Drugs Aging 2005; 22 (1): 1-21

THERAPY IN PRACTICE 1170-229X/05/0001-0001/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Management of Glaucoma: Focus on

Pharmacological Therapy
Robert E. Marquis and Jess T. Whitson
Department of Ophthalmology, The University of Texas Southwestern Medical Center at Dallas,
Dallas, Texas, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1. Physiology of Aqueous Humour and Intraocular Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. Medical Treatment of Glaucoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3. Cholinergics (Acetylcholine Receptor Agonists) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3.1 Direct-Acting Cholinergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.1.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.2 Indirect-Acting Cholinergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3.3 Dual-Mechanism Cholinergics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4. Adrenoceptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.1 Nonselective Adrenoceptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.1.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.2 Selective α2-Adrenoceptor Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4.2.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
5. Carbonic Anhydrase Inhibitors (CAIs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.1 Systemic CAIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.1.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2 Topical CAIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5.2.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
6. β-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
6.1 Nonselective β-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
6.1.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6.2 Selective β-Adrenoceptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
6.2.1 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7. Prostaglandin Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
8. Combination Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
9. Other Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
9.1 Laser Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
9.2 Surgical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

Abstract Glaucoma represents a major cause of vision loss throughout the world.
Primary open-angle glaucoma, the most common form of glaucoma, is a chronic,
progressive disease often, though not always, accompanied by elevated intraocu-
lar pressure (IOP). In this disorder, retinal ganglion cell loss and excavation of the
optic nerve head produce characteristic peripheral visual field deficits. Patients
with normal-tension glaucoma present with typical visual field and optic nerve
head changes, without a documented history of elevated IOP. A variety of
secondary causes, such as pigment dispersion syndrome and ocular trauma, can
result in glaucoma as well. Treatment of all forms of glaucoma consists of
2 Marquis & Whitson

reducing IOP. With proper treatment, progression of this disease can often be
delayed or prevented.
Treatment options for glaucoma include medications, laser therapy and inci-
sional surgery. Laser techniques for the reduction of IOP include argon laser
trabeculoplasty and selective laser trabeculoplasty. Both techniques work by
increasing outflow of aqueous humour through the trabecular meshwork. Surgical
options for glaucoma treatment include trabeculectomy, glaucoma drainage tube
implantation and ciliary body cyclodestruction. While each of these types of
procedures is effective at lowering IOP, therapy usually begins with medications.
Medications lower IOP either by reducing the production or by increasing the rate
of outflow of aqueous humour within the eye.
Currently, there are five major classes of drugs used for the treatment of
glaucoma: (i) cholinergics (acetylcholine receptor agonists); (ii) adrenoceptor
agonists; (iii) carbonic anhydrase inhibitors (CAIs); (iv) β-adrenoceptor antago-
nists; and (v) prostaglandin analogues (PGAs). Treatment typically begins with
the selection of an agent for IOP reduction. Although β-adrenoceptor antagonists
are still commonly used by many clinicians, the PGAs are playing an increasingly
important role in the first-line therapy of glaucoma. Adjunctive agents, such as
α-adrenoceptor agonists and CAIs are often effective at providing additional
reduction in IOP for patients not controlled on monotherapy. As with any chronic
disease, effective treatment depends on minimising the adverse effects of therapy
and maximising patient compliance. The introduction of a variety of well tolerated
and potent medications over the past few years now allows the clinician to choose
a treatment regimen on an individual patient basis and thereby treat this disorder
more effectively.

Glaucoma is a heterogeneous family of ocular
disorders that share common characteristics includ-
ing excavation of the optic nerve head and peripher-
al visual field loss. Retinal ganglion cell death,
which is thought to occur through apoptosis,[1] re-
sults in progressive optic nerve dysfunction and
visual impairment. According to the WHO,
glaucoma accounts for 13.5% of global blindness
(behind cataracts and trachoma that account for
41.8% and 15.5% of global blindness, respective-
ly[2]). In the US, glaucoma is the second leading
cause of blindness overall and the leading cause
among African-Americans and Hispanics.[3,4] Typi-
cally, glaucoma is asymptomatic until late in its
course, making early detection difficult. It is esti-
mated that as many as one-half of those with
glaucoma in developed countries may be unaware
that they have the disease.[5]
Primary open-angle glaucoma (POAG) is the
most common form of glaucoma throughout the
world accounting for about two-thirds of cases.[2] It
is defined as a multifactorial optic neuropathy in
which there is a characteristic acquired loss of reti-
nal ganglion cells and atrophy of the optic nerve.[6]
Risk factors for the development of POAG include
elevated intraocular pressure (IOP), family history
of the disease, advanced age and African heritage
(table I). While elevated IOP is considered an im-
portant risk factor for POAG, it is not essential for
Table I. Risk factors for the development and progression of
glaucoma
Elevated IOP
Diurnal fluctuation of IOP
Family history of glaucoma
Race (African heritage, Hispanics)
Advanced age
Other
increased optic nerve cup-to-disc ratio
compromised ocular blood flow
diabetes mellitus
myopia
corneal thickness (thin corneas – greater risk)
IOP = intraocular pressure.

