Mikael D. Jones
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Identify risk factors for the development of primary open-angle glaucoma (POAG) and acute angle-closure glaucoma.
2. Recommend a frequency for glaucoma screening based upon patient-specific risk factors.
3. Compare and contrast the pathophysiologic mechanisms responsible for open-angle glaucoma and acute angle-closure glaucoma.
4. Compare and contrast the clinical presentation of chronic open-angle glaucoma and acute angle-closure glaucoma.
5. List the goals of treatment for patients with POAG suspect, POAG, and acute angle-closure glaucoma.
6. Choose the most appropriate therapy based upon patient-specific data for open-angle glaucoma, glaucoma suspect, and acute angle-closure glaucoma.
7. Develop a monitoring plan for patients on specific pharmacologic regimens.
8. Counsel patients about glaucoma, drug therapy options, ophthalmic administration techniques, and the importance of adherence to the prescribed regimen.
KEY CONCEPTS
Practitioners can play an important role in eye care by assessing patients for risk factors and referring to an ophthalmologist for appropriate screening and evaluation.
Acute primary angle-closure glaucoma (PACG) is a medical emergency and requires laser or surgical intervention.
Patients with primary open-angle glaucoma (POAG) typically have a slow, insidious loss of vision. This is contrasted by the course of acute PACG, which can lead to rapid vision loss that develops over hours to days.
The goals of therapy are to prevent further loss of visual function; minimize adverse effects of therapy and its impact on the patient’s vision, preserve general health and quality of life; control intraocular pressure (IOP) to reduce or prevent further optic nerve damage; and educate and involve the patient in the management of their disease.
Current therapy is directed at altering the flow and production of aqueous humor, which is the major determinant of IOP.
Because POAG is a chronic, often asymptomatic condition, the decision of when and how to treat patients is difficult because the treatment modalities are often expensive and have potential adverse effects or complications. Therefore the clinician should evaluate the potential effectiveness, toxicity, and the likelihood of patient adherence for each therapeutic modality.
An initial target IOP should be set at 20% lower than the patient’s baseline IOP. The target IOP can be set lower (30–50% of baseline IOP) for patients who already have severe disease or have normal-tension glaucoma (NTG).
It is important to review the patient’s medication history for potential drug–drug and drug–glaucoma interactions, adherence, presence of systemic and ocular adverse drug reactions, and ability to use ophthalmic preparations.
INTRODUCTION
Glaucoma refers to a spectrum of ophthalmic disorders characterized by neuropathy of the optic nerve and loss of retinal ganglion cells, which leads to permanent deterioration of the visual field and potentially total vision loss. Glaucoma can be classified as primary and secondary. Primary glaucoma refers to glaucoma that cannot be attributed to a pre-existing ocular or systemic disease while, secondary glaucoma refers to glaucoma that can be attributed to preexisting ocular or systemic disease. Examples of primary glaucoma include open angle, closed angle, and congenital. Examples of secondary glaucoma include pigmentary glaucoma, neovascular glaucoma, traumatic glaucoma, and pseudoexfoliative glaucoma.
Primary open-angle glaucoma (POAG) is characterized by normal anterior-chamber angles, glaucomatous changes of the optic disc, and peripheral visual field loss. Patients with elevated intraocular pressure (IOP), without glaucomatous changes, are considered to have ocular hypertension.1,2 Patients with ocular hypertension that have normal appearing anterior-chamber angles and an eye exam suspicious of early glaucomatous damage are classified as POAG suspects. Primary angle-closure glaucoma (PACG) is the obstruction of the anterior angle by the iris causing moderate to high elevations in IOP. POAG and PACG represent the most common types of glaucoma and therefore will be the focus of this chapter.
Table 61–1 Recommended Frequency of Comprehensive Adult Medical Eye Evaluation
Table 61–2 Risk Factors for Glaucoma
EPIDEMIOLOGY AND ETIOLOGY
Over 66.8 million people worldwide have glaucoma making it the second leading cause of blindness worldwide.3 In the United States it is estimated that 2.22 million people are affected by POAG, and by 2020 this number will increase to 3.36 million. The prevalence varies with race and ethnicity and it is three to five times more prevalent in African Americans than Caucasian Americans. The prevalence of POAG increases with age and is rarely seen in patients less than 40 years of age.1,4,5 Of patients diagnosed with POAG, 15% to 40% actually meet the criteria for normal-tension glaucoma (NTG).1,2 Ocular hypertension is present in about 3 to 6 million of the U.S. population, however, less than 10% will have progression to POAG within 5 years.6
The prevalence of PACG is lower than POAG and varies significantly by race and ethnicity. It is low in patients of European descent (0.09–0.16%) but higher in patients of Chinese (1.3%), Eskimo (2.9–5%), and Asian Indian (4.33%) descent. PACG is also more prevalent with increasing age and among females.7,8
RISK FACTORS
Primary Open-Angle Glaucoma
Practitioners can play an important role in eye care by assessing patients for risk factors and referring to an eye care specialist for appropriate screening and evaluation. Risk factor evaluation is essential in determining the frequency of comprehensive eye exams for patients (Table 61–1). It is also useful in deciding when to start therapy and determining the sequence of pharmacotherapeutic or surgical treatment modalities.1
The five primary risk factors associated with POAG are family history, age, race, central corneal thickness (CCT), and elevated IOP (Table 61–2). Patients who have first-degree relatives with POAG are at a higher risk of developing glaucoma than patients with no family history of POAG. Even though IOP is no longer a diagnostic criterion, it is associated with an increased prevalence and progression of the disease.1,5,7 CCT has recently been recognized as a risk factor for POAG. The Ocular Hypertension Study (OHTS) found patients with ocular hypertension and thinner CCT (less than 555 µm) had a greater risk of progressing to POAG.1,6,9
The five major risk factors identified for PACG are hyperopia, family history of PACG, age (greater than 30 years), gender, and Eskimo or Asian ethnicity (Table 61–2). Patients who are hyperopic, female, or of Eskimo or Asian ethnicity tend to have more shallow anterior angles which predispose the eye to angle closure. Advancing age is associated with a decrease in the depth of the anterior angles because the lens becomes thickened and is displaced toward the anterior portion of the eye. Patients who have first-degree relatives with glaucoma are at greater risk for developing PACG with a prevalence of 1% to 12% for Caucasians.7,8,10
PATHOPHYSIOLOGY
The pathophysiologic alterations seen with POAG optic neuropathy are not fully understood. Elevated IOP is clearly associated with damage and eventual death of optic nerves; however, optic neuropathy can still occur in patients with normal IOP. Optic nerve degeneration without elevated IOP indicates the presence of independent factors that contribute to the death of the optic nerve. The key to understanding the pathophysiology and treatment of POAG relies on an understanding of aqueous humor dynamics, IOP, and optic nerve anatomy and physiology.5,7,11
Aqueous Humor
The eye is separated into two segments by the lens: the anterior segment and the posterior segment (Figs. 61–1 and 61–2). The anterior segment of the eye is separated by the iris into the posterior and anterior chambers. The ciliary body, a ring-like structure that surrounds and supports the lens, produces and secretes an optically neutral fluid called aqueous humor through the diffusion and ultrafiltration of plasma. The nonpigmented epithelium of the ciliary body secretes the aqueous humor into the posterior chamber. Aqueous humor formation can be modified pharmacologically through the α- and β-adrenoceptors, carbonic anhydrase, and sodium and potassium adenosine triphosphatase of the nonpigmented ciliary epithelium.
