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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


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

Correspondence: S.K. Gupta


e-mail: skgup@hotmail.com
GLAUCOMA THERAPY 72

relationship between age and chronic open angle glau- Miscellaneous drugs include forskolin, ethacrynic
coma has confirmed that the older the individual, acid, steroid antagonists, cannabinoids, angiotensin
greater the risk of glaucoma6. The Collaborative Glau- converting enzyme inhibitors, atrial natriuretic pep-
coma Study identified that visual field defects over a tide and neuroprotective agents.
13 year period were approximately 7 times higher in
Mechanisms of action of antiglaucoma agents
persons 60 years of age or older than in persons un-
der 40 years of age1. The hypothesis that race is a The antiglaucoma agents act on the aqueous humor
major risk factor for glaucoma is based on the data dynamics to reduce the intraocular pressure mainly
indicating a higher prevalence of the disease among by three mechanisms.
blacks. Several ocular parameters associated with
glaucoma are also known to be influenced by hered- Ø Decrease aqueous production in the ciliary body
ity and the presence of family history. Women of all Ø Increase aqueous humor outflow through the
races develop acute angle closure glaucoma 3 to 4 trabecular meshwork and
times as often as men. The global burden of glau- Ø Increase aqueous humor outflow via the
coma poses a challenge to the researchers, ophthal- uveoscleral pathway.
mologists and general practitioners to detect, prevent
and effectively treat this visual disability and make Pharmacokinetics of topical drugs
safer drugs available to mankind at an affordable price.
The availability of the drug at the receptor site is in-
Pharmacotherapy of Glaucoma fluenced by:

Prevention or modification of risk factors, particularly a. Drug kinetics in the conjunctival cul-de-sac.
the raised intraocular pressure is the primary goal in
Following topical instillation, the drug mixes with the
the management of glaucoma. The disease needs to
tears in the cul-de-sac. Bulk of the drug is lost through
be managed medically, by laser therapy or by con-
the lacrimal drainage system while small amount mixes
ventional surgery as the case may be.
with the precorneal tear film and enters the cornea.
Classification of antiglaucoma agents The extent of precorneal film saturation governs the
amount of drug crossing the cornea and the bioavail-
Depending on their route of administration ability of the drug. Newer developed vehicles have been
antiglaucoma agents may be classified as employed to prolong the stay of the drug in the con-
Topical drugs: junctival cul-de-sac thereby increasing the precorneal
film saturation. Some of these vehicles are soluble
1. Cholinergic agents e.g. pilocarpine, carbachol, polymers (methylcellulose, polyvinyl alcohol), oint-
demecarium bromide and echothiophate iodide. ments, soluble gels (high viscosity acrylic vehicle),
2. Adrenergic agonists e.g. epinephrine, dipivefrin, emulsions and suspensions.
brimonidine and apraclonidine.
b.Corneal penetration
3. Beta blockers e.g. timolol, carteolol, betaxolol,
levobunolol and metoprolol The cornea is a lipid-water-lipid sandwich due to which
drugs which are both lipid and water soluble are able
4. Prostaglandin analogs e.g. PGF2α , latanoprost, to penetrate the intact cornea. This is called the dif-
unoprostone and PHXA-85. ferential solubility concept.
5. Carbonic anhydrase inhibitors e.g. dorzolamide
and brinzolamide. c. Distrubution and rate of drug elimination within the eye.
1. Cholinergic drugs
Systemic drugs:
In the past, miotics were the drugs of first choice for the
1. Carbonic anhydrase inhibitors e.g. acetazolamide management of most types of glaucoma but currently
and methazolamide. due to their high side-effects, their use has declined,
2. Osmotic agents e.g. glycerine, mannitol and especially in the West. Miotics are used as an adjunct
urea. to β-blockers or sympathomimetics because of their well
73 ROHIT SAXENA et al.