© 2005 Adis Data Information BV. All rights reserved. Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
its diagnosis. Visual loss and progressive optic neu-
ropathy can occur in patients who do not demon-
strate elevations in IOP.[7] Patients who develop
typical optic nerve head and visual field changes in
the absence of documented high IOP are said to have
normal-tension glaucoma (NTG). NTG is believed
to account for about 30% of glaucoma cases in
Western countries[8] and over two-thirds of cases in
Japan.[9] Some investigators believe that NTG may
represent a variant of POAG,[10,11] whereas others
feel that the mechanisms of the two disorders are
different.[12,13]
Ocular hypertensive subjects are those who
demonstrate consistently elevated IOP without any
obvious cause and have normal visual fields and
optic discs. This condition is frequently encountered
by clinicians and may occur as much as ten times
more often than POAG.[14] Patients with ocular
hypertension are at risk for developing POAG as a
result of their elevated IOP. Recently, the OHTS
(Ocular Hypertension Treatment Study) has demon-
strated that lowering IOP with medical therapy in
patients with ocular hypertension can significantly
reduce the risk of developing POAG.[15]
While POAG accounts for a majority of cases of
glaucoma in the US, several other prevalent forms of
the disease exist as well (table II). Secondary causes
of open-angle glaucoma (OAG) result from either an
increased resistance to aqueous humour flow at the
trabecular meshwork (TM) or from elevated epis-
cleral venous pressure. Pigmentary glaucoma is
associated with pigment dispersion syndrome which
occurs when iris pigment accumulates in the anterior
chamber and deposits on the TM and in some cases
the corneal endothelium. The pigment is liberated
from the posterior iris surface as it makes contact
with the zonular fibres that support the lens.[16]
Another form of secondary OAG is seen in
pseudoexfoliation syndrome. Deposition of a fibril-
lar material on anterior segment structures, includ-
ing the TM, may result in increased IOP and
glaucoma. A third form of secondary OAG occurs in
some patients receiving corticosteroid therapy either
topically or (less frequently) systemically. Patients
with intraocular inflammation are typically treated
with corticosteroids. Because intraocular inflamma-
tion (uveitis) itself may cause elevated IOP, either
through blockage or inflammation of the TM, it is
© 2005 Adis Data Information BV. All rights reserved.
3
often difficult clinically to distinguish corticoste-
roid-induced glaucoma from inflammatory glauco-
ma.
Ocular trauma may lead to glaucoma by a variety
of mechanisms. In the acute post-traumatic period,
markedly elevated IOP may result from hyphaema
(anterior chamber haemorrhage), inflammation and
cellular debris that clog the TM. Normal red blood
cells (RBCs) may filter through the TM readily in
most cases; however, if RBCs denature and swell,
they may become lodged in the TM and cause an
elevation in IOP. Blunt anterior segment trauma
may also directly damage the TM and result in
angle-recession glaucoma. Finally, inflammation af-
ter trauma may cause scar-like adhesions between
Table II. The secondary glaucomas
Open-angle
Pigmentary (associated with pigment dispersion syndrome)
Pseudoexfoliation
Corticosteroid-induced
Uveitic (e.g. HLA-B27+, arthritic, sarcoidosis, idiopathic)
Haemolytic/ghost cell (after vitreous haemorrhage)
Elevated episcleral venous pressure (e.g. carotid-cavernous
fistula, Sturge-Weber syndrome)
Post-traumatic
Acute hyphaema
Lens dislocation into anterior chamber
Haemolytic/ghost cell
Angle recession
Lens-associated
Phacolytic (leakage of protein from hypermature cataract)
Lens particle (after cataract surgery or penetrating trauma)
Phacoantigenic (formerly phacoanaphylatic)
Other OAG associated with uveitis
Posner-Schlossman syndrome (glaucomatocyclitic crisis)
Fuchs’ heterochromic iridocyclitis
Postsurgical (e.g. after corneal transplant)
Closed-angle
Plateau iris syndrome
Phacomorphic (swollen or large lens pushing iris forward)
Uveal effusion or ciliary body anterior rotation
Posterior segment tumour
Neovascularisation of the angle (e.g. with retinal ischaemia)
Peripheral anterior synechiae (e.g. with chronic uveitis)
ICE syndromes (essential iris atrophy, Chandler syndrome and
Cogan-Reese syndrome)
HLA = human leukocyte antigen; ICE = iridocorneal endothelial;
OAG = open-angle glaucoma.
Drugs Aging 2005; 22 (1)
4 Marquis & Whitson
the peripheral iris and cornea, which can impede
egress of aqueous humour by blocking outflow
through the TM. If these adhesions, termed periph-
eral anterior synechiae (PAS), are extensive, angle-
closure glaucoma may result.
The angle-closure glaucomas are a group of con-
ditions caused by several mechanisms with the com-
mon anatomical result of peripheral iridocorneal
apposition and TM blockage (table II). Hyperopic
(far-sighted) eyes with short axial length, shallow
anterior chamber depth and narrow anatomical an-
gles are predisposed to angle-closure glaucoma. An
acute attack of angle-closure glaucoma may cause
markedly elevated IOP and symptoms, such as
headache, nausea, emesis and blurred vision from
corneal oedema. If the anatomical blockade of the
TM is not relieved by peripheral iridectomy (either
by laser peripheral iridectomy or incisional surgery),
extensive visual loss may result. Chronic angle-
closure glaucoma is much less common in Cauca-
sians than POAG,[17] but is a significant cause of
glaucoma-related blindness among Asians and Es-
kimos.[18]
Neovascularisation of the iris (rubeosis iridis)
and iridocorneal angle (NVA) can lead to chronic
angle-closure (neovascular) glaucoma if the aetiolo-
gy of the neovascularisation is left untreated. Chron-
ic uveitis and retinal ischaemia, often seen with
proliferative diabetic retinopathy and retinal vascu-
lar occlusion, are common causes of rubeosis iridis
and NVA that can result in neovascular glaucoma.
The main goal of treatment for all forms of
glaucoma is the preservation of visual function. The
cornerstone of therapy to achieve this goal is the
reduction of IOP. This report discusses the efficacy,
safety and basic pharmacology of currently availa-
ble agents that can be used as monotherapy or in
combination for the medical treatment of glaucoma.
The physiology of aqueous humour and IOP is re-
viewed in order to understand better the mechanism
of action of drugs used in the treatment of this
disorder. Finally, a brief description of other treat-
ment modalities for glaucoma, including laser ther-
apy and surgery, are provided.
© 2005 Adis Data Information BV. All rights reserved.
1. Physiology of Aqueous Humour and
Intraocular Pressure
IOP is determined by the balance that exists
between the rate of aqueous humour production
(inflow) and the rate of fluid exit from the eye
(outflow). Aqueous humour is produced by the cilia-
ry body and leaves the eye through either the TM
(conventional) or uveoscleral (unconventional)
pathway. The uveoscleral pathway is poorly under-
stood. In glaucoma, elevated IOP is typically caused
by decreased facility of outflow through the TM
pathway. Episcleral venous pressure can also influ-
ence IOP through its effect on TM outflow. The
relationship of IOP, aqueous humour production,
outflow and episcleral venous pressure can be de-
scribed as follows:
F−U
IOP = + Pv
C
where F is the aqueous humour formation (μL/min),
U is the uveoscleral outflow (μL/min), C is the
trabecular meshwork outflow facility (μL/min/
mm Hg) and Pv is the episcleral venous pressure
(mm Hg).
Aqueous humour is thought to be derived from
plasma within the capillary network of the ciliary
body (figure 1). Following ultrafiltration of plasma
into the extracellular space or stroma of the ciliary
processes, active transport and secretion of this fluid
into the posterior chamber of the eye by the nonpig-
mented epithelium of the ciliary body occurs at a
rate of 1.4–4.3 μL/min.[19] Aqueous humour produc-
tion decreases with age.[20] Patients with diabetes
mellitus[21] and inflammation of the eye (irido-
cyclitis)[22] also experience decreased rates of aque-
ous humour formation. A large fluid intake
(1000mL of water) has been shown to significantly
increase aqueous humour production after 90 min-
utes.[23] Carbonic anhydrase, adenosine triphos-
phatases and adrenoceptors located in the nonpig-
mented ciliary epithelium are thought to play an
important role in aqueous humour formation. Phar-
macological modulation of these enzymes and re-
ceptors can reduce aqueous humour formation and
lower IOP.
Following transport of aqueous humour into the
posterior chamber, it flows through the pupil into the
anterior chamber (figure 1). Once there, it maintains
Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
a physiological IOP and also nourishes the avascular
cornea and lens. It may aid in the metabolism of the
vitreous and retina as well.[24] As mentioned earlier,
aqueous humour exits the eye through one of two
pathways. Most of the aqueous humour (about 80%)
leaves the eye through the TM pathway. This path-
way consists of TM, a sieve-like structure which
consists of a connective tissue core surrounded by
endothelium, and Schlemm’s canal, a 360° collector
channel for aqueous humour that leads to the epis-
cleral venous system. A small amount of aqueous
humour (about 20%) flows directly through the iris
root and interstitial spaces of the ciliary muscle into
the suprachoroidal space (uveoscleral pathway). The
relative percentages of aqueous humour which exit
the anterior chamber through these two pathways is
variable and can change with age and presence of
disease.[20,25,26] Pharmacological modulation of ad-
renoceptors and prostanoid receptors located in the
TM or ciliary body can increase aqueous humour
outflow through one or both pathways and lead to a
reduction in IOP.
2. Medical Treatment of Glaucoma
The cornerstone of glaucoma therapy is the re-
duction of IOP to a level which safely halts progres-
sive visual loss. For most patients, initial treatment
begins with medication. Currently, there are five
main categories of medication for the treatment of
glaucoma (table III). Typically, treatment begins
with the selection of an agent as monotherapy. β-
Adrenoceptor antagonists have been a mainstay of
the medical treatment of glaucoma for many years
and are still often used as first-line therapy, particu-
larly in Europe and Latin America. Recently, the
prostaglandin analogues (PGAs) have emerged as a
popular choice for the first-line treatment of
glaucoma.[27] Following a therapeutic trial, the med-
ication is either continued or switched to a different
class of medication based on its effect. If expected
reduction in IOP is achieved, but additional pressure
reduction is required, another agent can be added to
the regimen. The past few years have seen an enor-
mous increase of new available medications for
glaucoma therapy (table III). A recent review esti-
mated that there are now over 56 000 possible com-
binations of medications for the treatment of
glaucoma.[28]
© 2005 Adis Data Information BV. All rights reserved.
5
Safety and tolerability are important considera-
tions when selecting glaucoma therapy as well.
Glaucoma drops can produce a variety of local ad-
verse effects ranging from induced miosis by
cholinergics (acetylcholine receptor agonists) to
lash growth by PGAs (see section 7). Topical drugs
can also produce important systemic adverse effects.
Once a glaucoma medication is instilled into the eye,
much of it (about 80%) passes through the naso-
lacrimal canal and is absorbed into the systemic
circulation. Such absorption avoids hepatic first-
pass metabolism, so with some agents, systemic
adverse effects can be significant.[29] Eyelid closure
and punctal occlusion following drop instillation
have been shown to significantly decrease the sys-
temic absorption of topical medications.[30]
3. Cholinergics (Acetylcholine
Receptor Agonists)
The cholinergics, also known as parasympath-
omimetics or miotics, were the first class of agents
used for the treatment of glaucoma, introduced over
100 years ago.[31] They can be divided into two
categories: the direct-acting agents work directly on
the parasympathetic receptors in the eye, whereas
the indirect-acting agents inhibit acetylcholinester-
Schemm's canal
Trabecular
meshwork Ciliary body
Cornea
Lens
Iris
Anterior
chamber
Posterior
chamber
Fig. 1. Schematic diagram of the anterior segment of an eye in
cross section. The dotted line indicates the flow of aqueous humour
from its source in the posterior chamber (the ciliary body), through
the pupil, into the anterior chamber and toward the trabecular
meshwork. A majority of aqueous humour traverses the trabacular
meshwork, collects in Schlemm’s canal, then drains into the venous
system (not shown).
Drugs Aging 2005; 22 (1)
6 Marquis & Whitson