After the transport of aqueous humor into the posterior chamber, it flows through the pupil into the anterior chamber where it provides oxygen and nutrition to the avascular lens and cornea. Aqueous humor then exits the anterior chamber through the trabecular meshwork and drains into the Schlemm’s Canal, which drains aqueous humor into the episcleral venous system.
Eighty percent of aqueous humor drains through the trabecular meshwork which is a lattice of connective tissue that surrounds the anterior chamber. The size of the trabecular meshwork can be altered by the contraction or the relaxation of the ciliary muscle. Stimulation of muscarinic receptors on the ciliary muscle causes contraction which in turn causes the pores of the trabecular meshwork to open, increasing aqueous humor outflow.
FIGURE 61–1. Anatomy of the eye. (From Lesar TS, Fiscella RG, Edward D. Glaucoma. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotheraphy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1552.)
FIGURE 61–2. Anterior chamber of the eye and aqueous humor flow. (From Lesar TS, Fiscella RG, Edward D. Glaucoma. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotheraphy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1552.)
A second pathway, uveoscleral outflow, comprises the other 20% of aqueous humor drainage. In the uveoscleral pathway, aqueous humor exits the anterior chamber through the iris root and through spaces in the ciliary muscles which then drains into suprachoroidal space. Uveoscleral outflow can be pharmacologically modulated by adrenoceptors, prostanoid receptors, and prostamide receptors. 5,11–15
Intraocular Pressure
IOP is dependent upon the balance between aqueous humor production and outflow, and is important because the refractive properties of the eye depend upon IOP to maintain the curvature of the cornea.16The distribution of IOP in the population is 10 to 21 mm Hg and is slightly skewed toward higher values; however, caution should be used in assigning this range as being “normal” for IOP because optic neuropathy can be present in the normal range and can be absent at higher IOPs. Elevated IOP is generally considered greater than 21 mm Hg. Optic nerve damage generally is slow and takes several years for noticeable progression between 20 and 30 mm Hg, while IOP of 40 to 50 mm Hg may lead to rapid optic nerve damage. IOP varies in a cyclic fashion over the 24-hour day. IOP was thought to be lowest at night and at its maximum in the morning; however, more recent evidence suggests that not all individuals follow this pattern. Patients with and without glaucoma may exhibit a rhythm that consists of a peak in IOP right after falling asleep. Nighttime peaks in IOP are detrimental to patients with glaucoma, because systemic blood pressure decreases during the night leading to a low ocular perfusion pressure. Decreased ocular perfusion pressure can lead to further optic nerve damage, therefore highlighting the importance of IOP control throughout a 24-hour period.17–19
IOP is clinically measured by tonometry and can be performed via applanation, indentation, and indirect tonometry.20 CCT affects the accuracy of IOP measurements. Thin corneas (less than 540 microns) can produce falsely low IOP readings, whereas thick corneas (greater than 555 microns) may produce falsely high readings. The potential consequences of this error in measurement may lead to overtreatment of patients with falsely high IOP and under-treatment of patients with falsely low IOP. The OHTS demonstrated that CCT is a strong predictive factor for the development of POAG. Patients with corneas less than 555 microns and IOP greater than 25.75 mm Hg had a 36% risk of progressing from ocular hypertension to glaucoma. The CCT of patient should be taken into account when evaluating a patient’s IOP.6IOP is no longer used as a diagnostic criterion for glaucoma, because the presence of glaucomatous changes can be absent at high IOPs and can be present at lower IOPs.
FIGURE 61–3. Normal fundus of the eye and optic disk and cup. (Reprinted with permission from Lesar TS, Fiscella RG, Edward D. Glaucoma. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotheraphy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1553.)
Optic disk
The posterior segment of the eye contains vitreous humor (a clear “jellylike” substance), the retina, retinal vasculature, and the optic nerve head. The retina transforms light energy into neural signals, which are transmitted out of the eye by the retinal ganglion cells. The axons of the retinal ganglion cells converge and exit at the optic nerve head (optic disc) to form the optic nerve (Fig. 61–3). The optic nerve contains 1 million nerve fibers and synapses at the lateral geniculate nucleus of the brain. The optic nerve head is the portion of the optic nerve that is susceptible to elevations in IOP and is visible on fundoscopic examination. The optic nerve head is vertically oval and pale yellow with a depression in the center of the optic nerve, called a physiologic cup which is formed by convergence of the axons. The area surrounding the optic nerve head is the nerve fiber layer which consists of converging retinal ganglion cell axons. Retinal nutrition is dependent upon the transport of trophic factors from the retinal cell ganglion axon to their cell bodies.
