2. Overall goal to manage all patients with glaucoma is to
preserve visual function while maintaining the best
possible quality of life.
This goal is achieved by preventing or slowing the
progression of glaucomatous damage by lowering IOP
to a level at which further damage is minimal.
3. WHEN TO TREAT..
Whether treatment is really indicated
When elevated IOP is present without glaucomatous
damage,the risk factors for progression to glaucoma
should be evaluated before deciding whether to treat.
When the patient presents with established
glaucomatous damage or dangerously high IOP,the
indication to initiate treatment is usually clear.
4. RISK FACTORS FOR PROGRESSION
EMGT- In Early glaucoma patients
ELEVATED IOP
OLDER AGE
BILATERALITY
EXFOLIATION
DISC HEMORRHAGES
THIN CENTRAL CORNEA
5. How to start..
Initiating treatment involves establishing the
target pressure, selecting the appropriate
medication, educating and instructing the
patient, and follow-up evaluations to establish
efficacy and safety of the treatment.
6. ESTABLISHING THE TARGET
PRESSURE
Elevated IOP is the most important causative risk
factor for glaucoma development and progression,
and it is the only one for which we have proven
treatment.
However, there is no single pressure value that is
appropriate for all patients.
Rather, the physician must establish a target
pressure that can prevent further glaucomatous
damage.
The target is based on the status of the optic nerve
head and other risk factors for progression.
7. Although there are no universal guidelines for
establishing the target pressure, the target for eyes with
minimal damage (e.g., early neural rim thinning without
visual field loss) may be in the middle to high teens (mm
Hg).
For eyes with moderate damage (e.g., cupping to the
disc margin in one quadrant with early field loss) should
probably be in the middle to low teens.
Eyes with advanced damage (e.g., extensive cupping
and field loss) usually require pressure in the low to
subteens.
8. RISK FACTORS TO BE CCONSIDERED IN
ESTABLISHING TARGET PRESSURE:
Central corneal thickness
Old age
Family h/o glaucoma
Africa heritage and myopia-increased risk for presence
and progression of COAG
Asian heritage and hyperopia-increased risk for ACG
Vascular factors-ischemia and vasospastic disease ,may
contribute to pathogenesis and increased risk of
glaucoma.
9. Exceptions to Medical
management
Patients with very high IOP
History of medical treatment without success or with
intolerable effects
Acute angle clossure glaucoma
Childhood Glaucoma
10. Educating and instructing the
patient..
About the disease
Why the medications
The therapeutic regimen
Follow up
11.
12.
13. When medically treating glaucoma, the goal
should be to treat with the least number of
medications, at the lowest concentrations, and at
the lowest frequencies of administration, taking
cost into account, if possible.
Generally, monotherapy is instituted first. If target
IOP is not reached with the first agent, a class
switch can be tried and next combination therapy.
If monotherapy reduces IOP yet fails to reach the
target IOP, one should examine the percentage
drop in IOP that was achieved to help determine
whether or not the drug should be substituted or
maintained with a drug addition.
14. Monotherapy should reduce IOP at least 15%
from baseline.
Below that figure, the patient qualifies as a
nonresponder to that medication.
If IOP reduction is less than 15%, initial
monotherapy should be substituted with
medication of another class.
If IOP drops 15% or more but the target
pressure is not reached, a second medication
should be combined with the initial therapy.
15. Switching within a class usually adds little
additional therapeutic effect.
However, switching from a less potent selective
beta1 blocker to the more potent nonselective
beta blockers can be effective, if not
contraindicated.
Switching between topical carbonic anhydrase
inhibitors does not appear justified in terms of IOP
reduction.
Switching among prostaglandin analogs is
somewhat controversial, with some studies
showing a percentage of patients to be more
responsive to one brand name drop over another.
16. Combination therapy
It is generally accepted that a 15% or greater
IOP lowering effect justifies continued use of
the first drug with an additional drug, instead of
substitution.
Combining medications is frequently
necessary to lower IOP adequately.
17. Best combination is that of a prostaglandin
analog (which increases outflow) with a beta
blocker(which decreases inflow)
It decreaes number of eyedrops to be instilled
into the eye,decreases preservative induced
conjunctival toxicity and increases compliance
along with providing equivalent IOP
reductions.
