.5% therapy, the IOP reduction was primarily due to an increase of fluorophotometric outflow facility (53%) and secondary by reduction of episcleral venous pressure (10%) and aqueous flow (12%).296 No significant effect on choroidal, retinal, or optic nerve blood flow has been found.297 Apraclonidine 1% has been shown to decrease conjunctival oxygen tension markedly, the significance of which is unknown.298
Efficacy.
Apraclonidine 1% produces at least a 20% fall in IOP within 1 hour of administration.299 This effect is maximal at about 4 hours, with a 30% to 40% pressure reduction, and lasts at least 12 hours. This acute reduction in IOP is greater than that seen with timolol. Either the 0.25% or 0.5% concentration appears at the top of the dose-response curve.290 Apraclonidine was FDA approved in 1987 to prevent acute increases in IOP after anterior segment laser procedures. In one study, 18% of placebo-controlled eyes versus no apraclonidine treated eyes developed an IOP spike greater than 10 mm Hg after ALT.300 In another study comparing the pressure spike blunting effect after 360° ALT of apraclonidine 1%, acetazolamide 250 mg, dipivefrin, pilocarpine 4%, and timolol 0.5%, only 3% of apraclonidine treated eyes developed IOP spikes above 5 mm Hg, compared with one third of the patients in each of the other groups.301 Apraclonidine has also been shown to blunt IOP spikes after YAG posterior capsulotomy,302,303 laser iridotomy,304 and cataract surgery.305 A 3-month double-masked trial found pressure lowered by equivalent amount with 0.25% apraclonidine three times daily, 0.5% apraclonidine three times daily, and timolol 0.5% three times daily306 when used chronically as a single agent.
Frequency and Dosing.
Apraclonidine is commercially available as lopidine (Alcon Laboratories) in concentrations of 0.5% in 5-mL bottles for long-term use and 1% in 0.1-mL dropperettes for short-term administration. It was initially approved by the FDA to prevent pressure spikes after anterior segment laser, and instillation either before or after these procedures seems effective. Apraclonidine 1% given 1 hour before cataract extraction was found to reduce postoperative acute IOP elevation, whereas it was ineffective when given at the conclusion of surgery.306
For chronic medical treatment, the current recommendation is to instill 0.5% solution twice daily or three times daily, although tachyphylaxis severely limits its long-term efficacy.
Combination Therapy.
Apraclonidine 0.5% twice daily produced an additive IOP-lowering effect when given to patients receiving chronic timolol 0.5% in a 3-month study.307 In a small double-masked, 3-month study, 0.125% apraclonidine used twice daily lowered pressure as well as the 0.25% concentration when added to timolol 0.5%.308 Interestingly, acute instillation of apraclonidine and timolol produces no greater pressure lowering than that seen with acute timolol alone.309
In 1993, the FDA approved apraclonidine 0.5% three times daily as an additive drug for patients receiving maximally tolerated antiglaucoma medical therapy. In a double-masked multicenter trial, apraclonidine 0.5% three times daily was given to patients on maximum therapy. At 90 days, 60% of the treated eyes and 32% of the placebo control eyes were able to avoid surgery. The mean pressure difference between the two groups at 90 days was approximately 2 mm Hg. In this study, patients already receiving two aqueous suppressants did not demonstrate a significant pressure lowering effect compared with placebo and the addition of apraclonidine.310
Systemic Adverse Reactions.
The most common systemic effect of topical apraclonidine use is dry nose or mouth, which is noted in about 20% of patients.291,294 In a double-masked study, topical apraclonidine produced no greater fatigue than placebo.311 Apraclonidine minimally affects exercise-induced pulse increases in normal volunteers, with no resting pulse or mean arterial blood pressure changes.312 There was one case report of a patient with chest tightness after instillation of apraclonidine before laser iridotomy.313
Local Adverse Reactions.