Glaucomatous changes to the optic nerve head precede visual field loss, making optic nerve head evaluation a useful screening and prognostic tool. The optic nerve head should be assessed for cupping, nerve fiber layer changes, and presence of splinter hemorrhages using a slit-lamp biomicroscope. Cupping refers to an increase in the size of the physiologic cup. The cup increases with the loss of retinal ganglion cell axons and the collapse of lamina cribrosa. The cup size is expressed as the ratio of the size of the cup to the size of the optic nerve head. A cup-to-disc ratio greater than 0.55 is associated with an increased risk of developing visual field loss. Other findings include atrophy and notching of the nerve fiber layer.5,7,20,21
Pathophysiology of Open-Angle Glaucoma
The pathophysiology of glaucomatous neurodegeneration has not been completely elucidated. It is unclear whether the optic neuropathy is caused by increased IOP, decreased retinal blood flow, or a combination of these factors.5,7Several theories, including autoimmune reactions, excess nitric oxide, and glutamate toxicity have been proposed as to what ultimately causes the retinal ganglion cells to undergo apoptosis.5,7
The level of IOP is related to the death of retinal ganglion cell and optic nerve fibers. As optic neurodegeneration progresses over time, the optic nerve becomes more susceptible to high IOP. Increased IOP causes the retinal ganglion cell axons to undergo mechanical stress, alters axonal protein transport, and decreases blood supply to the retina and the optic nerve leading to tissue ischemia.5,21,22 Glaucomatous optic neuropathy may also occur independent of increased IOP. Pressure independent causes of optic neuropathy include abnormal blood flow, systemic hypotension, and abnormal blood coagulability.19Current glaucoma therapies fail to target IOP-independent glaucoma pathophysiologic factors. However, IOP reduction may still be beneficial as the rate of visual field progression is decreased in some patients who receive IOP reduction via medical or surgical modalities.23,24
Pathophysiology of Angle-Closure Glaucoma
PACG involves a mechanical obstruction of aqueous humor outflow through the trabecular meshwork by the peripheral iris. Two major mechanisms of trabecular meshwork obstruction by the peripheral iris include pupillary block and an abnormality of the iris called iris plateau. Pupillary block is the more common mechanism of obstruction and results from a complete or functional apposition of the central iris to the anterior lens and is associated with mid-dilation. The trapped aqueous humor increases pressure behind the iris causing the peripheral iris to bow forward and obstruct the trabecular meshwork. Plateau iris refers to an anterior displacement of the peripheral iris caused by anteriorly positioned ciliary processes. In this configuration the peripheral iris bunches as the eye dilates. Both of these mechanisms result in the occlusion of aqueous humor outflow causing IOP elevation at extreme levels that can lead to vision loss in hours to days.7,10,20,25,26 The degree of obstruction or angle closure can be determined by gonioscopy.
The development of PACG is associated with several anatomical risk factors that lead to shallow anterior chambers. PACG patients may have a thick, anteriorly displaced lens that results from myopia or old age. The axial length of the eye is smaller in individuals with PACG which leads to a lens that is situated more anteriorly than those without PACG.25,26
Medications with anticholinergic properties induce mydriasis, which can lead to angle closure in pupillary block and plateau iris. Pupillary block may also be induced by drugs that cause miosis.12
PACG can be separated into three categories: acute primary angle closure, subacute primary angle closure, and chronic primary angle closure. Acute PACG is the sudden obstruction of the trabecular meshwork which leads to rapid increases in IOP resulting in pressure-induced optic neuropathy if left untreated. Acute PACG is a medical emergency and requires laser or surgical intervention. Subacute PACG is characterized by self-limiting angle closure that resolves spontaneously. Recurrent attacks or a prolonged acute attack can lead to the development of peripheral anterior synechia. Chronic PACG is characterized by the presence of peripheral anterior synechia that partially obstruct the flow of aqueous humor through the trabecular meshwork resulting in an elevated IOP that is similar to what is seen in POAG.10,25,26
Clinical Presentation and Diagnosis of POAG
General
• Adult onset (usually greater than 40 years of age)
• Patients may be unaware that they have glaucoma and may be diagnosed during routine eye evaluation
• POAG is usually bilateral with asymmetric disease progression
Symptoms
• Patients with severe disease progression may report loss of peripheral vision and may describe the presence of scotomata (blind spots) in their field of vision
Signs
• Ophthalmoscopic examination may reveal
• Optic nerve head (optic disc) cupping
• Large cup-to-disc ratio
• Diffuse thinning, focal narrowing, or notching of the optic nerve head rim
• Splinter hemorrhages
• Optic nerve head/nerve fiber layer changes occur before visual field changes can be detected
Diagnostic Tests
• Gonioscopy—anterior-chamber angles are to be open
• Applanation tonometry—elevated IOP (greater than 21 mm Hg) may be present. However, patient can have signs of optic neuropathy without elevated IOP
• Pachymetry—measures central corneal thickness. Thin corneas (less than 540 µm) are considered a glaucoma risk factor
• Automated static threshold perimetry—evaluates visual fields. Useful in diagnosis and determining if there is progression
• Other diagnostic tests—scanning laser polarimetry, confocal scanning laser ophthalmoscopy, and optical coherence tomography
Clinical Presentation and Diagnosis of PACG
General
• Medical emergency due to high risk of vision loss
• Unilateral in presentation, but fellow eye is at risk
Symptoms
• Ocular pain
• Red eye
• Blurry vision
• Halos around lights
• Systemic symptoms may develop
• Nausea/vomiting
• Abdominal pain
• Headache
• Diaphoresis
Signs
• Cloudy cornea caused by corneal edema
• Conjunctival hyperemia
• Pupil semidilated and fixed to light
• Eye will be harder on palpation through closed eye
Diagnostic Tests
• Gonioscopy—anterior-chamber angles will be closed. Peripheral anterior synechiae may be present
• Applanation tonometry—elevated IOP (greater than 21 mm Hg but when symptoms are present IOP may be greater than 30 mm Hg)
• Slit-lamp biomicroscopy—reveals shallow anterior-–chamber depth. Signs of previous attacks include Peripheral anterior synechiae, iris atrophy, glaukomflecken, and pupillary dysfunction
Clinical Course
Patients with POAG typically have a slow, insidious loss of vision. This is contrasted by the course of acute PACG which can lead to rapid vision loss that develops over hours to days. For POAG, only 4% to 8% of patients may progress to legal blindness. It may take 13 to 16 years for a patient to go blind from glaucoma. A patient’s quality of life may not be affected until significant visual field loss is present and the patient can no longer perform the activities of daily living.27 Vision loss does not occur until there has been significant loss of the retinal ganglion cells. Peripheral vision is the most susceptible to glaucomatous damage, with central vision being preserved until advanced disease progression has occurred. Visual field abnormalities include paracentral scotoma, nasal scotoma, and arcuate scotoma. Patients may also have problems with depth perception and contrast sensitivity. Peripheral vision may worsen until the patient has tunnel vision and ultimately total field loss. Visual fields can be measured by perimetry and can detect defects in the visual field before a patient may notice.5,7
Patient Encounter 1, Part 1: Risk Factor Evaluation and Recommended Frequency of Eye Care
A 65-year-old African American female with a history of type 2 diabetes, mild intermittent asthma, and hypertension presents to your clinic for her yearly checkup. She states that she is concerned about losing her eyesight because her sister has started losing her vision from glaucoma. She denies any changes in her vision.
