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Clinical Sciences | ONLINE FIRST

Diurnal and Nocturnal Variations in Aqueous Humor Dynamics of Patients With Ocular Hypertension Undergoing Medical Therapy FREE

Vikas Gulati, MD; Shan Fan, MD; Min Zhao, MD; Matthew A. Maslonka, BS; Chiraag Gangahar, MD; Carol B. Toris, PhD
[+] Author Affiliations

Author Affiliations: Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, Omaha.


Arch Ophthalmol. 2012;130(6):677-684. doi:10.1001/archophthalmol.2011.2573.
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Published online

Objective To evaluate the interaction of intraocular pressure (IOP)–lowering medications with physiologic day and night changes in aqueous humor dynamics in participants with ocular hypertension.

Methods Thirty participants were enrolled in this double-masked, randomized, crossover study. Each participant underwent aqueous humor dynamics measurements at baseline and at 2 weeks of dosing in random order with latanoprost in the evening and placebo in the morning, timolol maleate twice daily, and dorzolamide hydrochloride twice daily. Measurements included central corneal thickness by ultrasound pachymetry, anterior chamber depth by A-scan, seated and habitual IOP by pneumatonometry, blood pressure by sphygmomanometry, episcleral venous pressure by venomanometry, and aqueous flow by fluorophotometry. Outflow facility was assessed by fluorophotometry and by tonography. Uveoscleral outflow was mathematically calculated using the Goldmann equation.

Results Latanoprost use significantly decreased IOP during the day and night. It increased daytime uveoscleral outflow by a mean (SD) of 0.90 (1.46) μL/min (P = .048), but a nighttime increase of 0.26 (1.10) μL/min (P = .47) did not reach statistical significance. Timolol use decreased IOP during the day by reducing aqueous flow by 25%. Dorzolamide use lowered IOP only at the noon measurement and reduced daytime aqueous flow by 16%. Neither dorzolamide nor timolol use added to the physiologic 47% reduction in nighttime aqueous flow.

Conclusions The daytime IOP-lowering effects of latanoprost are mediated by an increase in uveoscleral outflow, and those of timolol and dorzolamide are mediated by aqueous flow suppression. Nighttime physiologic changes in uveoscleral outflow limit the nighttime pharmacodynamic efficacy of latanoprost. Aqueous flow suppression with timolol and dorzolamide was ineffective in obtaining IOP lowering at night.

Trial Registration clinicaltrials.gov Identifier: NCT00572936

Figures in this Article

Elevated intraocular pressure (IOP) is the primary risk factor for glaucomatous optic neuropathy and visual field damage.1,2 Lowering of IOP by medical or surgical means remains the only proven measure to slow the progression of glaucomatous damage.36 Most prescribed drugs lower IOP by decreasing aqueous flow7,8 (eg, β-blockers and carbonic anhydrase inhibitors), improving the outflow of aqueous humor9,10 (eg, prostaglandin analogues and cholinergic agents), or both11,122-adrenergic agonists).

The variables of aqueous humor dynamics undergo physiologic changes in a 24-hour period in people with ocular normotension13 and ocular hypertension.14 The nocturnal suppression of aqueous humor production has been well documented.15 Some evidence supports nighttime changes in outflow facility and uveoscleral outflow (Fu).13,14 The pharmacologic actions of drugs and the physiologic responses of the body may enhance or counteract each other, thereby affecting the pharmacodynamic efficacy of a drug throughout a 24-hour period. The daytime effects on IOP and aqueous humor dynamics of β-blockers,1618 carbonic anhydrase inhibitors,7,19 and prostaglandin analogues20,21 have been carefully studied in volunteers with ocular normotension and hypertension, but nighttime effects have not been as extensively investigated. There are studies2224 of nighttime drug effects on IOP and aqueous flow in control subjects, but there remains little information on the nighttime effects of these drugs on outflow in patients with elevated IOP. This study evaluated the effects of a prostaglandin analogue, a β-blocker, and a carbonic anhydrase inhibitor on daytime and nighttime IOP and variables of aqueous humor dynamics in individuals with ocular hypertension. Daytime and nighttime aqueous humor dynamics were measured in the same participants treated with each drug in a masked crossover manner, enabling a direct comparison while minimizing the variability due to sampling differences.

