CTC 2.18 Open-Angle Glaucoma.pdf

PAMANTASAN NG LUNGSOD NG MAYNILA College of Medicine

Department of Basic and Clinical Pharmacology, Toxicology, and Therapeutics

CLINICO-THERAPEUTIC CONFERENCE CASE #18

PRIMARY OPEN-ANGLE GLAUCOMA

Submitted in Partial Fulfillment of the Requirements in Medical Therapeutics

Date of Submission: August 29, 2014

THIRD YEAR SECTION A

CALAUNAN, Martin Joseph A.

Discussion of the Diagnosis

Epidemiology

Classifications of Open-Angle Glaucoma

Pathophysiology

ESNA of Cholinomimetics

ESNA of Alpha-Adrenergic Agonists

Compiler

LASCANO, Normilando V.

ESNA of Prostaglandin Analogues

ESNA of Drugs in p-Group and Selection of p-Drug

Sample Prescription

Non-Pharmacologic Management

PANGAN, Kimberly Anne M.

Therapeutic Objectives

ESNA Criteria

Overview of Drugs in Recommendation

ESNA of Beta-Adrenergic Antagonists

ESNA of Carbonic Anhydrase Inhibitors

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R. V. J., a 48-year-old male businessman, came to the eye referral center for routine check-up and change of corrective lenses. Tonometry exam revealed elevated value. He was subjected to gonioscopy examination which revealed normal result. His pupils were dilated using a medicine for fundoscopic examination and revealed cup-to-disc ratio of 0.6 on the right and 0.8 on the left. Visual field examination showed contracted peripheral fields. As an ophthalmologist, you highly considered open-angle glaucoma.

The salient features in this case are as follows: 48-year-old male, elevated value on tonometry exam, normal gonioscopy examination, cup-to-disc ratio of 0.6 on the right eye and 0.8 on the left eye, and contracted peripheral fields on visual field examination.

INTRODUCTION Glaucoma, colloquially known as the "silent stealer of sight," is a clinical term referring to a variety of conditions with the common feature of an optic neuropathy (i.e., glaucomatous optic neuropathy [GON]) characterized by a distinctive loss of retinal nerve fibers and optic disc changes (Canadian Ophthalmology Society, 2009). Primary open-angle glaucoma (POAG) is a progressive, chronic optic neuropathy in adults in which intraocular presure (IOP) and other currently unknown factors contribute to damage and in which, in the absence of other identifiable causes, there is a characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells and their axons. This condition is associated with an open anterior chamber angle on gonioscopy examination.

EPIDEMIOLOGY Glaucoma is the second leading cause of blindness worldwide, topped only by cataract. It is, however, the leading cause of irreversible loss of vision. As of 2010, it has affected at least 60 million people and caused blindness in 8.4 million people. By the year 2020, almost 80 million people will have glaucoma, with 11.2 million becoming bilaterally blind (Quigley and Broman, 2006). These increases in the number of glaucoma and glaucoma-associated blindness cases is possibly attributed to an aging world population as glaucoma is a condition of adult onset and commonly affects the older age group. Open-angle glaucoma constitutes 74% or about three-fourths of the worldwide cases. In Southeast Asia, about 2.1 million people have been diagnosed with open-angle

glaucoma as of 2010 and is expected to rise to 3 million by 2020. Glaucoma is the third leading cause of bilateral blindness in the Philippines, after cataract and refractive errors, according to the Third National Survey on Blindness in the Philippines by the Department of Health, conducted from October 2001 to May 2002.

PREDISPOSING FACTORS Intraocular pressure Older age African and Hispanic descent Family history of glaucoma Central corneal thickness Low ocular perfusion pressures Type 2 diabetes mellitus Myopia Migraine headache Peripheral vasospasm

PATHOPHYSIOLOGY The pathophysiology of glaucoma is believed to be multifactorial. Several mechanisms are likely to underlie the final common pathway of optic nerve dysfunction and ganglion cell death (Choplin and Lundy, 2007). According to various existing theories, factors like elevated intraocular pressure (IOP) and vascular dysregulation primarily contribute to the initial insult during glaucomatous atrophy in the form of obstruction to axoplasmic flow within the retinal ganglion cell axons at the lamina cribrosa, altered optic nerve microcirculation at the level of lamina, and changes in the laminar glial and connective tissue. The factors leading to secondary insult include excitotoxic

THE CASE

SALIENT FEATURES

PRIMARY OPEN-ANGLE GLAUCOMA

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damage caused by glutamate or glycine released from injured neurons and oxidative damage caused by over-production of nitric oxide (NO) and other reactive oxygen species. Whatever may be the primary and secondary factors, the end result in glaucomatous eyes is the dysfunction and death of RGCs leading to irreversible visual loss, as a result of a complex interplay of multiple factors rather than any one of them functioning individually (Agarwal et al, 2009).

SYMPTOMATOLOGY Majority of patients with primary open-angle glaucoma are symptomatic even with the increased intraocular pressure. They are typically only symptomatic in late disease, when they may become aware of constricted visual field or blurred vision. Occasionally, patients become aware of earlier visual field defects when performing monocular tasks (American Academy of Ophthalmology). Patients may notice a gradual loss of peripheral vision, or "tunnel vision" after loss of more than 40 percent of the nerve fibers. Open-angle glaucoma usually is an incidental finding during an adult eye evaluation performed for other indications (Distelhorst and Hughes, 2003).

DIAGNOSIS AND WORK-UP According to the Preferred Practice Pattern Guidelines of the American Academy of Ophthalmology (2010), the following are the clinical findings characteristics of primary open-angle glaucoma:

Evidence of optic nerve damage from either, or both, of the following:

Optic disc or retinal nerve fiber layer structural abnormalities

Diffuse thinning, focal narrowing, or notching of the optic disc rim, especially at the inferior or superior poles

Documented, progressive thinning of the neuroretinal rim with an associated increase in cupping of the optic disc

Diffuse or localized abnormalities of the peripapillary retinal nerve fiber layer, especially at the inferior or superior poles

Disc rim or peripapillary retinal nerve fiber layer hemorrhages

Optic disc neural rim asymmetry of the two eyes consistent with loss of neural tissue

Reliable and reproducible visual field abnormality considered a valid representation of the subject's functional status

Visual field damage consistent with retinal nerve fiber layer damage (e.g., nasal step, arcuate field defect, or paracentral depression in clusters of test sites)

Visual field loss in one hemifield that is different from the other hemifield, i.e., across the horizontal midline (in early/moderate cases)

Absence of other known explanations Adult onset Open anterior chamber angles Absence of other known explanations (i.e., secondary

glaucoma) for progressive glaucomatous optic nerve change (e.g., pigment dispersion, pseudoexfoliation [exfoliation syndrome], uveitis, trauma, and corticosteroid use)

Primary open-angle glaucoma represents a spectrum of disease in adults in which the susceptibility of the optic nerve to damage varies among patients. Many POAG patients present with elevated IOP, but a substantial minority with otherwise characteristic POAG may not have elevated IOP measurements. The vast majority of patients with POAG have disc changes or disc and visual field changes, but there are rare cases where there may be early visual field changes before there are detectable changes to the optic nerve (AAO, 2010).

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The comprehensive initial glaucoma evaluation (history and physical examination) includes all components of the comprehensive adult medical eye evaluation in addition to, and with special attention to, those factors that specifically bear upon the diagnosis, course, and treatment of primary open-angle glaucoma. The examination may require more than one visit. For instance, an individual might be suspected of having glaucoma on one visit but may return for further evaluation to confirm the diagnosis, including additional IOP measurements, gonioscopy, CCT determination, visual field assessment, and optic nerve head and retinal nerve fiber layer evaluation and documentation (American Academy of Ophthalmology, 2010).

ELEMENTS OF OPHTHALMIC EVALUATION HISTORY Ocular, family, and systemic history (e.g. asthma)

The severity and outcome of glaucoma in family members, including history of visual loss from glaucoma, should be obtained during initial evaluation.

Review of pertinent records, with particular reference to: Past IOP levels

Status of the optic nerve

Visual field Current ocular and systemic medications (e.g. corticosteroids) and known local or systemic

intolerance to ocular or systemic medications Ocular surgery

A history of LASIK or photorefractive keratectomy is associated with a falsely low IOP measurement due to thinning of the cornea.

Cataract surgery may also lower the IOP compared with the presurgical baseline. A history of prior glaucoma laser or incisional surgical procedures should be elicited.

VISUAL ACUITY MEASUREMENT

Visual acuity with current correction (the power of the present correction recorded) at distance and, when appropriate, at near should be measured. Refraction may be indicated to obtain the best corrected visual acuity.

PUPIL EXAMINATION For reactivity and afferent pupillary defect

ANTERIOR SEGMENT EXAMINATION

Slit-lamp biomicroscopic examination of the anterior segment can provide evidence of physical findings associated with narrow angles, such as shallow peripheral anterior chamber depth and crowded anterior chamber angle anatomy, corneal pathology, or a secondary mechanism for elevated IOP such as pseudoexfoliation (exfoliation syndrome), pigment dispersion with Krukenberg spindle and/or iris transillumination defects, iris and angle neovascularization, or inflammation.

