Dissertation Submitted to in Partial Fulfillment of the Regulations for The

A COMPARATIVE EVALUATION OF EFFICACY AND

TOLERABILITY OF FIXED DRUG COMBINATION OF

BRIMONIDINE AND TIMOLOL WITH TIMOLOL MONOTHERAPY

IN PATIENTS WITH PRIMARY OPEN-ANGLE GLAUCOMA: AN

OPEN LABELED PROSPECTIVE STUDY

Dissertation submitted to THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY

in partial fulfillment of the

regulations for the award of the degree of

M.D. (PHARMACOLOGY)

BRANCH – VI

GOVT. STANLEY MEDICAL COLLEGE & HOSPITAL

THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY

CHENNAI, INDIA

MAY 2019

CERTIFICATE

This is to certify that this dissertation entitled “A comparative evaluation of efficacy and tolerability of Fixed drug combination of Brimonidine and Timolol with Timolol monotherapy in patients with Primary Open-Angle Glaucoma: An Open Labeled Prospective Study” by the candidate Dr.SP.SUBAHAN, for M.D. (Pharmacology) is a bonafide record of the research work done by him under the guidance of Dr. R.JEYALALITHA, M.D., Professor, Department of Pharmacology, Government Stanley Medical College, during the period of study (2016- 2019), in the Department of Pharmacology, Government Stanley Medical College,Chennai-01. I also certify that this dissertation is the result of the independent work on the part of the candidate.

Dr.R.Jeyalalitha, M.D., Dr.M.Kulandaiammal, D.G.O., M.D., Professor, Professor & Head of the Department Department of Pharmacology Department of Pharmacology Govt.Stanley Medical College. Govt.Stanley Medical College.

Dr.S.Ponnambala Namasivayam, M.D., D.A., DNB

Dean Govt.Stanley Medical College Chennai.

DECLARATION

I hereby declare that this dissertation entitled in “A comparative evaluation of efficacy and tolerability of Fixed drug combination of Brimonidine and Timolol with Timolol monotherapy in patients with Primary Open-Angle Glaucoma: An Open Labeled Prospective Study” was written by me in the Department of Pharmacology, Government Stanley Medical College and Hospital, Chennai under the guidance and supervision of Dr.R.Jeyalalitha, M.D., Professor, Department of Pharmacology, Government Stanley Medical College, Chennai – 600 001. This dissertation is submitted to The Tamilnadu Dr. M.G.R. Medical University, Chennai in partial fulfillment of the university regulations for the award of Degree of M.D., Pharmacology(Branch -VI) Examination to be held in May 2019.

Date:

Place: Chennai Dr.SP.Subahan

ACKNOWLEDGEMENT

I express my sincere gratitude to Dr.S.Ponnambala Namasivayam

M.D., D.A., DNB., Dean, Govt. Stanley Medical College for permitting me to undertake this research work as a part of my MD curriculum.

I would like to convey my gratitude and indebtedness to

Dr.M.Kulandaiammal D.G.O., M.D., Professor and Head of the Department of

Pharmacology, Govt. Stanley Medical College for her sincere advice, unfailing support and attention throughout the study.

I owe my sincere thanks and appreciation to my guide Dr.R.Jeyalalitha

M.D., Professor, Department of Pharmacology, Govt. Stanley Medical College,

Chennai for her inspirational guidance and encouragement with which the dissertation has been prepared.

I would like to convey my gratitude to Dr.Baskar, M.S,D.O., Professor and Head of the Department of Ophthalmology, Govt.Stanley Medical College for permitting me to carry out this study in Ophthalmology department, Govt.Stanley medical college.

I express my sincere thanks to my Professors Dr.G.Hemavathy,M.D.,

Dr.R.Sivagami, M.D., and Dr.Baskaran, M.D., Department of Pharmacology for their constant support and advice.

I am thankful to Dr. M.Mohana Lakshmi D.G.O.,M.D., Dr.B.

Kalaimathi. M.D., Dr.N.Asvini M.D., Dr.M.Prakash M.D., Dr.M.Sangavai

M.D., Dr.B.Pushpa M.D., Dr.K.Thamayanthi M.D., Dr. C.R.Anuradha

D.G.O., M.D., Dr.J.Sam Anbu Sahayam D.L.O., M.D., Dr.R.Divakar M.D.,

Dr.Renuka Devi M.D., and Dr.Dharani Sudha M.D., for their unconditional co-operation and help.

I thank Dr.A.Preethi, Dr.G.vanitha, Dr.R.Punitha,

Dr.E.Tamilmathy and Dr.J.Vineeta Debbie Nesam, my fellow postgraduates for their help throughout this study.

I wish to place on record my gratitude to my parents and my family members for creating a congenial atmosphere and support when it was needed.

I thank all the staffs of the Department of pharmacology, Stanley medical college, for their cooperation in the completion of my study.

Finally I thank all my patients for willingly submitting themselves for this study.

CERTIFICATE-II

This is to certify that this dissertation work titled “A comparative evaluation of efficacy and tolerability of Fixed drug combination of

Brimonidine and Timolol with Timolol monotherapy in patients with

Primary Open-Angle Glaucoma: An Open Labeled Prospective Study” of the candidate Dr.SP.Subahan with registration number 201616052 for the award of M.D. Pharmacology in the branch of VI. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 5 percentage of plagiarism in the dissertation.

Guide & Supervisor sign with Seal

Dr.R.Jeyalalitha, M.D., Professor, Department of Pharmacology Govt.Stanley Medical College.

CONTENTS

S.No Title Page No

1. Introduction 12

2. Review of literature 15

3. Aim and Objectives 69

4. Methods 71

5. Results 81

6. Discussion 92

7. Conclusion 99

8. Bibliography 100

9. Annexures 107

ABBREVIATIONS

AAO -American Academy of Ophthalmology

ALT - Argon Laser Trabeculoplasty

CAIs -Carbonic Anhydrase Inhibitors

CB -Ciliary Body

CSLT -Confocal Scanning Laser Tomography

DLT -Diode Laser Trabeculoplasty

FDC -Fixed Drug Combination

HFA -Humphry Field Analyser

HRT -Hiedelberg Retinal Tomography

IOP -Intra Ocular Pressure

LTG -Low Tension Glaucoma

NFLA -Nerve Fibre Layer Analyser

NMDA -N Methyl-D-Aspartate

NTG -Normal Tension Glaucoma

OCT -Optical Coherence Tomography

OHTS -Ocular Hypertension Treatment Study

PAC -Primary Angle Closure

PACG -Primary Angle Closure Glaucoma

POAG -Primary Open Angle Glaucoma

RGC -Retinal Ganglion Cell

SL -Swalbe’s Line

SS -Scleral Spur

TM -Trabecular Meshwork

INTRODUCTION

Glaucoma, an optic neuropathy, is a worldwide leading cause of visual impairment and blindness1. It is a neurodegenerative disease associated with loss of Retinal Ganglion Cells and a raised intraocular pressure2 (IOP) which is the modifiable risk factor for glaucoma.

Glaucoma is an important cause of blindness in the developing world and a major health burden in the developed world. Glaucoma accounts for up to 8.2% of total visual loss in the world. It is also the leading cause of visual loss in India3. More than 85 percent of cases of glaucoma are remaining undiagnosed in India.

Raised intraocular pressure is an important known risk factor for the progression of visual field loss4 in patients with glaucoma.

Primary open angle glaucoma5 (POAG), is characterized by chronically elevated IOP with optic neuropathy and the cause is unknown for the elevated

IOP. It results from defective drainage of aqueous humor through the trabecular meshwork and uveoscleral pathways. Aqueous humor is formed by ciliary body and provides nourishment to anterior segment structures6.

Regardless of the cause of the disease, the aim of treatment is to control

IOP. Many clinical trials have proved that controlling IOP is an effective measure and prevents the development of glaucoma in patients with ocular hypertension and arrests the progression of established glaucoma.

Reduction of IOP with less complications or adverse effects remains the mainstay therapy for the first-line treatment of glaucoma7. Many anti glaucoma drugs achieve this control of IOP in glaucoma patients with a once- daily dose of a single drug. The preferred method is topical monotherapy8.

Initial management of glaucoma includes topical medications or laser treatment to control IOP. Frequently, more than one drug is required to achieve adequate control of IOP. Two or more medications are needed to reach a target IOP9 to arrest further visual loss in many patients with POAG.

The medical treatment approved for glaucoma management is IOP- reducing drugs10. The drugs commonly used to reduce IOP in glaucoma include topical prostaglandin analogues like bimatoprost, beta-blockers like timolol, alpha-agonists like brimonidine, carbonic anhydrase inhibitors like dorzolamide, and parasympathomimetics. The prostaglandin analogues are first choice of drugs used as initial monotherapy once-daily.

In recent years, fixed drug combinations11 have been approved for treatment of glaucoma. The available fixed combination drugs in the market are timolol 0.5% combined with bimatoprost, dorzolamide or brimonidine.

The benefits of fixed drug combinations are well achieved target IOP control, reduction in total amount of drug and preservative instilled per day, economic benefits, better tolerability and adherence, avoiding the washout effect resulting from simultaneous instillation of multiple medications concurrently. And also, this fixed drug combinations primarily promote the compliance of patients and persistence with treatment12. 13

Only IOP lowering treatment is not enough to prevent progressive vision loss as glaucoma is a multifactorial disorder. RGC damage and death are the final outcomes in untreated glaucoma. This urges an alternative treatment approach - neuroprotection approach to manage this problem more efficiently. Neuroprotection13 approach prevents neuronal injury or promotes neuronal recovery and protects the RGC from glaucomatous injuries.

