SURVEY OF OPHTHALMOLOGY VOLUME 45 • SUPPLEMENT 4 • MAY 2001

Mechanism of Action of Bimatoprost (Lumigan™)

Richard F. Brubaker, MD

Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, USA

Abstract. Bimatoprost is a new ocular hypotensive agent that lowers intraocular pressure (IOP) in
normal, ocular hypertensive, and glaucomatous eyes. Its mechanism of action has been studied in nor-
mal human subjects. Bimatoprost mildly stimulates the rate of aqueous humor flow during the day
(13%) and at night (14%). Its ocular hypotensive action is due primarily to a 26% reduction in the
tonographic resistance to outflow. Thus, bimatoprost enhances the pressure-sensitive outflow pathway.
Additional beneficial effects may include an increase in the rate of flow via the pressure-insensitive out-
flow pathway (sometimes called the “uveoscleral outflow pathway”) and a lowering of the extraocular
recipient pressure (sometimes called “episcleral venous pressure”). Reduction of tonographic resis-
tance to aqueous humor outflow reduces steady-state IOP, an effect that is beneficial for the treatment
of glaucoma. In addition to its effect on steady-state IOP, reduction of resistance allows the eye to
recover more quickly from transient IOP elevations. The former effect is common to all ocular
hypotensive drugs, but the latter effect is an exclusive property of drugs that reduce outflow resistance,
such as bimatoprost. (Surv Ophthalmol 45(Suppl 4):S347–S351, 2001. © 2001 by Elsevier Science Inc.
All rights reserved.)

Key words. aqueous humor outflow • bimatoprost • glaucoma • ocular hypertensive

Bimatoprost is a new ocular hypotensive agent
that is being developed for the treatment of glau-
coma. It is chemically related to prostamide F, a
newly discovered, naturally-occurring substance that
is biosynthesized from anandamide in a pathway that
includes the enzyme cyclooxygenase-2. Compounds
closely related to prostamide F, including bimato-
prost, have been classified as prostamides.
Little is known about how a prostamide might
lower intraocular pressure (IOP) in the human eye.
Previous studies demonstrating a lack of significant
binding affinity of bimatoprost to known receptors
have given no good clues as to how this compound
might interact with the eye.19,20 Because bimatoprost
has been demonstrated to be a very effective ocular
hypotensive agent in humans with ocular hyperten-
sion and glaucoma,5,18 its mechanism of action
would be of considerable interest, not only to scien-
tists who explore new pathways to control IOP, but
also to clinicians who must select rational treatment
programs from an increasing array of available drugs
and drug combinations.
As one of the scientific studies of an ophthalmic
preparation of 0.03% bimatoprost (Lumigan™), a
detailed protocol was carried out to measure the
clinically significant effects of this ophthalmic prepa-
ration on the important parameters of aqueous hu-
mor dynamics.7 That study showed that bimatoprost
has clinically significant effects on pressure-sensitive
outflow of aqueous humor, as well as clinically signif-
icant effects on pressure-insensitive outflow. This ar-
ticle will summarize the major points of the previous
study of bimatoprost’s mechanism of action and will
discuss the implications of the findings.