18.
19. PROSTAGLANDINS AND
HYPOTENSIVE LIPIDS
The prostaglandins are the newest class of
glaucoma drugs.
They offer a new mechanism of pressure
reduction through enhanced uveoscleral outflow.
The absence of common systemic side effects
and the superior IOP efficacy has made this
class of medications attractive for first-line
therapy.
20. Ocular side effects such as conjunctival
hyperemia, eyelash changes, iris
pigmentation, and darkening of the periocular
skin may cause some patients to object to
chronic use of the medications.
Less common but more serious ocular side
effects include cystoid macular edema in some
pseudophakic eyes and anterior uveitis. The
conjunctival changes also may influence the
outcome of filtering surgery.
21.
22. Latanoprost (0.005%) was the first topical
prostaglandin to be introduced.
It is a synthetic prodrug of prostaglandin F2 alpha
that is given once each day and seems to be more
effective when administered in the evening.
Its 24-hour IOP efficacy is superior to that of timolol
maleate (0.5%, used twice daily) in high-pressure
and normal-tension forms of glaucoma. Latanoprost
is additive to all other classes of glaucoma drugs.
In 2002, the U.S. Food and Drug Administration
(FDA) approved latanoprost as an initial treatment
for elevated IOP associated with open-angle
glaucoma or ocular hypertension.
23. Bimatoprost (0.03%) and travoprost (0.004%) are
similar in mode of action and effectiveness to
latanoprost .
One study suggested that travoprost might have a
potentially higher effectiveness in lowering IOP in
African Americans, although this has not been
substantiated.
The docosanoid unoprostone isopropyl (0.15%) is a
derivative of docosahexaenoic acid. It has less IOP
efficacy than the other prostaglandins, but it has
been approved by the FDA as adjunct therapy for
the treatment of mild to moderate glaucoma. The
results of blood flow studies with unoprostone have
been conflicting.
24. Bimatoprost is hydrolysed by the cornea to a
lesser extent than with latanoprost,
unoprostone and travoprost into the active free
acid form of the drug.
Has been shown to lower IOP in patients with
chronic angle clossure glaucoma.
25. TRAVOPROST
Also been shown to be effective in lowering IOP
in patients with chronic angle-clossure
glaucoma.
The greater IOP reduction was associated with
a higher baseline IOP and a thinner central
corneal measurement.
26. If treatment with a prostaglandin lowers the
IOP significantly (e.g., 20% to 30%), but the
target pressure is still not achieved, a
uniocular trial of an additional medication with
a different mechanism of action is usually
indicated as possible combined therapy.
27. Beta-blockers
We have the most experience in recent decades with
topical Beta-blockers, which were often used for the
initial medical management of open-angle glaucoma
since the FDA approved timolol in 1978.
These drugs, which lower IOP by reducing aqueous
production, are available as nonselective (i.e., blocking
Beta1 and Beta2 receptors) or as selective (i.e., primarily
blocking Beta1 receptors) agents.
28. Concentrations of Beta-blockers used in treating
glaucoma range from 0.25% to 1.0%, and are usually
instilled one or two times per day.
The selective Beta-blocker betaxolol may cause fewer
pulmonary and cardiovascular side effects, but it is less
effective in lowering IOP than the nonselective Beta-
blockers.
Some studies suggested that betaxolol might have a
neuroprotective effect by decreasing influx of calcium
into retinal ganglion cells.
29. Timolol
Non selective beta 1 and beta 2 adrenergic antagonist
Lacks the adverse effects related to corneal anaesthesia
and subconjunctival fibrosis compared with earlier beta
blockers.
With the availability of timolol in the gel-forming
solution,several clinical studies have shown
equivalence in IOP lowering for timolol gel dosed once
daily and timolol solution dosed twice daily.
30. Betoxolol
Levubunolol-effective with once-daily administration
Carteolol-non selective beta adrenergic antagonist with
intrinsic sympathomimetic activity;shown to cause lesser
ocular irritation than timolol in the first few minutes after
instillation.
Metipranolol-0.3%
Atenolol
Metoprolol
Pindolol
Nadolol
Befunolol
31. SIDE EFFECTS
OCULAR TOXICITY
Burning and conjunctival hyperemia-frequenntly
associated with superficial puctate keratopathy
and corneal anaesthesia.