established additive effect to control IOP7-8. Miotics can c. Membrane-controlled delivery system : This is an
be divided into two groups: direct acting miotics and insert device placed in the cul-de-sac where it gradu-
cholinesterase inhibitors. Pilocarpine is a direct acting ally releases pilocarpine at the rate of 20 µg/hour or
miotic while carbachol is a dual action 40 µg/hour, which is roughly equivalent to 2% and
parasympathomimetic due to its weak anticholinesterase 4% eye drops respectively. This is effective for 7 days
activity. Pure acetylcholinesterase inhibitors include and the constant rate of release (zero order kinetics)
physostigmine, ecothiophate iodide and demecarium provides good control of IOP throughout the day.
bromide.
d. Pilocarpine soaked soft contact lenses : Not as
Pilocarpine yet recommended for general clinical use.
Pilocarpine is the principal alkaloid of South Ameri- c. Transdermal drug delivery system : A new non ocu-
can shrubs of the genus Pilocarpus. In angle closure lar pharmaceutical device has been tested for pilo-
glaucoma, the miotic action of the drug relieves the carpine. In this system pilocarpine was applied in two
pupillary block and also pulls the iris away from the patches of 30 mg each over the supraclavicular skin
anterior chamber angle. It increases the trabecular of 24 patients. Substantial amount of pilocarpine was
outflow due to cilliary body contraction. This results released from the patches to the dermis with detect-
in pull on the scleral spur and strengthening of the able plasma drug levels at 12 hours and 24 hours
trabecular clamps. It is available in various concen- after administration. The advantage of the system is
trations ranging from 0.5 - 4% and is indicated in acute that it avoids ocular side effects of eye drops9.
and chronic narrow angle glaucoma, open angle glau-
coma and in secondary glaucoma resulting from f. Electronic medication alarm device : Another de-
pupillary block. Its onset of action is rapid, peak vice which enhances the compliance in glaucoma pa-
effect occurs between 30-60 minutes and lasts for 4- tients taking pilocarpine is the electronic medication
8 hours. Occasionally drug resistance can develop alarm device (Prescript TimeCap). A significant dif-
which is reversible. Ocular side effects are common ference in patient compliance level was observed
with pilocarpine and can interfere with the patient's (95.8% compliance level with the alarm device ver-
quality of life and compliance with recommended sus 83.1% without it)10.
therapy. Superficial punctate keratitis is the most trou- g. Liposomal pilocarpine : Liposome encapsulated pi-
blesome acute toxic effect of pilocarpine. Other side locarpine has shown prolonged effect in normal and
effects include ciliary muscle spasm which can lead glaucomatous rabbits11. However, clinically its effect
to browache, induced myopia, miosis, possible retinal remains to be substantiated.
detachments, progression of cataract and corneal
endothelial toxicity. Systemic toxicity is rare with the Cholinesterase inhibitors
usual doses. Cholinesterase inhibitors are another class of miotics
Delivery systems for pilocarpine which act by increasing the levels of endogenous ace-
tylcholine by inhibiting the enzyme acetylcho-
Drug delivery systems aim to achieve the desired
linesterase. Physostigmine, neostigmine and
pharmacological effect with the least amount of drug
demecarium are short acting cholinesterase inhibi-
and to prolong the duration of therapeutic effect
thereby decreasing the frequency of instillation and tors whereas ecothiophate and isofluorophate are long
associated side effects. acting cholinesterase inhibitors. Physostigmine and
neostigmine are useful in angle closure and open angle
a. Soluble polymers : Polymers like methylcellulose glaucoma, though their use has declined due to the
and polyvinyl alcohol increase the conjunctival sac high incidence of allergic reactions. Ecothiophate io-
retention time and increase corneal penetration . dide and demecarium bromide are no longer used in
b. Pilocarpine gel : The equivalent of 4% pilocarpine glaucoma. Isofluorophate is more oculotoxic than
hydrochloride in a highly viscous acrylic vehicle when ecothiophate and demecarium. Cholinergic toxicities
applied once daily at bed time has been reported to in the form of profound muscle weakness and cyst-
produce a significant reduction in IOP for 24 hours. oid macular edema have been reported with the use
GLAUCOMA THERAPY 74

of ecothiophate eye drops. These toxicities resolve 30 minutes and peak effect is observed in 1 hour. It
