Release Date: April, 2010
Expiration Date: April 30, 2012
Karen K. O’Brien, BS Pharm, PharmD
Pharmacy Sciences Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Alan W. Y. Chock, PharmD
Pharmacy Practice Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Catherine A. Opere, PhD
Pharmacy Sciences Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Glaucoma is a chronic disease of the eye characterized by progressive neuropathy of the optic nerve (ON) that can lead to irreversible blindness if untreated or inadequately treated. Primary open-angle glaucoma (POAG), the most common form of this disorder, affects approximately 2.2 million individuals in the United States and is strongly associated with increased intraocular pressure (IOP) and aging.1-3
As the proportion of elders in the U.S. continues to rise, estimates target greater than 3 million cases of POAG by 2020.3 Because the disease is largely asymptomatic, many persons may be unaware they have POAG until loss of vision occurs. Thus, glaucoma represents an important public health concern. The purpose of this article is to provide an overview of the disease process and treatment strategies, allowing pharmacists to help improve care for their patients with glaucoma.
Primary ACG represents a medical emergency because permanent blindness may quickly develop if it is not promptly treated.4 Further discussion will be limited to POAG.
The posterior chamber is bordered laterally by the ciliary processes. The lens surface forms the floor and the posterior surface of the iris forms the roof of the chamber (FIGURE 2).
From the posterior chamber, AH flows through the pupil into the anterior chamber to exit the eye via conventional and unconventional pathways. The conventional pathway accounts for the majority of outflow and refers to AH coursing through the trabecular meshwork and the canal of Schlemm, ultimately draining into the systemic circulation (FIGURE 2).
In unconventional pathways, AH seeps through tissues rather than flowing through the usual channels and vessels. The most common unconventional pathway is the uveoscleral pathway in which AH drains from the base of the ciliary muscle, through tissues in and around the uvea, and eventually into the sclera.5
Intraocular Pressure IOP refers to the pressure generated by flow of AH against resistance within ocular structures. IOP, maintained at about 15 mmHg in healthy individuals, is determined by a delicate balance between the rates of AH entering (inflow) and leaving (outflow) the eye. Whereas inflow is dependent upon rate of production of AH, outflow is regulated by resistance to aqueous drainage.7 Any condition that alters the equilibrium between inflow and outflow of AH may result in abnormal IOP levels. Resistance to outflow is usually responsible for elevated IOP, but other factors may contribute.5
Irrespective of cause, degeneration of retinal ganglion cells (RGCs) is a feature common to all forms of optic neuropathy. RGCs, specialized nerve cells localized within the retina, transmit visual information from retinal photoreceptor cells, via the ON, to the visual cortex in the brain. Axonal fibers projecting from RGCs converge at the optic disc and exit the eye through a meshwork of collagen fibers known as the lamina cribosa (FIGURE 3). In addition to RGC axons, the normal optic disc contains retinal vasculature (central artery and vein) and glial elements that provide support and protection to the neurons. The center of the optic disc does not contain RGC axons and is known as the cup because it appears as a concave indentation on ophthalmic examination (FIGURE 3).
Gonioscopy involves examination of the anterior chamber angle through a special contact lens (goniolens), while IOP is measured via tonometry. IOP is often elevated above the normal range (10-21 mmHg), but a significant portion of patients with POAG have normal IOP levels.1 Conversely, elevated IOP levels do not always indicate POAG. Patients with above-normal IOP but no evidence of ON damage are said to have ocular hypertension. These individuals may or may not receive treatment to lower IOP, based on patient-specific factors. However, they should be monitored closely over time since IOP elevation constitutes a risk for developing POAG. Of note, an IOP measurement only provides a snapshot of the pressure at a given moment in time. Diurnal fluctuation may mask elevated IOP. Tonometric assessment on different days or at varying times of the day may help supply a more accurate measure of IOP.1
Assessment of the optic disc and visual-field testing are also used to monitor for disease progression and efficacy of therapeutic interventions. While lowering IOP is presumed to decrease disease progression, it is not a surrogate measure of visual function.4
In addition to elevated IOP, increasing age, family history of glaucoma, and African or Hispanic/Latino race are consistently linked to an increased risk of glaucoma.1-4,11 A meta-analysis of population-based data identified three times the prevalence of POAG in black as compared to white persons. Prevalence in Hispanic/Latino persons was similar to that in white persons except in those over 65 years, in whom significantly higher rates were found.3 Other factors possibly related to POAG include thinner central corneal thickness, diabetes, systemic hypertension, a history of ocular trauma, reduced blood flow to the ON, myopia (nearsightedness), and vasospastic conditions such as Raynaud’s disease or migraines.1-4
Present options for managing glaucoma include pharmacologic therapy and surgical modalities such as laser trabeculoplasty and filtering or cyclodestructive surgery. Each has associated benefits and risks, and patient-specific factors and preferences must be considered when selecting appropriate initial therapy. Therapies may be combined to achieve treatment goals. Topical medications are an effective first approach in many patients, although laser trabeculoplasty may be an acceptable option. In some patients, filtering surgery may be preferred initially.1
Filtering Surgery: Trabeculotomy, which creates an alternative pathway for AH drainage, is often performed after medication and laser therapies have failed. Best results are achieved in patients with no prior eye surgeries. Cataracts, corneal problems, intraocular inflammation, growth of scar tissue, and infection are possible adverse effects.1
Cyclodestructive Surgery: This method for lowering IOP destroys the ciliary body epithelial tissue, resulting in a permanent reduction in AH production. Loss of visual acuity and blindness may occur, so this treatment option is usually reserved for patients with poor visual acuity or those in whom standard medical, laser, or surgical modalities have failed.4
Currently, prostaglandin analogues and beta-blockers are the most frequently used topical medications. Sympathomimetics, topical and oral carbonic anhydrase inhibitors, and cholinergics are used to a lesser degree.1,4 Adverse effects or inadequate clinical response may necessitate a therapeutic change, while drugs with different mechanisms of action may be used in combination to maximize IOP reduction.
