Indian Journal of Pharmacology 2002; 34: 71-85 EDUCATIONAL FORUM

ROHIT SAXENA et al.

PHARMACOTHERAPY OF GLAUCOMA

ROHIT SAXENA*, JAI PRAKASH, PRIYA MATHUR, SURESH KUMAR GUPTA

*Dr. Rajendra Prasad Centre for Opthalmic Sciences and Department of Pharmacology,
All India Institute of Medical Sciences. Ansari Nagar, New Delhi-110 029.

Manuscript Received: 9.5.2001 Revised: 26.7.2001 Accepted: 28.8.2001

ABSTRACT There has been a dramatic change in the medical therapy of glaucoma during the last two decades.
Until the 1980s, miotics were the drugs of first choice for treating this disease but at present, β-blockers
are regarded as the first choice drugs. Apart from β-blockers, a number of newer drugs which have
fewer systemic and ocular side effects and act by different mechanisms have become commercially
available for ophthalmic use. Important among these are latanoprost, unoprostone, brimonidine,
apraclonidine, dorzolamide and brinzolamide. In addition, attempts have been made to enhance patient
compliance and ocular delivery of already available antiglaucoma drugs like pilocarpine. Notable among
the delivery systems are electronic devices, ocular inserts, transdermal and mechanical drug delivery
systems and liposomes. Use of viscoelastic vehicles (soluble polymers to soluble gels) in ophthalmic
formulations, emulsions and soluble ophthalmic drug inserts (SODI) have also enhanced the patient
compliance and drug absorption by ocular tissues in patients on long term glaucoma therapy. The
present review deals with various classes of β-blockers, prostaglandin analogs, carbonic anhydrase
inhibitors, adrenergic agents, drugs affecting cholinergic pathway and hyperosmotic agents employed
in the management of glaucoma. It also throws light on the role of neuroprotective agents and other
drugs under investigation.

KEY WORDS IOP cholinomimetics adrenergic-blockers osmotics prostaglandins

ocular drug delivery systems

Introduction the optic disc and subsequent loss of retinal nerve

Glaucoma continues to be a major cause of irrevers-
ible visual disability all over the world. At present,
there are approximately 7.5 million diagnosed cases
of blindness, of which glaucoma accounts for 10-20%.
It is estimated that there are about 2.47 million cases
of primary open angle glaucoma in United States
alone, the commonest type of glaucoma in the West1.
A review of 15 population based glaucoma prevalence
surveys in Western Europe, US, West Indies and Ja-
pan shows that the disease remains underdetected in
nearly 50% of patients, the reasons for this being var-
ied in nature2. Among Asians, the incidence of angle
closure glaucoma is almost twice as high as that for
caucasians. The true picture of the disease incidence
in the Asian continent remains to be elucidated as yet.
Glaucoma is characterized by progressive damage
to the optic nerves resulting in increased cupping of
fibres. Current studies indicate the involvement of
excitatory and inhibitory neurotransmitters viz.
glutamate, gamma amino butyric acid (GABA) and
glycine in the development of glaucoma. The excess
supply of excitatory neurotransmitter glutamate is
particularly linked to glaucoma3. Apoptosis or geneti-
cally programmed cell death has also been implicated
as a mechanism for progression of glaucoma4.
Risk Factors
Elevated intraocular pressure (IOP) is accepted as
the single most important risk factor for chronic open-
angle glucoma. A few other factors like eye trauma,
concomitant use of drugs, pressence of diabetes
mellitus, hypothyroidism, cardiovascular and hema-
tological abnormalities etc., are important as well5.
Virtually every study that has examined the

Correspondence: S.K. Gupta

e-mail: skgup@hotmail.com

relationship between age and chronic open angle glau-
coma has confirmed that the older the individual,
greater the risk of glaucoma6. The Collaborative Glau-
coma Study identified that visual field defects over a
13 year period were approximately 7 times higher in
persons 60 years of age or older than in persons un-
der 40 years of age1. The hypothesis that race is a
major risk factor for glaucoma is based on the data
indicating a higher prevalence of the disease among
blacks. Several ocular parameters associated with
glaucoma are also known to be influenced by hered-
ity and the presence of family history. Women of all
races develop acute angle closure glaucoma 3 to 4
times as often as men. The global burden of glau-
coma poses a challenge to the researchers, ophthal-
mologists and general practitioners to detect, prevent
and effectively treat this visual disability and make
safer drugs available to mankind at an affordable price.
Pharmacotherapy of Glaucoma
Prevention or modification of risk factors, particularly
the raised intraocular pressure is the primary goal in
the management of glaucoma. The disease needs to
be managed medically, by laser therapy or by con-
ventional surgery as the case may be.
Classification of antiglaucoma agents
Depending on their route of administration
antiglaucoma agents may be classified as
Topical drugs:
1. Cholinergic agents e.g. pilocarpine, carbachol,
demecarium bromide and echothiophate iodide.
2. Adrenergic agonists e.g. epinephrine, dipivefrin,
brimonidine and apraclonidine.
3. Beta blockers e.g. timolol, carteolol, betaxolol,
levobunolol and metoprolol
4. Prostaglandin analogs e.g. PGF2α , latanoprost,
unoprostone and PHXA-85.
5. Carbonic anhydrase inhibitors e.g. dorzolamide
and brinzolamide.
Systemic drugs:
1. Carbonic anhydrase inhibitors e.g. acetazolamide
and methazolamide.
2. Osmotic agents e.g. glycerine, mannitol and
urea.
GLAUCOMA THERAPY 72
Miscellaneous drugs include forskolin, ethacrynic
acid, steroid antagonists, cannabinoids, angiotensin
converting enzyme inhibitors, atrial natriuretic pep-
tide and neuroprotective agents.
Mechanisms of action of antiglaucoma agents
The antiglaucoma agents act on the aqueous humor
dynamics to reduce the intraocular pressure mainly
by three mechanisms.
Ø Decrease aqueous production in the ciliary body