spontaneously on discontinuation of the therapy12-13. exerts its action by decreasing aqueous production
Local ocular side effects of anticholinesterase agents and enhancing the outflow facility. It is indicated for
similar to those of other miotics may be severe initial therapy or as an adjunct with other ocular hypo-
enough to warrant discontinuation of the drug e.g. iris tensive agents. It is available as 0.1% ophthalmic
cyst formation and cataract formation. In general, the solution to be administered twice daily. This concen-
use of anticholinesterase medications for the treat- tration represents a balance between efficacy and
ment of open angle glaucoma is reserved for cases mydriasis. Used as a single agent dipivefrin produces
in which the patient has become intolerant to pilo- a 20-24% reduction in IOP. Recently a multicentric
carpine or carbachol or when the pressure lowering study found dipivefrin equivalent to 0.5% betaxolol
effect of these agents is inadequate. Also these used twice daily as a single agent. It works well with
agents are more effective in secondary glaucoma like pilocarpine and with oral carbonic anhydrase inhibi-
aphakic or pseudoaphakic glaucoma. tors. Its advantages over epinephrine are lower car-
diovascular side effects. Like epinephrine it can be
2. Adrenergic agonists used in patients of asthma, in young patients intoler-
Epinephrine ant to miotics and in those with cataracts. Dipivefrin
does not easily discolor soft contact lenses and has
It is a direct acting sympathomimetic amine and it a much lower incidence of adenochrome deposits
acts by decreasing aqueous humor formation in the than epinephrine. A common adverse effect of
early phase presumably due to its α-adrenergic ef- dipevefrin is follicular conjunctivitis15.
fect. It also increases trabecular outflow probably by
stimulating β2-adrenergic receptors in the trabecular Apraclonidine
meshwork. Onset of action occurs at 1 hr with a peak Apraclonidine is an α 2-adrenergic agonist which is
effect at 4 hours and ocular hypotensive effect may basically a para amino derivative of clonidine. It acts
last upto 72 hours. Long term epinephrine therapy by decreasing aqueous production, increasing
achieves the same degree of IOP control as timolol14. trabecular meshwork outflow by reducing episcleral
Epinephrine is additive to pilocarpine and to oral car- venous pressure and may also increase uveoscleral
bonic anhydrase inhibitors. It is also partially addi- outflow by an increase in prostaglandin synthesis. It
tive to β-blockers. Epinephrine may be used as initial is now available commercially both as 1% and 0.5%
or adjunctive glaucoma therapy. It is available as hy- ophthalmic solution and is mainly indicated to control
drochloride, bitartarate and borate salt for topical oph- the acute IOP rise after ocular laser therapy as longer
thalmic use in concentration ranges varying from 0.25- treatment may lead to development of tolerance. Within
2% to be administered twice daily. Topical instillation one hour of instillation, apraclonidine 1% produces a
of epinephrine causes conjunctival decongestion and rapid drop in intraocular pressure of at least 20% from
transient mydriasis. Systemic hypertension, stinging, baseline. The maximal effect is produced 3-5 hours
browache, conjunctival hyperemia, adenochrome de- after dosing. Single postoperative administration of
posits and allergic lid reactions are reported with 0.5% apraclonidine has been found to be equally ef-
epinephrine. It needs to be administered topically with fective to that of 1% apraclonidine in the prevention
caution in patients of cardiovascular dysfunctions, of immediate post-operative IOP rise in a prospec-
hyperthyroidism or diabetes mellitus. tive randomized study on 83 patients of trabeculo-
Dipivefrin plasty, 62 patients of iridotomy and 52 patients of
capsulotomy16.
Dipivefrin is the prodrug which undergoes biotrans-
formation to epinephrine within the cornea. Due to The ocular hypotensive effect of apraclonidine alone
increased lipophilicity its penetration across the cor- is equal to 0.5% timolol maleate upto 8 hours post
nea is 17 times more than epinephrine, and lesser dose but less than timolol maleate upto 12 hours post
doses are needed to be administered as compared to dose. It may be used concomitantly with other
epinephrine. It is better tolerated than epinephrine. antiglaucoma agents and as many as 60% patients
The onset of its ocular hypotensive action is within do not require additional therapy for upto 5 months, if
75 ROHIT SAXENA et al.