Many minor local adverse effects of POAG medications are transient, and knowledge of this will encourage patients to continue using prescribed medications. If an adverse effect does not subside, the patient should notify his or her eye doctor before discontinuing use of a medication so that another drug can be prescribed. Refer to TABLE 2 for a summary of therapeutic and adverse effects of POAG medications.
Here are some general guidelines for the pharmacist to remember when counseling patients with POAG:
• Systemic adverse effects are rare complications of topical glaucoma medications, but they can be serious. Following instillation of topical medications, nasolacrimal occlusion (NLO) and closing the eyelid for 2 minutes will prevent excess medication from draining into the lacrimal ducts and greatly decrease the risk of systemic effects.4 Pharmacists should recommend these techniques to patients using POAG eye drops.
• Instruct patients in aseptic technique to prevent contamination of the container and product, and ultimately the eye. The tip of the medication container must not be allowed to contact the patient’s eye or the hand of whoever dispenses the drops.
• A patient using more than one POAG eye drop (multiple drops of the same medication or different medications) should wait at least 5 minutes between instillation of the drops.4
• If different ophthalmic formulations are being used, solutions should always be used before other formulations, such as gels and suspensions, to optimize absorption of each medication.
• Because POAG drugs pass through the placenta, women should inform their health care provider if they are pregnant or are trying to conceive.
Beta-Blockers: Medications in this class lower IOP via decreased production of AH and are considered first-line pharmacologic options.2,4,12 Nonselective (timolol, levobunolol, metipranolol, carteolol) and selective (betaxolol) forms of beta-blockers are available in the U.S.
Minor, usually transient, ocular adverse affects include blurred vision, irritation, burning, stinging, and tearing. Additional local adverse affects that should be reported to the eye doctor include loss of visual acuity, pain, inflammation, foreign body sensation, and erythema.
Systemic adverse effects are rarely reported for topical beta-blockers, and their occurrence will be minimized by NLO.
Nonselective beta-blockers are contraindicated in patients with asthma or severe chronic obstructive pulmonary disease (COPD) because they can cause bronchospasms, although betaxolol may be used due to its receptor selectivity. Because beta-blockers can both mask the early warning symptoms of hypoglycemia and prolong recovery from low blood sugars, they should be used cautiously in diabetes. All beta-blockers are contraindicated in patients with cardiac diseases such as sinus bradycardia, second- or third-degree atrioventricular block, heart failure, or cardiogenic shock.
Prostaglandin Analogues: Regarded as first-line therapeutic agents, analogues of prostaglandins (bimatoprost, latanoprost, travoprost) bind to prostanoid FP receptors located on the iris, promoting uveoscleral outflow of AH, which subsequently lowers IOP.13 Bimatoprost may also significantly affect AH outflow through the trabecular meshwork.
Common, frequently transient, adverse ocular effects include blurred vision or other decreased visual acuity, itching, burning or stinging, dry eyes, and excessive tearing. Patients have reported body aches, rash, upper respiratory infections, cold, and (rarely) flu. Systemic adverse effects are very rare with prostaglandin analogues. Patients with active intraocular inflammation should not be started on ophthalmic prostaglandin analogues because these could worsen their condition. Caution should be used in those with a past history of ocular inflammation.
Darkening of the iris, particularly in patients with hazel eyes, has been reported by persons using ophthalmic prostaglandins. In addition, these medications tend to darken the periorbital tissues to a brownish color. These effects may be permanent. A serendipitous side effect is darkening, thickening, and lengthening of the eyelashes. The FDA has approved Latisse, a form of bimatoprost, for the treatment of hypotrichosis, or inadequate eyelashes.14
While the American Academy of Ophthalmology and the American Optometric Association have not stated a definitive preference for pharmacologic treatment of glaucoma, it has been argued that prostaglandin analogues are preferable to beta-blockers because of a greater efficacy in lowering IOP and producing fewer systemic effects.1,2,12,15 However, there are no generic formulations of prostaglandin analogues, so where cost is an important issue, generic beta-blockers will more likely be used.
Carbonic Anhydrase Inhibitors (CAIs): This drug classification is available in both ophthalmic (brinzolamide and dorzolamide) and oral (acetazolamide and methazolamide) formulations. CAIs lower IOP by decreasing production of AH.16
Topical CAIs are normally well tolerated and are considered second-line therapeutic alternatives. Bitter taste and transient burning, stinging, blurred vision, and foreign body sensation are commonly reported. Corneal inflammation and ophthalmic allergic reactions occur rarely. Systemic adverse effects, including headache, tingling in the extremities, fatigue, liver disease, and kidney stones, are very rare with topical CAIs but are more common with the oral formulations.
While quite effective, oral CAIs are deemed third- or fourth-line agents for POAG because they are not well tolerated; thus, long-term use is uncommon.2 They are approved for adjunctive use when maximum topical therapy is inadequate, or for those persons who are intolerant of topicals.2 Metabolic acidosis is one of the most common reasons for discontinuing systemic CAIs.