S347
© 2001 by Elsevier Science Inc. 0039-6257/01/$–see front matter
All rights reserved. PII S0039-6257(01)00213-2
S348 Surv Ophthalmol 45 (Suppl 4) May 2001
Mechanisms of Ocular Hypotensive Agents
All ocular hypotensive agents produce their de-
sired effect by one or both of two mechanisms: 1) by
lowering the rate of aqueous humor formation, or
2) by facilitating the outflow of aqueous humor from
the eye. Many new ocular hypotensive agents intro-
duced in the last 25 years, with the notable excep-
tions of latanoprost,16 brimonidine,15 and apracloni-
dine,17 produce their effect on IOP by the former
mechanism, solely by suppressing aqueous humor
formation. This effect can now be quantified in a
clinical setting by using one of the various fluores-
cein clearance methods developed in 1966 by Jones
and Maurice.12 The calculated reduction in aqueous
humor flow caused by topical application of -adren-
ergic antagonists21 and carbonic anhydrase inhibitors11
is sufficient to explain the ocular hypotensive effect
of these drugs.
The lowering of IOP by any means, including sup-
pression of aqueous humor formation, is useful in
the treatment of glaucoma, but aqueous suppression
is not necessarily the ideal means to achieve this
end. Two lines of reasoning underpin this notion.
First, the physiological defect in glaucoma that leads
to elevated pressure, known for half of this century,
is the increased resistance to aqueous humor out-
flow.9 This parameter of aqueous dynamics has been
studied extensively with the use of Grant’s original
method of Schiötz tonography,10 which measures
the tonographic facility of outflow (“C”). Second,
the well-known Swedish pharmacologist, Bárány, has
warned that while reducing IOP at the expense of
aqueous humor formation may be expedient, over-
zealous inhibition of the rate of formation or com-
position of aqueous humor risks long-term damage
to the eye.3 Thus, there has been continuing interest
in finding ocular hypotensive agents that correct the
outflow defect found in glaucoma without diminish-
ing the rate of flow.
Methods Employed in the Bimatoprost
Mechanism Study
In the cited study,7 25 normal human volunteers
participated. The complete details of the methods
have been described previously.7 Bimatoprost 0.03%
(Lumigan™) was applied to one eye and a placebo
was applied to the fellow eye once daily for 3 days.
Subjects and investigators were masked as to which
eye was randomly assigned to receive the active
agent. IOP was measured by Goldmann tonometry
13 or 24 hours after dosing. Aqueous humor flow
and tonographic resistance to outflow were mea-
sured by objective, computerized methods that elim-
inate subjectivity. No attempt was made to measure
pressure-insensitive outflow (often termed “uveo-
scleral flow”) or extraocular recipient pressure (of-
BRUBAKER
ten termed “episcleral venous pressure”). However,
calculations were made to demonstrate the interac-
tion of these parameters with the measured parame-
ters in order to understand how bimatoprost lowers
IOP. Previous clinical studies of bimatoprost have
demonstrated that its ocular hypotensive effects af-
ter a single dose last many hours.18 Thus, the physio-
logical effects of bimatoprost have a long steady
state. Measurements of the aqueous parameters
were taken 16 to 24 hours after the last dose of the
drug, when the eye was in steady state.
Physiological Model of Aqueous
Humor Dynamics
The model used for understanding the interaction
of parameters that affect IOP combines the classical
concept of pressure-sensitive outflow8 and the more
recent concept of pressure-insensitive outflow.4
F = Fs + Fi = ( Pi – Pe ) ⁄ Rs + Fi (1)
F is the rate of flow of aqueous humor into and
out of the anterior chamber
Fs is the rate of pressure-sensitive outflow of
aqueous humor
Fi is the rate of pressure-insensitive outflow of
aqueous humor
Pi is the IOP in the anterior chamber
Pe is the extraocular recipient pressure
Rs is the resistance to pressure-sensitive outflow of
aqueous humor (the reciprocal of tonographic
“C”)
In addition to these parameters, an empirical pa-
rameter called “apparent resistance to outflow”, Ra,
was calculated, and is defined in the following way:14
Ra ≡ Pi ⁄ F
The extraocular recipient pressure is never known,
even if attempts are made to measure the pressure in
one or two episcleral veins. The extraocular recipi-
ent pressure is a weighted average pressure, defined
in the following way:
n
Pe ≡ ∑ ( vi xi )
i=1
where n is the number of discrete channels that
drain aqueous humor, vi is the pressure in the ex-
traocular receptacle into which the ith channel
drains, and xi is the fraction of the total pressure-
sensitive aqueous humor outflow carried by the ith
channel.
Effect of Bimatoprost on Aqueous
Humor Dynamics
Table 1 is a summary of the measured parameters of
aqueous dynamics in placebo-treated eyes compared
to bimatoprost-treated eyes as measured in the previ-
MECHANISM OF ACTION OF BIMATOPROST S349