INTRAOCULAR PRESSURE MEASUREMENT

Intraocular pressure is measured in each eye, preferably by Goldmann applanation tonometry, before gonioscopy or dilation of the pupil.

Recording time of day of IOP measurements may be helpful to assess diurnal variation. Unrecognized fluctuations in IOP may lead to progression of POAG. Therefore, additional

measurements may be indicated, either at different hours of the day on the same day or on different days.

GONIOSCOPY Diagnosis of primary open-angle glaucoma requires careful evaluation of the anterior chamber angle to exclude angle closure or secondary causes of IOP elevation, such as:

Angle recession

Pigment dispersion

Peripheral anterior synechiae

Angle neovascularization Inflammatory precipitates

OPTIC NERVE HEAD AND RETINAL NERVE FIBER LAYER EXAMINATION

Provides valuable structural information about glaucomatous optic nerve damage Visible structural alterations of the optic nerve head or retinal nerve fiber layer and

development of peripapillary choroidal atrophy frequently occur before visual field defects can be detected.

Careful study of the optic disc neural rim for small hemorrhages is important, since these hemorrhages often precede visual field loss and further optic nerve damage in patients with glaucoma.

Preferred technique for optic nerve head and retinal nerve fiber layer evaluation involves magnified stereoscopic visualization (as with the slit-lamp biomicroscope), preferably through a dilated pupil. In some cases, direct ophthalmoscopy complements magnified stereoscopic

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visualization, providing additional information of optic nerve detail due to the greater magnification of the direct ophthalmoscope. Red-free illumination of the posterior pole by stereo-biomicroscopy with an indirect lens at the slit lamp, the direct ophthalmoscope, or with digital red-free photography may aid in evaluating the retinal nerve fiber layer.

FUNDUS EXAMINATION Examination of the fundus, through a dilated pupil whenever feasible, includes a search for other abnormalities that may account for optic nerve changes and/or visual field defects (e.g. optic nerve pallor, disc drusen, optic nerve pits, disc edema from central nervous system disease, macular degeneration, retinovascular occlusion, and other retinal disease).

SUPPLEMENTAL OPHTHALMIC TESTING CENTRAL CORNEAL THICKNESS MEASUREMENT

Measurement of CCT aids the interpretation of IOP readings and helps to stratify patient risk for ocular damage.

Overestimation of the real IOP may occur in eyes with corneas that are thicker than average while underestimation of the real IOP tends to occur in eyes with corneas that are thinner than average.

VISUAL FIELD EVALUATION

Automated static threshold perimetry is the preferred technique for evaluating the visual field. The frequency doubling technology (FDT) method with the central 20-degree test program (C-20) and short-wavelength automated perimetry (SWAP) with the central 24-degree test program (24-2) are two of several alternative testing methods to screen for a defect before conducting more definitive threshold testing. Visual field testing based on SWAP and FDT may detect defects or progression of defects earlier than conventional white-on-white perimetry in some patients.

Careful manual combined kinetic and static threshold testing (e.g., Goldmann visual fields) is an acceptable alternative when patients cannot perform automated perimetry reliably or if it is not available.

Repeat, confirmatory visual field examinations may be required for test results that are unreliable or show a new glaucomatous defect before changing management. It is best to use a consistent examination strategy for visual field testing.

OPTIC NERVE HEAD AND RETINAL FIBER LAYER ANALYSIS

The appearance of the optic nerve should be documented. Color stereophotography is an accepted method for documenting optic nerve head

appearance. Computer-based image analysis of the optic nerve head and retinal nerve fiber layer is an alternative for documentation of the optic nerve.

As improvements in these instruments continue, the capacity for them to help the clinician diagnose glaucoma and identify progressive nerve damage becomes more reliable.

Stereoscopic disc photographs and computerized images of the nerve are distinctly different methods for optic nerve documentation and analysis.

Each is complementary with regard to the information they provide the clinician who must manage the patient. In the absence of these technologies, a nonstereoscopic photograph or a drawing of the optic nerve head should be recorded, but these are less desirable alternatives to stereophotography or computer-based imaging.

In patients with advanced glaucomatous optic neuropathy, there is limited benefit of using stereophotography to identify progressive optic nerve change.

Three types of computer-based imaging devices currently available for glaucoma: Confocal scanning laser ophthalmoscopy

Optical coherence tomography

Scanning laser polarimetry Taken together, computer-based imaging devices for glaucoma provide useful, quantitative

information for the clinician when analyzed in conjunction with other relevant clinical parameters. As device technology evolves (e.g., higher resolution spectral domain optical coherence tomography), the diagnostic performance is expected to improve accordingly.

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EYE STAGING AND SETTING OF TARGET IOP

Canadian Ophthalmology Society glaucoma clinical practice guidelines (2009).

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TREATMENT ALGORITHM FOR PATIENTS WITH PRIMARY OPEN-ANGLE GLAUCOMA

American Academy of Ophthalmology Preferred Practice Pattern Guidelines (2010).

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THERAPEUTIC OPTIONS PRINCIPLES. It is vital that treatment be tailored to the needs of the individual patient in partnership with the physician. Issues including compliance with therapy, patient understanding of the disease, cost of treatment, potential side-effects, and impact of therapy on the patients quality of life should be explicitly incorporated into the patients care plan. It is not sufficient to limit discussions to intraocular pressure, visual field, and optic nerve status; discussions about the implications of POAG and its care need to be addressed with the patient (Choplin and Lundy, 2007). Options for lowering IOP include the use of topical or systemic medications, laser trabeculoplasty, surgery to improve outflow facility, and cyclodestructive laser to reduce aqueous production (COS, 2009). According to the European Glaucoma Society guidelines (2008), medical therapy should start with one drug. The choice of management strategy must take into account efficacy, safety, tolerability, quality of life, adherence and cost. Prostaglandins or prostamides have been approved as first line treatment for several years. They are increasingly used as first choice treatment; the main reasons are fewer installations (QD vs. BID), lack of relevant systemic side effects, and IOP-lowering efficacy (peak of >30%). Cost is the only downside. If the first-choice monotherapy alone is not effective on IOP or not tolerated, it is preferable to switch to any of the other topical agents that can be initiated as monotherapy, If it is well tolerated and effective, but not sufficient to reach the target IOP, or there is evidence of progression and the target IOP is being reconsidered, then adjunctive therapy in the form of any other topical agent can be initiated (EGS, 2008).

First-choice treatment: A drug that a physician prefers to use as initial IOP

lowering therapy. First-line treatment:

A drug that has been approved by an official controlling body (i.e. EMEA, CPMP or FDA) for initial IOP lowering therapy.

INITIAL TREATMENT AND THERAPEUTICAL TRIAL. Where practical, topical treatment is started in one eye first. The differential IOP will give a better idea of the effect, with less influence from diurnal variations. For some drugs, a cross-over effect to the fellow eye must be taken into account. Treatment is considered "effective" on the IOP when the observed IOP lowering effect on the treated patient is comparable to the published average effect for the same compound on a similar population.

SWITCHING MONOTHERAPY AND ADJUNCTIVE THERAPY. Monotherapy fails to achieve a satisfactory IOP reduction in 40-75% of patients after more than 2 years of therapy (EGS, 2008). The Ocular Hypertension Treatment Trial showed that 40% of patients needed more than one medication to achieve a 20% reduction in IOP (Schultz, 2010). In the event of monotherapy failure, replacement or switching monotherapy should be attempted before adding a second drug (EGS, 2008). FIXED COMBINATIONS. There has been a substantial increase in the use of fixed combinations of IOP-lowering drugs for treatment of glaucoma in recent years. Fixed-dose combinations of ophthalmic drugs (usually a beta-blocker as base drug and a prostaglandin analog, a carbonic anhydrase inhibitor, brimonidine, or pilocarpine) have been developed to simplify therapy and increase patient compliance. In addition to making the treatments simpler, patient costs might be cut if fewer bottles of medicine were required for treatment (Schultz, 2010). Some of the fixed combinations that are currently available for lowering the IOP contain timolol and either CAI dorzolamide or alpha agonist brimonidine or prostaglandin analog, and the examples include Cosopt (timolol-dorzolamide), Combigan (timolol-brimonidine), Xalacom (timolol-latanoprost), Duotrav (timolol-travoprost), Ganfort (timolol-bimatoprost). Results from clinical studies indicated that fixed combination was more therapeutically effective than individual therapeutic agents alone in lowering IOP. Fixed combinations provide a better option for patients who need more than one drug to control IOP, and hence they can be considered as important adjuncts to the armamentarium of available therapies for treating glaucoma (Balabathula, 2013). How good as they may be, there are several difficulties to consider before prescribing fixed combinations. First, there is no dosing flexibility. For example, if a patient is doing well with a QD beta-blocker therapy, this is not an option with a fixed combination drug that is prescribed BID, such as Cosopt or Combigan, and this can lead to overtreatment with the beta-blocker. Second, the concentrations are fixed and will thus lead to excessive treatment in some patients who only require lower concentrations of individual drugs.