Neuroprotective drugs are useful to prevent the damage of RGCs and destruction of optic nerve fibers. NMDA receptor antagonists, antioxidants, calcium channel blockers, nitric oxide synthase antagonists and gene therapy are used as neurotropic drugs14.

In Ocular Hypertension Treatment Study, more than 41% of the patients needed two or more medications after 4 years to achieve the target

IOP. In Collaborative Initial Glaucoma Treatment Study, 80% of the patients required two or more medications after 2 years15.

Therefore this study is undertaken with the aim to compare and evaluate the efficacy and safety of a fixed drug combination of 0.2% brimonidine and 0.5% timolol with the effect of 0.5% timolol administered as monotherapy in patients with POAG.

REVIEW OF LITERATURE

Definition:

The word glaucoma meant ‘clouded’ in Greek; it was referred either to a mature cataract or to corneal edema due to chronic elevated pressure.

Glaucoma is defined16 as a disturbance of the structural or functional integrity of the optic nerve that can usually be arrested or diminished by adequate lowering of IOP.

Glaucoma is not a single disease process but a diverse group of disorders characterized by a potentially progressive optic neuropathy resulting in a characteristic appearance of the optic disc, a specific pattern of irreversible visual field defects as damage progresses and frequently but not invariably associated with raised intraocular pressure (IOP) and in which IOP is a key modifiable factor.

The term ‘ocular hypertension’ is defined as a constantly raised IOP without any associated glaucomatous damage. The term normal or low tension glaucoma (NTG/LTG) is suggested for the typical cupping of the disc and visual field defects associated with a normal or low IOP.

POAG - Primary open-angle glaucoma is characterized by optic nerve atrophy and Retinal Ganglion Cell death. Anterior chamber angles are open in this multifactorial disorder17.

The primary glaucomas are bilateral, not associated with known ocular or other systemic disorders and genetic predispositions are common. The secondary glaucomas are unilateral and acquired, associated with ocular or other systemic abnormalities18.

Intraocular pressure is determined by the rate of aqueous humor production of the ciliary body and the resistance to aqueous outflow at the angle of the anterior chamber. IOP is increased due to obstruction to aqueous humor outflow.

The optic nerve and visual field changes of glaucoma are determined by the resistance to damage of the optic nerve axons. In most cases of glaucoma, progressive changes in the visual field and optic nerve are related to elevated IOP; Reducing IOP to the normal range arrests or halts the glaucoma progression.

Classification

Glaucomas are classified as congenital or acquired.

Open-angle and angle-closure types are differentiated based on the mechanism by which aqueous outflow is impaired with respect to the anterior chamber angle configuration. Glaucomas are also grouped into primary and secondary types19.

Clinico-etiologically glaucoma is classified as follows:

(A) Congenital and developmental glaucomas

1. Primary congenital glaucoma

2. Developmental glaucoma

(B) Primary adult glaucomas

1. Primary open angle glaucomas (POAG)

2. Primary angle closure glaucoma (PACG)

3. Primary mixed mechanism glaucoma

Epidemiology

Glaucoma affects 2–3% of people over the age of 40 years; 50% may be undiagnosed. Primary open-angle glaucoma is the most common form in white, Latino and black individuals; the prevalence20 is especially high in black people. Primary angle closure (PAC) has a particularly high prevalence in individuals of Asian descent. PAC is known to be more prevalent in

Caucasian Individuals.

Glaucoma is the second leading cause of blindness worldwide, with a disproportional morbidity among women and Asians21. Globally, POAG affects more people than angle closure glaucoma (ACG) – with an approximate ratio of 3:1.

The prevalence of glaucoma has been reported by the Vellore Eye

Survey, Andhra Pradesh Eye Disease Study, Aravind Comprehensive Eye

Survey, Chennai Glaucoma Study, and West Bengal Glaucoma Study. On the basis of the available data, there are approximately 11.2 million persons aged

40 years and older with glaucoma in India. Primary open angle glaucoma is estimated to affect 6.48 million persons.

It is estimated that there are more than 60 million cases of glaucoma worldwide and it will increase to 80 million by 2020. The estimated prevalence of glaucoma is 2.65% in people above 40 years of age22.

Primary Open-Angle Glaucoma (POAG) is more prevalent than primary angle closure glaucoma (PACG) and responsible for around three fourth of all glaucoma cases in the world. Overall glaucoma is the second major cause of blindness after cataract and refractive errors. More importantly it is the most common cause of irreversible blindness globally.

It is estimated that more than 3 million people are blind due to glaucoma.

In India, the estimated number of cases of glaucoma is 12 million, around one fifth of the global burden of glaucoma.

Ocular Structures

Pathophysiology of glaucoma revolves around the aqueous humour dynamics23. The principal ocular structures concerned with it are ciliary body, angle of anterior chamber and the aqueous outflow system.

Ciliary body

It is the seat of aqueous production.

Angle of anterior chamber

Angle of anterior chamber plays an important role in the process of aqueous drainage. It is formed by root of iris, anterior-most part of ciliary body, scleral spur, trabecular meshwork and Schwalbe’s line (prominent end of Descemet’s membrane of cornea).

The angle width varies in different individuals and plays a vital role in the pathomechanism of different types of glaucoma. Clinically the angle structures can be visualised by gonioscopic examination. 19

Section of the anterior ocular structures showing region of the anterior chamber

Gonioscopic grading of the angle width:

The most commonly used system is the Shaffer’s system24 of grading the angle width.

Shaffer’s system of grading the angle width

Diagrammatic depiction of various angle structures (SL, Schwalbe's line;

TM, trabecular meshwork; SS, sclera spur; CBB, ciliary body band; ROI, root of iris) as seen in different grades of angle width (Schaffer's grading system):

Gonioscopic view

The van Herick method25 uses the slit lamp alone to estimate the AC angle width:

A thin but bright slit beam is set approximately perpendicularly to the corneal surface to the patient’s temporal side for each eye.

○ The beam is used to estimate the ratio of the corneal thickness to the most peripheral part of the AC.

○ It is useful as a screening tool, but overestimates angle width in a proportion of patients, particularly those with a plateau iris conformation.

Van Herick method for anterior chamber angle assessment

Aqueous outflow system

It includes the trabecular meshwork, Schlemm’s canal, collector channels, aqueous veins and the episcleral veins.

Aqueous outflow system

1. Trabecular meshwork: It is a sieve-like structure through which aqueous humour leaves the eye. It consists of three portions.

i. Uveal meshwork - It is the innermost part of trabecular meshwork

ii. Corneoscleral meshwork - It forms the larger middle portion

iii Juxtacanalicular (endothelial) meshwork – It forms the outermost portion of meshwork which offers the normal resistance to aqueous outflow.

2. Schlemm’s canal: This is an endothelial lined oval channel present circumferentially in the scleral sulcus.

3. Collector channels: These are about 25-35 in number and leave the

Schlemm’s canal to terminate into episcleral veins.

AQUEOUS HUMOUR DYNAMICS

The physiological processes concerned with the dynamics26 of aqueous humour are its production, drainage and maintenance of intraocular pressure.

Aqueous humour and its production

Volume:

The aqueous humour is a clear watery fluid filling the anterior chamber

(0.25 ml) and posterior chamber (0.06 ml) of the eyeball.

Functions:

- maintains a proper intraocular pressure.

- plays an important metabolic role by providing substrates and by removing metabolites from the avascular cornea and lens.

- maintains optical transparency.

- takes the place of lymph that is absent within the eyeball.

Production:

Aqueous humour is derived from plasma within the capillary network of ciliary processes. The normal aqueous production rate is 2.3 μl/min. The three mechanisms diffusion, ultrafiltration and secretion play a part in its production at different levels. Secretion is subject to the influence of the sympathetic nervous system, with opposing actions mediated by beta-2 receptors (increased secretion) and alpha-2 receptors (decreased secretion).

Enzymatic action – carbonic anhydrase is playing a key role.

Drainage of aqueous humour

Aqueous humour flows from the posterior chamber into the anterior chamber through the pupil against slight physiologic resistance. From the anterior chamber the aqueous is drained out by two routes

1. Trabecular (conventional) outflow (90%)

2. Uveoscleral (unconventional) outlow (10%)

Diagrammatic depiction of aqueous drainage

Maintenance of intraocular pressure

The intraocular pressure (IOP) refers to the pressure exerted by intraocular fluids on the coats of the eyeball. The normal IOP varies between

10 and 21 mm of Hg (mean 16 ± 2.5 mm of Hg). The average IOP in the general population is around 16 mmHg on applanation tonometry. The normal level of IOP is essentially maintained by a dynamic equilibrium between the formation and outflow of the aqueous humour.

Factors influencing IOP

(A) Local factors

1. Rate of aqueous formation

2. Resistance to aqueous outflow - From clinical point of view, this is the most important factor. Most of the resistance to aqueous outflow is at the level of trabecular meshwork.

3. Increased episcleral venous pressure may result in rise of IOP. The

Valsalva manoeuvre causes temporary increase in episcleral venous pressure and rise in IOP.

4. Dilatation of pupil in patients with narrow anterior chamber angle may cause rise of IOP owing to a relative obstruction of the aqueous drainage by the iris.

(B) General factors

1. Heredity - influences IOP, by multifactorial ways.

2. Age: The mean IOP increases after the age of 40 years, due to reduced facility of aqueous outflow.

3. Sex: IOP is equal between the sexes in ages 20- 40 years. In older age groups increase in mean IOP with age is greater in females.