Table III. Drugs used for the treatment of glaucoma

Drug class/drug Strength/dose Usual dosage
Cholinergics (acetylcholine receptor agonists)
Pilocarpine ophthalmic solution (%) 0.5, 1, 2, 4, 6, 8 qid
Pilocarpine ophthalmic gel (%) 4 hs
Carbachol (%) 0.75, 1.5, 3 tid
Ecothiophate iodide (%) 0.25 bid

Adrenoceptor agonists
Nonselective
epinephrine (adrenaline) [%] 0.5, 1, 2 bid
dipivefrine (%) 0.1 bid
Selective α2
apraclonidine (%) 0.5, 1.0 tid
brimonidine (%) 0.2 tid
brimonidine P (%) 0.15 tid

Carbonic anhydrase inhibitors

Systemic
acetazolamide (mg) 125, 250 qid
acetazolamide sustained release (mg) 500 bid
methazolamide (mg) 25, 50 bid to tid
Topical
brinzolamide suspension (%) 1 tid
dorzolamide solution (%) 2 tid

β-Adrenoceptor antagonists
Nonselective
carteolol (%) 1 bid
levobunolol (%) 0.25, 0.5 bid
metipranolol (%) 0.3 bid
timolol (%) 0.25, 0.5 bid
timolol GFS (%) 0.25, 0.5 qd
Selective
betaxolol suspension (%) 0.25 bid
betaxolol solution (%) 0.5 bid

Prostaglandin analogues
Bimatoprost (%) 0.03 qd
Latanoprost (%) 0.005 qd
Travoprost (%) 0.004 qd
Unoprostone (%) 0.15 bid

Combination agents
Dorzolamide/timolol (%) 2.0/0.5 bid

Hyperosmotic agents
IV mannitol 0.5–2 g/kg
IV urea 0.5–2 g/kg
PO glycerin 1–1.5 g/kg
bid = twice daily; GFS = gel-forming solution; hs = at bedtime; IV = intravenous; PO = oral; qd = every day; qid = four times daily; tid =
three times daily.