Ø Increase aqueous humor outflow through the
trabecular meshwork and
Ø Increase aqueous humor outflow via the
uveoscleral pathway.
Pharmacokinetics of topical drugs
The availability of the drug at the receptor site is in-
fluenced by:
a. Drug kinetics in the conjunctival cul-de-sac.
Following topical instillation, the drug mixes with the
tears in the cul-de-sac. Bulk of the drug is lost through
the lacrimal drainage system while small amount mixes
with the precorneal tear film and enters the cornea.
The extent of precorneal film saturation governs the
amount of drug crossing the cornea and the bioavail-
ability of the drug. Newer developed vehicles have been
employed to prolong the stay of the drug in the con-
junctival cul-de-sac thereby increasing the precorneal
film saturation. Some of these vehicles are soluble
polymers (methylcellulose, polyvinyl alcohol), oint-
ments, soluble gels (high viscosity acrylic vehicle),
emulsions and suspensions.
b.Corneal penetration
The cornea is a lipid-water-lipid sandwich due to which
drugs which are both lipid and water soluble are able
to penetrate the intact cornea. This is called the dif-
ferential solubility concept.
c. Distrubution and rate of drug elimination within the eye.
1. Cholinergic drugs
In the past, miotics were the drugs of first choice for the
management of most types of glaucoma but currently
due to their high side-effects, their use has declined,
especially in the West. Miotics are used as an adjunct
to β-blockers or sympathomimetics because of their well
73 ROHIT SAXENA et al.
established additive effect to control IOP7-8. Miotics can
be divided into two groups: direct acting miotics and
cholinesterase inhibitors. Pilocarpine is a direct acting
miotic while carbachol is a dual action
parasympathomimetic due to its weak anticholinesterase
activity. Pure acetylcholinesterase inhibitors include
physostigmine, ecothiophate iodide and demecarium
bromide.
Pilocarpine
Pilocarpine is the principal alkaloid of South Ameri-
can shrubs of the genus Pilocarpus. In angle closure
glaucoma, the miotic action of the drug relieves the
pupillary block and also pulls the iris away from the
anterior chamber angle. It increases the trabecular
outflow due to cilliary body contraction. This results
in pull on the scleral spur and strengthening of the
trabecular clamps. It is available in various concen-
trations ranging from 0.5 - 4% and is indicated in acute
and chronic narrow angle glaucoma, open angle glau-
coma and in secondary glaucoma resulting from
pupillary block. Its onset of action is rapid, peak
effect occurs between 30-60 minutes and lasts for 4-
8 hours. Occasionally drug resistance can develop
which is reversible. Ocular side effects are common
with pilocarpine and can interfere with the patient's
quality of life and compliance with recommended
therapy. Superficial punctate keratitis is the most trou-
blesome acute toxic effect of pilocarpine. Other side
effects include ciliary muscle spasm which can lead
to browache, induced myopia, miosis, possible retinal
detachments, progression of cataract and corneal
endothelial toxicity. Systemic toxicity is rare with the
usual doses.
Delivery systems for pilocarpine
Drug delivery systems aim to achieve the desired
pharmacological effect with the least amount of drug
and to prolong the duration of therapeutic effect
thereby decreasing the frequency of instillation and
associated side effects.
a. Soluble polymers : Polymers like methylcellulose
and polyvinyl alcohol increase the conjunctival sac
retention time and increase corneal penetration .
b. Pilocarpine gel : The equivalent of 4% pilocarpine
hydrochloride in a highly viscous acrylic vehicle when
applied once daily at bed time has been reported to
produce a significant reduction in IOP for 24 hours.
c. Membrane-controlled delivery system : This is an
insert device placed in the cul-de-sac where it gradu-
ally releases pilocarpine at the rate of 20 µg/hour or
40 µg/hour, which is roughly equivalent to 2% and
4% eye drops respectively. This is effective for 7 days
and the constant rate of release (zero order kinetics)
provides good control of IOP throughout the day.
d. Pilocarpine soaked soft contact lenses : Not as
yet recommended for general clinical use.
c. Transdermal drug delivery system : A new non ocu-
lar pharmaceutical device has been tested for pilo-
carpine. In this system pilocarpine was applied in two
patches of 30 mg each over the supraclavicular skin
of 24 patients. Substantial amount of pilocarpine was
released from the patches to the dermis with detect-
able plasma drug levels at 12 hours and 24 hours
after administration. The advantage of the system is
that it avoids ocular side effects of eye drops9.
f. Electronic medication alarm device : Another de-
vice which enhances the compliance in glaucoma pa-
tients taking pilocarpine is the electronic medication
alarm device (Prescript TimeCap). A significant dif-
ference in patient compliance level was observed
(95.8% compliance level with the alarm device ver-
sus 83.1% without it)10.
g. Liposomal pilocarpine : Liposome encapsulated pi-
locarpine has shown prolonged effect in normal and
glaucomatous rabbits11. However, clinically its effect
remains to be substantiated.
Cholinesterase inhibitors
Cholinesterase inhibitors are another class of miotics
which act by increasing the levels of endogenous ace-
tylcholine by inhibiting the enzyme acetylcho-
linesterase. Physostigmine, neostigmine and
demecarium are short acting cholinesterase inhibi-
tors whereas ecothiophate and isofluorophate are long
acting cholinesterase inhibitors. Physostigmine and
neostigmine are useful in angle closure and open angle
glaucoma, though their use has declined due to the
high incidence of allergic reactions. Ecothiophate io-
dide and demecarium bromide are no longer used in
glaucoma. Isofluorophate is more oculotoxic than
ecothiophate and demecarium. Cholinergic toxicities
in the form of profound muscle weakness and cyst-
oid macular edema have been reported with the use