CAIs are sulfonamides, but are structurally different from bacteriostatic sulfonamides. They may be used cautiously in patients with bacteriostatic sulfonamide allergy, but CAIs should be discontinued if reactions suggestive of sulfonamide hypersensitivity emerge.17 Patients at risk for acidosis, electrolyte imbalance, or kidney or liver dysfunction should avoid systemic CAIs.
Cholinergics: Direct-acting (pilocarpine and carbachol) and indirect-acting (cholinesterase inhibitor, echothiophate iodide) parasympathomimetics exert a miotic effect. As the pupil constricts, channels in the trabecular meshwork open, reducing resistance to outflow of AH.1 These third- or fourth-line glaucoma medications are rarely used today because of the need for frequent dosing and significant adverse effects such as blurred vision, cataracts, and retinal detachment.2,12,16 It is important to note that excessive miosis may severely restrict the flow of AH from the posterior to the anterior chamber. Thus, patients should be closely monitored for pupillary block leading to ACG. Systemic cholinergic adverse effects are also possible. Newer, safer drugs have generally eclipsed the need for cholinergics.
Sympathomimetics: The alpha-adrenergic agonists brimonidine and apraclonidine, first-line sympathomimetic agents, are selective to alpha2-receptors that increase uveoscleral outflow of AH, thereby decreasing IOP.2 In addition, brimonidine reduces the production of AH. The efficacy of apraclonidine typically wears off in less than a month, so it is used specifically for short-term adjunctive therapy.
Common ocular adverse effects include burning, stinging, irritation, tearing, and eyelid edema. Mild ocular allergic reactions, such as itching, are common with alpha-adrenergic agonists. More serious allergic reactions may develop over time and should be reported. Dizziness and drowsiness occur rarely, so patients should be cautious when performing hazardous activities that require alertness. These drugs can potentiate the effects of depressants, such as alcohol, barbiturates, and sedatives.
The nonspecific sympathomimetics epinephrine and dipivefrin (a prodrug of epinephrine) increase the outflow of AH through both the trabecular meshwork and uveoscleral route. If used long-term, they also decrease AH production.12,16 Ophthalmic epinephrine is no longer available in the U.S., and dipivefrin is rarely used because of frequent local adverse effects and significant systemic effects, including elevated blood pressure and irregular heartbeat.12 It must be used cautiously in the elderly and in persons with hypertension, diabetes, hypothyroidism, and heart disease. Dipivefrin produces mydriasis and may increase IOP by blocking outflow via the conventional pathway. This situation may lead to ACG. Dipivefrin is used primarily as an alternative treatment for those who respond inadequately to other, safer medications.
Failure to follow recommended therapeutic regimens may lead to continued optic neuropathy and vision loss. Health care professionals diagnose and educate about glaucoma, prescribe and dispense medication, and monitor therapy, but the patient is ultimately responsible for daily ongoing disease management. Home diagnostics allow patients with many chronic diseases to monitor for therapeutic efficacy: blood pressure readings (hypertension), blood glucose levels (diabetes), peak flow measurement (asthma). This valuable feedback allows patients to selfadjust behaviors or recognize the need to contact their health care providers. No day-to-day self-monitoring is available for patients with glaucoma. Moreover, because glaucoma is largely asymptomatic, few cues alert patients to disease progression.
Pharmacists are widely regarded as the most accessible health care providers, and they enjoy the public’s trust and respect. They are ideally positioned to serve as teachers and coaches for patients with glaucoma. Patients must be educated about the disease process and the significance of untreated or inadequately treated glaucoma. Therapeutic regimens must be clearly explained to patients, including the desired effect of therapy, possible side effects, and when to contact a health care provider. Careful counseling, augmented by periodic dialoguing, may help pharmacists identify barriers to adherence and offer solutions to improve outcomes. Pharmacists should assess patients’ understanding by asking questions and offering further explanation or clarification as necessary.20
The concept of neuroprotection, preserving existing RGCs, and rescuing damaged RGCs and their axons has been proposed as superior to treatment modalities aimed at lowering IOP because it would be effective irrespective of disease etiology.25
Several groups of compounds, including the antioxidant alpha-tocopherol, phenytoin, aminoguanidine, and the N-methyl-d-aspartate receptor antagonist memantine, have been proposed as possible candidates for RGC neuroprotection.26 Memantine showed promise in Phase I and II trials but failed to pass Phase III clinical trials.24 The quest for treatment modalities that can stop loss of vision remains a subject of intense investigation.
Karen K. O’Brien, BS Pharm, PharmD
Pharmacy Sciences Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Alan W. Y. Chock, PharmD
Pharmacy Practice Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Catherine A. Opere, PhD
Pharmacy Sciences Department
Creighton University School of Pharmacy & Health Professions,
Omaha, Nebraska
Glaucoma is a chronic disease of the eye characterized by progressive neuropathy of the optic nerve (ON) that can lead to irreversible blindness if untreated or inadequately treated. Primary open-angle glaucoma (POAG), the most common form of this disorder, affects approximately 2.2 million individuals in the United States and is strongly associated with increased intraocular pressure (IOP) and aging.1-3
As the proportion of elders in the U.S. continues to rise, estimates target greater than 3 million cases of POAG by 2020.3 Because the disease is largely asymptomatic, many persons may be unaware they have POAG until loss of vision occurs. Thus, glaucoma represents an important public health concern. The purpose of this article is to provide an overview of the disease process and treatment strategies, allowing pharmacists to help improve care for their patients with glaucoma.