© 2005 Adis Data Information BV. All rights reserved. Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
ase, the enzyme responsible for the degradation of
acetylcholine. The cholinergics lower IOP by in-
creasing outflow of aqueous humour through the
TM.
3.1 Direct-Acting Cholinergics
Pilocarpine is the most commonly prescribed
cholinergic compound. It works by directly stimu-
lating the muscarinic receptors of the ciliary muscle
that widens the anterior chamber angle, resulting in
increased outflow of aqueous humour through the
TM. Pilocarpine is available in multiple concentra-
tions ranging from 0.5% to 8%. It is a short-acting
agent and must be applied four times daily. It is also
available as a 4% gel, which is usually applied at
bedtime. Pilocarpine typically reduces IOP by about
20–30%.[32] It has been shown to decrease uveos-
cleral outflow,[33] which may have a significant
clinical effect in eyes with compromised TM out-
flow.
3.1.1 Adverse Effects
Ocular adverse effects of pilocarpine are related
to its effect on the ciliary and pupillary sphincter
muscle. Visual acuity is often diminished as a result
of pupillary constriction and accommodative spasm.
Other local adverse events include browache and,
rarely, retinal detachment. Systemic adverse effects
from pilocarpine are not common but can include
increased salivation and sweating, diarrhoea, vomit-
ing and tachycardia. While pilocarpine is an inex-
pensive and effective IOP-lowering agent, it is not
as commonly used today as in previous years be-
cause of its local adverse effects and multiple daily
dosage requirements.
3.2 Indirect-Acting Cholinergics
The indirect-acting cholinergics include ecothio-
phate iodide and demecarium bromide. These agents
work by inhibiting acetylcholinesterase, the enzyme
responsible for the degradation of acetylcholine.
Like pilocarpine, the indirect-acting miotics are
available in multiple concentrations. They are typi-
cally used twice daily. The reduction in IOP is
comparable to that seen with pilocarpine.[34] In addi-
tion to the potential adverse effects seen with pilo-
carpine, these agents deplete systemic cholinester-
ase and pseudocholinesterase. Prolonged respiratory
© 2005 Adis Data Information BV. All rights reserved.
7
paralysis can occur in patients treated with indirect-
acting cholinergics during general anaesthesia if
suxamethonium chloride is used as a muscle relax-
ant.[35] A cataractogenic effect has also been de-
scribed with chronic use of ecothiophate iodide for
the treatment of glaucoma.[36] The indirect agents
are still often used for the treatment of glaucomas in
aphakia or pseudophakia across much of Europe and
Latin America.
3.3 Dual-Mechanism Cholinergics
Carbachol works by directly stimulating musca-
rinic receptors within the eye as well as indirectly by
inhibiting acetylcholinesterase.[37] It is available in
concentrations ranging from 0.75% to 3.0% and is
typically applied three times daily. Carbachol re-
quires an adjuvant, such as benzalkonium chloride
to effectively penetrate the cornea and achieve ef-
fective levels in aqueous humour. Carbachol is more
potent than pilocarpine,[38] but is also more likely to
produce browache and accommodative spasm.[38] It
is no longer commonly used in current medical
practice.
4. Adrenoceptor Agonists
4.1 Nonselective Adrenoceptor Agonists
Epinephrine (adrenaline) stimulates both α- and
β-adrenoceptors within the eye. IOP reduction is
achieved primarily by increased aqueous humour
outflow through both the TM and uveoscleral path-
ways.[39] An acute decrease in aqueous humour pro-
duction from vasoconstriction following instillation
has been described,[40] but is not thought to be
important clinically. Epinephrine is available in con-
centrations ranging from 0.5% to 2.0% and is ap-
plied twice daily, although it is rarely used in mod-
ern clinical practice. Reductions in IOP ranging
from 15% to 25% have been reported.[41]
4.1.1 Adverse Effects
Local adverse effects of epinephrine include pu-
pillary dilation, conjunctival hyperaemia and ocular
irritation.[42] Cystoid macular oedema (CMO) has
been described in patients treated with topical epi-
nephrine following cataract surgery.[43] Long-term
administration of epinephrine can result in adre-
nochrome deposits in the conjunctiva[44] and cor-
Drugs Aging 2005; 22 (1)
8 Marquis & Whitson
nea.[45] Systemic adverse effects associated with epi-
nephrine therapy include headache, palpitations,
high blood pressure and anxiety.
Dipivefrine 0.1% is a pro-drug molecule of epi-
nephrine with two ester groups added. It was de-
signed to enhance corneal penetration and reduce
systemic and local adverse effects. Following drop
instillation, corneal esterases cleave the molecule
into an active metabolite, which then passes into the
anterior chamber.[46] IOP reduction with dipivefrine
is comparable to that seen with epinephrine, while
both local and systemic adverse effects are seen less
frequently.[47]
4.2 Selective α2-Adrenoceptor Agonists
Clonidine is a relatively selective α2-adrenocep-
tor agonist with some α1-adrenoceptor agonistic
activity. It lowers IOP by decreasing production of
aqueous humour.[48] It is a very lipophilic molecule
and readily crosses the blood-brain barrier. Systemic
hypotension can be seen following topical instilla-
tion of clonidine. It is still used clinically in parts of
Europe for the treatment of glaucoma.
Apraclonidine, or para-aminoclonidine hydro-
chloride, is a para-amino derivative of clonidine
with relatively selective α2-adrenoceptor agonistic
activity. It is a much more hydrophilic molecule
than clonidine and less likely to penetrate the blood-
brain barrier. Apraclonidine lowers IOP by reducing
aqueous humour production and increasing outflow
through the TM pathway.[49] It is available in 0.5%
and 1.0% concentrations. Mean reductions in IOP
for both concentrations range from 20% to 27%.[50]
The 0.5% concentration is typically used for short-
term adjunctive therapy (<3 months) in patients not
controlled with other agents, whereas the 1.0% con-
centration is indicated for the prevention of postop-
erative IOP elevation following anterior segment
laser surgery. Apraclonidine is rarely used for long-
term therapy because of its high rate of allergic
blepharoconjunctivitis.[51]
Brimonidine is a highly selective α2-adre-
noceptor agonist. It lowers IOP by decreasing aque-
ous humour production and increasing uveoscleral
outflow.[52] It is used as mono- or, more typically,
adjunctive therapy for the long-term management of
glaucoma or ocular hypertension. It is also effective
© 2005 Adis Data Information BV. All rights reserved.
for prevention of postoperative IOP elevations fol-
lowing anterior segment laser surgery. The original
0.2% formulation is approved for three times daily
administration in the US, although it is often used
twice daily by most clinicians It has received formal
approval for twice daily administration in other
countries. Brimonidine 0.2% has been shown to be
equivalent to timolol at reducing IOP at peak (hour 2
after administration), but is significantly less effec-
tive at trough.[53,54] Brimonidine 0.2% is significant-
ly more effective at reducing IOP than the cardiose-
lective β-adrenoceptor antagonist, betaxolol, at peak
effect (5.8mm Hg vs 3.8mm Hg, p = 0.004).[55] The
trough reduction in IOP; however, is comparable
between the two agents (3.9mm Hg
vs 3.2mm Hg).[55]
4.2.1 Adverse Effects
Local adverse effects associated with apracloni-
dine include allergic blepharoconjunctivitis
(15–48%), tearing and foreign body sensation.[56]
Eyelid retraction and pupillary mydriasis, through
α1-adrenoceptor stimulation, can be seen as well.
Systemic adverse effects include dry mouth, and
nose, headache and fatigue.[57] Unlike clonidine,
cardiovascular adverse effects, such as systemic hy-
potension are rarely seen with apraclonidine.[58]
Brimonidine is devoid of many of the α1-adre-
noceptor mediated adverse effects seen with
apraclonidine, such as pupillary mydriasis, eyelid
retraction and conjunctival blanching. The most
common ocular adverse event seen with brimoni-
dine is allergic blepharoconjunctivitis, occurring in
12–15% of patients after several months of ther-
apy.[53,54] Systemic adverse effects reported with
brimonidine use include dry mouth (33%), fatigue
(16%) and headache (18.7%).[53,54] Brimonidine
should be avoided in small children because of
associated CNS and respiratory depression.
A new formulation, brimonidine P, has recently
been introduced that contains a lower concentration
of brimonidine (0.15%) and a different vehicle with
stabilised oxychloro complex as a preservative in
place of benzalkonium chloride. Comparable reduc-
tion in IOP to the original 0.2% solution has been
reported along with a significantly lower rate of
allergy (9.2% vs 15.7%, p = 0.007).[59] Lower rates
Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
of fatigue, dry mouth and conjunctival hyperaemia
were also found with the new formulation.[59]
5. Carbonic Anhydrase Inhibitors (CAIs)
The carbonic anhydrase inhibitors (CAIs) are
sulfonamide drugs that lower IOP by reducing aque-
ous humour formation. In the ciliary epithelium,
carbonic anhydrase isoenzyme II catalyses the con-
version of CO2 and H2O to HCO3– and H+, a
process important for the production of aqueous
humour. By inhibiting this conversion, aqueous hu-
mour formation is decreased. CAIs are available as
both oral (systemic) and topical agents.
5.1 Systemic CAIs
Acetazolamide was first used for glaucoma ther-
apy in 1954.[60] It is currently available in 125mg
and 250mg tablets, and typically administered four
times daily. Sustained release capsules of 500mg are
also available and are used twice daily. Acetazo-
lamide produces reduction in IOP of about
20–30%.[61] Methazolamide, a slightly weaker CAI,
is available in 25mg and 50mg tablets. It can be
administered two or three times daily. It is slightly
less effective than acetazolamide, but is sometimes
better tolerated by patients.
5.1.1 Adverse Effects
The oral CAIs are effective IOP-lowering agents
but are limited in their clinical usefulness by their
numerous and often severe adverse effects. Paraes-
thesias of the hands and feet, nausea, vomiting,
fatigue and weight loss are all common complica-
tions of chronic oral CAI therapy. Less commonly,
renal stones may develop with long-term use. Sys-
temic acidosis, hypokalaemia, and hyponatraemia
often result from inhibition of carbonic anhydrase in
the kidney. Although uncommon, bone marrow de-
pression resulting in thrombocytopenia, agranulocy-
tosis and aplastic anaemia has been described.[62]
Rarely, Stevens-Johnson syndrome may result from
oral CAI therapy. Because of their poor tolerability
in most patients, the oral CAIs are typically reserved
for short-term use in patients on maximal medical
therapy, often as a temporising measure before sur-
gery.
© 2005 Adis Data Information BV. All rights reserved.
9
5.2 Topical CAIs
Dorzolamide was the first topical CAI to be used
