With the advent of several new topically active medications for glaucoma therapy, intraocular pressure (IOP) can be reduced to target levels in more patients before resorting to surgery. Some of these newer agents have a number of advantages over some of the older medications, several of which are seldom used now. The topically active carbonic anhydrase inhibitors are better tolerated than oral formulations, which are infrequently used despite their greater efficacy compared with the topical formulations. The α 2 -adrenergic agonists effectively reduce IOP with few systemic adverse effects. The prostaglandin analogues are even more effective and well tolerated when applied once daily without known systemic adverse effects. The variety of glaucoma medications forces the physician to be selective with various combinations before proceeding with surgery. This article critically reviews the literature pertaining to the newer glaucoma medications, thereby providing guidelines to make rational choices from among the available options.

Purpose.: The individual parameters of aqueous humor dynamics may influence each other to maintain intraocular pressure (IOP) homeostasis. Central corneal thickness (CCT) is known to be associated with onset and progression of glaucoma and can potentially influence the individual parameters of aqueous humor dynamics that maintain IOP. This study investigates the correlation between parameters of aqueous humor dynamics and the influence of CCT in healthy volunteers and compares it with the correlations seen in patients with ocular hypertension. Methods.: Aqueous humor dynamics (aqueous flow, outflow facility, and uveoscleral outflow), IOP, and pachymetry data from 94 healthy ocular normotensive (ONT) volunteers and 63 ocular hypertensive (OHT) patients was analyzed retrospectively. Linear correlations between individual aqueous humor dynamics parameters and pachymetry were evaluated using scatter plots and the Spearman correlation coefficient where appropriate. Results.: In both groups, a significant (P < 0.05) negative correlation was found between corneal thickness and aqueous flow (ONT, R 2 = 0.14; OHT, R 2 = 0.10) and between corneal thickness and uveoscleral outflow (ONT and OHT, R 2 = 0.10). A significant (P < 0.05) positive correlation was found between aqueous flow and outflow facility (ONT, R 2 = 0.24; OHT, R 2 = 0.10). In healthy controls, but not OHT patients, a significant (P < 0.001) positive correlation was found between aqueous flow and uveoscleral outflow (R 2 = 0.15). Conclusions.: Thicker corneas may be associated with lower aqueous production and lower uveoscleral outflow. The interplay between parameters of aqueous humor dynamics suggests possible autoregulatory mechanisms in the eye. OHT may differ from ONT subjects in their inability to increase the uveoscleral outflow with increases in aqueous inflow.

Objectives: To investigate the daytime vs nighttime differences in intraocular pressure (IOP), aqueous humor dynamics, central cornea thickness, and blood pressure among a cohort of healthy volunteers.Methods: Thirty healthy volunteers (mean [SD] age, 57.0 [8.6] years) were enrolled in the study. Individuals underwent 1 daytime visit and 1 nighttime visit for the measurement of aqueous humor dynamics. Measurements included IOP by pneumatonometry, aqueous flow by fluorophotometry, outflow facility by fluorophotometry and tonography, uveoscleral outflow by mathematical calculation, central cornea thickness by pachymetry, and blood pressure by sphygmomanometry.Results between visits were compared by appropriate t test. Dependence of the pneumatonometer probe results on position was tested in enucleated rabbit eyes at set pressures and probe positions. Results: Compared with daytime seated IOP, nighttime seated IOP was reduced by 16%, whereas nighttime supine IOP was increased by 17% (P <.001 for both). The IOP changes were independent of the pneumatonometer probe position. Central cornea thickness was increased at nighttime from a mean (SD) of 560 (37) mu m to amean (SD) of 574 (37) mu m(P <.001). Compared with daytime aqueous flow, nighttime aqueous flow was reduced by 49% (P <.001). During the night, fluorophotometric outflow facility was reduced by 45% (P=.05), and tonographic outflow facility was reduced by 17% (P <.01). Uveoscleral outflow at night was decreased when calculated using tonographic outflow facility but not fluorophotometric outflow facility in the Goldmann equation. All other measurements were unchanged.Conclusions: Significant changes in aqueous humor dynamics at night in healthy mature humans include reductions in aqueous flow, outflow facility, and possibly uveoscleral outflow. Nocturnal changes in IOP are independent of the pneumatonometer probe position and are dependent on an individual's posture during the measurement.