Most individuals receiving apraclonidine experience mild lid retraction and mydriasis.291,294 It can produce strong vasoconstriction, and conjunctival blanching occurs in 85% of patients.310 Significant acute local reactions are unusual. With chronic use, local allergic reactions manifesting as blepharoconjunctivitis or periocular dermatitis are unfortunately common and may limit the long-term usefulness in many patients. These responses may be dose and concentration dependent; at 90 days with three-times-daily therapy, 36% of the eyes treated with the 0.5% concentration compared with 9% of the eyes treated with the 0.25% concentration developed allergic blepharoconjunctivitis.314 In a different study using 0.5% twice daily, only 13.8% of patients exhibited this allergy.307
A mechanism for the high propensity of apraclonidine to produce local allergy has been proposed. It appears that bioactivation of the drug through oxidation occurs to a bis-iminoquinone, which conjugates with proteins to form immunologically active apraclonidine-protein haptens. Brimonidine, another α2-agonist available for glaucoma treatment, has a much lower oxidative potential, which may explain brimonidine’s reduced tendency to produce local allergic reactions.315,316
Indications.
Apraclonidine is FDA approved to prevent acute increases in IOP after anterior segment laser procedures. It may also be useful to blunt other acute pressure spikes, such as those after cataract surgery, vitreoretinal surgery,317 and cycloplegia.318
Apraclonidine is also FDA approved for topical administration as an additive drug for glaucoma patients receiving maximally tolerated medical therapy. It may be less effective in eyes already on two aqueous suppressants. Apraclonidine is occasionally useful as a second- or third-line agent; however, its high cost and frequent local allergic reactions are potential problems with chronic use.319
Brimonidine.
Brimonidine tartrate is a selective α2-agonist that is more lipophilic than apraclonidine.319 It also has a reduced oxidative potential compared with apraclonidine.315,316 Brimonidine’s ocular hypotensive efficacy is similar to timolol, and its twice daily dosing and low systemic side effects coupled with a reduced local allergy rate, compared with apraclonidine, have made it a popular second-line and frequently useful first-line agent.
Efficacy.
Brimonidine’s efficacy in reducing IOP both acutely and chronically is similar to that of apraclonidine.320 One study suggests that the predominant mechanism of IOP reduction with brimonidine is an aqueous suppressing effect initially but increased uveoscleral outflow chronically.321 It is as effective as apraclonidine in preventing acute IOP spikes following anterior segment laser procedures.322,323 As a chronic, first-line medication several studies have demonstrated that brimonidine tartrate 0.2% when dosed twice daily reduces IOP similarly to timolol 0.5% twice daily.324,325,326 However, brimonidine 0.2% loses roughly one third of its peak effect by the morning trough after evening use.326 Brimonidine 0.2% can be expected to reduce IOP by a transient maximum lowering of 25% peak effect at 2 hours after instillation, and the efficacy may diminish to 15% at 6 to 8 hours. In addition, early studies comparing the efficacy of 0.08%, 0.2%, and 0.5% brimonidine showed a dose-dependent peak reduction of IOP of 16.1%, 22.4% and 30.1%, respectively, in the first week of treatment.327 However, the dose-response relationship disappeared after 2 weeks, with mean peak IOP reduction with the 0.2% and 0.5% brimonidine groups waning to 15%. In patients already treated with a systemic β-blocker, brimonidine lowers IOP better than the addition of a topical β-blocker.326 The effect of brimonidine on IOP during sleep has not been published, but it probably acts similarly to apraclonidine to reduce IOP around the clock. This is a theoretical advantage over β-blockers, which are not effective during sleep. There is increasing evidence that nocturnal systemic hypotension may reduce optic nerve perfusion pressure.328,329