of ecothiophate eye drops. These toxicities resolve
spontaneously on discontinuation of the therapy12-13.
Local ocular side effects of anticholinesterase agents
similar to those of other miotics may be severe
enough to warrant discontinuation of the drug e.g. iris
cyst formation and cataract formation. In general, the
use of anticholinesterase medications for the treat-
ment of open angle glaucoma is reserved for cases
in which the patient has become intolerant to pilo-
carpine or carbachol or when the pressure lowering
effect of these agents is inadequate. Also these
agents are more effective in secondary glaucoma like
aphakic or pseudoaphakic glaucoma.
2. Adrenergic agonists
Epinephrine
It is a direct acting sympathomimetic amine and it
acts by decreasing aqueous humor formation in the
early phase presumably due to its α-adrenergic ef-
fect. It also increases trabecular outflow probably by
stimulating β2-adrenergic receptors in the trabecular
meshwork. Onset of action occurs at 1 hr with a peak
effect at 4 hours and ocular hypotensive effect may
last upto 72 hours. Long term epinephrine therapy
achieves the same degree of IOP control as timolol14.
Epinephrine is additive to pilocarpine and to oral car-
bonic anhydrase inhibitors. It is also partially addi-
tive to β-blockers. Epinephrine may be used as initial
or adjunctive glaucoma therapy. It is available as hy-
drochloride, bitartarate and borate salt for topical oph-
thalmic use in concentration ranges varying from 0.25-
2% to be administered twice daily. Topical instillation
of epinephrine causes conjunctival decongestion and
transient mydriasis. Systemic hypertension, stinging,
browache, conjunctival hyperemia, adenochrome de-
posits and allergic lid reactions are reported with
epinephrine. It needs to be administered topically with
caution in patients of cardiovascular dysfunctions,
hyperthyroidism or diabetes mellitus.
Dipivefrin
Dipivefrin is the prodrug which undergoes biotrans-
formation to epinephrine within the cornea. Due to
increased lipophilicity its penetration across the cor-
nea is 17 times more than epinephrine, and lesser
doses are needed to be administered as compared to
epinephrine. It is better tolerated than epinephrine.
The onset of its ocular hypotensive action is within
GLAUCOMA THERAPY 74
30 minutes and peak effect is observed in 1 hour. It
exerts its action by decreasing aqueous production
and enhancing the outflow facility. It is indicated for
initial therapy or as an adjunct with other ocular hypo-
tensive agents. It is available as 0.1% ophthalmic
solution to be administered twice daily. This concen-
tration represents a balance between efficacy and
mydriasis. Used as a single agent dipivefrin produces
a 20-24% reduction in IOP. Recently a multicentric
study found dipivefrin equivalent to 0.5% betaxolol
used twice daily as a single agent. It works well with
pilocarpine and with oral carbonic anhydrase inhibi-
tors. Its advantages over epinephrine are lower car-
diovascular side effects. Like epinephrine it can be
used in patients of asthma, in young patients intoler-
ant to miotics and in those with cataracts. Dipivefrin
does not easily discolor soft contact lenses and has
a much lower incidence of adenochrome deposits
than epinephrine. A common adverse effect of
dipevefrin is follicular conjunctivitis15.
Apraclonidine
Apraclonidine is an α 2-adrenergic agonist which is
basically a para amino derivative of clonidine. It acts
by decreasing aqueous production, increasing
trabecular meshwork outflow by reducing episcleral
venous pressure and may also increase uveoscleral
outflow by an increase in prostaglandin synthesis. It
is now available commercially both as 1% and 0.5%
ophthalmic solution and is mainly indicated to control
the acute IOP rise after ocular laser therapy as longer
treatment may lead to development of tolerance. Within
one hour of instillation, apraclonidine 1% produces a
rapid drop in intraocular pressure of at least 20% from
baseline. The maximal effect is produced 3-5 hours
after dosing. Single postoperative administration of
0.5% apraclonidine has been found to be equally ef-
fective to that of 1% apraclonidine in the prevention
of immediate post-operative IOP rise in a prospec-
tive randomized study on 83 patients of trabeculo-
plasty, 62 patients of iridotomy and 52 patients of
capsulotomy16.
The ocular hypotensive effect of apraclonidine alone
is equal to 0.5% timolol maleate upto 8 hours post
dose but less than timolol maleate upto 12 hours post
dose. It may be used concomitantly with other
antiglaucoma agents and as many as 60% patients
do not require additional therapy for upto 5 months, if
75 ROHIT SAXENA et al.
apraclonidine is added. The increased polarity of
apraclonidine limits its penetration through blood brain
barrier, reducing undesirable CNS effects so that it
minimally affects blood pressure and heart rate. Sys-
temic side effects include dry mouth and nose in 30-
50% patients. The most common reversible side ef-
fect is the local allergic reaction manifested as itch-
ing, burning and conjunctival inflammation in some 8-
30% patients17. It is contraindicated in patients re-
ceiving MAO-inhibitors and tricyclic antidepressants
because they affect metabolism and uptake of
catecholamines. Long term use of apraclonidine is
limited due to high incidence of local adverse reac-
tions and tachyphylaxis18.
Brimonidine
Since its introduction in 1996, it has emerged as a
new powerful first line agent for the treatment of el-
evated IOP. It is the drug of choice in chronic treat-
ment of glaucoma and in patients with cardiopul-
monary disease and who have contraindications to
β-blockers. It is a highly selective α 2-adrenoceptor
agonist. It is 7-12 fold and 23-32 fold more α 2 selec-
tive than clonidine and apraclonidine respectively. It
has lower incidence of ocular side effects because of
α 2 selectivity. It reduces the intraocular pressure by
suppressing the rate of aqueous humor flow and en-
hancing uveoscleral flow. It has good retinal bioavail-
ability, ocular hypotensive and neuroprotective action
in animal models19. Its peak IOP reduction efficacy
is comparable to that of timolol and does not cause
cardiopulmonary side effects as reported with timolol20.
However, there are reports suggesting similar efficacy
of brimonidine with that of timolol but with a greater
incidence of adverse local reactions18. In a recent dou-
ble blind clinical study brimonidine tartarate 0.2% twice
daily provided sustained IOP lowering efficacy com-
paring to timolol 0.5% twice daily with no significant
differences at trough or peak during 4 years of con-
tinuous use21.
3. Beta adrenergic antagonists
Drugs in this class have become the major therapeu-
tic agents for most forms of glaucoma. Due to their
almost universal efficacy and minimal ocular side ef-
fects, these drugs usually are the first line agents for
the medical therapy of all kinds of glaucoma. They
act solely by reducing the aqueous humor production
by their action on ciliary body15. They block the β-
receptors in the iris and ciliary body and thereby cause
significant reduction in IOP. This class of drugs has
several advantages over both cholinergic and adren-
ergic agonists. Majority of patients can be treated
solely by β-blockers. Unlike miotics, β-blockers have
little effect on pupil size or accomodation, eliminat-
ing the problems of dim vision, decreased night vi-
sion and blurred vision. Unlike adrenergic agonists,
β-blockers do not cause pupil size changes or
hyperemia. β-blockers also have a significant addi-
tive action when combined with pilocarpine or other
antiglaucoma agent.
Depending on their selective receptor inhibition, they
are classified as β 1-selective and non-selective
β-blockers respectively. Betaxolol, atenolol and me-
toprolol are selective β1 -blockers whereas timolol
maleate, nadolol, befunolol, carteolol, penbutolol,
labetalol, nipradilol are non-selective β-blockers. Cur-
rently the following five β-blockers are available for
topical ophthalmic use - timolol, betaxolol,
levobunolol, carteolol and metoprolol. The dosage
regimens, duration of action and side effects of
β-blockers and other selected antiglaucoma drugs are
given in Table 1.
Timolol
The introduction of timolol in 1978 was a milestone in
ocular pharmacology. It was the first topical β-adren-
ergic antagonist approved in US for the treatment of
glaucoma and elevated IOP22. It is currently the pro-
totype agent to which new antiglaucoma drugs are
compared in clinical trials. Timolol inhibits both β1 and
β2 adrenergic activity. It is being used extensively
worldwide as a first line agent for the treatment of
patients with open angle glaucoma and ocular hyper-
tension. It is instilled as one drop of 0.25% or 0.5%
solution twice a day and the duration of action ex-
ceeds 7 hours. At this dose timolol produces a sig-
nificant reduction in IOP in most cases. Although
numerous investigators have demonstrated the safety
of timolol, significant local and systemic side effects
have been documented, so this drug must be used
with caution. Localized irritation of the corneal epi-
thelium can result in blurred vision, conjunctival
hyperemia, superficial punctate keratopathy and dry
eye symptoms. Although several studies have con-
firmed the continued efficacy of chronic timolol therapy
 GLAUCOMA THERAPY 76