TABLE 1
Measured Parameters of Aqueous Dynamics in
Bimatoprost Treated Eyes
Change,
Placebo Bimatoprost %
IOP, mm Hg 12.2  2.2 9.7  2.6 ⇓20%
Aqueous inflow,
l/min 2.47  0.73 2.79  0.60 ⇑13%
Outflow resistance,
mm Hg/min/l 4.43  1.66 3.27  1.10 ⇓26%

ous study.7 Despite the normally low IOP in these vol-

Fig. 1. Effect of bimatoprost on measured parameters of
unteers, the drug lowered IOP by 20% (p  .001). aqueous dynamics, expressed as a percentage of placebo
The rate of aqueous humor flow increased by 13% values. Data from Brubaker et al.6
(p  .007). At the same time, the tonographic resis-
tance to outflow decreased by 26% (p  .001, Fig. 1).
Bimatoprost, like other drugs useful for the treat-
ment of glaucoma, lowers IOP in the normal eye. Because this study was performed in normal hu-
This effect is seen despite a small but statistically sig- man subjects, a study should be done to confirm
nificant increase in the rate of aqueous humor flow these findings in ocular hypertensive and glaucoma
during daytime hours. The stimulatory effect on flow patients.
seen during the day was also seen at night during Importance of the Pressure-Sensitive
sleep, a 14% increase (p  .014). Outflow Pathway
The ocular hypotensive effect was found to be due
primarily to a decrease in the tonographic resistance Clinicians are aware that it is important that the
to outflow. As is typical for an outflow enhancing therapeutic regimen they prescribe for their patients
drug,13 bimatoprost decreased apparent resistance both lower and stabilize IOP. Certain daily activities
from 5.36 to 3.68, a 31% reduction (p  .001). are likely to cause transient increases of IOP, and
The physiological model shown as equation 1 some, such as awakening from sleep, have been doc-
makes it possible to calculate the effect of bimato- umented to cause a pressure rise in glaucoma pa-
prost on pressure-insensitive outflow, as long as ex- tients.6,22 The best antidote to these transient rises is
traocular recipient pressure is assumed to be unaf- low resistance to outflow—in other words, a good fa-
fected. Likewise, the model permits one to calculate cility of outflow. A drug that lowers IOP only by sup-
the effect of bimatoprost on extraocular recipient pressing aqueous humor formation or enhancing
pressure if pressure-insensitive outflow is assumed to pressure-insensitive outflow does not give the eye
be unaffected. The previous investigators have car- this added protection.
ried out these calculations, and the results give inter- One can illustrate this principle by considering a
esting insights into how bimatoprost might affect theoretical patient. Suppose a typical glaucoma pa-
these difficult-to-measure parameters. tient has untreated IOPs of 28 mm Hg because of an
If bimatoprost has no effect on extraocular recipi- abnormal tonographic “C” value of 0.1 l/min/mm
ent pressure, then it must increase pressure-insensi- Hg. Table 2 gives typical parameters of aqueous dy-
tive outflow by approximately 50%. If bimatoprost
has no effect on pressure-insensitive outflow, then it
must decrease extraocular recipient pressure by 30%
or more. Such an effect would give an additional TABLE 2
boost to outflow via the pressure-sensitive pathway, Aqueous Parameters of Theoretical Patient
as one can see from equation 1. Treated, Treated,
The study cannot unequivocally resolve whether Parameter Untreated Drug A Drug B
beneficial effects occur on pressure-insensitive out-
Pi (mm Hg) 28 18 18
flow, extraocular recipient pressure, or both. In put- F (l/min) 2.5 1.5 2.5
ting these three alternatives into perspective, one Fi (l/min) 0.5 0.5 0.5
must keep in mind that normal human subjects have Fs (l/min) 2.0 1.0 2.0
low recipient pressure so the range available for fur- “C” (l/min/mm Hg) 0.1 0.1 0.2
ther lowering is limited. Pe (mm Hg) 8 8 8
S350 Surv Ophthalmol 45 (Suppl 4) May 2001
namics of such a patient. Now also suppose that the
patient’s IOP can be reduced to 18 mm Hg with an
ocular hypotensive agent that acts by inhibiting
aqueous humor formation, called Drug A. Finally,
suppose that Drug B is also available that can reduce