Ocular cicatricial pemphigoid-topical timolol
Metipranolol-granulomatous anterior uveitis-
mutton fat keratic precipitates,flare,cells,IOP
elevation.
35. Selective alpha adrenergic
agents
The alpha-2-adrenergic agonists primarily lower IOP
by reducing aqueous production.
Apraclonidine in a 1% concentration is useful in
preventing IOP spikes that may occur after anterior
segment laser procedures.
Apraclonidine in a 0.5% concentration can also be
used short term in glaucoma patients on maximally
tolerated medical therapy who require additional
reduction in IOP, but its chronic use is limited by
frequent allergic reactions.
36. Brimonidine is more selective than apraclonidine and
appears to elicit a lower incidence of ocular allergic
reactions. Like apraclonidine, it can be used to prevent
IOP spikes after argon laser trabeculoplasty (ALT).
Brimonidine is additive to timolol and latanoprost and
can be used as combination or replacement therapy,
although it is not as effective as latanoprost.
37. In addition to reducing aqueous production, it
appears to enhance uveoscleral outflow, and
animal studies have suggested a
neuroprotective effect through mechanisms
that are not clearly understood.
Brimonidine has not been tested for children
younger than 2 years of age and should be
used with extreme caution for patients
between the ages of 2 and 7 years .
38. Dipivefrin and Epinephrine:
Direct-acting sympathomimetic that stimulates
both alpha and beta adrenergic receptors.
39. OCULAR TOXICITY:
APRACLONIDINE:
Follicular conjunctivitis with or without contact dermatitis.
Eyelid retraction,mydriasis,conjunctival blanching due to
cross reactivity with alpha-1 adrenergic receptors in
Muller muscle,iris sphincter muscle ,and arterial smooth
muscle.
40. Reactive hyperemia-Epinephrine>dipivefrin
Oxidation and polymerisation-convert the drug
to adrenochrome,which occurs as dark deposits
in several ocular structures.
Epinephrine associated cystoid macular
oedema in aphakic eyes.
42. CARBONIC ANHYDRASE
INHIBITORS
Only type of drugs that are used as systematically
administered agents in chronic glaucoma therapy.
Belong to sulphonamide class of drugs
Lower IOP by decreasing aqueous humor flow through
inhibition of carbonic anhydrase in ciliary epithelium.
The main therapeutic target of CAIs in the ciliary
processes is the ciliary cytosolic CA II isoform(formerly
called type C).
When dorzolamide is added to timolol,there is an additive
effect to suppress aqueous humor flow.
43. CARBONIC ANHYDRASE
INHIBITORS
Oral and topical CAIs lower IOP by reducing
aqueous production.
To achieve the therapeutic effect,more than 90%
of the CA activity needs to be inhibited.
Oral CAIs were introduced in the 1950s and are
much less commonly used since the availability of
topical CAIs, largely because of the frequent
systemic side effects of the pills.
Acetazolamide is administered as 250-mg tablets
four times daily or 500-mg sequels one or two
times per day, and methazolamide (25 to 50 mg)
is given two or three times per day.
44. For children,the recommended dose of
acetazolamide is 5 to 10mg/kg of body weight
every 4 to 6 hrs.
Acute angle clossure glaucoma-250mg of
acetazolamide can be given intravenously.
Methimazole-longer plasma half life than
acetazolamide .
These drugs, especially acetazolamide, may be
effective when topical medical therapy is
inadequate, and they are still used today in
some patients to achieve the target pressure.
45. Topical CAIs include 2% dorzolamide and 1%
brinzolamide.
When used as adjunctive therapy, dorzolamide
is approximately equivalent to 2% pilocarpine in
further lowering IOP.
Brinzolamide is equal to dorzolamide in IOP
efficacy but causes less burning. Both drugs are
given two or three times daily and are additive to
timolol.
Topical CAIs also appear to increase ocular
blood flow.
46. DORZOLAMIDE:
Lowers IOP by reducing aqueous humor flow by
inhibiting tha CA II isoenzyme in the ciliary body.
At 2 hours after using,dorzolamide causes
14.7% to 27% reduction in IOP and at 8 hours
after dosing,12.9% to 17.5% reduction in IOP.