Meds: Metformin 1,000 mg orally twice a day, albuterol two puffs every 6 hours as needed for wheezing, lisinopril 10 mg orally daily
What risk factors does this patient have for glaucoma?
Based on the available information, how often would you recommend that this patient receive a comprehensive eye evaluation?
TREATMENT
Primary Open-Angle Glaucoma
Desired Outcomes and Goals
The goals of therapy are to prevent further loss of visual function; minimize adverse effects of therapy and impact on the patient’s vision, general health, and quality of life; maintain IOP at or below a pressure at which further optic nerve damage is unlikely to occur; and educate and involve the patient in the management of their disease.
Current therapy is directed at altering the flow and production of aqueous humor, which is the major determinant of IOP.
General Approach
Because POAG is a chronic, often asymptomatic condition, the decision of when and how to treat patients is difficult, as the treatment modalities are often expensive and have potential adverse effects or complications. The clinician should evaluate the potential effectiveness, toxicity, and the likelihood of patient adherence for each therapeutic modality. The ideal therapeutic regimen should have maximal effectiveness and patient tolerance to achieve the desired therapeutic response. The American Academy of Ophthalmology (AAO) publishes Preferred Practice Patterns for POAG and POAG Suspect.1
Table 61–3 Select Nonpharmacologic Treatment Options for POAG
Before the selection of a therapeutic modality, the target IOP should be determined for each patient. The target IOP ideally represents an IOP range that will slow the progression of optic neuropathy and not simply obtaining an IOP in the range of 10 to 21 mm Hg. Currently, the initial target IOP is an estimate, but it should be modified based on the progression of the disease at each follow-up visit. The AAO recommends an initial target IOP to be set at 20% lower than the patient’s baseline IOP. The target IOP can be set lower (30–50% of baseline IOP) for patients who already have severe disease or have NTG.1,23,24
Initial IOP control can be achieved by medical, laser, surgical, or combination of these therapies. The AAO guidelines do not provide a specific recommendation on which therapeutic modality should be selected first, but patients in the early stages of glaucoma should receive treatment. The Early Manifest Glaucoma Trial evaluated the effectiveness of reducing IOP in early untreated POAG. The trial demonstrated that patients who received a topical medication combined with laser therapy had slower progression of glaucoma by an average of 18 months.28 Initial therapy with laser trabeculoplasty is at least as effective as treatment with topical β-adrenergic antagonist in preserving visual function and optic nerve head status and can be considered as initial treatment.1 Even though initial treatment of POAG with surgical trabeculectomy compared to medical therapy has similar visual field outcomes at 5 years, surgical intervention is associated with more eye discomfort and increased risk of cataract development.2,23,24 Surgical therapy is typically not considered as a first-line therapy.5 Laser or surgical candidates may require additional procedures or medical therapy to main long-term IOP control.1,5Table 61–3 describes nonpharmacologic treatment modalities for POAG.