Table 1. Dosage regimens, duration of action and side effects of selected drugs used in the therapy of glaucoma

Group Agent Dosage regimen Duration of action Side effects

Cholinergic Pilocarpine 0.5-4% eyedrops 8 hours Ocular : miosis, follicular conjun-

agonists 2-4 times daily ctivitis, ciliary spasm, lacrimation
Systemic :salivation, urination

Ocuserts,
applied once a week 7 days Accidental loss, membrane break,
tachyphylaxis, ciliary muscle
changes
Cholinesterase Physostigmine 0.25-0.5% eyedrops 12-36 hours Pain, irritation, iris cysts
inhibitors or 1 cm ointment
4 times daily
Echothiophate 0.125-0.06% 12 hours Ocular: corneal anaesthesia,
eyedrops, once daily uveitis, retinal detachment,
ptosis, cataract
Systemic : headache, palpitation,
bradycardia, memory disturbances
Adrenergic Epinephrine 0.25-2% eyedrops 12 hours Ocular : irritation, conjunctival
agonists twice daily hyperemia
Systemic : Headache, palpitation,
sweating
Apraclonidine 0.5-1% eyedrops 5-8 hours Ocular: hyperemia, mydriasis,
twice daily dryness
Systemic :diarrhoea, bradycardia,
insomnia
Dipivefrin 0.1% eyedrops 12 hours Fewer side effects, minimum
2-3 times daily systemic absorption, less allergic
reactions
β-Adrenergic Timolol 0.25-0.5% eyedrops 12-24 hours Ocular : irritation, diplopia, ptosis
antagonists twice daily Systemic : headache, dizziness,
bronchospasm, bradycardia,
hypotension
Betaxolol 0.5% eyedrops 12 hours Reduced side effects compared to
twice daily timolol
Levobunolol 0.5% eyedrops 12-24 hours Stinging, bradycardia, hypotension
1-2 times daily
Metoprolol 0.3% or 0.6% 12-24 hours Ocular : hyperemia of conjunctiva,
eyedrops twice daily blurred vision, photophobia
Systemic : potential cardiac,
respiratory side effects, allergic
reaction, headache, nausea,
nervousness, rashes
Carteolol 1% eyedrops 12 hours Same as timolol
1-2 times daily
Carbonic Acetazolamide 250 mg tablets 8-12 hours Systemic : GIT upset, nausea,
anhydrase 2-4 times daily, p.o. diuresis, renal calculi, aplastic
inhibitors anaemia. Ocular : transient myopia
Methazolamide 50 mg tablets 10-18 hours Minor side effects, fatigue, malaise
2-3 times daily, p.o. nausea, vertigo, paresthesia
Dorzolamide 2% eyedrops Minimal side effects : burning,
3 times daily stinging in the eye
Prostaglandin Latanoprost 0.005% solution 20-24 hours Iris pigmentation, mild conjunctival
analogs 1 drop once daily hyperemia, local irritation, increased
at bed time growth of eyelashes and cystoid
macular edema
77 ROHIT SAXENA et al.
in a significant number of cases, the pressure respon-
siveness decreases with continuous use. The timolol
therapy is associated with the phenomenon of short
term escape and long term drift. In short term es-
cape, most patients experience a good IOP reduc-
tion after start of timolol therapy, but the pressure rises
after a few days to finally level off by 3-4 weeks. One
must therefore wait for at least one month after start-
ing timolol to determine its efficacy. In long term drift,
after around one year of timolol therapy, few patients
show a slow decline in pressure responsiveness to
timolol. Many of these will regain responsiveness to
timolol after a washout period. The efficacy of timolol
hemihydrate 0.5% solution given once a day has been
found to be comparable in its IOP reducing efficacy to
timolol gel 0.5% given once a day23.
Timolol has been shown to be more effective in low-
ering IOP than either epinephrine or pilocarpine. Sys-
temic toxicity from topical timolol occurs more fre-
quently than local toxicity and can affect the pulmo-
nary, cardiac and central nervous system24. These
include bronchospasm, bradycardia, hypotension,
arrhythmias, heart failure, myocardial infarction, de-
pression, anxiety and confusion.
Timolol maleate (ophthalmic gel forming solution,
Timoptic XE) is a new formulation of timolol. The vehi-
cle is an anionic polysaccharide derived from gellan
gum. Upon contact with the cations in the tear film,
the product forms a gel allowing the drug to remain in
contact with the eye for a longer period of time. Dos-
age is once daily and has the potential advantage of
greater compliance, reduced cost and less systemic
absorption.
Carteolol
Carteolol is the second most commonly prescribed
topical β-blocker in the world. A multicentric trial com-
paring carteolol and timolol showed equivalent pres-
sure lowering efficacy over three months to one year.
The half life of its metabolite, the 8-hydroxycarteolol
is 2-3 times that of the parent molecule and this may
allow for the better bioavailability and increased du-
ration of action compared with other β-adrenergic an-
tagonists.
It is a non-selective β-blocker with intrinsic
sympathomimetic activity and ability to partially ac-
tivate β-receptors in the absence of catecholamines25.
Efficacy of carteolol is comparable to that of timolol
and has been better tolerated as regards stinging and
irritation26-27. Since carteolol has fewer deleterious
effects on lipid profile, some ophthalmologists prefer
it in patients with hypercholesterolemia.
Betaxolol
Betaxolol hydrochloride was introduced in the early
1980s as the first topical, cardioselective β1-adrener-
gic antagonist to be used in ophthalmology. Most clini-
cal trials comparing betaxolol with timolol have shown
betaxolol to be statistically less effective in both pres-
sure lowering and reducing aqueous outflow. Onset
of action is noted in 30 minutes, maximum effect oc-
curs at 2 hours after topical administration and a sin-
gle dose provides 12 hours of pressure reduction. The
advantage of betaxolol over timolol is the absence of
β2-adrenergic inhibition which minimizes the risk of
respiratory side effects. Betaxolol causes more burn-
ing and stinging than non-cardioselective β-blockers.
Marketed as 0.5% ophthalmic solution for all types
of glaucomas, it requires to be instilled twice daily. It
is reported to cause less impairment of respiratory
and cardiovascular functions when compared to timolol
particularly in the elderly. Betaxolol also has
neuroprotective action on the eye and slows down
the changes seen in retina after raised IOP induced
ischemia/reperfusion28,15,29.
Levobunolol
It reduces intraocular pressure by reducing aqueous
humor formation as well as by enhancing the outflow
facility30. It is as effective in reducing IOP as timolol
maleate, metoprolol and carteolol14. The potential
advantage of levobunolol is once daily dosing due to
longer duration of action. It is cost effective, causes
less ocular discomfort and has better compliance31.
Topical levobunolol or timolol when instilled one drop
for one week have been found to slightly increase the
retinal blood flow in healthy volunteers32. Levobunolol
is contraindicated in patients predisposed to cardiac
or respiratory disease. Caution is required in diabet-
ics and those undergoing major surgery33.
Metoprolol
It is a cost effective, selective β1 adrenergic antago-
nist similar to timolol in clinical efficacy. It reduces
the intraocular pressure in normal eyes, chronic open