47. When Brinzolamide 1% was compared with
dorzolamide 2%,the absolute IOP lowering and
percentage IOP lowering were similar,with upto
19.1% lowering with brinzolamide dosed 3 times
daily and 20.1% lowering with dorzolamide
dosed similarly.
48. SIDE EFFECTS
OCULAR SIDE EFFECTS:
Transient reaction.
Ultrasonography of a patient with induced
myopia associated with sulphonamide therapy
revealed shallowing of the AC without thickening
of the lens, suggesting that ciliary body oedema
might cause forward movement of the lens-iris
diaphragm,which can also account for a
mechanism of angle clossure due to the forward
shift of the lens-iris diaphragm.
49. M/C-irritation immediately after instillation
Transient blurred vision
Occasional hypersensitivity reactions
Periorbital dermatitis
Corneal oedema(in few cases since CA isoenzymes I &
II are
expressed in corneal endothelium and are involved in
maintaining corneal transperency).
50. SYSTEMIC SIDE EFFECTS
Parasthesia of fingers and toes and around the
mouth.
Increased urinary frequency due to diuretic
action
Serum electrolyte imbalances
Malaise,fatigue,weight
loss,anorexia,depression, renal calculi formation
Blood dyscrasias
Maculopapular and urticarial types of skin
erruptions.
51. MIOTIC AGENTS
After its introduction in 1870s, pilocarpine was
the cholinergic agent most commonly used in
treatment of open-angle glaucoma.
It is still occasionally used in concentrations
ranging from 0.5% to 4%, typically
administered four times daily.
It was once available in a gel preparation and
as an ocular insert, both of which reduced the
ocular side effects that are common with this
class of drugs.
52.
53. CHOLINERGIC STIMULATORS AND
HYPEROSMOTIC AGENTS
Pharmacologic agents that mimic the cholinergic effects
of acetylcholine are are referred to as cholinergic
agonists,parasympathomimetic stimulators,or miotics
because of their effect on the pupil.
They are the class of compounds administered
systematically,in short term,emergency situations,like
acute angle clossure glaucoma or other glaucomas
involving dangerously high intraocular pressures.
54. CHOLINERGIC STIMULATORS
The cholinergic agents are indicated for use in
all forms of open angle glaucoma where the
aqueous outflow system is functionally intact.
They share a common mechanism of action by
stimulating muscarinic cholinergic receptors-
mainly the m3 muscle receptor which is the
predominant subtype expressed in human ciliary
muscle cells and iris sphincter.
55. PILOCARPINE solution is applied topically and is
largely degraded in the cornea,with less than 3%
entering the anterior chamber.
The IOP lowering effect is dose related upto
Pilocarpine,4%;
In darkly pigmented eyes,pilocarpine,6%,may produce
additional IOP reduction.
Although not commonly prescribed,another formulation
of 4% pilocarpine hydrochloride is a high viscosity
acrylic vehicle(Pilopine),which is applied at bedtime and
produces a significant IOP reduction for 24 hours.
56. Carbachol is a dual action parasympathomimetic that
produces direct muscarinic receptor stimulation and an
indirect parasympathomimetic effect by inhibiting
acetylcholinesterase.
Another route of administration is intracameral injection
of either carbachol or acetylcholine to achieve miosis
during surgery.
After cataract surgery,intacameral carbachol has been
shown to provide better IOP control in the early
postoperative period,compared with intracameral
acetylcholine or placebo using balanced salt solution.
57. SIDE EFFECTS
Stimulation of glands,contraction of smooth muscle,and
cardiac and central cognitive effects.
Symptoms include diaphoresis,salivation,tearing,and
bronchial secretion.
Smooth muscle contraction may cause nausea,
vomiting, diarrhoea,bronchospasm,abdominal pain,and
genitourinary effects.
58. Ciliary muscle spasm leads to a brow ache.
Transient myopia is caused by an axial thickening and forward shift
of the lens.
Rhegmatogenous retinal detachment since the ciliary body
contraction exerts vitreoretinal traction,which causes retinal tears.
Pilocarpine-Cataractogenic effect
Superficial corneal haze
Cicatricial pemphigoid-in patients undergoing long term topical
glaucoma therapy.