Brimonidine is marketed as brimonidine 0.2% solution with benzalkonium chloride as the preservative (Bausch & Lomb) and 0.15% as Alphagan-P (Allergan) with purite as the preservative. A 3-month randomized double-masked trial comparing the efficacy of brimonidine purite 0.15% BID with brimonidine 0.2% BID, showed that there was no significant difference between the two with respect to IOP-lowering effects or overall incidence of adverse events.330 Activation of α2-receptors by brimonidine has been suggested to promote the survival and function of retinal ganglion cells in various animal models of optic nerve injury relevant to glaucoma, such as the chronic ocular hypertensive rat and rat optic nerve crush. Brimonidine has also been shown to be neuroprotective in a rat ischemia-reperfusion model that evaluates general hypoxic damage to the whole retina. The mechanisms by which stimulation of α2-adrenergic receptors protect retinal ganglion cells are not understood. α2-Adrenergic receptor stimulation can activate the antiapoptotic phosphatidyl inositol-3-(PI3) kinase and protein kinase/Akt (protein kinase B) pathways, which are pathways in the promotion of cell survival that block apoptosis by phosphorylation-dependent inhibition of proapoptotic signaling molecules, including BAD (BCL-2 associated death promoter), caspase-9, and activation of antiapoptotic molecules such as NF-kappaB.331 α2-Adrenergic stimulation also leads to activation of extracellular signal-regulated kinase (ERK), and increased synthesis of survival factors, such as bFGF and BCL-2 (B cell lymphoma-2).332,333 In the animal models where brimonidine was shown to have a neuroprotective effect, the drug was usually administered either subcutaneously or intraperitoneally. In the rat model of ischemia-induced RGC death where ischemia/reperfusion injury was induced by transient ligation of ophthalmic vessels, 0.5% brimonidine was applied topically.334,335 In order for a pharmacological agent for glaucoma to deliver its potential neuroprotective effect, it must be able to reach the retina in neuroprotective concentrations after clinical dosing.336 In a study measuring the vitreous concentrations of brimonidine after topical application of the marketed formulation of brimonidine for 4 to 14 days to the eyes of phakic, pseudophakic, and aphakic patients schedule for pars plana vitrectomy, researchers measured a mean brimonidine concentration in the vitreous sample higher than the 2 nM level that is required to maximally activate α2-adrenergic receptors.337 In a 3-month study of 16 newly diagnosed previously untreated glaucoma patients who were randomly assigned to either timolol 0.5% or brimonidine 0.2%, patients who were initiated on brimonidine 0.2% exhibited improved contrast sensitivity compared to timolol 0.5%.338
However, a 3-month, double-masked, placebo-controlled, randomized European multicenter trial conducted on 36 patients with first eye involvement of acute nonarteritic anterior ischemic optic neuropathy failed to show any statistically significant difference in visual acuity or visual field between brimonidine 0.2% or placebo.339 The clinical significance of the potential neuroprotective properties of brimonidine remain uncertain.
Frequency and Dosing.
Brimonidine tartrate 0.2% is commercially available as Alphagan (Allergan). When used as monotherapy and dosed twice daily the trough IOP reduction is similar to timolol dosed twice daily. Nevertheless, the package insert recommends three times daily dosing. Tachyphylaxis, or loss of pressure lowering effect, may occur after chronic use, and the rate and duration it takes for this to occur is uncertain. The magnitude and frequency of the tachyphylaxis is certainly less than with its cousin, apraclonidine.
Combination Therapy.
Brimonidine is additive to all other classes of ocular hypotensive agents. The combination of brimonidine and timolol was more effective than dorzolamide and timolol.340 In a study of 96 patients in whom brimonidine twice daily was added to otherwise maximally tolerated medical therapy, additional IOP reduction of 16% to 32% was a short-term finding depending on glaucoma subtype. Most such patients maintained IOP control beyond 6 months of follow-up.341 In a multicenter, retrospective analysis, addition of latanoprost to timolol lowered IOP by 6.3 mm Hg, whereas brimonidine added to timolol reduced IOP by 4.2 mm Hg, and dorzolamide added to timolol reduced IOP by 3.1 mm Hg.342
Systemic Adverse Reactions.
Brimonidine has less effect on pulse rate than timolol.324,325,343 Brimonidine is also a safer medication than β-blockers in patients with reactive airway disease. CNS reactions such as fatigue, drowsiness, and headache were similar to timolol in the Brimonidine Study Group.326 There is a case report of suspected brimonidine induced psychosis.344 There have been several reports of severe systemic toxicity in premature infants.345,346,347 Cases of hypotension, hypothermia, or bradycardia in infants after topical ocular brimonidine have been reported.346,347,348 We feel that this drug is contraindicated in infants, and use in small children should be done with caution. Many patients notice dry mouth with chronic use. Brimonidine is contraindicated in patients treated with a monoamine oxidase inhibitor. In addition, because the sedative effect may vary, patients should be warned about driving a motor vehicle or operating hazardous machinery after use.
Local Adverse Reactions.