the IOP to the same extent but does so by enhancing
pressure-sensitive aqueous outflow facility. Table 2
gives the parameters of both of these scenarios.
At this point, the two treatment regimens appear
to be identical from the clinical standpoint. How-
ever, because the underlying reasons for the thera-
peutic effects are different, the appearance of equiv-
alence is an illusion of examining the eye only when
the dynamics are in their steady state.
The differences in Drug A and Drug B will begin
to be apparent when the hypothetical patient en-
gages in activities that disturb the steady-state of the
eye. Some examples include pressure on the eye
from a pillow at night, rapid eye movement episodes
during sleep, awakening from a night’s sleep, and
straining or commencing vigorous exercise. Each of
these events can be accompanied by significant vol-
ume redistributions in or around the eye with a con-
sequent rise in IOP that must be dissipated.
Consider the daily event of waking up. The blood
pressure rises, an event that is likely to increase the
volume of the choroid, one of the most vascular tis-
sues of the body. A 20% increase in choroidal vol-
ume would result in approximately a 20 l increase
in the volume of the eye and a rise in IOP.
Fig. 2 is a simulation of what that transient rise in
pressure would look like in our hypothetical patient
on each of the two drug regimens. This graph has
been created using a differential equation that com-
bines equation 1 and the Friedenwald equation of
BRUBAKER
ocular rigidity.1 With the aqueous suppressant, the
recovery to near baseline takes almost twice as long
as with the outflow enhancing drug. Whether tran-
sient higher pressures are of any consequence to the
health of the optic nerve or not is a matter of specu-
lation. But the calculation of the kinetics of IOP
when the eye is not in steady state is straightforward
and has been useful for understanding other clinical
trade-offs.2
Conclusions about Bimatoprost
Bimatoprost is a member of a new class of drugs
that lowers IOP. Bimatoprost is a mild stimulant of
aqueous humor flow, both during the day and at
night. It is speculated that enhancement of uveo-
scleral outflow, the primary mechanism of action of
latanaprost, is partly responsible for the ocular hy-
potensive effect of bimatoprost. However, in normal
subjects, bimatoprost increases tonographic facility
of outflow by 35%, and this effect is regarded as its
primary mechanism of ocular hypotension. Bimato-
prost may also lower extraocular recipient pressure,
but this mechanism cannot explain its ocular hy-
potensive effects in patients with ocular hyperten-
sion and glaucoma.
The physiological defect of the glaucomatous eye
that leads to chronic elevation of IOP is an increase
in the resistance to aqueous humor outflow from the
eye. This defect not only causes the chronic elevated
IOP but also slows the eye’s recovery from transient
pressure spikes. Improvement of pressure-sensitive
outflow by reducing resistance to outflow is theoreti-
cally optimal for lowering IOP in the glaucomatous
eye. By this means not only can the pressure be low-
ered but the ability of the eye to recover from tran-
Fig. 2. IOP profile immediately fol-
lowing a sudden 20 l increase in
choroidal blood volume for “patient”
with aqueous dynamics parameters
listed in Table 2. Curves calculated
from combination of equation 1 and
Friedenwald’s equation with ocular
rigidity of 0.0215.1
MECHANISM OF ACTION OF BIMATOPROST
sient pressure disturbances can be partly or com-
pletely restored.
The results of the clinical study of the mechanism
of action of bimatoprost on the human eye do not
give information about which anatomic pathways are
responsible for the outflow enhancements. Addi-
tional studies must be done to work out the details.
However, one is certain that outflow enhancement is
responsible for the hypotensive effect and that this
enhancement comes about primarily by a reduction
in the resistance to outflow of the pressure-sensitive
pathways. What remains to be done is to study bi-
matoprost in patients who suffer impaired pressure-
