The effects of antiglaucoma and systemic medications on ocular blood flow

Progress in Retinal and Eye Research 22 (2003) 769–805

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doi:10.1016/S135

The effects of antiglaucoma and systemic medicationson ocular blood flow

Vital P. Costaa,b,*, Alon Harrisc, Einar Stef!anssond, Josef Flammere, GunterK. Krieglsteinf, Nicola Orzalesig, Anders Heijlh, Jean-Paul Renardi, Luis Metzner Serraj

aGlaucoma Service, University of Campinas, Rua Bauru, 40, S *ao Paulo 01248-010, BrazilbUniversity of S *ao Paulo, S *ao Paulo 01248-010, Brazil

c Indiana University School of Medicine, Indianapolis, IN, USAdUniversity Eye Clinic, Reykjavik, IcelandeUniversity Eye Clinic, Basel, SwitzerlandfUniversity Eye Clinic, Cologne, Germany

gUniversity Eye Clinic, Milan, ItalyhUniversity Eye Clinic, Malmo, SwedeniHopital du Val de Grace, Paris, FrancejUniversity of Lisbon, Lisbon, Portugal

Abstract

Based on the body of evidence implicating ocular blood flow disturbances in the pathogenesis of glaucoma, there is great interest

in the investigation of the effects of antiglaucoma drugs and systemic medications on the various ocular vascular beds. The primary

aim of this article was to review the current data available on the effects of antiglaucoma drugs and systemic medications on ocular

blood flow. We performed a literature search in November 2002, which consisted of a textword search in MEDLINE for the years

1968–2002. The results of this review suggest that there is a severe lack of well-designed long-term studies investigating the effects of

antiglaucoma and systemic medications on ocular blood flow in glaucomatous patients. However, among the 136 articles dealing

with the effect of antiglaucoma drugs on ocular blood flow, only 36 (26.5%) investigated the effects of medications on glaucoma

patients. Among these 36 articles, only 3 (8.3%) were long-term studies, and only 16 (44.4%) were double-masked, randomized,

prospective trials. Among the 33 articles describing the effects of systemic medications on ocular blood flow, only 11 (33.3%)

investigated glaucoma patients, of which only one (9.1%) was a double-masked, randomized, prospective trial. Based on this

preliminary data, we would intimate that few antiglaucoma medications have the potential to directly improve ocular blood flow.

Unoprostone appears to have a reproducible antiendothelin-1 effect, betaxolol may exert a calcium-channel blocker action,

apraclonidine consistently leads to anterior segment vasoconstriction, and carbonic anhydrase inhibitors seem to accelerate the

retinal circulation. Longitudinal, prospective, randomized trials are needed to investigate the effects of vasoactive substances with no

hypotensive effect on the progression of glaucoma.

r 2003 Elsevier Ltd. All rights reserved.

s

ionale for modulating ocular blood flow in the treatment of glaucoma . . . . . . . . . . . . . . . . 770

lar blood flow measurement techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772

. Color Doppler imaging (CDI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772

. Scanning laser ophthalmoscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 773

. Heidelberg retina flowmetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774

. Laser Doppler velocimetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774

. Oculo-oscillo-dynamography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 775

g author. Glaucoma Service, University of Campinas, Rua Bauru, 40, S*ao Paulo 01248-010, Brazil. Tel./fax: +55-11-3865-9630.

s: [email protected] (V.P. Costa).

front matter r 2003 Elsevier Ltd. All rights reserved.

0-9462(03)00064-8

ARTICLE IN PRESS

2.6. Blue field entoptic simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776

2.7. Laser speckle flowmetry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776

2.8. Pulsatile ocular blood flow (POBF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777

2.9. Hydrogen clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777

2.10. Intraluminal corrosion casting (ICC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777

2.11. Fluorescent microsphere imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777

3. Ocular penetration of topically applied antiglaucoma medications . . . . . . . . . . . . . . . . . . . . . 777

3.1. Pilocarpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778

3.2. Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778

3.3. Alpha-agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778

3.4. Prostaglandin analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 778

3.5. Carbonic anhydrase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779

4. Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779

5. The effects of antiglaucoma drugs on ocular blood flow . . . . . . . . . . . . . . . . . . . . . . . . . . 779

5.1. Pilocarpine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 779

5.1.1. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780

5.1.2. Studies in healthy individuals and ocular hypertensive patients . . . . . . . . . . . . . . . 780

5.1.3. Studies in glaucoma patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780

5.2. Beta-blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780

5.2.1. Timolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 780

5.2.2. Betaxolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782

5.2.3. Levobunolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 783

5.2.4. Carteolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784

5.3. Alpha-agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784

5.3.1. Apraclonidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 784

5.3.2. Brimonidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 785

5.4. Prostaglandin analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786

5.4.1. Latanoprost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786

5.4.2. Unoprostone isopropyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 787

5.5. Carbonic anhydrase inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788

5.5.1. Acetazolamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 788

5.5.2. Dorzolamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789

5.5.3. Brinzolamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791

5.5.4. Timolol and dorzolamide fixed combination . . . . . . . . . . . . . . . . . . . . . . . . 791

6. The effects of systemic medications on ocular blood flow . . . . . . . . . . . . . . . . . . . . . . . . . 791

6.1. Calcium channel blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 791

6.1.1. Experimental studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 792

6.1.2. Studies in healthy individuals and ocular hypertensive patients . . . . . . . . . . . . . . . 792

6.1.3. Studies in glaucoma patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793

6.2. Inhibitors of the renin-angiotensin system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 793

6.3. Ginkgo biloba . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794

6.4. Magnesium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 794

6.5. Dipyridamole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795

7. Perspectives and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 795

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796

V.P. Costa et al. / Progress in Retinal and Eye Research 22 (2003) 769–805770

1. Rationale for modulating ocular blood flow in the

treatment of glaucoma

Glaucoma refers to a multifactorial disease character-ized by a progressive optic neuropathy followed bygradual visual field loss. Elevated intraocular pressure(IOP), which previously was part of the definition ofglaucoma, is now recognized as the major risk factor forthe development of the disease. Years ago, adrenergicdrugs, parasympathomimetics, beta-blockers and sys-

temic carbonic anhydrase inhibitors (CAIs) were theonly available drugs to treat glaucoma. Despite thechange in concept and the development of newantiglaucoma medications, reducing the IOP remainsthe mainstream of glaucoma therapy.There is sufficient evidence to suggest that high IOPs

are not responsible for the development of all glaucomacases and that reducing IOP is not effective in avoidingthe progression of each and every glaucoma patient.Epidemiologic studies have demonstrated that the

ARTICLE IN PRESSV.P. Costa et al. / Progress in Retinal and Eye Research 22 (2003) 769–805 771

conversion rate of ocular hypertensive patients toglaucoma is low (Leibowitz et al., 1980; Bengtsson,1981; Hollows and Graham, 1996), indicating that notall patients with high IOPs develop glaucomatous opticneuropathy. Furthermore, other studies report that asmany as half of patients with glaucoma have normalIOPs when the diagnosis is first made (Bengtsson, 1981;Leibowitz et al., 1980; Sommer et al., 1991).In a retrospective study, Hattenhauer et al. (1998)

evaluated 295 newly diagnosed patients with open-angleglaucoma between 1965 and 1980, with a mean follow-up of 15 years. Patients with primary open-angleglaucoma (POAG) had a 9% chance of becoming blindin both eyes and a 26% chance of becoming blind in atleast one eye at 20 years despite treatment. One mightargue that the number of medications available at thattime was limited, or that the study did not report theseverity of glaucoma damage, or even that the IOPcontrol of those patients was not evaluated, never-theless, the estimated risk of blindness at 20 yearsamong treated patients is both significant and disturbingto those who treat glaucoma.Collaborative Normal-Tension Glaucoma Study

Group (1998) designed a prospective, randomized,multicenter study to evaluate the effect of a 30%reduction in IOP. Although the group achieving thisgoal had a lower progression rate than the controlgroup, 20% of patients achieving the desired IOPreduction were estimated to progress after 5 years,whereas 40% of the patients with no treatment wereestimated to remain stable.The Advanced Glaucoma Interventional Study

(AGIS) Investigators (2000) was another multicenter,randomized study designed to compare two treatmentsequences in patients with advanced glaucoma. In theso-called associative analysis, the authors divided thepatients in groups according to the IOPs measuredthroughout 8 years of follow-up. Group A comprisedpatients with 100% of IOP measurements below18mmHg, whereas Group B included patients with75–99% of the IOPs below 18mmHg, Group C hadpatients with 50–74% of the measurements below18mmHg and Group D included patients with less than50% of IOP measurements below 18mmHg. Althoughthe risk for visual field deterioration was significantlylower for Group A, compared to the other groups,14.4% of the patients in this group were estimated toprogress after 7 years. This data is comparable withprevious studies that demonstrate that the visual fieldloss of some patients with a history of increased IOPcontinues to progress despite IOP reduction, even afterfiltering surgery (Werner et al., 1977; Jerndal andLundstrom, 1980; Kidd and O’Connor, 1985; Stewartet al., 2000).A report from the Ocular Hypertension Treatment

Study (Kass et al., 2002) revealed that 4.4% of the

treated eyes and 9.5% of the untreated eyes developedglaucoma after 5 years of follow-up. In this multicenterstudy, the goal of treatment was to reduce the IOP by20% and to reach an IOP of 24mmHg or less. Recently,the results of the Early Manifest Glaucoma Trialbecame available (Heijl et al., 2002). This study, whichrandomized patients with early glaucomatous damage totreatment vs. no treatment, indicated that 45% of thetreated patients (mean IOP decrease=25%) and 62% ofthe untreated group showed progression after a medianfollow-up period of 6 years. The authors later publishedthat standard treatment reduced the risk of progressionby 50% (Leske et al., 2003).All the above-mentioned studies parallel the clinical

impression that IOP reduction is beneficial for patientswith normal tension glaucoma (NTG), POAG andocular hypertension, but it is not 100% effective inpreventing the progression of glaucomatous optic nervedamage. Glaucoma is a multifactorial condition, withIOP being one of the identifiable risk factors, and it isessential to recognize the other factors that participatein the pathogenesis of the disease. In a previous article,we discussed the rationale for including ocular bloodflow (OBF) disturbances as one of the possible factorsinvolved in the pathogenesis of glaucoma (Flammeret al., 2002).In summary, a number of systemic vascular disorders

have been associated with glaucoma; including diabetes,hypertension, peripheral vascular disease, and migraine(Becker, 1971; Corbett et al., 1986; Phelps and Corbett,1985; Drance et al., 1988; McLeod et al., 1990; Flammeret al., 2001). Different techniques were employed todemonstrate, on average, a reduced ocular perfusion inglaucoma patients at the optic nerve head (ONH)(Hamard et al., 1994; Findl et al., 2000; Piltz-Seymouret al., 2001; Ciancaglini et al., 2001; Harju and Vesti,2001), choroid (Duijm et al., 1997; Greve et al., 1999),retina (Michelson et al., 1996, 1998; Chung et al.,1999a, b; Harju and Vesti, 2001), and retrobulbar vessels(Galassi et al., 1992; Costa et al., 1994; Trible et al.,1994; Rankin et al., 1995; Nicolela et al., 1996a, b).Whether these blood flow abnormalities are secondaryto IOP changes or whether they cause intrinsic damageis debatable. However, experimental studies havedemonstrated that glaucomatous damage can be repro-duced in animals by injecting a vasoactive substance(endothelin-1), with no change in IOP (Cioffi andSullivan, 1999; Oku et al., 1999). A number ofmechanisms have been suggested to explain why OBFreduction may lead to glaucoma (Flammer et al., 2002),including increased resistivity to flow, reduced perfusionpressure, and impaired autoregulation. Increased resis-tivity could be caused by anatomical variations,vasculitis, arteriosclerosis, or vasospasm. Several studieshave indicated the association between peripheral orocular vasospasm and glaucoma (Rojanapongpun and

ARTICLE IN PRESSV.P. Costa et al. / Progress in Retinal and Eye Research 22 (2003) 769–805772

Drance, 1993; Harris et al., 1994; Flammer, 1997;Broadway and Drance, 1998; O’Brien, 1998; Flammeret al., 1999). Reduced perfusion pressure might besecondary to an increased IOP or decreased bloodpressure, with both being firmly associated withglaucoma (Drance et al., 1973; Kaiser and Flammer,1991; Kaiser et al., 1993; Hayreh et al., 1994; Grahamet al., 1995; Bonomi et al., 2000; Kashiwagi et al., 2001).Finally, autoregulation deficits, characterized by theinability to compensate for changes in IOP or bloodpressure in order to maintain adequate perfusion (Harriset al., 1998a), have also been described in the retinal(Geijer and Bill, 1979; Grunwald et al., 1984; Sponselet al., 1997) and ONH circulations (Geijer and Bill,1979; Evans et al., 1999b) in both experimental studiesand glaucoma patients (Pillunat et al., 1997).Based on the body of evidence suggesting the

participation of OBF disturbances in the pathogenesisof glaucoma, great interest has ensued in the investiga-tion of the effects of antiglaucoma drugs and systemicmedications on the various ocular vascular beds (Harriset al., 2001b; Harris and Jonescu-Cuypers, 2001). Withthe possibility that reduced OBF or a dysfunctionalautoregulation may play an important role in thepathogenesis of glaucoma, creating either acute orchronic vasoconstriction in diseased eyes may beharmful, partially counteracting the expected increasein perfusion pressure secondary to an IOP reduction.The purposes of this review article are:

(a)
To summarize the rationale behind the pharmaco-logical modulation of OBF in the treatment ofglaucoma.
(b)
To briefly review the various techniques available toevaluate OBF.
(c)
To review studies investigating the availability ofantiglaucoma drugs in the vascular beds relevant tothe pathogenesis of glaucoma.
(d)
To review the current data regarding the effectsof antiglaucoma drugs and systemic medicationson OBF.
Fig. 1. The CDI image consists of a grayscale image of the globe with

color-coded velocity data overlaid. Flow toward the CDI probe

(arterial) is displayed in red; flow away from the probe (venous) is

displayed in blue.

2. Ocular blood flow measurement techniques

In the last 30 years, the assessment of ocularcirculation has evolved from a subjective descriptionof visible vessels to direct quantitative measurement ofocular blood velocity and flow. Since no single techniqueprovides a complete description of ocular hemody-namics, it is impossible to obtain a measurement from asingle device and extrapolate a complete and accurateunderstanding of OBF. Therefore, a number of mea-surements are used to quantify the various vascular bedscomprising the ocular circulation.

The retinal circulation accounts for approximately15% of total OBF. Uveal blood flow comprises theremaining 85%, including flow to the choroid, ciliarybody, and iris (Alm, 1992). The techniques discussedbelow, when used in concert, provide a comprehensiveexamination of ocular hemodynamics. However, eachmethod of assessing some portion of ocular hemody-namics is likely to have its own inherent limitations. Adetailed description of the techniques that measure OBFcan be found elsewhere (Harris et al., 1999a; Flammeret al., 2002). In order to facilitate the understanding ofthe articles that will be discussed, a brief review of thesemethods is presented below.