4. Diurnal variation of IOP: Normal IOP varies with time of day (diurnal variation), heartbeat, blood pressure and respiration. Usually, there is a tendency of higher IOP in the morning and lower in the evening. This has been related to diurnal variation in the levels of plasma cortisol. Normal eyes have a smaller fluctuation (< 5 mm of Hg) than glaucomatous eyes (> 8 mm of Hg).

5. Postural variations: IOP increases when changing from the sitting to the supine position.

6. Blood pressure does not have chronic effect on IOP. But, prevalence of glaucoma is marginally more in hypertensives than the normotensives.

7. Osmotic pressure of blood: An increase in plasma osmolarity (after intravenous mannitol, oral glycerol) is associated with a fall in IOP, while a reduction in plasma osmolarity is associated with a rise in IOP.

8. General anaesthetics and some drugs also influence IOP e.g., alcohol lowers IOP, tobacco smoking, caffeine and steroids may cause rise in IOP.

PATHOGENESIS OF GLAUCOMA

All glaucomas are characterized by a progressive optic neuropathy. It has been recognized that progressive optic neuropathy results from the death of retinal ganglion cells (RGCs) in a typical pattern which results in characteristic optic disc appearance and specific visual field defects.

Pathogenesis of retinal ganglion cell death

Retinal ganglion cell (RGC) death27 is initiated when the transport of growth factors (neurotrophins) from the brain to the RGCs is blocked by some pathologic events. The blockage of these neurotrophins initiates a damaging cascade, and the cell is not able to maintain its normal function. The RGCs losing their ability to maintain normal function undergo apoptosis and trigger apoptosis of adjacent cells. Retinal ganglion cell death is associated with loss of retinal nerve fibers. The characteristic optic disc changes and specific visual field defects become apparent over the time.

Etiological factors

Factors involved in the etiology of retinal ganglion cell death and in the etiology of glaucomatous optic neuropathy can be grouped as primary and secondary insults.

A. Primary insults

1. Raised intraocular pressure (Mechanical theory)

Raised intraocular pressure causes mechanical stretch on the lamina cribrosa leading to axonal deformation and ischaemia by altering capillary blood flow. As a result of this, neurotrophins are not able to reach the retinal ganglion cell bodies in sufficient amount needed for their survival.

2. Pressure independent factors (Vascular insufficiency theory)

Factors affecting vascular perfusion of optic nerve head in the absence of raised IOP have been implicated in the glaucomatous optic neuropathy in patients with normal tension glaucoma.

B. Secondary insults (Excitotoxicity theory)

Neuronal degeneration is believed to be driven by toxic factors such as glutamate (excitatory toxin), oxygen free radicals, or nitric oxides which are released when RGCs undergo death due to primary insults.

PRIMARY OPEN ANGLE GLAUCOMA

It is a type of primary glaucoma, where there is no obvious systemic or ocular cause of rise in the intraocular pressure. It occurs in eyes with open angle of the anterior chamber.

Primary open angle glaucoma also known as chronic simple28 glaucoma of adult onset and is typically characterized by slowly progressive raised intraocular pressure (>21 mmHg recorded on at least a few occasions) associated with characteristic optic disc cupping and visual field defects.

Etiopathogenesis of POAG is not known, idiopathic.

(A) Predisposing and risk factors

1. Heredity - POAG has a polygenic inheritance. The approximate risk of getting disease is 10% in the siblings, and 4% in the offspring of patients with

POAG.

2. Age - The risk increases with increasing age. The POAG is more commonly seen in elderly between 5th and 7th decades.

3. Race - POAG is significantly more common, develops earlier and is more severe in black people than in white.

4. Myopes are more predisposed than the normals.

5. Diabetics have a higher prevalence of POAG than non-diabetics.

6. Cigarette smoking is also thought to increase its risk.

7. High blood pressure is not the cause of rise in IOP.

8. Thyrotoxicosis is also not the cause of rise in IOP, but the prevalence of

POAG is more in patients suffering from Graves’ ophthalmic disease than the normals.

(B) Pathogenesis of rise in IOP

It is certain that rise in IOP occurs due to decrease in the aqueous outflow facility due to increased resistance to aqueous outflow caused by age- related thickening and sclerosis of the trabeculae and an absence of giant vacuoles in the cells lining the canal of Schlemm.

Patients with POAG and their offspring and sibilings are more likely to respond to six weeks topical steroid therapy with a significant rise of IOP.

INCIDENCE OF POAG

It varies in different populations. In general, it affects about 1 in 100 of the general population (of either sex) above the age of 40 years29. It forms about one third cases of all glaucomas.

CLINICAL FEATURES

Symptoms

1. The disease is insidious and usually asymptomatic, until it has caused a significant loss of visual field.

2. Patients may experience mild headache and eye ache.

3. Occasionally, patient may notice a defect in the visual field.

4. Reading and close work often present increasing difficulties. Therefore, patients usually complain of frequent changes in presbyopic glasses.

5. Patients develop delayed dark adaptation

Signs

I. Anterior segment signs - Slit-lamp biomicroscopy may reveal normal anterior segment. In late stages pupil reflex becomes sluggish and cornea may show slight haze.

II. Intraocular pressure changes - In the initial stages the IOP may not be raised permanently, but there is an exaggeration of the normal diurnal variation. Therefore, repeated observations of IOP (every 3-4 hour), for 24 hours is required during this stage. In most patients IOP falls during the evening. A variation in IOP of over 5 mm Hg (Schiotz) is suspicious and over

8 mm of Hg is diagnostic of glaucoma. In later stages, IOP is permanently raised above 21 mm of Hg and ranges between 30 and 45 mm of Hg.

III. Optic disc changes - Optic disc changes, usually observed on routine fundus examination, provide an important clue for suspecting POAG. These are typically progressive, asymmetric and present a variety of characteristic clinical patterns. It is essential to record the appearance of the nerve head which will accurately reveal subtle glaucomatous changes over the course of follow-up evaluation.

Examination techniques - Careful assessment of disc changes can be made by direct ophthalmoscopy, slitlamp biomicroscopy using a + 90D lens, Hruby lens or Goldmann contact lens and indirect ophthalmoscopy.

The recording and documentation techniques include serial drawings, photography and photogrammetry. Confocal scanning laser topography

(CSLT) i.e., Heidelberg retinal tomograph (HRT) is an accurate and sensitive method for this purpose. Other advanced imaging techniques include optical coherence tomography (OCT) and scanning laser polarimetry i.e., Nerve fibre analyser (NFA).

Glaucomatous changes in the optic disc can be described as early changes, advanced changes and glaucomatous optic atrophy30.

NORMAL OPTIC DISC

GLAUCOMATOUS OPTIC DISC

(A) Early glaucomatous changes

1. Vertically oval cup due to selective loss of neural rim tissue in the inferior and superior poles.

2. Asymmetry of the cups - A difference of more than 0.2 between two eyes is significant.

3. Large cup i.e., 0.6 or more (normal cup size is 0.3 to 0.4) may occur due to concentric expansion.

4. Splinter haemorrhages present on or near the optic disc margin.

5. Pallor areas on the disc.

6. Atrophy of retinal nerve fiber layer

Early glaucomatous changes

(B) Advanced glaucomatous changes in the optic disc:

1. Marked cupping (cup size 0.7 to 0.9), excavation may even reach the disc margin, and the sides are steep and not shelving.

2. Thinning of neuroretinal rim which occurs in advanced cases is seen as a crescentric shadow adjacent to the disc margin.

3. Nasal shifting of retinal vessels which have the appearance of being broken off at the margin is an important sign (Bayonetting sign).

4. Pulsations of the retinal arterioles may be seen at the disc margin (a pathognomic sign of glaucoma), when IOP is very high.

5. Lamellar dot sign the pores in the lamina cribrosa are slit-shaped and are visible up to the margin of the disc.

Advanced glaucomatous changes

(C) Glaucomatous optic atrophy - As the damage progresses, all the neural tissue of the disc is destroyed and the optic nerve head appears white and deeply excavated.

Pathophysiology of disc changes - Both mechanical and vascular factors play a role in the cupping of the disc.

 Mechanical effect of raised IOP forces lamina cribrosa backwards and

squeezes nerve fibres within its meshes to disturb axoplasmic flow.

 Vascular factors contribute in ischaemic atrophy of the nerve fibres

without corresponding increase of supporting glial tissue. As a result,

large caverns or lacunae are formed (cavernous optic atrophy).

Glaucomatous optic atrophy

IV. Visual field defects - run parallel to the changes at the optic nerve head and continue to progress if IOP is not controlled. These can be described as early and late field defects.

Progression of field defects - Visual field defects in glaucoma are initially observed in Bjerrum’s area (10 - 25 degree from fixation) and correlate with optic disc changes. The natural history of the progressive glaucomatous field loss, more or less, takes the following sequence:

1. Isopter contraction refers to mild generalized constriction of central as well as peripheral field.

2. Baring of blind spot is an early glaucomatous change

3. Small wing-shaped paracentral scotoma is the earliest clinically significant field defect. It appears either below or above the blind spot in Bjerrum's area

4. Seidel’s scotoma - With the passage of time paracental scotoma joins the blind spot to form a sickle shaped scotoma known as Seidel’s scotoma

5. Arcuate or Bjerrum’s scotoma is formed at a later stage by the extension of

Seidel’s scotoma in an area either above or below the fixation point to reach the horizontal line.

6. Ring or double arcuate scotoma develops when the two arcuate scotomas join together

Visual Field Defects

Field defects in POAG: A, Baring of blind spot; B, superior paracentral scotoma; C, Seidel's scotoma; D, Bjerrum's scotoma; E, double arcuate scotoma and Roenne's central nasal step.

