Study of Ocular Hypotensive Effect and Tolerability of Fixed Combination Brinzolamide 1% and Brimonidine 0.2% in Indian Eyes with Open Angle Glaucoma
STUDY OF OCULAR HYPOTENSIVE EFFECT AND TOLERABILITY OF FIXED COMBINATION BRINZOLAMIDE 1% AND BRIMONIDINE 0.2% IN INDIAN EYES WITH OPEN ANGLE GLAUCOMA
DISSERTATION SUBMITTED TOWARDS FULFILMENT OF THE RULES AND REGULATIONS FOR THE M.S. BRANCH III OPHTHALMOLOGY EXAMINATION OF THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY TO BE HELD IN APRIL, 2018
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STUDY OF OCULAR HYPOTENSIVE EFFECT AND TOLERABILITY OF FIXED COMBINATION BRINZOLAMIDE 1% AND BRIMONIDINE 0.2% IN INDIAN EYES WITH OPEN ANGLE GLAUCOMA
Christian Medical College , Vellore Dr. Sujitha Ramesh
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BONAFIDE CERTIFICATE
This is to certify that this dissertation entitled “Study of ocular hypotensive effect and tolerability of fixed-combination Brinzolamide 1% and brimonidine 0.2% in Indian eyes with open angle glaucoma ” done towards fulfillment of the requirements of the Tamil Nadu Dr MGR Medical University, Chennai for MS Branch III (Ophthalmology) examination to be conducted in April 2018, is the bonafide original work of Dr. Sujitha Ramesh, Post Graduate student in the Department of Ophthalmology, Christian Medical College, Vellore
Dr. Andrew David Braganza, MS The Principal, Professor and Head of the Department, Christian Medical College, Department of Ophthalmology, Vellore- 632001 Christian Medical College, Vellore- 632001
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BONAFIDE CERTIFICATE
This is to certify that this dissertation entitled “Study of ocular hypotensive effect and tolerability of fixed-combination Brinzolamide 1% and brimonidine 0.2% in Indian eyes with open angle glaucoma ” done towards fulfillment of the requirements of the Tamil Nadu Dr MGR Medical University, Chennai for MS Branch III Ophthalmology examination to be conducted in April 2018, is the bonafide original work of Dr. Sujitha Ramesh, Post Graduate student in Ophthalmology, Christian Medical College, Vellore
Guide Dr. Arathi Simha R Associate Professor, Department of Ophthalmology, Christian Medical College, Vellore- 632001.
Co guides:
Dr. Andrew Braganza ( Professor)
Dr. Lekha Mary Abraham (Professor)
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BONAFIDE CERTIFICATE
This is to certify that this dissertation entitled “Study of ocular hypotensive effect and tolerability of fixed-combination Brinzolamide 1% and brimonidine 0.2% in Indian eyes with open angle glaucoma ” done towards fulfillment of the requirements of the Tamil Nadu Dr MGR Medical University, Chennai for MS Branch III Ophthalmology examination to be conducted in April 2018, is the bonafide original work of Dr. Sujitha Ramesh, Post Graduate student in Ophthalmology, Christian Medical College, Vellore
Dr. Sujitha Ramesh Post Graduate student, Department of Ophthalmology, Christian Medical College, Vellore - 632001
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ACKNOWLEDGEMENT
At the outset, I want to thank God for bringing me this far and guiding me in every step of my career.
I would like to express my sincere gratitude to my guide, Dr. Arathi Simha R, for her patience, guidance, suggestions, healthy criticism in the conduct of this work, from its inception to the conclusion. Her advice has been invaluable in the final presentation of the thesis in its current form. Her insight into this work and immense knowledge has been invaluable and a great learning experience. Also, her inputs for the statistical analysis were very useful. This is my first insight into research and I feel privileged to have her as my mentor.
I would also like to express my heartfelt gratitude to my co guides Dr. Andrew Braganza and Dr. Lekha Mary Abraham. Their time, patience, suggestions, encouraging and reassuring words, moral support have been pivotal in the completion of this work. There’s a kind of inspiration that’s not much more than doing the right thing in the right way, and I feel extremely lucky to have Sir and madam as my co guide. Their help was indispensible for this study. I would also like to thank my biostatistician, Mrs. Mahasampath Gowri for helping me with the statistical analysis inspite of her busy schedule.
I am extremely indebted to all my colleagues for being understanding and extending their support in helping me to complete this work. A special thanks to Sharmili , Nidhi
Priyanka , Bhavagna , Roshini , Joseph , Bharath , Shiju and Swetha . My heartfelt thanks to all those who have contributed in ways, small and big, to complete this endeavor
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ANTI PLAGARIASM CERTIFICATE:
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TABLE OF CONTENTS
Content Page number
Introduction 1
Aims and Objectives 3
Literature Review 5
Materials and Methods 44
Results 51
Discussion 67
Limitations 73
Conclusion 74
References 76
Annexure
IRB approval letter 95
Patient information sheet 100
Consent form 103
Clinical research proforma 111
Colour plate 115
Excel sheet 116
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INTRODUCTION
Glaucoma represents a progressive optic neuropathy characterized by nerve fiber layer defects which lead to characteristic optic disc changes and visual field defects (1). It has a multifactorial aetiology with intraocular pressure (IOP) being the only major modifiable risk factor (2).The mainstay of treatment involves lowering of the intraocular pressure by various methods. Although there is no absolutely ‘safe’ pressure that guarantees prevention of progression, lowering intraocular pressure to the low-normal range usually arrests or slows the progression of glaucoma. The two main modalities of treatment include surgical and medical. Usually 25% - 30% reduction in baseline intraocular pressure (3)(4)(5) or achievement of Target intraocular pressure is the goal of treatment. Target intraocular pressure is defined as the upper limit of the range of measured intraocular pressures adequate to stop progressive pressure induced damage of optic nerve head. Medical management consists of topical administration of various classes of anti-glaucoma medications in the form of eye drops. The anti-glaucoma medications available include β blockers (Timolol 0.5%,
Betaxolol 0.5%), alpha adrenergic agonists (brimonidine 0.2%), Prostaglandin analogs
(latanoprost 0.005%, Travaprost 0.004%, Bimataprost 0.03%), Carbonic anhydrase inhibitors
(dorzolamide 2% ,brinzolamide 1%) and Parasypathomimetics (Pilocarpine 1-4%).
Monotherapy is often insufficient to achieve the optimal reduction of Intraocular pressure .
Combination of drugs is hence often required. In order to achieve ease of administration and reduction of side effects of preservatives of multiple drops, fixed combinations are used. Also compliance is better with fixed therapy than individual mutiple medications(6). Till recently,
Timolol, a beta blocker was the only additional drug available in fixed combination along with various other antiglaucoma medications like Prostaglandin analogues, Carbonic
1 anhydrase inhibitors and Alpha adrenergic agonists (7). However beta blockers cannot be used in asthmatics and patients with heart blocks. Also, in patients with uveitis as well as those planned for intraocular surgeries, prostaglandin analogues are best avoided due to the risk of increased incidence of cystoid macular oedema or worsening of uveitis (8). Carbonic anhydrase inhibitor and Alpha adrenergic agonist are the drugs preferred in these patients.
Recently fixed combination Carbonic anhydrase inhibitor and Alpha adrenergic agonist is available in the market. It can be used as first line therapy (9)(10) or added on in patients wherein intraocular pressure control is inadequate with monotherapy with Prostaglandin analogs and Beta blockers are contraindicated(11)(12). The efficacy of fixed combination of carbonic anhydrase inhibitor and alpha adrenergic agonist has been studied in various
Caucasian studies (6)(13)(14) and has been shown to achieve a 32% to 34 % (15) (16) reduction of intraocular pressure. They have also been used as an additional therapy along with Prostaglangin analogs and has been found to achieve additional 25 % reduction in
Intraocular pressure (11). The fixed dose combination has now recently become available in the Indian market as the preparation – Simbrinza TM (Fixed combination of brinzolamide
1% and brimonidine 0.2% ,Alcon laboratories). However there are no studies in Indian eyes.
Hence we looked at the ocular hypotensive effect and tolerability of fixed dose combination of Carbonic anhydrase inhibitor and Alpha adrenergic agonist in our patients.
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AIM:
This study aims to assess the ocular hypotensive effect and tolerability of fixed combination of brinzolamide 1% and brimonidine 0.2% in Indian patients with
Open angle glaucoma.
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PRIMARY OBJECTIVES:
1. To determine the reduction in Intraocular pressure achieved in patients with
open angle glaucoma by the fixed combination brinzolamide1% and
brimonidine 0.2% at 1 month as measured during office hours.
2. To determine the tolerability and side effect profile of fixed combination
brinzolamide 1% and brimonidine 0.2% .
Secondary objective:
To determine the 24 hour profile of intraocular pressure in patients on fixed combination of brinzolamide1% and brimonidine 0.2%
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LITERATURE REVIEW:
Glaucoma comprises a multifactorial group of diseases characterised by chronic progressive anterior optic neuropathy that is accompanied by a characteristic cupping and atrophy of the optic disc, and visual field loss, with elevated intra-ocular pressure being the only modifiable risk factor. (17)
About 12 million people in India are affected by glaucoma accounting for 12.8% of the blindness in the country. Early population based studies reported a prevalence of glaucoma between 2% and 13% (21). The Vellore Eye Survey (VES) reported a prevalence of Primary open angle glaucoma (POAG) as 0.41%, ocular hypertension
(OHT) 3.08 %(22). The Andhra Pradesh Eye Disease Survey (APEDS) reported a prevalence of 1.62% for POAG, 0.32% for OHT of the study population (23).
AQUEOUS HUMOR DYNAMICS AND INTRAOCULAR PRESSURE
In the human eye there is a balance between production of aqueous humor as well as its drainage. The intraocular pressure is held in a stable balance through different mechanisms. The aqueous humor is secreted by the ciliary epithelium lining the ciliary processes. Three physiological processes contribute to the formation and chemical composition of the aqueous humor: diffusion (5 %), ultrafiltration (15 %) and active secretion (80 %). (18)
The normal intraocular pressure amounts to 15.8 ± 2.6 mmHg as found by
Leydhecker and co-workers who performed Schiotz tonometry in 10,000
5 normal individuals. The diurnal fluctuation in normal individuals is 3-6mmHg
(19)(20). Aqueous humor leaves the eye by passive bulk flow via two pathways: the trabecular route and the uveoscleral route.
DEFINITION OF TERMS
Primary open angle glaucoma is a chronic, progressive, anterior optic neuropathy that is accompanied by a characteristic cupping and atrophy of the optic disc, visual field loss, open angles, and no obvious causative ocular or systemic condition. In the majority of cases, intra-ocular pressure is elevated above the statistically normal range
(>2 standard deviations from the mean, or 21 mmHg) , and is the major risk factor.
Normal tension glaucoma refers to typical glaucomatous optic disc cupping and visual field loss in eyes that have normal corrected intraocular pressure (≤
21 mmHg) open angles, and the absence of any contributing ocular or specific systemic disorders (17)
Pigmentary glaucoma and Pseudoexfoliation (PEX) glaucoma are secondary open angle glaucomas wherein the pigments and pseudoexfoliation material respectively clog the trabecular meshwork causing raised intraocular pressure.
Ocular hypertension refers to the condition wherein the intraocular pressure is high, > 24 mmHg but there are no glaucomatous disc or field changes.
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These patients are at a risk of developing disc and field changes due to the high intraocular pressure and often are treated with anti- glaucoma medications to keep the intraocular pressure under control.
TARGET INTRAOCULAR PRESSURE AND THERAPY FOR
GLAUCOMA
Target intraocular pressure is defined as the upper limit of the range of measured intraocular pressures adequate to stop progressive pressure induced damage of optic nerve head. Reduction in Intraocular pressure forms the mainstay of management of glaucoma.