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THERAPEUTIC OBJECTIVES Preserve the current visual function of the patient by reducing intra-ocular pressure

To compute for the target Intra-ocular pressure for each eye

To reduce the IOP of the left eye to 30% from baseline

To reduce the IOP of the right eye to at least 25% from baseline Prevent further progression of visual defects

DRUGS UNDER CONSIDERATION DRUG DOSE NUMBER OF DAYS

PARASYMPATHOMIMETICS/CHOLINOMIMETICS

(as maintenance therapy)

Pilocarpine hydrochloride (Isopto Carpine eye drops 2%) 15 ml container

1 drop per eye QID

ALPHA-2-ADRENERGIC AGONISTS

Brimonidine tartrate (Alphagan P ophthalmic solution 0.15%) 5 ml container

1 drop in the affected eye/s TID if monotherapy; BID if adjunctive

BETA-ADRENERGIC ANTAGONISTS

Betaxolol (Betoptic 0.5%) 5 ml container

1 drop in the affected eye/s BID

Timolol (Celsus Timolol Maleate 0.5%) 5 ml container

1 drop in the affected eye/s BID

CARBONIC ANHYDRASE INHIBITORS

Acetazolamide (Cetamid) 250 mg/tablet #120 tablets

Take 1 tablet every 6 hours everyday Refill: every month

Dorzolamide HCl (Trusopt 2%) 5 ml container

1 drop in the affected eye/s TID

PROSTAGLANDIN DERIVATIVES

Latanoprost (Xalatan ophthalmic solution 50 mcg/ml) 2.5 ml container

1 drop QD Travoprost (Travatan ophthalmic solution 0.004%) 2.5 ml container

Bimatoprost (Lumigan ophthalmic solution 0.03%) 3 ml

PHARMACOLOGIC MANAGEMENT

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CRITERIA

EFFICACY

Drug is able to effectively lower the intraocular pressure to target limits 1 point

Drug is able to reduce fluctuations in intraocular pressure during diurnal and inter-visit periods

1 point

Drug has a long duration of action 1 point Clinical trials/evidence showing better response rates 1 point

SAFETY

Drug has absent to minimal reversible side effects especially those that affect vision 1 point Drug is not associated with or has no rare life-threatening ADRs which would require discontinuation of use

1 point

Drug needs only "once-daily" dosing for better compliance 1 point Drug has few drug-drug interactions or rare hypersensitivity reactions 1 point

NECESSITY

Drug outweighs other treatment options 1 point Drug is an effective stand-alone drug 1 point Drug has no contraindication for use in relation to host factors 1 point Drug has few reports of non-response 1 point

AFFORDABILITY

Total cost per month: 100.00-500.00 PhP 4 points

Total cost per month: >500.00-1000.00 PhP 3 points Total cost per month: >1000.00-2000.00 PhP 2 points

Total cost per month: >2000.00 PhP 1 point

Parasympathomimetics increase aqueous outflow by action on the trabecular meshwork through contraction of the ciliary muscle. Stimulation of the longitudinal muscle of the ciliary body (via the parasympathetic pathways mediated by acetylcholine) increases traction on the scleral spur, which in turn increases the tension on the trabecular meshwork, resulting in increased outflow facility. This effect on IOP may be achieved by direct stimulation of the cholinergic receptors by drugs which mimic naturally occurring acetylcholine (directly applied acetylcholine is ineffective, because it is broken down by esterases in the cornea) or by indirect stimulation with drugs that inhibit the enzymatic breakdown of naturally occurring acetylcholine. Pilocarpine, a direct-acting cholinergic agonist, is generally better tolerated than the rest of the parasympathomimetics and is considered the standard cholinergic agent for the treatment of open-angle glaucoma (Brunton et al, 2008).

EFFICACY EFFECTIVITY IN LOWERING IOP TO TARGET LIMITS. Parasympathomimetic agents such as pilocarpine increase aqueous outflow by action on the trabecular meshwork through contraction of the ciliary muscle. Activation of the constrictor pupillae muscle in these circumstances lowers the intraocular pressure. Pilocarpine can reduce the

intraocular pressure by 20-25% (European Glaucoma Society, 2008). In a study on comparative efficacy of antiglaucoma medications using experimental models by Gupta et al (2007), pilocarpine exhibited a maximum IOP-lowering rate of 28.91%. CONTROL OF IOP FLUCTUATIONS. The physiologic diurnal IOP curve peaks at around noon and gradually goes down toward the night. Ticho et al (1979) compared the long-term effects of pilocarpine HCl 2% and Piloplex wherein pilocarpine HCl 2% did not prevent the peaking of IOP at the 12th hour and subsequent rises at the 15th and 21st hour, and the mean diurnal IOP was higher by 2.89 mm Hg with pilocarpine. However, a more recent study by Bozorgi and Sarchahi (2011) on latanoprost and pilocarpine using experimental models showed that pilocarpine provided significant protection against the rise in IOP induced by water loading (simulated ocular hypertension). DURATION OF ACTION. Pilocarpine (2% eye drops) exerts its IOP-lowering effect within a few minutes (Brunton et al, 2008) and has a relatively short duration of action of 6-7 hours (European Glaucoma Society and Canadian Ophthalmologic Society).

ESNA DISCUSSION

PILOCARPINE (PARASYMPATHOMIMETIC)

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RESPONSE RATES. No literature specifically focusing on the response rates with pilocarpine has been found. Ticho et al (1979) reported that pilocarpine ophthalmic solutions, even with increased pilocarpine concentration, have a limited hypotensive effect on the increased intraocular pressure.

SAFETY SIDE EFFECTS. Pilocarpine is infrequently used nowadays because the numerous side effects, especially ocular side effects, significantly negate the therapeutic usefulness of this drug. Cholinergic agonists can markedly affect vision due to their effects on pupil size and ciliary muscle tone. Stimulation of ocular cholinergic receptors causes accommodative spasm with induced myopia due to stimulation of the circular muscle of the ciliary body, and miosis with decreased vision due to stimulation of the iris sphincter. Prolonged use may result in conjunctival hyperemia, pigment epithelial cysts of the iris sphincter, inability to dilate the pupil due to fibrosis and posterior synechiae, and uveitis due to breakdown of the blood-aqueous barrier (Choplin and Lundy, 2007). Cholinergic agonists in general may exacerbate the following: severe asthma, bronchial obstruction, acute cardiac failure or recent myocardial infarction, active peptic ulcer, gastrointestinal spasms, hyperthyroidism, urinary tract obstruction, and parkinsonism (Netland, 2008). Nevertheless, reports of adverse systemic effects from miotics, such as pilocarpine, are rare (Everitt and Avorn, 1990). Systemic exposure to pilocarpine can prevented by instructing patients to perform punctal occlusion after topical administration. DOSING AND COMPLIANCE. Because of the short action of pilocarpine (2% eye drops) of 6-7 hours, pilocarpine is administered on a QID basis which is an inconvenient regimen to the patient and may result in poor compliance. SIGNIFICANT DRUG-DRUG INTERACTIONS AND HYPERSENSITIVITY REACTIONS. Although pilocarpine causes ciliary muscle contraction which reduces uveoscleral outflow (site of action of the prostaglandin analogs), several studies have shown that pilocarpine does not attenuate or antagonize the therapeutic effects of prostaglandin analogs; the IOP reduction caused by

cholinergics may even be partially additive to that of the uveoscleral outflow-enhancing prostaglandin derivative latanoprost (Netland, 2008).

NECESSITY DRUG AS FIRST-LINE TREATMENT AND AS MONOTHERAPY. Pilocarpine, once a mainstay in pharmacologic treatment of glaucoma, has been overtaken by better drug groups such as beta-blockers and prostaglandin derivatives as first-line therapies and has been relegated as an adjunct to either a beta-blocker or a prostaglandin derivative for the treatment of open-angle glaucoma. CONTRAINDICATION FOR USE IN RELATION TO HOST FACTORS. There was no mention of host factors (e.g. conditions in which pupilloconstriction will be undesirable such as acute iritis) in the case that will make pilocarpine a contraindication. NON-RESPONSE. David, Livingston, and Luntz (1977) did a study on long-term follow-up treated and untreated glaucoma patients and reported that pilocarpine treatment did not prevent glaucoma in about 10% of the treated group and was not advantageous in patients whose mean initial IOP was below 30 mm Hg. Meanwhile, Shroff (1982) reported in his study that pilocarpine did not control the IOP in 66% of the ocular hypertensive and open-angle glaucoma subjects.

AFFORDABILITY Pilocarpine is the most commonly used cholinergic and one of the least expensive glaucoma medications (Choplin and Lundy, 2007). It is available in the Philippines as Isopto Carpine 2% eye drops and costs PhP 299.00 per 15 mL container (MIMS, 2014). The dosing for Isopto Carpine 2% eye drops is 1 drop per eye QID, so our patient's total number of drops per day and per month will be 8 drops/day and around 240 drops/month respectively. Assuming 1 mL = 20 drops, 12 mL of the container will be consumed per month; therefore, 1 container will be enough to meet the 240 drops/month requirement, costing PhP 299.00/month.