for glaucoma therapy, introduced into the US mar-
ket in 1994. It is available as a 2.0% ophthalmic
solution with a relatively acidic pH of 5.5 and is
approved for three times daily administration. At
this dosage it lowers IOP by 18–22%.[63] It has been
shown to be less effective at lowering IOP than oral
acetazolamide or 0.5% timolol used twice daily, but
comparable to 0.5% betaxolol used twice daily.[63] It
is additive in hypotensive efficacy to timolol[64] and
latanoprost.[65] Comparisons between 2% dorzo-
lamide and 0.2% brimonidine used as monotherapy
have shown similar efficacy at both peak and
trough.[66,67]
Brinzolamide was introduced into the US market
in 1998. It is available as a 1.0% ophthalmic suspen-
sion with a more physiological pH of 7.4, roughly
equivalent to that of human tears. Like dorzolamide,
brinzolamide is approved for three times daily ad-
ministration. It has been shown to lower IOP equally
as well as dorzolamide.[68] Brinzolamide has been
reported to be better tolerated than dorzolamide by
most patients, presumably as a result of its more
physiological pH.[69]
5.2.1 Adverse Effects
When introduced in the mid 1990s, the topical
CAIs represented a major advance over the oral
agents for the medical management of glaucoma.
Thus far, they appear to be devoid of many of the
significant systemic adverse effects seen with the
oral CAIs. Bitter taste has been reported in about
25% of patients.[70] Local adverse events seen with
dorzolamide include stinging (12%), burning (19%)
and itching (12%).[63] Irreversible corneal decom-
pensation has been reported in patients with marked
endothelial compromise.[71] In a large, multicentre,
comparative trial, brinzolamide caused less ocular
discomfort than dorzolamide, with reported rates of
burning and stinging of 3.0% and 16.4%, respective-
ly.[72] Other ocular adverse events associated with
brinzolamide include foreign body sensation
(1.8%), itching (1.2%) and dry eyes (1.2%).[72] Like
the oral CAIs, dorzolamide and brinzolamide are
sulfonamides and should be avoided in patients with
sulfonamide hypersensitivity.
Drugs Aging 2005; 22 (1)
10
6. β-Adrenoceptor Antagonists
β-Adrenoceptor antagonists are a commonly pre-
scribed class of agents for the treatment of
glaucoma. Since their introduction for ophthalmic
use in 1979, they have been a mainstay of glaucoma
treatment and a frequent choice for first-line ther-
apy. Their popularity has declined somewhat in
recent years, however, with the introduction of more
effective, safer drugs, in particular, the PGAs.[27]
Most topical ophthalmic β-adrenoceptor antagonists
used today are nonselective agents, inhibiting both
β1- and β2-adrenoreceptors. These include timolol,
levobunolol, metipranolol and carteolol. A β1-selec-
tive agent, betaxolol, is also available for use. β-
adrenoceptor antagonists lower IOP by reducing
aqueous humour formation, most likely through the
inhibition of catecholamine-stimulated synthesis of
cyclic adenosine monophosphate in the ciliary epi-
thelium.[73] While β-adrenoceptor antagonists are
very effective IOP-reducing agents, tachyphylaxis,
or ‘drift’ may occur after long-term therapy.[74] A
recent study has shown that after 2 years, as many as
50% of patients treated initially with a β-adre-
noceptor antagonist as monotherapy will require a
different or additional medication for IOP con-
trol.[75]
6.1 Nonselective
β-Adrenoceptor Antagonists
Timolol was the first ophthalmic β-adrenoceptor
antagonist approved for the treatment of glaucoma.
Like other β-adrenoceptor antagonists, it lowers IOP
by decreasing aqueous humour formation.[73] It is
most effective during waking hours, having little to
no effect on aqueous humour production during
sleep and producing less reduction in IOP at
night.[73,76] Timolol reduces IOP by 20–35% on av-
erage.[77,78] As a result of its binding to iris melanin,
timolol is often less efficacious in patients with dark
irides.[79] It is available in 0.25% and 0.5% concen-
trations, which are typically used twice daily. Once
daily gel-forming solutions (Timoptic-XE®, 1
Merck & Co., Inc., West Point, PA, USA and
Timolol Maleate Gel-Forming Solution®, Alcon
Laboratories, Inc., Fort Worth, TX, USA) are also
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2005 Adis Data Information BV. All rights reserved.
Marquis & Whitson
available as 0.5% preparations. Once daily 0.5%
Timoptic XE® lowers mean IOP as effectively as
timolol 0.5% solution used twice daily.[80] Timolol
Maleate Gel-Forming Solution® and 0.5% Timoptic
XE® produce clinically equivalent reductions in
IOP.[81] Timolol remains the US FDA’s ‘gold stan-
dard’ drug for glaucoma therapy against which all
new medications must be compared prior to approv-
al.
Levobunolol is available in 0.25% and 0.5% so-
lutions and is typically administered twice daily.
Most patients can maintain adequate IOP control
with once daily therapy as a result of its active
metabolite, dihydrolevobunolol, which is also effec-
tive at lowering IOP.[82] Like timolol, levobunolol
lowers IOP by decreasing aqueous humour forma-
tion.[83] Its efficacy is equivalent to that of
timolol.[84]
Carteolol is available as a 1% solution and, like
timolol and levobunolol, it is administered twice
daily. Its efficacy is comparable to timolol with
average reported IOP reductions of 20–32%.[85,86]
Carteolol demonstrates intrinsic sympathomimetic
activity (ISA) which produces an early, transient β-
adrenoceptor agonist response not seen with other
topical β-adrenoceptor antagonists. It was hoped
that the ISA of carteolol might protect against some
of the systemic adverse effects seen with other β-
adrenoceptor antagonists, such as reduced pulse and
blood pressure. While this has not proven to be the
case, carteolol has been shown to have fewer delete-
rious effects on serum lipids than timolol. In a
comparative study involving 58 normolipidemic
adult men, topical carteolol therapy was associated
with a 3.3% decrease in plasma high-density lipo-
protein-cholesterol (HDL-C) and a 4% increase in
total cholesterol/HDL-C ratio, whereas timolol pro-
duced changes of 8% and 10%, respectively.[87] Me-
tipranolol 0.3% solution is used twice daily. Like the
other topical β-adrenoceptor antagonists, it lowers
IOP by reducing aqueous humour production.[88]
Studies have shown comparable efficacy to timolol
and levobunolol with average IOP reductions of
21–33%.[89,90]
Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
6.1.1 Adverse Effects
In general, topical nonselective β-adrenoceptor
antagonists are effective and well tolerated by most
patients. Reported local adverse effects include con-
junctival hyperaemia, stinging, superficial punctuate
keratitis and worsening dry eye symptoms.[91] Sev-
eral reports of reversible anterior granulomatous
uveitis following long-term use of metipranolol
have been published since the early 1990s.[92,93]
These agents can exert serious systemic adverse
effects from inhibition of β1-adrenoceptors of the
heart and β2-adrenoceptors of the lung. Bradycardia,
arrhythmia, cardiac block, congestive heart failure
and bronchospasm have been reported following the
use of topical nonselective β-adrenoceptor antago-
nists.[94,95] These agents should, therefore, be avoid-
ed in patients with severe heart disease, asthma or
chronic obstructive pulmonary disease. They should
also be used with caution in patients with diabe-
tes,[96] due to their masking of hypoglycaemia, and
in patients with myasthenia gravis.[97] CNS adverse
effects, including depression, anxiety, impotence,
fatigue and hallucinations have also been described
following the use of topical nonselective β-adre-
noceptor antagonists.[94,95,98]
6.2 Selective β-Adrenoceptor Antagonists
Betaxolol is a cardioselective β1-adrenoceptor
antagonist that lowers IOP by reducing aqueous
humour formation.[99] It is a less effective IOP-
lowering agent than timolol and the other nonselec-
tive agents with average reductions in IOP ranging
from 18% to 26%.[100,101] Despite its weaker IOP-
lowering efficacy, two reports have shown trends
for better visual field preservation with long-term
betaxolol therapy than with timolol therapy.[102,103]
Although increasing ocular perfusion has not yet
been proven to be beneficial for the treatment of
glaucoma, several investigators have speculated that
enhanced retinal and optic nerve head blood flow
from the calcium channel blocking properties of
betaxolol may account for this observed enhanced
visual field preservation.[104,105] Betaxolol is availa-
ble as a 0.25% suspension and a 0.5% solution that
are each administered twice daily.
© 2005 Adis Data Information BV. All rights reserved.
11
6.2.1 Adverse Effects
Except for occasional transient stinging upon in-
stillation, betaxolol is typically well tolerated local-
ly. It was designed to be specific for β1-adre-
noceptors, thereby minimising the potential for pul-
monary (β2-adrenoceptor mediated) adverse effects.
In most patients with restrictive airway disease,
betaxolol does not exacerbate breathing
problems.[106] However, exceptions have been re-
ported, so caution must be used when prescribing
betaxolol for patients with respiratory ail-
ments.[107,108] While cardiovascular adverse effects,
such as bradycardia and congestive heart failure
have been reported with betaxolol therapy, they
appear to be less common than those which are seen
with the nonselective agents.[109,110] CNS adverse
effects are also less common with betaxolol than
with nonselective β-adrenoceptor antagonists.[111]
7. Prostaglandin Analogues
Since their introduction into the US market in
1996, the PGAs have emerged as a popular choice
for the first-line treatment of glaucoma.[27] The
once-daily PGAs, latanoprost, travoprost and bi-
matoprost, are typically the most potent class of
IOP-reducing drugs available. They also offer excel-
lent control of diurnal IOP fluctuation that occurs
commonly among glaucoma patients and increases
their risk of visual field progression over the long
term.[112,113] Finally, except for minor cosmetic is-
sues, such as mild conjunctival hyperaemia and
eyelash growth, they pose few, if any, systemic
safety concerns. A fourth PGA, unoprostone, is also
available, although it is less effective than other
members of this class and must be used twice daily.
The PGAs are all multicarbon-chain, lipophylic
molecules, derived from arachidonic acid and shar-
ing similar structural features to PGF2α (figure 2).
They lower IOP by increasing outflow of aqueous
humour, primarily through the uveoscleral path-
way.[114] Their exact mechanism of action is still not
clear, but they are thought to exert their effect by
binding to the prostanoid FP receptors of the ciliary
body, upregulating production of various metal-
loproteinases. These metalloproteinases then re-
model the surrounding extracellular matrix making
it more permeable to aqueous humour, which leads
to enhanced outflow of aqueous humour and reduc-
Drugs Aging 2005; 22 (1)
12 Marquis & Whitson