CLASSIFICATION
Glaucoma is not a single disease, but a group of disorders resulting in optic neuropathy and vision loss. These may be broadly classified as open angle or angle-closure glaucoma (ACG) based on the anatomy of the eye’s anterior chamber, and are further classified as primary or secondary. Primary glaucoma refers to a glaucomatous eye with no pre-existing disease, while secondary glaucoma results from other ocular or systemic disease, trauma, or the effects of some drugs.2,4 Underlying pathology must be addressed when treating secondary glaucomas.Primary ACG represents a medical emergency because permanent blindness may quickly develop if it is not promptly treated.4 Further discussion will be limited to POAG.
ANATOMY AND PHYSIOLOGY
The eye is broadly divided into the anterior and posterior segments (FIGURE 1). The anterior segment begins at the limbus and consists of the cornea, anterior and posterior chambers (not to be confused with anterior and posterior segments), pupil, iris, lens, zonules, and ciliary body. The posterior segment lies posterior to the anterior segment and consists of the vitreous chamber, retina, choroid, sclera, optic disc, and ON. The trabecular meshwork and Schlemm’s canal are part of the limbus, a transitional structure between the sclera and cornea (FIGURE 2). The uvea is the vascular middle layer of the eye, consisting of the iris and ciliary body in the anterior segment and the choroid in the posterior segment. The anterior segment is further divided into anterior and posterior chambers by the lens-iris diaphragm. The anterior chamber is defined by the iris (forms the floor) and cornea (forms the roof) (FIGURE 2). The trabecular meshwork is positioned at the point where the cornea and iris meet, and forms the apex of the anterior chamber angle of the eye. The trabecular meshwork is a sievelike structure that filters and controls the flow of aqueous humor (AH) from the anterior chamber into Schlemm’s canal, ultimately leading to the bloodstream.The posterior chamber is bordered laterally by the ciliary processes. The lens surface forms the floor and the posterior surface of the iris forms the roof of the chamber (FIGURE 2).
Aqueous Humor Hydrodynamics
AH functions to maintain the global shape of the eye; supply nourishment to the avascular lens, cornea, and trabecular meshwork; and remove metabolic waste. AH also participates in immunologic responses, contributes to the optical system by providing a transparent refractive medium between lens and cornea, and facilitates some ocular distribution of drugs.5 AH is derived from plasma within the capillary network of the ciliary processes (FIGURE 2) and is continually secreted into the posterior chamber at a rate of approximately 2.7 μL per minute in healthy individuals.6 The entire chamber content is replaced every 100 minutes to 2 hours.From the posterior chamber, AH flows through the pupil into the anterior chamber to exit the eye via conventional and unconventional pathways. The conventional pathway accounts for the majority of outflow and refers to AH coursing through the trabecular meshwork and the canal of Schlemm, ultimately draining into the systemic circulation (FIGURE 2).
In unconventional pathways, AH seeps through tissues rather than flowing through the usual channels and vessels. The most common unconventional pathway is the uveoscleral pathway in which AH drains from the base of the ciliary muscle, through tissues in and around the uvea, and eventually into the sclera.5
Intraocular Pressure IOP refers to the pressure generated by flow of AH against resistance within ocular structures. IOP, maintained at about 15 mmHg in healthy individuals, is determined by a delicate balance between the rates of AH entering (inflow) and leaving (outflow) the eye. Whereas inflow is dependent upon rate of production of AH, outflow is regulated by resistance to aqueous drainage.7 Any condition that alters the equilibrium between inflow and outflow of AH may result in abnormal IOP levels. Resistance to outflow is usually responsible for elevated IOP, but other factors may contribute.5
PATHOPHYSIOLOGY AND ETIOLOGY
A basic understanding of the relationship between elevated IOP and visual loss will help the pharmacist appreciate clinical findings and the importance of lowering IOP in glaucoma.Irrespective of cause, degeneration of retinal ganglion cells (RGCs) is a feature common to all forms of optic neuropathy. RGCs, specialized nerve cells localized within the retina, transmit visual information from retinal photoreceptor cells, via the ON, to the visual cortex in the brain. Axonal fibers projecting from RGCs converge at the optic disc and exit the eye through a meshwork of collagen fibers known as the lamina cribosa (FIGURE 3). In addition to RGC axons, the normal optic disc contains retinal vasculature (central artery and vein) and glial elements that provide support and protection to the neurons. The center of the optic disc does not contain RGC axons and is known as the cup because it appears as a concave indentation on ophthalmic examination (FIGURE 3).