7. Roenne's central nasal step is created when the two arcuate scotomas run in different arcs to form a sharp right-angled defect at horizontal meridian.

8. Peripheral field defects - These appear sometimes at an early stage and sometimes only late in the disease. The peripheral nasal step of Roenne's results from unequal contraction of the peripheral isopter.

9. Advanced glaucomatous field defects - The visual field loss gradually spreads centrally as well as peripherally, and eventually only a small island of central vision (tubular vision)31 and an accompanying temporal island are left.

The temporal island of the vision is more resistant and is lost in the end leaving the patient with no light perception.

Diagnosis of glaucoma field defects on HFA single field printout:

Glaucomatous field defects should always be interpreted in conjunction with clinical features (IOP and optic disc changes). Further, before final interpretation, the fields must be tested twice, as there is often a significant improvement in the field when plotted second time. The standard HFA single field printout is obtained using a software called Statpac printout. For the purpose of evaluation, the Humphry single-field printout32 (Statpac printout) with central 30-2 test can be studied in eight parts or zones I to VIII.

Criteria to grade glaucomatous field defects: The criteria to label early, moderate and severe glaucomatous field defect from the HFA central 30-2 test

INVESTIGATIONS

1. Tonometry - Applanation tonometry and Schiotz tonometry33

techniques are used to measure IOP.

Technique of Schiotz tonometry

Schiotz tonometer is an indentation tonometer, measuring the intraocular pressure (IOP) by measuring the depth produced on the surface of the cornea by a load of a known weight. The indentation of corneal surface is indirectly proportional to the IOP.

Technique of Applanation Tonometry

Applanation tonometry. Contact between the tonometer prism and

the cornea

Fluorescein-stained semicircular mires – the diagram at right shows the correct end-point using mires of appropriate thickness

2. Diurnal variation test is especially useful in detection of early cases.

3. Gonioscopy is a method of evaluating the AC angle34, and can be used therapeutically for procedures such as laser trabeculoplasty and goniotomy. It reveals a wide open angle of anterior chamber. Its primary importance in

POAG is to rule out other forms of glaucoma.

Goldmann goniolens - Three mirrors

4. Documentation of optic disc changes is of utmost importance

5. Slit-lamp examination of anterior segment to rule out causes of secondary open angle glaucoma.

6. Perimetry and Bjerrum’s screen to detect the visual field defects35.

Bjerrum’s screen

Humphrey field analyser

Automated perimeter

Humphrey Perimetry – SITA-Fast printout

7. Nerve fibre layer analyzer (NFLA) is a recently introduced device which helps in detecting the glaucomatous damage to the retinal nerve fibres before the appearance of actual visual field changes and/or optic disc changes.

8. Provocative tests are required in border-line cases. The test commonly performed is water drinking test

IMAGING IN GLAUCOMA

Pachymetry

The measurement of corneal thickness36, in recent years has become an essential part of the assessment of glaucoma patients. Ultrasonic (e.g.

Pachmate) and optical methods are available.

Stereo disc photography

It has historically been regarded as the reference standard in optic disc imaging, and remains a valuable option. The images are taken by repositioning slightly between shots, either manually or using a stereo separator built into the camera.

Optical coherence tomography

OCT has become a routine part of the management of macular and other retinal disease; the same machine can be used for the assessment of glaucoma

Glaucoma-protocol OCT showing optic nerve head, peripapillary retinal nerve fibre layer and ganglion cell complex analysis

Confocal Scanning Laser Ophthalmoscopy

Heidelberg Retinal Tomograph of a glaucomatous eye

DIAGNOSIS

Depending upon the level of intraocular pressure (IOP), glaucomatous cupping of the optic disc and the visual field changes the patients are assigned to one of the following diagnostic entities:

Triad of abnormalities in disc, field and intraocular pressure (IOP) for the diagnosis of glaucoma37.

1. Primary open angle glaucoma (POAG)

Characteristically - raised IOP ( >21 mm of Hg) associated with definite glaucomatous optic disc cupping and visual field changes.

2. Ocular hypertension or glaucoma suspect - IOP constantly more than

21 mm of Hg but no optic disc or visual field changes

3. Normal tension glaucoma (NTG) or low tension glaucoma (LTG) -

Typical glaucomatous disc cupping with or without visual field changes is associated with an intraocular pressure constantly below 21 mm of Hg.

MANAGEMENT

General considerations

Baseline evaluation and grading of severity of glaucoma:

The aim of treatment is to lower intraocular pressure to a level where

(further) visual loss does not occur. It is important to perform a good baseline examination with which future progress can be compared. The initial data should include: visual acuity, slit-lamp examination of anterior segment, tonometry; optic disc evaluation, gonioscopy and visual field charting.

American Academy of Ophthalmology (AAO) grades severity38 of glaucoma damage into mild, moderate and severe.

Severity of glaucoma damage

Therapeutic Modalities of POAG:

I. Medical therapy – Antiglaucoma drugs

II. Argon or diode laser trabeculoplasty

III. Filteration surgery.

I. Medical therapy

- Antiglaucoma drugs39

Classification

A. Parasympathomimetic drugs (Miotics)

B. Sympathomimetic drugs (Adrenergic agonists)

C. β-blockers

D. Carbonic anhydrase inhibitors

E. Hyperosmotic agents

F. Prostaglandins

G. Calcium channel blockers

A. Parasympathomimetic drugs (Miotics)

Also called as cholinergic drugs39, stimulate the effects of acetylcholine.

Classification

Depending upon the mode of action, these can be classified as follows:

1. Direct-acting or agonists e.g., pilocarpine 1%, 2%, 4% eye drops

2. Indirect-acting parasympathomimetics or cholinesterase inhibitors:

Reversible (e.g., physostigmine 0.5%) and irreversible (e.g., echothiophate iodide, demecarium and diisopropyl-fluoro-phosphate, DFP3) anticholinesterases.

3. Dual-action parasympathomimetics, i.e., which act as both a muscarinic agonist as well as a weak cholinesterase inhibitor e.g., carbachol 0.75%, 3% eye drops

Mechanism of action

1. In primary open-angle glaucoma the miotics reduce the intraocular pressure (IOP) by increasing the aqueous outflow facility. This is achieved by changes in the trabecular meshwork produced by a pull exerted on the scleral spur by contraction of the longitudinal fibres of ciliary muscle.

2. In primary angle-closure glaucoma these reduce the IOP due to their miotic effect by opening the angle. The mechanical contraction of the pupil moves the iris away from the trabecular meshwork.

Side-effects

1. Systemic side-effects noted are: bradycardia, increased sweating, diarrhoea, excessive salivation anxiety.

2. Local side-effects are reduced visual acuity in the presence of polar cataracts, impairment of night vision and generalized contraction of visual fields, spasm of accommodation which may cause myopia and frontal headache, retinal detachment, lenticular opacities, iris cyst formation, mild iritis, lacrimation and follicular conjunctivitis.

B. Sympathomimetic drugs

Also known as adrenergic agonists40, act by stimulation of alpha, beta or both the receptors.

Classification

Depending upon the mode of action, these can be classified as follows:

1. Both alpha and beta-receptor stimulators e.g., epinephrine 0.5%, 1%, 2% eye drops, dipivefrine 0.1%

2. Direct alpha-adrenergic stimulators e.g., norepinephrine, clonidine hydrochloride 0.125%, 0.25%, brimonidine 0.2% and apraclonidine 0.5%,

1% eye drops

3. Indirect alpha-adrenergic stimulators e.g., pargyline.

4. Beta-adrenergic stimulator e.g., isoproterenol.

Mechanisms of action

1. Increased aqueous outflow results by virtue of both alpha and beta-receptor stimulation.

2. Decreased aqueous humour production occurs due to stimulation of alpha- receptors in the ciliary body.

Side-effects

1. Systemic side-effects include hypertension, tachycardia, headache, palpitation, tremors, nervousness and anxiety.

2. Local side-effects are burning sensation, reactive hyperemia of conjunctiva, conjunctival pigmentation, allergic blepharo-conjunctivitis, mydriasis and cystoid macular oedema (in aphakics).

C. Beta-adrenergic blockers

These are, currently, the most frequently used antiglaucoma drugs. The commonly used preparations41 are timolol 0.25%, 0.5% and betaxolol 0.25%,

0.5%. Other available preparations include levobunolol, carteolol and metipranolol.

Mechanism of action:

The drugs timolol and levobunolol lower IOP by blockade of beta-2 receptors in the ciliary processes, resulting in decreased aqueous production. The exact mechanism of action of betaxolol (cardioselective beta-blocker) is unknown.

Side-effects

1. Ocular side-effects include burning and conjunctival hyperaemia, superficial punctate keratopathy and corneal anaesthesia.

2. Systemic side-effects include (i) Cardiovascular effects due to blockade of beta-1 receptors are bradycardia, arrhythmias, heart failure and syncope.

(ii) Respiratory reactions due to blockade of beta-2 receptors are bronchospasm and airway obstruction, especially in asthmatics.

(iii) Central nervous system effects include depression, anxiety, confusion, drowsiness, disorientation, hallucinations, emotional lability and dysarthria

(iv) Miscellaneous effects are nausea, diarrhoea, decreased libido, skin rashes, alopecia and exacerbation of myasthenia gravis.

(D) Carbonic anhydrase inhibitors (CAIs)

These are potent and most commonly used systemic antiglaucoma drugs.