Hypersensitivity and toxic reactions-due to use of Pilocarpine or the
preservative.
Allergic reactions-eyelids and conjunctiva –with a giant papillary
reaction of superior tarsal conjunctiva
Toxic reactions-follicular response in the conjunctiva.
59. HYPEROSMOTIC AGENTS
The most widely accepted mechanism is the reduction
of vitreous volume due to a change in osmotic gradient
between the blood and ocular tissues,which lowers the
IOP.
The systemic administration of a hyperosmotic agent is
occasionally used as an emergency method of lowering
IOP or preoperatively to minimize the ‘posterior
pressure’ effect of the vitreous in a supine position.
60. Glycerin(Osmoglyn) is administered orally in a dose of 1
to 1.5/kg of body weight of a 50% solution.
The ocular hypotensive effect occurs within 10 minutes
of administration,peaks in 30 minutes,and lasts for
almost 5 hours.
Mannitol is administered intravenously with a filter
administration set over 30 minutes in a dose of 1-2 g/kg
of body weight of a 25% solution.
61. 20% mannitol may be given intravenously
over 60 minutes, either 1 g/kg or 20 g total,
preferably starting 1 h before surgery in order
to reduce severe intraoperative/postoperative
complications in select predisposed patients.
62.
63. SIDE EFFECTS
Diuresis,headache,acidemia,anaphylactic
reaction,backache, cardiovascular overload resulting
from transient rise in blood volume,fever,disorientation
Mannitol has been shown to increase aqueous flare in
humans,which may have implications regarding
increased postoperative inflammation
65. Neuroprotection in glaucoma is the targeted
treatment of neurons of the visual pathway
(particularly RGCs) that are damaged in the
glaucomatous process.
In neuroprotection, the goal is to directly
stimulate or inhibit specific biochemical
pathways that either prevent injury or stimulate
recovery of these neurons.
Indirect treatments, such as IOP lowering, by
definition are not neuroprotection.
66. Rho-associated coiled-coil-forming protein kinase
(ROCK)
inhibitors
The Rho family consists of guanosine
triphosphate-binding protein which plays a vital role in
regulating cell shape, motility, contractility, proliferation,
and apoptosis.
Rho-associated coiled-coil-forming protein kinase
(ROCK) is serine/threonine inhibitors which act as
selective inhibitors of the actin cytoskeleton contractile
tone of smooth muscle in the trabecular meshwork.
This results in increased aqueous outflow directly
through the conventional pathway, thereby lowering IOP.
There are also animal studies indicating that ROCK
inhibitors may improve optic nerve head blood supply.
67. Ripasudil (K-115, Kowa Ltd, Nagoya, Japan) is the first
Rho kinase inhibitor which has been approved in Japan
for ocular hypertension (OHT) and glaucoma therapy.
Nearly 0.4% of drug is to be used as a twice-daily
application.
Results from a Phase II clinical trial showed that the
drug reduced IOP by 3.2, 2.7, and 3.1 mmHg from a
baseline of 23 mmHg when used in concentrations of
0.1%, 0.2%, and 0.4%, respectively.
The drug displayed a favorable safety profile, and 50%
of enrolled patients had only mild conjunctival
hyperemia in Phase I and II of the trial.
68. Netasurdil (AR 13324) (Aerie
Pharmaceuticals, North Carolina, USA) has a
dual action of being a ROCK inhibitor and
norepinephrine transporter inhibitor.
It facilitates uveoscleral outflow in addition to
the trabecular outflow and decreases the
episcleral venous pressure.
69. Prostanoid agents:
These drugs enhance aqueous outflow
through the uveoscleral pathway and
cause IOP lowering.
Recently, EP2, EP3 receptors have
emerged as new targets of interest for
IOP-lowering therapy.
70. DE-117 (Santen Pharmaceutical, Japan) is an
EP2 agonist.
These agonists cause relaxation of endothelial
cells in
the Schlemm’s canal, facilitating uveoscleral
outflow.
They also increase conventional outflow by acting
on the
trabecular meshwork, decreasing cell contractility
and
collagen deposition (Vis-a-vis latanoprost which
71. Taprenepag isopropyl (PF-04217329) is an EP2 agonist.
Escalating topical doses of 0.0025% to 0.02% as once daily
administration in patients diagnosed with POAG or OHT was
compared with latanoprost 0.005%.