angle glaucoma and ocular hypertensive patients. The
recommended dose in glaucoma is one drop of 0.3%
or 0.6% solution twice a day. IOP lowering effect is
comparable to that of levobunolol and carteolol14. It is
associated with more eye burning, stinging and
granulomatous anterior uveitis than other drugs34. It
also carries the risk of respiratory and cardiac toxicity.
4. Prostaglandin analogs
Latanoprost
It is a highly lipophilic 17-phenyl substituted PGF2α
isopropyl ester prodrug having a novel mechanism of
action. It undergoes enzymatic hydrolysis in cornea and
gets activated to the acid of latanoprost. Its response
seems to be mediated by prostanoid receptors.
Latanoprost is more selective than PGF2α in this re-
spect and thereby has superior therapeutic profile35-36. It
acts by enhancing uveoscleral outflow rather than
altering the conventional trabeculo-canalicular aque-
ous outflow. It is available as 0.005% ophthalmic
solution and requires to be instilled once at night.
A single dose of topical 0.005% latanoprost is equi-
effective to that of 0.5% timolol (bd dose) in patients
suffering from primary open angle glaucoma and ocu-
lar hypertension and has a duration of action ranging
from 20-24 hours. It is well tolerated with no detect-
able systemic side effects. Some 3-10% patients
have shown iris pigmentation after 3-4.5 months treat-
ment due to increased synthesis of melanin in the
melanocytes of the iris stroma and cystoid macular
edema37. Other local side effects include mild con-
junctival hyperemia, punctate corneal erosions and
lengthening and thickening of eyelashes.
In a recent phase III clinical trial, latanoprost 0.005%
once daily produced sustained reduction of IOP in
ocular hypertension and primary open angle glaucoma
patients to a greater extent than timolol38. The effi-
cacy of once a day 0.005% latanoprost is more than
twice a day administration of 0.12% of unoprostone
in patients of primary open angle glaucoma and ocu-
lar hypertension39. Latanoprost can be administered
as monotherapy and has good efficacy when com-
bined with other drugs lowering IOP, including sys-
temic acetazolamide40. It can be used safely in pa-
tients of glaucoma with concomitant bronchial
asthma41.
GLAUCOMA THERAPY 78
Unoprostone
Unoprostone isopropylate is the first docosanoid de-
rivative for glaucoma therapy. It acts by enhancing
uveoscleral outflow without affecting aqueous humour
production42,43. It is available as 0.12% ophthalmic
solution and requires twice a day instillation. Its
oculohypotensive effect is similar to or slightly infe-
rior to that of timolol 0.5%44. It has also been seen in
some studies to increase the optic nerve head blood
flow. It has an additive efficacy with latanoprost and
can safely improve the diurnal curve characteristics
in patients who continue to have an elevated IOP on
latanoprost 0.005% alone45.
PhXA-85
11-Deoxy-PGE1 or PhXA-85 is another prostaglandin
analog. It also acts by increasing uveoscleral out-
flow. It has also been shown to reduce the collagen
turnover in the matrix surrounding the human ciliary
smooth muscles in culture, in a dose dependent man-
ner. The reduction in extracellular matrix components
is suggested to lower the hydraulic resistance to aque-
ous flow thus contributing to pressure reduction46.
5. Carbonic anhydrase inhibitors
Systemic carbonic anhydrase inhibitors have been
an integral part of glaucoma medical therapy for the
past 40 years. These are the reserved group of drugs
and are given orally (with the exception of dorzolamide
and brinzolamide which are available for topical ad-
ministration) as an adjunct when IOP is not control-
led adequately with topical medication. Approximately
50% patients have shown intolerable side effects with
the use of systemic carbonic anhydrase inhibitors47.
Therefore these drugs are currently used to control
IOP in patients waiting for surgery or till the time topi-
cal drugs become effective. Acetazolamide and
methazolamide are the two potent systemically ad-
ministered carbonic anhydrase inhibitors.
Acetazolamide
This is the most widely prescribed carbonic anhydrase
inhibitor. However, approximately 50% patients stop
treatment with acetazolamide as a consequence of
intolerable side effects due to extraocular inhibition
of carbonic anhydrase. It reversibly blocks the en-
zyme carbonic anhydrase in the ciliary body and thus
suppresses aqueous humor production. The aqueous
79 ROHIT SAXENA et al.
fluid rich in sodium and bicarbonate ions is
hyperosmotic as compared to plasma. Water is at-
tracted to the posterior chamber as a result of osmo-
sis and the high concentration of bicarbonate ions is
diluted. When given orally, plasma levels attain a peak
at 2 hours, persisting for 4-6 hours and then rapidly
drop because of urinary excretion. Acetazolamide is
available as tablets and as capsules. The usual oral
dose is 125-250 mg four times daily. The effect of
acetazolamide may be sustained by dispensing in
'coated granules form' and using an osmotic pump
delivery system48. Gastrointestinal upset is the most
frequent symptom of acetazolamide intolerance. Se-
vere side effects include myopia, pulmonary failure,
renal stones, aplastic anaemia, metabolic acidosis,
hypersensitivity reactions and peripheral neuropathy.
Methazolamide
It is more potent than acetazolamide and has struc-
tural similarity to it. It is indicated in patients of chronic
open angle glaucoma where IOP is not controlled
adequately with acetazolamide or topical medications.
Its penetration across blood aqueous barriers is 50
times that of acetazolamide due to its good lipid solu-
bility and low plasma protein binding49. Its dose is 25-
50 mg three times daily. Methazolamide is associ-
ated with drowsiness, fatigue, malaise and little gas-
trointestinal disturbances. Few incidences of phos-
phate renal stones have also been reported.
Dorzolamide
Dorzolamide is a non-bacteriostatic sulfonamide de-
rivative devoid of systemic side effects as seen after
oral administration of carbonic anhydrase inhibitors.
It has become commercially available since 1995 for
topical ophthalmic use. It is thought to reduce the
raised IOP by the same mechanism as that the car-
bonic anhydrase inhibitors. It penetrates cornea, in-
hibits carbonic anhydrase-II in the ciliary body, slows
the production of local bicarbonates and thus de-
creases sodium and fluid transport which in turn re-
duces the secretion of aqueous humor50.
It is available as 2% ophthalmic solution and the dose
is one drop instilled twice daily alone or in conjunc-
tion with β blockers. The drug reduces the IOP by
approximately 3.5-6.0 mm Hg in patients of primary
open angle glaucoma or hypertension. It is of com-
parable efficacy to that of betaxolol, and slightly less
than timolol. It is an effective second line agent for
patients of open angle glaucoma and ocular hyper-
tension who are unable to tolerate ophthalmic β block-
ers50. When combined with timolol therapy, it shows
efficacy similar to that of pilocarpine.
In lower concentrations it may be equally effective
with better compliance which may further widen the
therapeutic potential of this drug. It is associated with
lower cardiovascular side effects than topical β block-
ers and less ocular side effects than pilocarpine. How-
ever, it can cause irreversible corneal edema in pa-
tients having a compromised endothelium51.
Brinzolamide
It is also commercially available since 1998. Its 1%
suspension is comparable to 2% dorzolamide in low-
ering IOP. It is administered three times daily. Though
it has a lower incidence of burning and stinging, it
elicits more blurred vision52. 1% brinzolamide three
times daily used adjunctively with timolol 0.5% twice
daily produces a significantly additive IOP reduction
in open angle glaucoma and ocular hypertensive pa-
tients with fewer side effects53.
6. Osmotic agents
These agents act by enhancing the osmotic pres-
sure of plasma with respect to intraocular structures
thereby setting an osmotic gradient. Consequently
the fluid moves from the eye to hyperosmotic plasma
of ocular blood vessels, thereby reducing the vitre-
ous volume which is responsible for lowering of IOP.
Mannitol, glycerol, urea, isosorbide etc are the os-
motic agents used for short term reduction of IOP.
The use of these drugs is currently limited to short
term emergency situations such as acute angle clo-
sure glaucoma or pre-operative control of raised IOP.
The side effects of these drugs include nausea, vom-
iting, diuresis, headache, diarrhea, chills and fever.
Rarely life-threatening problems such as cardiovas-
cular overload, intracranial hemorrhage, pulmonary
edema and acidemia may occur.
7. Miscellaneous agents
Forskolin
Forskolin is derived from methanolic extract of the roots
of Coleus forskohlii. It has been shown to be an effec-
tive ocular hypotensive agent both experimentally and