2.1. Color Doppler imaging (CDI)

CDI is an ultrasound technique that combines b-scangrayscale imaging of tissue structure, and color repre-sentation of blood velocity computed from Doppler-shifted reflections (Taylor and Holland, 1990). Inophthalmology, CDI is used to measure blood flowvelocities in veins and arteries, which supply and drainthe eye. Current CDI analysis focuses primarily onvelocities in arteries: specifically, the ophthalmic artery(OA), central retinal artery (CRA), and short posteriorciliary arteries (SPCAs) immediately behind the globe(Trible et al., 1994; Williamson et al., 1995). Blood flowvelocities in these arteries are measured and displayed inreal time.The CDI image consists of a grayscale image of the

globe with color-coded velocity data overlaid (Fig. 1).The direction of blood flow is used to color codeDoppler shifts. Blood flow away from the center of thebody and toward the instrument’s probe is generally


arterial and displayed in red; blood flow toward thecenter of the body and away from the probe is venousand displayed in blue. It is important that the examinerhas knowledge of both retrobulbar vascular anatomyand the characteristic waveforms of the relevant arteriesand veins.Two blood velocity values are measured during

spectral analysis: the peak systolic velocity (PSV) andthe end diastolic velocity (EDV). A horizontal line onthe screen is placed on the PSV, and a second line on theEDV. With this information, the CDI unit displays thevelocity values and calculates Pourcelot’s (1975) resistiveindex (RI) as

RI ¼PSV� EDV

PSV:

RI is a dimensionless parameter ranging in valuebetween 0 and 1. The value 0 represents completelynon-pulsatile flow with EDV equal to PSV, and 1represents purely pulsatile flow, with velocity equal tozero during diastole.Reproducibility of CDI measurements has been

studied using a test/retest analysis (Williamson et al.,1995). The coefficient of variation for each of themeasurement parameters PSV, EDV and RI in the OA,CRA, TSPCA, and NSPCA are displayed in Tables 1and 2. Accurate, consistent positioning of the probe isessential for good reproducibility.

Table 1

Coefficients of variation for each parameter of the four vessels

measured by CDI

Coefficient of variation (%)

PSV EDV RI

OA 5.1 9.6 1.7

CRA 5.3 17.9 4.6

TSPCA 11.6 8.8 7.6

NSPCA 12.0 14.2 4.9

Table 2

Interpretations of CDI measurements are based on a combination of in vitro,

observations

Condition Interpretation

Carotid occlusion Greatly reduced or absent flow

Carotid stenosis Broadening of Doppler spectra

Carotid stenosis Increased PSV

Post-optic nerve sheath decompression Increased PSV in the OA and

Post-optic nerve sheath decompression Post-operative edema may ind

Post-optic nerve sheath decompression CDI results are inconclusive; c

Proximal stenosis 86% proximal stenosis require

Distal stenosis/systemic and in vitro models Increased RI

Increased IOP/in vivo ocular model Increased RI in CRA and PCA

Carbon dioxide induced vasodilation CDI cannot isolate the distal v

2.2. Scanning laser ophthalmoscopy

Since Flower and Hochheimer first successfullyperformed indocyanine green (ICG) angiography inhumans in the early 1970s (Hochheimer, 1971; Flowerand Hochheimer, 1972), clinicians and researchers haveattempted to acquire high-resolution images of thechoroid. The recent introduction of the scanning laserophthalmoscope (SLO) has elevated quantitative angio-graphy to new heights.The SLO is a confocal laser device that overcomes

many of the limitations of traditional photographic orvideo angiography. Reflected light exits the eye throughthe pupil and must pass through a confocal aperturebefore reaching a solid-state detector. Scattered lightand reflected light from sources outside the focal planeare blocked by the confocal aperture. Overall retinalillumination is reduced and contrast is improved, as onlya single spot is illuminated by the laser beam, at anymoment. The resulting images are similar to thoseobtained with standard video angiography, but withimproved spatial resolution and contrast.A new method to analyze ICG SLO angiography is

based on dye-dilution curve analysis, which has beenstudied since the 1920s. The dye duration area (the timebetween first arterial appearance and the extrapolatedzero concentration time) is analyzed (Fig. 2) and theaverage measured dye concentration is calculated. Inophthalmology, dilution curve techniques have beenused to quantify retinal hemodynamics, including thearterial-venous passage time (AVP time). Using com-puter video analysis techniques, the concentration of adye, fluorescein, is quantified by measuring the bright-ness of fluorescence from within the blood. Dilutioncurves are used to provide the time delay between dyearrival to two points. Measuring the distance betweenthose points, and knowing the time for blood passagebetween them allows calculation of dye velocity (Wolfet al., 1990) (Fig. 3).Harris et al. (1998a, b) applied video dye dilution

technology to ICG angiograms: the area dilution

in vivo, and mathematical models (Evans et al., 1980); as well as clinical

in ocular vessels

at the site

CRA, increased flow (?)

uce vessel narrowing and decreased flow in similar manner to stenosis

aution needed in interpretation

d to alter RI distal to the point of measurement

, but not the OA

essels which effect changes in RI

ARTICLE IN PRESS

Time between dye arrival to two points on an artery

Fig. 3. Mean dye velocity within a single artery can be calculated from

dye dilution curves from two points on an artery.

Concentration

Time

InjectionDye arrival

Dye Duration

Fig. 2. The dye dilution curve displays the concentration of an injected

indicator. Concentration is monitored at an arterial location and

graphed over time.


analysis (ADA). The entire 40� ICG angiogram isdivided into a number of small regions, and dilutioncurves are created for each region. Six locations, each a6� square, are identified for analysis (Fig. 4). Theaverage brightness of the area contained in each box iscomputed for each frame of the angiogram. Areabrightness is graphed with time on the X-axis andbrightness on the Y-axis. ADA identifies three para-meters from the brightness maps: slope (which repre-sents the speed of blood as it enters the choroid), 10%arrival time, and dye duration.

2.3. Heidelberg retina flowmetry

The Heidelberg retina flowmeter (HRF, HeidelbergEngineering, Germany) is a non-invasive confocalscanning laser imaging device that maps blood flow

magnitudes in retinal capillaries (Zinser, 1999). Quanti-fication of retinal blood flow is accomplished through aseries of point measurements, each with a resolution ofapproximately 10� 10 mm on the retinal plane, and fielddepth of 400 mm. Various studies have been publishedmeasuring the effects of disease and medications onblood flow in the fundus (Kagemann et al., 1998).However, many questions on the validity of HRF stillremain. One concern is the arbitrary unit in the HRFreport. Despite previous experiments (Chauhan andSmith, 1997), physical units have not been successfullycorrelated to the arbitrary units. Furthermore, thefunctional range for these units as well as the normalvalues are yet to be determined (see Figs. 5 and 6).The HRF noise estimation and correction algorithm,

as conveyed in correspondences with Heidelberg En-gineering, is based on the assumption that brighterimages have proportionally more noise than darkerimages. This algorithm has not been published nor peerverified for flow measurement applications. It wouldproduce higher flow readings for darker areas, sinceonly a small correction would be subtracted from theraw scan spectrum (Tsang et al., 1999). Since thesecorrections are derived globally and subtracted locally,the reported values are distorted between regions of thesame image and among different images. When per-forming repeated examinations of a single normal eye, itis imperative to align the image perfectly and to set theillumination to the same level by control of thesensitivity setting and camera-to-eye distance from oneexamination to the next. Different individuals would beexpected to have different levels of fundus pigmentationand geometry. It is unlikely that a simple intensityadjustment can compensate for the complex conse-quences of these noise corrections. Finally, the progres-sive disc pallor characteristic of glaucoma will result inprogressively darker images in longitudinal measure-ments, even under strict control. A flow change reportedin these circumstances is likely to be confounded by theoptical properties of the fundus (Kagemann et al., 2001).

2.4. Laser Doppler velocimetry

Bi-directional laser Doppler velocimetry (LDV) mea-sures the maximum blood cell velocity in large retinalvessels (Feke et al., 1989; Milbocker et al., 1991).Velocity is calculated from an analysis of Doppler shiftsobserved in light scattered by moving blood cells. Theinstrument consists of a modified fundus camera withthe 35mm camera body replaced with a unit containingfiber optics. A low-powered laser light source illumi-nates the large vessels. The operator can position thebeam so that it lies over a retinal vessel. By placing theoptical fibers on the reflected laser spot, the returninglaser light is sampled by photomultiplier tubes, andconverted to an electrical signal. The signal contains

ARTICLE IN PRESS

Fig. 5. Bovine blood flowed through a heparinized capillary tube, and

down a glass slide (to control surface tension). Images of the flow were

taken by HRF without optical magnification.

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Fig. 4. Using indocyanine green angiography, multiple dye dilution curves have been used to compare hemodynamic characteristics from multiple

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information about the frequency spectra of the laserlight that can be recorded and analyzed. The shift infrequency is proportional to the velocity of the movingblood cells. At some point, a maximum velocity isattained by some cells in the blood stream that isreflected by a final peak in the spectra. From this finalfrequency, originally identified by the operator (Fekeet al., 1989) but more recently by an automatedcomputer algorithm, the maximum velocity, or Vmax;can be calculated. This, in turn, has been used tocalculate the average blood cell velocity, Vmean; using theformula Vmean ¼ Vmax=1:6 (value established experimen-tally) (Damon and Duling, 1979).

2.5. Oculo-oscillo-dynamography

In 1985, Ulrich and Ulrich (1985) introduced oculo-oscillo-dynamography (OODG), a method that assessesblood pressure in central retinal and ciliary arteries.OODG combines scleral suction with the recording ofthe ocular pulse. Ocular pulsatility refers to changes inIOP over time due to the change in the eye’s volumeduring the cardiac cycle. Each of the vessels supplyingthe eye contributes to the ocular pulse wave.The OODG instrument consists of a scleral suction

cup connected to a suction pump and to a pressuretransducer. Ocular pulsation produces pressure changesthat are converted by the transducer into an electronicsignal and sent to a microcomputer. Oscillating pulsewaves are digitized and recorded by the computer. As

ARTICLE IN PRESS

HRF Velocity vs. True mean velocity

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background material from paper to gauze induced a large shift in velocity measurements.


the suction cup is placed on the sclera, the IOP increasesand the ocular pulse wave becomes shallower and isfinally extinguished when IOP surpasses systolic bloodpressure (Ulrich et al., 1989).Once the ocular pulse is extinguished, the suction is

slowly released. As the IOP falls, ocular pulse wavesreappears. The CRA pulse reappears first, followed bythe ciliary artery pulse. Finally, the IOP falls below thediastolic pressure in the vessels. The source of the pulseshas been confirmed by Ulrich & Ulrich by performingfluorescein angiography simultaneously with OODG(Ulrich et al., 1989).

2.6. Blue field entoptic simulation

The blue field entoptic phenomenon refers to theeffect created by gazing into bright blue illumination.This allows a person to see the movement of leukocytesthrough their perimacular capillaries. The source of thephenomenon, leukocytes shadows on the retina, hasbeen confirmed experimentally (Sinclair et al., 1989). Inan early attempt to take advantage of this effect toassess perimacular hemodynamics, subjects were askedto count the number of particles passing a given spot in30 s while staring at a blue field of light (Riehm et al.,1972).In 1980, Riva and Petrig (1980) introduced their Blue

Field Entoptic Simulator. The instrument allows sub-jects to view their entoptic image and then attempt tomatch the velocity and density of simulated leukocyteson a computer screen to that of their own. Thesimulation is displayed on a color monitor. When theblue light source is on, the simulation is masked behinda tilted glass pane. The simulation is controlled by a

simple panel, which can adjust the velocity and densityof the leukocytes.Although the blue field entoptic simulation is a

subjective test, repeated measures in the same subjectshave been shown to be reproducible (Yap and Brown,1994). An investigator must rely on the subject’s abilityto perform a psychophysical matching task that maydepend on the subject’s cognitive skills. The relationshipbetween the recreated leukocyte velocity and density andthe actual speed and prevalence of leukocytes in theperimacular capillaries is unknown. This and the lack ofan actual blood flow measurement from the techniquemake its quantitative results difficult to interpret.

2.7. Laser speckle flowmetry

Illumination of the fundus with a coherent lightsource produces a number of interference phenomena.The speckle phenomenon is observed as a speckledpattern of light, which is scattered from the fundus whenilluminated by a coherent source. The pattern variesrapidly with the cardiac cycle and the rate of patternvariation depends on the magnitude of retinal bloodflow. The laser speckle flowmeter quantifies the rate ofvariation in the speckle pattern as a surrogate forvolumetric retinal blood flow. Variations in the specklepattern are quantified point by point throughout thefundus, and a flow map is created. Earlier photographicmethods using the speckle phenomenon were able todisplay the distribution of velocity in the retina.However, despite the advantage of producing a dis-tributive description of retinal blood velocities, it onlyallowed a semi-quantitative estimation of retinal micro-circulation and could not follow time course changes.


Tamaki et al. (1993) described an improved apparatusfor non-contact two-dimensional measurement of themicrocirculation in the ONH. Their apparatus consistsof a fundus camera equipped with an 808 nm diodelaser. Normalized blur is calculated for each pixel withina 0.62� 0.62mm area of the retina. Normalized blur isequal to the average reflected intensity divided by theabsolute difference between average intensity and a 98point floating average. The laser speckle technique is anon-invasive technique capable of measuring bloodvelocity with good reproducibility, albeit in arbitraryunits. The two greatest disadvantages of the techniqueare that it is not commercially available, and that themeaning of the raw normalized blur measurement is notclearly understood.

2.8. Pulsatile ocular blood flow (POBF)

POBF, described by Langham et al. (1989a, b) anddetermined tonographically from the IOP pulse, hasbeen widely employed because it is rapid, easy to use,and relatively inexpensive. POBF reflects the pulsatile,and not the steady component of arterial inflow to theeye, and is influenced by refractive error and axiallength. Although the exact proportion of the total bloodflow that is pulsatile is presently unknown, estimatesindicate it to be between 50% and 80% (Langham et al.,1989a; Krakau, 1995).The OBF instrument samples IOP at 200Hz over a

time interval of 5–20 s using a disposable probe. A built-in processor analyzes different characteristics of the IOPpulse waves and selects the five most representativepulses for the calculation of POBF. Despite wide inter-individual variation, the technique is characterized byexcellent reproducibility (Butt and O’Brien, 1995;Schmetterer et al., 1998).Nonetheless, the physiological interpretation of

POBF recordings remains uncertain. Because most ofthe blood flow into the eye is within the choroidalcirculation, it is presumed that POBF primarily mea-sures the pulsatile component of choroidal perfusion,independent from the retinal circulation (Langham et al.,1989a, b).

2.9. Hydrogen clearance

The measurement of blood flow by hydrogen clear-ance is an extension of the Fick principle (Auckland,1964; Fieschi et al., 1965). In Fick’s method, oxygenconsumption and oxygen concentration on the arterialand venous sides are measured. The total blood flow iscalculated as the ratio between oxygen consumption andthe difference between arterial and venous oxygenconcentration. Measurement of retinal or ONH bloodflow with diffusible tracers requires a knowledge of thevolume of the tracer introduced into the body, and real

time measurement of the concentration of the tracer inthe tissue of interest. In the case of hydrogen clearance,a hydrogen microprobe surgically placed adjacent to thefundus or ONH, and the concentration is measured inreal time. Hydrogen is used because it is readily diffusedinto the tissue from retinal capillaries.

2.10. Intraluminal corrosion casting (ICC)

ICC is an in vitro technique used to study themicrovascular anatomy of the retina and ONH. Afterclearing the blood vessels of intravascular clots byflushing with a tissue plasminogen activator, methylmethacrylate is injected into the CRA and/or the PCAs.The plastic is allowed to polymerize, and then the tissueis removed by dissolution in a high concentration causticsolution; 6M potassium hydroxide. The casts of thevasculature are mounted, coated with gold palladium,and examined by scanning electron microscopy (Oliveret al., 1994, 1995).