Lowering Intraocular pressure to an individualized target level (typically a
>25% reduction from initial Intraocular pressure) and maintaining that level reduces the risk of vision loss and improves outcomes (3)(4)(5). Reduction of
Intraocular pressure can be achieved by antiglaucoma medications or by glaucoma surgery . Also Intraocular pressure reduction slows the progression of disease.
Antiglaucoma medications in the form of topical medications (drops) include
β-blockers (eg. Timolol), prostaglandin analogs (eg.. latanoprost),carbonic anhydrase inhibitors (eg. Dorzolamide, brinzolamide) and α2-adrenergic agonists (eg.brimonidine) and cholinergic agonists (eg.pilocarpine) (4)(24).
The drug usefulness is determined by efficacy, potency, duration of action, and therapeutic index.
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DIURNAL VARIATION OF INTRAOCULAR TENSION (DVT) :
The intraocular pressure exhibits a rhythmic pattern which peaks in the morning and troughs in the evening. In normotensive patients , the 24-hr Intraocular pressure fluctuation lies within a 5 mmHg range ( 26). The fluctuations of intraocular pressure is also influenced by body posture, rate of aqueous humor formation. The aqueous production has an nocturnal dip and rises during day in response to circulating catecholamines. Intraocular pressure measured in the sitting position is generally lower than that measured in the supine position at any given time (27).
DVT in Normals
Drance ( 28) measured the Intraocular pressure of 404 normal subjects between 6:00 am and 10:00 pm and results showed that 16% of cases showed a fluctuation more than 6 mmHg, while 42% of them showed their peak pressure at 06:00 am. The mean intraocular pressure fluctuation was 3.7 ± 1.8 mmHg.
In another study by Katavisto et al (20). showed that the highest IOP values at 8.00 am in 41% and at midnight in 20% of subjects subjects with normal IOP. In a similar fashion, Newell and Krill et al (29) documented that the greatest frequencyof peak
Intraocular pressure readings are between 6:00 and 8:00 am.
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DVT in primary open Angle glaucoma , ocular hypertension and pseudoexfoliation glaucoma :
Wilensky et al. conducted a study [30] with a group of 176 patients with Primary open angle glaucoma and 55 subjects with Ocular hypertension and 18 normal controls who performed home self-tonometry 5 times daily for 4 to 8 consecutive days. These three groups showed well-defined diurnal Intraocular pressure fluctuations with peak at morning or mid-day .The mean fluctuation of IOP was
5.0 mmHg in normal , 5.8 mmHg in patients with primary open angle glaucoma and
6.8 mmHg in patients with ocular hypertension.
Pseudoexfoliation glaucoma patients typically exhibit greater 24-h fluctuation, peak and trough Intraocular pressure than primary open angle glaucoma patients. Konstas et al. (95) showed a 24-h intraocular pressure fluctuation more than 15 mmHg in
35% of pseudoexfoliation glaucoma patients but only in 7.5% of primary open angle glaucoma patients. It reported peak intraocular pressure between 10:00 pm to 6:00 am in 45% pseudoexfoliation glaucoma patients and 22.5% of primary open angle glaucoma patients.
TOPICAL ANTIGLAUCOMA MEDICATIONS :
Definition of pharmacological terms:
Efficacy is defined as maximum therapeutic effect obtainable.
The dose producing 50% of the maximum drug effect is defined as potency.
The length of time a drug dose exerts its biologic action is duration of action.
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Th ratio of dose of a drug producing a toxic effect divided by the dose producing the desired effect is therapeutic index.
Compliance is defined as the degree or extent of conformity to the recommendations about day to day treatment by the provider with respect to the timing ,dosage and frequency.
The rate and extent of absorption across a tissue is referred as bioavailability.
Various factors influencing the bioavailability of topical medication are corneal barriers, drug formulation, and drug elimination . The limitations for bioavailability are compliance and efficiency of instillation.(25)
Various classes of topical anti-glaucoma medications:
Parasympathomimetic or Cholinergic agents
They mimic the action of Acetylcholine , which is a neurotransmitter present at the postganglionic parasympathetic nerve endings. Acetylcholineesterase is an enzyme which hydrolyses acetylcholine in order to limit its action.The Parasympathomimetic agents act directly by mimicking acetylcholine or indirectly by inhibiting the acetycholinesterase thus retarding the degradation of acetylcholine and prolonging its action. Parasympathetic nervous system innervates the ciliary body and iris sphincter.
Hence these parasympathomimmetic agents causes contraction of longitudinal muscle of ciliary body which leads to increase in aqueous outflow and contraction of circular muscle which leads to accommodation and miosis. There are two types of cholinergic
10 receptors Nicotinic and Muscarinic. Of which M1, M2, M3 receptor subtypes are abundantly present in the eye.
Topical agents are
1. Pilocarpine
2. Carbachol
3. Ecthiophate (indirectly acting agent)
Pilocarpine (1-4% ):
It is a directly acting cholinergic agonist which acts on muscarinic receptor. It stimulate the ciliary muscle, causing traction on the scleral spur and the trabecular meshwork, which separates the trabecular sheets and prevents Schlemm’s canal from collapsing. This mechanical change in the configuration of the meshwork increases fluid conductivity(31)(32). It also causes constriction of iris sphincter muscle and causes miosis which is useful in angle closure as it pulls the peripheral iris away from trabecular meshwork.
It is a water soluble hydrochloride or nitrate and is stable at a slightly acidic pH .
Intraocular pressure lowering is dose related. Pilocarpine binds to melanin in iris and ciliary body hence iris colour influences intraocular pressure response. Pilocarpine has rapid onset of action . Maximum response is seen in 2 hours lasting for 8 hours.
Intraocular pressure reduction is around 20% at peak time. Drug delivery system for pilocarpine are Pilocarpine gel which is a high viscosity acrylic vehicle applied once
11 at bed time which prolongs and increases drug penetration.( 33). Another delivery system is OCUSERT which is a membrane controlled delivery system for constant release f 20 and 40 micrograms of drug every hour (34). Other delivery systems are soft contant lens and pilocarpine polymer. Pilocarpine effect is additive to most available antiglaucoma medications such as Beta blockers, prostaglandin analogues.
Carbachol (1.5- 3%) :
It is a parasympathomimmetic which acts directly on motor end plate and
indirectly by inhibiting acetyl cholinesterase. It is more potent and has prolonged
pressure lowering effect but has poor corneal penetration .Also provides better
Intraocular pressure control in early postoperative period.(35)
Echothiphate Iodide (0.06%) :
It inhibits acetyl cholinesterase and prolongs the effect of acetyl choline. It is an
indirectly acting parasympathomimmetic and has prolonged action due to slow
hydrolyses.
Ocular side effects of Parasympathomimetic drugs:
Miosis
Ciliary muscle spasm
Headache and browache
Lid twitching & pain
Conjunctival and iris hyperemia
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Increased vascular permeability
Cataract formation
Hypersensitivity reactions
Stinging, irritation , lacrimation
Myopic shift
Cyst of the iris pigment epithelium
Rhegmatogenous retinal detachment
Cicatricial pemphigoid
Systemic side effects of parasympatomimetic drugs :
Bronchospasm
Nausea, vomiting,
Diarrhea, abdominal pain
Weakness, fatigue
Paresthesia
Sweating, salivation, lacrimation
Hypotension, bradycardia
Depression
Due to the adverse effects of ciliary spasm and miosis and the availability of newer more effective drugs, parasympathetic durgs are nowadays rarely used in the management of open angle glaucoma . They are also contraindicated in patients with acute anterior uveitis , hypersensitivity , high myopia, history of retinal
13 detachment,peripheral retinal degeneration, chronic obstructive pulmonary disease, peptic ulcer, Parkinson’s disease, bradycardia, hypotension and myasthenia gravis.
Parasympathomimetics in the present day is mainly used in the management of angle closure glaucoma for short periods of time in acute angle closure in appropriate cases awaiting definitive management.
Beta blockers or Adrenergic antagonists:
Beta receptors are of three subtypes β1, β2 and β3. Of which Ocular beta adrenergic receptors are β2 subtype. Normally Beta receptor agonists stimulate G protein to activate adenylate cyclase enzyme which catalyses conversion of ATP to cyclic AMP.
Cyclic AMP act as second messenger to trigger a cascade of biochemical events necessary for regulation of ion channels and enzymes in ciliary epithelium which is responsible for aqueous production.
Beta blockers act on β2 subtype receptors and causes inhibition of catecholamine stimulated synthesis of cyclic AMP and results in decrease in aqueous humour production. (Timolol maleate 0.5%, Betaxolol 0.5% ) decrease aqueous humor formation by antagonizing a resting β-adrenergic tone in the ciliary processes. Such a tone would have to be supplied by either the sympathetic nervous system or circulating catecholamines.(36)
Other mechanism of action are β2 receptors are present in the blood vessels of ciliary body and hence blockage of these receptors causes unopposed alpha receptor
14 mediated vascular constriction . This results in reduced blood supply to ciliary body which reduces capillary perfusion pressure and decreases aqueous formation. (37)(38)
The topical Beta blockers are:
1. Timolol maleate
2. Betaxolol
3. Levobunolol
4. Carteolol
5. Metipranolol
Timolol maleate (0.25, 0.5%)
It is a nonselective β1 and β2 adrenergic antagonist without intrinsic sympathomimetic activity and membrane-stabilizing properties.
properties. It is available as a solution (0.25% or 0.50%) which can be
administered twice daily and as a hydrogel (0.1% or 0.5%) which can be
administered once daily
It causes reduction in intraocular pressure within 30 minutes to one hour with peak action after 2 hours. The intraocular pressure lowering by beta blockers may show short term escape phenomenon and long term drift . Timolol in combination with other antiglaucoma medications produces additional intraocular pressure lowering effect.It is the most commonly combined drug with other anti-glaucoma medications like fixed combination timolol with prostaglandin analogues and topical carbonic
15 anhydrase inhibitors and alpha 2 agonistsThe advantages of fixed combination are increased adherence, decrease in cost and less exposure to preservative. It has short term escape phenomenon due to an increase in the number of -adrenergic receptors in the ciliary processes under the condition of prolonged -adrenergic blockade.
In about 10–20% of patients may have some loss of drug effect over subsequent
months. This is termed as ‘long-term drift’ due to decrease in cellular sensitivity
to adrenergic antagonists.
Betaxolol ( 0.5 or 0.25%):
It is a selective β1-adrenergic antagonist. It does not have intrinsic sympathomimetic activity and membrane-stabilizing properties. Betaxolol reaches the ciliary epithelium at high concentration and blocks β2 receptors. Other explanations are presence of β1 receptors in ciliary body or a nonadrenergic effect of betaxolol on Intraocular pressure.( 39) . In addition to reduction in intgraocular pressure by decreasing aqueous humour formation. It has neuroprotective effect and reduce the progression of visual field defects in comparison with timolol (40) .
It also increases retinal sensitivity and relaxes the smooth muscle of retinal arterioles and hence increases retinal blood flow (41). Betaxolol has less effect than timolol to induce β2-adrenergicmediated bronchial constriction and hence can be used in patients with bronchial astma or chronic obstructive pulmonary disease. (42).
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Levobunolol (0.25 or 0.5 %) :
It is a lipophillic non-selective β1 and β2 adrenergic antagonist. It lacks intrinsic sympathomimetic activity . It is equivalent to timolol in its efficacy.
Carteolol (1% or 2%) :
It is a non selective hydrophilic β adrenergic antagonist with intrinsic sympathomimmetic activity. It has similar efficacy as timolol . Buts as it has intrinsic sympathomimmetic activity it might produce cardiovascular effect such as bradycardia , hypotension and pulmonary effects..
