Glaucoma

1
Glaucoma

• Glaucoma is widely known as a disease related to
  the intraocular pressure

2
Glaucoma Changing views

• Glaucoma is an optic neuropathy with
  characteristic structural damage to the
• optic nerve, associated with progressive
• retinal ganglion cell death,
• loss of nerve fibres and visual field loss

American Academy of Ophthalmology
3
Glaucoma Multifactorial Disease

• Glaucoma is a complex multifactorial disease
  associated with
• Elevated IOP ,
• Pressure-independent factors like aging
• Diabetes
• Hypertension

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Glaucoma Optic Nerve Damage

• Elevated IOP
• Mechanical back pressure
• On the junction of optic nerve/retina
• Reduce the blood supply to the optic nerve
• Loss of blood supply (lt in pOBF)
• Ischemia
• RGC cell loss

"Lost my Eye to Glaucoma, not to Pirates!
Blindness
5
Neuronal Degeneration Causes

• Ionic Imbalance
• Excessive Free radical generation
• Excessive accumulation of Neurotransmitters like
  glutamate
• Depletion of nerve growth factors

6
Glaucoma Thus has Multiple Causes,
Resulting in Multiple Damages like Optic nerve
Damage,Ischemic Blood Vessels of Retina Thereby
Multiple Treatment /Therapeutic Options are of
utmost importance for Glaucoma
Multiple Damages
Requires
Multiple Medications
Multiple Causes
7
Glaucoma Management
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For more than 150 years, IOP has been implicated
in the initiation and pathogenesis of
glaucomatous optic neuropathy.
9
AAO Guidelines Target IOP
reduction from baseline
Ref Surveys of Ophthalmology 2003 48 (suppl 1)
53-57
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IOP control is not only mainstay of glaucoma
therapy, but something beyond

• Glaucoma Management
• Where new ideas are vital

11

• Optic Neuropathy plays a major role in the
  pathogenesis of glaucoma and vision loss.
• Neuroprotection and Decrease in IOP play a major
  role in delaying the progression of glaucoma

12

• NEUROPROTECTION

Ample evidence exists in the literature stating
that reducing ocular tension is
neuroprotective. Hence , using an neuroprotective
agent like brimonidine in reducing IOP, would
offer double benefits
13
Neuroprotection Aim

• The aim of this therapy is to protect neurons
  from
• the factors thought to damage and destroy
  them,
• and uphold their function

14
Neuroprotection Potential Strategies

• Adrenoreceptor agonists Brimonidine
• Glutamate-receptor antagonists
• Sodium /Ca2 blockers
• Scavengers of free radicalsAnti-oxidants
• Nitric Oxide Inhibitors Gingko extract
• .

15
For Treating a Multifactorial Disease , Multiple
Medications May Be Required

• Achieve Target Multiple Medications Required

16
Multiple drug therapy Limitations

• 5 or 6 topical instillations each day
• Older patients find it difficult to follow
  complex regimens
• Younger patients lifestyle makes it difficult
• Patient might not feel the compulsive need to
  take medications regularly.
• Complex dosing regimens have been clearly
  associated with nonadherence and non-compliance.
• Increased exposure of ocular surface to
  Benzalkonium chloride ,may cause surface toxicity
  and may increase the prevalence of dry eye
• J Glaucoma 1999, 8(5), 315-324

17
Fixed Dose Combination Advantages

• Potential risk of confusion between the two
  bottles is overcome.
• Fewer daily drops than concomitant therapy
• Convenient dosing regimen
• Risk of elimination of first drop from
  conjunctival sac by instillation of second drops
  is completely eliminated.
• Ensures increased patient convenience and
  compliance
• Improves therapeutic efficacy.
• Am J Ophthalmol 2000, 130832-833

The idea of combining two or more drugs is to
produce the additivity of desired therapeutic
effect but not of the side effects
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Approved Combinations Currently Available

• Dorzolamide Timolol
• Latanoprost Timolol
• Brimonidine Timolol
• Travoprost Timolol
• Bimatoprost Timolol