2.11. Fluorescent microsphere imaging

Fluorescent microsphere imaging uses polystyrenelatex microspheres that incorporate one or more dyes.These microspheres are injected intravenously into ananimal and are excited in the eye through the residentlasers of a SLO. The excited particles are detected by theophthalmoscope, and its output is then digitized directlyor recorded on a videocassette recorder, for subsequentimage analysis. Multiple-dye microspheres use theprinciple of resonance energy transfer for the activationof the final dye in a non-radiative cascade. Thesemicrospheres enable the investigator to tailor theexcitation and emission spectra of the particles for theinvestigation of different ocular tissues (Alm and Bill,1973; Khoobehi et al., 1997).

3. Ocular penetration of topically applied antiglaucoma

medications

Most glaucoma drugs are applied topically to the eye.A small fraction of the drug dosage is absorbed directlythrough the cornea, conjunctiva, and sclera, and a largerfraction is absorbed into the systemic circulation.Penetration across the cornea is proposed as the primarypathway by which drugs reach the anterior segmentafter topical administration, whereas the conjunctiva/scleral route is more important to allow the access toposterior tissues (Burstein and Anderson, 1985; Grassand Robinson, 1988; Maurice, 2002). With regard toIOP lowering, the drug levels in the anterior segment ofthe eye, in particular the ciliary body and iris, have beenextensively studied (Araie et al., 1982; Yamamura et al.,


1999; Shih and Lee, 1990; Ashton et al., 1991; Babioleet al., 2001).Before assuming that one drug is capable of modify-

ing blood flow in one of the above-mentioned vascularbeds, one has to evaluate if the drug is capable ofreaching this vascular bed in an effective concentration.In vitro studies analyzing the effect of one medicationon blood flow may utilize concentrations that are notobtained following a single or chronic instillation.Evaluation of the in vivo action of pharmacologicalagents is incomplete without knowledge of theirdisposition and metabolism in target tissues. Unfortu-nately, studies investigating the concentration of anti-glaucoma medications at the ONH, retina, and choroidare rare.Recently, a review article investigating drug delivery

to the posterior segment from drops was published(Maurice, 2002). However, although consideration wasgiven to the possible mechanisms associated with drugpenetration into the globe and the artifacts that mayinfluence the measurement of a drug level in a tissuesample, the author did not include information regard-ing the specific concentrations of antiglaucoma drugs inthe vitreous, retina or choroid following the instillationof drops. This information is displayed in the followingparagraphs.

3.1. Pilocarpine

Salminen et al. (1984) examined the absorption of 2%pilocarpine eye drops in the rabbit eye. They reportedmean levels of pilocarpine of 3–6 mg/g in the iris andciliary body in albino rabbits and 10–15 mg/g inpigmented rabbits, 30min after application. In thevitreous, the levels were 0.07–0.08 mg/g, and in thechoroid/retina the levels were 0.7 mg/g in the albinorabbits and 2.1 mg/g in the pigmented rabbits.

3.2. Beta-blockers

Urtti et al. (1988, 1990) studied the penetration oftimolol into the rabbit eye. After topical application of 1drop of timolol (125 mg), they found average levels of14 mg/g in the iris and ciliary body and 0.03 mg/g in thevitreous. Similar levels were reported by Salminen andUrtti (1984), who found a significant increase in tissuelevels following multiple topical doses of timolol in therabbit eye.Araie et al. (1982) studied the absorption of timolol in

the rabbit eye and reported mean levels of 9 mg/g in theiris and ciliary body, 0.02 mg/g in the vitreous, 1.6 mg/g inthe retina and vitreous, and 0.08 mg/g in the optic nerve2 h after topical application.Levobunolol, its metabolite, dihydrobunolol, and

timolol concentrations were measured in various oculartissues and compartments at eight time points after

topical administration of levobunolol 0.5% or timolol0.5% to albino rabbits (Acheampong et al., 1995). Twohours after topical application, the mean levels oflevobunolol were 0.5 mg/g in the iris and ciliary body,0.004 mg/g in the vitreous, 0.06 mg/g in the retina andchoroid, and 0.016 mg/g in the optic nerve. Timololconcentrations were higher than the correspondinglevobunolol and dihydrobunolol in the choroid-retinaand optic nerve. In fact, there was a 30-fold differencebetween the maximum concentrations of timolol(16.9 nmol/ml) and levobunolol+dihydrobunolol(0.58 nmol/ml) in the optic nerve. Similar results wereobtained with radiolabeled compounds in rabbit eyes(Chen et al., 1987, 1988).

3.3. Alpha-agonists

Urtti et al. (1984) studied the penetration of topicallyapplied adrenaline (30 ml of 1% solution) in the albinorabbit eye. Three hours after instillation, adrenalinelevels were on average 0.24 mg/g in the iris and ciliarybody, 0.011 mg/g in the vitreous, and 0.45 mg/g in theretina/choroid.Recently, Acheampong et al. (2002) evaluated the

distribution of [14C] brimonidine into anterior andposterior ocular tissues of monkey and rabbit eyes. Theauthors demonstrated that the concentrations of radio-activity in the different ocular tissues increased aftermultiple dosing, especially in pigmented tissues (iris,ciliary body, and choroid/retina). Since measurementsof tissue levels of drugs that bind to melanin canoverestimate the amount of drug available for receptoractivation, the authors emphasized the concentrationsfound in the vitreous. After 2 weeks of treatment withbrimonidine 0.2% in monkeys, mean vitreous concen-tration was 82745 nM, higher than the 2 nM requiredto activate 50% of alpha-2 receptors in isolated assaysystems (EC50).In humans, Kent et al. (2001) measured brimonidine

levels in vitreous samples from patients who hadreceived 0.2% brimonidine tartate 2 or 3 times a dayfor 4–14 days. In phakic eyes, the average brimonidinelevel in the vitreous was 9 nM, which corresponds to0.003 mg/g.

3.4. Prostaglandin analogues

Sj .oquist et al. (1999) studied the pharmacokinetics oflatanoprost 0.005% in cynomolgus monkeys. Thirtyminute following topical application, latanoprost levelswere on average 0.28 mg/g in the iris and 0.08 mg/g in theretina. Sj .oquist et al. (1998) found higher levels in therabbit eye, where the maximal concentration of latano-prost following topical application was 0.3–0.4 mg/g inthe iris and ciliary body, although the levels in thevitreous and choroid were very low.


3.5. Carbonic anhydrase inhibitors

Sugrue (1996, 2000) investigated dorzolamide levels inthe retina and other tissues of the rabbit eye, andreported peak levels of 24.0 mg/g in the rabbit cornea,7.8 mg/g in the aqueous humour and 27.0 mg/g in the iris-ciliary body, whereas Stef!ansson et al. (unpublisheddata) found 16.5, 2.2, and 30.9 mg/g, respectively.Schmitz et al. (1999) measured the concentration ofdorzolamide in the human aqueous humor followingtopical application, and their results were similar tothose obtained in the rabbit. In the retina, Sugruereported 4.26 mg/g at 1 h after application, 4.16 mg/g at2 h, 5.29 mg/g at 4 h, and 2.09 at 8 h, whereas Stef!anssonet al. (unpublished data) found lower levels (0.16, 0.52,0.77, and 0.88 mg/g, respectively). In contrast, Conroy(1997) tested the ocular absorption of two topicallyapplied sulfonamides (not dorzolamide) in the rabbiteye, and found that these did not reach the retina,suggesting that different sulfonamides may have differ-ent ocular pharmacokinetics.The levels of dorzolamide found in the retina and

optic nerve are in the range of 1.0 mg/g and always above0.1 mg/g 2–8 h after application (Stef!ansson et al.,unpublished data). The 50% inhibition levels ofcarbonic anhydrase isoenzyme II and IV (IC 50) fordorzolamide are 0.18 nM or 65 mg/g and 6.9 nM or2.5 mg/g, respectively. Hence, the reported levels aftertopical application of dorzolamide are higher than theIC 50 for both isoenzymes. It is reasonable to assumethat dorzolamide at these levels inhibits most of thecarbonic anhydrase II and IV in the retina and opticnerve.Similar to dorzolamide, brinzolamide was found to

penetrate the eye and reach the retina in effectiveconcentrations. DeSantis (2000) measured brinzolamidelevels in the retina in pigmented rabbits and found amean concentration of 0.338 mg/g.

4. Literature search

We performed a literature search in November 2002which consisted of a textword search in MEDLINE forthe years 1968–2002. It used the combination of theterms blood flow and pilocarpine, timolol, betaxolol,levobunolol, carteolol, apraclonidine, brimonidine, dor-zolamide, brinzolamide, acetazolamide, latanoprost,travoprost, bimatoprost, and unoprostone. Articlesdealing with OBF were then selected and reviewed. Thissearch retrieved 136 citations. Articles investigating theeffects of systemic medications on OBF were alsoreviewed through the combination of the terms bloodflow and calcium channel blocker, magnesium, ginkgobiloba, dipyridamole, and renin-angiotensin inhibitor.This search retrieved 33 citations. Studies investigating

the effect of medications on peripheral blood flow,visual field or other psychophysical tests were notincluded. We found no study evaluating the influenceof travoprost or bimatoprost on OBF.The information gathered, following the literature

search is shown according to the drug. For each drug,we discussed the pharmacology (with emphasis on thetheoretical influence on blood flow), and reviewedstudies investigating the effects on OBF according tothe different techniques.Although the literature dealing with the topic

discussed in this review is vast, it is comprised of severalunmasked, short-term, non-controlled studies, wherethe possible influence of IOP reduction on the observedblood flow changes was not taken into account.Furthermore, most of the studies dealing with systemicdrugs do not compensate for the possible influence ofconcomitant antiglaucoma medication.Prudence is required when speculating on OBF in

glaucoma patients on the basis of results from animalstudies. Results from in vitro or animal studies providevaluable information, but their findings cannot beautomatically extrapolated to humans. Regarding hu-man studies, there are some indications that patientswith glaucoma may behave differently whenexposed to vasoactive drugs when compared to healthyindividuals and ocular hypertensives, limiting theimportance of studies including such populations. Thefindings of experimental studies, as well as studiesinvestigating healthy individuals and ocular hyperten-sives are listed, but the reader is warned to interpretthem with caution.For these reasons, a greater emphasis is given to in

vivo studies evaluating the effect of drugs on glaucomapatients, which unfortunately represent a minority.These studies were analyzed in detail, including adescription of their design, sample size, duration,and undesirable influence of other variables.

5. The effects of antiglaucoma drugs on ocular blood flow

5.1. Pilocarpine

Pilocarpine is a parasympathomimetic drug thatpromotes its effect directly at the neuromuscularjunction. Cholinergic stimulation of the ciliary muscleby pilocarpine results in traction of the scleral spur,altering the configuration of the trabecular meshworkand leading to enhanced outflow and reduced IOP(Drance and Nash, 1971; Fellman and Starita, 1990). Ingeneral, parasympathomimetic drugs tend to inducevasodilation, although Stjernschantz (1990) suggesteda colinergic-induced vasoconstriction in the anterioruvea.


5.1.1. Experimental studies

The effect of pilocarpine on the isolated rabbit ciliaryartery was investigated using isometric tension recordingmethods, by Yoshitomi et al. (2000), who were able toshow a dose-dependent muscle relaxation that wasinfluenced by the endothelium and nitric oxide synthesis.Green and Hatchett (1987) measured the blood flow inrabbit eyes following the instillation of pilocarpine 4%t.i.d. for 5 weeks employing the radioactive microspheretechnique. Pilocarpine-treated eyes showed a trendtoward reduction in anterior segment (iris and ciliarybody) blood flow, but no significant change wasobserved in either retinal or choroidal blood flow. Onthe other hand, Alm et al. (1973) found a significantvasodilation in the anterior segment of primates 45–60min after a single drop of pilocarpine 4%. Otherexperimental studies employing the labeled microspheretechnique demonstrated that pilocarpine did not changeretinal and choroidal blood flow in normal rabbits(Chiou and Yan, 1986), but improved flow in bothvascular beds in ocular hypertensive rabbits (Chiou andChen, 1992), and cats (Kaskel et al., 1978). Mittag et al.(1994) measured the POBF of glaucomatous monkeysfollowing the instillation of pilocarpine 4% andobserved a significant increase that was positivelycorrelated with the IOP lowering effect of the drug.

5.1.2. Studies in healthy individuals and ocular

hypertensive patients

In a study evaluating the effects of pilocarpine 2% on10 healthy subjects, retinal and ciliary perfusionpressures were measured using the OODG, but nosignificant change was detected (Pillunat and Stodrme-ister, 1988). In a double-blind, placebo-controlled,randomized, crossover study involving 10 healthysubjects, pulsatile choroidal and optic disc blood flow,and blood flow velocities in the CRA and OA (measuredby CDI) were not found to change following theinstillation of pilocarpine 2% (Schmetterer et al.,1997). Conflicting results have been published regardingthe effect of pilocarpine on POBF of ocular hypertensivepatients. While Shaikh and Mars (2001) described asignificant increase in POBF following the instillation ofpilocarpine 2% (n ¼ 16), Mittag et al. (1994) observedno significant change in the ocular pulse amplitude afterpilocarpine 4% (n ¼ 6).

5.1.3. Studies in glaucoma patients

The only study evaluating the effect of pilocarpine onglaucoma patients was performed by Claridge (1993),who measured the POBF of 18 POAG patients using acombination of pilocarpine and timolol, re-measuredthe parameters 2 weeks after withdrawing pilocarpineand again 1 week after reinstituting full treatment.Recordings from 20 patients receiving only timolol wereused as control values. There was no significant change

in POBF when pilocarpine was withdrawn, despite asignificant rise in IOP, suggesting that pilocarpine hadno direct effect on POBF.

5.2. Beta-blockers

Drugs that bind to b receptors but do not activatethem are known as beta-adrenergic antagonists or beta-blockers. Depending on the specificity for b1 or b2receptors, beta-blockers are classified as non-selective(when they bind with equal affinity to both receptors) orselective (when they show greater affinity for a specificreceptor).Timolol, levobunolol, metipranolol, and carteolol are

examples of non-selective beta-blockers, whereas betax-olol is a selective beta-blocker, with greater affinity forb1 receptors. All beta-blockers reduce IOP by decreas-ing aqueous humor production by approximately 30–50%. The exact mechanism involved in this inhibition isunknown, although some authors suggest that b2receptors are blocked in the non-pigmented ciliary bodyepithelium, impairing aqueous humor production. b1antagonists such as betaxolol would also be able toinhibit b2 receptors (cross-receptor blocking), providedthat its concentration in the anterior segment issufficiently high (Novak, 1987).A number of studies have investigated the effects of

several beta-adrenergic blocking agents on OBF, espe-cially since it has been suggested that the blockade of b2receptors may interfere with endogenous vasodilation(Collignon-Brach, 1992), thus potentially adverselyaffecting ocular circulation.

5.2.1. Timolol

The first beta-blocker to be routinely used in thetreatment of glaucoma was timolol maleate. Since itremains the gold standard to which all new antiglauco-ma medications are compared to and because non-selective beta-blockers are felt to potentially have avasoconstrictive effect, the effects of timolol on all theabove-mentioned vascular beds were extensively inves-tigated. Animal studies, in vitro investigations, andclinical trials including normal volunteers, ocularhypertensive patients, POAG and NTG patients thatwill be described herein were never consistent enough toindicate a pernicious effect of timolol maleate on theretinal, choroidal, or ONH circulations. In fact, for eachstudy suggesting a possible deleterious effect, two otherreports indicate either no influence or even a beneficialeffect of timolol on OBF.