Metipranolol (0.3%):
It is a lipophilic non-selective β1- and β2-adrenergic antagonist. Its Intraocular pressure lowering effect is similar to Timolol. One of the side effect reported is granulomatous uveitis .( 43 )
Ocular side effects of β blockers:
Burning, stinging, itching , irritation
Superficial punctate keratitis, dry eye, decreased corneal sensation
Systemic side effects of beta blockers:
Depression , Hallucinations ,confusion
Bradycardia , Arrhythmia , Heart failure ,Hypotension , Heart blocks
Airway obstruction/asthma , Pulmonary failure
Maculopapular rash , Alopecia
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Nausea , Vomiting , Diarrhea , Abdominal cramping
Non selective β blockers are contraindicated in patients with asthma , chronic obstructive pulmonary disease, sinus bradycardia, and heartblock.
Prostaglandins :
Arachidonic acid metabolism results in production of prostaglandins .Prostaglandin receptors are G protein coupled receptors. There are 4 types of prostaglandin receptors EP, FP, IP and
TP which are specific for prostaglandins PGD2, PGE2, PGF2α ,PGI2 or TxA2 .
Topical prostaglandin analogs are :
1. Latanoprost (0.005 %)
2. Travoprost (0.004%)
3. Bimataprost (0.03%)
4. Unoprostone (0.15%)
Mechanism of action :
Prostaglandins reduce intraocular pressure by increasing uveoscleral outflow. It stimulates enzyme which degrades and remodels the extracellular matrix such as metalloproteinases and transcription factors.
Few of them like Unoprostone 0.15% ,Bimataprost 0.03%, increase the trabecular meshwork outflow of aqueous humor as well(44)(45). Unoprostone opens the potassium channels which reaches an activation threshold during depolarisation and high intracellular calcium
18 levels . Hence it increases conventional outflow following calcium dependant tissue contraction.
Latonoprost ,travoprost are all esterified prodrugs and are hydrolyzed by corneal esterases to their active part. Bimataprost is a prodrug with an ethyl amide instead of an isopropyl ester.
Hence it is partially hydrolyzed by amidase . No short term escape or long term drift phenomenon is seen with prostaglandins.
Latanoprost (0.005%) :
Latanoprost is a potent prodrug which is rapidly converted by cornea into its active ingredient. It reaches its peak aqueous humor level 1–2 hours after topical application with a half-life of 2–3 hours. Its peak level in bloodstream is 5 minutes with a half-life of 17 minutes. The acid is metabolized in the liver by oxidation and eliminated through feces and urine. It is used once daily at night. Latanoprost has an additive effect with other antiglaucoma medications such as beta blockers, carbonic anhydrase inhibitors.
Travaprost (0.004%)
Travoprost is a synthetic prostaglandin F2α analogue and is a prodrug. It is an isopropyl ester of prostaglandin F2α agonist. It is hydrolyzed into its active part by cornea and sclera which has high selectivity to FP receptor .(46). It is the only prostaglandin that is available with a different preservative other than benzalkonium chloride hence it can be used in patients with Benzakonium chloride (BAK) toxicity and in those on multiple medications. Among the other available prostaglandin
19 analogues travoprost has maximum affinity for the FP receptors followed by bimatoprost,latanoprost and uniprostone respectively.
Bimataprost (0.01% ,0 .03%):
It is a prostaglandin F2α analog where neutral ethylamide replaces carboxylic acid .It has little direct effect on prostaglandin F2α receptors (47) .It is not converted to its active counterpart and enters into the eye unchanged which acts on prostamide receptor. Compared to other prostaglandin analogues , conjunctival hyperaemia is reported more in bimetaprost .
Isopropyl Unoprostone ( 0.15 %)
This prodrug is a docosanoid which is derived from docosahexanoic acid. It is an analogue of pulmonary metabolite of PGF2α . It also increases conventional outflow.
The ocular side effects are :
The unique side effects of the prostanoids is the darkening and increase in length of the eyelashes, iris discolouration , uveitis and cystoid macular edema. The most common side effects in the three multicenter, international, comparative studies after 6 months of latanoprost treatment were conjunctival hyperemia, foreign body sensation, eye irritation, and superficial punctate keratopathy (52). Other side effects are periocular hyperpigmentation ,
Blurred vision , Dry eye Superficial punctate keratitis, PG associated peri-orbitopathy, and choroidal effusions
Systemic side effects are uncommon. Few systemic side effects of prostaglandins include
Upper respiratory infection , headache
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Myalgia ,arthralgia , abdominal cramps
Cough and possible uterine contraction
Prostaglandin analogs are contraindicated during pregnancy and lactation. (17)
Carbonic anhydrase inhibitors (dorzolamide 2% ,brinzolamide 1%)
They are sulphonamide derivatives. It reduces aqueous production through
inhibition of sulfonamide-susceptible carbonic anhydrase isozymes.(48). Carbonic
anhydrase is an enzyme for catalytic hydration CO2 and dehydration of H2CO3
in ciliary epithelium. This results in formation of bicarbonate and hydrogen ion
which is important in aqueous humor formation. There are multiple isoenzyme
forms of carbonic anhydrase enzyme of which type I and II both present in the
corneal endothelium and lens. The type II carbonic anhydrase isoenzyme is
present in the ciliary epithelium.(53). Carbonic anhydrase inhibitors interferes
with the function of enzyme and reduces aqueous production. The enzyme
carbonic anhydrase (CA) catalyzes the following reaction:
- CO2 + OH HCO3-
Systemic carbonic anhydrase inhibitors are:
Acetazolamide :
It is a non-selective carbonic anhydrase inhibitor acting on both carbonic anhydrase I and II isoenzymes. . The available doses are 125mg, 250mg and 500mg tablets .
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Effective Introcular pressure lowering is achieved by maximum dose which can be given in 250mg four times a day and 500 mg twice day. In pediatric patients dose according to body weight is 5- 10mg/kg six hourly. Intraocular pressure drops in 1–2 hours after oral administration and reaches minimum in 2–4 hours following which returns to baseline in 4–12 hours. In sustained release preparations, Intraocular pressure drops in 2-4 hours, reaches minimum in 8 hours following which reaches baseline in 12-24 hours. It is also available in 500 mg ampoule which can be dissolved in 5- 10ml of distilled water and can be used intravenously or intramuscularly. Acetazolamide has high plasma protein binding and its half-life is
4 hours. It is actively secreted by renal tubules and passively reasorbed by non-ionic diffusion.
It is used in conditions wherein there is an acute elevation of intraocular pressure when topical medications are not effective due to the high pressure causing iris ischemia and non-absorption of topical medications and also for short term management of raised intraocular pressures as seen following routine cataract surgeries, trauma etc.
Methazolamide:
Methazolamide is available in 25 and 50 mg tablets and is less effective than acetazolamide in reducing the intraocular pressure. It is less plasma protein bound. It is metabolized in liver and excreted unchanged in kidney in contrast to acetazolamide.
Most common treatment regimen is 50 mg twice daily. Intraocular pressure falls in 1–
2 hours, reaches a minimum in 4–6 hours following which returns to baseline in 12–
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24 hours. Methazolamide less likely to produce urolithiasis than acetazolamide because it causes less suppression of urinary citrate and less alkalinisation of urine
(54). Hence preferred in patients with a history of renal stones.
Side effects of systemic carbonic anhydrase inhibitors :
Paresthesias of fingers, toes, circumoral region
Electrolyte disturbances such as metabolic acidosis , hypokalemia
Gastrointestinal effects are Metallic taste , Nausea , vomiting , abdominal cramps and urolithiasis.
Central nervous system effects are Fatigue, malaise , Confusion , Depression ,
Drowsiness , Headache
Agranulocytosis
Rash , Stevens-Johnson syndrome
Myopic shift
Contraindicated in patients with hypersensitivity , adrenal insufficiency , hepatic cirrhosis, renal failure, diabetic ketoacidosis , hypokalemia , hyponatremia, pregnancy and lactation.
Topical carbonic anhydrase inhibitors :
1. Dorzolamide
2. Brinzolamide
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Dorzolamide (2%) :
Dorzolamide has both a free sulfonamide group and second amine group, which is responsible for good corneal penetration due to lipid and aqueous solubility. It effectively inhibits isoenzymes II and IV, with a weaker effect on isoenzyme I.
A small amount of drug is metabolized by the liver to the des-ethyl form and it is excreted by kidneys. Des – ethyl form has inhibitory effect on isoenzyme
I. (55.). Dorzolamide and its metabolite are largely bound to RBC cholinesterase and are not present to any extent as free molecules in plasma hence systemic effects are minimal, but RBC carbonic anhydrase decreased to 21% of normal levels (56).
An 8 hourly dose is recommended for monotherapy and 12 hourly dose for adjunctive therapy. It is available as 2% solution with peak effect seen in 3 hours. It has an additive effect with both aqueous suppressants such as timolol and aqueous outflow enhancing agents such as pilocarpine and prostaglandin analogues . (57)(58)
It is well tolerated in children less than 6 years of age compared to oral acetazolamide.
Brinzolamide (1%):
It is lipophillic drug with good corneal permeability and is available as 1% suspension. Brinzolamide as monotherapy is administered three times a day. As it is a suspension it has prolonged duration of action due to increased contact time and reduced surface irritation. Intraocular pressure reduction reaches a peak at 2 hours.
Some studies suggest that brinzolamide may be more comfortable than dorzolamide. (
59). Both brinzolamide 1% and dorzolamide 2% used twice daily when each was added to timolol 0.5% twice daily showed equivalent intraocular pressure reduction,
24 but brinzolamide had significantly less ocular burning and stinging compared to dorzolamide according to Michaud et al (96).
Ocular side effects of topical carbonic anhydrase inhibitors:
Stinging , allergy
Dryness , superficial punctate keratopathy
Induced myopia
Systemic side effects of topical carbonic anhydrase inhibitors:
Metallic taste, gastrointestinal distress,
Urticaria , neutropenia,
Headache, , dizziness, paresthesias
Steven Johnson syndrome
Topical carbonic anhydrase inhibitors are contraindicated during pregnancy and lactation. (17)
Adrenergic agonists :
Adrenergic agonists can be classified as non-selective which acts on alpha and beta receptors and selective which acts only on alpha receptors . There are three alpha one adrenergic receptors (α1A, α1B , α1D) and three alpha two adrenoreceptors (α2A ,
α2B , α2D) . Of which α1A and α2A are found in ocular tissuses.
Topical non selective adrenergic agonists are :
25
1. Epinephrine
2. Dipivefrin
Epinephrine (0.5%, 1% or 2%):
It reduces intraocular pressure by decreasing aqueous production via early β adrenergic mediated effect and increases aqueous outflow facility both conventional and uveoscleral via late α adrenergic mediated effect. It is available as epinephrine hydrochloride , epinephrine borate, epinephrine bitartarate. The intraocular pressure lowering effect peaks in 2 to 6 hours and returns to baseline in 12 – 24 hours.
Dipivefrine (0.1%):
It is a prodrug and is converted to epinephrine by esterease enzyme in cornea .
Dipivefrine has limited sympathomimetic activity. Two molecules of pivalic acid is added to the parent molecule hence dipivefrin is synthetic analogue of epinephrine.
And hence it increases lipid solubility and ocular penetration in comparison with epinephrine. It is also converted to other metabolites but action of other metabolites is unknown. Its concentration is 0.1% and intraocular pressure decreasesin 30 – 60 minutes with peak effect in 1-4 hours and returns to baseline in
12- 24 hours. Dipivefrin produced similar percent reductions in intraocular pressure
(18.6%) to epinephrine (21.0%) and also there is lower incidence of burning and stinging after drug instillation was noted with dipivefrin therapy. (60)
26
Norepinephrine :
It increases trabecular outflow a through alpha adrenergic mediated effect and thus decreases intraocular pressure. The concentration of epinephrine as topical administration is 2–4%. However its clinicial effectiveness in humans is limited due to limited intraocular penetration.
The ocular side effects are
Hyperemia , Blepharoconjunctivitis ,Skin blanching,
Adrenochrome deposits ,Madarosis, Ocular pemphigoid,
Corneal Epithelial and endothelial toxicity, l acrimal stones, cystoids macular edema and iridocyclitis.