apraclonidine is added. The increased polarity of by their action on ciliary body15. They block the β-
apraclonidine limits its penetration through blood brain receptors in the iris and ciliary body and thereby cause
barrier, reducing undesirable CNS effects so that it significant reduction in IOP. This class of drugs has
minimally affects blood pressure and heart rate. Sys- several advantages over both cholinergic and adren-
temic side effects include dry mouth and nose in 30- ergic agonists. Majority of patients can be treated
50% patients. The most common reversible side ef- solely by β-blockers. Unlike miotics, β-blockers have
fect is the local allergic reaction manifested as itch- little effect on pupil size or accomodation, eliminat-
ing, burning and conjunctival inflammation in some 8- ing the problems of dim vision, decreased night vi-
30% patients17. It is contraindicated in patients re- sion and blurred vision. Unlike adrenergic agonists,
ceiving MAO-inhibitors and tricyclic antidepressants β-blockers do not cause pupil size changes or
because they affect metabolism and uptake of hyperemia. β-blockers also have a significant addi-
catecholamines. Long term use of apraclonidine is tive action when combined with pilocarpine or other
limited due to high incidence of local adverse reac- antiglaucoma agent.
tions and tachyphylaxis18.
Depending on their selective receptor inhibition, they
Brimonidine are classified as β 1-selective and non-selective
β-blockers respectively. Betaxolol, atenolol and me-
Since its introduction in 1996, it has emerged as a toprolol are selective β1 -blockers whereas timolol
new powerful first line agent for the treatment of el- maleate, nadolol, befunolol, carteolol, penbutolol,
evated IOP. It is the drug of choice in chronic treat- labetalol, nipradilol are non-selective β-blockers. Cur-
ment of glaucoma and in patients with cardiopul- rently the following five β-blockers are available for
monary disease and who have contraindications to topical ophthalmic use - timolol, betaxolol,
β-blockers. It is a highly selective α 2-adrenoceptor levobunolol, carteolol and metoprolol. The dosage
agonist. It is 7-12 fold and 23-32 fold more α 2 selec- regimens, duration of action and side effects of
tive than clonidine and apraclonidine respectively. It β-blockers and other selected antiglaucoma drugs are
has lower incidence of ocular side effects because of given in Table 1.
α 2 selectivity. It reduces the intraocular pressure by
Timolol
suppressing the rate of aqueous humor flow and en-
hancing uveoscleral flow. It has good retinal bioavail- The introduction of timolol in 1978 was a milestone in
ability, ocular hypotensive and neuroprotective action ocular pharmacology. It was the first topical β-adren-
in animal models19. Its peak IOP reduction efficacy ergic antagonist approved in US for the treatment of
is comparable to that of timolol and does not cause glaucoma and elevated IOP22. It is currently the pro-
cardiopulmonary side effects as reported with timolol20. totype agent to which new antiglaucoma drugs are
However, there are reports suggesting similar efficacy compared in clinical trials. Timolol inhibits both β1 and
of brimonidine with that of timolol but with a greater β2 adrenergic activity. It is being used extensively
incidence of adverse local reactions18. In a recent dou- worldwide as a first line agent for the treatment of
ble blind clinical study brimonidine tartarate 0.2% twice patients with open angle glaucoma and ocular hyper-
daily provided sustained IOP lowering efficacy com- tension. It is instilled as one drop of 0.25% or 0.5%
paring to timolol 0.5% twice daily with no significant solution twice a day and the duration of action ex-
differences at trough or peak during 4 years of con- ceeds 7 hours. At this dose timolol produces a sig-
tinuous use21. nificant reduction in IOP in most cases. Although
numerous investigators have demonstrated the safety
3. Beta adrenergic antagonists of timolol, significant local and systemic side effects
Drugs in this class have become the major therapeu- have been documented, so this drug must be used
tic agents for most forms of glaucoma. Due to their with caution. Localized irritation of the corneal epi-
almost universal efficacy and minimal ocular side ef- thelium can result in blurred vision, conjunctival
fects, these drugs usually are the first line agents for hyperemia, superficial punctate keratopathy and dry
the medical therapy of all kinds of glaucoma. They eye symptoms. Although several studies have con-
act solely by reducing the aqueous humor production 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- Efficacy of carteolol is comparable to that of timolol
siveness decreases with continuous use. The timolol and has been better tolerated as regards stinging and
therapy is associated with the phenomenon of short irritation26-27. Since carteolol has fewer deleterious
term escape and long term drift. In short term es- effects on lipid profile, some ophthalmologists prefer
cape, most patients experience a good IOP reduc- it in patients with hypercholesterolemia.
tion after start of timolol therapy, but the pressure rises
Betaxolol
after a few days to finally level off by 3-4 weeks. One
must therefore wait for at least one month after start- Betaxolol hydrochloride was introduced in the early
ing timolol to determine its efficacy. In long term drift, 1980s as the first topical, cardioselective β1-adrener-
after around one year of timolol therapy, few patients gic antagonist to be used in ophthalmology. Most clini-
show a slow decline in pressure responsiveness to cal trials comparing betaxolol with timolol have shown
timolol. Many of these will regain responsiveness to betaxolol to be statistically less effective in both pres-
timolol after a washout period. The efficacy of timolol sure lowering and reducing aqueous outflow. Onset
hemihydrate 0.5% solution given once a day has been of action is noted in 30 minutes, maximum effect oc-
found to be comparable in its IOP reducing efficacy to curs at 2 hours after topical administration and a sin-
timolol gel 0.5% given once a day23. gle dose provides 12 hours of pressure reduction. The
advantage of betaxolol over timolol is the absence of
Timolol has been shown to be more effective in low-
β2-adrenergic inhibition which minimizes the risk of
ering IOP than either epinephrine or pilocarpine. Sys-
respiratory side effects. Betaxolol causes more burn-
temic toxicity from topical timolol occurs more fre-
ing and stinging than non-cardioselective β-blockers.
quently than local toxicity and can affect the pulmo-
nary, cardiac and central nervous system24. These Marketed as 0.5% ophthalmic solution for all types
include bronchospasm, bradycardia, hypotension, of glaucomas, it requires to be instilled twice daily. It
arrhythmias, heart failure, myocardial infarction, de- is reported to cause less impairment of respiratory
pression, anxiety and confusion. and cardiovascular functions when compared to timolol
particularly in the elderly. Betaxolol also has
Timolol maleate (ophthalmic gel forming solution,
neuroprotective action on the eye and slows down
Timoptic XE) is a new formulation of timolol. The vehi-
the changes seen in retina after raised IOP induced
cle is an anionic polysaccharide derived from gellan
ischemia/reperfusion28,15,29.
gum. Upon contact with the cations in the tear film,
the product forms a gel allowing the drug to remain in Levobunolol
contact with the eye for a longer period of time. Dos-
age is once daily and has the potential advantage of It reduces intraocular pressure by reducing aqueous
greater compliance, reduced cost and less systemic humor formation as well as by enhancing the outflow
absorption. facility30. It is as effective in reducing IOP as timolol
maleate, metoprolol and carteolol14. The potential
Carteolol advantage of levobunolol is once daily dosing due to
longer duration of action. It is cost effective, causes
Carteolol is the second most commonly prescribed
less ocular discomfort and has better compliance31.
topical β-blocker in the world. A multicentric trial com-
Topical levobunolol or timolol when instilled one drop
paring carteolol and timolol showed equivalent pres-
for one week have been found to slightly increase the
sure lowering efficacy over three months to one year.
retinal blood flow in healthy volunteers32. Levobunolol
The half life of its metabolite, the 8-hydroxycarteolol
is contraindicated in patients predisposed to cardiac
is 2-3 times that of the parent molecule and this may
or respiratory disease. Caution is required in diabet-
allow for the better bioavailability and increased du-
ics and those undergoing major surgery33.
ration of action compared with other β-adrenergic an-
tagonists. Metoprolol
It is a non-selective β-blocker with intrinsic It is a cost effective, selective β1 adrenergic antago-
sympathomimetic activity and ability to partially ac- nist similar to timolol in clinical efficacy. It reduces
tivate β-receptors in the absence of catecholamines25. the intraocular pressure in normal eyes, chronic open
GLAUCOMA THERAPY 78