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EFFICACY

Drug is able to effectively lower the intraocular pressure to target limits 0

1 Drug is able to reduce fluctuations in intraocular pressure during diurnal and inter-visit periods

1

Drug has a long duration of action 0

Clinical trials/evidence showing better response rates 0

SAFETY

Drug has absent to minimal reversible side effects especially those that affect vision 0

2 Drug is not associated with or has no rare life-threatening ADRs which would require discontinuation of use

1

Drug needs only once-daily dosing for better compliance 0

Drug has few drug-drug interactions or rare hypersensitivity reactions 1

NECESSITY

Drug outweighs other treatment options 0

1 Drug is an effective stand-alone drug 0 Drug has no contraindication for use in relation to host factors 1 Drug has few reports of non-response 0

AFFORDABILITY


4 Total cost per month: >500.00-1000.00 PhP 3 points Total cost per month: >1000.00-2000.00 PhP 2 points Total cost per month: >2000.00 PhP 1 point

PILOCARPINE (PARASYMPATHOMIMETIC) 8

Brimonidine, a selective alpha-adrenergic agonist and a derivative of clonidine, primarily inhibits aqueous production and secondarily increases aqueous outflow; thus, it can be used to lower intraocular pressure in patients with ocular hypertension or open-angle glaucoma (Brunton et al, 2008). Furthermore, it appears to bind to pre- and postsynaptic alpha-2 receptors. By binding to the presynaptic receptors, the drugs reduce the amount of neurotransmitter release from sympathetic nerve stimulation and thereby lower IOP. By activating postsynaptic alpha-2 receptors, these drugs stimulate the G pathway, reducing cyclic AMP production and thereby reducing aqueous humor production. Brimonidine is the only clinically relevant alpha-adrenergic agonist for long-term treatment of glaucoma (Schultz, 2010).

EFFICACY EFFECTIVITY IN LOWERING IOP TO TARGET LIMITS. Alpha-adrenergic agonists reduce intraocular pressures by 20-25%, which is comparable to that of the beta-blockers and parasympathomimetics, and can reach IOP reductions of 27% as monotherapy (EGS, 2008). The efficacy of the highly-selective alpha-2-adrenergic agonist brimonidine in reducing intraocular pressure is similar to that of the beta-adrenoceptor antagonist timolol (Brunton et al, 2008). A study by Thomas et al (2003) on the efficacy and safety of brimonidine in Indian eyes showed that only half of the subjects on brimonidine had reduction rates of >25%.

RESPONSE RATES. Schuman et al (1997) conducted a multicenter, double-masked, randomized, parallel-group, active-controlled comparison clinical trial on brimonidine bid for 1 year and reported that brimonidine-treated subjects showed an overall mean peak reduction in intraocular pressure (IOP) of 6.5 mm Hg as compared to timolol-treated subjects showing a mean peak IOP reduction of 6.1 mm Hg. Meanwhile, Joshi et al (2013) did a prospective, open, randomized, comparative controlled clinical trial on brimonidine and timolol and noted that the mean IOP reduction in brimonidine (-5.5 mm Hg) is comparable to that of timolol (-6.2 mm Hg). CONTROL OF IOP FLUCTUATIONS. A cross-over, open-label study by Thomas et al (2003) reported that brimonidine, like latanoprost, also significantly reduces diurnal fluctuations, albeit less than that of the latter. In the study by Spaeth et al (2011), it was reported that brimonidine decreased the short-term (daily) and long-term (inter-visit) fluctuations by 18.9% and 11.3% respectively. DURATION OF ACTION. Brimonidine peaks at 4-6 weeks, and its duration of action ranges from 8 to 12 hours (Parikh, 2008), longer than that of pilocarpine eye drops but significantly shorter than beta-blockers or prostaglandin analogs.

BRIMONIDINE (ALPHA-ADRENERGIC AGONIST)

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RESPONSE RATES. Thomas et al (2003) reported in their study that latanoprost had a higher mean IOP reduction than brimonidine after 6 weeks; only 46.4% of the brimonidine-treated patients attained an IOP reduction of at least 25% and even less patients (28%) achieved at least 30% IOP reduction. On the other hand, a 3-month, multicenter, double-masked, parallel-group, 4-visit study on the efficacy and tolerability of brimonidine and latanoprost in adults with open-angle glaucoma or ocular hypertension (Dubiner et al, 2001) showed that at peak effect, brimonidine BID was as effective as latanoprost QD in lowering IOP. In treatment-naive patients, latanoprost was associated with a significantly higher rate of nonresponse (defined in the study as IOP reduction of less than 20%) after 3 months of treatment compared with brimonidine, and significantly more patients achieved clinical success with brimonidine monotherapy than with latanoprost monotherapy. Dubiner et al (2001) suggested that brimonidine may be the more reliable choice for first-line therapy of newly diagnosed open-angle glaucoma or ocular hypertension.

SAFETY SIDE EFFECTS. According to Schuman et al (1997), brimonidine is well tolerated and has a low rate of allergic response (more commonly, allergic blepharoconjunctivitis). The lower incidence of the ocular adverse effects is due to its greater alpha-2 selectivity, according to Apatachioae and Chiselita (1999). Among the different preparation, brimonidine 0.2% was more associated with ocular allergies; brimonidine was formulated in concentrations of 0.15% and 0.1% to reduce the rate of allergy (Choplin and Lundy, 2007). Brimonidine P 0.15% uses Purite instead of benzalkonium chloride which has been known to cause ocular allergies and fibrosis. Brimonidine also has a neuroprotective effect, which is an important feature in the new contexts of glaucoma pathogenesis. However, brimonidine is associated with a greater incidence of adverse local reactions than timolol. In terms of systemic effects, it has no effects on cardiopulmonary function. Serious systemic, especially CNS, adverse effects are seen more in brimonidine-treated children and more so in glaucoma-affected infants and children below 2 years of age who are susceptible to life-threatening adverse reactions such as CNS depression and apnea brought about by the drug. This may be due to brimonidine's ability to cross the blood-brain barrier. Nevertheless, this is not very much applicable in our 48-year-old patient. DOSING AND COMPLIANCE. Brimonidine, although commonly prescribed with a bid dosing, is best dosed thrice daily as approved by the US FDA for round-the-clock IOP control. As reported by Fedorchak et al (2014), 97% of

patients do not take it as prescribed because of such regimen. SIGNIFICANT DRUG-DRUG INTERACTIONS AND HYPERSENSITIVITY REACTIONS. Brimonidine significantly interacts with CNS depressants (alcohols, barbiturates, opioids, sedatives, anesthetics, and tricyclics) and may potentiate the depressive effects of the said drugs (APGG and EGS). Ocular allergies e.g. allergic conjunctivitis associated with brimonidine 0.2% are significantly lessened with a formulation that has less concentration of brimonidine (e.g. 1% or 1.5%).

NECESSITY DRUG AS FIRST-LINE TREATMENT AND AS MONOTHERAPY. Apatachioae and Chiselita (1999) recommended brimonidine as first-line therapy in patients who have contraindications to beta-blockers. Nevertheless, numerous trials such as the one by Thomas et al (2003) comparing brimonidine versus prostaglandin analogs have significantly proven that the prostaglandin analogs hold a clear advantage over the former as a treatment option based on therapeutic parameters. Brimonidine is useful as monotherapy (EGS, 2008). Investigators of a multicenter open-label study on brimonidine (Abelson, 2001) reported that brimonidine monotherapy is an efficacious and cost-effective alternative to dual therapy for glaucoma and ocular hypertension. CONTRAINDICATIONS FOR USE IN RELATION TO HOST FACTORS. Contraindications to brimonidine include hypersensitivity to the drug or its components, infants and children less than 2 years of age, and use of monoamine oxidase inhibitors (EGS, 2008). As with all alpha-agonists, this drug should be used with caution in patients with cardiovascular disease (Brunton et al, 2008). However, our patient did not have any of the above conditions which would preclude brimonidine use, making it a suitable option in our case. NON-RESPONSE. Thomas et al (2003) reported that 39.3% of the brimonidine-treated eyes had IOP reduction of less than 20% as compared to a 2% non-response rate for latanoprost-treated eyes.

AFFORDABILITY Brimonidine is available in the Philippines as Alphagan P ophthalmic solution 0.15% and costs 905.75 PhP per 5 mL container (MIMS, 2014). The dosing for this formulation is 1 drop in affected eye/s TID, so our patient's total number of drops per day and per month will be 6 drops/day and around 180 drops/month respectively. 9 mL of the container will be consumed per month; therefore, it will take 2 containers of brimonidine to meet the 180 drops/month requirement, costing PhP 1810.00/month.

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EFFICACY



1



SAFETY



1

Drug needs only "once-daily" dosing for better compliance 0


NECESSITY



AFFORDABILITY



BRIMONIDINE (ALPHA-2-ADRENERGIC AGONIST) 10

Beta-blockers decrease intra-ocular pressure by reducing aqueous humor production. They reach their peak effect after 2 hours.