These include acetazolamide (most frequently used), methazolamide, dichlorphenamide and ethoxzolamide.

Topical42 CAIs are dorzolamide 2% and brinzolamide 1%

Mechanism of action: CAIs inhibit the enzyme carbonic anhydrase which is

Related to the process of aqueous humour production. Thus, CAIs lower the

IOP by reducing the aqueous humour formation.

E. Hyperosmotic agents

These include: glycerol, mannitol, isosorbide and urea. These are the second class of compounds, which are administered systemically to lower the IOP.

Mechanism of action: Hyperosmotic agents increase the plasma tonicity.

Thus, the osmotic pressure gradient created between the blood and vitreous draws sufficient water out of the eyeball, thereby significantly lowering the

IOP.

F. Prostaglandin derivatives

1. Latanoprost (0.005%). It is a synthetic drug, an ester analogue of prostaglandin F2-α. It s acts by increasing uveoscleral outflow and by causing reduction in episcleral venous pressure. It is as effective as timolol. It has additive effect43 with pilocarpine and timolol. Its duration of action is 24 hours and is administered once daily. Its side effects include conjunctival hyperaemia, foreign body sensation and increased pigmentation of the iris.

2. Bimatoprost (0.03%). It is a prostamide which decreases IOP by decreasing ocular outflow resistance. It is also used once a day (OD).

3. Travoprost (0.004%). It is a synthetic prostaglandin F2 analogue and decreases IOP by increasing uveoscleral outflow of aqueous.

4. Unoprostive isopropyl (0.12%) It lowers IOP by increasing uveoscleral outflow of aqueous. It also increases retinal blood flow.

G. Calcium channel blockers

Nifedipine, diltiazem and verapamil are commonly used antihypertensive drugs. Recently, some of these have been used as anti-glaucoma drugs. It has a place in the management of patients with POAG, where miotics, beta- blockers and sympathomimetics are all contraindicated. It can also be used for additive effect45 with pilocarpine and timolol.

Mechanism of action: The exact mechanism of lowering IOP of topically used remains to be elucidated. It might be due to its effects on secretory ciliary epithelium.

Dosage: Verapamil 0.125 percent and 0.25 percent eyedrops twice a day.

FIXED DOSE DRUG COMBINATIONS (FDC)

Combined preparations46 with similar ocular hypotensive effects to the sum of the individual components improve convenience and patient compliance.

They are also more cost effective.

Examples include:

• Timolol 0.5% and Dorzolamide 2%, administered twice daily.

• Timolol 0.5% and Latanoprost 0.005% once daily.

• Timolol 0.5% and Brimonidine 0.2% twice daily.

• Timolol 0.5% and Brinzolamide 1% twice daily.

• Brimonidine 0.2% and Brinzolamide 1%; a new combination - the only one that does not contain the beta-blocker timolol; administered twice daily.

TREATMENT GOALS

Target pressure:

An IOP level is identified below which further damage is considered unlikely: the target pressure47. This is identified taking into account the severity of existing damage, the level of IOP, CCT, the rapidity with which damage occurred if known, and the age and general health of the patient.

Therapy should maintain the IOP at or below the target level. If not achievable by more conservative measures, a decision is made regarding whether to proceed with surgery or to continue monitoring with an above-target IOP.

• Proportional reduction: An alternative strategy is to aim for a reduction in

IOP by 30% – and then monitor, aiming for a further reduction if progression occurs. Although it is not possible to predict the safe level of IOP, progression is uncommon if IOP is maintained at less than 16 to 18 mm of Hg in patients having mild to moderate damage. Lower target pressures (12-14 mmHg) are required in patients with severe damage.

• Response to progression: As damage progresses the loss of each remaining ganglion cell has a greater proportional impact on visual function, and there is less reserve capacity. If damage progresses despite a target pressure having been reached consistently, the target IOP is set to a lower level; there is evidence that each 1 mmHg reduction in IOP leads to a 10% reduction in the rate of nerve fibre loss48. If further damage is sustained despite apparently good IOP control, surgery may be appropriate.

TREATMENT REGIMES

A. Single drug therapy

1. Topical beta-blockers are being recommended49 as the first drug of choice for medical therapy of POAG in low socio-economic patients. These lower

IOP by reducing the aqueous secretion due to their effect on beta - receptors in the ciliary processes.

Preparations:

 Timolol maleate (0.25, 0.5%: 1-2 times/day) is most popular as initial

therapy. it should not be used in patients having associated bronchial

asthma and/or heart blocks50.

 Betaxolol (0.25%: 2 times/day). Being a selective beta-1 blocker it is

preferred as initial therapy in patients with cardiopulmonary problems.

 Levobunolol (0.25, 0.5%: 1-2 times/day). Its action lasts the longest

and so is more reliable for once a day use than timolol.

 Carteolol (1%: 1-2 times/day). It raises triglycerides and lowers high

density lipoproteins the least. Therefore, it is the best choice in patients

with POAG having associated hyperlipidemias or atherosclerotic

cardiovascular disease.

2. Pilocarpine (1, 2, and 4%: 3-4 times/day). It is a very effective drug.

Presently it is not being preferred as the first drug of choice or even as second choice. It is because of the fact that in younger patients it causes problems due to spasm of accommodation and miosis51. Currently pilocarpine is being

considered only as an adjunctive therapy52 where other combinations fail and as second choice in poor patients.

Mechanism of action: Pilocarpine contracts longitudinal muscle of ciliary body and opens spaces in trabecular meshwork, thereby mechanically increasing aqueous outflow.

3. Latanoprost (0.005%: once daily). It is a prostaglandin analogue and decreases the IOP by increasing the uveo-scleral outflow of aqueous.

Presently, it is being considered the drug of first choice53 for the treatment of

POAG. Therefore, it is a very good adjunctive drug to beta-blockers, dorzolamide and even pilocarpine when additional therapy is indicated.

4. Dorzolamide (2%: 2-3 times/day). It is a recently introduced topical carbonic anhydrase inhibitor54 which lowers IOP by decreasing aqueous secretion. It has replaced pilocarpine as the second line of drug and even as an adjunct drug.

5. Adrenergic drugs: Role55 in POAG is as follows: i. Epinephrine hydrochloride (0.5, 1, 2%: 1-2 times/ day) and Dipivefrine hydrochloride (0.1%: 1-2 times/day). These drugs lower the IOP by increasing aqueous outflow by stimulating beta receptors in the aqueous outflow system. Dipivefrine may be combined with beta-blockers in patients where other drugs are contraindicated. ii. Brimonidine (0.2%: 2 times/day). It is a selective alpha-2-adrenergic agonist and lowers IOP by decreasing aqueous production. It is used as second drug of choice and also for combination therapy with other drugs. 61

B. Combination topical therapy

If one drug is not effective, then a combination of two drugs—one drug which decreases aqueous production (timolol or other betablocker, or brimonidine or dorzolamide) and other drug which increase aqueous outflow (latanoprost or brimonidineor pilocarpine) may be used.

C. Role of oral carbonic anhydrase inhibitors in POAG

Acetazolamide and methazolamide are not recommended for long-term use56 because of their side effects. However, these may be added to control IOP for short term.

II. Argon or diode laser trabeculoplasty (ALT or DLT)

It should be considered in patients where IOP is uncontrolled despite maximal tolerated medical therapy57. It can also be considered as primary therapy where there is non-compliance to medical therapy. It has an additive effect to medical therapy. Its hypotensive effect is caused by increasing outflow facility, possibly by producing collagen shrinkage on the inner aspect of the trabecular meshwork and opening the intra-trabecular spaces. It has been shown to lower IOP by 8-10 mm of Hg in patients on medical therapy and by 12-16 mm in patients who are not receiving medical treatment. SLT is often as effective as medical monotherapy, and has been gaining in popularity as a first-line treatment.

III. Surgical therapy

Indications

1. Uncontrolled glaucoma despite maximal medical therapy and laser trabeculoplasty.

2. Non-compliance of medical therapy and non availability of ALT.

3. Failure with medical therapy and unsuitable for ALT either due to lack of cooperation or inability to visualize the trabeculum.

4. Eyes with advanced disease i.e., having very high IOP, advanced cupping and advanced field loss should be treated with filtration surgery as primary line of management.

Types of surgery

Surgical treatment of POAG primarily consists of a fistulizing

(filtration) surgery which provides a new channel for aqueous outflow and successfully controls the IOP (below 21 mm of Hg). Trabeculectomy58 is the most frequently performed filtration surgery now-a-days.

STUDY DRUGS

1. Timolol

2. Brimonidine

TIMOLOL

Timolol is a potent, non-selective β receptor antagonist. It has no intrinsic sympathomimetic or membrane-stabilizing activity59. It is used for hypertension, congestive heart failure, acute MI, and migraine prophylaxis.

Substitution of an isopropyl group or other bulky substituent on the amino nitrogen favors interaction with β receptors. There is a rather wide tolerance for the nature of the aromatic moiety in the nonselective β receptor antagonists.

In ophthalmology, timolol has been used in the treatment of open-angle glaucoma and intraocular hypertension. Its mechanism of action in treating open angle glaucoma is not precisely known; but the drug appears to reduce aqueous humour production through blockade of β receptors on the ciliary epithelium60.

In approximately 10% of cases the response decreases with time

(tachyphylaxis), sometimes within only a few days. There may be limited supplementary effect if a topical timolol is added when a patient already takes a systemic beta-blocker; the combination may also involve a relatively high risk of systemic side effects.