Furthermore, unfixed combinations of the agonist with
latanoprost were compared with latanoprost monotherapy in
a 28-day trial.
Results from Phase II showed that taprenepag was
comparable to
latanoprost 0.005% in IOP reduction.
Preclinical animal studies demonstrated a dose-related iritis
and increased corneal thickness with 0.015% and higher
concentrations that resolved within 28 days of discontinuing
the drug.
72. ADENOSINE RECEPTOR
AGONISTS
Many physiological and biochemical pathways in the body are
mediated through G protein-coupled adenosine receptors.
Adenosine receptor agonists stimulate secretion of matrix
metalloproteinases (MMPs) in the endothelial cells lining the
trabecular meshwork. This causes cell volume shrinkage and
extracellular matrix remodeling,which ultimately facilitates
conventional aqueous outflow.
Trabodenoson (INO 8875) (Inotek Pharmaceuticals, USA) is an
adenosine A1 receptor agonist currently in Phase III clinical trial.
It demonstrated a favorable safety profile including an unremarkable
electrocardiogram and the conjunctival hyperemias produced were
generally mild and transient.
73. Memantine is a selective
N-methyl-d-aspartate receptor antagonist with
a potential to prevent glutamate-induced
excitotoxicity of RGCs.
74. The full role of nitric oxide in the eye is not fully
understood, but it appears to have a physiologic
role in aqueous humor dynamics maintaining a
clear cornea,ocular blood flow, retinal function ,
and optic nerve function .
Excessive nitric oxide appears to contribute to
pathologic eye problems, such as uveitis and
glaucoma .
75. In an experimental rat model of glaucoma with high IOP
for 6 months, the optic nerves showed features
compatible with damage characterized by pallor,
cupping, and ganglion cell loss .
After 6 months of treatment with aminoguanidine, a
selective inhibitor of iNOS, the optic nerves appeared
normal, and there was less ganglion cell loss despite
elevated IOP.
This study was the first to demonstrate that excess nitric
oxide generated by iNOS in optic nerve astrocytes and
microglia was associated with optic nerve damage. This
study has led to research on the use of selective iNOS
inhibitors as a neuroprotective approach in the
76. NTG- calcium channel blocker therapy-
significant reduction in the rate of disc and
field change progression
77. Systemic calcium channel blockers (CCB)
cause vasodilation by preventing the
intracellular uptake of Ca2+.
CCB may improve optic nerve head perfusion,
particularly in patients with normal-tension
glaucoma
78. Contact lens-based drug
delivery
Silicone hydrogel soft contact lenses loaded
with nanoparticles containing timolol have
been found to elute the drug for more than a
month in animal models.
The drug diffuses from the lens into the tear
film, increasing the bioavailability potential by
50%, as against topical formulations with only
1%–5% bioavailability.
79. Ocular inserts are polymers filled with the
drug, which are designed to be placed in the
conjunctival cul-de-sac or in the puncta.
Inserts are composed of matrix-based,
biodegradable polymers such as chitosan.
The drug is directly absorbed by the mucosal
lining. These inserts have the advantage of
providing a prolonged drug delivery directly to
the target tissue, decreasing the systemic side
effects.
80. GENE THERAPY IN
GLAUCOMA
Both viral and nonviral vectors are used to deliver
genes to target tissue of interest such as trabecular
meshwork, ciliary epithelium, ciliary body, and RGC.
Gene therapy can be used to delete,
replace/inactivate an aberrant gene, or introduce a
new gene which helps in targeted therapeutic protein
expression.
Downregulation of MMP1 expression in the trabecular
meshwork is postulated to play a role in the
pathophysiology of steroid-induced OHT.
Animal studies have shown that intracameral injection
of adenovius carrying the recombinant MMP1 resulted
in reversal of corticosteroid-induced OHT.
81. Loss of cyclooxygenase (COX-2) in
nonpigmented ciliary epithelial cells has been
implicated in the pathophysiology of POAG.
Animal studies have demonstrated that
intracameral delivery of lentivirus vectors
expressing COX-2 and FP resulted in
transduction of trabecular meshwork and
ciliary epithelium and ultimately IOP reduction.