Elevated IOP and RGC Degeneration
As indicated inFIGURE 3, elevation in IOP exerts pressure posteriorly to cause both structural and functional damage to the optic disc. The tough sclera that envelops most of the posterior segment of the eye is relatively immobile, but the gelatinous lamina cribosa is pushed posteriorly with increased IOP. This displacement is thought to cause structural changes in the meshwork of the lamina cribosa. The deformed meshwork is presumed to pinch the nerve fibers and blood vessels present in the ON bundle, resulting in damage to RGC axons and ultimately death to RGCs.5 This pathologic process can be seen upon ophthalmic examination as increased optic disc cupping. The diameter of the cup can be compared to that of the entire optic disc (cup-to-disc ratio). The cup-to-disc ratio correlates with extent of ON fiber damage. Disc cupping is important for differential diagnosis of glaucoma from other ocular neuropathies. Functional changes include progressive loss of visual field, short wavelength color sensitivity, spatial resolution, and temporal contrast sensitivity.5 Damaged ON fibers cannot be regenerated, and loss of vision is irreversible.CLINICAL FINDINGS
POAG is a chronic eye disease that is generally progressive. Typically, both eyes are affected, although not necessarily to the same extent. Because symptoms are minimal or absent early in the disease process, a thorough eye examination is essential. In establishing a diagnosis of POAG, the clinician seeks evidence of ON damage. Structural abnormalities in the optic disc or retinal nerve bundle and/or loss of visual field confirm damage. A dilated eye examination is preferred to properly assess the ON. Perimetry testing is used to evaluate the visual field, the full visible range when the eye is fixated straight ahead. In POAG, vision loss usually begins peripherally and moves centrally. Most commonly, structural defects precede vision deficits.1 Refer to TABLE 1 for other characteristic clinical findings.| Evidence of optic nerve damage (from either or both categories) 1. Optic disc or retinal nerve fiber structural abnormality 2. Visual field abnormality Adult onset Open anterior chamber angles Absence of other reasons for glaucomatous changes Elevated IOP (may or may not be present) |
IOP: intraocular pressure; POAG: primary open-angle glaucoma. Source: Reference 1. |
Assessment of the optic disc and visual-field testing are also used to monitor for disease progression and efficacy of therapeutic interventions. While lowering IOP is presumed to decrease disease progression, it is not a surrogate measure of visual function.4
RISK FACTORS
IOP is a significant risk factor in the pathogenesis of glaucoma. There is evidence that an increase in IOP is proportional to the prevalence of glaucoma.8 Large variation in IOP is an additional risk factor for glaucoma. In nonglaucomatous eyes, IOP varies with circadian rhythm by about 2 to 4 mmHg over a 24-hour period, with peak values observed in the morning hours.9 An increase in magnitude of variation above 10 mmHg increases the risk of ON head (optic disc) damage and is considered pathologic.10In addition to elevated IOP, increasing age, family history of glaucoma, and African or Hispanic/Latino race are consistently linked to an increased risk of glaucoma.1-4,11 A meta-analysis of population-based data identified three times the prevalence of POAG in black as compared to white persons. Prevalence in Hispanic/Latino persons was similar to that in white persons except in those over 65 years, in whom significantly higher rates were found.3 Other factors possibly related to POAG include thinner central corneal thickness, diabetes, systemic hypertension, a history of ocular trauma, reduced blood flow to the ON, myopia (nearsightedness), and vasospastic conditions such as Raynaud’s disease or migraines.1-4
GOALS OF THERAPY
The primary purpose of therapy is to enhance the patient’s quality of life by preserving vision and minimizing adverse therapeutic effects.1,4 Goals that support therapeutic purpose include stabilizing ON/retinal nerve fiber status and visual fields; controlling IOP; and educating and involving the patient in disease management.1TREATMENT STRATEGIES
All current treatment modalities aim to reduce IOP.1,4 Finding an IOP range that allows for stabilization of visual fields and ON/retinal nerve fiber status is often a process of trial and error. The upper limit of that range is referred to as the target pressure. The clinician assumes pretreatment IOP resulted in optic neuropathy and endeavors to reduce initial IOP target pressure by at least 20%. Once therapy is initiated, IOP measurement and ON assessment guide therapeutic adjustments.1Present options for managing glaucoma include pharmacologic therapy and surgical modalities such as laser trabeculoplasty and filtering or cyclodestructive surgery. Each has associated benefits and risks, and patient-specific factors and preferences must be considered when selecting appropriate initial therapy. Therapies may be combined to achieve treatment goals. Topical medications are an effective first approach in many patients, although laser trabeculoplasty may be an acceptable option. In some patients, filtering surgery may be preferred initially.1
Surgical Management of Glaucoma
Laser Trabeculoplasty: This procedure increases outflow via the conventional pathway. Inflammation is the most common adverse effect. Pharmacologic therapy may be necessary posttreatment, and beneficial effects may dissipate over time, necessitating further treatment.4Filtering Surgery: Trabeculotomy, which creates an alternative pathway for AH drainage, is often performed after medication and laser therapies have failed. Best results are achieved in patients with no prior eye surgeries. Cataracts, corneal problems, intraocular inflammation, growth of scar tissue, and infection are possible adverse effects.1
Cyclodestructive Surgery: This method for lowering IOP destroys the ciliary body epithelial tissue, resulting in a permanent reduction in AH production. Loss of visual acuity and blindness may occur, so this treatment option is usually reserved for patients with poor visual acuity or those in whom standard medical, laser, or surgical modalities have failed.4