The systemic side effects are
Headache, Tachycardia ,Premature ventricular contractions ,
anxiety , tremor, Increased blood pressure ,
Cerebrovascular accident and Myocardial infarction.
Alpha1-Adrenergic agonists :
Phenylephrine :
Phenylephrine hydrochloride lacks hydroxyl group on 4 position of benzene ring. It is a potent sympathomimetic agent and acts on alpha1-adrenergic receptors .
Phenylephrine used topically in concentrations of 0.125–10% . The effects of phenylephrine are vasoconstriction , reduces intraocular pressure and causes
27 dilatation of pupil inorder break posterior synechiae. It prevents formation of iris cysts hence was mostly used in combination with echothiophate. It can cause an increase in Intraocular pressure in patients with pigment dispersion syndrome due to release of iris pigment. (61)
Alpha 2 –adrenergic agonists
1. Clonidine
3. Brimonidine
Clonidine (0.125%,0.05%)
Clonidine is the first alpha 2-adrenergic agonis acts both centrally and peripherally
which inhibits norepinephrine release and decreases sympathetic outflow system.
It used as antihypertensive agent. The topical concentration of clonidine are
0.125% and 0.05%, clonidine which reduces intraocular pressure for 6–8hrs . The
0.125% concentration of clonidine is slightly less effective in reducing intraocular
pressure than 2% pilocarpine.( 62). Topical clonidine is generally well tolerated
except for minor drowsiness and dryness of the mouth.
Apraclonidine (0.5%)
Apraclonidine 0.5% is a derivative of clonidine by presence of amino ring in paraposition of benzene ring. It also reduces blood–brain barrier penetration and hence reduces systemic hypotension. Hence it has less CNS systemic side effects in
28 comparison with clonidine. Its reduces intraocular pressure by reducing episcleral venous pressure and increases trabecular outflow.
Brimonidine : (0.2%, 0.15 and 0.1%)
Brimonidine is a selective alpha 2-adrenergic agonist. It reduces intraocular pressure by by reducing aqueous formation and by increasing uveoscleral outflow(49). It has neuroprotective effect in addition. (50) which has been demonstrated objectively in rabbits only and not in human eyes . It is the most commonly used antiglaucooma medication in this group due to its low side effect profile . It was first marketed as a
0.2% concentration solution. Other concentration available are 0.15% and even 0.1% solution. Brimonidine is contraindicated in children due to cardiovascular instability, lethargy and sleepiness. The systemic absorption of brimonidine occurs with peak plasma concentration within 1-4 hours. It is metabolised by liver and eliminated by urinary excretion . It is also available in fixed combination with timolol. It has an additive effect with beta blockers, carbonic anhydrase inhibitors and miotics. As monotherapy it is used as thrice daily dosing and as twice daily if used in fixed combinations.
Systemic side effects of alpha 2 agonists:
Dy mouth, fatigue, drowsiness, headache, hypotension and bradycardia .
It also causes hypothermia and bradycardia in neonates.
29
Ocular side effects of alpha 2 agonists:
Itching , blurred vision, burning,
follicular conjunctival response, hyperaemia and photophobia.
Alpha 2 adrenergic agonists are contraindicated in infants and children as bradycardia, hypotension, hypothermia , hypotonia , CNS depression and apnea has been reported.(17)
Monotherapy vs combination therapy:
With monotherapy it is often insufficient to achieve the target intraocular pressure.
Combination of drugs is hence often required.
With administration of multiple medications, administration of a second drug within 5 minutes of an initial medication may cause substantial reductions in the concentration of the first drug because of washout of the first drug, thereby potentially reducing overall Intraocular pressure-lowering efficacy (63).
Additionally, exposure to more than one preserved topical medication (and therefore a greater cumulative exposure to irritating preservatives) may increase ocular symptoms (64)(65) and may predispose patients to discontinue their therapy.
Cost may also be a significant burden (66) Hence fixed combnation Anti glaucoma medications are used . The combination of drugs possible mainly depends upon the duration of action, ie dosing pattern as well as the mechanism of action. Till recently
Timolol was the only drug used in combination with other Anti glaucoma
30 medications. Recently fixed combination Carbonic anhydrase inhibitors and alpha2 agonists are available in the market.
The various Fixed-combination medications available include :
1. Timolol with Latanoprost
2. Timolol with Bimataprost
3. Timolol with Travaprost
4. Timolol with Brimonidine
5. Timolol with Dorzolamide
6. Timolol with pilocarpine
Fixed combination dugs have the advantages of ease of administration, increased tolerability, reduction of ocular symptoms through reduced cumulative exposure to preservatives, reduced cost , and very importantly compliance. (92).
Amount of Intraocular pressure reduction (%) achieved by various classes of
Antiglaucoma medications :
Among Intraocular pressure -lowering monotherapy treatments, prostaglandin analogs generally provide the greatest Intraocular pressure-lowering efficacy
Vanderwalk et al (51) in a meta-analysis of intraocular pressure lowering effect of commonly used antiglaucoma drugs randomized clinical trials determined the percentage Intraocular pressure change from baseline at peak of the commonly used antiglaucoma medications.
31
The % reduction is as below:
Prostaglandin analogs (31%–33%) (51)
β-blockers (23%–27%)
α2-adrenergic agonist (25%)
Carbonic anhydrase inhibitors (17%–22%) (51).
Betablocker with prostaglandin (33%)
Carbonic anhydrase inhibitor with Betablocker (26%)
Alpha 2 agonist and Beta blocker (22%)
The 24 hour efficacy of various classes of antiglaucoma medications:
Prostaglandins:
Stewart et al in a metaanalysis found that throughout the circadian cycle , prostaglandin efficacy as monotherapy is fairly uniform ( 67). The peak 24 hour efficacy of prostaglandin is usually 8–12 h after administration (68). With evening dose its efficacy is greater during daytime.(69).
Orzalesi et al and Quaranta et al (70)(68) which evaluated the 24-hr efficacy of prostaglandin showed that latanoprost was more efficacious than timolol from 10:00 pm to 6:00 am. Also it showed no significant differences in intraocular pressure between 8:00 am and 8:00 pm between latanoprost and timolol, whereas topical carbonic anhydrase inhibitor was as effective as latanoprost from 10:00 pm to
6:00am
32
Beta Blocker:
The mean circadian efficacy of timolol ranges from 10% to 25% in patients with
POAG (71). In another study by Orzalesi et al. (68) established that the nocturnal efficacy was only about half the daytime efficacy. This suggests that there is greater daytime intraocular pressure reduction and a smaller, but still significant, nighttime reduction .(70) ).Beta blockers have decreased nocturnal efficacy which may be explained by normally occurring reduction in endogenous circulating catecholamines at night (72).
Topical carbonic anhydrase inhibitors:
Orzalesi et al. (68) in 24 hour efficacy study compared dorzolamide, timolol and latanoprost and found that mean intraocular pressure was significantly lower with latanoprost whereas there was no significant difference between dorzolamide and timolol . Dorzolamide is as effective as latanoprost in reducing nighttime intraocular pressure (10:00 pm to 6:00 am) and less effective than timolol or latanoprost during daytime (6:00 am to 8:00 pm) (70) .
A meta-analysis by Stewart et al showed that dorzolamide reduced mean intraocular pressure by 16% at daytime and 21% at nighttime (67
33
Alpha2 agonists ( Brimonidine ) :
The mean 24 hour Intraocular pressure reduction of brimonidine 0.2 % used twice daily was 14 % to 19%. (67) (73)(74)The 24-h efficacy of brimonidine was similar to dorzolamide at daytime (8:00 am to 8:00 pm) and to timolol at nighttime (10:00 pm to
6:00 am).(70)
In a study by Orzalesi et al showed that brimonidine has minimal effect during late night time and early morning (between 3:00am and 6:00 am) but there is no significant difference from baseline. (75) .
A 24 hour study peformed by Liu et al. showed that brimonidine given three-times daily reduced the mean daytime Intraocular pressure by 12.5% but had no Intraocular pressure-lowering effect during night which was done in a sleep laboratory with 15 patients of open-angle glaucoma or Ocular hypertension, (76)
A 24 hour efficacy study conducted in primary open angle glaucoma patients by
Konstas et al. compared efficacy of brimonidine 0.2% administered twice, or three- times daily versus timolol maleate 0.5% given twice daily which showed mean 24-h
Intraocular pressure for brimonidine twice daily and three-times daily was 19.2 mmHg and 18.0 mmHg, respectively, whereas for timolol it was 17.7 mmHg. Hence it showed that thrice-daily brimonidine or twice-daily timolol reduced Intraocular pressure more than twice-daily brimonidine at every time point after 10:00 am. Also it was reported that three-times-daily brimonidine provided significantly better late afternoon and early nighttime efficacy than twice-daily dosing of brimonidine . (77)
34
A study conducted by Stewart et al comparing Brimonidine 0.2% versus dorzolamide
2% each given three times daily showed similar mean Intraocular pressure reduction at both trough and peak efficacy time points.(74)
The 24 hour efficacy of combination therapy :
Combination of prostaglandin analogs and with beta blockers:
1. Combination of latanoprost with Timolol :
A meta-analysis on 24-hour efficacy of Intraocular pressure -lowering medications reported that a combination of latanoprost with timolol showed an average reduction of 33% (67) A study conducted by Larsson et al in 20 patients with ocular hypertension with 1month follow-up showed that latanoprost with timolol was more efficacious than placebo both at daytime (10:00 am to 10:00 pm) and at nighttime (5.6 and 3.1 mmHg, respectively). (78)
A 24 hour efficacy study which compared (79) timolol used twice daily and combination of latanoprost with timolol dosed in the evening in 34 patients with
Primary open angle glaucoma. It showed mean intraocular pressure being reduced from 25 mmHg at baseline to16.4 and 19.3 mmHg in patients with latanoprost and timolol combination and timolol alone.
A 2 month cross over trial conducted in 37 patients with primary open angle glaucoma compared the 24 hour efficacy of Latanoprost with timolol combination with latanoprost alone (80). This study reported that baseline IOP was significantly reduced from 24.2 to 16.7 mmHg and 19.2 mmHg with Latanoprost and
35 timolol combination and Latanoprost alone. Also mean and individual time point
Intraocular pressure reduction were significantly lower with Latanoprost and timolol combination.
2. Combination of Travoprost with Timolol
In a study comparing 24 hour efficacy of morning versus evening administration of
Travaprost with timolol showed significant Intraocular pressure reduction at all time points. In comparison to morning dosing, the evening dosing of Travaprost with timolol showed significant 24 hour intraocular pressure reduction (18.4 vs. 19.2 mmHg) and reduced 24-hr fluctuation (3.8 vs. 5.1 mmHg). (81)
3. Combination of Bimatoprost with Timolol
A 24 hour efficacy study by Konstas et al showed that morning and evening dosing of Bimataprost with timolol was efficacious than bimataprost monotherapy at all time points. In comparison with mean 24 hour intraocular pressure reduction with morning dosing and the evening dosing of bimataprost with timolol (10.2 and 9.8mmHg with
P= 0.005), evening dose is more efficacious than morning dose (82)
Another study comparing 24 hour efficacy of combination drug Bimataprost with timolol and Latanoprost monotherapy reported that the mean untreated 24-h IOP was
31.1 mmHg and at the end of 3-months the mean 24-hour intraocular pressure reduction of bimataprost with timolol showd significant reduction than latanoprost
(18.9 vs. 21.2 mmHg; P<0.001). (83)
36
Combinations of Carbonic Anhydrase Inhibitors with Beta-Blockers
Combination of Dorzolamide and Timolol :
The 24 hour efficacy of average Intraocular pressure reduction reported with
Dorolamide and timolol is 26% based on a metanalysis (67)
A study conducted by Feldman et al compared the 24 hour efficacy of dorzolamide with timolol combination and timolol alone in 232 patients with open-angle glaucoma or OHT . This showed that Dorzolamide with timolol combination significantly reduced Intraocular pressure at all time points and also resulted in significant daytime reduction of intraocular pressure in comparison with timolol alone (84)
Eren et al. compared 24 hour efficacy of combination Dorzolamide with timolol and
Latanoprost with timolol in 33 Primary open angle glaucoma patients which reported that Latanoprost with timolol was more efficacious than Dorzolamide with timolol in lowering the mean 24-h Intraocular pressure (16.3 vs. 17.3 mmHg) and the peak 24-h
Intraocular pressure (18.5 vs. 19.9 mmHg).(85)
Another study which compared 24-hour efficacy of Dorzolamide with timolol to that of Timolol with brimonidine showed that Dorzolamide with timolol was more effective and the difference (mean -0.7 mmHg; 95% CI -1.0 to -0.3;P\0.001) reached statistical significance. (86)
Combination of Brinzolamide and Timolol :
One study showing 24hour efficacy of brinzolamide/timolol and brimonidine/timolol fixed combination as adjunctive therapies to travoprost . This study reported that brinzolamide/timolol fixed combination provided significantly better mean 24-hour intraocular pressure reduction (17.2 mmHg) than the
37 brimonidine/timolol fixed combination (18.0 mmHg) also brinzolamide/timolol fixed combination provided superior Intraocular pressure reduction in late afternoon and in night (6:00 pm till 2:00 am). (87)
Combinations of Carbonic Anhydrase Inhibitors with a Prostaglandin :
Dorzolamide/Brinzolamide and Latanoprost :
Three studies have reported the 24-h efficacy of dorzolamide when added to latanoprost found that when dorzolamide was added to latanoprost has an additive oculohypotensive effect than monotherapy.(88) (89).