angle glaucoma and ocular hypertensive patients. The Unoprostone


recommended dose in glaucoma is one drop of 0.3%
or 0.6% solution twice a day. IOP lowering effect is Unoprostone isopropylate is the first docosanoid de-
comparable to that of levobunolol and carteolol14. It is rivative for glaucoma therapy. It acts by enhancing
associated with more eye burning, stinging and uveoscleral outflow without affecting aqueous humour
granulomatous anterior uveitis than other drugs34. It production42,43. It is available as 0.12% ophthalmic
also carries the risk of respiratory and cardiac toxicity. solution and requires twice a day instillation. Its
oculohypotensive effect is similar to or slightly infe-
4. Prostaglandin analogs rior to that of timolol 0.5%44. It has also been seen in
some studies to increase the optic nerve head blood
Latanoprost
flow. It has an additive efficacy with latanoprost and
It is a highly lipophilic 17-phenyl substituted PGF2α can safely improve the diurnal curve characteristics
isopropyl ester prodrug having a novel mechanism of in patients who continue to have an elevated IOP on
action. It undergoes enzymatic hydrolysis in cornea and latanoprost 0.005% alone45.
gets activated to the acid of latanoprost. Its response PhXA-85
seems to be mediated by prostanoid receptors.
Latanoprost is more selective than PGF2α in this re- 11-Deoxy-PGE1 or PhXA-85 is another prostaglandin
spect and thereby has superior therapeutic profile35-36. It analog. It also acts by increasing uveoscleral out-
acts by enhancing uveoscleral outflow rather than flow. It has also been shown to reduce the collagen
altering the conventional trabeculo-canalicular aque- turnover in the matrix surrounding the human ciliary
ous outflow. It is available as 0.005% ophthalmic smooth muscles in culture, in a dose dependent man-
solution and requires to be instilled once at night. ner. The reduction in extracellular matrix components
is suggested to lower the hydraulic resistance to aque-
A single dose of topical 0.005% latanoprost is equi-
ous flow thus contributing to pressure reduction46.
effective to that of 0.5% timolol (bd dose) in patients
suffering from primary open angle glaucoma and ocu- 5. Carbonic anhydrase inhibitors
lar hypertension and has a duration of action ranging
Systemic carbonic anhydrase inhibitors have been
from 20-24 hours. It is well tolerated with no detect- an integral part of glaucoma medical therapy for the
able systemic side effects. Some 3-10% patients past 40 years. These are the reserved group of drugs
have shown iris pigmentation after 3-4.5 months treat- and are given orally (with the exception of dorzolamide
ment due to increased synthesis of melanin in the and brinzolamide which are available for topical ad-
melanocytes of the iris stroma and cystoid macular ministration) as an adjunct when IOP is not control-
edema37. Other local side effects include mild con- led adequately with topical medication. Approximately
junctival hyperemia, punctate corneal erosions and 50% patients have shown intolerable side effects with
lengthening and thickening of eyelashes. the use of systemic carbonic anhydrase inhibitors47.
Therefore these drugs are currently used to control
In a recent phase III clinical trial, latanoprost 0.005%
IOP in patients waiting for surgery or till the time topi-
once daily produced sustained reduction of IOP in cal drugs become effective. Acetazolamide and
ocular hypertension and primary open angle glaucoma methazolamide are the two potent systemically ad-
patients to a greater extent than timolol38. The effi- ministered carbonic anhydrase inhibitors.
cacy of once a day 0.005% latanoprost is more than
twice a day administration of 0.12% of unoprostone Acetazolamide
in patients of primary open angle glaucoma and ocu- This is the most widely prescribed carbonic anhydrase
lar hypertension39. Latanoprost can be administered inhibitor. However, approximately 50% patients stop
as monotherapy and has good efficacy when com- treatment with acetazolamide as a consequence of
bined with other drugs lowering IOP, including sys- intolerable side effects due to extraocular inhibition
temic acetazolamide40. It can be used safely in pa- of carbonic anhydrase. It reversibly blocks the en-
tients of glaucoma with concomitant bronchial zyme carbonic anhydrase in the ciliary body and thus
asthma41. suppresses aqueous humor production. The aqueous
79 ROHIT SAXENA et al.