19
Introducing
Brimocom
20
BRIMOCOM

• Brimonidine-Timolol Fixed Combination
• Brimonidine tartrate 0.2
• Timolol 0.5

21
Timolol
First Topical Beta Blocker Considered A Bench mark
22
Timolol Beta Blocker

• Timolol, the first ?-blocker to be approved for
  glaucoma in 1974
• Widely used as first-line therapy
• Benchmark against which other ?-blockers and
  second line glaucoma therapies are assessed for
  efficacy and tolerability
• Ref Drugs and Aging 2000 17(6) 477-496

23
Timolol

• Non selective beta blocker
• Reduces IOP by inhibiting aqueous humor
  production.
• Mainstay of glaucoma medical therapy (first line
  agent)
• About 27-35 reductions in IOP are reported
  during long term treatment.
• Drugs 2000, 57(3), 411-434

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• Alpha-2- agonist Brimonidine

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Brimonidine Mechanism of Action

• Brimonidine is a highly selective alpha-2-
  agonist
• Dual mechanism of action
• Reduces the aqueous humor production by 20
• Increases the uveoscleral outflow by 5 fold

Drugs and Aging,mar 1998,12 (3, 225-241)
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Brimonidine Mechanism of Action

• Attaches to ?2-receptors on ciliary processes
• Constriction of afferent blood vessels to ciliary
  processes
• Decreases Aqueous Humour Production
• Ref Therapeutic drugs, Second Edition, 1998,
  A195-A198

27
Brimonidine Neuroprotection

• Brimonidine brings about vasodilation of the
  endothelial cells of the blood vessel.
• Therefore, flow of blood to the retinal layers
  increases.

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pOBF Implications

• pOBF Pulsatile Ocular Blood Flow is blood supply
  to the retina and optic nerve head , which
  supplies oxygen and nutrients to retina.
• With an increase in pOBF , there is reduction in
  ischemia , and thereby loss of RGC is reduced,
  thus enhancing neuroprotection
• A dramatic drop in POBF, representing diminished
  ocular perfusion, is usually followed by a
  significant rise in IOP.

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Brimonidine Effect on pOBF
Change
Time (h)

• One drop of brimonidine increased the pOBF value
  from 15.7to 26.1 with a peak of 29.9 after 8
  hours.
• An increase in pOBF was seen since day 1 of
  treatment which was consistent throughout.

Clinical Therapeutics,2001,23(9),1519-1528
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Brimonidine Highlights

• Neuroprotection
• Higher rate of retinal ganglion cell (RGC)
  survival with brimonidine
• Neuroprotective effect is seen with brimonidine,
  but not with timolol
• Consistent increase in pulsatile ocular blood
  flow (pOBF) seen from day one of treatment

Should be prescribed when neuroprotection is to
be enhanced
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Brimocom Clinical Efficacy
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Effect of BTFC on Aqueous humor flow in human
eyes compared with monotherapy.

• Design
• A randomized, double-masked, placebo-controlled
  study
• Patients (n) 20
• Medications instilled twice daily the day before
  and again on the morning of the day of the
  measurements.
• Aqueous humor flow and IOP was measured.

Arch Ophthalmol. 2001 Apr 119(4) 492-5.
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BTFC Effect on Aqueous Humour Production and IOP
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Effect On Aqueous humour production and IOP
Effect of BTFC on aqueous humour suppression and
IOP reduction was more than individual molecules
. Effect was observed to be partially additive
35
BTFC therapy versus monotherapy patients with
glaucoma or ocular hypertension
3 month multicenter, double-masked studyPatients
with glaucoma or ocular hypertension were
randomized to receive fixed

The primary outcome measure was decrease from
baseline IOP.
Arch Ophthalmol. 2006 1241230-1238
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BTFC therapy versus monotherapy a 3-month
randomized trial in patients with glaucoma or
ocular hypertension