Beta-blockers should not be instilled at bedtime61 as they may cause a profound drop in blood pressure while the individual is asleep, thus reducing optic disc perfusion and potentially causing visual field deterioration; the IOP- lowering effect is also believed to be less marked during sleep, as nocturnal aqueous production is normally less than half the daytime rate.

Timolol is available in various forms, including 0.25% and 0.5% solutions used twice daily; there is no evidence of a clinically significant difference in efficacy between the two solution concentrations. Gel-forming preparations of 0.1%, 0.25% and 0.5% are used once daily.

Absorption, Fate, and Excretion: Timolol is well absorbed from the GI tract. It is metabolized extensively by CYP2D6 in the liver and undergoes first-pass metabolism. Only a small amount of unchanged drug appears in the urine. The t1/2 in plasma is ~4 hours.

Ocular formulation62 of timolol, used for the treatment of glaucoma, may be extensively absorbed systemically; adverse effects can occur in susceptible patients, such as those with asthma or congestive heart failure. The systemic administration of cimetidine with topical ocular timolol increases the degree of β blockade, resulting in a reduction of resting heart rate, intraocular pressure, and exercise tolerance.

For ophthalmic use Timolol is available combined with other medications (e.g., with dorzolamide or travoprost or brimonidine).

Timolol also provide benefits to patients with coronary heart disease63: in the acute post MI period, timolol produced a 39% reduction in mortality in the Norwegian Multicenter Study.

Side effects

• Ocular - Ocular side effects are allergy and punctate keratitis.

• Systemic - Though severe problems are extremely rare, numerous deaths have been associated with topical betablocker use.

 Bronchospasm - This may be fatal63 in asthma or other reversible

airways disease. About 1 in 50 patients without asthma will develop

reversible airways disease requiring treatment within 12 months of

commencing a topical beta-blocker.

 Cardiovascular - cardiovascular mortality is higher in patients taking a

topical beta-blocker. Effects64 include heart block, bradycardia,

worsening of heart failure and hypotension, induction of the latter by

topical beta-blocker having been reported as a common cause of falls in

elderly patients. A peripheral vasoconstrictive effect means that it

should be avoided or used with caution in patients with peripheral

vascular disease, including Raynaud phenomenon.

 Unpleasant but less severe side effects include sleep disorders, reduced

exercise tolerance, hallucinations, confusion, depression, fatigue,

headache, nausea, dizziness, decreased libido and dyslipidaemia.

BRIMONIDINE

It is clonidine derivative65 that is administered ocularly to lower intraocular pressure in patients with ocular hypertension or POAG.

Brimonidine is a α2-selective agonist that reduces intraocular pressure both by decreasing aqueous humor production and by increasing outflow.

Ocular alpha-2 receptor stimulation decreases aqueous synthesis via an effect on the ciliary epithelium, and increases uveoscleral outflow. There is probably a neuroprotective effect66. The efficacy of brimonidine in reducing intraocular pressure is similar to that of the β receptor antagonist timolol.

It can cross the blood-brain barrier and can produce hypotension and sedation, although these CNS effects are slight compared to those of clonidine. As with all α2 agonists, this drug should be used with caution in patients with cardiovascular disease.

It should be used with great caution67 in young children, in whom severe central nervous system (CNS) depression and hypotension been reported, and is contraindicated under the age of 2 years. It should not be given with oral monoamine oxidase inhibitor antidepressants due to the risk of hypertensive crisis.

Brimonidine 0.2% twice daily in isolation generally has a slightly less marked IOP-lowering effect than timolol. Allergic conjunctivitis68 is relatively common; its onset may be delayed for up to 18 months after commencement of therapy. Granulomatous anterior uveitis can occur, but is rare. Systemic side effects include xerostomia and fatigue.

A brimonidine preparation, containing a proprietary preservative,

Purite, has been introduced as an alternative to the more common benzalkonium containing forms and may have greater ocular surface tolerability69.

AIM and OBJECTIVES

AIM

To compare and evaluate the efficacy and tolerability of fixed-dose combination of Brimonidine-Timolol with Timolol monotherapy in patients with Primary Open-Angle Glaucoma for achieving Target Intra Ocular

Pressure.

Primary objective

1. To study the Intra Ocular Pressure lowering effect of fixed dose

combination of Brimonidine-Timolol with Timolol

monotherapy in patients with Primary Open-Angle Glaucoma

2. To study the duration of achieving target pressure

3. To assess the effects of fixed dose combination of Brimonidine-

Timolol on visual acuity and visual field changes

Secondary objective

1. To study the neuroprotective effects of Brimonidine timolol

combination in preventing or slowing visual loss.

2. To assess the safety benefits of fixed dose combination of

Brimonidine-Timolol and patients compliance.

Justification

This study was conducted to study and compare the Intra Ocular

Pressure lowering effects and Visual Field changes in patients with Primary

Open-Angle Glaucoma attending Ophthalmology Department in a Tertiary care hospital.

Using fixed dose combination Brimonidine-Timolol70 may prevent the visual loss by the way of neuroprotection in addition to marked reduction of

Intra Ocular Pressure.

Fixed dose combination therapy reduces the exposure to preservatives, total number of eye drops instillation per day and washout effects71 and thus improves the patients compliance with better IOP control.

METHODS

Study design:

Single centre, prospective, open label, parallel group, comparative study

Study centre:

Ophthalmology department,

Govt. Stanley Medical College and Hospital, Chennai-1.

Study population

Patients with Primary Open Angle Glaucoma

Sample size

Total 60 patients [30 patients in Fixed dose combination of Brimonidine-

Timolol group and 30 patients in Timolol monotherapy]

Study duration

12 weeks for each patient

Study drugs

1. Fixed dose-combination Brimonidine-Timolol eye drop – 2 times per day

2. Timolol 0.5% eye drop – 2 times per day

Source of drug

1. Timolol 0.5% eye drops obtained from government supply at

Stanley medical college hospital Pharmacy.

2. Fixed dose combination of Brimonidine-Timolol eye drops

obtained from Ophthalmology department at Stanley medical

college hospital.

Dosage forms used

1. Fixed dose drug combination 0.2% Brimonidine - 0.5%Timolol

eye drop

2. 0.5%Timolol eye drop

Both drugs were administered topically.

SELECTION CRITERIA:

 Inclusion criteria

1. Patients age 30-65 years

2. Both male and female

3. Patients with Primary Open-Angle Glaucoma with IOP of 22

mmHg at presentation and above with open anterior chamber

angle, characteristic optic disk cupping and/or visual field loss72,

and who have failed to respond to monotherapy of timolol .

4. IOP range above 25 - 30mmHg at diagnosis which warrants use

of combination therapy

5. Snellens's visual acuity of 6/60 or better

6. Patients who satisfy the inclusion criteria and are willing to give

informed consent for participation in the study.

Exclusion criteria

1. Patients less than 30 years and more than 65 years

2. Patients having anterior synechiae, clinically dry eye syndrome,

active ocular infection, inflammation and significant ocular

trauma.

3. Patients taking other systemic or ocular medications that could

have substantial effect on intraocular pressure.

4. Patients with bronchial asthma or other reactive airway disease,

severe heart failure, sinus bradycardia, hypotension and diabetes

mellitus or any other contraindication to the test drugs .

5. Patients with history of ocular surgery in last 3 months.

6. Patients with only one sighted eye.

7. Patients using contact lenses and patients with corneal

abnormalities.

8. Patients with history of herpetic keratitis and corneal ulcer in the

last 1 year

9. Female patients of child bearing age group not using medically

approved contraceptives.

10. Patients who are not willing to participate in the study.

11. Other comorbid conditions like renal and hepatic failure

IEC approval:

The study was commenced after obtaining approval from the Institutional

Ethics Committee.

Methodology:

The patients for this study were recruited from the outpatient department of Ophthalmology, Govt Stanley Medical College Hospital,

Chennai. Informed written consent was obtained from the eligible patients according to inclusion criteria. Details of the study were explained to the participants and the informed consent was obtained in their regional language.

The drugs used in this study are as follows,

1. Fixed drug dose combination 0.2% Brimonidine-0.5%Timolol

eye drop

2. 0.5%Timolol eye drop

Both drugs were obtained from ophthalmology department at Stanley hospital.

It was a non-sponsored study.

Procedure:

A total of 60 patients satisfying the selection criteria were included in the study. After getting informed consent they were randomized into 2 groups. Group A and Group B. Each group consisting of 30 patients.

Group A patients [Test group]: Fixed dose combination of Brimonidine-

Timolol eye drop instilled twice daily

Group B patients: Timolol 0.5% eye drop instilled twice daily

Each patient was registered as POAG case and a case record form was maintained for each patient.

Thorough ocular examination of the patient including intraocular pressure recording, visual acuity, direct ophthalmoscopy, and slit lamp examination was performed. The intraocular pressure was recorded with

Goldman applanation tonometry.

Vital signs of pulse, Systolic blood pressure and diastolic blood pressure were recorded during each visit.

Drug administration:

The patients were educated regarding the proper method of topical application of the eye drops and the importance of maintenance of proper hand hygiene was emphasized.

Follow up:

After enrollment into the study and initiation of the study drugs, the follow-up was done after 2 weeks, 4 weeks, 8 weeks and 12 weeks. After 12 weeks of study period the patients were followed up in the Ophthalmology department.

Adverse effects:

The study drugs were safe and were not known to produce any serious adverse events. Participants were educated and instructed to report any type of effects such as irritation, itching redness, dryness etc. following administration of the study drugs. They were instructed to report immediately in the study centre.

Compliance:

The patients was educated and instructed regarding adherence to the treatment schedule. A compliance dairy was maintained by the patient and monitored during each visit.