O
O O
O
HO HO

O CF3
HO HO
OH OH

PGF2α isopropyl ester Travoprost

O O
O
O
HO HO

HO HO
OH O

Latanoprost Unoprostone

NH
O
HO

HO
OH

Bimatoprost
Fig. 2. Chemical structures of prostaglandin F2α (PGF2α) and commercially available prostaglandin analogues.

tion of IOP.[115] PGAs have also been shown to relax
the ciliary muscle, further facilitating uveoscleral
outflow.[33] Some increased outflow may occur
through the TM pathway as well.[116] Only one pub-
lished report has compared the safety and efficacy of
all three once-daily PGAs (latanoprost, travoprost
and bimatoprost) in a single, large, prospective,
multicentre trial. This study, which involved more
than 400 patients with glaucoma or ocular hyperten-
sion, showed statistically equivalent reduction in
IOP among the three agents after 3 months of ther-
apy.[117] Significantly more conjunctival hyperaemia
occurred with bimatoprost compared with lata-
noprost (p = 0.001).
Latanoprost was introduced into the US market
in 1996. It has since become the most widely pre-
scribed drug for the treatment of glaucoma in the US
and in available countries around the world. Lata-
noprost has been compared with timolol in several
multicentre studies involving over 800 pa-
tients.[118-120] Once-daily latanoprost administered in
the evening was significantly more effective at low-
ering IOP than twice daily timolol. Mean IOP reduc-
tion was 6.7 ± 3.4mm Hg for latanoprost compared
with 4.9 ± 2.9mm Hg for timolol after 6 months of