OBJECTIVE:To evaluate the differences in aqueous humor dynamics between nighttime and daytime in participants with ocular hypertension.METHODS:Thirty participants (mean [SD] age, 59.2 [11.1] years) with ocular hypertension were enrolled in the study, which included 1 daytime and 1 nighttime visit. During each visit, measurements included central cornea thickness by ultrasound pachymetry, intraocular pressure (IOP) by pneumatonometry, aqueous flow by fluorophotometry, outflow facility by tonography, and blood pressure by sphygmomanometry. Uveoscleral outflow was calculated using the Goldmann equation. Daytime measurements were made only of episcleral venous pressure by venomanometry, anterior chamber depth by A-scan, and outflow facility by fluorophotometry. Repeated-measures analysis of variance and 2-tailed t tests were used for statistical comparisons.RESULTS:Compared with daytime seated IOP (21.3 [3.5] mm Hg), nighttime seated IOP (17.2 [3.7] mm Hg) was reduced (P < .001) and nighttime supine IOP (22.7 [4.6] mm Hg) was increased (P = .03). Central cornea thickness was increased at night from 570 (39) μm to 585 (46) μm (P < .001). There was a 48% nocturnal reduction in aqueous flow from 2.13 (0.71) μL/min during the day to 1.11 (0.38) μL/min at night (P < .001). Uveoscleral outflow was significantly reduced (P = .03) by 0.61 μL/min at night when using supine IOP, tonographic outflow facility, and episcleral venous pressure adjusted for postural changes in the Goldmann equation. All other measurements had no significant changes.CONCLUSIONS:Significant ocular changes occur at night in individuals with ocular hypertension, including a reduction in seated IOP but an increase in habitual IOP, thickening of the cornea, and decreases in aqueous flow and uveoscleral outflow. Outflow facility does not change significantly at nighttime.

OBJECTIVETo assess aqueous humor dynamics in pigment dispersion syndrome (PDS).METHODSFour groups of age-matched participants included 2 experimental groups with PDS (PDS with ocular hypertension [PDS-OHT], 17 eyes; PDS without ocular hypertension [PDS-ONT], 18 eyes) and 2 control groups without PDS (OHT, 18 eyes; ONT, 18 eyes). Assessments included intraocular pressure measured by pneumatonometry, episcleral venous pressure by venomanometry, aqueous flow and outflow facility by fluorophotometry, corneal thickness and anterior chamber depth by pachymetry, and uveoscleral outflow by mathematical calculation. Comparisons were made by analysis of variance and 2-tailed unpaired t tests.RESULTSThe PDS-OHT group had higher intraocular pressures than the ONT and PDS-ONT groups (P < .001) and higher episcleral venous pressure (P = .04) and lower outflow facility (P = .01) than the ONT group. Anterior chamber volume was larger in the PDS-OHT group than in the other groups (P < .05 for all). No other comparisons between the PDS-OHT group and the other groups yielded statistically significant differences at a significance level of less than .05.CONCLUSIONSThe elevated intraocular pressure in PDS is caused by reduced outflow facility. This differs from OHT without PDS, in which reductions in uveoscleral outflow and outflow facility have been reported.