Drug administration:

Group A Fixed dose Brimonidine-Timolol eye drop at morning and night for 12 weeks (Test therapy) (Study)

Group B Timolol 0.5% eye drop at morning and night for 12 weeks

(Control) (Standard therapy)

Withdrawal criteria:

The patients were free to withdraw from the study at any time during the

study period for any reason of their own and if any adverse drug effect occurs.

Outcome measures

The primary efficacy end point was the change from baseline

intraocular pressure to the target pressure. Safety was assessed in terms of

ocular and systemic adverse effects both subjective and objective. Subjective

symptoms such as itching, stinging, dry mouth and headache, were assessed

by questioning the patient at each visit. Objective signs were obtained by

examining the patient in detail by ocular and clinical examinations.

Study outline:

SCREENING(67)

RECRUITMENT

INCLUDED ( 60) EXCLUDED (7)

Patients with POAG

Randomized

FDC Brimondine - Timolol Timolol eye drop BD eye drop OD (Test - 30) (Control - 30)

Follow up at 2,4,8,12 weeks

Assessment at the end of

12 weeks weeks

Ocular parameters

S.No Parameters 0 week 2ndweek 4thweek 8thweek 12thweek

1. Visual acuity √ √ √ √ √

2. IOP √ √ √ √ √

3. Gonioscopy √ 4. Pachymetry √ √ √ √ √ 5. Visual field √ √ √ 6. Direct √ √ √ ophthalmoscopy

Statistical analysis:

Data were expressed as mean ± standard deviation. Students

independent‘t’ test was used for comparing quantitative data between

the two groups. Quantitative data was analysed by paired t test and unpaired

t test while qualitative data of frequency of adverse events were analysed by

the Chi-square test using Graphad73 software system. At the end of the

study the effects of Timolol eye drop alone and fixed dose combination

of Brimonidine-Timolol eye drop on IOP control was compared in terms

of therapeutic efficacy and adverse effects.

RESULTS

This study was conducted to compare and evaluate the efficacy and tolerability of fixed-dose combination of Brimonidine-Timolol with Timolol monotherapy in patients with Primary Open-Angle Glaucoma for achieving

Target Intra Ocular Pressure. After screening of 67 patients, 7 patients were excluded based on selection criteria ( 3 patients - not willing to participate in the study, 4 patients – known case of DM and Hypertension) and a total of 60 patients who had features of POAG were enrolled into the study based on selection criteria. After getting informed consent they were randomized into 2 groups. Group A and Group B. Each group consisting of 30 patients.

Group A patients were treated with Fixed dose combination of

Brimonidine-Timolol eye drop instilled twice daily. Group B patients were treated with Timolol 0.5% eye drop instilled twice daily.

At the first visit patients were given study drugs for 4 weeks, and reviewed at 2nd week, 4th week, 8th week and 12th week.

During each visit compliance of the patients, subjective improvements, adverse events were monitored and medications were given till end of 12 weeks.

Demographic factors including age and gender were assessed and analyzed at the end of study.

Thorough ocular examination74 of the patient including intraocular pressure recording, visual acuity, slit lamp examination. gonioscopy, visual field, patchymetry and direct ophthalmoscopy were assessed at baseline and at end of study and analyzed statistically.

Vital signs of pulse, Systolic blood pressure and diastolic blood pressure were recorded during each visit.

Adverse effects of the study drugs were evaluated and analyzed at the end of the study.

1) DEMOGRAPHIC FACTORS

Table no 1 Age and Gender Distribution

Age in years Gender Male % Female % Total 31-40 7 11.66% 6 10% 13 41-50 7 11.66% 16 26.66% 23 51-60 12 20% 12 20% 24 Total 26 43.33% 34 56.66% 60

Table 1 shows the demographic characteristics of the study participants, like age and gender distribution.

FIGURE 1a

Figure 1a shows the gender distribution, there is a female predominance.

FIGURE 1b

Figure1b shows the age distribution. Patients in the age groups of 41 -50 and 51- 60 are predominant.

2) OCULAR PARAMETERS

TABLE NO 2a :- Intra Ocular Pressure in FDC BT group Parameter Baseline End of treatment Unpaired MEAN S.D., MEAN S.D., 't' test

IOP in mmHg 28.93 2.97 16.23 1.88 P = 0.0001

This table 2a shows the baseline and at end of treatment values of IOP in FDC BT group. Statistical analysis is done by unpaired 't' test . There is significant change in these parameter at the end of study, p<0.05

TABLE NO 2b :- Intra Ocular Pressure in Timolol group Parameter Baseline End of treatment Unpaired MEAN S.D., MEAN S.D., 't' test

IOP in mmHg 26.77 3.27 20.14 1.49 P < 0.001

This table 2b shows the baseline and at end of treatment values of IOP in Timolol group. Statistical analysis is done by unpaired 't' test . There is significant change in these parameter at the end of study, p<0.05

TABLE NO 2c :- IOP – FDC BT VS TIMOLOL GROUP End of FDC BT TIMOLOL Unpaired treatment 't' test

MEAN S.D., MEAN S.D.,

IOP in mmHg 16.23 1.88 20.14 1.49 P= 0.0001

This table 2c shows the values of IOP in FDC BT group vs Timolol group at the end of study. Statistical analysis is done by unpaired 't' test . There is significant change in these parameter at the end of study, p<0.05

TABLE NO 2d :- IOP – FDC BT VS TIMOLOL GROUP

Figure 2d is a graphical representation of mean IOP reduction levels . Significant reduction in FDC BT group

TABLE NO 3 :- Central Corneal Thickness(CCT) – FDC BT vs TIMOLOL GROUP Parameters BASELINE End of treatment Unpaired 't' test MEAN S.D., MEAN S.D., CCT in µm FDC BT 537 6.62 537 5.51 P =1 TIMOLOL 538 6.72 538 5.53 P= 1

This table 3 shows the baseline and at end of treatment values of CCT in FDC BT group vs Timolol group. Statistical analysis is done by unpaired 't' test . There is no significant changes in these parameters at the end of study, p>0.05

TABLE NO 4:- Visual field testing – FDC BT vs TIMOLOL group VISUAL FIELD Early defects Moderate Severe

TEST Mean deviation Mean deviation Mean deviation

< -6Db -6dB to -12Db >-12Db

Baseline End Baseline End Baseline End

FDC BT (n) 7 2 3 1 0 0

(23%) (6%) (10%) (3%)

TIMOLOL (n) 6 9 4 5 0 0

(20%) (30%) (13%) (16%)

This table 4 shows the percentage of patients with the visual field defects in FDC BT group vs Timolol group tested in Humphrey visual field analyser at baseline and end of treatment.

TABLE NO 5 :- GONIOSCOPY– FDC BT vs TIMOLOL GROUP Grading Gr IV - Gr III - Gr II - Gr I - Gr 0 -

wide open moderately very closed

open angle narrow narrow angle

FDC BT (n) 9 (30%) 0 0 0 21 (70%)

TIMOLOL (n) 24 (80%) 6(20%) 0 0 0

This table 5 shows the percentage of patients with the gonioscopy findings in FDC BT group and Timolol group

TABLE NO 6 :- VISUAL ACUITY – FDC BT vs TIMOLOL GROUP BCVA 6/6 6/12 6/18 6/24 6/36 6/60

Baseline End B E B E B E B E B E

FDC BT (n) 5 7 8 9 6 7 9 5 3 1 3 1

TIMOLOL 4 5 9 9 5 4 6 5 4 5 2 2

(n)

This table 6 shows the number of patients with Best Corrected Visual Acuity in FDC BT group and Timolol group

TABLE NO 7 :- CUP DISC RATIO – FDC BT vs TIMOLOL GROUP Parameters Baseline End of treatment Unpaired 't' test CDR MEAN S.D., MEAN S.D., FDC BT 0.7 0.13 0.7 0.19 P = 1 TIMOLOL 0.6 0.11 0.6 0.18 P= 1

This table 7 shows the baseline and at end of treatment values of Cup Disc Ratio in FDC BT group vs Timolol group. Statistical analysis is done by unpaired 't' test . There is no significant changes in these parameters at the end of study, p>0.05

TABLE NO 8a :- Effects of Blood Pressure and Heart rate in Timolol group Parameter Baseline End of treatment Unpaired 't' test MEAN S.D., MEAN S.D.,

Systolic BP 126.77 2.27 125.14 2.45 P < 0.009 in mmHg Diastolic BP 84.86 1.17 83.34 1.02 P < 0.0001 in mmHg Heart rate 75 2.6 70 1.92 P < 0.0001 per min This table 8a shows the baseline and at end of treatment values of Blood Pressure and Heart Rate in Timolol group. Statistical analysis is done by unpaired 't' test . There is significant changes in these parameters at the end of study, p<0.05

TABLE NO 8b :- Effects of Blood Pressure and Heart rate in FDC BT group Parameter Baseline End of treatment Unpaired 't' test MEAN S.D., MEAN S.D.,

Systolic BP 128.77 2.79 124.14 2.05 P < 0.0001 in mmHg Diastolic BP 86.81 1.27 84.34 1.12 P < 0.0001 in mmHg Heart rate 76 2.62 72 1.96 P < 0.0001 per min

This table 8b shows the baseline and at end of treatment values of Blood Pressure and Heart Rate in FDC BT group. Statistical analysis is done by unpaired 't' test . There is significant changes in these parameters at the end of study, p<0.05

Table no 9 Subjective Symptoms

Subjective symptoms FDC BT (%) TIMOLOL (%)

Baseline 23 (76.6 %) 28(93%)

End of treatment 9 (30%) 21(70%)

Table no 9 shows percentage of patients with subjective symptoms like eye pain , headache and visual disturbances.