© 2005 Adis Data Information BV. All rights reserved. Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
treatment.[118] Unlike timolol, which decreases
aqueous humour production during waking hours
only, latanoprost has been found to be equally as
effective at reducing IOP during the evening as
during the day.[121] Other studies have shown lata-
noprost to be significantly more effective at reduc-
ing IOP than dorzolamide[122] and brimonidine.[123]
A long-term study involving over 300 patients with
glaucoma or ocular hypertension has shown no loss
of efficacy after 5 years of use of latanoprost as an
adjunctive agent.[124] At this time, latanoprost is the
only PGA to have received a formal first-line usage
approval from the FDA. It requires refrigeration for
long-term (>1 year) storage as well as protection
from sunlight to maintain stability.[125] It does not
require refrigeration once opened by the patient. It is
available as a 0.005% solution administered once
daily, typically in the evening.
Travoprost was introduced into the US market in
the spring of 2001. Similar to the other PGAs, it
works by increasing outflow of aqueous humour
through the uveoscleral pathway. It differs from the
other PGAs, which exhibit partial agonist activity, in
that it is a full agonist at the PGF2α receptor.[126]
Like latanoprost, travoprost is thought to reduce IOP
by interaction with this receptor resulting in in-
creased outflow of aqueous humour.[126] In a large,
multicentre trial involving over 800 patients with
glaucoma or ocular hypertension, 0.004% travoprost
was found to be equal or superior to 0.005% lata-
noprost using pooled data, and superior to 0.5%
timolol at reducing IOP after 1 year with final IOP
values ranging from 17.7mm Hg to 19.1mm Hg for
travoprost, 18.5mm Hg to 19.2mm Hg for lata-
noprost and 19.4mm Hg to 20.3mm Hg for timo-
lol.[127] Travoprost and latanoprost produced clini-
cally and statistically equivalent reductions in IOP at
the majority of individual time points evaluated
throughout this 1 year study. Two other multicentre
trials have confirmed its greater efficacy when com-
pared with timolol.[128,129] Travoprost has also been
shown to be an effective adjunctive agent offering
an additional 5–7mm Hg IOP reduction in patients
inadequately controlled on timolol.[130] Subgroup
analysis has revealed that travoprost is significantly
more effective at reducing IOP (by almost 2mm Hg)
in Blacks compared with non-Blacks.[127]
Postmarketing studies have shown that travoprost
© 2005 Adis Data Information BV. All rights reserved.
13
offers excellent diurnal IOP control and long dura-
tion of action, with significant reduction in IOP
(approximately 6mm Hg) remaining for at least 84
hours after its final dose.[131] It is a very stable
compound and does not require refrigeration or pro-
tection from sunlight.[132] Travoprost is available as
a 0.004% solution and, like latanoprost, is adminis-
tered once daily in the evening.
Bimatoprost was also introduced into the US
market in the spring of 2001. It is termed a pros-
tamide because of its unique structural presence of
an amide rather than an ester group at the carboxy-
terminal end of the α carbon chain (figure 2). It is
still not clear whether bimatoprost is hydrolysed to a
free acid during its passage through the cornea (as
are the other members of this class of agents) ena-
bling it to bind to the prostanoid FP receptor, or
whether it enters the eye as an intact molecule to
interact with a unique, as yet, unidentified, pros-
tamide receptor.[133,134] It lowers IOP by increasing
aqueous humour outflow through both the uveos-
cleral (pressure-insensitive) pathway as well as the
TM (pressure-sensitive) pathway.[135] In a large,
randomised, clinical trial involving over 1100 pa-
tients with glaucoma or ocular hypertension, once-
daily bimatoprost was found to be significantly
more effective at lowering IOP than timolol
(8.1mm Hg vs 5.6mm Hg, p < 0.001).[136] Bimato-
prost was also found to be equal or superior at
reducing IOP compared with latanoprost after 3
months of therapy in 232 patients.[137] When signifi-
cant baseline IOP differences were accounted for in
this study, both drugs produced equivalent mean
reductions in IOP. More recently, a large, randomis-
ed multicentre trial involving 269 patients has
shown bimatoprost to produce significantly greater
reduction in IOP than latanoprost at all assessment
points after 6 months of treatment.[138] However, in
this study, the mean IOP lowering effect of lata-
noprost at 8:00am. (24.1%) was much less than that
reported in previous studies (approximately
30–35%).[118-120] Bimatoprost has also been com-
pared with the fixed combination 2% dorzolamide/
0.5% timolol (Cosopt®, Merck & Co., Inc., West
Point, PA, USA). Bimatoprost produced significant-
ly greater reduction in IOP than Cosopt® at the early
morning timepoint at each visit throughout the 3-
month study.[139] Furthermore, about twice as many
Drugs Aging 2005; 22 (1)
14
patients had an IOP <16mm Hg at the final visit with
bimatoprost (31% vs 14%). However, it is important
to note that Cosopt® performed less well in this
study than in earlier reports,[64,140] producing reduc-
tions in IOP ranging from only 4.4mm Hg to
5.6mm Hg versus a more typical range of about
7.5–9.0mm Hg. Bimatoprost is available as a 0.03%
solution and is administered once daily in the eve-
ning. It does not require refrigeration to maintain
stability.[141]
Unoprostone was introduced in Japan in 1994
and became available in the US in the summer of
2000. It differs structurally from the other PGAs in
having a 22-carbon chain backbone instead of the
typical truncated 20-carbon structure found in the
other agents (figure 2). When used as monotherapy,
studies have shown twice daily unoprostone to be
significantly less effective than either timolol[142] or
latanoprost.[143] It has demonstrated comparable ef-
ficacy to brimonidine or dorzolamide when used as
an adjunctive agent to timolol.[144] It is available as a
0.15% formulation and is administered twice daily.
Because unoprostone is less effective at lowering
IOP than the other PGAs and requires more frequent
administered, its clinical use has been somewhat
limited.
In general, the PGAs are well tolerated drugs
with typically <5% of patients discontinuing regis-
tration studies as a result of adverse events. Report-
ed systemic adverse effects have been limited to
headache and upper respiratory tract symptoms.
Specifically, latanoprost has been shown to have no
deleterious effect on blood pressure, pulse and pul-
monary function in patients with chronic obstructive
pulmonary disease.[145] Local cosmetic effects, on
the other hand, are common with these agents. Con-
junctival hyperaemia has been reported in 3–15% of
patients treated with latanoprost.[118-120] Hyperaemia
is more commonly seen with the newer agents with
reported rates of 15–45% for bimatoprost[136,137] and
35–50% for travoprost.[127-129] Typically, the con-
junctival hyperaemia seen with these agents is fairly
mild in most patients. About 3% of patients in phase
III studies discontinued therapy with bimatoprost
and travoprost because of hyperaemia.
An increase in iris pigmentation, most often in
multicoloured irides, can occur with long-term use
of the PGAs. Rates of iris colour change ranging
© 2005 Adis Data Information BV. All rights reserved.
Marquis & Whitson
from 1.1% to 23% have been reported with the once-
daily PGAs.[119,127,136] The incidence with unopros-
tone appears to be much lower. The increase in
pigmentation is irreversible and is a result of in-
creased production of melanin within iris melano-
cytes, not a proliferation of melanocytes.[146] Eye-
lash growth is also common with long-term use of
these agents with reported rates ranging from 26%
to 57%.[127,136] Exacerbations of anterior uveitis[147]
and herpetic keratitis[148] have been reported with
latanoprost use. CMO has been reported with use of
latanoprost after complicated cataract surgery and in
those with a history of CMO.[149,150] The PGAs
should probably be avoided in these patients.
8. Combination Therapy
The selection of agents for combination therapy
in the treatment of glaucoma is a task commonly
encountered by clinicians. In the OHTS, almost 50%
of patients required two or more medications to
reach the required, relatively modest, target IOP
reduction of 20% from baseline and a final IOP of
<24mm Hg.[15] For many years, β-adrenoceptor an-
tagonists have been a mainstay of glaucoma therapy
and remain a popular choice for first-line therapy
among some ophthalmologists. Recently, however,
the once-daily PGAs have assumed a leading role in
the initial medical treatment of glaucoma.[27] Once a
first-line agent is chosen, its efficacy is evaluated
after a brief trial period. If less than expected IOP
reduction is produced, the drug is usually stopped
and an alternate class of agents is tried. If the ex-
pected IOP reduction occurs but a lower IOP is
needed for that particular patient, selection of an
adjunctive agent is typically performed.
When selecting an adjunctive agent, its safety
and tolerability are of paramount concern. A simple
dosage regimen can enhance patient compliance.
Also, an agent’s ability to work well with the initial
drug chosen is important to consider. A drug used
for the treatment of glaucoma lowers IOP by one of
two ways, as mentioned earlier: reduction of aque-
ous humour production or increased outflow of
aqueous humour (table IV). When choosing agents
for combination therapy, those drugs with comple-
mentary mechanisms of action usually work well
together.
Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
Table IV. Mechanism of action of drugs used to treat glaucoma
Decrease aqueous humour production
α-Adrenoceptor agonists
β-Adrenoceptor antagonists
Carbonic anhydrase inhibitors
Increase aqueous humour outflow
α-Adrenoceptor agonists
Cholinergics (acetylcholine receptor agonists)
Prostaglandin analogues
Assuming a PGA is chosen for initial monother-
apy, agents which are typically used for adjunctive
treatment include β-adrenoceptor antagonists,
α2-adrenoceptor agonists (brimonidine), or topical
CAIs. β-Adrenoceptor antagonists are additive to a
PGA, and the use of a once-daily gel-forming β-
adrenoceptor antagonist in the morning combined
with a PGA in the evening has been a popular
combination for ophthalmologists for several years.
However, recent studies which have investigated the
additional IOP reduction provided by β-adre-