clinically. It is a potent stimulator of adenylate cyclase
and does not require cell membrane bound receptors.
The ocular hypotensive effect of forskolin is directly
proportional to the extent of stimulation of adenylate
cyclase.
In a clinical trial on 17 patients of open angle glau-
coma, 1% topical forskolin reduced IOP significantly.
A pressure reduction of 15.4% was observed 3 hours
after instillation with onset at half an hour. Then pres-
sure reduction began to decline after 3 hours and re-
duced to a level of 10% after 6 hours. No significant
ocular or systemic side effects were observed54. The
combination of 1% forskolin and 0.25% timolol had
an additive effect which was more than the additive
effect of 1% forskolin plus 2% pilocarpine.
Phenoxyacetic acid derivatives
Ethacrynic acid, a sulfhydryl reactive phenoxyacetic
acid is a promising new drug that substantially low-
ers IOP both after topical and intracameral adminis-
tration. It has been shown to increase the aqueous
humor outflow facility both in vitro and in vivo55. This
effect was attributed to change in cell shape, attach-
ment and correlated to the microtubule alterations and
chemical sulfhydryl reactivity. Although the changes
in outflow facility and pressure reduction have been
impressive, the potential for corneal toxicity remains
a drawback. Current evidence suggests that it may
prove as a useful drug that can be administered at
the time of surgery to prevent postoperative pressure
spikes. However, further work is needed to develop
less toxic, more efficacious, longer lasting and more
easily administered forms if the drug is to be used for
chronic treatment.
Indacrinone and ticrynafen which are also phenoxy
acetic acids with non-sulfhydryl reactivity have re-
cently been investigated in bovine and postmortem
eyes, in cultured pulmonary artery epithelial and hu-
man trabecular meshwork cells. These agents im-
proved aqueous flow, however the mechanism of ac-
tion was not similar to that of ethacrynic acid, as these
agents did not alter microtubules or act through
sulfhydryl groups56. The encouraging results of this
study need further experimental and clinical evalua-
tion before they can be included into the therapeutic
armamentarium of glaucoma.
GLAUCOMA THERAPY 80
Steroid antagonists
Animal studies of mifepristone (RU-486) and related
compounds show the promise of these drugs as ocu-
lar hypotensive agents despite our poor understand-
ing of the mechanism of the ocular hypotensive ef-
fect57. Progression of the experimental work to hu-
man clinical trials is needed to ascertain their clinical
usefulness. A more complete understanding of the
physiological mechanism of steroid antagonists in-
duced ocular hypotension may lead to improved or
novel strategies for lowering IOP in patients of glau-
coma.
Angiotensin converting enzyme inhibitors
Components of the renin angiotensin system are
present in peripheral tissues, including the eye and
may play a role in controlling aqueous humor produc-
tion, retinal blood flow or retinovascular disease.
Angiotensin II receptors of the retinal vasculature may
play a significant role in the autoregulation of blood
supply to the retina and optic nerve head. Topical
angiotensin converting enzyme (ACE) inhibitors have
been shown to lower IOP in rabbits, monkeys and
humans58. Experimental evidence suggests that ACE
inhibitors might inhibit breakdown of bradykinin, pro-
mote formation of endogenous prostaglandins and
also enhance uveoscleral outflow. Thus, inhibitors of
ACE activity might be useful pharmacological agents
in the medical therapy of glaucoma.
Atrial natriuretic peptide
The anterior uvea is also rich in atrial natriuretic pep-
tide (ANP) and ANP receptors. Experimentally, ANP
has been shown to reduce IOP via reduced secretion
of aqueous humor by a direct effect on ciliary proc-
esses59. An improved understanding of the physiologi-
cal role of ANP and the elements of the renin
angiotensin system present in the eye may lead to
new and interesting treatment strategies for lowering
IOP in glaucoma patients.
Cannabinoids
Marijuana or cannabis has been used as a herbal
medication in many societies for centuries. Marijua-
na's ability to lower IOP in humans has spurred a
great effort to identify not only the mechanism by
81 ROHIT SAXENA et al.
which this effect occurs but also to identify either
members of this family, or a delivery system of these
drugs to the eye, that can effectively reduce pres-
sure without the well known psychotropic side
effects60.
Ocular hypotensive lipids
AGN-191129 and AGN-192024, are the two new
antiglaucoma agents belonging to the class of com-
pounds termed as ocular hypotensive lipids (OHL).
These compounds contain a neutral substituent for
the carboxylic acidic group of PGF2α and are not fatty
acids. These are relatively metabolically stable un-
like the prodrug latanoprost and the esterified PGF2α
analogue that is readily metabolized into active PGF2α.
These compounds do not interact with the FP or other
known prostanoid receptors. These compounds have
different pharmacological profiles yet are potent ocu-
lar hypotensive agents. Clinical trials were conducted
on these OHL in open angle glaucoma and ocular
hypertension cases. Twice daily dosing at concentra-
tion of 0.01% produced significant IOP lowering (26%
decrease from baseline) and was certainly superior
to that of timolol (0.5% bd). These new compounds
continue to produce a significant IOP lowering effect
upto 24 hours after the last drug instillation. These
compounds are well tolerated and have a very fa-
vourable ocular and systemic safety profile with no
patient drop out due to adverse events. These com-
pounds will be an excellent alternative as a first and
second line IOP lowering agent for the therapy of ocu-
lar hypertension and open angle glaucoma.
Neuroprotective agents
Neuroprotection has been projected as one of the
important strategies for vision sparing through the pro-
motion of retinal ganglion cell survival61. Retinal cell
death is initiated when pathological events like
ischaemia, axonal injury and changes in the lamina
cribrosa block the transport of growth factors from
the brain to retinal ganglion cells. Blockade of these
neurotrophins initiates a damaging cascade and the
cell is unable to maintain its normal functions. When
retinal ganglion cells undergo apoptosis and release
oxygen free radicals, gene expression changes fa-
vourably, mitochondria alter and excitatory toxins are
released during optic nerve injury.
Drugs which can affect this cell death pathway through
differing mechanisms and provide effective
neuroprotection are : brimonidine, latanoprost, N-me-
thyl-D-aspartate (NMDA) antagonists (memantine and
dizocilpine, eliprodil), calcium channel blockers
(lomarizine), glutamate antagonists (riluzole), L-
deprenyl, 5-HT1A agonists, nitric oxide synthase in-
hibitors, neurotrophic factors, free radical scavengers,
antiapoptotic agents, naftidrofuryl, polyamine antago-
nists, aspirin, melatonin, cannabinoids, and
vitamin B1219,62-68.
Monotherapy versus combination therapy
β blockers are the most commonly prescribed first
line therapy though the use of latanoprost and
brimonidine as primary therapy is also increasing in
the West. Latanoprost, brimonidine and topical car-
bonic anhydrase inhibitors are effective as early ad-
junctive therapy in cases where a single drug alone
is inadequate to control IOP. Adrenergic agonists and
miotics are also useful as secondary or tertiary therapy
but their use in the west is declining due to their sig-
nificant topical and systemic side effects. It is thus
evident that when therapy with a single agent is inad-
equate to control IOP, combined treatment is indi-
cated. The additive benefit of two drugs depends to
some extent on whether they reduce IOP by similar
mechanisms. Miotics and carbonic anhydrase inhibi-
tors in combination may be useful, prabably because
miotics increase aqueous outflow, whereas carbonic
anhydrase inhibitors reduce inflow. It must be stressed
that if the initial agent is only slightly effective at low-
ering IOP, it should be discontinued and other drugs
tried individually before going on to combination
therapy. The combination therapy in contrast to
monotherapy has the possibility of delaying the need
for surgery.
Timpilo, a new formulation combining pilocarpine hy-
drochloride (3%) and timolol maleate (0.5%) is useful
in patients whose IOP is not controlled by
monotherapy. Each of the two components reduces
IOP by different but complementary mechanisms.
While pilocarpine alone requires 4 times daily admin-
istration, twice daily administration of Timpilo is
adequate. Dorzolamide 2%/timolol 0.5% is a well
tolerated and effective fixed dose combination for