Purpose: The study of aqueous humor dynamics (AHD) in mice is becoming more prevalent as more strains with elevated intraocular pressure (IOP) are developed. High IOP is usually associated with reduced outflow facility making this one of the more important AHD parameters to evaluate. Ocular measurements in mice require anesthesia that has profound effects on IOP but unknown effects on outflow facility. This study evaluates the effects of anesthesia duration and latanoprost treatment on outflow facility and IOP in BALB/c mice.Methods: IOPs were measured in conscious and anesthetized mice by tonometry. Outflow facility was evaluated in 15-min intervals at three pressure levels over two 45-min periods. Comparisons were made between latanoprost-treated eyes and untreated contralateral eyes. To determine the effect of anesthesia duration on IOP, a microneedle method was used to follow IOP for 120 min in separate mice.Results: IOP was 9.7 +/- 0.3 mmHg (mean +/- SEM) in conscious mice and 7.1 +/- 0.02 within 10min of anesthesia initiation (p < 0.01). IOP changed significantly between but not within assessment periods. IOP at 75min was significantly (p=0.004) reduced compared to IOP at 15min after initial anesthesia. In control eyes, outflow facility did not change between the two 45-min assessment periods during the 120 min test (p=0.80). In latanoprost-treated eyes, outflow facility increased compared with control eyes during both assessment periods (p=0.03). A test of filters in series with known resistance found that the method was sensitive enough to detect a change in outflow facility of 0.001 mu l/min/mmHg.Conclusions: Administration of ketamine/xylazine anesthesia for 120min did not alter outflow facility or lessen the effect of latanoprost on outflow facility in mice as determined by a new analysis system. Accurate IOP measurements must be made within minutes of anesthesia administration but outflow facility measurements can be made with less haste.

PURPOSE:To determine the day and night differences in intraocular pressure (IOP), aqueous flow, outflow facility, uveoscleral outflow, and central corneal thickness (CCT) in juvenile and adult rabbits.METHODS:Studies were performed on twelve 3-month-old and ten 12-month-old male New Zealand White rabbits. Daytime measurements were made between 9 AM (3 hours after lights on) and 3 PM, and nighttime measurements were made between 11 PM and 5 AM. IOP was measured by pneumotonometry and aqueous flow by fluorophotometry. Outflow facility was determined by both fluorophotometry and tonography. Uveoscleral outflow was calculated by the Goldmann equation. CCT was measured by ultrasound pachymetry. Repeated-measures ANOVAs and Student's two-tailed t-tests were used for statistical comparisons.RESULTS:When nighttime versus daytime readings were compared, IOP, aqueous flow and uveoscleral outflow were higher, fluorophotometric outflow facility was lower, and CCT was thinner in both age groups. When the juvenile rabbits were compared to adult rabbits, IOP was lower, aqueous flow and uveoscleral outflow were higher, and fluorophotometric outflow facility and CCT were not different during the day or night. Tonographic outflow facility did not change in a 24-hour period in the juvenile rabbits.CONCLUSIONS:The increased IOP at night in rabbits can be explained mainly by a decrease in outflow facility. An increase in aqueous flow at night is counterbalanced by an increase in uveoscleral outflow. Although the rates of aqueous flow and uveoscleral outflow slow with maturity, their relative day/night differences remain the same.

Purpose: To investigate whether the intraocular pressure (IOP) reduction and mechanism of action of timolol and latanoprost change between 1 and 6 weeks of treatment.Patients and Methods: Thirty participants on no ocular medications completed this double-masked, 6-visit, crossover study. At each visit IOP was determined by pneumatonometry, aqueous flow by fluorophotometry, and outflow facility by fluorophotometry and tonography. Separate values of uveoscleral outflow were calculated using the Goldmann equation, an episcleral venous pressure of 11 mm Hg, and each of the 2 outflow facility values. In a randomized fashion, both eyes were treated for 6 weeks with latanoprost 0.005% once daily or timolol 0.5% twice daily. Measurements were repeated at 1 and 6 weeks of dosing. After 6 weeks of washout, the second drug was administered in a crossover manner. One and 6 weeks of treatment were compared with appropriate baselines using 1-way analyses of variance (ANOVA).Results: Timolol reduced aqueous flow by 27% at week 1 (P < 0.001) and 16% at week 6 (P = 0.03). Latanoprost increased uveoscleral outflow several fold at each visit (P < 0.05). Neither drug altered outflow facility. Neither drug showed a detectable change in aqueous humor dynamics at week 6 compared with week 1. Both drugs significantly (P < 0.001) reduced IOP at 1 and 6 weeks of treatment.Conclusions: Timolol and latanoprost significantly reduce IOP by different mechanisms. Timolol reduces aqueous flow whereas latanoprost increases uveoscleral outflow. Continued treatment with timolol or latanoprost for 6 weeks did not alter effects on aqueous humor dynamics. Outflow facility changes sometimes reported with prostaglandin analogues were not detected in this study.