This study of 30 participants with ocular hypertension had a prospective, double-masked, randomized, multiple-crossover design. The exclusion criteria included a history of ocular inflammation; glaucomatous visual field defects; a history of ocular trauma or infection within 6 months before enrollment; abnormalities that prevent reliable IOP or fluorophotometric readings; anterior chamber angles of less than a grade of 2 on gonioscopic examination; a cup-disc ratio greater than or equal to 0.8; a history of intolerance to topical fluorescein, timolol, latanoprost, or dorzolamide; a history of severe or unstable cardiovascular, pulmonary, hepatic, or renal disease; inability to discontinue contact lens wear during the study visits; and a history of ocular surgical procedures. Ocular hypertension was defined as documentation of IOPs of 21 mm Hg or greater in both eyes on 2 separate occasions at least 3 months apart with no glaucomatous optic nerve or visual field defects. Participants with ocular hypertension rather than glaucoma (with optic nerve or visual field damage) were sought for the study because of the ethical concern with the required prolonged (18 weeks total) periods without ocular medication use. This study was approved by the institutional review board of the University of Nebraska Medical Center. Informed consent was signed by all the participants before enrollment in the study and was verbally reconfirmed at all the subsequent study visits.

This study entailed 9 visits per participant (Figure 1). The screening visit included a detailed ophthalmologic and medical history and slitlamp examination. The examination included a gonioscopy, and the average of the superior, inferior, nasal, and temporal anterior chamber angles was scored, with 0 being closed and 4 being wide open.25 In addition, a dilated stereoscopic fundus examination was performed, and the cup-disc ratio was recorded. After the screening visit, participants were asked to stop taking their current IOP-lowering medication, if applicable. During this and subsequent washout periods (duration dependent on the medication being washed out), IOP was checked every 2 weeks to ensure that it did not rise significantly above the target pressures (as determined by the treating physician). If the IOP was significantly higher than the target pressure, participants were treated with dorzolamide hydrochloride (because of its short washout period) until 1 week before the next study visit. Participants with IOPs greater than 35 mm Hg were withdrawn from the study and returned to their previously prescribed IOP-lowering therapy.

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Figure 1. Schedule of study visits.

All 30 participants underwent a baseline daytime visit and a baseline nighttime visit 2 days later. The 2 days of rest between visits gave the participants' eyes time to recover before initiating the numerous nighttime measurements. At the completion of the nighttime visit, participants started self-administering 1 of the masked randomly assigned study drugs, which included placebo in the morning and latanoprost, 0.004%, in the evening or timolol maleate, 0.5% (Falcon Pharmaceuticals), twice daily or dorzolamide hydrochloride, 2% (Falcon Pharmaceuticals), twice daily. The drops were administered at 9 AM and 9 PM each day. On the day of the aqueous humor dynamics measurements, the morning dose was administered after the 9 AM IOP measurement. Duration of treatment with each study drug was set at 2 weeks, which was considered adequate to obtain the full effect of the study drugs on aqueous humor dynamics. Two weeks later, participants underwent repeated daytime and nighttime study visits. At the end of the nighttime visit with the first drug, participants were instructed to discontinue using the study drug and to start the 6-week washout period, during which time IOP was monitored as before. After 6 weeks of washout, participants started taking the second randomly selected study drug and used it for 2 weeks before the next daytime and nighttime measurements. The same procedure was repeated for the third study drug.

The study procedures at each daytime and nighttime visit are summarized in Table 1. Between 10 PM and 4 AM on the night before each daytime visit, participants instilled 1 drop of 2% fluorescein into each eye at 5-minute intervals for a total of 6 to 8 drops. On the morning of the daytime visit, central corneal thickness and anterior chamber depth were measured by ultrasound pachymetry and A-scan (PacScan series 300; Sonomed, Inc), respectively. From these measurements, the anterior chamber volume was calculated for each eye.16 The IOP was measured using a pneumatonometer (Model 30 Classic; Reichert Technologies). Four sets of duplicate fluorophotometric scans of the cornea and anterior chamber were collected using a scanning ocular fluorophotometer (Fluorotron Master; OcuMetrics, Inc) (Table 1). These values were used to calculate baseline aqueous flow (the method is described in detail elsewhere).26 With the participant in the seated position, episcleral venous pressure (Pev) was measured using an episcleral venomanometer (Eyetech Ltd)27 during the morning of the daytime visit. Two measurements were made per eye and averaged. If the difference between the 2 measurements was more than 2 mm Hg, a third measurement was taken. Except for tonography, all the daytime visit measurements were made with the participant in the seated position.