lowering IOP in the treatment of open angle glaucoma
and may be used in those patients who do not re-
spond adequately to first line monotherapy.
Conclusions and future directions
The wide variety of topically effective antiglaucoma
drugs which are available today and few others in the
developmental stage represent significant advance-
ment in ocular therapeutics. Though, these topical
ophthalmic preparations have reduced the risk of
systemic toxicity to quite an extent, their long term
use causes systemic as well as ocular toxicity, rarely
leading to death. Ophthalmologists must select the
drugs individually and replace them regularly in order
to prevent habituation phenomenon and negative side
effects.
A new futuristic glaucoma therapeutic management
paradigm where clinical success is no longer simply
measured by achieved level of intraocular pressure
control but also long term preservation of visual func-
tion and patient's quality of life is expected to dra-
matically improve upon current treatment algorithms
for ocular hypertension and glaucoma. Ideal drug can-
didates for this new combination therapy will offer
better IOP lowering efficacy with fewer side effects
and provide additional means of vision sparing through
direct protection of optic nerve with currently avail-
able antiglaucoma agents.
A few but important problems need to be addressed
in future from the point of view of glaucoma therapy.
Acute studies with β blockers and adrenergic agents
have shown that these agents reduce choroidal and
optic disc blood flow. Timolol has a better influence
on visual field and is considered as an outstanding
agent for the management of glaucoma. Therefore
newly developed antiglaucoma drugs must be com-
pared with this agent. Such drugs must be designed
which do not affect ocular hemodynamics, have bet-
ter patient compliance and are cost effective.
Latanoprost and brimonidine represent a promising
approach to IOP lowering with the potential of en-
hancing retinal ganglion cell survival. In addition,
retinal ganglionic cell death elicited by the high lev-
GLAUCOMA THERAPY 82
els of glutamate may be overcome by memantine or
other compounds that effectively block this common
secondary neuropathological pathway. Ideally
neuroprotection in glaucoma shall be achieved by
combining agents that effectively reduce IOP and di-
rectly protect the optic nerves (marginally damaged,
undamaged but at risk) through the promotion of cel-
lular survival or inhibition of cell death signals.
New and more sensitive procedures that are able to
detect ganglion cell damage in humans before occur-
rence of visual field defects are developed and we
shall be able to expedite the evaluation of
neuroprotective efficacy of available and new drugs
and new drug combinations in development.
Research into the basic pathophysiological mecha-
nisms of glaucomatous optic neuropathy will eventu-
ally open new therapeutic pathways. Better under-
standing of the underlying genetic basis of heritable
forms of glaucoma should provide new diagnostic
tools and potential for new therapeutic avenues. There
are reports on the involvement of an autoimmune com-
ponent in certain types of glaucoma. Our understand-
ing of these complex immune disorders is required
and we may be able to tailor therapies to address this
potential confounding issue. Promising new focus on
vision sparing, greater patient safety and tolerability
will provide improved treatment options and long term
preservation of vision and quality of life.
A great deal of research is being directed towards
applying new molecular and cellular techniques to
induce regeneration of mammalian central nervous
axons. This shall be an important step in therapy for
glaucomatous optic nerve atrophy (which can lead to
at least partial recovery of optic nerve function fol-
lowing atrophy from glaucoma).
Synthesis of cytokines and growth factors for reac-
tive astrocytes and altered expression of cell surface
adhesion molecules including neural cell adhesion
molecule (N-CAM) hold promise. The search for phar-
macological and neuroregenerative agents for the treat-
ment of glaucoma promises to be most exciting path-
ways for the future treatment of glaucoma.
83 ROHIT SAXENA et al.
REFERENCES
1. Quigley HA, Vitale S. Models of open angle glaucoma
prevalence and incidence in the United States. Invest
Ophthalmol Vis Sci 1997;38:83-91.
2. Tuck MW, Crick RP. Screening for glaucoma : Why is the
disease underdetected. Drugs Aging 1997;10:1-9.
3. Kalloniatis M. Amino acids in neurotransmission and dis-
ease. J Am Optom Assoc 1995;66:750-7.
4. Nickells RW, Zack DJ. Apoptosis in ocular disease : A
molecular overview. Ophthalmic Genet 1996;17:145-65.
5. Koliopoulos JX. Time as a risk factor for primary open
angle glaucoma : A scientific and philosophical approach.
Ann Ophthalmol 1996;28:354-6.
6. Bella Hiag AL, Abana Mvogo C, Ngosso A, Ellong A.
Intraocular pressure in a young Cameroonian population.
J Fr Ophthalmol 1996;19:583-90.
7. Keath EU. Evaluation of timolol maleate combination
therapy in chronic open angle glaucoma. Am J Ophthalmol
1979;88:565-71.
8. Geyer O, Loewenstein A, Shalmon R, Neudorfer M, Lazar
M. The additive miotic effects of dapiprazole and pilo-
carpine. Graefes Arch Clin Exp Ophthalmol 1995;
233:448-51.
9. Dinslage S, Diestelhorst M, Hille T, Otto K. A new
transdermal drug delivery system for pilocarpine in glau-
coma treatment. Ger J Ophthalmol 1996;5:275-80.
10. Laster SF, Martin JL, Flemming JB. The effect of a medi-
cation alarm device on patient compliance with topical
pilocarpine. J Am Optom Assoc 1996;67:654-58.
11. Monem AS, Ali FM, Ismail MW. Prolonged effect of
liposomes encapsulating pilocarpine HCl in normal and
glaucomatous rabbits. Int J Pharm 2000;198:29-38.
12. Manoguerra A, Whitney C, Clark RF, Anderson B, Turchen
S. Cholinergic toxicity resulting from ocular instillation of
echothiophate iodide drops. J Clin Toxicol 1995;33:463-5.
13. Halperin LS, Goldman HB. Cystoid macular edema asso-
ciated with topical echothiophate iodide. Ann Ophthalmol
1993;25:457-8.
14. Sorensen SJ, Abel SR. Comparison of the ocular beta
blockers. Ann Pharmacother 1996;30:43-54.
15. Schmetterer L, Strenn K, Findl O, Breiteneder H, Graselli
U, Agneter E, et al. Effects of antiglaucoma drugs on
ocular hemodynamics in healthy volunteers. Clin
Pharmacol Ther 1997;61:583-95.
16. Rosenberg LF, Krupin T, Ruderman J, McDaniel DL,
Siegfried C, Karalekas DP, et al. Apraclonidine and ante-
rior segment laser surgery, comparison of 0.5% vs 1%
apraclonidine for prevention of postoperative intraocular
pressure rise. Ophthalmol 1995;102:1312-18.
17. Stewart WC. Effects and side effects of apraclonidine.
Klin Monatsbl Augenheilkd 1996;209:A7-13.
18. Apatachioae I, Chiselita D. Alpha-2 adrenergic agonists in
the treatment of glaucoma. Oftalmologia 1999;47:35-40.
19. Burke J, Schwartz M. Preclinical evaluation of brimonidine.
Surv Ophthalmol 1996;41:S9-18.
20. Wilensky JT. The role of brimonidine in treatment of open
angle glaucoma. Survey Ophthalmol 1996;41:S3-7.
21. Cantor LB. The evolving pharmacotherapeutic profile of
brimonidine, an α2 adrenergic agonist after 4 years of
continuous use. Expert Opin Pharmacother 2000;1:15-
34.
22. Zimmerman TJ, Kaufman HE. Timolol, a β adrenergic
blocking agent for the treatment of glaucoma. Arch
Ophthalmol 1977;95:601-4.
23. Stewart WC, Leland TM, Cate EA, Stewart JA. Efficacy
and safety of timolol solution once daily vs timolol gel in
treating elevated intraocular pressure. J Glaucoma
1998;7:402-7.
24. Nelson WL, Fraunfelder FT, Sills JM, Arrowsmith JB,
Kuritsky JN. Adverse respiratory cardiac events attrib-
uted to timolol ophthalmic solution. Am J Ophthalmol
1986;102:606-11.
25. Stewart WC. Carteolol, an ophthalmic β-adrenergic blocker
with intense sympathomimetic activity. J Glaucoma
1994;3:339.
26. Fraunfelder FT, Meyer SM. Sexual dysfunction second-
ary to topical ophthalmic timolol. JAMA 1985;253:3092-3.
27. Duff GR, Newcombe RG. The twelve hour control of
intraocular pressure on carteolol 2% twice daily. Br J
Ophthalmol 1988;72:890-1.
28. Ischikawa Y, Kiuchi Y, Takamatsu M, Mashima H. Effects
of beta adrenergic blockers on retinal circulation. Nippon
Ganka Gakkai Zasshi 1996;100:798-802.
29. Osborne NN, Ugarte M, Chao M, Chidlow G, Bae JH,
Wood JP, et al. Neuroprotection in relation to retinal
ischaemia and relevance to glaucoma. Surv Ophthalmol
1999;43:S102-28.