5.2.1.1. Experimental studies. A classic study by VanBuskirk et al. (1990) employing the microvascularcorrosion casting technique described vasoconstrictionof ciliary arteries in rabbit eyes induced by timolol,betaxolol, and phenylephrine. The initial vasoconstric-


tive effect of timolol was less dramatic than that inducedby betaxolol and phenylephrine, but after 50 days oftreatment, timolol resulted in marked vasoconstriction.Reduced iris and ciliary body perfusion, detected by thelaser speckle or the microsphere methods, was alsodescribed by other authors following the instillation oftimolol in rabbit eyes (Watanabe and Chiou, 1983;Tamaki et al., 1995). Although other experimentalstudies failed to demonstrate a timolol-induced decreasein anterior segment blood flow in rabbit eyes (Green andHatchett, 1987; Jay et al., 1994), Chiou and Chen (1992)described a biphasic action of l-timolol on the bloodflow of the iris and ciliary body of rabbits using thecolored microsphere technique. An initial reduction inblood flow observed after 30min was followed by amarked increase later at 90min and thereafter.If there is an agreement that timolol may cause a

vasoconstriction of the anterior uvea in experimentalstudies, the same does not hold true regarding posteriorsegment blood flow. While two experiments usingradiolabeled microspheres found decreased choroidalblood flow in arterially perfused bovine eyes (Millaret al., 1995) and ocular hypertensive rabbits (Chiou andChen, 1993) treated with timolol, other studies employ-ing the same technique indicated either no significantchange (Green and Hatchett, 1987; Chiou and Chen,1992; Jay et al., 1994) or an improvement (Chiou andYan, 1986; Jay et al., 1994) in retinal, choroidal, orONH blood flow of rabbits. The same trend (i.e. nochange or improvement) was observed in studiesemploying the laser speckle method to detect modifica-tions in choroidal and ONH blood flow in rabbits(Tamaki et al., 1997b, c; Tomidokoro et al., 1999) andmonkeys (Ishii and Araie, 2000b). Kiel and Patel (1998)employed laser Doppler flowmetry to demonstrate thattimolol does not alter the rabbit choroidal response toacute changes in perfusion pressure. The same techniquewas used by Yan and Chiou (1987), who described asignificant reduction in the retinal blood flow (17%) ofrabbits with l-timolol, but a slight improvement (9%)with d-timolol. The microvasculature of the ONH, wasinvestigated with the corrosion casting technique, byOrg .ul et al. (1995), who reported no observable opticnerve vasomotor effects promoted by timolol in therabbit eye. Finally, in vitro studies investigating thedirect effect of drugs on isolated segments of precon-tracted porcine long posterior ciliary arteries (Hesteret al., 1994) or bovine retinal microarteries (Hoste et al.,1990) showed that timolol does not have a potentrelaxant effect, possibly because it lacks the Ca2+-antagonistic properties of other beta-blockers such asbetaxolol.

5.2.1.2. Studies in healthy individuals and ocular hyper-

tensive patients. The analysis of the effects of timolol onthe retinal, choroidal and ONH circulations in healthy

subjects also give conflicting results. Studies employingLDV, laser Doppler flowmetry, or measurements ofpulsatile choroidal and optic disc blood flow suggestedthat timolol might be detrimental to the choroidal,retinal, and epipapillary circulations (Schmetterer et al.,1997; Yoshida et al., 1998; Haefliger et al., 1999). Incontrast, Yoshida et al. (1991) in a double-masked,placebo-controlled study using LDV, found that timolol0.5% did not induce changes in retinal arterial bloodflow rate or ONH capillary blood velocity, findings thatwere reproduced by Ishikawa et al. (1996) with the laserspeckle method. Netland et al. (1999) were unable todetect ONH blood flow changes induced by timolol inocular hypertensive patients.While some authors found that timolol had no effect

on the retinal circulation of ocular hypertensive patients(Wang et al., 1997), others have demonstrated increasedretinal blood flow of normal volunteers and ocularhypertensive patients employing LDV (Grunwald, 1990,1991), or measurements of the AVP time (Wolf et al.,1989; Arend et al., 1998). Digital analysis of scanninglaser fluorescein angiograms also demonstrated in-creased macular and epipapillary blood flow velocitiesfollowing the instillation of timolol in healthy volunteers(Arend et al., 1998). According to some authors(Yoshida et al., 1991) POBF measurements in timolol-treated eyes of normal individuals were found todecrease, and to remain unchanged according to others(Yamazaki et al., 1992; Sponsel et al., 2000); while CRAblood flow velocities measured with CDI have beenshown to increase (Steigerwalt et al., 1993, 2001) or toremain unchanged (Schmetterer et al., 1997) undertimolol therapy.

5.2.1.3. Studies in glaucoma patients. As previouslymentioned, the OBF response of glaucoma patients tomedications should be emphasized. Some authorsreported the effects of timolol on the retinal circulationof NTG patients (Truckenbrodt et al., 1992) to benegligible. However, this was an unmasked studyinvestigating the short-term (2-week) effect of timolol0.5% on 31 NTG patients with 2-point fluorometry andautomatic measurement of arterial and venous dia-meters. A prospective, controlled study by Lubeck et al.(2001) concluded that no significant change could bedetected in the ONH circulation (measured with theHRF) of 12 POAG patients following timolol treatmentfor 3 weeks. The same study investigated 12 age- andsex-matched healthy volunteers, who received timololfor the same period and did not show significant changesin ONH blood flow.Retrobulbar hemodynamic parameters (measured

with CDI) in patients with POAG or NTG were foundto remain unchanged in timolol-treated eyes by severalauthors (Harris et al., 1995c; Nicolela et al., 1996a;Evans et al., 1999a, b). In a double-masked, crossover


study, Harris et al. (1995c) observed that timolol did notinduce statistically significant changes in CDI para-meters of 13 NTG patients at 1 month, following the useof timolol 0.5% twice daily. In another double-masked,crossover study, Nicolela et al. (1996a, b) also concludedthat 7 days of timolol treatment did not significantlyalter the retrobulbar blood flow of 9 POAG and 6 ocularhypertensive patients. Only one study suggested thattimolol might be associated with a significant increase inthe resistance index of the temporal SPCA, with nochange detected in other retrobulbar vessels (Altan-Yaycioglu et al., 2001). This was a short-term (1 month)study including a total of 40 POAG patients, amongwhich 10 received timolol 0.5%. Conversely, Bergstrandet al. (2001) observed a significant increase (41%) in theEDV and a significant decrease in the RI (5.8%) of theCRA of 15 POAG patients after 1 month of timololtreatment. Interestingly, the same authors were not ableto detect the same effect in 12 eyes with ocularhypertension, suggesting the existence of a defectiveautoregulation in POAG patients.POBF measurements in POAG were not influenced

by timolol treatment according to the majority of thestudies (Trew and Smith, 1991; Claridge and Smith,1994; Morsman et al., 1995; Vetrugno et al., 1998) withthe exception of one long-term, unmasked study, whichsuggested that timolol was associated with reducedPOBF values (Boles-Carenini et al., 1994). POBF hasbeen recorded in 15 POAG patients receiving timolol0.25% in both the erect and supine positions, andsubsequently repeated 2 weeks after withdrawal of thetreatment (Trew and Smith, 1991). The authors foundno statistically significant differences in POBF betweenthe treated and untreated phases of the study. Claridgeand Smith (1994) measured the POBF at 3-hourlyintervals over a 24-h period in 10 ocular hypertensives, 8patients with POAG and 8 control subjects. All POAGpatients were on timolol tretament. In this group,measurements were also made 2 weeks after discontinu-ing timolol for 2 weeks, a wash-out period inferior to the4 weeks recommended for beta-blockers. Similar to theprevious study, the authors observed that when timololwas withdrawn from POAG subjects, there was nochange in POBF despite an increase in IOP, suggestingthat timolol did not result in POBF changes.

5.2.2. Betaxolol

The hypothesis that betaxolol, a selective beta-blocker, could improve OBF by avoiding non-selectivebeta-blocker-induced vasoconstriction has led severalauthors to investigate the effects of this drug on variousvascular beds, both in vitro and in vivo.

5.2.2.1. Experimental studies. The laser speckle methodshowed significant increases in tissue blood flow velocityin the iris and ONH of albino rabbits following 20-day

treatment with betaxolol 0.5% bid (Araie and Muta,1997). Betaxolol was also found to inhibit the reductionin choroidal blood flow induced by ET-1 injections inthe vitreous of albino rabbits (Kim et al., 2002), and toincrease ciliary body and retinal blood flow of rabbits asmeasured with the hydrogen clearance method (Satoet al., 2001). Segments of bovine retinal microarteriesand porcine long posterior ciliary arteries were mountedin an organ bath perfused with betaxolol for measure-ment of contractile forces (Hoste and Sys, 1994; Hesteret al., 1994). Both experiments demonstrated thatbetaxolol is capable of reducing K+-induced contrac-tions in a dose-dependent manner, possibly by inhibitingvoltage-gated Ca2+ entry in vascular smooth muscle.However, a high concentration of betaxolol (10�4M)was required for this effect to be observed. In a well-designed study intended to measure choroidal bloodflow employing laser Doppler flowmetry following acutechanges in perfusion pressure of rabbits, Kiel and Patel(1998) reported that a single drop of betaxolol 0.5% didnot alter the choroidal response to acute changes inperfusion pressure. Finally, although treatment witheither timolol or betaxolol has resulted in markedvasoconstriction of the arteries that supply the ciliarybody or rabbit eyes (Van Buskirk et al., 1990), theexamination of the microvasculature of the optic nervewith an ICC technique was unable to detect anyvasomotor effects of a long-term treatment with thesedrugs in the rabbit model (Org .ul et al., 1995).


tensive patients. Studies investigating the acute effects ofbetaxolol instillation in healthy humans tended to showno significant change in retinal circulation as measuredby the laser speckle method (Ishikawa et al., 1996;Tamaki et al., 1997a), OODG (Pillunat and Stodrme-ister, 1988), the blue field entoptic phenomenon (Harriset al., 1995b), or the HRF (Haefliger et al., 1999). Incontrast, two studies documented increased retinalblood flow following the use of betaxolol in healthyvolunteers. Arend et al. (1998) observed a 25%reduction in AVP time and a 20% increase in macularand epipapillary blood velocities not only with betax-olol, but also with timolol and levobunolol. In a double-masked, placebo-controlled, randomized study, Schmet-terer et al. (1997), did not observe statistically significantchanges in either pulsatile choroidal and ONH bloodflow, or in the retrobulbar hemodynamic parameters(measured by CDI) in healthy volunteers treated withbetaxolol. However, chronic use (2–3 weeks) of betax-olol has been shown to improve both retinal and ONHblood flow (Yoshida et al., 1998; Tamaki et al., 1999b).In ocular hypertensive patients, betaxolol was found

to improve CRA hemodynamic parameters measuredwith CDI (Steigerwalt et al., 2001). Gupta et al. (1994)demonstrated a statistically significant increase in the


retinal blood flow of a major temporal vein 2 h followingthe instillation of the drug in 10 ocular hypertensivesubjects in a randomized, placebo-controlled study.

5.2.2.3. Studies in glaucoma patients. Morsman et al.(1995) performed POBF measurements in 21 POAG and12 ocular hypertensive patients randomly assigned toreceive timolol, betaxolol or levobunolol twice daily for1 week. The measurements were performed, by amasked investigator, at baseline, and 2 h after adminis-tration. Compared to baseline, there was a 22% increasein POBF values after levobunolol administration(p ¼ 0:02), a 23% reduction after betaxolol administra-tion (p ¼ 0:04), and no statistically significant changeafter timolol use. The authors were unable to correlatethese findings with changes in IOP or blood pressure.In a long-term study, Boles-Carenini et al. (1994)

compared the effects of timolol and betaxolol on thePOBF of 25 POAG patients. During the 12 months offollow-up, betaxolol (n ¼ 14) was found to maintainstable POBF measurements, whereas timolol (n ¼ 11)resulted in a statistically significant reduction. The IOPlowering efficacy of both drugs were not statisticallydifferent, and, thus, could not explain the findings.However, the examiner was not masked to patienttreatment, and the washout period from previous beta-blocker therapy was only 15 days.Harris et al. (2000) were unable to detect a statistically

significant change in AVP time or CDI parameters inthe OA and CRA following the use of betaxolol for 1month in 9 NTG patients. In a double-masked, cross-over study, CDI measurements of the retrobulbar bloodflow velocity of 13 NTG patients were performedfollowing a 1-month treatment with timolol andbetaxolol (Harris et al., 1995c). There was no significantchange in the hemodynamic parameters of all analyzedvessels after timolol or betaxolol treatment. However,when the four-vessel average resistance index wascalculated, a statistically significant decrease inducedby betaxolol was detected.In an unmasked study, without placebo control,

betaxolol was found to significantly reduce the resis-tance index of the OA of 18 NTG patients after 1 year oftwice-daily bilateral instillation (Turacli et al., 1998). Inanother prospective, randomized trial, betaxolol 0.5%significantly reduced the resistance index of the CRAand temporal SPCA of 10 POAG patients 1 month aftertreatment (Altan-Yaycioglu et al., 2001).Other investigators identified an improvement of

retrobulbar hemodynamic parameters promoted bybetaxolol in 11 POAG patients with ocular vasospasm,defined as a statistically significant increase in OA bloodflow velocity or a significant decrease in OA resistanceindex during hypercapnia (Evans et al., 1999a, b). Thiswas a double-masked, crossover study that comparedthe effects of a 4-week treatment period with betaxolol

or timolol on CDI measurements and contrast sensitiv-ity. The authors reported no statistically significantchange in retrobulbar hemodynamics or visual functionwith timolol, but did observe a statistically significantdecrease in the OA resistance index (p ¼ 0:04), astatistically significant improvement in contrast sensi-tivity (p ¼ 0:006), and a positive correlation betweenchange in contrast sensitivity and OA resistance index(r ¼ 0:70; p ¼ 0:15) with betaxolol treatment.

5.2.3. Levobunolol

Levobunolol is another non-selective beta-blockerwith a unique characteristic. Once administered, levo-bunolol is converted by the corneal epithelium andciliary body into an active polar metabolite known asdihydrolevobunolol (Di Carlo et al., 1977). It has beensuggested that the polarity of this metabolite may inhibitits diffusion into the retina and choroid, theoreticallyinducing less vasoconstriction in these vascular bedsthan other beta-blockers. As previously mentioned,experimental studies confirm that levobunolol and itsmetabolite are found in a statistically significantly lowerconcentration than timolol in the choroid/retina andONH (Acheampong et al., 1995).

5.2.3.1. Experimental studies. The only experimentalstudy evaluating the OBF effects of levobunolol wasperformed by Chiou and Chen (1993), who employedlabeled microspheres and found that all beta-blockerstested (betaxolol, levobunolol, metipranolol, and timo-lol) tended to decrease OBF in ocular hypertensiverabbits.


tensive patients. In humans, levobunolol 0.5% wasshown to result in a statistically significant increase inPOBF measurements in healthy volunteers 2 h after asingle dosage instillation (Bosem et al., 1992), however,Ogasawara et al. (1999), were unable to reproduce thesefindings. The data available on the effects of levobunololon the retinal circulation are also inconsistent. Althoughsome authors described an improvement in retinal andONH blood flow measured with the HRF (Ogasawaraet al., 1999) or by digital image analysis of scanning laserfluorescein angiograms (Arend et al., 1998), studiesemploying blue entoptic simulation and LDV failed todetect a similar effect (Harris et al., 1995b; Leung andGrunwald, 1997; Bloom et al., 1997). Finally, levobu-nolol was found not to influence choroidal, ONH orretrobulbar blood flow after a single instillation inhealthy subjects (Schmetterer et al., 1997).