Table Graphic Jump LocationTable 1. Study Schedule and Proceduresa

After the fourth set of scans, participants received oral acetazolamide (two 250-mg tablets). Because acetazolamide has been shown to reduce IOP by reducing aqueous flow17,23,28 without affecting outflow variables,29,30 it was used to facilitate the calculation of fluorophotometric outflow facility as the ratio of the change in aqueous flow to the change in IOP induced by the aqueous flow suppressant.

After the administration of acetazolamide, fluorophotometric outflow facility was calculated 3 times at 45-minute intervals. Values were averaged and reported as fluorophotometric outflow facility. Seated systolic and diastolic blood pressures were measured by sphygmomanometry at approximately 11:30 AM.

At the end of the study visit, supine 2-minute tonography was performed using the tonography setting on the pneumatonometer. Data were imported into a spreadsheet program (Excel; Microsoft Corp), and a regression line of all points (approximately 4000 data points per eye) was generated. Tonographic outflow facility was calculated using the ocular pressure volume tables and formulas published previously,31 with the initial and final IOPs obtained from the regression line at times 0 and 2 minutes, respectively. Hence, the slope used to obtain the tonographic outflow facility incorporated all data points recorded during the 2 minutes rather than just the initial and final recorded IOPs.

On the day of the nighttime visit, at 5 PM, 1 drop of proparacaine hydrochloride followed by 3 to 4 drops of fluorescein were instilled in each eye. The nighttime measurements were made in a hospital-based private hotel room. Fluorophotometric scans and IOP measurements were performed throughout the night at the times listed in Table 1. The IOPs were taken in dim lighting with the participant in the supine position followed by the seated position. Participants were instructed to return to sleep between measurements. Blood pressure and central corneal thickness were measured at 2 AM. Based on our past experience with aqueous humor suppressants failing to lower IOP at night, nighttime measurements of fluorophotometric outflow facility were not attempted.13 The last measurement was 2-minute tonography at 5 AM.

Nighttime Pev was not measured but was calculated as 2 mm Hg less than the individual daytime value for the seated position and 1.5 mm Hg higher than the daytime value for the supine position. These values are based on 2 previous studies32,33 reporting the diurnal and positional variation of Pev.

The Fu was calculated using the following formula: Fu = Fa − C (IOP − Pev), where Fa indicates aqueous flow; and C, outflow facility. The daytime Fu was calculated with Pev measured during the daytime visit and C determined by either the acetazolamide method or tonography. Nighttime Fu was calculated using tonographic C, supine IOPs at 2 AM, and nighttime calculated supine Pev.

STATISTICAL ANALYSIS

Mean values of each variable for the 2 eyes were used for the analysis. In cases in which measurements could be obtained for 1 eye only, that eye was used for the analysis. Normality of data distribution for each variable was checked using the Kolmogorov-Smirnov test. Parametric (analysis of variance [ANOVA] with the Tukey post hoc test) and nonparametric (Kruskal-Wallis test with Dunn post hoc comparisons) tests were used for comparison of means between different groups as appropriate. Measurements were compared between daytime and nighttime using paired tests (paired t test or Wilcoxon rank sum test). P ≤ .05 was considered statistically significant. Unless otherwise indicated, values are reported as mean (SD).

Thirty-two patients with ocular hypertension were screened for this study. One patient who was taking latanoprost for ocular hypertension did not have an IOP rise greater than 20 mm Hg after discontinuing treatment for up to 12 weeks. A second patient who initially expressed interest chose to withdraw from the study. Of the 30 participants enrolled in the study, 17 were not taking topical drops, 7 were using a prostaglandin analogue in both eyes, 4 were using a prostaglandin analogue in 1 eye, and 2 were using timolol in both eyes. All 30 participants underwent baseline daytime and nighttime measurements. After the baseline visit, 1 participant was withdrawn from the study owing to a possible mild allergic response to acetazolamide, and a second participant opted out with reports of backache. One participant had a motor vehicle crash after completing the daytime and nighttime visits with the first drug and had to withdraw. Three participants had an IOP increase to unacceptable levels (as determined by the treating physician) during the washout period and were withdrawn from the study. One of these participants had an excessive rise in IOP between visits 5 and 6 (after completing visits with 1 study drug), and 2 had excessive increases in IOP between visits 7 and 8 (after completing visits with 2 study drugs). Overall, 24 participants successfully completed all the study visits. Participants completing daytime and nighttime measurements with individual drugs were 28 with latanoprost, 24 with timolol, and 26 with dorzolamide.