CASE STUDY: GLAUCOMA M.M., a 52-year-old African American woman, presents to the clinic today for an ophthalmic exam. Her last exam (5 years ago) indicated a normal IOP (10-21 mmHg).Family History: Mother: cataracts; father: death from myocardial infarction at age 63 Social History: Nonsmoker, nondrinker, married with 2 daughters Allergies: PCN (anaphylaxis) Medications: None Personal Medical History: Unremarkable Vital Signs: BP 112/78, P 70, RR 14, T 36.9°C, HT 168 cm, WT 59.3 kg General: Healthy, ambulatory female Eye Exam: Elevated IOP OU. IOP by tonometry is 25/25 mmHg. Optic disc shows mild cupping, and gonioscopy reveals open angles in the anterior chambers OU. Visual fields are normal, and visual acuity without correction is 20/20 OD and 20/40 OS. No signs of cataract formation are evident. Labs: None Physician’s Assessment: POAG 1. What signs in the visual examination are consistent with diagnosis of POAG? • Elevated IOP by tonometry—25 mmHg OU. • Optic disc shows mild cupping. • Gonioscopy reveals open angles in anterior chambers OU. 2. What are the goals of therapy for this patient? • Reduce IOP to stop optic nerve damage. • Preserve vision. • Maintain patient’s quality of life—select cost-effective pharmacologic treatment with minimal adverse effects. 3. What available ophthalmic medication would provide appropriate initial treatment of POAG for this patient? • Since she does not have any other medical problems listed, a selective or nonselective beta-blocker or a prostaglandin analogue is recommended first line. 4. What counseling should the pharmacist provide to this patient? • Discuss treatment plan and rationale, so patient understands its importance. • Discuss adheren/USPExams/compliance with treatment plan. Explain that although glaucoma may be asymptomatic, it can lead to blindness if inadequately treated. • Discuss common transient adverse effects—continue medication if possible. • Discuss possible (serious/frequent) adverse effects—report to eye doctor. • NLO and closing eye to decrease risk of systemic effects and promote optimal drug effect. • Appropriate interval between drops if more than one drop per eye is ordered. • Proper/aseptic technique to use with eye drops—preparation, administration, and storage. • Shake bottle if it contains a suspension. M.M. was treated with the recommended regimen. Her IOP normalized to 18 mmHg within 3 months, following several dosage adjustments. Two years later her IOP remains normal, and her visual fields and optic nerves are stable. |
BP: blood pressure; HT: height; IOP: intraocular pressure; NLO: nasolacrimal occlusion; OD: right eye; OS: left eye; OU: each eye; P: pulse; PCN: penicillin; POAG: primary open-angle glaucoma; RR: retinal reflex; T: temperature; WT: weight. |
Pharmacologic Management of Glaucoma
Medications used to manage POAG decrease IOP by two primary mechanisms: decreasing AH production or increasing AH outflow (through either the conventional or unconventional pathways). Glaucoma is a chronic disease—there is no cure, and medical management must be continued throughout a person’s life.Currently, prostaglandin analogues and beta-blockers are the most frequently used topical medications. Sympathomimetics, topical and oral carbonic anhydrase inhibitors, and cholinergics are used to a lesser degree.1,4 Adverse effects or inadequate clinical response may necessitate a therapeutic change, while drugs with different mechanisms of action may be used in combination to maximize IOP reduction.
Many minor local adverse effects of POAG medications are transient, and knowledge of this will encourage patients to continue using prescribed medications. If an adverse effect does not subside, the patient should notify his or her eye doctor before discontinuing use of a medication so that another drug can be prescribed. Refer to TABLE 2 for a summary of therapeutic and adverse effects of POAG medications.
| Drug Name | Brand Name | Formulation | Dosage | Notes |
| Beta-blockers | ||||
| Betaxolol hydrochloride | Betoptic Betoptic S | 0.25%, 0.5% solution 0.25% suspension | 1-2 drops BID 1 drop BID | Clinical effect: decreases production of AH One of the most commonly used medications for treatment Nonselective: timolol, levobunolol, metipranolol, carteolol Beta1-selective: betaxolol Contraindications: 1. All beta-blockers: sinus bradycardia, atrioventricular block (second or third degree), heart failure, or cardiogenic shock 2. Nonselective beta-blockers: asthma, COPD |
| Carteolol | Ocupress | 1% solution | 1 drop BID | |
| Levobunolol hydrochloride | Betagan | 0.25%, 0.5% solution | 1-2 drops Q day-BID | |
| Metipranolol | Optipranolol | 0.3% solution | 1 drop BID | |
| Timolol | Betimol, Istalol, Timoptic Timolol-XE | 0.25%,0.5% solution 0.25%,0.5% gel-forming solution | 1 drop Q day-BID 1 drop Q day | |
| Prostaglandins | ||||
| Bimatoprost | Lumigan | 0.03% solution | 1 drop Q day | Clinical effect: increases uveoscleral outflow; bimatoprost may have additional effect on outflow at trabecular meshwork One of the most commonly used medications for treatment Pigmentation of the eye and eyelid as the most common form of adverse effects, eyelash effects Avoid in those with active intraocular inflammation |
| Latanoprost | Xalatan | 0.005% solution | 1 drop Q day | |
| Travoprost | Travatan, Travatan Z | 0.004% solution | 1 drop Q day | |
| Carbonic Anhydrase Inhibitors | ||||
| Acetazolamide | Diamox Sequels | 250-mg, 500-mg tablet/ER capsules | Max: 1 g Q 24 h | Clinical effect: decreases production of AH Topical: used as alternative to monotherapy or adjunctive therapy Oral: used as adjunctive therapy Caution in those with sulfonamide allergies, renal insufficiency Avoid using concurrent ophthalmic and oral CAIs |
| Brinzolamide | Azopt | 1% susp | 1 drop TID | |
| Dorzolamide hydrochloride | Trusopt | 2% solution | 1 drop TID | |
| Methazolamide | (none in U.S.) | 25-mg, 50-mg tablets | 50 mg-100 mg BID-TID | |
| Cholinergics | ||||
| Direct-acting agonists | Clinical effect: increases AH outflow Good efficacy, but not commonly used due to frequent adverse effects and frequent dosing Excessive miosis may induce angle-closure glaucoma secondary to pupillary block May produce systemic cholinergic effects | |||