5.2.3.3. Studies in glaucoma patients. In a randomized,double-masked, placebo-controlled study, Bosem et al.(1992) reported a statistically significant increase(13.3%, po0:006) in POBF 2h after the instillation of


levobunolol in 14 POAG patients. However, a simulta-neous 28% decrease in IOP was observed, but theauthors failed to investigate a possible correlationbetween IOP reduction and POBF improvement.In a study including 21 POAG and 12 ocular

hypertensive patients, Morsman et al. (1995) observeda 22% increase in POBF values after 1 week oflevobunolol administration (p ¼ 0:02), a change thatwas not correlated with IOP or blood pressure changes.In a prospective trial of 40 POAG patients, Altan-

Yaycioglu et al. (2001) compared the retrobulbarhemodynamic effects of levobunolol, timolol, carteolol,and betaxolol. At the end of the first month of treatmentwith levobunolol, the authors did not disclose statisti-cally significant changes in CDI parameters in the OA,CRA, and SPCA.

5.2.4. Carteolol

Carteolol is a non-selective beta-adrenergic blockingagent with partial beta-agonistic activity, known asintrinsic sympathomimetic activity (ISA). The contribu-tion of ISA to beta-blocker therapeutic potential hasbeen studied extensively for systemic hypertension, withinconclusive results (Taylor, 1987). Although a beta-blocker with ISA might be expected to theoreticallydecrease peripheral vascular resistance and improveblood flow, no definitive data supports this hypothesis.Similarly, the effectiveness of the ISA of carteolol inimproving OBF is questionable.

5.2.4.1. Experimental studies. Experimental studies em-ploying the laser speckle method revealed increased bloodflow velocities in the iris, with no change in the choroidalor ONH circulation of rabbits following a single instilla-tion of carteolol 2% (Tamaki et al., 1998; Tomidokoroet al., 1999). However, after a 20-day treatment withcarteolol 2%, a statistically significant increase in theONH blood velocity was measured in rabbit eyes withthe same method, both in the treated (15% increase) andcontralateral eyes (11%) (Tamaki et al., 1998). Anotherstudy in rabbits demonstrated that continuous intrave-nous injection of carteolol (5 mg/kg/h) was effective inincreasing the ONH blood flow as measured with thehydrogen clearance method (Sugiyama et al., 1998). Incontrast to these findings, Millar et al. (1995) reportedmarked reduction of perfusion in the iris, ciliary body andchoroid (measured with radiolabeled microspheres) in-duced by carteolol in arterially perfused bovine eyes,whereas Sato et al. (2001) showed reduced ciliary body,choroidal and retinal blood flow in rabbits using thehydrogen clearance method. An in vitro study thatevaluated the contractile forces in segments of porcinelong posterior ciliary arteries demonstrated that carteololwas significantly less effective than betaxolol in promotingrelaxation of vascular smooth muscle (Hester et al., 1994).Such findings were confirmed by Brogiolo et al. (2002),

who observed that porcine ciliary arteries precontractedwith KCl were relaxed by high concentrations ofcarteolol, an effect modulated by extracellular Ca2+.


tensive patients. In humans, the use of carteolol inhealthy individuals was found to result in a statisticallysignificant increase of POBF measurements (Yamazakiet al., 1992; Yamazaki and Baba, 1993). The laserspeckle method was used in 6 normal individuals after asingle instillation of carteolol 2%, and disclosed astatistically significant increase in ONH blood flowvelocities (Tamaki et al., 1998). Carteolol promoted amarked increase in the peak systolic and end diastolicvelocities of the OA (determined by CDI), and astatistically significant increase in the blood flow volumeof the peripapillary retina of normal human eyes(Mizuki and Yamazaki, 2000).On the other hand, two independent, double-masked,

placebo-controlled studies investigating the effect ofcarteolol on the normal retinal circulation employingthe blue field entoptic phenomenon (Harris et al., 1995b)and LDV (Grunwald and Delehanty, 1992) failed todemonstrate any change induced by this drug. Finally,retinal and ciliary perfusion pressures of 10 healthyindividuals were found to significantly decrease with asingle drop of carteolol (Pillunat and Stodrmeister,1988).Steigerwalt et al. (2001) evaluated the effect of topical

timolol 0.5%, betaxolol 0.5% and carteolol 2% on theblood flow velocity of the OA, CRA, and SPCA in 14patients with ocular hypertension. The authors de-scribed statistically significant increases in the CRApeak systolic velocity for all 3 drugs, and a statisticallysignificant increase in the CRA end diastolic velocity fortimolol and carteolol.

5.2.4.3. Studies in glaucoma patients. Altan-Yayciogluet al. (2001) described a statistically significant decreasein the resistance index of the CRA of 10 POAG patientsfollowing the use of carteolol 1% for 1 month.Montanari et al. (2001) reported the results of anunmasked study comparing the influence of timolol andcarteolol on the retrobulbar hemodynamics of 20 POAGpatients. All patients received timolol 0.5% initially,followed by 6 months of therapy with carteolol 2%.Although no statistically significant changes weredetected for IOP measurements, the authors observeda statistically significant decrease in the resistance indexof the SPCA following the use of carteolol (p ¼ 0:017).

5.3. Alpha-agonists

5.3.1. Apraclonidine

Apraclonidine hydrochloride is an amino derivativeof clonidine and a relatively selective a2 agonist with


minimal adverse systemic cardiovascular effects. Apra-clonidine is less lipophilic than clonidine, whichdecreases its penetration through the blood-brainbarrier and reduces the occurrence of CNS-mediatedside effects. Apraclonidine lowers IOP by reducingaqueous humor production up to 35%, without alteringaqueous outflow. The mechanisms involved in thereduction of aqueous humor production are notcompletely understood, although it is felt that part ofits effect may be secondary to vasoconstriction of theciliary body (Torris et al., 1995b). While a2 agonistsreduce IOP, the presence of vasoconstrictor postsynap-tic a2 receptors on vascular smooth muscle raise thepossibility that these drugs may compromise OBF.

5.3.1.1. Experimental studies. In the anterior segment,topical apraclonidine 1% produces constriction of pre-capillary sphincters in the vessels supplying the ciliarybody (Fahrenbach et al., 1989). A study using labeledmicrospheres in monkeys demonstrated reduced bloodflow in the anterior tissues, but unchanged blood flow inthe retina, choroid, and optic nerve (Chandler andDeSantis, 1985). Another experimental study employingthe Langham OBF instrument showed no change inpeak pulse volume of glaucomatous monkey eyestreated with topical apraclonidine 1% (Mittag et al.,1994).


tensive patients. In humans, apraclonidine was found tocause conjunctival vasoconstriction (Robin, 1988;Serdahl et al., 1989) and to lower conjunctival oxygentension by 76% 1h following instillation (Serdahl et al.,1989). The results of studies investigating the influenceof apraclonidine on the retrobulbar circulation areconflicting. In a double-blind, placebo-controlled, cross-over study, Harris et al. (1995a) showed that apraclo-nidine 0.5% was effective in reducing the IOP of 13healthy subjects, but had no effect on retrobulbar bloodflow (as measured with CDI). On the other hand, otherdouble-masked studies (Oruc and Sener, 1999; Celikeret al., 1996) indicated decreased blood flow velocitiesand increased resistivity indices in the OA following theadministration of a single dose of apraclonidine 1% inhealthy individuals, with no detectable change in theCRA.Changes in the retinal circulation of healthy indivi-

duals were not detected following the instillation ofapraclonidine as measured with the blue-field entopticsimulation (Harris et al., 1995a) or laser Dopplerflowmetry (Kim and Dim, 1997). Mittag et al. (1994)and coworkers measured the ocular pulse amplitudefollowing the instillation of apraclonidine 1% in sixocular hypertensive patients, and found a statisticallysignificant decrease only 4 h after dosing compared tothe placebo-treated contralateral eye.

5.3.1.3. Studies in glaucoma patients. In a double-masked, randomized clinical trial, Avunduk et al.(2001) investigated the retrobulbar hemodynamic effectsof topical betaxolol, dorzolamide, and apraclonidine in22 newly diagnosed POAG patients. Patients receivingapraclonidine (n ¼ 8) for 1 month showed a statisticallysignificant decrease in the PSV in the OA (p ¼ 0:012)and had a statistically significant lower EDV in the OAcompared to the other groups (po0:05), suggesting apossible deleterious effect in the retrobulbar circulation.

5.3.2. Brimonidine

Brimonidine is a less lipophilic analog of clonidinethat provides clinically significant lowering of IOP.Brimonidine is a potent a-adrenoceptor agonist that is1000-fold more selective for a2 vs. the a1 adrenoceptor,7–12-fold more a2 selective than clonidine and 23–32-fold more a2 selective than apraclonidine (Torris et al.,1995a). The majority of animal and human studiesdiscussed below suggest a lack of influence of brimoni-dine on retinal, choroidal, or ONH blood flow.

5.3.2.1. Experimental studies. Bhandari et al. (1999)performed a placebo-controlled study in rabbits toinvestigate the influence of brimonidine tartrate 0.2%on the optic nerve blood flow by means of intraluminalmicrovascular corrosion casting technique and intravas-cular injection of colored microspheres. After 4 weeks oftreatment with brimonidine, there was no statisticallysignificant difference in the average constriction ofshort posterior ciliary arterial branches between thetreated and control groups. Similarly, no statisticallysignificant difference was found between the opticnerve blood flow, measured with microspheres in bothgroups.

5.3.2.2. Studies in healthy individuals and ocular

hypertensive patients. Randomized, double-masked,placebo-controlled studies investigating the effects ofbrimonidine on the retinal circulation (as measured withscanning laser Doppler flowmetry and the SLO)(Carlsson et al., 2000; Jonescu-Cuypers et al., 2001)and retrobulbar blood flow (determined with CDI)(Lachkar et al., 1998; Jonescu-Cuypers et al., 2001) ofnormal individuals and ocular hypertensive patientsfailed to demonstrate a statistically significant change inthese vascular beds.

5.3.2.3. Studies in glaucoma patients. An open-labelstudy including 10 POAG patients followed for 6months revealed that brimonidine 0.2% was effectivein reducing IOP and increasing POBF from 9.2% (atday 180) to 22.5% (at day 30) (Vetrugno et al., 2001).However, in a double-masked, randomized, prospectivestudy, Sponsel et al. (2002a) were unable to observe astatistically significant effect of brimonidine on the


POBF of 20 patients with POAG or ocular hypertensiontreated for 4 weeks.In a comparative study that included 72 POAG

patients receiving betaxolol (n ¼ 24), brinzolamide(n ¼ 24), or brimonidine (n ¼ 24), scanning laser Dop-pler flowmetry was employed to measure the ONHblood flow (Sampaolesi et al., 2001). The authorsconcluded that neither drug had the ability to increaseONH blood flow.

5.4. Prostaglandin analogues

5.4.1. Latanoprost

Latanoprost is a lipophilic, esterified pro-drug, whichis inactive until it undergoes enzymatic hydrolysis in thecornea, becoming the biologically active acid oflatanoprost. Latanoprost is a prostaglandin F2a analo-gue that lowers IOP by increasing uveoscleral outflow(Serle et al., 1998). Since many naturally occurringprostaglandins have marked effects on the cardiovas-cular system, it is conceivable that synthetic prostaglan-dins may exert microvascular effects in the eye.

5.4.1.1. Experimental studies. The effects of latanoprost0.005% on regional blood flow in monkey eyes weremeasured with radioactively labeled microspheres.Following the instillation of a single dose containing6 mg/g of latanoprost, no statistically significant changein regional blood flow was observed up to 6 h after theadministration, with the exception of the anterior sclera,in which a moderate increase in blood flow was detected(Stjernschantz et al., 1999). Latanoprost has been shownto cause anterior segment vasodilation in cats, with nochange in blood volume or flow in other ocular tissues(Stjernschantz et al., 2000). Astin et al. (1994) reportedthat the vasodilation observed in the conjunctiva,anterior sclera and anterior uvea of rabbits followingthe instillation of PGF2a was partly mediated by nitricoxide synthase.The laser speckle analyzer was employed to determine

that combined 6-day instillation of timolol and latano-prost had no effect on the retinal blood flow, butsignificantly increased ONH blood flow in monkeys(Ishii and Araie, 2000a). A similar increase wasdescribed following the instillation of latanoprost inrabbits and monkeys (Ishii et al., 2001). However,latanoprost has recently been found to promote a dose-dependent contraction of quiescent porcine ciliaryarteries (maximum: 6873%), and was not able to evokerelaxation of KCl or entothelin-1 precontracted vessels(Brogiolo et al., 2001).


tensive patients. Two double-masked, placebo-con-trolled studies indicated that latanoprost produces anincrease in POBF in normal individuals (Geyer et al.,

2001; Sponsel et al., 2002a, b), a finding that was notconfirmed by a similarly well-designed study (Kubaet al., 2001). Another randomized, double-masked studydemonstrated that latanoprost caused no statisticallysignificant change in retinal, ONH or peripapillary flowas measured with the HRF 24 h after the instillation of asingle dose in 26 healthy volunteers (Seong et al., 1999).On the other hand, other authors (Ishii et al., 2001;Tamaki et al., 2001a) reported an increase in ONHblood velocity (as measured with the laser specklemethod) of normal individuals following a singleinstillation or a 7-day once-daily regimen of latanoprost.Regarding the retrobulbar circulation, latanoprost wasfound to have no effect on CDI parameters of normalindividuals (Tamaki et al., 2001a).

5.4.1.3. Studies in glaucoma patients. There are rela-tively few studies that have evaluated the effect ofprostaglandin analogues on OBF of glaucoma subjects.In a double-masked crossover study, Nicolela et al.(1996a, b) were the first to compare the effects of topicaltimolol and latanoprost on retrobulbar vessel blood flowvelocity in 15 patients with POAG or ocular hyperten-sion using CDI. The only statistically significant changeobserved in retrobulbar blood flow velocity with timololwas a reduction of EDV in the OA 12 h after the firstdose, a change that was not observed 7 days later. Nochange in blood velocity was observed with latanoprost.Overall, topical timolol and latanoprost producedstatistically significant reduction in IOP without creatingsubstantial hemodynamic changes in the retrobulbarvessels.Vetrugno et al. (1998) compared the effect of

latanoprost and timolol on 12 POAG patients (24 eyes)followed for 6 months with the POBF system. Eachpatient had one eye treated with latanoprost 0.005%and the other with timolol 0.05%. In the latanoprost-treated eyes, POBF values increased by as much as55.8% in the first day and then settled at 22.6% at theend of the study. Timolol showed a similar pressureprogress, but its haematic perfusion values weredistinctly lower.McKibbin and Menage (1999) studied the effect of 3–

4 weeks once-daily 0.005% latanoprost on the IOP andPOBF in 32 eyes of 19 NTG patients. The IOP reductioncorrelated with the initial IOP before treatment and wasaccompanied by a statistically significant increase inmedian POBF from 656 to 796 ml/min (po0:001).Georgopoulos et al. (2002) investigated the effect of

topical latanoprost on POBF in 20 POAG and 4 ocularhypertensive subjects in a prospective, open-label study.After 1 week of latanoprost treatment, POBF measure-ments increased statistically significantly by 201.27167.4 ml/min in OD (po0:001) and 203.87187.3 ml/minin OS (po0:001). Ocular pulse amplitude and ocularpulse volume showed statistically significant increases


(po0:05 and po0:001; respectively). Recently, Liu et al.(2002) compared the effect of brimonidine tartrate 0.2%and latanoprost 0.005% on POBF in 25 NTG subjects.In their randomized, investigator masked, crossoverstudy, each patient received 4 weeks each of latanoprost,lubricant, and brimonidine. In this study, latanoprostincreased POBF by 2137257 ml/min (22.8%, po0:001)while brimonidine increased it by 977183 ml/min(10.4%, p ¼ 0:014). Also, POBF increased at 8 am(p ¼ 0:004), 12 noon (p ¼ 0:002), and 4 pm (po0:001)with latanoprost, while it only increased at 8 am(p ¼ 0:016) with brimonidine. After adjusting forchanges in IOP, neither latanoprost nor brimonidineincreased POBF statistically significantly.