30. Calugaru M. The effect of levobunolol eyedrops on
trabecular outflow of aqueous humour in chronic simple
glaucoma. Klin Monatsbl Augenheilkd 1989;194:164-9.
31. Afako SK, Thompson JR, Rosenthal AR. A cross over
trial comparing once daily levobunolol with once and twice
daily timolol. Eur J Ophthalmol 1995;5:172-6.
32. Bloom AH, Grunwald JE, Dupont JC. Effect of one week
of levobunolol hydrochloride 0.5% on the human retinal
circulation. Curr Eye Res 1997;16:191-6.
33. Hong YL, Shin DH, Ahn BH, McCarty B. Intraocular pres-
sure after two week washout following long term timolol or
levobunolol. J Ocular Pharmacol Ther 1995;11:107-12.
34. Burvenich H. Metoprolol associated granulomatous ante-
rior uveitis: Not so common as thought. Bull Soc Belge
Ophthalmol 1995;257:63-7.
35. Karlsson M. Receptor profile of PhXA41, a new phenyl
substituted prostaglandin ester. Exp Eye Res 1992;
55:S50.
36. Stzernschantz J, Nilsson SFE, Astin M. Vasodynamic and
angiogenic effects of eicosanoids in eye. In: Bito LZ, edi-
tor. New York: The Ocular Effects of Prostaglandins and
other Eicosanoids; 1989.
37. Patel SS, Spencer CM. Latanoprost : A review of its phar-
macological properties, clinical efficacy and tolerability in
the management of primary open angle glaucoma and
ocular hypertension. Drugs Aging 1996;9:363-78.
38. Nomura S, Hashomoto M. Pharmacological profiles of
latanoprost (xalatan), a novel antiglaucoma drug. Nippon
Yakurigaku Zasshi 2000;115:280-6.
39. Susanna R Jr, Giampani J Jr, Borges AS, Vessani RM,
Jordao ML. A double masked, randomized clinical trial
comparing latanoprost with unoprostone in patients with
open angle glaucoma or ocular hypertension. Ophthalmol
2001;108:259-63.
40. Rulo AH, Greve EL, Hoyng PF. Additive ocular hypoten-
sive effect of latanoprost and acetazolamide : A short
term study in patients with elevated intraocular pressure.
Ophthalmol 1997;104:1503-7.
41. Hedner J, Everts B, Moller CS. Latanoprost and respira-
tory function in asthmatic patients: Randomized, double
masked, placebo controlled crossover evaluation. Arch
Ophthalmol 1999;117:1305-9.
42. Eisenberg DL and Cameras CB. A preliminary risk benefit
assessment of Latanoprost and Unoprostone in open
angle glaucoma and ocular hypertension. Drug safety
1999;20:505-14.
GLAUCOMA THERAPY 84
43. Haria N, Spencer CM. Unoprostone (isopropyl
unoprostone). Drugs Ageing 1996;9:213-20.
44. Sussana Jr R, Medeiros FA. The pros and cons of differ-
ent prostanoids in the medical management of glaucoma.
Curr Opin Ophthalmol 2001;12:149-56.
45. Stewart WC, Sharpe ED, Stewart JA, Holmes KT, Latham
KE. Additive efficacy of unoprostone isopropyl 0.12%
(rescula) to latanoprost 0.005%. Am J Ophthalmol
2001;131:339-44.
46. Lindsey JD, To HD, Weinreb RN. Induction of cfos by
PGF 2α in human ciliary smooth muscles. Invest
Ophthalmol Vis Sci 1994;35:242-50.
47. Drake MV. New medical therapies for glaucoma. Int
Ophthalmol Clin 1996;36:53-60.
48. Joyce PW, Mills KB, Richardson T, Mawer GE. Equiva-
lence of conventional and sustained release oral dosage
formulations of acetazolamide in primary open angle
glaucoma. Br J Clin Pharm 1989;27:597-606.
49. Maren TH, Haywood JR, Chapman SK, Zimmerman TJ.
The pharmacology of methazolamide in relation to the
treatment of glaucoma. Invest Ophthalmol Vis Sci 1977;
16:730-42.
50. Balfour JA, Wilde MI. Dorzolamide : A review of its phar-
macology and therapeutic potential in the management of
glaucoma and ocular hypertension. Drugs Aging 1997;
10:384-403.
51. Konowal A, Morrison JC, Brown SV, Cooke DL, Maguire
LJ, Verdier DV, et al. Irreversible corneal decompensation
in patients treated with topical dorzolamide. Am J
Ophthalmol 1999;127:403-6.
52. Sugrue MF. Pharmacological and ocular hypotensive prop-
erties of topical carbonic inhibitors. Prog Retin Eye Res
2000;19:87-112.
53. Shin D. Adjunctive therapy with brinzolamide 1% ophthal-
mic suspension (Azopt R) in patients with open angle
glaucoma and ocular hypertension maintained on timolol
therapy. Surv Ophthalmol 2000;44:163-8.
54. Sood NN, Agrawal HC, Rajpal, Bandopadhyay GP, Gupta
SK. Forskolin : An ocular hypotensive agent. In : Gupta
SK, editor. Ocular Pharmacology-Recent Advances.
New Delhi: Parallel Lines Editorial Agency; 1991.
55. Epstein DL, Freddo TF, Bassett-Chu S, Chung M,
Karageuzian L. Influence of ethacrynic acid on outflow
facility in monkey and calf eye. Invest Ophthalmol Vis Sci
1987;28:2067-75.
85 ROHIT SAXENA et al.

56. Epstein DL, Roberts BC, Skinner LL. Non sulfhydryl re-
active phenoxy acetic acids increase aqueous humor
outflow facility. Invest Ophthalmol Vis Sci 1997;38:1526-
34.
57. Green K, Cheeks L, Slagle T, Philips CI. Effects of
mifepristone on rabbit intraocular pressure in presence
and absence of dexamethasone. Ophthalmic Res
1990;22:247-5.
58. Constad WH, Fiore P Samson C, Cinotti AA. Use of an
angiotensin converting enzyme inhibitor in ocular hyper-
tension and primary open angle glaucoma. Am J
Ophthalmol 1988;105:674-77.
63. Gu Z, Yamamoto T, Kawase C, Matsubara M, Kawase K,
Sawada A, et al. Neuroprotective effect of N-methyl-D-
aspartate receptor antagonists in an experimental glau-
coma model in the rat. Nippon Ganka Gakkai Zasshi
2000;104:11-6.
64. Pang IH, Wexler EM, Nawy S, DeSantis L, Kapin MA.
Protection by eliprodil against excitotoxicity in cultured rat
retinal ganglion cells. Invest Ophthal Vis Sci 1999;40:
1170-6.
65. Hartwick AT. Beyond intraocular pressure: Neuropro-
tective strategies for future glaucoma therapy. Optom Vis
Sci 2001;78:85-94.

59. Korenfeld MS, Becker B. Atrial natriuretic peptide : Effects

on intraocular pressure, cGMP and aqueous flow. Invest
Ophthalmol Vis Sci 1989;30:2385.
60. EI Sohly MA. Cannabinoids in glaucoma II : The effect of
different cannabinoids on intraocular pressure of rabbit.
Curr Eye Res 1989;3:841.
61. Weinreb RN, Levin LA. Is neuroprotection a viable therapy
for glaucoma. Arch Ophthalmol 1999;117:1540-4.
62. Drago F, Valzelli S, Emmi I, Marino A, Scalia CC, Marino V.
Latanoprost exerts neuroprotective activity in vitro and in
vivo. Exp Eye Res 2001;72:479-86.
66. Ettaiche M, Fillacier K, Widmann C, Heurteaux C,
Lazdunski M. Riluzole improves functional recovery after
ischemia in the rat retina. Invest Ophthalmol Vis Sci
1999;40:729-36.
67. Ragaiey T, Ma JX, Jiang WJ, Greene W, Seigel GM, Stewart
WC. L-deprenyl protects injured retinal precursor cells in
vitro. J Ocul Pharmacol Ther 1997;13:479-88.
68. Osborne NN, Wood JP, Melena J, Chao HM, Nash MS,
Bron AJ, et al. 5-HT1A agonists : Potential use in glau-
coma. Evidence from animal studies. Eye 2000;14:454-
63.

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