Table no 10 Incidence of Adverse Effects Sl.no Adverse effects FDC BT (%) TIMOLOL(%) 1 Burning/stinging 4 (0.13%) 11(0.36%) sensation 2 Foreign body 6(0.2%) 9(0.3%) sensation 3 Allergy/pruritus 2(0.06%) 6(0.2%) 4 Dry eye 0 2(0.06%)

5 Hyperemia 0 2(0.06%)

Table no 10 shows the incidence of adverse effects in FDC BT and TIMOLOL groups

DISCUSSION

Glaucoma is a leading cause of visual impairment and blindness in the world. It is associated with Retinal Ganglion Cells death and a raised intraocular pressure which is a mutable risk factor for glaucoma.

Glaucoma is accounted to have affected more than 60 million people worldwide75. It causes more than 8% of total blindness in the world. The estimated population of glaucoma in India is 20 million.

Primary open angle glaucoma (POAG), the most common type of glaucoma, is characterized by chronically elevated IOP and optic neuropathy with characteristic visual field defects.

Treatment strategy is mainly focused on reduction of IOP to prevent the visual loss. Topical anti glaucoma drugs are the mainstay of treatment in patients with POAG. Two or more drugs are required to achieve the target

IOP. For this purpose, Fixed Drug Combinations have been approved in recent years. Also an alternative approach like Neuroprotection is needed to prevent RGC death in chronic glaucoma patients.

According to Ocular Hypertension Treatment Study and Collaborative

Initial Glaucoma Treatment study76, two or more medications are needed to achieve the target IOP after 2 to 4 years of glaucoma management.

With the above mentioned evidences, this study was conducted to compare and evaluate the efficacy and safety of a fixed drug combination of

0.2% brimonidine and 0.5% timolol with the effect of o.5% timolol monotherapy in patients with POAG. The drugs were administered topically twice daily in the morning and the evening for a period of 12 weeks to the patients who were recruited in our study and satisfied selection criteria. A total of 60 patients, each group consisting of 30 patients were included in the study.

The following data like demographic factors, ocular factors, heart rate and blood pressure were collected and analyzed statistically by unpaired’t’ test using Graphad software system. Advere events of the study drugs were collected and analyzed at the end of study.

In this study the mean age of patients in study group is 48.21±6.69 years and the age group of 41- 50 years constitute 38.3 % of patients, and the

51-60 age group constitute 40 % of patients (vide table no 1a and figure no

1b). Previous studies in India have also revealed the mean age of general

Indian glaucoma patients to be between 35 and 50yrs. Other studies have also shown that the prevalence of POAG increases with age, with the majority of cases occurring between the age of 40 and 60 years. In our study, the prevalence of POAG is in the age group of 40-60 years.

There was female preponderance in the study groups. Female patients contributed 56.6 % of patients and male patients contributed 43.3 % of patients (vide table no 1a and figure no 1a) in both groups. Data from the

Early Manifest Glaucoma Trial77 have shown that POAG is common in females (35%) than males (28%). These findings may complement higher prevalence of POAG in female patients across India. Our study also shows increased prevalence in female patients.

Ocular factors

The primary efficacy end point was the change from baseline intraocular pressure. In this study, we have observed that timolol, and brimonidine-timolol fixed drug combination are effective agents in reducing intraocular pressure throughout the study period when measured at 2nd, 4th, 8th and 12th weeks. When efficacy of brimonidine-timolol fixed combination was compared with timolol monotherapy, we found that brimonidine-timolol fixed combination was more effective in reducing IOP compared to timolol alone.

In our study the mean IOP of the FDC BT group was 28.93mmHg and 16.23 mmHg at baseline and the end of study and the mean IOP of the Timolol group was 26.72 mmHg at baseline and 20.14 mmHg at the end of study (vide table no 2a and 2b). Statistical analysis is done by unpaired’t’ test. There is significant changes in these parameters at the end of study, p<0.05.

In both groups, at the end of treatment mean IOP is reduced from baseline IOP. The mean IOP was significantly reduced by an average of 12.70

± 1.09 mmHg compared with baseline value with the use of the FDC brimonidine-timolol combination. Comparing to timolol group, mean IOP is markedly reduced in FDC BT group at the end of treatment, p<0.05. (vide table no 2c and 2d).

In our study the patients with IOP range of 25 to 30 mmHg were selected for screening. Raised IOP is commonly associated with Retinal ganglion cell damage and might lead to cause blindness in untreated glaucoma patients. Data from the Early Manifest Glaucoma Trial78 have shown that even

1 mm Hg of additional IOP lowering reduces the risk of glaucoma progression by 10%. Thus more IOP lowering effect of the fixed combination should prove beneficial for preserving the patient vision.

Other than IOP lowering effect the brimonidine - timolol fixed combination has two more potential benefits79. First, as benzalkonium is most commonly used in ophthalmic medications as a preservative and as the treatment of the glaucoma is life long, it may have dose-related harmful effects on the corneal surface. Use of FDC BT twice daily results in a daily ocular exposure to preservative that is one third of that associated with the use of both component drugs given separately.

Second, when more than one drug is administered topically in the eye, the first drug may be diluted due to application of the second drug. As the formulation allows the delivery of 2 ocular drugs in a single drop it also ensures full exposure to both medications by preventing dilution of the first drug by application of a second drop before the first has been absorbed.

Mean CCT of the FDC BT group was 537µm at baseline and the end of study and the mean CCT of the Timolol group was and 538µm at baseline and at the end of study (vide table no 3). Statistical analysis is done by unpaired 't' test. There is no significant changes in these parameters at the end of study, p>0.05. Central corneal thickness is an important predictive factor for development of glaucomatous damage.

Visual fielding test was done on Humphrey’s Automated Perimetry at baseline and the end of study. Early defects were noted in 23% of patients in

FDC BT group at baseline and reduced to 6% of patients at the end of study.

Moderate defects were noted in 10% of patients in FDC BT group at baseline and reduced to 3% of patients at the end of study. In timolol group, 20% of patients showed early defects at baseline and 30% of patients at the end of study. Moderate effects were noted 13% of patients at baseline and 16% of patients at the end of study(vide table no4). Overall visual field improvements are noted in FDC BT group.

On gonioscopy grading, 70% of patients with GradeIV wide open angle and 30% of patients with GradeIII open angle were present in FDC BT group.

In Timolol group, 80% of patients with GradeIV and 20% of patients with

GradeIII open angle were present (vide table no5). Open angles are important in management of POAG. On testing visual acuity at baseline and the end of treatment, all patients in both groups had best corrected visual acuity (vide table no 6).

On direct ophthalmoscopy, Cup Disc changes were visualized in both groups. In FDC BT group and Timolol group, mean CDR was o.7 and 0.6 respectively at baseline and the end of study (vide table no7). Statistical analysis is done by unpaired’t’ test. There is no significant changes in these parameters at the end of study, p>0.05. Neuronal protection80 is supposed to stabilize the neuroretinal rim of optic disc.

Effects on Vital Parameters

Heart rate and Blood pressure in both groups were recorded at baseline and the end of study (vide table no 8a and 8b). Statistical analysis is done by unpaired’t’ test. There is significant changes in these parameters at the end of study, p<0.05 in both groups.

Effects of patients subjective symptoms

Most of the patients in both groups were asymptomatic. Some patients had symptoms like headache and eye pain. In this study, 76.6% of patients had subjective symptoms at baseline and 9% of patients at the end of study in

FDC BT group. In timolol group, 93% of patients at baseline and 70% of patients at the end of study had subjective symptoms (vide table 9).

Adverse events

The use of anti glaucoma drugs in this study was associated with fewer adverse effects of lesser severity in both groups. Burning/stinging sensation,

Foreign body sensation, Allergy/pruritus, Dry eye and Hyperemia81 were noted in both groups. In this study, 4 patients of FDC BT group and 11 patients of Timolol group developed burning or stinging sensation. 6 patients of FDC BT group and 9 patients of Timolol group developed foreign body sensation in the eyes. 2 patients of FDC BT group and 6 patients of Timolol group developed allergic pruritus. Dry eye and hyperemia (each in 2 patients) were present in Timolol group. Comparing to Timolol group, patients in FDC

BT group had less side effects. There was no serious adverse effects noted in both groups (vide table 10).

CONCLUSION

In our study both Fixed drug dose combination of Brimonidine-

Timolol and Timolol monotherapy have been shown to be efficacious in

POAG. Compared to Timolol monotherapy, FDC Brimonidine-Timolol therapy has shown a more significant reduction in IOP. Moreover, FDC

Brimonidine-Timolol therapy was found to have produced less number of side effects in comparison. Thus based on the results of our study, it can be concluded that brimonidine-timolol fixed combination is more effective and safer in lowering IOP in comparison to Timolol monotherapy for the treatment of primary open angle glaucoma. In addition, the neuroprotective effects of brimonidine, could prove to be beneficial on arresting the progression of the disease on long term.

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ANNEXURES

CASE RECORD FORM

Name Age and Sex Hospital number Complaints Present History Past History Personal History:- Alcoholism / smoking / diet Treatment History DM/ SHT/ any other drug history

General examination Pulse BP

Ocular examination RE LE

Vision Anterior segment Anterior chamber depth Pupil Lens IOP Visual fields Cup disc ratio

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Systemic examination CVS, RS Abdomen CNS

Clinical diagnosis :

Treatment prescribed:

Clinical progress:

108

109

110