5.4.2. Unoprostone isopropyl

Unoprostone isopropyl is a derivative of a prosta-glandin metabolite. It is classified as a docosanoid,contains 22 carbon atoms and a keto group at C-15,whereas latanoprost and primary prostaglandins areclassified as eicosanoids, with 20 carbon atoms and ahydroxyl group at C-15. Unoprostone is hydrolyzedduring its passage through the cornea by esterases,resulting in a free carboxylic acid, which is thepharmacologically active substance. There is not enoughexperimental evidence to conclusively define the wayunoprostone exerts its IOP lowering effect. Someauthors reported an increase in aqueous outflow viathe conventional (trabecular) pathway, whereas othersspeculated that unoprostone might increase outflow viathe uveoscleral or via both uveoscleral and conventionalpathways (Taniguchi et al., 1996; Serle et al., 1998).

5.4.2.1. Experimental studies. Several animal studieshave investigated the effect of unoprostone on OBF.In one experiment employing the hydrogen gas clear-ance flowmeter (Sugiyama and Azuma, 1995), the effectof endothelin-1, applied to the rabbit eye in order tocause vasoconstiction, was significantly reduced 2.5 and3.5 h after the intravitreal injection of 10 ml of unopros-tone 0.06%, with no significant reduction in IOP. In asubsequent study (Sugiyama and Azuma, 1997), thesame authors reported that the endothelin-1-inducedblood flow reduction was inhibited in a dose-dependentmanner following the instillation of 1 drop of unopros-tone 0.03%, 0.06% and 0.012%. However, this studydid not investigate changes in IOP, not elucidatingwhether the observed blood flow effect was secondary toan IOP lowering effect.Similar antiendothelin-1 effects were described by Yu

et al. (2001), who investigated the results of intraluminaland extraluminal administration of unoprostone iso-propyl and its free acid to segments of perfused porcineretinal arterioles. Increasing doses of unoprostone andits free acid (10�10–10�4mM) were shown to inhibit thevasoconstrictive effect of ET-1.


tensive patients. In a placebo-controlled, randomized,double-masked study, endothelin-1 (2.5 ng/kg/min for150min) was administered intravenously to 24 healthyindividuals (Polska et al., 2002). After the instillation of10 drops of unoprostone in 90min, subfoveal andpulsatle choroidal blood flow were measured using laserDoppler flowmetry and laser interferometric assessmentof fundus pulsation amplitude, respectively. The authorsdemonstrated that unoprostone was effective in inhibit-ing the decrease in both choroidal blood flow andpulsation amplitudes induced by endothelin-1.Kojima et al. (1997) utilized the laser speckle method

to examine changes in the ONH and choroid-retinalcirculation of 9 normal human eyes following theinstillation of unoprostone 0.12%. Although no changewas observed in the ONH circulation, there was astatistically significant increase (8–11%) in the choroid-retinal blood flow. Double-masked, placebo-controlledstudies employing the same method in healthy indivi-duals demonstrated that chronic administration ofunoprostone 0.12% was effective in increasing bothONH and choroid-retinal blood flow (Makimoto et al.,2000; Tamaki et al., 2001b).In a small, unmasked study, CDI was used to measure

the retrobulbar blood flow of healthy individuals after asingle dose of unoprostone 0.12% (Nishimura andOkamoto, 1998). The authors reported increased peaksystolic and end diastolic blood flow velocities in theCRA and SPCA with no change in pulsatility indices.On the other hand, Tamaki et al. (2001b) did not reporta statistically significant change in the CRA hemody-namic parameters of normal volunteers following theinstillation of unoprostone 0.12% for 7 days. In adouble-masked, placebo-controlled study, POBF mea-surements were not found to increase statisticallysignificantly after the instillation of unoprostone0.12% in 9 healthy volunteers (Kitaya et al., 1997).

5.4.2.3. Studies in glaucoma patients. Only three studiesevaluated the effects of unoprostone on the OBF ofpatients with glaucoma. An unmasked study in a smallpopulation (n ¼ 14) of NTG patients suggested thatchronic administration of unoprostone 0.12% was noteffective in changing the hemodynamic parameters ofthe entire study population. When a post-hoc analysiswas performed in a subgroup of NTG patients withearly stage disease, the peak systolic velocities of the OAwere found to have significantly increased statistically(Nishimura and Okamoto, 1998).Sponsel et al. (2002a) recently compared the effect on

POBF between topical 0.005% latanoprost (given to oneeye once daily) and 0.15% unoprostone (twice daily inthe contralateral eye) in 25 bilateral open-angle glauco-ma or glaucoma suspect patients. POBF increased 30%relative to baseline in eyes receiving latanoprost


(po0:0001), and 16% in eyes receiving unoprostone(p ¼ 0:05) by the morning of day 28. That afternoon,mean POBF increased 30% (po0:0001) relative toafternoon baseline values among eyes receiving latano-prost and 18% (p ¼ 0:03) among those receivingunoprostone (interdrug change difference, p ¼ 0:05).However, it should be mentioned that there was astatistically greater IOP reduction in those eyes receivinglatanoprost compared to unoprostone, which may haveinfluenced the results.Beano et al. (2001) evaluated unoprostone’s OBF

effect on glaucoma subjects using laser Dopplerflowmetry. In a prospective, randomized, observer-masked, crossover, placebo-controlled trial, they eval-uated 12 vasospastic NTG subjects at baseline and after1 week of treatment. No statistically significant differ-ence was found between unoprostone and placebo withrespect to choroidal or ONH blood flow.

5.5. Carbonic anhydrase inhibitors

CAIs are non-bacteriostatic sulphonamide-derivativeseffective in the control of fluid secretions in variousparts of the body. Many isoenzymes of CA are foundthroughout the body. CA-I, CA-II, and CA-IV areconsidered to be most pertinent to the eye. CA-I andCA-II are present in the corneal endothelium, while onlyCA-II is present in the ciliary process and the retina(Wistrand and Garg, 1979; Dobbs et al., 1979; Hagemanet al., 1991). Studies have consistently shown thatinhibiting CA-II within the eye, in normal andglaucomatous persons, reduces the rate of aqueoushumor secretion and results in a statistically significantIOP reduction (Brubaker, 1989; Becker, 1955; Carprioli,1992; Wang et al., 1991; Yamazaki et al., 1994).Secretion of aqueous humor by non-pigmented

epithelium of the ciliary processes depends on CA-IIfor providing bicarbonate (HCO3

�), utilized by activeATPases to shuttle solutes (i.e. Na+) into the posteriorchamber with water passively following (Wax et al.,1997; Macknight et al., 2000). Blockade of CA-IIreduces aqueous humor production (and IOP) bydecreasing available HCO3

� and the activity of ATPasesin the ciliary body epithelium.

5.5.1. Acetazolamide

Acetazolamide, an orally active systemic CAI, is theprototype CAI and selectively inhibits CA in red bloodcells, glial cells, capillary endothelium, and choroidplexus. In 1954, it was first reported that orallyadministered acetazolamide lowered the IOP of glauco-ma patients (Becker, 1954). Serious side effects (Epsteinand Grant, 1977; Clineschmidt et al., 1998; Hutzelmannet al., 1998) of systemic CAIs, however, have led to thedevelopment of topical CAIs.

Intravenous injections (IV) of acetazolamide havelong been used to estimate cerebral vasoreactivity(Volstrup et al., 1986; Sullivan et al., 1987; Volstrup,1988; Rogg et al., 1989; Kuroda et al., 1993). SystemicCA inhibition also results in altered CO2 clearance andtissue pH levels (Sponsel and Shipman, 1997). Anincrease in tissue PCO2 may promote local controlactivation and an increased Bohr effect, resulting inlocal vasodilation, although many other pathways canlead to cerebral vasodilation. Several investigators haveconfirmed that acetazolamide is capable of increasingcerebral blood flow in a dose-dependent manner (Haugeet al., 1983; Ringelstein et al., 1992), which may, at leastin part, be attributed to extracellular acidification(Severinghaus and Cotev, 1968; Volstrup et al., 1984;Faraci et al., 1987; Volstrup, 1988; Sponsel andShipman, 1997).

5.5.1.1. Experimental studies. In 1993, Chiou and Chenperformed an experimental study in ocular hypertensiverabbits receiving different antiglaucoma medicationsand measured ocular tissue blood flow with the micro-sphere method. Acetazolamide was found to produce astatistically significant increase in retinal and choroidalblood flow.


tensive patients. In 1993, Rassam et al. employed LDVand computerized digital image analysis of monochro-matic fundus photographs to demonstrate that a 500mgIV dose of acetazolamide statistically significantlyincreased retinal blood flow in healthy volunteers. Kertyet al. (1994) demonstrated that IV acetazolamideaffected retrobulbar blood flow velocity, using transcra-nial and transorbital Doppler ultrasonography anddynamic tonometry. The authors showed that 1 g IVacetazolamide resulted in statistically significantly in-creased blood flow velocities through the internalcarotid and middle cerebral arteries, while blood flowvelocity in the OA was significantly decreased in healthypatients. Changes in blood flow velocity in the OA mayhave been induced by an autoregulatory response tomaintain constant OBF. However, this suppositioncannot be answered with velocity measurements alonebut requires concurrent knowledge of vessel diametermeasurements, as used in the previously mentionedstudy by Rassam et al. (1993).Previous publications did not find alterations in the

hemodynamic parameters of the OA or CRA aftertreatment with an oral 1 g dose of acetazolamide alone(Ehrenreich et al., 1961; Harris et al., 1996b), althoughHarris et al. (1996a, b) observed a statistically significantdecrease in the CRA resistance index when CO2 wasused in addition to acetazolamide. Subsequently,another group, studying retrobulbar blood flow ofhealthy volunteers, showed that acetazolamide


improved OA blood flow velocity by as much as 19%(p ¼ 0:003), when measured by CDI (Kiss et al., 1999).It is unclear why these reports showed contradictoryfindings. However, it is significant to note thatKerty et al. (1994) administered acetazolamide intra-venously, while in the latter studies, the drug was givenorally.In 1998, Dallinger et al. were the first to show that

choroidal blood flow was increased in healthy humansby IV acetazolamide. Measured by laser interferometrictechniques, acetazolamide increased fundus pulsationamplitude in a dose-dependent manner. This wassupported by additional evidence, which showed anincrease in blood flow as measured by POBF (Kiss et al.,1999). However, Grunwald and Zinn (1992) were notable to detect a statistically significant change inducedby 500mg acetazolamide in the macular blood flow of20 healthy subjects as measured by the blue-fieldsimulation technique.The latest evidence regarding systemic acetazolamide

and OBF is limited, but in general, supports the drug’sability to increase OBF. Acetazolamide has been shownwith the most recent technology to increase choroidaland retinal blood flow (Rassam et al., 1993; Dallingeret al., 1998; Kiss et al., 1999). Retrobulbar findings aresomewhat controversial, showing decreased, increasedor no change in OA blood flow. However, it isimportant to remember differences in inclusion andexclusion criteria and variations of drug administration(IV versus oral), as well as dosing when evaluating orcomparing studies.

5.5.2. Dorzolamide

Dorzolamide hydrochloride 2% was developed formaximum corneal and scleral penetration to reach thetarget of CA inhibition and reduce aqueous humorformation (Wang et al., 1991; Sugrue et al., 1997;Sugrue, 2000). Dorzolamide has been shown to be awater-soluble potent inhibitor of human CA-II and CA-IV inside the ciliary processes of the eye (Sugrue et al.,1997; Maren et al., 1997). Dorzolamide has an IC50value of 0.18 nM in vitro, while its inhibitory activityagainst human CA isoenzyme I is much weaker (IC50value of 600 nM) (Kobayashi and Naito, 2000). Accu-mulation of the drug in red blood cells is detectable for 8days, then remains unchanged through the normalcourse of treatment for up to a 4 month half-life, andbinds moderately to plasma proteins (Sugrue et al.,1997; Kobayashi and Naito, 2000).It is important to note that the low pH of dorzolamide

(Dobbs et al., 1979; Volstrup, 1988), while possiblycausing discomfort at instillation, may have a role inlowering local pH and thereby increasing OBF. It hasbeen reported that dorzolamide lowers the pH ofaqueous humour more than any other tested glaucomamedication (latanoprost, pilocarpine, and timolol),

requiring 240min before aqueous humour levels reachbaseline pH values (Veselovsky et al., 2001).

5.5.2.1. Experimental studies. In 1999, Tamaki et al.investigated the effect of 1% topical dorzolamide ontissue circulation in the ONH of Dutch rabbits with thelaser speckle tissue circulation analyzer. One eye of eachrabbit received 1% topical dorzolamide twice daily for20 days, and the fellow eye received the vehicle in amasked, randomized manner. At the end of the follow-up period, the authors found no significant change inONH blood flow either in dorzolamide-treated orvehicle-treated eyes.


tensive patients. In a double-masked, randomized,crossover study, 11 healthy volunteers received eitherplacebo or two drops of 2% dorzolamide 2 h prior toCDI examination (Harris et al., 1996a, b). Scanninglaser ophthalmoscopy was used to examine retinal andsuperficial ONH blood linear velocity. Dorzolamide wasnot shown to significantly affect retrobulbar hemody-namic parameters. However, dorzolamide did enhanceretinal blood flow velocity indices and, when associatedwith unchanged retinal arterial and venous diameters,was shown to improve retinal blood flow and toincrease capillary velocity in the superficial vessels ofthe ONH.Subsequently, investigators used POBF technology to

show a statistically significant increase in ocular pulseamplitude (OPA) after dorzolamide treatment in a seriesof randomized, prospective, masked clinical trialsincluding healthy individuals and glaucoma patients(Schmidt et al., 1997, 1998). Since POBF is an indirectmeasurement of generalized OBF volume, it is assumedthat OPA is largely influenced by choroidal hemody-namics (85% of OBF volume). Although POBFtechnology is an indirect measurement and its reprodu-cibility is highly debated (Vogel et al., 2001), this was thefirst study to suggest that dorzolamide directly affectedchoroidal blood flowIn 1999, Pillunat et al. (1999) studied the effects of

topical dorzolamide on the ONH blood flow of healthysubjects in a double-masked, randomized clinical trial.Dorzolamide was applied to both eyes of 15 healthysubjects TID for 3 days, while placebo was given to 15healthy volunteers under the same protocol. LaserDoppler flowmetry and scanning laser Doppler flow-metry were unable to detect any significant change inONH blood flow during either dorzolamide or placebotherapy.The effects of dorzolamide on the retinal circulation

of 20 healthy subjects were investigated in 1997, using adouble-masked randomized study design (Grunwaldet al., 1997). Main temporal retinal vein blood flowparameters were measured with bi-directional LDV


and monochromatic fundus photography 2 h afteradministration of 1 drop of 2% dorzolamide in oneeye and placebo in the other eye. Although dorzolamidewas found to change vessel diameter, maximumerythrocyte velocity, and volumetric blood flow rate,none of these changes proved to be statisticallysignificant when comparison to baseline.