Medical treatment is the most commonly selected therapeuticmodality. A well-tolerated ocular antihypertensive, at the lowest concentration, should be selected as the initial mediation (Table 61–4). If monotherapy alone lowers IOP but does not reach target pressure, then combination therapy or switching to another agent is appropriate. Increasing the concentration or dose frequency can also be tried when possible. A uniocular trial can be used to assess the safety and effectiveness of a topical medication before initiation in both eyes; however uniocular drug trials do not always predict the IOP response of the second eye. The lack of correlation between IOP of fellow eyes may be explained by asymmetric IOP in each eye or the potential for contralateral IOP lowering of a uniocular applied medication. Uniocular trials may be more predictive of fellow eye response to a medication in POAG suspects than POAG patients. Ideally, the effect of a medication should be assessed independently using baseline IOP measurements.29,30
Treatment Considerations for POAG Suspects POAG suspects should be considered for topical medication therapy if they can be expected to develop optic nerve damage or they may already have early glaucomatous nerve damage that cannot reliably be diagnosed because of inconclusive exam findings. The Ocular Hypertension Treatment Study demonstrated that a 20% decrease in IOP can reduce the progression from ocular hypertension to POAG over a 5-year period. The incidence of progression to POAG in the treatment (4.4%) and control (9.5%) groups was small which underscores the importance of selecting patients at high risk of progressing to POAG.31 When medical therapy is indicated, a well-tolerated agent should be selected and optimized following the POAG algorithm (Fig. 61–4). The risk to benefit of therapy should be reassessed in patients who may require third or fourth line agents to control IOP. Surgical or laser intervention are rarely indicated in the treatment of glaucoma suspects.32
Primary Angle-Closure Glaucoma
Desired Outcomes and Goals
Therapeutic modalities for PACG are targeted at decreasing IOP. The goals of therapy are to preserve visual function by controlling the elevation in IOP; manage an acute attack of angle closure; reverse or prevent angle closure using a laser and/or surgical intervention; educate and involve the patient in the management of the disease.10
General Approach
The treatment of choice for PACG is laser iridotomy. Medical therapy is used to lower IOP, reduce pain, and reverse corneal edema before the iridotomy. Laser iridotomy uses laser energy to cut a hole into the iris to alleviate the aqueous humor buildup behind the iris resulting in reversal of appositional angle closure. IOP should first be lowered with topical β-blockers, topical α-agonist, prostaglandin F2α analog, systemic carbonic anhydrase inhibitors, or hyperosmotic agents. Once the IOP has been controlled, miotics (i.e., pilocarpine) can be used to break the pupillary block. A topical IOP-lowering agent should be continued to control IOP until laser iridotomy can be performed. Corneal indentation with a cotton-tipped applicator or gonioscopic lens may break pupillary block. If laser iridotomy cannot be performed incisional iridectomy is used. Incisional iridectomy is the surgical removal of a small portion of the iris to allow drainage of aqueous humor trapped in the posterior chamber. Topical corticosteroid may be employed to decrease inflammation. The fellow eye is at high risk of having acute attack and should receive prophylactic iridotomy. Patients with chronic angle closure should also receive laser iridotomy. Acute and chronic angle-closure patients may require chronic medical therapy if the patient has PACG superimposed on pre-existing POAG or if synechia formation causes continued increases in IOP.7,10,33
Table 61–4 Topical Drugs Used in the Treatment of Glaucoma
FIGURE 61–4. Algorithm for the pharmacotherapy of open-angle glaucoma. a ourth-line agents not commonly used any longer. bMost clinicians believe laser procedures should be performed earlier (e.g., after three-drug maximum, poorly adherent patient). CAI, carbonic anhydrase inhibitor. (From Lesar TS, Fiscella RG, Edward D. Glaucoma. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotheraphy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1557.)
Pharmacologic Therapy
β-Adrenergic Antagonists
Topical β-adrenergic antagonists (β-blockers) are generally considered first-line agents for the treatment of POAG unless contraindications are present.11,13 Topical β-blockers decrease IOP by reducing the formation of aqueous humor made by the ciliary body which results in 20% to 35% reduction in IOP.11,13,34 Timolol, levobunolol, metipranolol and carteolol are nonselective for β- and β2-adrenergic receptors, while betaxolol has β1-selective properties. All of the topical β-blockers have similar efficacy and adverse effect profile. Betaxolol reduces IOP to a lesser extent than the nonselective β-blockers, but may cause less exacerbation of pulmonary disease. Despite the intrinsic sympathomimetic activity demonstrated by carteolol, this does not translate to a clinically significant decrease in pulmonary or cardiovascular adverse effects.
Topical β-blockers are typically administered twice daily. A gel-forming solution of timolol (Timoptic-XE) can be administered once daily. Tachyphylaxis may occur in 20% to 50% of patients on mono therapy with a β-blocker resulting in the need for a different agent or combination therapy. Patients on concurrent systemic β-blockers may experience less IOP reduction than patients on only topical β-blockers.11,35
Ocular medication requires the use of concentrated drug solutions to penetrate the eye. Excess drug drains into the nose via the nasolacrimal duct where it is absorbed into the systemic circulation. β-Blockers can cause significant systemic adverse effects through this pathway, because first-pass hepatic metabolism is bypassed resulting in pharmacologically significant serum drug concentrations.36 Bronchospasm is the most common pulmonary effect of topical β-blockers. Pulmonary edema, status asthmaticus, and respiratory arrest have been reported with β-blockers as well. Cardiovascular effects include bradycardia, hypotension, and congestive heart failure exacerbation. As with systemic β-blockers, topical β-blockers have also been reported to cause depression, hyperlipidemia, and mask symptoms of hypoglycemia. Topical β-blockers are generally contraindicated in patients with asthma, chronic obstructive pulmonary disease (COPD), sinus bradycardia, second or third degree heart block, cardiac failure, and hypersensitivity to the product.11,36,37
Local side effects are usually tolerable and may be caused by preservatives, therefore switching from one product to another may alleviate the local side effects. Stinging of the eyes upon instillation is the most common adverse effect. Other local adverse effects include conjunctivitis, keratitis, dry eyes, and uveitis.11,13
Patients prescribed topical β-blockers should be counseled on the nasolacrimal occlusion technique to decrease systemic absorption.
Ocular Hypotensive Lipids
The ocular hypotensive lipids in typical ophthalmology practice are considered first-line alternatives to topical β-blockers because of their superior efficacy and safety profiles. Many clinicians may choose to use the ocular hypotensive lipids as first line, especially in patients who have an initial requirement to lower IOP by greater than 25%, or in patients who have relative or absolute contraindications to topical β-blockers.11,35 Bimatoprost and latanoprost currently have an FDA indication for first-line therapy. Travoprost is indicated by the FDA for patients who are intolerant of other IOP-lowering therapy or insufficiently responsive to another IOP-lowering medication. Latanoprost and travoprost have dosing aids that help patients administer each medication. Travoprost dosing aid is electronic and allows practitioners to track usage of travoprost.