EFFICACY CRITERION 1. DRUG IS ABLE TO EFFECTIVELY LOWER THE INTRAOCULAR PRESSURE TO TARGET LIMITS. For years, topical beta-blockers were the most common first line of therapy for reducing intra-ocular pressure. To decrease aqueous production, a nonspecific beta-blocker eye drop such as levobunolol (Betagan) was, until recently, the first drug class to be chosen. In a study by Potocky and Vodrazkova, the influence of non-selective betablockers (TIMOPTOL 0.5%, VISTAGAN 0.5%) and selective betablocker (BETOPTIC 0.5%) on the intraocular pressure, pulse frequency, systemic blood pressure and lung capacity was evaluated. Authors concluded that all three drugs reliably lowered intraocular pressure. According to the European Glaucoma Society, beta blockers have the ability to reduce intra-ocular pressure from 20-25%. However central corneal thickness may have an effect on the efficacy of the drug since thicker corneas were shown to not respond as well to beta blocker therapy. The advent of newer agents however, particularly prostaglandin analogues, has given physicians and doctors

a wider variety of choices for both initial and adjunctive medical therapy. But beta-blockers have been the gold standard against which all new pressure lowering medications are measured, and this is unlikely to change. In the case, beta blockers would be sufficient to reduce the intra-ocular pressure of the right eye to target limits however it would not be enough for the left eye which needs at least a 30% reduction from baseline. Because of this, we do not give a point to beta-blockers for this criterion. CRITERION 2. DRUG IS ABLE TO REDUCE FLUCTUATIONS IN INTRA-OCULAR PRESSURE DURING DIURNAL AND INTER-VISIT PERIODS. Elevated IOP is a known risk factor for glaucoma and for progression of glaucoma; the higher a patient's IOP, the greater the risk of progression. Increasingly, data suggest that fluctuation in IOP throughout the day, even in the so-called "normal" range, may also be a risk factor for progression. In a study conducted in 408 glaucoma patients with low IOP, it was shown that even though IOP was less than 18 mmHg at all times, patients whose standard deviation was 2 mmHg or greater had a three times greater risk of progression of damage (30- vs. 10-percent risk) than those with deviations of less than 2 mmHg.

BETA-ADRENERGIC ANTAGONISTS

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These studies therefore affect the drugs we choose to treat glaucoma. It is found out through studies that yesterday's gold standard medical treatment, beta-blocker therapy, does not control IOP at night, while some newer ocular hypotensive medications control IOP throughout the 24-hour cycle. We remember that the MOA of beta-blockers is to reduce production of aqueous humor however during the night there is a natural decrease of aqueous humor flow by about 50%. This renders a drop that targets aqueous production (i.e., beta blocker) less efficacious. Because of this finding, we do not give a point for beta-blockers for this criterion. CRITERION 3. DRUG HAS A LONG DURATION OF ACTION. Beta-blockers reach their peak action 2 hours after instillation. To reach their maximum effect however they need a few weeks to stabilize. The duration of action of beta-blockers ranges from 12 to 24 hours. Comparing to carbonic anhydrase inhibitors whose duration of action usually lasts for only 8 to 18 hours, beta-blockers have a longer duration. For this criterion, beta blockers get a point. CRITERION 4. CLINICAL TRIALS/EVIDENCE SHOWING BETTER RESPONSE RATES. In the Ocular Hypertension Treatment Study (OHTS), there were no statistically significant differences in IOP response to non-selective beta blockers or prostaglandin analogues between self-identified African-Americans and White Americans. Beta-blockers are not given a point under this criterion because prostaglandin analogues show better response rates.

SAFETY CRITERION 1. DRUG HAS ABSENT TO MINIMAL REVERSIBLE SIDE EFFECTS ESPECIALLY THOSE THAT AFFECT VISION. Ocular side effects for beta blockers are uncommon. They include, epithelial keratopathy, and slight reduction in corneal sensitivity. Systemic side effects meanwhile include bradycardia, arrhythmia, heart failure, syncope, bronchospasm and airway obstruction. Systemic side effects can be minimized by closing the eyes following application or using a technique called punctal occlusion that prevents the drug from entering the tear drainage duct and systemic circulation. Although systemic side effects can be prevented, the conditions enumerated are serious enough to have beta-blockers lose a point for this criterion. CRITERION 2. DRUG IS NOT ASSOCIATED WITH OR HAS NO RARE LIFE-THREATENING ADRs WHICH WOULD REQUIRE DISCONTINUATION OF USE. Physicians should avoid using beta-blocker eye drops in patients with reactive airway disease, cardiac conduction defects, or heart failure. Systemic absorption of these eye drops can cause bradycardia, bronchospasm, and even fatalities from bronchospasm in patients with asthma and

heart conditions. If the physician is well-aware of the possible complications of this drug, these systemic effects can be effectively avoided. Also, based on a systemic review on the different drugs for glaucoma, subjects on timolol (beta-blocker) were seen to less likely drop out of studies due to side effects than those on brimonidine (alpha-adrenergic agonist), latanoprost (prostaglandin analog), travoprost (prostaglandin analog), or betaxolol (beta-blocker). Beta-blockers are given 1 point for this criterion. CRITERION 3. DRUG NEEDS ONLY ONCE-DAILY DOSING FOR BETTER COMPLIANCE. Beta-blockers with a duration of action lasting 12-24 hours usually requires a daily dosing of once to twice a day. Levobunolol, a beta blocker, often can be used "once-daily". Studies have shown that dosing more than twice daily will not give any further pressure lowering effect. Beta-blockers are given 1 point for this criterion. CRITERION 4. DRUG HAS FEW DRUG-DRUG INTERACTIONS OR RARE HYPERSENSITIVITY REACTIONS. If the patient is already taking a systemic beta blocker, the physician should consider using another class of eye drops, because systemic beta-blocker therapy may reduce the ocular hypotensive effects of beta-blocker eye drops [Evidence level A, RCT]. Caution should be used in the co-administration of beta-blockers and oral and intravenous calcium antagonists because of possible atrioventricular conduction disturbances, left ventricular failure and hypotension. Beta-blockers can also have a drug interaction with digitalis and have an additive effect in prolonging conduction time. An additive effect in producing hypotension and/or marked bradycardia is also produced with catecholamine-depleting drugs. Beta-blockers are given a point under this criterion because the case is assumed to be not taking any of the aforementioned drugs.

NECESSITY CRITERION 1. DRUG OUTWEIGHS OTHER TREATMENT OPTIONS. Used in a variety of glaucoma eye drops, beta-blockers were at one time the drugs of choice in treating glaucoma. However, many glaucoma specialists now report that prostaglandins have taken the lead in recent years as a first-line therapy for glaucoma (EyeWorld, January 2007). It should be emphasized however that the emergence of prostaglandins as first-line therapy has not eliminated other options, such as beta-blockers. Beta-blockers are still a viable option for glaucoma treatment and, in some cases,

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are the best therapy for some patients. Many glaucoma patients will still end up using a beta-blocker at some point in their treatment. They are good drugs just not the drug used as first-line therapy anymore (Thimons, 2004). Beta-blocker drugs do not get a point for this criterion. CRITERION 2. DRUG IS AN EFFECTIVE STAND-ALONE DRUG. Beta-blockers can be used as the only therapy for primary open angle glaucoma. However, there are times when monotherapy fails. When this happens, a dorzolamide and timolol maleate combination (Cosopt) is available to decrease aqueous production by two different mechanisms in a single agent. Beta-blockers get a point for this criterion. CRITERION 3. DRUG HAS NO CONTRAINDICATION FOR USE IN RELATION TO HOST FACTORS. Major contraindications for the use of beta blockers are asthma, history of obstructive pulmonary disease, sinus bradycardia, heart block and cardiac failure. Since these diseases were not given in the case, it is assumed that no host factor is contraindicated for the use of beta blockers. Beta-blockers get a point for this criterion. CRITERIA 4. DRUG HAS FEW REPORTS OF NON-RESPONSE. With longer-term use of timolol or levobunolol, tachyphylaxis is not uncommon. In a significant number of cases, the pressure responsiveness decreases with continuous use. The timolol therapy is associated with the phenomenon of short-term escape and long term drift. In short-term escape, most patients experience a good IOP reduction after the start of timolol

therapy, but the pressure rises after a few days to finally level off after 3-4 weeks. One must therefore wait for at least one month after starting timolol to determine its efficacy. In long term drift, after about 1 year of timolol therapy, few patients show a slow decline in pressure responsiveness to timolol. Many of these will regain responsiveness after a washout period. Secondary analysis of phase three clinical trials comparing twice daily treatment with 0.5% timolol versus .0005% latanoprost daily demonstrated that 28% of patients treated with timolol and 18% of those treated with latanoprost were non-responders. Beta-blockers do not get a point for this criterion.