fluid rich in sodium and bicarbonate ions is patients of open angle glaucoma and ocular hyper-
hyperosmotic as compared to plasma. Water is at- tension who are unable to tolerate ophthalmic β block-
tracted to the posterior chamber as a result of osmo- ers50. When combined with timolol therapy, it shows
sis and the high concentration of bicarbonate ions is efficacy similar to that of pilocarpine.
diluted. When given orally, plasma levels attain a peak
at 2 hours, persisting for 4-6 hours and then rapidly In lower concentrations it may be equally effective
drop because of urinary excretion. Acetazolamide is with better compliance which may further widen the
available as tablets and as capsules. The usual oral therapeutic potential of this drug. It is associated with
dose is 125-250 mg four times daily. The effect of lower cardiovascular side effects than topical β block-
acetazolamide may be sustained by dispensing in ers and less ocular side effects than pilocarpine. How-
'coated granules form' and using an osmotic pump ever, it can cause irreversible corneal edema in pa-
delivery system48. Gastrointestinal upset is the most tients having a compromised endothelium51.
frequent symptom of acetazolamide intolerance. Se-
Brinzolamide
vere side effects include myopia, pulmonary failure,
renal stones, aplastic anaemia, metabolic acidosis, It is also commercially available since 1998. Its 1%
hypersensitivity reactions and peripheral neuropathy. suspension is comparable to 2% dorzolamide in low-
Methazolamide ering IOP. It is administered three times daily. Though
it has a lower incidence of burning and stinging, it
It is more potent than acetazolamide and has struc- elicits more blurred vision52. 1% brinzolamide three
tural similarity to it. It is indicated in patients of chronic times daily used adjunctively with timolol 0.5% twice
open angle glaucoma where IOP is not controlled daily produces a significantly additive IOP reduction
adequately with acetazolamide or topical medications. in open angle glaucoma and ocular hypertensive pa-
Its penetration across blood aqueous barriers is 50 tients with fewer side effects53.
times that of acetazolamide due to its good lipid solu-
bility and low plasma protein binding49. Its dose is 25- 6. Osmotic agents
50 mg three times daily. Methazolamide is associ-
These agents act by enhancing the osmotic pres-
ated with drowsiness, fatigue, malaise and little gas-
sure of plasma with respect to intraocular structures
trointestinal disturbances. Few incidences of phos-
thereby setting an osmotic gradient. Consequently
phate renal stones have also been reported.
the fluid moves from the eye to hyperosmotic plasma
Dorzolamide of ocular blood vessels, thereby reducing the vitre-
ous volume which is responsible for lowering of IOP.
Dorzolamide is a non-bacteriostatic sulfonamide de-
rivative devoid of systemic side effects as seen after Mannitol, glycerol, urea, isosorbide etc are the os-
oral administration of carbonic anhydrase inhibitors. motic agents used for short term reduction of IOP.
It has become commercially available since 1995 for The use of these drugs is currently limited to short
topical ophthalmic use. It is thought to reduce the term emergency situations such as acute angle clo-
raised IOP by the same mechanism as that the car- sure glaucoma or pre-operative control of raised IOP.
bonic anhydrase inhibitors. It penetrates cornea, in- The side effects of these drugs include nausea, vom-
hibits carbonic anhydrase-II in the ciliary body, slows iting, diuresis, headache, diarrhea, chills and fever.
the production of local bicarbonates and thus de- Rarely life-threatening problems such as cardiovas-
creases sodium and fluid transport which in turn re- cular overload, intracranial hemorrhage, pulmonary
duces the secretion of aqueous humor50. edema and acidemia may occur.
It is available as 2% ophthalmic solution and the dose 7. Miscellaneous agents
is one drop instilled twice daily alone or in conjunc-
tion with β blockers. The drug reduces the IOP by Forskolin
approximately 3.5-6.0 mm Hg in patients of primary
open angle glaucoma or hypertension. It is of com- Forskolin is derived from methanolic extract of the roots
parable efficacy to that of betaxolol, and slightly less of Coleus forskohlii. It has been shown to be an effec-
than timolol. It is an effective second line agent for tive ocular hypotensive agent both experimentally and
GLAUCOMA THERAPY 80