noceptor antagonists when added to a PGA have
been rather disappointing, with most reports show-
ing only about 1mm Hg additional reduction in IOP
by timolol when added to latanoprost.[151,152] The
newly formulated 0.15% brimonidine P solution,
when added to bimatoprost, has been shown to have
equal or better IOP-lowering efficacy compared
with a timolol gel-forming solution used with lata-
noprost (mean IOP reduction at 10:00am of
8.5mm Hg vs 7.7mm Hg).[153]
The topical CAIs appear especially promising for
adjunctive agents used in combination with a PGA.
Recent studies have shown an overall reduction in
IOP of about 11mm Hg, or 40%, from baseline
when dorzolamide is added to latanoprost.[65,154] A
recent review compared the additional IOP reduc-
tion provided by β-adrenoceptor antagonists,
brimonidine or dorzolamide in 73 patients inade-
quately controlled by latanoprost monotherapy. Af-
ter 1 year, the topical CAI, taken either two or three
times daily produced the most additional IOP reduc-
tion (3.9mm Hg) compared with β-adrenoceptor
antagonists (2.5mm Hg) and brimonidine
(2.0mm Hg).[155]
If a β-adrenoceptor antagonist is used as initial
treatment, topical CAIs are an excellent choice for
adjunctive therapy. Although both drugs work by
© 2005 Adis Data Information BV. All rights reserved.
15
decreasing production of aqueous humour, they do
so by different mechanisms – β-adrenoceptor antag-
onists by inhibition of circulating catecholamines on
the ciliary epithelium and topical CAIs by inhibition
of carbonic anhydrase. The combination drop
Cosopt® has been shown to produce equivalent
reduction in IOP to its two components taken sepa-
rately (ranging from 27% to 33% overall reduction
in IOP), whereas offering patients a simpler regimen
that requires fewer bottles and daily drop instilla-
tions.[64] Recently, Cosopt® has been shown to pro-
duce equivalent reduction in IOP compared with a
regimen of 0.5% timolol and 0.2% brimonidine tak-
en separately.[156] Orzalesi et al.[157] have shown that
Cosopt® and latanoprost produce equivalent reduc-
tions in IOP throughout 24 hours, while each agent
performed significantly better than 0.2% bromoni-
dine during the night when compared as monother-
apy. Another combination product comprised 0.5%
timolol and 0.004% latanoprost (Xalacom®, Pfizer
Inc., New York, NY, USA), has been recently ap-
proved for use in several countries across Europe,
Latin America and Canada. A large multicentre
study involving >400 patients with glaucoma or
ocular hypertension has shown that treatment with a
fixed combination of latanoprost and timolol result-
ed in significantly (p < 0.001) lower IOP
(19.9 ± 3.4mm Hg) than either latanoprost
(20.8 ± 4.6mm Hg) or timolol (23.4 ± 5.4mm Hg)
taken individually for 6 months.[152] Combination
products of timolol and pilocarpine (Timpilo®,
Merck & Co., Inc., West Point, PA, USA), and
metipranolol and pilocarpine (Normoglaucon®,
Bausch & Lomb Pharmaceuticals, Inc., Tampa, FL,
USA) have been developed and have shown similar
efficacy when compared with the agents taken sepa-
rately.[158,159] Although not available in the US, these
two combination products are still commonly used
in many other parts of the world.
Several new fixed combination products have
recently been developed and are currently being
reviewed by the FDA for potential use in the US.
These include a combination 0.2% brimonidine/
0.5% timolol drop (Combigan®, Allergan, Inc., Ir-
vine, CA, USA), a combination 0.004% travoprost/
0.5% timolol drop (Extravan®, Alcon Laboratories,
Inc., Fort Worth, TX, USA), and a combination
Drugs Aging 2005; 22 (1)
16
0.03% bimatoprost/0.5% timolol drop (Allergan,
Inc., Irvine, CA, USA).
9. Other Treatment Options
Glaucoma is a chronic disease and typically re-
quires long-term administration of IOP-lowering
drugs. Patients are followed up periodically with
assessment of IOP, optic discs and visual fields to
exclude progressive damage and monitor the suc-
cess of the chosen treatment regimen. Medications
are usually added in a step-wise fashion until the
desired pressure-lowering effect is obtained. Should
maximal tolerated medical therapy not reach the
desired target pressure goal, or if adverse effects,
cost, or noncompliance preclude use of topical
drugs, other treatment modalities for glaucoma, in-
cluding laser therapy or incisional surgery can be
considered.
9.1 Laser Therapy
Argon laser trabeculoplasty (ALT) was original-
ly described over 20 years ago.[160] This procedure
involves placing evenly spaced nonpenetrating ar-
gon laser burns around the circumference of the TM.
The procedure is performed at the slit lamp with the
aid of a gonioprism; 50–100 evenly spaced spots are
applied to the TM over 180–360° of the angle.
Commonly used treatment parameters are 50μm
spot size, 0.1 second pulse duration and 800mW
power. ALT lowers IOP by improving the outflow
facility at the TM. The mechanism is not fully
understood, but may relate to fibrosis and traction at
each burn site which stretches and opens adjacent
meshwork.[161] Reported short-term success rates
range from 65% to 97%.[162,163] Most investigators
report a 5-year success rate of about 50%.[164] Com-
plications of ALT include transient IOP eleva-
tion,[165] iritis[166] and PAS formation.[167]
Selective laser trabeculoplasty (SLT) has recent-
ly been described.[168] SLT selectively delivers ener-
gy to pigmented TM cells in a process termed
photothermolysis. The system employs a Q-
switched, frequency-doubled Nd : YAG laser. Com-
monly used treatment parameters are 400μm spot
size, 3 nanosecond pulse duration and 0.8mJ energy.
The theoretical advantage of targeting pigmented
cells is that nonpigmented TM cells may sustain less
© 2005 Adis Data Information BV. All rights reserved.
Marquis & Whitson
damage compared with ALT.[169] SLT is also
thought to lower IOP by improving outflow facility
at the TM. The mechanism of this action is not
understood but may involve cytokine release from
pigmented TM cells, subsequent recruitment of
macrophages, and removal of cellular debris.[169] In
a study comparing eyes treated with ALT versus
SLT, both groups achieved reductions in IOP of
about 22% from baseline after 6 months.[170] Eyes
with previously failed ALT had a better reduction in
IOP with SLT than with repeat ALT
(6.8 ± 2.4mm Hg vs 3.6 ± 1.8mm Hg, p = 0.01).[170]
SLT has similar potential complications to those of
ALT.
9.2 Surgical Therapy
For glaucoma patients who are refractory to med-
ical and laser therapy, incisional surgery can be
performed. The modern trabeculectomy technique
was described over 30 years ago[171] and remains the
initial glaucoma surgical procedure for most pa-
tients. The procedure involves creating a fistula
underneath a scleral flap into the anterior chamber.
Aqueous humour exits the eye through this opening
and collects in a ‘bleb’ in the subconjunctival space.
IOP is reduced by increased outflow of aqueous
humour through the surgical site. A limiting factor
for the long-term success of filtration surgery is
scarring at the fistula site that leads to decreased
aqueous humour outflow. Antifibrotic agents, such
as fluorouracil and mitomycin, diminish the postop-
erative subconjunctival scarring response and have
been shown to enhance the success rate of
trabeculectomy surgery.[172,173] Complications of
trabeculectomy surgery include hypotony, cataract
formation, choroidal effusion or haemorrhage and
endophthalmitis. Nonpenetrating trabeculectomy
(NPT) in which the innermost layer of the TM is left
intact allowing aqueous humour to percolate
through under a scleral flap has been described.[174]
A recent study revealed that compared with standard
trabeculectomy, NPT resulted in fewer early postop-
erative complications, but also produced significant-
ly less reduction in mean IOP after 18 months
(25.1% vs 35.7%, p = 0.0015).[175]
For those patients in whom the trabeculectomy is
not successful, drainage tube implant surgery can be
performed. The basic design of a glaucoma drainage
Drugs Aging 2005; 22 (1)
Pharmacological Therapy of Glaucoma
device consists of a silicone tube that extends from
the anterior chamber to a plate or disc beneath the
subconjunctival space. A variety of glaucoma drain-
age implant devices have been described in the
literature.[176] Cyclodestructive procedures, which
lower IOP by destroying part of the ciliary body,
thus reducing aqueous humour production, are typi-
cally reserved for eyes which are refractory to all
other forms of therapy. These procedures include
cyclocryotherapy,[177] cyclodiathermy[178] and laser
cyclophotocoagulation.[179]
10. Conclusion
The medical management of glaucoma has
evolved greatly in the past few years. A variety of
new, effective and safer agents for the treatment of
glaucoma introduced in the mid 1990s, including the
PGAs, the α2-adrenoceptor agonists and the topical
CAIs have largely supplanted many older agents
that were once mainstays of therapy, including the
oral CAIs, the cholinergics and epinephrine. While
β-adrenoceptor antagonists remain a good choice for
both first-line and adjunctive therapy, the PGAs
have recently gained favour among most ophthal-
mologists. One great benefit to arise from this
change for both clinicians and patients alike is that
selection of glaucoma medication can now truly be
made on an individual patient basis. Should one
class of agents prove ineffective or poorly tolerated
by a patient, another safe and effective drug can
readily be chosen. Accumulating evidence in the
literature supports the use of adjunctive agents as
safe and effective second- or third-line drugs for use
in combination with PGAs or β-adrenoceptor antag-
onists when these are used as initial monotherapy.
Reduction in IOP remains a cornerstone of glauco-
ma therapy. Future directions of research, including
neuroprotection, enhanced ocular blood flow and
genetic therapy, offer exciting potential avenues for
the management of this debilitating disease.
Acknowledgements
Supported in part by an unrestricted research grant from
Research to Prevent Blindness, Inc., New York, NY, USA.
The authors have no conflicts of interest that are directly
relevant to the content of this review.
© 2005 Adis Data Information BV. All rights reserved.
17
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Correspondence and offprints: Dr Jess T. Whitson, Depart-
ment of Ophthalmology, UT Southwestern Medical Center,
5323 Harry Hines Blvd., Dallas, TX 75390-9057, USA.
E-mail: Jess.Whitson@UTSouthwestern.edu
Drugs Aging 2005; 22 (1)