Latanoprost and travoprost are analogs of prostaglandin F2α and are agonists of the prostanoid FP receptor which appears to lower IOP by increasing aqueous humor outflow through the uveoscleral pathway. Bimatoprost is a prostamide analog and appears to lower IOP by activating prostamide receptors in the uveoscleral pathway and possibly through increasing outflow through the trabecular meshwork. The exact mechanism of how uveoscleral outflow is increased is still unclear but stimulation of prostanoid FP receptors and prostamide receptors in the ciliary body cause remodeling of the extracelluar matrix making it more permeable to aqueous humor, thus increasing aqueous humor outflow through the ciliary muscles.14,15,38
Latanoprost, travoprost, and bimatoprost are administered once daily at bedtime and should not be increased to twice daily, as this may decrease effectiveness. These agents lower IOP by 25% to 35% and, unlike topical β-blockers, can effectively lower nocturnal IOP, providing IOP control throughout a 24-hour period. The prostaglandin analogs can be used as mono- or combination therapy.11,35 For patients nonresponsive to latanoprost, switching to brimatoprost may allow some patients to reach their IOP goal presumably because of the proposed difference in the site of action of each drug.39,40
The ocular hypotensive lipids are well tolerated and rarely cause systemic side effects (headache has been reported). Local effects include conjunctival hyperemia, stinging on instillation, increase in iris pigmentation, hypertrichosis, and darkening of the eyelashes. Increases in iris pigmentation occur most commonly in patients with multicolored irides on long-term prostaglandin analog therapy. The mechanism of this effect is by its action on melanocytes of the iris, in which the irides become darker because of increased production of melanin in the iris.41,42 The 12-month incidence of iris pigmentation varies among the agents. Latanoprost appears to have the highest incidence of iris pigmentation after 12 months of therapy (5.2–25%) compared to travoprost (3.1%) and bimatoprost (1–5.5%).43–48 The increase in pigmentation may be irreversible or may reverse at a very slow rate. Increased iris pigmentation appears to be only a cosmetic effect but may affect your product selection especially when choosing monocular therapy. Conjunctival hyperemia or engorgement of conjunctival blood vessels is a common adverse effect caused by a vasodilatory effect on scleral blood vessels. It is most prominent early in therapy and usually subsides over time. While generally a benign adverse effect, patients may have a concern if it affects their cosmetic appearance.43–48 The ocular hypotensive lipids should be used with caution in patients, since they may worsen anterior uveitis and herpetic keratitis. Cystoid macular edema has been reported during treatment with the ocular hypotensive lipids, therefore, use caution in patients with intraocular inflammation, aphakic patients, pseudophakic patients with a torn posterior lens capsule, or in patients with risk factors for macular edema.11,35
Patients prescribed ocular hypotensive lipids should be counseled on potential adverse effects and appropriate administration. Patients receiving latanoprost therapy should be instructed to refrigerate the dropper bottle until opened. After the bottle has been opened it can be stored at room temperature for 6 weeks.
a2-Adrenergic Agonists
Brimonidine and apraclonidine are α2-adrenergic agonists that decrease IOP by reducing aqueous humor production. Brimonidine has a higher selectivity to the α2-receptor than apraclonidine and has a dual mechanism of action by increasing uveoscleral outflow.11,14 Apraclonidine is often used for the prevention and treatment of postsurgical IOP elevations and no longer commonly used for long-term treatment of POAG because of tachyphylaxis and high rate of blepharoconjunctivitis. Brimonidine lowers IOP by 14% to 28%. Peak IOP-lowering effect is similar to that of timolol, but the trough IOP-lowering effect is less than timolol. Brimonidine is usually administered every 8 hours. A 12-hour dosing schedule may be employed by using nasolacrimal occlusion when instilling the drops. Brimonidine-purite 0.1% and 0.15% solution (Alphagan-P) has similar efficacy compared to the brimondine 0.2% solution, because the purite solution’s higher pH allows for more drug to penetrate the cornea.11,13,14
Apraclonidine and brimonidine cause both local and systemic effects. Local effects of apraclonidine include blepharoconjunctivitis, foreign body sensation, pupillary mydrasis and eyelid retraction. Brimonidine does not cause the α1-mediated mydrasis and eyelid retraction but does cause blepharoconjunctivitis though at a lesser rate than apraclonidine. The brimonidine-purite solution has a lower incidence of ocular allergy. Systemic effects of both agents include headache, dry mouth, and fatigue.
Brimonidine is typically used as an adjunctive agent in combination with other agents but could be used as a first-line agent as well. The frequency of dosing and local adverse effects may lead to nonadherence in some patients. Patients prescribed brimonidine should be counseled on the nasolacrimal occlusion technique to reduce systemic adverse effects and to improve efficacy.11,13 A combination product of brimonidine (0.2%) and timolol (0.5%) (Combigan) is available and can be administered twice daily.
Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors decrease aqueous humor production by inhibition of the carbonic anydrase isoenzyme II located in the ciliary body. In the eye, carbonic anhydrase catalyzes the conversion of H2O and CO2 to HCO3–and H+, which is a significant step in aqueous humor production. Carbonic anhydrase inhibitors are available in systemic and topical preparations.11,13,14
Topical Carbonic Anhydrase Inhibitors Dorzolamide and brinzolamide are the only topical carbonic anhydrase inhibitors available on the market and lower IOP by 15% to 24%. Both medications are administered every 8 hours and are used as adjunctive therapy or as monotherapy for patients who cannot tolerate first-line therapies. Nasolacrimal occlusion may allow for an every 12-hour dosing interval.11,13 Recently the European Glaucoma Prevention Study found that dorzolamide did not prevent the progression of patients with ocular hypertension to POAG despite a 15% to 22% reduction of IOP over 5 years. Unlike the Ocular Hyper tension Treatment Study, a goal IOP reduction of at least 20% was not required for treatment and surprisingly, the placebo treatment had a clinically significant effect on IOP.49
Local side effects include burning, stinging, itching foreign body sensation, dry eyes, and conjunctivitis. Brinzolamide may have fewer incidences of these side effects since the drug is in a neutral pH solution. Dorzolamide has been reported to cause irreversible corneal decompensation. Taste abnormalities have been reported with each agent. Both topical carbonic anhydrase inhibitors are sulfonamides and are contraindicated in patients with history of sulfonamide hypersensitivity.11,13
A combination product of timolol (0.5%) and dorzolamide (2%) (Cosopt) is available, can be administered twice daily, and provides an additive reduction in IOP.