clinically. It is a potent stimulator of adenylate cyclase Steroid antagonists


and does not require cell membrane bound receptors.
The ocular hypotensive effect of forskolin is directly Animal studies of mifepristone (RU-486) and related
proportional to the extent of stimulation of adenylate compounds show the promise of these drugs as ocu-
cyclase. lar hypotensive agents despite our poor understand-
ing of the mechanism of the ocular hypotensive ef-
In a clinical trial on 17 patients of open angle glau- fect57. Progression of the experimental work to hu-
coma, 1% topical forskolin reduced IOP significantly. man clinical trials is needed to ascertain their clinical
A pressure reduction of 15.4% was observed 3 hours usefulness. A more complete understanding of the
after instillation with onset at half an hour. Then pres- physiological mechanism of steroid antagonists in-
sure reduction began to decline after 3 hours and re- duced ocular hypotension may lead to improved or
duced to a level of 10% after 6 hours. No significant novel strategies for lowering IOP in patients of glau-
ocular or systemic side effects were observed54. The coma.
combination of 1% forskolin and 0.25% timolol had
Angiotensin converting enzyme inhibitors
an additive effect which was more than the additive
effect of 1% forskolin plus 2% pilocarpine. Components of the renin angiotensin system are
present in peripheral tissues, including the eye and
Phenoxyacetic acid derivatives
may play a role in controlling aqueous humor produc-
Ethacrynic acid, a sulfhydryl reactive phenoxyacetic tion, retinal blood flow or retinovascular disease.
acid is a promising new drug that substantially low- Angiotensin II receptors of the retinal vasculature may
ers IOP both after topical and intracameral adminis- play a significant role in the autoregulation of blood
tration. It has been shown to increase the aqueous supply to the retina and optic nerve head. Topical
humor outflow facility both in vitro and in vivo55. This angiotensin converting enzyme (ACE) inhibitors have
effect was attributed to change in cell shape, attach- been shown to lower IOP in rabbits, monkeys and
ment and correlated to the microtubule alterations and humans58. Experimental evidence suggests that ACE
chemical sulfhydryl reactivity. Although the changes inhibitors might inhibit breakdown of bradykinin, pro-
in outflow facility and pressure reduction have been mote formation of endogenous prostaglandins and
impressive, the potential for corneal toxicity remains also enhance uveoscleral outflow. Thus, inhibitors of
a drawback. Current evidence suggests that it may ACE activity might be useful pharmacological agents
prove as a useful drug that can be administered at in the medical therapy of glaucoma.
the time of surgery to prevent postoperative pressure
Atrial natriuretic peptide
spikes. However, further work is needed to develop
less toxic, more efficacious, longer lasting and more The anterior uvea is also rich in atrial natriuretic pep-
easily administered forms if the drug is to be used for tide (ANP) and ANP receptors. Experimentally, ANP
chronic treatment. has been shown to reduce IOP via reduced secretion
of aqueous humor by a direct effect on ciliary proc-
Indacrinone and ticrynafen which are also phenoxy esses59. An improved understanding of the physiologi-
acetic acids with non-sulfhydryl reactivity have re-
cal role of ANP and the elements of the renin
cently been investigated in bovine and postmortem angiotensin system present in the eye may lead to
eyes, in cultured pulmonary artery epithelial and hu- new and interesting treatment strategies for lowering
man trabecular meshwork cells. These agents im-
IOP in glaucoma patients.
proved aqueous flow, however the mechanism of ac-
tion was not similar to that of ethacrynic acid, as these Cannabinoids
agents did not alter microtubules or act through
sulfhydryl groups56. The encouraging results of this Marijuana or cannabis has been used as a herbal
study need further experimental and clinical evalua- medication in many societies for centuries. Marijua-
tion before they can be included into the therapeutic na's ability to lower IOP in humans has spurred a
armamentarium of glaucoma. great effort to identify not only the mechanism by
81 ROHIT SAXENA et al.

which this effect occurs but also to identify either Drugs which can affect this cell death pathway through
members of this family, or a delivery system of these differing mechanisms and provide effective
drugs to the eye, that can effectively reduce pres- neuroprotection are : brimonidine, latanoprost, N-me-
sure without the well known psychotropic side thyl-D-aspartate (NMDA) antagonists (memantine and
effects60. dizocilpine, eliprodil), calcium channel blockers
(lomarizine), glutamate antagonists (riluzole), L-
Ocular hypotensive lipids
deprenyl, 5-HT1A agonists, nitric oxide synthase in-
AGN-191129 and AGN-192024, are the two new hibitors, neurotrophic factors, free radical scavengers,
antiglaucoma agents belonging to the class of com- antiapoptotic agents, naftidrofuryl, polyamine antago-
pounds termed as ocular hypotensive lipids (OHL). nists, aspirin, melatonin, cannabinoids, and
These compounds contain a neutral substituent for vitamin B1219,62-68.
the carboxylic acidic group of PGF2α and are not fatty
acids. These are relatively metabolically stable un- Monotherapy versus combination therapy
like the prodrug latanoprost and the esterified PGF2α β blockers are the most commonly prescribed first
analogue that is readily metabolized into active PGF2α.
line therapy though the use of latanoprost and
These compounds do not interact with the FP or other
brimonidine as primary therapy is also increasing in
known prostanoid receptors. These compounds have the West. Latanoprost, brimonidine and topical car-
different pharmacological profiles yet are potent ocu-
bonic anhydrase inhibitors are effective as early ad-
lar hypotensive agents. Clinical trials were conducted
junctive therapy in cases where a single drug alone
on these OHL in open angle glaucoma and ocular is inadequate to control IOP. Adrenergic agonists and
hypertension cases. Twice daily dosing at concentra-
miotics are also useful as secondary or tertiary therapy
tion of 0.01% produced significant IOP lowering (26%
but their use in the west is declining due to their sig-
decrease from baseline) and was certainly superior nificant topical and systemic side effects. It is thus
to that of timolol (0.5% bd). These new compounds
evident that when therapy with a single agent is inad-
continue to produce a significant IOP lowering effect
equate to control IOP, combined treatment is indi-
upto 24 hours after the last drug instillation. These cated. The additive benefit of two drugs depends to
compounds are well tolerated and have a very fa-
some extent on whether they reduce IOP by similar
vourable ocular and systemic safety profile with no
mechanisms. Miotics and carbonic anhydrase inhibi-
patient drop out due to adverse events. These com- tors in combination may be useful, prabably because
pounds will be an excellent alternative as a first and
miotics increase aqueous outflow, whereas carbonic
second line IOP lowering agent for the therapy of ocu-
anhydrase inhibitors reduce inflow. It must be stressed
lar hypertension and open angle glaucoma. that if the initial agent is only slightly effective at low-
Neuroprotective agents ering IOP, it should be discontinued and other drugs
tried individually before going on to combination
Neuroprotection has been projected as one of the therapy. The combination therapy in contrast to
important strategies for vision sparing through the pro- monotherapy has the possibility of delaying the need
motion of retinal ganglion cell survival61. Retinal cell for surgery.
death is initiated when pathological events like
ischaemia, axonal injury and changes in the lamina Timpilo, a new formulation combining pilocarpine hy-
cribrosa block the transport of growth factors from drochloride (3%) and timolol maleate (0.5%) is useful
the brain to retinal ganglion cells. Blockade of these in patients whose IOP is not controlled by
neurotrophins initiates a damaging cascade and the monotherapy. Each of the two components reduces
cell is unable to maintain its normal functions. When IOP by different but complementary mechanisms.
retinal ganglion cells undergo apoptosis and release While pilocarpine alone requires 4 times daily admin-
oxygen free radicals, gene expression changes fa- istration, twice daily administration of Timpilo is
vourably, mitochondria alter and excitatory toxins are adequate. Dorzolamide 2%/timolol 0.5% is a well
released during optic nerve injury. tolerated and effective fixed dose combination for
GLAUCOMA THERAPY 82