A study by Nakamura et al.(90) compared the adjunctive 24-h efficacy of dorzolamide versus that of brinzolamide when added to latanoprost. It showed no significant difference in efficacy between the two drugs brinzolamide versus dorzolamide respectively.
Combination of an Alpha-2 Agonist and a Beta-Blocker:
Brimonidine and Timolol
A 6-month study evaluated the 24-hour efficacy of the fixed combination of brimonidine and timolol versus monotherapy which showed that both reduced baseline mean untreated intraocular pressure from 24.6 to 19.2 mmHg (91)
38
STUDIES ON FIXED COMBINATION BRINZOLAMIDE 1% AND
BRIMONIDINE 0.2% :
Fixed combination brinzolamide and brimonidine being only recently available in the market, there are only few studies evaluating this fixed combination
Nguyen et al (16) conducted a randomizied controlled trial (N= 690) fixed component Brinzolamide / Brimonidine (BBFC) with that of its components brinzolamide and brimonidine . At the 3-month primary endpoint, mean intraocularpressure of the BBFC group was significantly lower than that of either the brinzolamide group or the brimonidine group (P ≤ 0.005) across all time points. A total of 143 patients experienced at least 1 treatment-related adverse event (AE; BBFC group, n = 58, 26.2%; brinzolamide group, n = 44, 18.8%; brimonidine group, n = 41,
17.4%), the majority of which were ocular Adverse events such as blurred vision,eye irritation,pain ,pruritus,conjunctivitis,conjunctival hyperaemia,dry eye .
Another 6 month randomized trial (n= 690) by Whitson et al (93) showed that six- month mean Intraocular pressure values were similar to those at three months, when the mean Intraocular pressure in patients treated with BBFC was significantly lower than that of either monotherapy group. A total of 175 patients experienced at least one treatment-related adverse event (BBFC, 33.0%; brinzolamide, 18.8%; brimonidine,
24.7%), eight of which were severe, and five resulted in discontinuation. Seventy- seven patients discontinued participation due to treatment-related adverse events
(BBFC, 17.2%; brinzolamide, 2.1%; brimonidine, 14.5%). There were 21 serious
39 adverse events (n = 7 in each group), none of which was related to treatment. No new or increased risks were identified with use of BBFC relative to either monotherapy.
This study showed that, after six months of treatment, the safety profile of BBFC was similar to that of its individual components and its Intraocular pressure-lowering activity was similar to its efficacy at three months, when it was superior to both brinzolamide 1% alone and brimonidine 0.2% alone.
Another study by Katz et al (15) enrolled a total of 660 patients. At 3 months, the mean Intraocular pressure of the brinzolamide-brimonidine group (16.3-19.8mmHg) was significantly lower than that of either the brinzolamide group (19.3-20.9 mm Hg;
P≤0.002) or the brimonidine group (17.9-22.5mmHg; P<.001) across all time points.
One of 10 serious adverse events (chest pain, brinzolamide group) was judged as treatment related. A total of 129 patients experienced at least 1 treatment-related adverse effect (brinzolamide-brimonidine, 22.9%; brinzolamide, 18.6%; and brimonidine, 17.3%; P=.31), most of which were ocular. This registrational study provides evidence that the fixed combination of brinzolamide, 1%, and brimonidine,
0.2%, can safely and effectively lower Intraocular pressure in patients with open-angle glaucoma or ocular hypertension, showing significantly superior Intraocular pressure- lowering activity compared with either brinzolamideor brimonidine monotherapy while providing a safety profile consistent with that of its individual components
40
This study by Realini et al (94) enrolled a total of 1350 patients (BBFC,N=437; brinzolamide, n=458; brimonidine,n=455). Baseline mean Intraocualar pressure levels were similar among the three treatment groups. At 3 months, mean Intraocular pressure of the BBFC group was significantly lower than that of either monotherapy group (P<0.0001) at all the four time points. A total of 272 patients (20.1%) experienced at least one treatment-related Adverse effects (BBFC, 24.6%; brinzolamide, 18.7%; brimonidine, 17.4%), the majority of which were ocular
Adverse effect. One serious Adverse effect, moderate intensity chest pain, was considered related to brinzolamide treatment and resulted in study discontinuation.
This analysis strengthens the conclusions drawn from the two individual phase 3 studies showing that, in patients with open-angle glaucoma or ocular hypertension,
BBFC had significantly superior Intraocular pressure-lowering activity compared with either brinzolamide or brimonidine alone and a safety profile consistent with that of its individual components
This study by Aung et al (14) showed that Baseline diurnal Intraocular pressure was similar among groups (mean ± standard deviation: BBFC, 25.9 ± 0.19 mmHg; brinzolamide, 25.9 ± 0.20 mmHg; brimonidine, 26.0 ± 0.19 mmHg). At month 3,
BBFC lowered mean diurnal Intraocular pressure from baseline to a significantly greater extent than brinzolamide (least squares [LS] mean difference: -1.4 mmHg; P <
0.0001; t test) and brimonidine (LS mean difference: -1.5 mmHg; P < 0.0001). All supportive end points corroborated the results of the primary efficacy analysis. Mean percentage reductions in Intraocular pressure from baseline were 26.7% to 36.0% with
BBFC, 22.4% to 27.9% with brinzolamide, and 20.6% to 31.3% with brimonidine.
41
The most common adverse drug reactions were ocular side effects, including hyperemia, blurred vision, allergic-type reactions, and discomfort. The incidence of hyperemia of the eye was slightly lower with brinzolamide than with BBFC and brimonidine, whereas blurred vision and ocular discomfort were slightly more common with BBFC than with brinzolamide or brimonidine. Brinzolamide 1% and brimonidine 0.2% fixed combination administered BID had a significantly greater
Intraocular pressure -lowering effect than either brinzolamide or brimonidine alone and displayed a safety profile consistent with its individual components
Gandolfi et al (6) showed that The mean diurnal Intraocular pressure change from baseline with BBFC (least squares mean ± standard error -8.5 ± 0.16 mmHg) was noninferior to that with BRINZ +BRIM (–8.3 ± 0.16 mmHg; mean difference -0.1 mmHg; 95% CI -0.5 to 0.2 mmHg.The most common ocular adverse drug reactions were hyperemia of the eye (reported as ocular or conjunctival hyperemia), visual disturbances, ocular allergic reactions, and ocular discomfort .Common systemic adverse drug reactions included dysgeusia, oral dryness, and fatigue/drowsiness.
Brinzolamide 1%/brimonidine 0.2% fixed combination was as well tolerated and effective as concomitant therapy with its components. BBFC reduces treatment burden in patients who require multiple Intraocular pressure-lowering medications .
Greater reductions in mean Intraocular pressure with Brinzolamide 1% with brimonidine 0.2% compared with brinzolamide or brimonidine were observed at week
2 in both Phase III trials (15)(16) and continued for up to 6 months (mean reductions from baseline to month 6: 4.9–8.0 mmHg with BBFC, 4.1–5.8 mmHg with
42 brinzolamide, and 3.0–6.3 mmHg with brimonidine).(93) Thus, the therapeutic benefit of Brinzolamide 1% with brimonidine 0.2% occurs shortly after initial administration
(ie, within the first 2 weeks) and continues for up to 6 months.
Stefano et al (92) conducted a phase 3 multicenter 6-month trial in which he evaluated the efficacy of fixed-combination brinzolamide 1%/brimonidine 0.2%
(BBFC) versus concomitant administration of brinzolamide 1% plus brimonidine
0.2% . 890 patients were randomly allocated to two groups in this study .The mean diurnal IOP change from baseline with fixed combination brinzolamide and brimonidine (−8.5 ± 0.16 mmHg)was non inferior to that with concomitant administration of brinzolamide and brimonidine (–8.3 ± 0.16 mmHg) with a mean difference −0.1 mmHg; 95% CI −0.5 to 0.2 mmHg. Also the most common ocular side effects reported were conjunctival hyperemia , ocular allergic reactions, and ocular discomfort. Some systemic adverse drug reactions included dysgeusia, oral dryness, and drowsiness.
All the above studies of fixed combination brinzolamide 1% and brimonidine 0.2% are done in non - Indian eyes but there are no studies done in Indian eyes. Hence we conducted this study to evaluate the oculohypotensive effect of this fixed combination brinzolamide 1% and brimonidine 0.2% in our patients with open angle glaucoma.
43
MATERIALS AND METHODS:
This is a hospital based cross sectional observational study conducted in the
Department of Ophthalmology, Christian Medical College, Vellore.
Patients who visited the General Outpatient Department (OPD) of the Department of
Ophthalmology, Christian Medical College, Vellore who fulfilled the eligibility criteria were included in the study . An information sheet describing the aim and methodology of the study were given to all the participants. The information sheet was available in English and Tamil. The content of the information sheet was read out and explained to illiterate patients. Following this, an informed consent was obtained from each participant in a language understood by him/her. After obtaining an informed consent, a complete ophthalmic & systemic history and ophthalmological examination was performed on all patients. A medical history from each subject was obtained, including a list of all systemic medications. The examination included subjective and objective refraction, best corrected Snellen’s visual acuity, slit lamp examination, intraocular pressure measurement by Goldman applanation tonometry, gonioscopy and dilated fundus examination including stereoscopic biomicroscopic examination of the optic disc with 90 D lens. Field testing was done with Humphrey
Field Analyser , Central Corneal Thickness measurements was done as a part of the routine management of glaucoma not specifically as a part of the study design.
Patients satisfying the below inclusion and exclusion criteria were recruited into the study after informed consent:
44
Inclusion criteria:
1. Above the age of 18
2. Patients newly diagnosed to have Primary open angle glaucoma,
Pseudoexfoliation glaucoma, pigmentary glaucoma or Ocular hypertension
with intial intraocular pressure office hour ≥21mmHg .