Oxidative stress and TGFβ-induced disturbance of cells and tissues are implicated in initiation and progression of pathophysiology of cells/tissues. Using primary human Trabecular Meshwork (TM) cells from normal and glaucomatous subjects, this study demonstrated that peroxiredoxin (PRDX) 6, an antioxidant, offsets the deleterious effects of oxidative stress on TM cells by optimizing ROS and TGFβ levels. An analysis of glaucomatous TM cells revealed a reduced expression of PRDX6 mRNA and protein. Biochemical assays disclosed enhanced levels of ROS, as well as high levels of TGFβs and these cells expressed elevated extracellular matrix (ECM) and Tsp1 proteins with reduced MMP2; conditions implicated in the pathophysiology of glaucoma. Non-glaucomatous TM cells exposed to TGFβs/ROS showed similar features as in glaucomatous cells. The abnormalities induced were reversed by delivery of PRDX6. The data provide evidence that oxidative stress-induced abnormality in TM may be related to reduced PRDX6 expression and provide a foundation for antioxidant-based therapeutics for treating glaucoma.

The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT(2A/B/C)), 5HT(1A), 5HT(7), alpha(2B), and dopamine-2/3 (D(2/3)) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT(2), 5HT(1A) and D(2/3) receptors but an antagonist at 5HT(7) and alpha(2) receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC(50)=19+/-7 nM in TM; 76 nM in h-CM) and intracellular Ca(2+) ([Ca(2+)](i)) mobilization (EC(50)=570+/-83 nM in h-TM; EC(50)=900+/-320 nM in h-CM). Cabergoline-induced [Ca(2+)](i) mobilization in h-TM and h-CM cells was potently antagonized by a 5HT(2A)-selective antagonist (M-100907, K(i)=0.29-0.53 nM). Cabergoline also stimulated [Ca(2+)](i) mobilization more potently via human cloned 5HT(2A) (EC(50)=63.4+/-10.3 nM) than via 5HT(2B) and 5HT(2C) receptors. In h-CM cells, cabergoline (1 microM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1 microM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300-500 microg) in Dutch-belted rabbit eyes yielded 4.5 microMM and 1.97 microM levels in the aqueous humor 30 min and 90 min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6 microg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6+/-3.6% with 50 microg at 3h post-dose; 30.4+/-4.5% with 500 microg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300 microg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69+/-0.7 microL/min-1.61+/-0.97 microL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity involves activation of 5HT(2), 5HT(1A), and D(2/3) receptors. Since 5HT(1A) agonists, 5HT(7) antagonists, and alpha(2) antagonists do not lower IOP in conscious ocular hypertensive monkeys, the 5HT(2) and dopaminergic agonist activities of cabergoline probably mediated the IOP reduction observed with this compound in this species.

A stable rate of production and drainage of aqueous humor is essential for the health of the eye and maintenance of normal visual function. This chapter reviews the contributions of aqueous humor dynamics in normal and pathological conditions affecting intraocular pressure (IOP). IOP remains relatively stable throughout one's lifetime but subtle changes do occur in the outflow pathways that could increase IOP and the risk for glaucoma. Abnormalities in aqueous humor dynamics have been found in various clinical syndromes that affect IOP. Most of the abnormalities have been localized to the aqueous humor outflow pathways. Surprisingly, aqueous humor production remains relatively stable in all of these conditions and ranges of IOPs. Some older drugs to treat elevated IOP work by reducing aqueous humor production, theoretically, placing the avascular lens and cornea at risk for damage from limited nutrients and accumulation of toxic metabolites. The recently approved drugs and the ones currently under development for future glaucoma therapy are those that target the outflow pathways. From a physiological perspective, this is a logical approach because this is the location of the pathology in glaucoma and the region in need of repair. These drugs and their effects on aqueous humor dynamics also are discussed in this chapter.