lowering IOP in the treatment of open angle glaucoma els of glutamate may be overcome by memantine or
and may be used in those patients who do not re- other compounds that effectively block this common
spond adequately to first line monotherapy. secondary neuropathological pathway. Ideally
neuroprotection in glaucoma shall be achieved by
Conclusions and future directions
combining agents that effectively reduce IOP and di-
The wide variety of topically effective antiglaucoma rectly protect the optic nerves (marginally damaged,
drugs which are available today and few others in the undamaged but at risk) through the promotion of cel-
developmental stage represent significant advance- lular survival or inhibition of cell death signals.
ment in ocular therapeutics. Though, these topical
New and more sensitive procedures that are able to
ophthalmic preparations have reduced the risk of
detect ganglion cell damage in humans before occur-
systemic toxicity to quite an extent, their long term
rence of visual field defects are developed and we
use causes systemic as well as ocular toxicity, rarely
shall be able to expedite the evaluation of
leading to death. Ophthalmologists must select the
neuroprotective efficacy of available and new drugs
drugs individually and replace them regularly in order
and new drug combinations in development.
to prevent habituation phenomenon and negative side
effects. Research into the basic pathophysiological mecha-
nisms of glaucomatous optic neuropathy will eventu-
A new futuristic glaucoma therapeutic management
ally open new therapeutic pathways. Better under-
paradigm where clinical success is no longer simply
standing of the underlying genetic basis of heritable
measured by achieved level of intraocular pressure
forms of glaucoma should provide new diagnostic
control but also long term preservation of visual func-
tools and potential for new therapeutic avenues. There
tion and patient's quality of life is expected to dra-
are reports on the involvement of an autoimmune com-
matically improve upon current treatment algorithms
ponent in certain types of glaucoma. Our understand-
for ocular hypertension and glaucoma. Ideal drug can-
ing of these complex immune disorders is required
didates for this new combination therapy will offer
and we may be able to tailor therapies to address this
better IOP lowering efficacy with fewer side effects
potential confounding issue. Promising new focus on
and provide additional means of vision sparing through
vision sparing, greater patient safety and tolerability
direct protection of optic nerve with currently avail-
will provide improved treatment options and long term
able antiglaucoma agents.
preservation of vision and quality of life.
A few but important problems need to be addressed
in future from the point of view of glaucoma therapy. A great deal of research is being directed towards
Acute studies with β blockers and adrenergic agents applying new molecular and cellular techniques to
have shown that these agents reduce choroidal and induce regeneration of mammalian central nervous
optic disc blood flow. Timolol has a better influence axons. This shall be an important step in therapy for
on visual field and is considered as an outstanding glaucomatous optic nerve atrophy (which can lead to
agent for the management of glaucoma. Therefore at least partial recovery of optic nerve function fol-
newly developed antiglaucoma drugs must be com- lowing atrophy from glaucoma).
pared with this agent. Such drugs must be designed
Synthesis of cytokines and growth factors for reac-
which do not affect ocular hemodynamics, have bet-
tive astrocytes and altered expression of cell surface
ter patient compliance and are cost effective.
adhesion molecules including neural cell adhesion
Latanoprost and brimonidine represent a promising molecule (N-CAM) hold promise. The search for phar-
approach to IOP lowering with the potential of en- macological and neuroregenerative agents for the treat-
hancing retinal ganglion cell survival. In addition, ment of glaucoma promises to be most exciting path-
retinal ganglionic cell death elicited by the high lev- ways for the future treatment of glaucoma.
83 ROHIT SAXENA et al.

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sciences starting 1 June 2002. The fellow would be expected to work full time in the Editorial
office of The National Medical Journal of India and to do a brief research study during his/her
tenure. A fellowship allowance of Rs. 10,000/- per month (all inclusive) would be offered. Inter-
ested candidates should apply with their curriculum vitae along with a 1000 word write-up on
how she/he expects to benefit from this programme and her/his future plans.Applications should
be received in the Office of The National Medical Journal of India, All India Institute of Medical
Sciences, Ansari Nagar, New Delhi-110 029, latest by 10 May 2002.