AFFORDABILITY Based on the website of MIMS, betaxolol and timolol are both available in the Philippines. The drugs are usually dispensed in 5 ml containers. The most expensive is Betoptic which is available for 470 pesos per 5 ml container. Other brands under timolol include Celsus Timolol Maleate eye drops (320 PhP), Nyolol eye drops .5% (550 PhP), and Oftan eye drops 5 mg/ml (392 PhP). If we compute for the total expense for a month, considering we distill 4 drops per day (2 for each eye) and that 1 ml has 20 drops. The most expensive which is Betoptic will have a total of 564 PhP for one month, while the least expensive which is Celsus Timolol Maleate will have a total of 384 PhP for a month. Considering this, beta-blockers are considered affordable drugs and are given 4 points.

EFFICACY



0



SAFETY



1



NECESSITY



AFFORDABILITY



BETA-ADRENERGIC ANTAGONISTS 10

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The mode of action of carbonic anhydrase inhibitors in lowering intra-ocular pressure is the reduction of aqueous humor formation.

EFFICACY CRITERION 1. DRUG IS ABLE TO EFFECTIVELY LOWER THE INTRAOCULAR PRESSURE TO TARGET LIMITS. Most of the available medications used to lower intraocular pressure today come in the form of eye drops. In keeping with that trend, when carbonic anhydrase inhibitors (CAIs) are prescribed, they tend to be in topical form. The shift away from oral carbonic anhydrase inhibitors, such as acetazolamide and methazolamide, has also been hastened by the development of potent classes of topical drugs such as prostaglandin analogs and alpha agonists. Often CAIs are overlooked when deciding how to treat a patient. However, they can do a very effective job of lowering IOP and keeping it at a safe level. Diamox (acetazolamide) has been found to reduce aqueous flow 21-30% during the day and 24% at night. Data from the European Glaucoma Society on the other hand observed that CAIs can decrease IOP by 15-20%. Dr. Todd Perkins of the University of Wisconsin also found oral CAIs to be significantly more effective than topical CAIs in many patients with a patient having an IOP of 40 mmHg drop to 25 mmHg. However not all the literature agrees about the comparative value of oral vs. topical CAIs; some studies have found the oral drugs to be more effective than topical, while others have found little difference. Although effective, long-term use of CAIs is avoided because of the potential for side effects. These drugs are sometimes reserved for situations when a patient's glaucoma is severe and also for short-term therapy. Because these drugs can achieve a lowering of IOP by as much as 30%, they are given a point for this criterion. CRITERION 2. DRUG IS ABLE TO REDUCE FLUCTUATIONS IN INTRAOCULAR PRESSURE DURING DIURNAL AND INTER-VISIT PERIODS. Again, according to Perkins, Diamox (acetazolamide) has been found to reduce aqueous flow 21 to 30 percent during the day and 24 percent at night which is an advantage over the beta-blockers. A study by Orzalesi, evaluated circadian IOP patterns in patients taking several type of ocular hypotensive drugs

one of which was dorzolamide, a topical CAI. The study found out that prostaglandins have the most consistent coverage for 24 hours particularly in the nocturnal period. As you can see in the figure below, dorzolamide did not have much control in fluctuation of IOP, with measurements of about 20 mmHg at 3 pm and 16 mmHg at midnight. This might mean a better control of fluctuation by oral CAIs than topical CAIs.

Even though prostaglandins are better controllers for IOP fluctuations, CAIs were still able to provide control so they are given a point for this criterion. CRITERION 3. DRUG HAS A LONG DURATION OF ACTION. Compared to other medications for open-angle glaucoma, Carbonic Anhydrase Inhibitors have the shortest duration of action leading to more frequent dosing. Oral CAIs usually have a duration of 8-12 hours having 2-4 times daily intake. On the other hand, topical CAIs have a slightly longer duration of action at 10-18 hours. Instillation is usually 2-3 times daily. The CAIs do not get a point for this criterion. CRITERION 4. CLINICAL TRIALS/EVIDENCE SHOWING BETTER RESPONSE RATES. According to Singh and Shrivastava, the role of other contemporary classes of glaucoma medications, including topical carbonic anhydrase inhibitors, is limited for first-line use due to the necessity of using these drugs more than twice a day and because the quality of IOP lowering, even when dosed three or four times a day, is not as desirable as that seen with the prostaglandin analogs. CAIs do not get a point for this criterion.

SAFETY CRITERION 1. DRUG HAS ABSENT TO MINIMAL REVERSIBLE SIDE EFFECTS ESPECIALLY THOSE

CARBONIC ANHYDRASE INHIBITORS

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THAT AFFECT VISION. One of the important factors which limit the use of carbonic anhydrase inhibitors is their capacity to produce systemic effects. Their side effect profile tends to limit their use to situations involving acute IOP elevation or chronically elevated IOP in a patient on maximal topical agents prior to a more definitive procedure to lower IOP (Canadian Opthalmological Society). Ocular side effects can potentially include idiosyncratic sulfonamide-related transient angle-closure, myopia and choroidal thickening, but these are rare. Systemic effects common with prolonged use include gastrointestinal upset, paresthesias, diuresis, metabolic acidosis, malaise, anorexia, metallic taste, tingling of fingers and potassium depletion. CAIs are not given a point for this criterion. CRITERION 2. DRUG IS NOT ASSOCIATED WITH OR HAS NO RARE LIFE THREATENING ADRs WHICH WOULD REQUIRE DISCONTINUATION OF USE. Systemic carbonic anhydrase inhibitors may produce adverse reactions common to all sulphonamide derivatives like anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, bone marrow depression, pancytopenia, thrombocytopenic purpura, haemolytic anemia and agranulocytosis. Some of the above symptoms are irreversible and lethal (European Glaucoma Society). CAIs are not given a point under this criterion. CRITERION 3. DRUG NEEDS ONLY "ONCE-DAILY" DOSING FOR BETTER COMPLIANCE. Most of the oral or topical carbonic anhydrase inhibitors need two to three times daily dosing. This may decrease compliance to the drug. CAIs are again not given a point in this criterion. CRITERION 4. DRUG HAS FEW DRUG-DRUG INTERACTIONS OR RARE HYPERSENSITIVITY REACTIONS. Systemic CAIs should be used with caution in patients on steroid and systemic hypertension diuretic therapy because of the potential for developing hypokalemia (European Glaucoma Society). Additive side effects or increased toxicity have been reported for systemic CAIs taken together with systemically administered ciclosporin, digitalis, lithium, and aspirin (increased toxicity). Systemic acetazolamide decreases the effects of oral antidiabetics, and diminishes cholinesterase activity. Stevens-Johnson syndrome also produces a serious but rare hypersensitivity reaction. CAIs are not given a point for this criterion.

NECESSITY CRITERION 1. DRUG OUTWEIGHS OTHER TREATMENT OPTIONS. The short-term use of carbonic anhydrase inhibitors to avoid systemic effects plus its

multiple daily dosing requirements puts CAIs at a disadvantage as the preferred treatment option. CAIs are not given a point for this criterion. CRITERION 2. DRUG IS AN EFFECTIVE STAND-ALONE DRUG. The topical carbonic anhydrase inhibitors, dorzolamide and brinzolamide, often are used as adjunctive therapy but rarely as initial therapy (Distelhorst, 2003). Systemic carbonic anhydrase inhibitors are the reserved group of drugs given orally as an adjunct when IOP is not controlled adequately with topical medication. However, in another study by Serle and Rabinowitz, dorzolamide, a topical CAI, is proven to be effective in reducing IOP as a single-agent therapy. Thus, in some patients dorzolamide may be used two or three times daily as a first-line drug for the treatment of glaucoma. Because of this, CAIs are given a point for this criterion. CRITERION 3. DRUG HAS NO CONTRAINDICATION FOR USE IN RELATION TO HOST FACTORS. According to the European Glaucoma Society, topical CAIs are contraindicated for patients with hypersensitivity reactions for any of the drug components. On the other hand, major contraindications for systemic CAIs include decreased sodium and potassium levels, kidney and liver disease or dysfunction, suprarenal gland failure and hyperchloremic acidosis. All of these conditions are presumed to be absent in the patient so CAIs are given a point in this criterion. CRITERIA 4. DRUG HAS FEW REPORTS OF NON-RESPONSE. No reports on non-response for carbonic anhydrase inhibitors can be found. This may be attributed to the use of CAIs only as last-line treatment for IOPs that cannot be controlled by other topical drugs. In other words, these drugs are reserved for situations when a patient's glaucoma is severe. A point is given for CAIs in this criterion.

AFFORDABILITY A 5 ml container for dorzolamide (Trusopt) is 875.93 pesos. Considering it is instilled 3 times a day, computation will show that a patient will spend approximately 1577 PhP a month. Brinzolamide (Azopt), another topical CAI is priced at 942 PhP per 5 ml bottle. Considering it is instilled twice a day, computation will that a patient will spend 1130.40 PhP in a month. Acetazolamide (Cetamid) an oral CAI, comes in packs of 100 pieces. Each piece is priced at 25 PhP. Thus, if you take 4 tablets in one day, you spend 3000 pesos in one month. Taking into consideration the availability of cheaper topical CAIs, 2 point will be given for this drug group.