Systemic Carbonic Anhydrase Inhibitors There are three systemic carbonic anhydrase inhibitors: acetazolamide, dichlorphenamide, and methazolamide. These agents effectively lower IOP by 20% to 30% but are reserved as third-line agents because of their significant adverse effects. They are typically used as bridge therapy from maximal medical therapy to laser or surgical intervention. The systemic carbonic anhydrase inhibitors can also be used to lower IOP in acute angle-closure glaucoma. Acetazolamide has an IV formulation that can be used in patients having nausea due to the angle-closure attack. Acetazolamide and methazolamide are the best tolerated of the three agents.
Patient Encounter 1, Part 2
The patient was referred to an ophthalmologist for a comprehensive eye evaluation. The ophthalmology report reveals the patient has an IOP (as assessed by applanation tonometry) of 26 mm Hg. Gonioscopic examination reveals open anterior angles in both eyes. Pachymetry reveals a corneal thickness of 510 microns. Ophthalmoscopy reveals cupping of the optic discs in both eyes. Visual field examination reveals a nerve fiber bundle defect consistent with glaucoma.
Given this additional information, what additional risk factors does this patient have for glaucoma?
What is your assessment of this patient’s glaucoma type?
What pharmacologic and nonpharmacologic treatment modalities are available for the patient?
The systemic carbonic anhydrase inhibitors are associated with significant adverse effects that include paresthesias of the hands and feet, nausea, vomiting, and weight loss. Patients can develop systemic acidosis, hypokalemia, hyponatremia, and nephrolithiasis due to the inhibition of renal carbonic anhydrase. Sulfonamide allergy, renal failure, hepatic insufficiency, COPD, and decreased serum potassium and sodium levels are all contraindications of systemic carbonic anhydrase inhibitor therapy. Blood dyscrasias from bone marrow suppression have been reported and include agranulocytosis, aplastic anemia, neutropenia, and thrombocytopenia.11,13
Cholinergic Agents
Cholinergic agents (also called parasympathomimetics or miotics) were the first class of agents to treat glaucoma. The class can be divided into direct-acting cholinergic agents and indirect-acting cholinergic agents.
Direct-Acting Cholinergic Agents
Pilocarpine directly stimulates the muscarinic (M3) receptors of the ciliary body which causes contraction of the ciliary muscle. This results in widening of the spaces in the trabecular meshwork, which causes an increase in aqueous humor outflow and reduces IOP by 20% to 30%.
Pilocarpine requires administration four times daily, since the IOP-lowering effect lasts only 6 hours. Pilocarpine is available in 1%, 2%, 4%, 6%, and 8% concentrations. Higher concentrations may be needed for patients with dark irides to obtain adequate IOP reduction. A pilocarpine 4% gel is available and allows for once daily dosing at bedtime.11,13 In the treatment of PACG, it is important to delay use until IOP has been controlled, because pilocarpine could worsen angle closure by causing anterior displacement of the lens. Once IOP is controlled pilocarpine can be given to break pupillary block by instilling one drop applied twice in an hour.
The adverse effects of pilocarpine are caused by the induction of miosis. The contraction of the ciliary muscle causes the lens to displace forward, which can lead to accommodation spasm and myopia, and can lead to brow ache. Pupillary constriction can also affect night vision. Pilocarpine should be avoided in patients with severe myopia as it increases the risk of developing retinal detachment. Systemic effects may occur at higher concentrations and include nausea, vomiting and diarrhea, and bradycardia.
Carbachol stimulates the same muscarinic receptor as pilocarpine and also inhibits acetylcholinesterase, the enzyme that metabolizes acetylcholine. Carbachol is more potent than pilocarpine, but it causes more accommodation spasm and brow ache and may also cause anterior uveitis. Carbachol is rarely used today because of the side effect profile.
Indirect-Acting Cholinergic Agents
Echothiophateiodide and demecarium bromide inhibit acetylcholinesterase. Inhibition of this enzyme increases the availability of acetylcholine at the nerve junction, thus increasing the stimulation of the muscarinic (M3) receptors of the ciliary body. These products are given twice daily and have similar efficacy to pilocarpine in the degree of IOP reduction. The side effect profile is similar to pilocarpine, however, they can deplete systemic cholinesterases and pseudocholinesterases and may cause the formation of cataracts. These agents should be discontinued at least 1 week before general surgical procedures. Succinylcholine and some local anesthetics are metabolized by pseudocholinesterases, therefore, depletion of this enzyme by echothiopate or demecarium may lead to toxic effects. These agents are typically used when other topical agents have failed and are limited to patients who have had their lenses removed or who have artificial lenses.11,13
Hyperosmotics
Glycerin, isosorbide, and mannitol are hyperosmotic agents that increase the osmolality of blood. These agents create an osmotic gradient that draws water from the vitreous humor thus decreasing IOP. The resulting dehydration of the vitreous humor may cause posterior movement of the lens, which then causes the anterior chamber to deepen, thus opening the anterior angle. If the patient is not vomiting, glycerin (1–1.5 g/kg of a 50%) solution and isosorbide (1.5–2 g/kg) can be given orally. Isosorbide is preferred in patients with diabetes because it is not metabolized into glucose. If the patient has nausea or vomiting, mannitol (20%) can be given IV at a dose of 1 to 2 g/kg over 45 minutes. The hyperosmotic agents are rapid acting, reaching peak effect in 30 to 60 minutes. Headache and thirst are common complaints. Patients who are already dehydrated are at risk of developing CNS dehydration, which can lead to coma. These agents should be used with caution in patients with renal or cardiovascular disease as extracellular water is increased.33
Nonselective Adrenergic Agonists
Epinephrine and its prodrug, dipivefrine, are rarely used for the treatment of glaucoma and are considered last line agents because of their systemic side effect profile. Dipivefrine increases the corneal penetration. Once it is absorbed through the cornea, it is enzymatically cleaved to epinephrine. Epinephrine has α and β-agonist activity and is thought to increase the outflow of aqueous humor through the trabecular meshwork and the uveoscleral pathway. Both products are instilled twice daily and reduce IOP by 15% to 25%. Local adverse effects include mydriasis, conjunctival hyperemia, and ocular irritation. Aphakic patients should not use these medications because they cause a reversible cystoid macular edema. Epinephrine and dipivefrine should not be used in patients with narrow angles since these agents can cause acute angle closure. Systemic side effects include palpitations, increased blood pressure, and arrhythmia and, therefore, these drugs should be used with caution in patients with cardiovascular disease, cerebrovascular disease, and hyperthyroidism. Using the nasolacrimal technique may decrease systemic effects.11,13
SPECIAL CONSIDERATIONS: DRUG-INDUCED GLAUCOMAS
Medications have the potential to cause or exacerbate both POAG and PACG; however, PACG is more likely to be exacerbated by medications than POAG. The use of medications with anticholinergic or sympathomimetics properties can precipitate angle closure. Sulfa-based drugs cause swelling of the ciliary body, which causes an anterior displacement of the lens resulting in a decrease in anterior-chamber depth. Controlled POAG is rarely exacerbated by anticholinergics, sympathomometics, and sulfa-based drugs unless the patient is concomitantly at risk for angle closure. For uncontrolled or untreated POAG, the risk-benefit should be considered before employing these agents. POAG can be exacerbated by corticosteroids. Corticosteroids increase IOP by causing obstruction of the trabecular meshwork with extracellular material. The increase in IOP appears to increase with potency and intraocular penetration. Ophthalmic corticosteroid preparations carry the highest risk of increasing IOP.12
Patient Encounter 1, Part 3
The practitioner and patient agree to start medication therapy. Develop a patient-specific care plan.