3. Open angles on gonioscopy
Exclusion criteria:
1. Intraocular pressure more than 36 mmHg at diagnosis or during treatment
wash out
2. Cup-to-disc ratio 0.80 (horizontal or vertical measurement) in either eye
3. History of any antiglaucoma medications in the past 6 weeks.
4. History of using steroid eye drops within the past 1 month
5. Any patient with more than 1 recording of IOP less than 21 mm Hg out of the
3 IOP recordings at 8am , 12pm and 4pm during baseline visit.
6. History of intraocular surgery including laser procedure within 3 months of
enrollment in the study
7. Ocular surface disorders
8. Pregnant and lactating women
9. History or evidence of ocular inflammation or infection within the last 3
months
10. Central visual field loss in either eye
45
11. Ocular trauma any time in the past
12. Active or prior severe, unstable, or uncontrolled cardiovascular,
cerebrovascular, hepatic, or renal disease that would prevent safe
administration of topical a-adrenergic agonists or carbonic anhydrase
inhibitors, according to the investigator
13. Patients on oral Beta blockers
14. Current or anticipated treatment with any psychotropic drugs that augment
adrenergic response (e.g., desipramine, amitriptyline)
15. History of Hypersensitivity to a-adrenergic agonist drugs (e.g., brimonidine),
topical or oral Carbonic anhydrase inhibitor (brinzolamide), sulphonamide
derivatives, or any components of the study medication
16. Diabetic patients on Insulin therapy
Methodology :
Patients eligible for the study were examined at baseline, 2weeks ± 2 days and at
4weeks ± 2 days. At each visit all patients underwent routine ophthalmological examination which includes Best corrected visual acuity, slit lamp examination and fundus examination with 90 D condensing lens. Patients were evaluated for any conjunctival hyperemia, discharge, papillae or follicles, corneal Punctate epithelial erosions, anterior chamber flare or cells followed by intraocular pressure measurements using Goldmann Applanation Tonometry (GAT) .
46
At all visits intra ocular pressure were measured at 8 am (±1 hour), 12 pm (±1 hour), and 4pm (±1 hour). At 1 month visit patients were admitted for 24 hour phasing and
IOP was measured at 8am (±1 hour),12pm (±1 hour) , 4pm (±1 hour),8pm(±1 hour),12am(±1hour) and 4 am (±1hour)
After the IOP measurement at the baseline visit , patients were started on fixed combination brinzolamide (1%) and brimonidine (0.2%) (Simbrinza ) twice a day.
Patients were instructed to instill eye drops preferably at the same time every day (8 a.m. and 8 p.m.)
Patients were then reviewed at 2 weeks to check Intraocular pressureand to assess for any ocular and systemic side effects as below
Ocular surface adverse effects :
Hyperemia grading – Redness: None/ Mild / Moderate / Severe (Grading will be done by standard clinical photograph) (40) (pg 115 )
Burning : Mild** / Moderate** / Severe**
Watering: Mild / Moderate / Severe
Pain : Mild / Moderate / Severe
Pricking/foreign body sensation/irritation: Mild / Moderate / Severe
Sensation of dryness: Mild / Moderate / Severe
Itching, Swelling around the eyes: Mild / Moderate / Severe
Crusting of the lids: Mild / Moderate / Severe
47
**Mild : did not interfere with patients activities of daily life
**Moderate: interfered to some extent with patients activities of daily life, but not severe enough to consider discontinuation of the drug
**Severe: Interfered significantly with patients activities of daily life i.e severe enough to consider discontinuation of the drug or actually lead to the patient to discontinuing the drug
Systemic side effects:
Drowsiness, somnolence, dryness of mouth, altered taste sensations, fatigue
Any patient with ocular side effects which were graded as severe, as well as patients with any systemic side effects were taken out of the study and started on other anti- glaucoma medications as per routine standard of care. Also any patient who presented with these side effects prior to the 2 week scheduled visit were taken out of the study and started on other anti-glaucoma medications as per routine standard of care
Patients were asked to continue the drops and were subsequently seen at 4 weeks ± 2 days .Similar to the previous visits patient underwent routine ophthalmological examination which includes Best corrected visual acuity, slit lamp examination and fundus examination with 90D condensing lens. Patients were evaluated for any conjunctival hyperemia, discharge, papillae or follicles, corneal Punctate epithelial erosions, anterior chamber flare or cells followed by intraocular pressure measurements using Goldmann Applanation Tonometry (GAT) .
48
In addition to the office hours IOP in order to obtain the diurnal IOP profile, patients were admitted for phasing and additional IOP measurement were obtained at 8pm(±1 hour),12am(±1hour) and 4 am (±1hour).
At the end of the study period patients who had no side effects were continued on
Simbrinza if the target IOP was achieved and the patient could affird the medications.
If the target IOP was not achieved or the patient could not afford long term continuation of this combination due to economic reasons, additional or alternate , routine standard of care was provided as discussed and decided by the patient and the treating doctor and followed up in the out patient department .
49
FLOW CHART:
Identification of individuals with newly diagnosed open angle glaucoma not any antiglaucoma medications fulfilling the criteria from general Outpatient ,department of ophthalmology
Informed consent and recruitment
Questionnaire, routine ophthalmological examination and relevant investigations.
Baseline Intraocular pressure will be measured at 8 am (±1hr), 12 pm(±1 hr), 4pm (±1hr)
Patients will then be started on fixed combination of brinzolamide1% with brimonidine 0.2% twice a day
At 4 weeks , questionanaire for side effects , routine
ophthalmological examination, Intraocular pressure will be measured at 8am (±1hr), 12pm(±1 hr ) , 4pm (±1hr) ,
8pm (±1hr), 12 am (±1hr ) and 4 am (±1hr)
Data collection and analysis
50
RESULTS:
The study was conducted between March 2017 to August 2017.
25 patients were recruited into the study of whom 9 were males and 16 females (Table
1). Most of the patients were in the sixth or seventh decade. (Figure 2 ).Out of the 25 patients 13 were diabetics, 14 were hypertensives and 11 were both diabetic and hypertensive. None of the patients had heart block, bradycardia, cardiac failure, renal or liver diseases which are contraindications for use of brimonidine / alpha agonists.
Of the 14 hypertensives in the study none of them were on beta blockers. . Also none of 13 diabetics in our study were on insulin.
Table 1: Demographic data
Total number of Patients 25
No of males 9
No of females 16
Average Age 59.08 years
(Range ) ( 45- 70 years)
Diabetics 13
Hypertensives 14
Both diabetic and 11 hypertensive
51
Figure 1 : Age distribution of patients included in the study.
AGE
9
8
7 Number of patients 6
5
4
3
2
1
0 45 -50 51-55 56-60 61-65 66-70
Age in years
52
Ocular diagnosis - Type of glaucoma among the participants
Details of the distribution of type of glaucoma are given in (Table 2. and Figure2):
Table 2: Distribution of type of glaucoma among the participants
Type of glaucoma Frequency Percentage
Ocular hypertension 21 84%
Primary open angle 4 16% glaucoma
Pseudoexfoliation glaucoma 0 0%
Figure 2 : Distribution of type of glaucoma among the study patients
OCULAR DIAGNOSIS OCULAR HYPERTENSION
PRIMARY OPEN ANGLE GLAUCOMA 16%
84%
Majority of the participants were ocular hypertensives.
53
Pretreatment baseline intraocular pressure values (office hours ):
The average pre-treatment baseline IOP (average of the three IOP recordings at 8am,
12pm and 4pm)was 25.04± 2.55mmHg. Details of the IOP at each time – 8am, 12pm and 4pm are given in ( Table 3)
Table 3: Pre treatment baseline intraocular pressure (office hours)
Time Pre treatment IOP (Mean ± SD)
8am 25.48± 2.90 mm Hg
12pm 24.96 ± 2.79 mm Hg
4pm 24.68 ± 3.06 mm Hg
Average 25.04± 2.55 mm Hg
54
Post -treatment intraocular pressure at 1 month (office hours):
The average post -treatment baseline IOP (average of the three IOP recordings at
8am, 12pm and 4pm) at 1 month was 20.61 ± 1.73 mm Hg. Details of the IOP at each time – 8am. 12pm and 4pm are given in ( Table 4 ).
Table 4: Post- treatment intraocular pressure (office hours)
Time Post treatment IOP (Mean ± SD)
8am 21.28±2.23 mm Hg
12pm 20.64±2.02 mm Hg
4pm 19.92±1.82 mm Hg
Average 20.61±1.73 mm Hg
55
Comparison of pre-treatment and post treatment intraocular pressure (office hours):
The mean pre- treatment IOP was 25.04±2.55mm Hg and post- treatment IOP was
20.61±1.73 mm Hg. There was a 4.43 ± 3.13 mm Hg reduction in IOP which was statistically significant (Table 5).
The paired wise comparison between pre-treatment and post-treatment according to time is shown in (table 5, Figure 3 and 4 )
Table 5: Comparison between pre-treatment and post-treatment intraocular pressure
(Office hours)
Time Pre treatment IOP Post treatment IOP P value
Mean ± SD Mean ± SD
( mm Hg) ( mm Hg)
8am 25.48± 2.90 21.28±2.23 0.000
12pm 24.96 ± 2.79 20.64±2.02 0.000
4pm 24.68 ± 3.06 19.92±1.82 0.000
Average 25.04± 2.55 20.61±1.73 0.000
The fall in IOP was statistically significant at all time points.
56
Figure 3: Comparison between pre-treatment and post-treatment IOP according to time (Office hours)
Pre treatment and post treatment office hours 26
25
24
23 pretreatment 22 post treatment
Mean Mean IOPmmHg 21
20
19 '8am 12pm 4pm
Figure 4: Comparison between pre-treatment and post-treatment IOP according to time (Office hours) in bar graph
Pre treatment and post treatment office hours 26
25
24
23 pretreatment 22 post treatment
MeanIOP mmHg 21
20
19 '8am 12pm 4pm
Paired wise comparison between pre-treatment and post-treatment in office hours showed significant reduction in IOP at all office time recordings.
57
Amount of reduction in IOP pre and post treatment (office hours):
The average reduction in IOP was 4.43 ± 3.13 mm Hg (17.69% , Range 4.76-
36.58%). The IOP reductions at various time points were similar as shown in Table 6.
Table 6: Fall in intraocular pressure during office hours
Time Fall in IOP Reduction of IOP
Mean ± SD in percentage
( mm Hg)
8am 4.2± 2.75 16.48%
12pm 4.32 ±3.33 17.30%
4pm 4.76 ± 3.14 19.28%
Average 4.43± 3.13 17.69%
Though the drop in IOP post-treatment was significant, the amount of reduction in
IOP was less as compared to that reported in other studies. Hence we looked at individual patient data of these 25 patients – there were 4 patients in whom intraocular pressure reduction was ≤2 mm Hg post treatment as compared to pre- treatment. This poor response could most likely be due to non-compliance rather than the patients being non-responders as lack of response to both the components of the fixed combination (i.e both brimonididne and brinzolamide) is highly unlikely Hence we excluded these 4 patients and did an analysis on the remaining 21. In these 21 patients
, the mean pre-treatment IOP was 25.38±2.38 mm Hg and post-treatment at 1month
58 was 20.38±1.72 mm Hg. The average drop in intraocular pressure was 5.00±3.54 mm
Hg. There was 19.70% (range 9.98 – 36.58 %) reduction in intraocular pressure.
Distribution of amount of IOP reduction among patients:
The details of percentage of IOP reduction among patients is given in (figure 5 )
Figure 5 : Distribution of amount of IOP reduction among patients
Distribution of amount of IOP reduction
14
12
10 No of patients 8
6 % of IOP reduction
4
2
0 0-10% 11-20% 21-30% 31-40% % of IOP reduction
Most patients had IOP reduction between 11-20% (13 patients ) and 21-30 %
(6patients).
59
24 hour IOP profile of patients on fixed dose Brinzolamide 1% and brimonidine
0.2% at 1 month:
Diurnal variation (phasing) of IOP post- treatment:
Patients on treatment at the 1 month follow up were admitted to evaluate the nocturnal and early morning IOP. IOP was checked at 8am, 12pm, 4pm, 8pm, 12am and
4am.The IOP at each of these times is shown in Table 7 and Figure 6.