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EFFICACY



1



SAFETY



0



NECESSITY



AFFORDABILITY



CARBONIC ANHYDRASE INHIBITORS 7

Prostaglandins reduce IOP by increasing outflow of aqueous humor mostly by enhancing the uveoscleral pathway. They have no effect on aqueous production. It is believed that prostaglandins improve the uveoscleral pathway by altering the ciliary body and scleral architecture, making it more amenable to aqueous egress through stimulation of collagenases and matrix metalloproteinases, and the relaxation of ciliary muscle bundles. The exact mechanism of action, however, remains to be fully elucidated.

EFFICACY EFFECTIVITY IN LOWERING IOP AND DURATION OF ACTION. Currently, the only approach proven to be efficient in preserving visual function is lowering the IOP. Lowering the pre-treatment IOP by 25% or more has been shown to inhibit progression of POAG. It is reasonable to select an initial target pressure of at least 25% lower than pre-treatment levels. However, in this case, it has been established that the target IOP reduction from the baseline is 25% for the right eye and 30% for the left eye. Prostaglandins are the most potent topical agents for lowering IOP. In a recent meta-analysis of articles published up to 2003, prostaglandins had the highest peak mean difference from baseline IOP compared with any other class of topical anti-glaucoma agent. Their relative

change from mean baseline at peak was 31% to 33% and at trough 28% to 29%. (Van der Valk, 2005). As to the IOP lowering effectivity of prostaglandin analogs during diurnal periods, there has been a study which was conducted by Orzalesi, et. al. The results showed that the drugs' effect was significantly greater during the daytime (9 am-9 pm) than during the night-time (midnight-6 am) with all prostaglandin analogs. In 7 of 44 patients (16%), nocturnal IOP was significantly higher than diurnal IOP, both at baseline and under the 3 prostaglandin analogs. Reduction of the intraocular pressure starts approximately 2-4 hours after the first administration with peak effect reached within approximately 8-12 hours. Maximum IOP lowering is often achieved 3 to 5 weeks from commencement of treatment. Also, topical application of prostaglandin analogs is recommended to be done in the evening to reduce the early morning diurnal spike. RESPONSE RATES TO TREATMENT. In a meta-analysis study by Robert, the average mean percentage IOP reduction values at 13 weeks showed that the prostaglandin analogues generally provided better response rates as evidenced by a greater percentage of IOP reduction than the beta-blockers, achieving an average mean IOP reduction 4.9 mmHg superior to that produced by the beta-blockers.

PROSTAGLANDIN ANALOGS

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SAFETY SIDE EFFECTS/ADVERSE DRUG REACTIONS. According to the European Glaucoma Society, side effects of prostaglandin analogs include cystoid macular edema, conjunctival irritation, increased eyelash growth, periocular hyperpigmentation, iris color change, uveitis, possible herpes virus activation. In a study by Parrish, et.al., it has been mentioned that although generally well tolerated, prostaglandins do have local side effects and that conjunctival hyperemia and irritation are the most common of them. However, these side effects are easily managed and are reversible. Conjunctival irritation caused by application of prostaglandin analogs can be managed by just washing the substance from the eye with water for 4-5 minutes. DOSING AND COMPLIANCE. Better compliance to taking medications is affected by the dosing procedures of the drugs. Among the five families of anti-glaucoma agents, only the prostaglandin analogs are administered "once-daily". DRUG-DRUG INTERACTIONS AND HYPERSENSITIVITY REACTIONS. Topical preparations containing thiomersal as preservative form a precipitate with latanoprost, and hence must be instilled with a gap of at least 5 minutes between the two (Shah, 2011). Clinical studies have demonstrated additive effects of prostaglandins with all other anti-glaucoma medications, including beta-blockers, alpha-adrenergic medications, carbonic anhydrase inhibitors and cholinergic agonists. As to hypersensitivity reactions, it has been mentioned above that conjunctival irritation is common among patients using prostaglandin analogs. However, these hypersensitivity reactions may easily be reversed.

NECESSITY DRUG AS FIRST-LINE TREATMENT. Prostaglandins rapidly replaced topical beta-blockers as first-line IOP-lowering agents, mostly because of their potency, safe systemic side-effect profile, and once-daily dosing. (Higginbotham, 2002).

EFFECTIVITY AS STAND-ALONE DRUG. As the prostaglandin analogs and nonselective beta-blockers may both be effective with OD dosing, fixed drug combination of timolol 0.5% with each of the three frontline prostaglandin analogs are commercially available. These have been shown to have significantly more IOP lowering effect than either drug used alone (Shah, 2011). The European Glaucoma Society, on the other hand, suggests that prostaglandin analogs, when used as stand-alone treatment, is capable of lowering the IOP up to 33% from baseline. This lowering effect is enough since the target is just 25% from the baseline. Satisfaction of the recommended lowering effect suggests that prostaglandin analogs are effective as stand-alone drugs. According to the Asia-Pacific Glaucoma Guidelines, higher targets, as in the cases in which there is a high suspicion of visual loss, may require fixed-combination drugs, which include timolol plus a prostaglandin analog, as mentioned above. CONTRAINDICATIONS. Contraindications for the use of prostaglandin analogs include pregnancy, breast-feeding, known cardiac or pulmonary conditions and uncontrolled systemic diseases (Robert, 2010). These conditions were not mentioned as present in our case which makes it safe for prostaglandin analogs to be used.

AFFORDABILITY COST FOR 1 MONTH DOSING. The following drugs are the least expensive among the prostaglandin analogs available in the Philippines: Bimatoprost (0.03%) Lumigan P1,077.00/container (3

mL) Latanoprost (0.005%) Xalatan P1,253.49/container (2.5

mL) Travoprost (0.004%) Travatan P1,244.00/container (2.5

mL) Each container may be used up to one month since they are administered via one drop, "once-daily." A 2.5- or 3-mL container contains 50-60 drops respectively, which is enough for one month.

EFFICACY



1



SAFETY



1



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NECESSITY



AFFORDABILITY



PROSTAGLANDIN ANALOGS 14

E S N A TOTAL

PILOCARPINE (PARASYMPATHOMIMETIC) 1 2 1 4 8 BRIMONIDINE (ALPHA-2-ADRENERGIC AGONIST) 2 3 3 2 11 BETA-ADRENERGIC ANTAGONISTS 1 3 2 4 10 CARBONIC ANHYDRASE INHIBITORS 2 0 3 2 7 PROSTAGLANDIN ANALOGS 4 3 4 2 14

PROSTAGLANDIN ANALOGS (LATANOPROST AND TRAVOPROST)

These drugs are lipid structural derivatives and are synthetic prostaglandin F2a analogues. They are actually prodrugs and these arachidonic acid derivatives are hydrolyzed by corneal esterases to a biologically active free acid. The respective free acids then bind to to specific PGF2 receptors in the trabecular meshwork and the ciliary body in turn increasing the aqueous outflow through these routes. Latanoprost requires maintenance of cold chain prior to uncapping of the bottle and, thereafter, has limited shelf life

of 44 days at room temperature. Travoprost has no such considerations.

PROSTAMIDE (BIMATOPROST) Bimatoprost is an active drug in contrast to latanoprost and travoprost which, as described above, require activation by corneal enzymes. Bimatoprost increase aqueous outflow by increasing both trabecular outflow facility and uveoscleral outflow. Bimatoprost acid is 3 to 10 times as potent as latanoprost acid. Inspite of this, the therapeutically used concentration of bimatoprost is 6 times that of latanoprost. This is because of the slow conversion of bimatoprost to bimatoprost acid.

SUMMARY ESNA SCORES OF

DRUGS UNDER CONSIDERATION

ESNA: PROSTAGLANDIN ANALOGS

LATANOPROST, TRAVOPROST, BIMATOPROST

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PROSTAGLANDIN ANALOGS AND PROSTAMIDES

The recommended dosing regimen for these three drugs is "once-daily" topical application preferably in the evening to

reduce the early morning diurnal spike. Studies have shown that all the available classes of prostaglandins have excellent 24-hour IOP control despite once a day dose, making it extremely patient convenient.

CRITERIA L T B

Efficacy 1 Drug is able to effectively lower the intraocular pressure to target limits 1 1 1

2 Drug is able to reduce fluctuations in intraocular pressure during diurnal and inter-visit periods 1 1 1

3 Drug has a long duration of action 1 1 1

4 Clinical trials/evidence showing better response rates 1 0 1

Safety

1 Drug has absent to minimal reversible side effects especially those that affect vision 0 0 1


0 0 1

3 Drug needs only "once-daily" dosing for better compliance 1 1 1 4 Drug has few drug-drug interactions or rare hypersensitivity reactions 1 1 1

Necessity

1 Drug outweighs other treatment options 0 0 1

2 Drug is an effective stand-alone drug 1 1 1

3 Drug has no contraindication for use in relation to host factors 1 1 1

4 Drug has few reports of non-response 1 1 1

Affordability

1 Total cost per month: 100.00-500.00 PhP

2 Total cost per month: >500.00-1000.00 PhP

3 Total cost per month: >1000.00-2000.00 PhP

4 Total cost per month: >2000.00 PhP

TOTAL 11 10 14

Legend: L Latanoprost; T Travoprost; B - Bimatoprost

ESNA scores of each drug under prostaglandin derivatives.