sensitive outflow, and patients with ocular hyperten-
sion or glaucoma with elevated pressures. If such a
study confirms the previous findings in normal
subjects, the importance of bimatoprost as a po-
tential treatment, where therapeutic intervention
is clinically indicated and where restoration of a
more nearly normal outflow facility is desirable, will
be underscored.
References
1. Hart WM Jr (ed): Adler’s Physiology of the Eye, ed 9. St.
Louis, Mosby, 1992, p 261
2. Aronowitz JD, Brubaker RF: Effect of intraocular gas on in-
traocular pressure. Arch Ophthalmol 94:1191–6, 1976
3. Bárány EH: A pharmacologist looks at medical treatment in
glaucoma—in retrospect and in prospect. Ophthalmology
86:80–94, 1947
4. Bill A: Conventional and uveo-scleral drainage of aqueous
humour in the cynomolgus monkey (Macaca irus) at normal
and high intraocular pressures. Exp Eye Res 5:45–54, 1966
5. Brandt J for the HTL™ Study Group I: Phase III, 3-month
comparison of timolol with AGN 192024: a new Ocular Hy-
potensive Lipid (HTL™) for glaucoma management [ab-
stract]. American Academy of Ophthalmology Annual Meet-
ing, 2000
6. Brown B, Burton P, Mann S, Parisi A: Fluctuations in intra-
ocular pressure with sleep: II. Time course of IOP decrease
after waking from sleep. Ophthalmic Physiol Opt 8:249–52,
1988
7. Brubaker RF, Schoff EO, Nau CB, et al: Effects of AGN
192024, a new ocular hypotensive agent, on aqueous dynam-
ics (1). Am J Ophthalmol 131:19–24, 2001
8. Goldmann H: Abflussdruck, Minutenvolumen und Wider-
S351
stand der Kammerwasserstromung des Menschen. Doc Oph-
thalmol 5:278–356, 1951
9. Grant WM: Clinical measurements of aqueous outflow.
AMA. Arch Ophthalmol 46:113–31, 1951
10. Grant WM: Tonographic method for measuring the facility
and rate of aqueous flow in human eyes. AMA. Arch Oph-
thal 44:204–14, 1950
11. Ingram CJ, Brubaker RF: Effect of brinzolamide and dor-
zolamide on aqueous humor flow in human eyes. Am J Oph-
thalmol 128:292–6, 1999
12. Jones RF, Maurice DM: New methods of measuring the rate
of aqueous flow in man with fluorescein. Exp Eye Res 5:208–
20, 1966
13. Maus TL, Nau C, Brubaker RF: Comparison of the early ef-
fects of brimonidine and apraclonidine as topical ocular hy-
potensive agents. Arch Ophthalmol 117:586–91, 1999
14. Reiss GR, Brubaker RF: The mechanism of betaxolol, a new
ocular hypotensive agent. Ophthalmology 90:1369–72, 1983
15. Toris CB, Camras CB, Yablonski ME: Acute versus chronic
effects of brimonidine on aqueous humor dynamics in ocu-
lar hypertensive patients. Am J Ophthalmol 128:8–14, 1999
16. Toris CB, Camras CB, Yablonski ME: Effects of PhXA41, a
new prostaglandin F2 alpha analog, on aqueous humor dy-
namics in human eyes. Ophthalmology 100:1297–304, 1993
17. Toris CB, Tafoya ME, Camras CB, Yablonski ME: Effects of
apraclonidine on aqueous humor dynamics in human eyes.
Ophthalmology 102:456–61, 1995
18. VanDenburgh AM, Laibovitz RA, Felix C: A novel ocular hy-
potensive lipid: Initial safety and efficacy of AGN 192024 . In-
vest Ophthalmol Vis Sci 39(Suppl):S258, 1998
19. Woodward DF, Krauss AH, Chen J, et al: Replacement of the
carboxylic acid group of prostaglandin F(2alpha) with a hy-
droxyl or methoxy substituent provides biologically unique
compounds. Br J Pharmacol 130:1933–43, 2000
20. Woodward DF, Tang-Liu DDS, Madhu C, et al: Prostaglan-
din F2 (PGF2) 1-ethanolamide: a pharmacologically
unique local hormone synthesized from anandamide [ab-
stract]. 11th International Conference on Advances in Pros-
taglandin and Leukotriene Research, 2000
21. Yablonski ME, Zimmerman TJ, Waltman SR, Becker B: A flu-
orophotometric study of the effect of topical timolol on
aqueous humor dynamics. Exp Eye Res 27:135–42, 1978
22. Zeimer RC, Wilensky JT, Gieser DK: Presence and rapid de-
cline of early morning IOP peaks in glaucoma patients. Oph-
thalmology 97:547–50, 1990
Dr. Brubaker is a consultant for Allergan, Inc., but has no pro-
prietary interest in LumiganTM or any other pharmaceutical prod-
uct for glaucoma.
Reprint address: Richard F Brubaker, MD, 601 Memorial Park-
way SW, Rochester, MN 55902.