The major local reaction seen with brimonidine use is an allergic conjunctivitis or periocular dermatitis. Several studies have demonstrated that this reaction is likely in only 9% to 23% of patients known to be allergic to apraclonidine. However, it appears to be the most common reason for stopping the drug. Side effects may occur within a few minutes or may take many months to occur. The mean time to the development of this allergy is 8 months. In a 1-year study comparing brimonidine twice daily with timolol twice daily, allergy developed in 11.5% of brimonidine-treated study subjects compared with 1% of timolol-treated study subjects.325 Brimonidine, like many other topical medications, can alter subconjunctival fibroblast populations, perhaps leading to reduced success if trabeculectomy is required.349 Brimonidine was formulated with purite as the preservative (Alphagan-P), with the hope of reducing side effects associated with benzalkonium chloride. The manufacturer reports a rate of approximately 10% to 20% associated with Alphagan-P compared to 10% to 30% with Alphagan 0.2%.350 However, an allergic reaction associated with the use of brimonidine may be due to the formation of immunologically active drug-protein haptens instead of the preservatives. Patients known to have allergic reactions to brimonidine should not be rechallenged with brimonidine purite (Alphagan-P).
OCULAR PARASYMPATHOMIMETIC AGENTS
Parasympathomimetic agents, drugs that mimic the end effects of the postganglionic parasympathetic neurotransmitter ACh, are also termed cholinergic agents. This class of drug has been used to treat glaucoma since 1876, when Laqueur showed that physostigmine lowered IOP.351,352
Cholinergic agonists bind to ACh receptors and appear to act through G-protein–coupled second-messenger pathways.353 Glaucoma-related responses involve the muscarinic receptors. Although these receptors are found in the ciliary epithelium, cholinergic agents have little effect on aqueous production. Their usefulness in chronic ocular hypotensive therapy is derived from their ability to increase conventional outflow facility.
The most obvious ocular effects of cholinergic muscarinic agonists are caused by contraction of the iris sphincter and ciliary muscle, both of which are predominantly parasympathetically innervated smooth muscles. Iris sphincter contraction produces miosis, often pulling the peripheral iris away from the trabecular meshwork. Cholinergic drugs, when applied to the eye, are thus often termed miotics. Experiments on aqueous dynamics after removal of the iris demonstrate unchanged IOP and resting outflow facility, and pilocarpine induced changes in outflow facility.354 Contraction of the longitudinal ciliary muscle fibers is thought to create the cholinergically mediated increase in outflow facility, whereas contraction of the circular ciliary muscle leads to accommodation. The outflow facility increase is believed to be mediated primarily by the ciliary muscle pulling on the scleral spur, altering the cellular configuration of the trabecular meshwork and Schlemm’s canal.355,356 Evidence for this includes abolition of pilocarpine’s outflow response after disinsertion of the ciliary muscle from the scleral spur.357,358 This argues against evidence for a direct outflow effect of pilocarpine on the meshwork or Schlemm canal.359,360,361
Although miotics often can pull the peripheral iris away from the trabecular meshwork by centripetal iris contraction, they also can increase relative pupil block. The accommodative effects tend to push the crystalline lens forward. In some cases, particularly with strong miotics, the increase in pupil block aggravates iris bombé and causes peripheral anterior chamber shallowing or angle closure.
Dissociation of the accommodative and outflow responses to miotics should reduce the induced myopia that makes cholinergic drugs so difficult to tolerate in young patients. To date, experiments using antagonists selective for muscarinic subtypes suggest that both the increase in outflow facility and the accommodation induced by pilocarpine are mediated by the M3 receptor subtypes.27 There is some evidence that aceclidine, a cholinergic agent available in Europe, enhances outflow facility with less of an accommodative effect than pilocarpine.362,363,364,365
The ocular parasympathomimetic drugs have been divided into two classes based on method of action. Direct-acting drugs mimic ACh, directly stimulating the cholinergic receptor and producing muscle contraction. Members of this group include ACh, pilocarpine, and carbachol (carbamyl ester of choline). These direct-acting cholinergic agonists can be further subdivided based on structure. ACh and carbachol are choline esters and are degraded by the enzyme cholinesterase, whereas pilocarpine is non–choline ester resistant to this enzyme.
Indirect-acting cholinergics, also known as cholinesterase inhibitors, block the degradation of ACh, thereby enhancing cholinergic receptor stimulation. Included in this class are demecarium bromide (Humorsol; Merck, Sharpe & Dohme, West Point, Pennsylvania), echothiophate iodide (Phospholine Iodide; Wyeth-Ayerst), and diisopropyl fluorophosphate (DFP or Floropryl; Merck & Co.). Carbachol is both a direct-acting agonist in addition to having indirect agonist activities. Although the indirect-acting agents are used less frequently in glaucoma management, they are generally much more potent and longer-acting than the direct-acting agents.

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Jul 11, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on Medical Therapy of Glaucoma

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