| Carbachol | Miostat | 0.01% solution | 1 mL to anterior chamber of eye | |
| Pilocarpine | Pilopine HS | 4% gel | 1/2-in ribbon on lower conjunctiva at bedtime | |
| Cholinesterase inhibitor | ||||
| Echothiophate iodide | Phospholine Iodide | 0.03%, 0.06%, 0.125%, 0.25% solution | 1 drop BID | |
| Sympathomimetics | ||||
| Alpha2-selective adrenergic agonists | ||||
| Apraclonidine hydrochloride | Iopidine | 0.5%, 1% solution | 1-2 drops TID | Clinical effects: increases AH uveoscleral outflow Apraclonidine efficacy wears off in <1 mo Rate of allergic reactions limits use of apraclonidine |
| Brimonidine tartrate | Alphagan P | 0.1%, 0.15%, 0.2% solution | 1 drop TID | |
| Nonspecific adrenergic agonists | ||||
| Dipivefrin hydrochloride | Propine | 0.1% solution | 1 drop BID | Clinical effects: increases conventional outflow (primary); chronic use decreases AH production (secondary) Epinephrine formulation no longer available in the U.S. Dipivefrin is a prodrug of epinephrine Limited use due to frequency of adverse effects Monitor for angle-closure glaucoma, cardiovascular and metabolic effects |
| Epinephrine | (none in U.S.) | 0.5%, 1%, 2% solution | 1-2 drops BID | |
AH: aqueous humor; CAIs: carbonic anhydrase inhibitors; COPD: chronic obstructive pulmonary disease; ER: extended release; Max: maximum. Source: References 27, 28. | ||||
• Systemic adverse effects are rare complications of topical glaucoma medications, but they can be serious. Following instillation of topical medications, nasolacrimal occlusion (NLO) and closing the eyelid for 2 minutes will prevent excess medication from draining into the lacrimal ducts and greatly decrease the risk of systemic effects.4 Pharmacists should recommend these techniques to patients using POAG eye drops.
• Instruct patients in aseptic technique to prevent contamination of the container and product, and ultimately the eye. The tip of the medication container must not be allowed to contact the patient’s eye or the hand of whoever dispenses the drops.
• A patient using more than one POAG eye drop (multiple drops of the same medication or different medications) should wait at least 5 minutes between instillation of the drops.4
• If different ophthalmic formulations are being used, solutions should always be used before other formulations, such as gels and suspensions, to optimize absorption of each medication.
• Because POAG drugs pass through the placenta, women should inform their health care provider if they are pregnant or are trying to conceive.
Beta-Blockers: Medications in this class lower IOP via decreased production of AH and are considered first-line pharmacologic options.2,4,12 Nonselective (timolol, levobunolol, metipranolol, carteolol) and selective (betaxolol) forms of beta-blockers are available in the U.S.
Minor, usually transient, ocular adverse affects include blurred vision, irritation, burning, stinging, and tearing. Additional local adverse affects that should be reported to the eye doctor include loss of visual acuity, pain, inflammation, foreign body sensation, and erythema.
Systemic adverse effects are rarely reported for topical beta-blockers, and their occurrence will be minimized by NLO.
Nonselective beta-blockers are contraindicated in patients with asthma or severe chronic obstructive pulmonary disease (COPD) because they can cause bronchospasms, although betaxolol may be used due to its receptor selectivity. Because beta-blockers can both mask the early warning symptoms of hypoglycemia and prolong recovery from low blood sugars, they should be used cautiously in diabetes. All beta-blockers are contraindicated in patients with cardiac diseases such as sinus bradycardia, second- or third-degree atrioventricular block, heart failure, or cardiogenic shock.
Prostaglandin Analogues: Regarded as first-line therapeutic agents, analogues of prostaglandins (bimatoprost, latanoprost, travoprost) bind to prostanoid FP receptors located on the iris, promoting uveoscleral outflow of AH, which subsequently lowers IOP.13 Bimatoprost may also significantly affect AH outflow through the trabecular meshwork.
Common, frequently transient, adverse ocular effects include blurred vision or other decreased visual acuity, itching, burning or stinging, dry eyes, and excessive tearing. Patients have reported body aches, rash, upper respiratory infections, cold, and (rarely) flu. Systemic adverse effects are very rare with prostaglandin analogues. Patients with active intraocular inflammation should not be started on ophthalmic prostaglandin analogues because these could worsen their condition. Caution should be used in those with a past history of ocular inflammation.
Darkening of the iris, particularly in patients with hazel eyes, has been reported by persons using ophthalmic prostaglandins. In addition, these medications tend to darken the periorbital tissues to a brownish color. These effects may be permanent. A serendipitous side effect is darkening, thickening, and lengthening of the eyelashes. The FDA has approved Latisse, a form of bimatoprost, for the treatment of hypotrichosis, or inadequate eyelashes.14
While the American Academy of Ophthalmology and the American Optometric Association have not stated a definitive preference for pharmacologic treatment of glaucoma, it has been argued that prostaglandin analogues are preferable to beta-blockers because of a greater efficacy in lowering IOP and producing fewer systemic effects.1,2,12,15 However, there are no generic formulations of prostaglandin analogues, so where cost is an important issue, generic beta-blockers will more likely be used.
Carbonic Anhydrase Inhibitors (CAIs): This drug classification is available in both ophthalmic (brinzolamide and dorzolamide) and oral (acetazolamide and methazolamide) formulations. CAIs lower IOP by decreasing production of AH.16
Topical CAIs are normally well tolerated and are considered second-line therapeutic alternatives. Bitter taste and transient burning, stinging, blurred vision, and foreign body sensation are commonly reported. Corneal inflammation and ophthalmic allergic reactions occur rarely. Systemic adverse effects, including headache, tingling in the extremities, fatigue, liver disease, and kidney stones, are very rare with topical CAIs but are more common with the oral formulations.