5.5.2.3. Studies in glaucoma patients. Harris et al. stu-died the OBF effects of dorzolamide on glaucomapatients in 1999 (Harris et al., 1999b). Eighteen patientswith NTG, after medication washout, were treatedfor 4 weeks with 2% topical dorzolamide TID,while a control group of 11 NTG patients receivedplacebo treatment. Measurements were taken atbaseline and after 2 and 4 weeks of treatment. RetinalAVP time and retinal arterial/venous diameterswere measured with SLO, while blood flow velocitiesin the OA, CRA, and SPCAs were measured withCDI. When compared to baseline measurements,dorzolamide was found to significantly accelerateretinal AVP time at 2 and 4-week post-drug measure-ments, while leaving the major retinal arterial andvenous diameters unchanged. Additionally, in agree-ment with previous results (Harris et al., 1996a, b),blood flow velocity measurements in the retrobulbarvessels were not significantly altered by dorzolamidetreatment.Martinez et al. (1999) also measured dorzolamide’s

effect on the OA, CRA and central retinal vein (CRV),using CDI. Twenty-six eyes of 26 patients withdocumented POAG and 13 normal eyes of 8 age-matched controls were studied. Study populations werefurther divided into patients with initial and advancedPOAG (based on visual field defects) and healthyvolunteers. Measurements were taken at baseline and2 h after administration of 2 drops of dorzolamide 2%.In the OA, dorzolamide was found to significantlyimprove the EDV and resistance index without changingthe PSV, in both healthy and glaucomatous eyes. In theCRA, dorzolamide significantly increased the PSV inglaucoma patients but did not affect the same measure-ment in healthy controls. The effect of the drug byimproving the EDV and the resistance index in the CRAwas similar in both glaucomatous patients and healthycontrols.Harris et al. (2000) compared the effects on OBF of

dorzolamide and betaxolol. Because betaxolol anddorzolamide have similar IOP-lowering effects, changesin OBF would be independent from IOP. Nine patientswith NTG were randomly assigned to either 1 drop of2% dorzolamide TID or 0.5% betaxolol BID (open-label) in the right eye, after a 3-week washout of all eyemedications. Using CDI and SLO technologies, dorzo-lamide was found to have no effect on flow velocities ineither the CRA or OA, but significantly accelerated

inferotemporal retinal AVP time, whereas betaxolol didnot affect any of the retrobulbar vessels or retinal AVPtime.In a retrospective, open clinical trial, dorzolamide eye

drops were administered to 28 POAG patients in botheyes, 3 times daily for a mean follow up of 9 months. Indorzolamide-treated patients, the IOP dropped from 18to 15.5mmHg after 9 months therapy (po0:01) and astatistically significant increase was found for POBFmeasurements from 543 to 675 ml/min (po0:05) (Berndet al., 2001).In 2001, Avunduk et al. compared the effects of 0.5%

betaxolol BID, 2% dorzolamide TID, and 1% apraclo-nidine TID on OBF. In a double-masked, prospective,randomized trial, 22 patients with newly diagnosedPOAG who had never previously used eye medicationswere randomly assigned to one of the three treatmentgroups, and CDI measurements were taken at baselineand after 15 and 30 days of treatment. In thedorzolamide group, the resistance index in the SPCAwas significantly lower on days 15 and 30, compared topretreatment measurements. In addition, resistanceindex values on day 30 were significantly lower thanthose of day 15. Dorzolamide did not have anystatistically significant effect on either the OA orCRA. In comparison to the apraclonidine or betaxololgroups, peak systolic velocities in the OA weresignificantly higher in patients receiving dorzolamidetreatment; a similar comparison between betaxolol andapraclonidine did not show any statistically significantdifference.Galassi et al. (2002) investigated the effect of

dorzolamide and timolol on retrobulbar hemodynamicsusing CDI. Twenty POAG patients (20 eyes) randomlyselected who had not received previous glaucomatreatment were studied at baseline and after 4 weeks ofeither 0.5% timolol BID or 2% dorzolamide TID.Measurements were taken 20 h after the last dose wasgiven. Statistical analysis suggested that timolol didnot induce significant changes in retrobulbar hemody-namics in this study. In the same patients, dorzolamidetreatment did not modify blood flow parametersin the OA and CRA; however, temporal SPCAsshowed a statistically significant decrease in the RI(po0:05).In a double-masked, randomized, prospective trial, no

correlation between dorzolamide and OBF was found ina group of 47 previously untreated POAG patients(Bergstrand et al., 2002). Using CDI and fluoresceinSLO, none of the flow parameters, retrobulbar orretinal, changed significantly with dorzolamide therapy.Multi-variable statistical analysis and non-simultaneoustests failed to reveal any statistically significant changesin the CRA, OA, SPCAs or retinal blood flowparameters (AVP time, mean dye velocity or macularcapillary velocity).


5.5.3. Brinzolamide

Brinzolamide 1% is another topical CAI administeredto patients with ocular hypertension or open-angleglaucoma. Following topical ocular administration,brinzolamide is absorbed into the systemic circulation.Due to its affinity for CA-II, brinzolamide distributesextensively into the red blood cells and exhibits a longhalf-life in whole blood (approximately 111 days). Inhumans, the metabolite N-desethyl brinzolamide isformed, which also binds to CA and accumulates inred blood cells.

5.5.3.1. Experimental studies. Barnes et al. comparedthe effects of brinzolamide 2%, dorzolamide 2%, andplacebo on microvascular ONH blood flow in Dutchrabbits (Barnes et al., 2000). Using a three-way cross-over study design, microvascular ONH blood flow wasmeasured by LDF before treatment and after drug-freewashout periods of 7–14 days. One drop of brinzola-mide, dorzolamide, or placebo was administered twicedaily (9 am and 5 pm) in the right eye only, for 7 days.Experimental measurements were made 90min after the9 am topical dose was administered on day 8. ONHblood flow was significantly increased in topical-CAI-treated rabbits, as compared to placebo-treated con-trols. The changes in ONH blood flow and IOP were notsignificantly different between the CAI groups (brinzo-lamide vs. dorzolamide). Based on these results, it wasconcluded that topical ocular CAI treatment for 1 weekwith either brinzolamide or dorzolamide significantlyreduced IOP and significantly increased ONH bloodflow in tranquilized Dutch-belted rabbits.

5.5.3.2. Studies in glaucoma patients. In 2001, Sampao-lesi et al. studied the OBF effects of betaxolol,brinzolamide and brimonidine on 72 glaucomatousONHs and retinal vasculatures in humans. Patientswere examined with scanning laser Doppler flowmetry(638 nm wavelength), and flow, volume, and velocityindices were assessed in each report. Perfusion mapswere analyzed with the new scanning laser Dopplerflowmeter software, version 3.2 (automatic full fieldperfusion image analyzer). None of the drugs was shownto produce a statistically significant effect on ONHcapillary blood flow.

5.5.4. Timolol and dorzolamide fixed combination

Dorzolamide hydrochloride and timolol maleate werecombined in one ophthalmic solution for the treatmentof patients with ocular hypertension (OHT) or open-angle glaucoma (OAG). The drug consists of twocomponents that decrease aqueous production.Both dorzolamide and timolol are systemically

absorbed following topical application, although plasmalevels of either agent are not always detectable.Significant accumulation of dorzolamide occurs in

erythrocytes, with slow release (half-life=4 months).Absorbed dorzolamide and timolol undergo hepaticmetabolism; both agents are excreted renally.

5.5.4.1. Experimental studies. In 2002, Sherbini et al.(2002) compared the vasoactive effects of latanoprostand the fixed combination of timolol and dorzolamide inisolated quiescent porcine ciliary arteries. Dilutedpreparations of latanoprost induced a statisticallysignificant, however small (3.271.0%) contraction incomparison to the fixed combination (�0.670.2%).

5.5.4.2. Studies in glaucoma patients. In 1999, 14 OAGpatients were run in for 4 weeks on timolol and thentreated for 4 weeks with timolol and dorzolamidecombination. The fixed combination was shown tosignificantly increase the ocular pulse amplitude asmeasured with POBF. Since POBF is assumed to bemostly a measure of chorodial blood flow, the resultssuggest a positive effect on increasing choroidal circula-tion during this treatment (Schmidt et al., 1999).Harris et al. (2001a) investigated 15 patients with

POAG, after 1 month on timolol or dorzolamide-timolol treatment. Patients were first placed on amedication-dependent 1-week to 4-week washout, thenbaseline measurements were taken. The fixed combina-tion significantly reduced IOP and decreased AVP timein the superior temporal artery (2.13 to 1.76 s, p ¼ 0:01),while having no statistically significant effects on visualfunction. Thus, timolol in combination with dorzola-mide did not alter the latter’s drug effect on increasingretinal blood flow. Conversely, the fixed combinationwas not shown to alter OBF in the retrobulbarvasculature or choroidal blood flow, as measured byCDI and SLO ICG angiography, respectively.

6. The effects of systemic medications on ocular blood

flow

The effects of systemic medications with vasoactiveproperties on OBF have also been evaluated, especiallywith regard to calcium channel blockers. There are othersubstances that could theoretically improve OBF andhave also been included in the list of potentially usefuldrugs in the treatment of glaucoma.

6.1. Calcium channel blockers

Calcium, which may influence a variety of cellularfunctions, enters excitable cells through voltage-gatedcalcium channels. There are six classes of calciumchannels: L, T, N, P, Q, and R. Among them, theL-type is the predominant calcium channel in skeletal,cardiac, and vascular smooth muscle (Piepho, 1983;Varadi et al., 1995; Kanellopoulos et al., 1996).


Drugs that decrease intracellular calcium levels byinhibiting calcium entry into the cells are called calciumchannel blockers (CCBs). These agents lead to smoothmuscle cell relaxation and cerebral, coronary, andperipheral vasodilation (Braunwald, 1982; Bussey andTalbert, 1984). In 1985, the World Health Organizationclassified CCBs in 6 groups according to their clinicaland pharmacological properties (Vanhoutte andPaoletti, 1987). Type I are verapamil-like drugs, typeII are nifedipine-like drugs, type III are diltiazem-likedrugs, type IV are flunarizine-like drugs, type V areprenylamine-like drugs, and type VI are all other CCBs(e.g., perhexiline, caroverine). CCBs types I, II, and IIIare used in the treatment of several conditions, includingessential hypertension, vasospastic and chronic stableangina pectoris, Raynaud syndrome, migraine, asthma,and supraventricular tachyarrhythmias (Braunwald,1982; Bussey and Talbert, 1984).Due to their vasodilatory properties, the potential role

of CCBs in the management of glaucoma has beeninvestigated. Several studies, most of them retrospective,have suggested that CCBs may be successful incontrolling visual field progression in patients withNTG (Flammer and Guthauser, 1987; Kitazawa et al.,1989; Netland et al., 1993; Gaspar et al., 1994; Sawadaet al., 1996; Daugeliene et al., 1999). Others havedemonstrated that systemic and topical CCBs maylower IOP both experimentally and in humans (Segarraet al., 1993; Netland et al., 1996; Abelson et al., 1988;Siegner et al., 2000). However, as mentioned before, theanalysis of such studies are beyond the scope of thisreview.

6.1.1. Experimental studies

In 1995, Meyer et al. investigated the effects of twoCCBs (lacidipine and nifedipine) on isolated porcineciliary arteries, and found that both reduced thecontractions and decreased the sensitivity to endothe-lin-1. However, vasodilation mediated by bradykininand sodium nitroprusside were unaffected by thesedrugs. Experiments by Nyborg et al. (1991) and Langet al. (1997) also showed inhibitory effects of nitrendi-pine, amlodipine, and lomerizine on endothelin-1-induced contractions in bovine retinal arteries andporcine ciliary arteries, respectively. Similarly, nitrendi-pine and D600, a verapamil analogue, have been foundto cause relaxation of prostaglandin-induced constric-tion of isolated calf retinal vessels (Nielson and Nyborg,1989), whereas diltiazem and verapamil promotedrelaxation of cat ophthalmociliary artery ring segmentsin vitro (Yu et al., 1992).Low doses of intravenous nicardipine (20 mg/kg) have

been shown to have little effect on the cat retinal bloodflow, whereas a high dose (100 mg/kg) produced astatistically significant transient decrease in retinal bloodflow as measured by LDV. By contrast, both doses

resulted in a significant increase in ONH blood flowmeasured with laser Doppler flowmetry, which werefollowed by a statistically significant increase in thevitreous PO2 just in front of the ONH (Harino et al.,1992). Lomerizine, nilvadipine, and pranidipine werefound to inhibit the endothelin-1-induced perturbationsof the ONH circulation of rabbits measured with thehydrogen clearance method and laser Doppler flowme-try, however, the last two drugs also resulted instatistically significant blood pressure reductions (Toriuet al., 2001). Intravenous doses of 0.01 and 0.1mg/kgnicardipine promoted an average dilation of rabbitretinal vessels of 3% and 22%, respectively (Kohzuka,1984).Tomita et al. (1999a) studied the effects of nilvadipine

(3.2 mg/kg IV) on the ONH, choroid, and retina ofrabbits using the laser speckle and the hydrogen gasclearance methods. The normalized blur measured inthese tissues increased by 10–25% in the nilvadipinegroup compared to the control group (po0:0001).Blood flow rate in the ONH determined by the hydrogengas clearance method also showed a 25% increase in thenilvadipine group (Tomita et al., 1999a).

6.1.2. Studies in healthy individuals and ocular

hypertensive patients

CDI was employed to evaluate the orbital hemody-namic effects of 10mg nifedipine (sublingual) in 12healthy volunteers. The authors observed statisticallysignificant increases in the peak systolic velocities of theOA and SPCA (Gobel and Lieb, 1995). Topicalverapamil was found to promote a statistically signifi-cant reduction of the RI of the CRA in normal humansubjects undergoing CDI examination (Netland et al.,1995).In a double-blind, randomized, crossover study,

Schocket et al. (1999) employed laser Doppler flowmetryand LDV to investigate the retinal, choroidal, and ONHblood flow of 10 normal individuals who received oralfelodipine. Despite statistically significant decreases indiastolic blood pressure and perfusion pressure, nostatistically significant change in retinal, choroidal, orONH blood flow were observed following the adminis-tration of felodipine.A randomized, double-blind study was performed by

Strenn et al. (1998), who evaluated the effects ofnifedipine 5mg on the ocular hemodynamics of 12healthy subjects as assessed by laser interferometricmeasurements of the fundus pulsation amplitude andlaser Doppler flowmetry of the ONH. Although nostatistically significant changes were detected followingthe administration of nifedipine in baseline conditions,the drug was able to reverse the endothelin-1-induced(2 ng/kg/min) constriction in ocular vasculature.The effects of topical verapamil on the ONH blood

flow of 12 healthy subjects were evaluated using the laser


Doppler technique in a randomized, double-maskedstudy. The authors reported statistically significantincreases in ONH blood flow in both verapamil 0.25%and fellow placebo-treated eyes, and attributed thisfinding to a possible crossover effect (Netland et al.,1996).