Address the patient’s (a) drug-related needs, (b) goals of therapy, (c) potential pharmacologic therapies, and (d) plan for follow-up therapy.
List the monitoring parameters for effectiveness and safety for the chosen therapy.
Explain how you would counsel the patient on the chosen therapy, including the administration of an ophthalmic preparation.
OUTCOME EVALUATION
Primary Open-Angle Glaucoma
Evaluate patients 2 to 4 weeks after the initiation or alteration of medical therapy. The clinician should elicit the status of ocular health since the last visit, systemic medical history, medication history, and presence of local and ocular adverse effects of medications. IOP measurement, visual acuity assessment, and slit-lamp biomicroscopy at every POAG follow-up visit is necessary. The frequency of visual fields and optic nerve evaluation depends on whether IOP is controlled, the length of time IOP has been controlled, and whether there is progression of the disease. Patients who are at target IOP and have no disease progression should have optic nerve head evaluation and visual field testing every 6 to 18 months. Patients with disease progression or who are not at target IOP should receive optic nerve head evaluation every 2 to 12 months and visual field testing every 1 to 6 months.1 Assess the patient’s ability to use topical eye drops.1,32 (See Application of Ophthalmic Solutions of Suspensions textbox.) Finally, evaluate the patient’s adherence to their medical regimen. Nonadherence among patients on topical medical therapy ranges from 5% to 80%. Suspect nonadherence in patients who have visual field and optic nerve progression despite a low IOP measurement, as patients may be more adherent to their medical regimen before their visit. Specific patient factors related to the risk of nonadherence have yet to be established, therefore there are few objective measures of adherence. Pharmacy refill histories may be useful in assessing adherence but do not confirm that the patient is actually taking the regimen as prescribed. Using adherence aids, prescribing the least complex regimen, and educating patients about their glaucoma are ways to reduce nonadherence.50
Application of Ophthalmic Solutions or Suspensions
1. Clean hands with soap and water.
2. Avoid touching the dropper tip with your fingers or against your eye to maintain sterility of product; shake dropper bottle if product is a suspension.
3. Tilt head back; pull down the lower eye lid with index finger.
4. Hold the dropper bottle with other hand as close as possible without touching the eye. The dropper should be pointing toward the eye with remaining fingers bracing against the face.
5. Gently squeeze the bottle so that one drop is placed into the pocket.
6. Close your eye for 2 to 3 minutes to allow for the maximum corneal penetration of drug
7. Use a tissue to wipe away any excess liquid.
8. Replace and retighten the cap to the dropper bottle.
9. Wait at least 5 minutes before instilling another ophthalmic drug preparation
10. Application of some ophthalmic preparations (suspension and gels) may cause blurring of vision.
Adjust therapy if patients fail to reach their target IOP. Patients who have achieved target IOP yet have progressive damage of the optic nerve or who have worsening of their visual fields should have further adjustment of their therapy. Evaluate these patients further for possible reasons of continued disease progression. Consider determining the diurnal pattern of IOP and looking for signs of poor ocular perfusion pressure. Establish a lower target IOP. Adjust therapy in patients who are intolerant, nonadherent, or develop contraindications to their drug therapy regimen. Consider increasing the target IOP and reducing drug therapy for patients who have stable disease and who have maintained a low IOP; closely follow these patients to assess their response.1,32
Patient Care and Monitoring
1. In undiagnosed patients assess their risk factors for glaucoma and their recommended interval of glaucoma screening
2. Obtain a thorough history of the patient’s prescription, nonprescription, and natural product use. Review for potential drug-drug and drug-glaucoma interactions
3. Evaluate diagnostic tests (IOP, visual fields, optic nerve evaluations, etc.) to determine if patient’s current glaucoma therapy is effective
4. Assess the patient’s ability to use ophthalmic preparations
5. Determine patient’s adherence level to prescribed medication regimen and factors contributing to poor adherence
6. Evaluate the patient for systemic and ocular adverse drug reactions and drug allergy
7. Provide patient education regarding disease state, drug therapy, and surgical/laser therapy:
• What causes glaucoma or puts people at risk for glaucoma
• Possible complications of glaucoma
• How to use ophthalmic preparations appropriately
• When to take medications
• Potential adverse drug reactions of medical therapy
• Potential benefits and complications of laser or surgical procedures
Primary Angle-Closure Glaucoma
Follow-up of PACG occurs in the postoperative period. Evaluate the patency of the iridotomy and IOP in the postoperative period. Perform gonioscopy and optic nerve head evaluation if not already performed. Treat patients according to POAG guidelines if they have underlying POAG or areas of peripheral anterior synechia with the presence of optic neuropathy.10
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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