Table 7: Post- treatment 24 hour intraocular pressure phasing measurement
Time Mean ± SD
IOP
mm Hg
8am 21.28±2.23
12pm 20.64±2.02
4pm 19.92±1.82
8pm 20.52±1.85
12 am 20.32±2.23
4 am 20.40±2.58
Average 20.51± 0.44
60
Figure 6 : Diurnal variation of intraocular pressure post treatment
Post- treatment Diurnal variation of tension 26
25
24
23
post treatment
22 Mean IOP mm Hg mm IOP Mean 21
20
19 '8am 12pm 4pm 8pm 12am 4am
There was a tendency for intraocular pressure to rise from early morning 4am till it peaked at 8am and subsequently decline till late in the afternoon when the intraocular pressure recordings were at the lowest levels at 4pm. There was again a small rise in the intraocular pressure till 8pm after which it plateaued till 4am . Subsequently the intraocular pressure tended to rise to reach the peak at 8am.
Intraocular pressure fluctuated the least during night between 8pm to 4am. However comparison with pre-treatment nocturnal intraocular pressures was not possible as patients were started on treatment after office hour baseline IOP measurements and not admitted for full day phasing prior to treatment. Irrespective of pre-treatment nocturnal intraocular pressure , nocturnal intraocular pressure post- treatment showed good control of intraocular pressure with minimal fluctutation during night- sleep hours.
61
Comparison of Fluctuation in intraocular pressure during office hours pre and post treatment:
The details of fluctuation of IOP during office hours pre and post treatment are shown in the figure 7.
Figure 7 : Comparison of fluctuation of intraocular pressure pre and post treatment during office hours
Fluctuation in IOP ( office hours)
12
10
No. of 8 patients
6 pre treatment
post treatment 4
2
0 0 1 2 3 4 5 6 7 IOP fluctuation
Among the 25 patients recruited into the study, the pre-treatment office hours IOP fluctuated between 1 – 6 mmHg . Intraocular pressure variation was ≥4 mmHg in 9 patients (Figure 7).
Post-treatment , intraocular pressure fluctuation among the recruited patients was between 0-7 mmHg (Figure 7 ). IOP variation of ≥4 mmHg was seen in only 2
62
patients as compared to 9 patients pre-treatment . IOP fluctuation was lesser post treatment as compared to pre-treatment though the numbers are too small to make statistically significant conclusions.
However one patient had high fluctuation of upto 7 mmHg post-treatment . Hence we looked at the data of this patient and found that the IOP at 8am, 12pm and 4pm was respectively 29,27,27 mm Hg pre treatment and 25,19,18 mmHg post-treatment. In this patient, the greater reduction in IOP during afternoon hours as compared to the early morning IOP (8am) lead to the wider fluctuation , though there was a reduction in the mean IOP from 27.66 mmHg pre-treatment to 20.66 mmHg post treatment as well as lower IOPs at all time points post –treatment as compared to pre-treatment.
The intraocular pressure peak post-treatment persisted at the 8am recording in this patient causing the wide variation.
63
Fluctuation of intraocular pressure over 24 hour post- treatment:
Figure 8: 24 hour intraocular pressure fluctuation post treatment
24 hour IOP fluctuation post treatment
9
8
7 No. of patients 6 5 no of patients 4 post treatment 3
2
1
0 0 1 2 3 4 5 6 7
IOP fluctuation
Among the 25 patients recruited into the study, the post treatment IOP fluctuated between 1 – 7 mmHg . IOP fluctuation was between 1-4 mmHg in most patients (20 out of 25 patients) indicating good overall control of IOP during 24 hour IOP measurements. IOP variation > 4 mmHg was seen in only 5 patients. (figure 8).
Side effect Profile :
Details of the ocular side effects are shown in Table 8. None of the study patients experienced any systemic side effects or adverse events.
64
Table 8: Side effect profile at 2 and 4 weeks
Number of patients
Ocular side effects At 2 weeks After 4 weeks
Burning sensation 6 4
Watering 7 5
Pain Nil Nil
Foreign body / pricking sensation 10 8
Sensation of dryness Nil Nil
Itching Nil Nil
Swelling around eyes Nil Nil
Crusting of lids Nil Nil
Ocular Hyperemia 2 2
Systemic side effects
Drowsiness Nil Nil
Somnolence Nil Nil
Dryness of mouth Nil Nil
Altered taste sensation Nil Nil
Fatigue Nil Nil
65
The most common side effects were ocular surface symptoms of burning, watering foreign body sensation and hyperaemia. Out of the 25 patients enrolled in the study, burning was seen in 6 people at 2 weeks and 4 people at 4 weeks; foreign body sensation in 10 people at 2 weeks and 8 people at 4weeks and ocular hyperaemia in 2 people at 2 and 4 weeks. Thes symptoms were reported at the 2 week follow up and tended to get better at the 1 month follow up. None of these were severe enough to cause discontinuation of the medications.
None of the patients had swelling of the lids, itching or crusting.
None of the patients had any systemic side effects like drowsiness, altered taste sensation, dryness of mouth or fatigue.
No patients discontinued the eye drops due to any intolerable side effects or severe side effects.
66
DISCUSSION
Newly diagnosed primary open angle glaucoma and ocular hypertension patients alone were recruited into the study. We did not wash out patients already on anti- glaucoma medications for recruitment into the study since most patients with previously diagnosed glaucoma attending the out patient department had well controlled IOP on their present anti-glaucoma medications . It was not ethical to washout these patients with well controlled IOP for the study purpose since adequate data about this new fixed combination drug are available by phase 3 trials , though these studies have not been done in Indian eyes.
Also patients with IOP > 35mm Hg and disc cupping > 0.8 were excluded since these patients have advanced glaucoma or very high IOPs wherein appropriate aggressive treatment with necessary established antiglaucoma medications is necessary .
Recruitment of these patients would mean deviation from standard of care and could be potentially harmful to the patient as well..
Pre-treatment intraocular pressure was measured only during office hours. Ideally a full time 24 hour phasing could have been done pre-treatment; but this was not done due to logistic problem from the patient’s perspective and hence the possibility that the patient may not come for such a evaluation.
However we did a 24 hour phasing post-treatment, as by this visit, patients would have acquired knowledge of the disease, would be familiar with the system and also in a state to understand the purpose of the study and not worried that the admission is due to any major eye problem that he/she has. 24-hour intraocular pressure profile
67 and fluctuation of intraocular pressure through the day and night in patients on this fixed combination has not been looked at in any of the previous studies of this fixed dose combination.
25 eyes were recruited into this study between March 2017 to August 2017 and most of them were in the 6th to 7 thdecade . 13 were diabetic, 14 were hypertensive and 11 were both diabetic and hypertensive.
None of the 14 hypertensives in the study were on beta blockers. Patients with hypertension on oral beta blockers were not recruited into the study since beta blockers can reduce IOP and confound the results of the study.
None of 13 diabetics in our study were on insulin.Diabetics on insulin were not included in the study since hypoglycaemia can produce symptoms which are similar to and can be confused with the central nervous system side effects of brimonidine , the alpha agonist component of the fixed combination. The CNS side effects include drowsiness, headache, hypothermia , hypotension , apnea and CNS depression.
Of the 25 patients recruited into the study, 21 patients had Primary Open Angle
Glaucoma (POAG) , 4 had ocular hypertension and none had pseudoexfoliation glaucoma. Patients with normal tension glaucoma , angle closure glaucoma were not included in this study as the pathogenesis is different in these.
The mean IOP pretreatment was 25.04± 2.55mmHg and post treatment at 1 month was 20.61±1.73mmHg. The average drop in IOP was 4.43± 3.13 mmHg.(Table 4, figure 3 and 4) .There was 17.69% ( range 4.76 – 36.58 %)
68 reduction in IOP which was statistically significant at all time points. (Table 4 and page no 55.)
The amount of intraocular pressure reduction ( office hours) achieved in our study by this fixed combination was lower compared to that reported in other studies.
Katz et al (15) reported intraocular pressure reduction of 24.1 to 34.9 %.Whitson et al (93) reported IOP reduction of 20.0 to 30.7 %, Stefano et al reported intraocular pressure reduction of 28.6 to 37.6 % .(92). To find out the possible reason of thelesser ocular hypotensive effect in our patients, we looked at the data of individual patients and found 4 patients had intraocular pressure reduction of < 2 mm Hg post treatment
(which could most likely to be non-compliance rather than non- response since non- response to both components of the fixed combination is unlikely) . Even after excluding these patients the IOP reduction in the remaining 21 patients was 19.70%
(range 9.98 – 36.58 %) , which is still less compared to other studies. It is noteworthy tht all the other studies were on Caucasians. Hence it is possible that the poorer response seen in our patients could be due to racial variation – perhaps the darker iris pigmentation in our population leading to altered uptake and availability of the topical medication in this fixed combination. We searched for studies on Indian eyes of the individual components of BBFC to see if the component drugs had lesser efficacy in
Indian eyes as compared to Caucasian eyes. In Caucasian eyes IOP reduction of 16.9 to 22% with Brinzolamide monotherapy(15) and 14.3 to 25.8% (15) has been reprted. We found only one Indian study on Brimonidine monotherapy by Thomas
RT et al (98)but no Indian studies on Brinzolamide or Dorzolamide monotherapy. In this study(n= 28 ) IOP reduction of 22% at 6 weeks follow up was reported. Hence
69 the IOP reduction of 17.69% seen in our study seems to be lower than the individual component as well.We are unable to postulate any reason for the lower IOP reduction achieved by this fixed combination. Though a separate study, the individual component (Brimonidine) seems to have more ocular hypotensive effect in Indian eyes than the fixed combination – indicating that the fixed combination reduces the efficacy of the individual components. However it has been confirmed in large phase
3 trials (15)(16)(94) that the fixed combination has better efficacy than the individual components. More studies on the individual components as well as this fixed combination is necessary in our population to obtain more consistent data on the amount of IOP reduction achieved by these drugs in our population before we can conclude that it could be due to racial variation in response to the drugs or if it is due to any other factors. All previous studies have measured office hours IOP; none of the studies looked at nocturnal or 24 hour profile of IOP in these patients.
The diurnal variation 24 hour plot at 1 month post- treatment in our study showed a peak in the early morning (8am). Nocturnal pressures were low with minimal fluctuations . The early morning peak could be a part of diurnal variation pattern seen in many patients with glaucoma as well as normals and this fixed drug combination is likely to have reduce overall IOP without causing any change in the diurnal pattern .
However pretreatment diurnal pattern were not obtained as a part of the study design as reasons mentioned earlier . Irrespective of pre-treatment diurnal pattern of variation, this fixed dose showed good 24 hour control of IOP especially with minimal fluctuation during night – sleep hours. The early morning peak was also within 2 mm Hg of trough seen at 4pm.
70
On looking at the range of fluctuation in each patient pre and post -treatment during office hours (figure 7) , less patients had IOP variation of ≥ 4mm Hg following treatment ( 2 patients post-treatment vs 9 patients pre- treatment) indicating that the
IOP fluctuation was lesser post- treatment but the numbers were too small for statistical significance.
During 24- hour IOP recording also, most patients had IOP fluctuation between 1-
4mmHg and indicating good overall control of IOP through the day and night. IOP variation of >4mmHg was seen in only 5 patients(Figure 8 ). We did not find any previous studies looking into the IOP profile and fluctuation on patients on this fixed dose combination in literature for comparison. However studies have been done looking at the 24-hour IOP profiles of the individual components- Brinzolamide (or its equivalent Dorzolamide ) and Brimonidine. Orzalesi et al. (68) showed that
Dorzolamide is effective in reducing nighttime intraocular pressure .The same author in another study l (75) showed that brimonidine has minimal effect during late night time and early morning. These indicate that the nocturnal IOP reduction of this fixed combination is attributable mainly to Brinzolamide.