6.1.3. Studies in glaucoma patients

Several authors reported on the effects of CCBs onthe retrobulbar blood flow of glaucoma patients, but allstudies were non-randomized and unmasked. Harriset al. (1997) investigated 21 patients with NTG beforeand after 6 months treatment with nifedipine (30mg/day). Among the 16 patients who finished the studyprotocol, there was no statistically significant change inretrobulbar hemodynamics after treatment. In a post-hoc analysis of a subgroup of patients who respondedwith an increase in contrast sensitivity (n ¼ 8), statisti-cally significant increases of peak systolic and enddiastolic velocities in the OA were detected. Wilson et al.(1997) confirmed that nifedipine (30mg/day for 6 weeks)was not associated with changes in retrobulbar bloodflow of 18 patients with OAG, but identified aremarkable variability in patients’ response to nifedi-pine. Similar negative results, had been previously,reported by Geyer et al. (1996), who employed CDI toinvestigate 11 patients with NTG receiving nifedipine30mg/day for 3 weeks.On the other hand, studies published by Japanese

investigators (Yamamoto et al., 1998; Tomita et al.,1999a, b; Niwa et al., 2000) determined a positive effectof nilvadipine on OBF. In all studies, statisticallysignificant decreases in the RI of the CRA and SPCAswere measured following treatment with nilvadipine2mg/day for 2–4 weeks in patients with NTG. Oraladministration of flunarizine was also found to increasepeak systolic velocities and decrease the RI of the OAand SPCA in 20 patients with NTG (Cellini et al., 1997).The only double-masked study investigating the effect ofa CCB in a glaucoma population was performed byTomita et al. (1999a), who employed the laser speckletechnique to measure the ONH blood flow followingthe administration of oral nilvadipine (4mg/day) for12 weeks. The authors observed a statisticallysignificant increase in the normalized blur in theONH of nilvadipine-treated patients compared to theplacebo-treated patients throughout the follow-upperiod.Schmidt et al. (1996) performed POBF measurements

in 32 NTG patients, and described two differentpatterns of response to nifedipine. According to thisstudy, only those patients with a vasospastic responseshowed a statistically significant increase in ocular pulseamplitude after 3 months of nifedipine treatment.Rainer et al. (2001) measured the ocular funduspulsation amplitude of 30 patients with open angle

glaucoma who received nifedipine 30mg/day for 3months. Among the 25 patients who tolerated themedication, there was no statistically significant changein ocular fundus pulsation amplitude. In a double-masked, placebo-controlled, crossover, short-term study,Piltz et al. (1998) failed to demonstrate any effect of60mg nimodipine on the macular blood flow of 13NTG patients as measured by the blue field entopticsimulator.It is important to emphasize that the chronic use of

CCBs may be associated with intolerable side effects(Wilson et al., 1997; Harris et al., 1997; Rainer et al.,2001). In one study (Wilson et al., 1997), 2 out of 18patients could not tolerate nifedipine 30mg/day,whereas in another report (Harris et al., 1997), 3 outof 21 patients experienced intolerable side effects,and two additional patients showed a significantreduction in visual function and had to discontinuethe medication.

6.2. Inhibitors of the renin-angiotensin system

The circulating renin angiotensin system plays animportant role in the regulation of systemic bloodpressure, and may also modify organ-specifc blood flow(Luscher and Vanhoutte, 1990). Renin is the enzymethat transforms angiotensinogen in angiotensin I, whichis biologically inactive. Angiotensinogen mRNA hasbeen detected in the choroid and retina of rats (Murataet al., 1997). In humans, angiotensinogen has beenidentified in the cytoplasm of the non-pigmented ciliaryepithelium, as well as in the blood vessels lumina of theuvea and retina (Sramek et al., 1992). Angiotensin I isactivated into angiotensin II by the angiotensin con-verting enzyme (ACE), whose activity has been demon-strated in the human, feline, and bovine retinalvasculature (Ferrari-Dileo et al., 1988). Angiotensin IIis a potent vasoconstrictor, and has been shown to causecontractile effects in human, bovine, and porcine ciliaryarteries (Nyborg and Nielsen, 1990; Meyer et al.,1995a, b), possibly through the activation of AT1receptors (Meyer et al., 1995a). Furthermore, there arespecific binding sites to angiotensin II in ONH vessels(Ferrari-Dileo et al., 1991). ACE also inactivatesbradykinin, a substance released from endothelial cellsthat stimulates the formation of prostacyclin and nitricoxide, two potent vasodilators (Mombouli et al., 1992).Experimental studies in cats have demonstrated that thevasoconstrictor properties of the renin angiotensinsystem reduced the ability of the ONH vasculature toautoregulate when challenged by an IOP increase (Sossiand Anderson, 1983).Inhibition of the renin angiotensin system can be

accomplished with ACE inhibitors, which have beensuccessfully employed in the treatment of patients withhypertension and congestive heart failure (Consensus


Trial Study Group, 1987). Several reports suggest thatACE inhibitors are ocular hypotensive agents in rabbitsand humans, an effect secondary to an increase inoutflow facility (Constad et al., 1988; Costagliola et al.,1995; Shah et al., 2000). Meyer et al. (1995b) investi-gated the effect of ACE inhibitors enalaprilat andbenazepril on isolated porcine ciliary arteries and onperfused porcine eyes. The authors reported that neitheragent modified the vascular tone or ophthalmic flow inbaseline conditions. However, both substances en-hanced the relaxation of ciliary arteries to bradykinin,and prevented the vasoconstrictive effects of angiotensinI. Steigerwalt et al. (1998) evaluated the effect oftrandolapril, an oral ACE inhibitor, on the retrobulbarblood flow of 12 non-glaucomatous patients withsystemic hypertension who received the drug for 1week, and described a statistically significant increase inCRA and SPCA blood flow velocities.Another way to inhibit the renin angiotensin system is

by employing AT1-receptor antagonists, such as valsar-tan or losartan potassium. Similarly to ACE inhibitors,losartan potassium has been found to have an IOP-lowering effect associated with an increase in outflowfacility (Costagliola et al., 2000). Valsartan (10�9 to10�5M) blocked the vasocontricion induced by angio-tensin II in isolated porcine ciliary arteries (Meyer et al.,1995a, b). In a placebo-controlled, randomized, double-masked study, Matulla et al. (1997) investigated theeffect of losartan 100mg on the retrobulbar blood flowand pulsatile choroidal blood flow of 10 healthysubjects. Although losartan significantly increased pul-satile choroidal blood flow, retrobulbar blood flow wasnot affected. However, the drug was successful inpreventing the hemodynamic changes induced by theadministration of angiotensin II to these individuals.The authors suggested that angiotensin II is not amajor determinant of OBF in vivo. Similar findingswere reported by Spicher et al. (2002), who were notable to detect a significant change in choroidal laserDoppler flowmetry parameters following a singleoral 50mg dose of losartan potassium to 12healthy subjects.

6.3. Ginkgo biloba

The ginkgo tree, also known as the maiden-hair orkew tree, is the last survivor of the Ginkgoaceae family.The ginkgo tree may be the longest living extant tree,and its fossils have been dated back as far as 250 millionyears (Deng, 1988). The ginkgo tree, which is indigenousto Korea, China, and Japan, may grow to 40m in heightand may live for more than 1000 years.Ginkgo biloba extract (GBE) is a concentrate

obtained from dried or fresh leaves in an acetone-watersolution. It contains over 60 known bioactive sub-stances, including 24% flavonoids, 6% terpenes, 7%

proanthocyanidines, and other uncharacterized com-pounds (De Feudis, 1991). A typical daily dose is 120mgGBE in two or three oral doses. Today, ginkgo isprobably the most widely used herbal treatment toaugment cognitive function, especially in Europe(Ritch, 2000; Gold et al., 2002). A recent review of theliterature suggested that ‘‘clear evidence for or againstthe possibility that ginkgo enhances learning andmemory is not available at this time’’ (Gold et al.,2002). For this reason, the United States NationalInstitute on Aging is currently supporting a clinical trialto investigate the efficacy of ginkgo in treatingAlzheimer’s disease.The use of GBE in the treatment of glaucoma has

been suggested due to several potential biologicalactions, including reduction of serum viscosity, antiox-idant activity, platelet activating factor inhibitoryactivity, inhibition of apoptosis, and inhibition ofexcitotoxicity (Ritch, 2000; Rhee et al., 2001). Further-more, GBE has been found to improve both peripheraland cerebral blood flow, an effect which has beenattributed to the non-flavone fraction (Chang andChang, 1997).However, there is very little information on the

influence of GBE therapy on OBF. In fact, the onlyavailable study was published by Chung et al. (1999a, b)who performed a crossover trial, in 11 healthyvolunteers. The individuals were treated with 120mgGBE or placebo for 2 days, with a 2-week washoutperiod between treatments. GBE significantly increasedEDV in the OA, with no change seen in the placebo-treated arm. There were no experimental studies orstudies in glaucoma patients investigating the effects ofGBE on OBF.

6.4. Magnesium

Although magnesium is the least abundant serumelectrolyte, it influences the metabolism of Ca, K, P, Zn,Fe, Na, acetylcholine, and nitric oxide, modulates theaction of several enzymes, and helps promoting in-tracellular homeostasis and the activation of thiamine(Johnson, 2001).Magnesium, known as ‘‘nature’s physiological cal-

cium blocker’’ (Iseri and French, 1984), has been shownto lower baseline vascular tension, and decrease reactionto vasoconstrictors (Altura and Altura, 1981; Faragoet al., 1991; Torregrosa et al., 1994; Kumasaka et al.,1996). These effects have been attributed to a calcium-antagonist like mechanism (Kumasaka et al., 1996),possibly through the inhibition of calcium influx acrossthe vascular smooth muscle cell membranes. Magnesiumhas been prescribed for a variety of conditions, includingvascular disorders (Mroczeck et al., 1977), arrhythmiasdue to acute myocardial infarction (Schechter, 1991),and migraine (Mauskop et al., 1995).


Very little is known about the effects of magnesiumon OBF. In an experiment employing isolated porcineciliary arteries, high concentrations of extracellularmagnesium were found to evoke dose-dependent relaxa-tions of endothelin-1 precontracted vessels, possiblythrough a calcium-antagonist effect (Dettmann et al.,1998). The range of normal plasmatic concentrations ofmagnesium varies between 0.7 and 1.1mmol/l. Atphysiological magnesium concentrations (1.0mmol/l),the authors observed a 50% relaxation in precontractedvessels, but the complete inhibition of endothelin-1-induced contractions were obtained with very highconcentrations (10.0mmol/l), sufficient to provokecardiac arrest.The only study investigating the use of magnesium in

humans was performed by Gaspar et al. (1995), whoreported a statistically significant improvement inperipheral blood flow (measured with video-nailfold-capillaroscopy), as well as a tendency to improve visualfield scores in 10 glaucoma patients receiving 121.5mgbid for 1 month. There are no prospective, placebo-controlled studies evaluating the effect of magnesium onthe OBF of glaucoma patients.

6.5. Dipyridamole

Dipyridamole is a pyrimidopyrimidine derivativethat prevents the development of platelet clots byinhibiting the uptake of adenosine into the cells,and by inhibiting cyclic AMP phosphodiesterase(Klabunde, 1983; Fitzgerald, 1987). Dipyridamole isknown to produce vasodilation of coronary andpulmonary arteries (Alonso and O’Brian, 1967; Win-burry et al., 1971), and to reduce endothelin-provokedvasoconstriction. Its vasodilatory effect is dependent onthe endothelial cell layer, and is blocked by the presenceof L-NAME (nitro-L-arginine methyl ester) and indo-methacine (Meyer et al., 1995a, b).In 1988, Braunagel et al. employed radio labeled

microspheres and laser Doppler to measure the OBFfollowing intravitreal injection of two adenosine uptakeinhibitors: papaverine and dipyridamole. The authorswere able to observe a statistically significant increase inblood flow in all ocular tissues, including iris, ciliarybody, retina, and choroid. The effect of dipyridamole onisolated porcine ciliary arteries, was investigated byMeyer et al. (1995) who reported a vasodilatory effect,probably mediated by endothelial nitric oxide andprostacyclin. Kaiser et al. (1996) employed CDI tomeasure the retrobulbar blood flow velocities in aprospective open trial including a heterogeneous groupof 23 patients with AION, vasospastic syndrome,glaucoma, or central retinal vein occlusion, andobserved a statistically significant increase in meansystolic and diastolic blood velocities in the OA, CRA,and SPCAs.

7. Perspectives and conclusions

The results of this review suggest that there are veryfew well-designed studies investigating the long-termeffects of antiglaucoma or systemic medications on theOBF of glaucomatous patients. Among the 136 articlesdealing with the effect of antiglaucoma drugs on OBF,only 36 (26.5%) investigated the effects of medicationson glaucomatous patients. Among these 36 articles, only3 (8.3%) were long-term studies (duration of at least 3months), and only 16 (44.4%) were double-masked,randomized, prospective trials. Among the 33 articlesdescribing the effects of systemic medications on OBF,only 11 (33.3%) investigated glaucoma patients, ofwhich only one (9.1%) was a double-masked, rando-mized, prospective trial.Based on this preliminary data, we suggest that few

antiglaucoma medications have the potential to directlyimprove OBF. Unoprostone appears to have a repro-ducible anti-ET-1 effect, betaxolol may exert a Ca2+-channel blocker activity, apraclonidine consistentlyleads to anterior segment vasoconstriction, and CAIsseem to accelerate the retinal circulation. Regarding thesystemic drugs, CCBs apparently do not evoke auniform response in glaucoma patients. Some show animprovement of OBF, whereas others either do notshow a change or develop deteriorations of hemody-namic parameters and visual function. Until it ispossible to reliably discriminate between those patientswho would benefit from the long-term treatment withCCBs and those who might be harmed by the side effectsof the medication, it seems reasonable to use them withcaution. The use of other vasoactive substances in thetreatment of glaucoma is not supported by the evidencewe have.Before we conclude that modulating OBF is beneficial

for glaucoma patients, it is important to recognize thatseveral steps need to be taken. Initially, the technologiesemployed to analyze OBF need to overcome somelimitations, allowing a more reproducible and reliableway of measuring blood flow in vivo. Secondly, we needto design experimental studies to assess the realparticipation of blood flow changes in the developmentof glaucoma. Finally, we still do not have longitudinal,prospective, randomized trials demonstrating that theuse of vasoactive substances with no effect on IOP iscapable of improving the control of glaucoma. Thesestudies need to be done, but to test the efficacy of a givensubstance in a population with a chronic, slowlyprogressive disease, may require at least 3–5 yearsbefore the results become available. However, we needthe results of such studies in order to base our clinicaldecisions on scientifically proven information and noton indirect evidence. On the other hand, we haveextensive literature suggesting the participation of bloodflow in the pathogenesis of glaucoma. Excluding the


possibility of modulating blood flow as a way to treatglaucoma is as inadequate as claiming it to be anundisputed truth.In summary, we believe that reducing the IOP is not

the only way to treat glaucoma. In the future, we willprobably be able to treat glaucoma not only by reducingIOP, but also employing other strategies that will beadditive or synergistic to IOP control. Coming back tothe definition of glaucoma, it is easy to realize that itincludes the outcomes of the disease, with no mechan-istic information. What we today call POAG is possiblyconstituted by a myriad of diseases, each one with asingular genetic background and a unique pathogenesis.Improving our knowledge about the pathogenesis ofthese diseases is essential to further the development ofnew treatment modalities, which may include OBFmodulation, neuroprotection, neuroregeneration, genetherapy, or others.

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The effects of antiglaucoma and systemic medications on ocular blood flow

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