• Results

Mean IOP reductions from baseline were
significantly larger with BTFC than with
brimonidine at 8 AM, 10 AM, and 3 PM (P lt
0.001) the difference was greater than 1.5 mmHg.
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8 a.m
FIXED-COMBINATION THERAPY FOR IOP
26
A
22
22
20
Mean IOP (mm Hg, SEM)
18
lt0.001 vs timolol
p
16
lt 0.001 vs brimonidine
p
14
0
1
2
3
Months of treatment
38
5 p.m
D
26
22
22
20
Mean IOP (mm Hg, SEM)
18
16
14
0
1
2
3
Months of treatment
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Percentage of patients who had a mean diurnal IOP
of less than 18 mmHg at all visits.
plt.001 vs timololplt.001 vs brimonidine
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12-week study comparing the BTFC with Concomitant
Therapy

• 1.To evaluate the efficacy and safety of BTFC
  ophthalmic solution dosed BID
• 2.Demonstrate non-inferiority of BTFC to
  concomitant use of individual molecules in
  patients with IOP uncontrolled on monotherapy.
• METHODS
• 371 patients with inadequate IOP control (IOP
  from 22 to 34 mmHg)
• gt or 3 weeks of run-in on any monotherapy.
• Fixed-combination group n 188
• Concomitant Group n 183
• IOP was assessed pre-dose and 2 hours after
  morning dosing at weeks 2, 6, and 12.

Eur J Ophthalmol. 2005 Sep-Oct 15(5) 581-90.
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Fixed Combination Vs Concomitant Therapy

• Results
• BTFC was as effective as concomitant therapy
• No unexpected side effects were associated with
  the fixed combination.
• Both treatments were well tolerated with no
  difference in adverse events between groups.

42
Mean IOP over 12 weeks (Hour-2)
Brimonidine/timolol fixed-combination therapy is
as safe and effective as concomitant treatment
with the individual components. Its simplified
dosing regimen has the potential to improve
compliance.
43
Brimocom Safety Tolerability
BTFC is safe and effective as concomitant
treatment with individual molecules.
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Brimocom Indications

• Reduction of intraocular pressure (IOP) in
  patients with chronic open-angle glaucoma or
  ocular hypertension who are insufficiently
  responsive to topical beta-blockers.

45
Brimocom Dosage and Administration

• Recommended dosage in adults (including the
  elderly)
• The recommended dose is one drop of Brimocom in
  the affected eye(s) twice daily, approximately 12
  hours apart.
• If more than one topical ophthalmic product is to
  be used, the different products should be
  instilled at least 5 minutes apart.

46
Brimocom Special Populations

• (a) Pregnancy Category C
  Administer on a
  risk to benefit ratio
• (b) Nursing mothers Not recommended
• (c) Paediatrics Not recommended
•  

47
Brimocom Contraindications

• Reactive airway disease including
• bronchial asthma or a history of bronchial
  asthma,
• severe COPD.
• Sinus bradycardia, second or third degree
  atrioventricular block, overt cardiac failure,
  cardiogenic shock.
• Use in neonates
• Patients receiving monoamine oxidase (MAO)
  inhibitor therapy.
• Patients on antidepressants which affect
  noradrenergic transmission (e.g. tricyclic
  antidepressants and mianserin)
• Hypersensitivity to the active substances or any
  of the excipients

48
Brimocom Highlights

• Brimonidine timolol fixed combination produces
  a statistically significant greater lowering of
  IOP as compared to either Timolol or Brimonidine
  monotherapy
• Brimonidine-timolol fixed combination reduced IOP
  by up to 33 (7.6 mm Hg) from an untreated
  baseline of 23.3mmHg.
• Safe and Well Tolerated
• Added advantage of NEUROPROTECTION.
• Brimocom - BD convenience.
• No need for refrigeration

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• Post surgical patients especially those who have
  had cataracts removed are excellent candidates
  for Brimonidine-Timolol Fixed Combination
• Canadian physicians are increasingly using BTFC
  to control postoperative pressure spikes.
• Dr. Crichton

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I find BTFC to be well tolerated than
brimonidine and timolol taken separately. Dr.Pete
r Galloway Consultant Ophthalmologist
Significant number of patients experience
stinging. We dont have this fear with
Brimonidine-timolol Combination , which shows a
much better tolerability profile with respect to
stinging. Dr.Francisco Goni Consultant
Ophthalmologist
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Comparison Of Individual Molecules
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Thank You