LATANOPROST Latanoprost lowers the IOP up to 33% from the baseline (Van der Valk, 2005). In a commercial study by Pfizer, it has been found out that latanoprost dosed "once-daily" showed similar IOP reduction capacity with timolol, a beta-blocker, which is dosed twice daily. Patients with mean baseline intraocular pressure of 24-25 mmHg who were treated for 6 months in multi-center, randomized, controlled trials demonstrated 6-8 mmHg reductions in intraocular pressure. Reduction of the intraocular pressure starts approximately 3 to 4 hours after administration and the maximum effect is reached after 8 to 12 hours. As to its safety, a study, still conducted by Pfizer, has shown that one side effect of long-term use of latanoprost is the pigmentation of the iris. Results showed that the onset of noticeable increased iris pigmentation occurred within the first year of treatment for the majority of the patients who developed noticeable increased iris pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the five years of the study. With an increasing pigmentation of the iris, there is

also an increasing chance for visual loss. This is one of the reasons why some latanoprost users discontinue the drug. Latanoprost is preserved in benzalkonium chloride and it is responsible for most of the hypersensitivity reactions to the drug. Although human in-vivo studies have generated rare reports of BAC induced IgE-mast cell type reactions, a recent study demonstrated bronchoconstriction in asthmatics when challenged with BAC suggesting a nonspecific trigger (Lee, 2007). However, since the patient in the case has no known asthma problem, this drug is not contraindicated in relation to the patient.

TRAVOPROST Travoprost lowers the IOP up to 31% from the baseline (Van der Valk, 2005). Reduction of intraocular pressure starts approximately 2 hours after administration of travoprost. The maximum effect is observed 12 hours after administration and is maintained throughout the day. As to the safety profile of travoprost, since it is much similar to latanoprost, the adverse drug reactions, drug-drug

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interactions and contraindications for both drugs are the same. Based on the guidelines provided by the European Glaucoma Society, travoprost is only a second-line drug indicating that it is prescribed for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension who are intolerant of other intraocular pressure lowering medications or insufficiently responsive (failed to achieve target IOP determined after multiple measurements over time) to another intraocular pressure-lowering medication.

BIMATOPROST Bimatoprost has been proven to lower the IOP up to 31% from the baseline (Van der Valk, 2005). A study by Gandolfi, et. al. showed that Bimatoprost provided lower mean pressures than latanoprost at every time point throughout the 3-month period of the study and was statistically superior in achieving low target pressures. More patients reached low target pressures with bimatoprost. Also, in a study by Cantor, et. al, they have concluded that Bimatoprost provided greater mean IOP reductions than travoprost. The result was taken after 6 months and the mean IOP reduction at 09:00 h was 7.1 mm Hg (27.9%) with bimatoprost and 5.7 mm Hg (23.3%)

with travoprost. At 13:00 h, mean IOP reduction was 5.9 mm Hg with bimatoprost (25.3%) and 5.2 mm Hg (22.4%) with travoprost. At 16:00 h, the mean IOP reduction was 5.3 mm Hg (22.5%) with bimatoprost and 4.5 mm Hg (18.9%) with travoprost. Reduction of the intraocular pressure starts approximately 4 hours after the first administration with maximum effect reached within approximately 8 to 12 hours. Bimatoprost may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. In clinical trials, the most frequent events associated with the use of bimatoprost ophthalmic solutionoccurring in approximately 15% to 45% of patients, in descending order of incidence, included conjunctival hyperemia, growth of eyelashes, and ocular pruritus. Approximately 3% of patients discontinued therapy due to conjunctival hyperemia. These side effects, however, are not life-threatening and are reversible therefore, the safety of bimatoprost as therapy to primary open-angle glaucoma is still not in question.

Based on the above ESNA criteria of each drug under the category of prostaglandin analogs, bimatoprost acquired the highest points. Aside from this, there are also other evidences which led to the selection of bimatoprost as the p-drug for the treatment of primary open-angle glaucoma. Below is a meta-analysis of different studies comparing the IOP lowering ability of the three prostaglandin drugs:

It has been noted that bimatoprost is the most effective of the three. This, along with a lower cost for medication, makes it the prescribed drug for treatment of primary open-angle glaucoma.

SELECTING THE P-DRUG

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Surgery is indicated when glaucomatous optic neuropathy worsens (or is expected to worsen) at any given level of IOP and the patient is on maximum tolerated medical therapy (MTMT). MTMT varies considerably between individuals, and it may consist of medicines from 1 or several classes (including a beta-adrenergic antagonist, a prostaglandin agent, an alpha-agonist, and a topical carbonic anhydrase inhibitor). Some patients are observed to progress simply because compliance with the medical regimen becomes too difficult because of the following: high drug costs, inability to remember the schedule of multiple medications, inability to instill them in the eyes properly secondary to arthritis or other incapacitation (especially common among elderly patients or those with other chronic systemic conditions), or intolerable ocular and systemic adverse effects.

LASER TRABECULOPLASTY Argon Laser Trabeculoplasty Argon Laser Trabeculoplasty (ALT) was introduced as a treatment modality for open angle glaucoma because it has been demonstrated that argon laser treatment of angle structures could lower intraocular pressure (IOP) without causing full-thickness openings through the trabecular meshwork (TM) (Samples, 2011). Two theories have been presented as to how this procedure lowers the IOP. It is thought that (1) thermal energy directed towards the TM causes focal scarring of trabecular beams that constitute the TM, thereby opening up space in adjacent structures (mechanical theory), or that (2) inflammatory cytokines induce structural changes and allow repopulation of the TM with dividing trabecular epithelial cells from untreated areas, which are more effective in phagocytosis and produce a different composition of extracellular matrix with improved outflow facility properties (biological theory). Long-term studies such as that of Spaeth, et. al. have shown that ALT maintains IOP control in 67-80% of eyes 1 year after the procedure and in 35-50% of eyes 5 years after the procedure. ALT can be repeated, targeting the reminder of the TM (typically half of the angle is treated initially), but the effect to be expected is modest, especially if the first treatment session had poor outcomes. Selective Laser Trabeculoplasty Selective Laser Trabeculoplasty (SLT) is basically the same with ALT except only that it uses a lower power laser. SLT protects trabecular meshwork against thermal or

coagulative effects by selectively targeting only the pigmented cells and preserving surrounding tissue. Several prospective and retrospective studies indicate that SLT appears comparable to but not better than ALT in lowering IOP (Van de Veire, 2006). Selective laser trabeculoplasty also appears to be comparable in efficacy to medical therapy with prostaglandin analogs, although in one prospective study, SLT was only comparable to latanoprost when 360 degrees of the trabecular meshwork was treated. In this study, latanoprost had a better IOP-lowering effect compared with 90 and 180 degrees of treatment (Nagar, 2005).

INCISIONAL GLAUCOMA SURGERY Trabeculectomy Filtering surgery is effective in lowering IOP; it is generally indicated when medicine or laser therapy is insufficient to control disease and can be considered in selected cases as initial therapy. Filtering surgery provides an alternative path for the escape of aqueous humor, and it often reduces IOP and the need for medical treatment. Estimates of success rates over time range from 31% to 56% in different populations (Law, 2007). While long-term control is often achieved, many patients may require further therapy or a reoperation, which carries a higher failure rate (Law, 2009). Furthermore, filtering surgery increases the likelihood that phakic eyes may undergo cataract surgery. In eyes that have undergone previous cataract surgery involving the conjunctiva, the success rate of initial glaucoma surgery is reduced (Hylton, 2003). Aqueous Shunts All aqueous shunts (also known as tube shunts, glaucoma drainage devices, and setons) consist of a tube that diverts aqueous humor to an end plate located in the equatorial region of the eye. The primary resistance to flow through these devices occurs across the fibrous capsule that develops around the end plate. Aqueous shunts differ in their design with respect to the size, shape, and material from which the end plate is made. They may be further subdivided into valved and nonvalved shunts, depending on whether or not a valve mechanism is present to limit flow through the shunt if the IOP becomes too low. Aqueous shunts have traditionally been used to manage medically uncontrolled glaucoma when trabeculectomy has failed to control IOP or is deemed unlikely to succeed. This

NON-PHARMACOLOGIC INTERVENTIONS

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includes eyes with neovascular glaucoma, uveitic glaucoma, extensive conjunctival scarring from previous ocular surgery or cicatrizing diseases of the conjunctiva, and congenital glaucoma in which angle surgery has failed. However, the indications for using aqueous shunts have been broadening, and these devices are being increasingly utilized in the surgical management of glaucoma.

A systematic review concluded that aqueous shunts are comparable with trabeculectomy for IOP control and duration of benefit, that larger end-plate surface area provides better IOP control, and that there appears to be no advantage to the use of antifibrotic agents or systemic corticosteroids as adjuncts to aqueous shunt procedures (Minckler, 2008).

SAMPLE PRESCRIPTION

Bimatoprost 0.03% (Lumigan)

3mL/container #1 container

Sig: Instill one drop on the affected eye "once-daily" in the evening. Refill: None Warning: Stop medication and seek consult if the following occurs: eye itching, redness

and changes in color.

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