While quite effective, oral CAIs are deemed third- or fourth-line agents for POAG because they are not well tolerated; thus, long-term use is uncommon.2 They are approved for adjunctive use when maximum topical therapy is inadequate, or for those persons who are intolerant of topicals.2 Metabolic acidosis is one of the most common reasons for discontinuing systemic CAIs.
CAIs are sulfonamides, but are structurally different from bacteriostatic sulfonamides. They may be used cautiously in patients with bacteriostatic sulfonamide allergy, but CAIs should be discontinued if reactions suggestive of sulfonamide hypersensitivity emerge.17 Patients at risk for acidosis, electrolyte imbalance, or kidney or liver dysfunction should avoid systemic CAIs.
Cholinergics: Direct-acting (pilocarpine and carbachol) and indirect-acting (cholinesterase inhibitor, echothiophate iodide) parasympathomimetics exert a miotic effect. As the pupil constricts, channels in the trabecular meshwork open, reducing resistance to outflow of AH.1 These third- or fourth-line glaucoma medications are rarely used today because of the need for frequent dosing and significant adverse effects such as blurred vision, cataracts, and retinal detachment.2,12,16 It is important to note that excessive miosis may severely restrict the flow of AH from the posterior to the anterior chamber. Thus, patients should be closely monitored for pupillary block leading to ACG. Systemic cholinergic adverse effects are also possible. Newer, safer drugs have generally eclipsed the need for cholinergics.
Sympathomimetics: The alpha-adrenergic agonists brimonidine and apraclonidine, first-line sympathomimetic agents, are selective to alpha2-receptors that increase uveoscleral outflow of AH, thereby decreasing IOP.2 In addition, brimonidine reduces the production of AH. The efficacy of apraclonidine typically wears off in less than a month, so it is used specifically for short-term adjunctive therapy.
Common ocular adverse effects include burning, stinging, irritation, tearing, and eyelid edema. Mild ocular allergic reactions, such as itching, are common with alpha-adrenergic agonists. More serious allergic reactions may develop over time and should be reported. Dizziness and drowsiness occur rarely, so patients should be cautious when performing hazardous activities that require alertness. These drugs can potentiate the effects of depressants, such as alcohol, barbiturates, and sedatives.
The nonspecific sympathomimetics epinephrine and dipivefrin (a prodrug of epinephrine) increase the outflow of AH through both the trabecular meshwork and uveoscleral route. If used long-term, they also decrease AH production.12,16 Ophthalmic epinephrine is no longer available in the U.S., and dipivefrin is rarely used because of frequent local adverse effects and significant systemic effects, including elevated blood pressure and irregular heartbeat.12 It must be used cautiously in the elderly and in persons with hypertension, diabetes, hypothyroidism, and heart disease. Dipivefrin produces mydriasis and may increase IOP by blocking outflow via the conventional pathway. This situation may lead to ACG. Dipivefrin is used primarily as an alternative treatment for those who respond inadequately to other, safer medications.
ADHERENCE TO MEDICAL THERAPY
Poor adherence to therapy is a common problem with chronic diseases. Patients with glaucoma face many challenges as they attempt to lower IOP and preserve their vision through medical therapy regimens. Many studies have attempted to identify obstacles to adherence and define strategies for improving therapeutic outcomes.18-23 Some of the most common factors associated with poor therapeutic adherence are listed in TABLE 3.| Patient-Specific | Therapy | Provider | Life Circumstances |
| Dexterity Vision Health literacy Understanding of disease/treatment Concern about vision loss Comorbidities | Doses per day Cost Adverse effects Complexity of regimen | Rapport with patient Patient perception of provider skill | Lack of support system Traveling/vacation Transportation Complicated lifestyle |
Source: References 18-23. | |||
Pharmacists are widely regarded as the most accessible health care providers, and they enjoy the public’s trust and respect. They are ideally positioned to serve as teachers and coaches for patients with glaucoma. Patients must be educated about the disease process and the significance of untreated or inadequately treated glaucoma. Therapeutic regimens must be clearly explained to patients, including the desired effect of therapy, possible side effects, and when to contact a health care provider. Careful counseling, augmented by periodic dialoguing, may help pharmacists identify barriers to adherence and offer solutions to improve outcomes. Pharmacists should assess patients’ understanding by asking questions and offering further explanation or clarification as necessary.20
NEW HORIZONS
Visual function can be preserved by reducing IOP and protecting RGCs from degeneration through pharmacologic and surgical therapies previously described. Unfortunately, in some patients, loss of RGCs progresses in spite of well-controlled IOP. It appears RGC degeneration could also be attributed to vascular insufficiency, axonal transport blockade, diffusion of toxic agents into nerve cells, initiation of apoptosis (programmed cell death), and other causes.24The concept of neuroprotection, preserving existing RGCs, and rescuing damaged RGCs and their axons has been proposed as superior to treatment modalities aimed at lowering IOP because it would be effective irrespective of disease etiology.25
Several groups of compounds, including the antioxidant alpha-tocopherol, phenytoin, aminoguanidine, and the N-methyl-d-aspartate receptor antagonist memantine, have been proposed as possible candidates for RGC neuroprotection.26 Memantine showed promise in Phase I and II trials but failed to pass Phase III clinical trials.24 The quest for treatment modalities that can stop loss of vision remains a subject of intense investigation.