The effect of the fixed dose combination Brinzolamide 1% and brimonidine 0.2%was evaluated at 1 month in our study. The patients hence were on treatment short –term
.But previous phase III trials by Katz G et al (15) and Nguyen et al (16) have shown that the initial lowering in IOP achieved at 2weeks by this fixed dose combination is sustained for up to 6 months. They concluded that the therapeutic benefit of
71
Brinzolamide and brimonidine occurs after initial few weeks of administration
( within first 2weeks) and continues for upto 6 months. Hence the results of our study too is most likely to reflect long term efficacy of Brinzolamide and brimonidine in our population.
The most common side effects were ocular surface symptoms -4 patients with burning sensation (16%), 8 patients with foreign body sensation (32 %), 5 patients with watering (20%), 2 patients with hyperaemia (8%) which compares with similar to other studies . Also other studies have reported lesser incidence of ocular surface symptoms varying from 1.1 to 5.3% ( 94); but this could be due to variation in methodology of adverse effects with our study looking at mild degrees of ocular surface symptoms/signs. Details of the exact method of grading of side effects in the other studies are not available for comparison.
It is noteworthy that none of them require discontinuation of treatment. The symptoms also tended to be better at 4 weeks compared to 2 weeks indicating a trend to better tolerability long term. However in the study by Nguyen et al more side effects at 6 months compared to 3 months (16)(93)
There were no systemic adverse effects were observed or reported by any patients .
The incidence of systemic side effects from other are around 0 - 8.3% ( 94) our study numbers were too small to pick up any systemic side effects.
72
LIMITATIONS :
1. Our study followed up patients only for 1 month . Since glaucoma
medications are applied over long term, longer duration of study would further
confirm the results of the study. However previous studies (15)(16) which have
recruited patients at 2 weeks ,6 weeks and 3 month had found the amount of
IOP reduction seen at 3 months is similar to the fall in IOP achieved in the
intial part of the study at 2 weeks and is maintained over longer follow up of 6
month. Hence the results of this study are likely to be representative of the long
term IOP control achieved by this fixed dose combination.
2. It would have been ideal to obtain pre-treatment 24 hour diurnal variation plots
for comparison of post- treatment diurnal variation. But due to logistics reasons
form patient’s perspective, this was not planned as part of the study design.
3. Though no serious side effects were seen or reported by any of the patients in
our study , the number of patients were too small and the duration of follow up
was short. Longer follow up of larger number of patients would be needed to
obtain the true spectrum of the long term ocular side effects.
73
CONCLUSIONS:
1. Fixed combination ofBrinzolamide 1% and Brimonidine 0.2 % achieved mean
reduction of 4.43± 3.13 mm Hg ; 17.69% ( range 4.76 – 36.58 %) at 1 month
in our patients with primary open angle glaucoma and ocular hypertension .
The amount of IOP reduction was statistically significant but lower compared
to that reported in other studies reported in Caucasian eyes.
More studies are required to get more data on the ocular hypotensive effect of
this fixed dose combination in our population and possibly find out the resaons
for lower ocular hypotensive effects if found in these studies in our population
as compared to Caucasian eyes .
2. There were no patients with severe ocular surface or any systemic side effects.
None needed discontinuation of the drug.Patients had mild ocular surface
symptoms which did not interfere with daily activities or quality of life.
Since the incidence of serious adverse effects are low as reported in other
studies , larger no of patients are needed to be studied to detect the occurrence
of serious adverse effects.
3. No previous studies have looked into the 24 hour IOP profile of patients of
this fixed combination. In our study, the 24 hour IOP recordingsin patients
on treatment of this drug showed low nocturnal IOPs with minimal
nocturnal fluctuation but an early morning peak (8am).
74
4. On looking at IOP fluctuation in each of the study patients, IOP fluctuation
of ≥ 4 mm Hg was seen seen in 9 pre-treatment compared to 2 patients
post-treatment indicating overall reduction in fluctuation following
treatment . However the numbers are too small for statistical analysis.
5. Though our study evaluated effects of fixed combination Brinzolamide and
Brimonidine short term(1 month), the results of this study are likely to be
representative of the long term IOP control achieved by this fixed dose
combination as previous studies have shown that the reduction in IOP
achieved at 2 weeks are maintained over 6 months ( 15)(16)
It would be appropriate to follow up these patients at 3 and 6 month to
confirm the continued ocular hypotensive effect and obtain data on the side
effects of fixed combination Brinzolamide and brimonidine over long term.
75
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Patient information sheet:
Study of ocular hypotensive effect and tolerability of fixed-combination
Brinzolamide 1% and brimonidine 0.2% in Indian eyes with open angle glaucoma
Name of participant: Hospital number:
You are invited to take part in this study. The information in this document is meant to help you decide whether or not to take part in the study. Please feel free to ask if you have any queries or concerns.
What is the study about?
Glaucoma is a disease of the eye in which there is progressive damage to the optic nerve along with gradual decrease in vision from the peripheries. It does not usually have any symptoms in the early stages, and is usually detected when the vision loss affects the centre of the retina, or macula. At this point the vision loss is irreversible. It is the second leading cause of blindness in the world and the leading cause of irreversible blindness. Multiple factors have been thought to play a role in the disease, but a raised intra-ocular pressure ( pressure in the eye ) has been found to be the one that is most causally associated. In addition to this, Intraocular pressure is the only modifiable factor identified till date i.e. a reduction in Intraocular presssure has been found to slow/stop the progression of the disease. There are many drugs available which controls intraocular pressure.and lots of information available about many drugs which controls intraocular pressure. But this is a new drug Brinzolamide 1% with Brimonidine 0.2% (Simbrinza) in Indian market which has been said to decrease 34% reduction in intraocularpressure. Since it is a new drug we would like get a little more information on how much reduction in intraocular pressure at various time points it achieves as well as assess if it can be tolerated well without causing any discomfort in the eyes. However at any point in this study if we found that you are not tolerating it or it is not causing desired decrease of intraocular pressure we will change to previously available drug. This is not going to cause any serious side effects as has already been tested in other studies done in other countries. Hence in this study we will study the intraocular pressure lowering ability of the fixed combination drug brinzolamide 1% and brimonidine 0.2% also the side effect profile of the drug. Also it would help in comparing how much reduction in intraocular pressure it achieves
100 compared to the medications that you are currently using for glaucoma .
If you take part, what will you have to do?
If you take part in the study, you will be asked a few questions which are relevant to the study. . If you are newly diagnosed patient after checking intraocular presuure from morning till evening you will be started on fixed combination (simbrinza) brinzolamide 1% and brimonidine 0.2% . Also if you are already on any antiglaucoma medication which has not achieved the target intraocular pressure, the antiglaucoma medication which you were using will be stopped and after 4 weeks intraocular pressure will be checked from morning till evening , following which will be started on Simbrinza . In view of stopping the previously used antiglaucoma medication you will be reviewed to check intraocular pressure 2 weeks after stopping the drug , if high you will be restarted on antiglaucoma medication. Similarly after 4 weeks of starting the Simbrinza drug Intraocular pressure will be checked from morning till evening (8 am, 12pm and 4 pm).. Hence you would need to come for a check up atleast 4 times within the next 2 months.
Are there any risks for you if you take part in the study?
As a result of repeated intra-ocular pressure measurements, you may have some erosions on the surface of your cornea that may cause discomfort. This however can happen during routine eye exam also apart from the study. To avoid this you will be administered lubricating eye drops after each Intraocular pressure measurement, and followed-up in the out-patient department till the condition heals completely free of cost. We do not expect any long-term or serious ocular side-effects as a result of participation in this study, but if you do develop any other ocular side effects or problems due to the study, these will be treated at no cost to you. However, we are unable to provide any monetary compensation.
Do you have to pay?
You will have to pay only for the tests that are required for the routine management of your disease. All additional investigations for the study will be done free of cost.
What are the benefits to you if you take part in the study?
If you participate in the study, you will develop a greater understanding of glaucoma
101 and the importance of Intraocular pressure control. If the medication you are on are found to be inadequate in controlling your IOP fully, you will be changed to previously available drug . This will ultimately help in slowing the progression of disease and prevent further damage to the nerve.
What are the possible benefits to other people?
The results of this study may provide benefit to the society in terms of advancement of medical knowledge, disease prevention, and therapeutic benefit to future patients. We hope that this study will help us determine the efficacy and tolerability of brinzolamide 1% and brimonidine 0.2% in our population with open angle glaucoma.
What will happen if I withdraw from the study?
There will be no adverse consequences of withdrawing from the study and there will be no disturbances in your routine eye care. You can withdraw at any point of study without affecting your medical and legal rights. Participation in the study is entirely voluntary and you may withdraw at any time.
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Study title: Study of oculohypotensive effect and tolerability of fixed-combination
Brinzolamide 1% and brimonidine 0.2% in Indian eyes with open angle glaucoma
Study Number: ______
Subject’s Name: ______
Date of Birth / Age: ______
(i) I confirm that I have read and understood the information sheet dated ______for the above study and have had the opportunity to ask questions. [ ]
(ii) I understand that my participation in the study is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected. [ ]
(iii) I understand that the Ethics Committee and the regulatory authorities will not need my permission to look at my health records both in respect of the current study and any further research that may be conducted in relation to it, even if I withdraw from the trial. I agree to this access. However, I understand that my identity will not be revealed in any information released to third parties or published. [ ]
(iv) I agree not to restrict the use of any data or results that arise from this study provided such a use is only for scientific purpose(s). [ ]
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(v) I agree to take part in the above study. [ ]
Signature (or Thumb impression) of the Subject/Legally Acceptable
Signatory’s Name: ______
Signature:
(Or)
Representative: ______
Date: _____/_____/______
Signatory’s Name: ______
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Signature of the Investigator: ______
Date: _____/_____/______
Study Investigator’s Name: ______
Signature or thumb impression of the Witness: ______
Date: _____/_____/______
Name of the Witness: ______
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DATA COLLECTION SHEET
Name: Date of examination:
Age: Study serial no:
Gender: Schell hospital no:
Contact number: CMC Hospital no if any:
Address:
General History
Systemic illness: Diabetes mellitus- Y/N
Hypertension- Y/N
Heart block- Y/N
Bradycardia-Y/N
Cardiac failure- Y/N
Renal diseases- Y/N
Liver diseases- Y/N
Bronchial asthma- Y/N
Any other illness-
Treatment History:
If hypertensive, medications on-
Antipsychotic medications-Y/N
If yes , medications-
Ocular history:
Right eye Left eye
Primary Ocular diagnosis
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Details of medication (If on topical ocular hypotensive medication- name and timings of medication)
IOP Measurement – Newly diagnosed Patients not on any AGM
IOP Baseline IOP - 1st On Simbrinza On Simbrinza visit At 2 weeks At 4 weeks Right eye Left eye Right eye Left eye Right eye Left eye
8 am
12pm
4pm
IOP Measurement – Newly diagnosed Patients not on any AGM
IOP On Simbrinza At 4 weeks Right eye Left eye
8 pm
12am
4am
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Side effect Proforma
Questionnaire:
Ocular side effects:
Right eye Left eye
Mild Moderate Severe Mild Moderate Severe
Burning sensation
Watering
Pain
Foreign body / pricking sensation
Sensation of dryness Itching
Swelling around eyes Crusting of lids
*Mild : Did not interfere with patients activities of daily life
Moderate: Interfered to some extent with patients activities of daily life, but not severe enough to consider discontinuation of the drug
Severe: Interfered significantly with patients activities of daily life i.e severe enough to consider discontinuation of the drug or actually lead to the patient to discontinuing the drug
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Ocular hyperaemia : Based on clinical photography
none Mild moderate severe Right eye Left eye
Systemic side effects:
Drowsiness – Y/N
Somnolence - Y/ N
Dryness of mouth- Y/N
Altered taste sensation- Y/N
Fatigue-Y/N
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Grading of ocular hyperemia : Based on clinical photography **
**Blood-Aqueous Barrier Changes After the Use of Prostaglandin Analogues in Patients With Pseudophakia and AphakiaA 6-Month
Randomized Trial Arch Ophthalmol. 2005;123(2):186-192. doi:10.1001/archopht.123.2.186
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