The mean (SD) age of the 30 study participants was 59.3 (11.0) years. There were 9 men and 21 women. Regarding race, 22 participants were white, 6 were African American, 1 was Hispanic, and 1 was American Indian.

INTRAOCULAR PRESSURE

Figure 2 shows the effects on IOP of the 3 study drugs. Latanoprost and timolol significantly lowered the mean (SD) 9 AM IOP (17.6 [3.7] mm Hg and 16.4 [2.3] mm Hg, respectively) compared with the baseline value of 21.6 (5.0) mm Hg (P < .05, by ANOVA with the Tukey post hoc test). The mean (SD) 20.2 (4.8) mm Hg IOP with dorzolamide was not statistically significantly lower than the baseline value at 9 AM (12 hours after administration of the last dose). The mean (SD) noon IOPs (17.0 [3.2] mm Hg with latanoprost, 17.1 [2.5] mm Hg with timolol, and 17.6 [2.4] mm Hg with dorzolamide) were significantly decreased compared with the baseline value (20.9 [4.2] mm Hg) (P < .05 for all). During the nighttime, latanoprost significantly lowered the seated (10 PM and midnight) and supine (10 PM and 2 AM) IOPs compared with baseline (P < .05 for all, by ANOVA with the Tukey post hoc test). The mean reduction in IOP at night (13% seated and 10% supine) with latanoprost was less than the reduction obtained during the day (19%). Neither timolol nor dorzolamide lowered the seated or supine IOP compared with baseline at any of the nighttime measurements.

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Figure 2. Seated (A) and habitual (B) intraocular pressure (IOP) at baseline and when taking each of the 3 study drugs. Error bars represent 1 SEM. The asterisks indicate statistically significant IOP changes from baseline. The x-axis is discontinuous between the daytime and nighttime data.

BIOMETRY AND BLOOD PRESSURE

No study drug affected central corneal thickness during the day or night (P > .90 for all, by ANOVA). Values of central corneal thickness at night were higher compared with daytime values (P < .01 in all groups, by paired t test). Anterior chamber volume at 2 weeks of treatment with any of the study drugs was comparable with baseline (P = .84, by ANOVA). The Pev, measured during the day only, showed no change with any of the study drugs (P = .84, by ANOVA). None of the study drugs had any effect on the daytime or nighttime seated systolic or diastolic blood pressure (P > .30 for all, by ANOVA). No day and night differences in blood pressure were found at baseline or with any study drug. These data are summarized in Table 2.

Table Graphic Jump LocationTable 2. CCT, ACV, Pev, and BP at Baseline and After Treatment With 3 Study Medicationsa
AQUEOUS FLOW

Aqueous flow data at all visits were found to be normally distributed (baseline mean [SD], 2.09 [0.71] μL/min) (Figure 3). Using ANOVA for comparison of all daytime values, P = .006. Post hoc group comparisons were performed using the Tukey test. Timolol achieved a significant 25% reduction in daytime aqueous flow (mean [SD], 1.57 [0.44] μL/min; P < .01). The 16% reduction in daytime aqueous flow caused by dorzolamide (mean [SD], 1.75 [0.54] μL/min) reached significance when using a paired t test (P = .03) but did not reach significance when using the more rigorous Tukey post hoc test after ANOVA.

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Figure 3. Daytime and nighttime aqueous flow in participants with ocular hypertension at baseline and after 2 weeks of treatment with latanoprost, timolol maleate, or dorzolamide hydrochloride. Using analysis of variance, P = .006 for daytime and P = .96 for nighttime. During the day, the difference between baseline and timolol treatment was statistically significant. Daytime changes in aqueous flow with dorzolamide were significant (P = .03 by paired t test). Error bars represent 1 SEM.

Compared with the baseline daytime visit, aqueous flow at the baseline nighttime visit (mean [SD], 1.11 [0.38] μL/min) was reduced by 47% (P < .001, by paired t test). Neither timolol nor dorzolamide produced any further aqueous humor suppression. Latanoprost had no effect on either daytime or nighttime aqueous flow. For change in nighttime aqueous flow with all the study drugs, P = .96 (by ANOVA).

OUTFLOW FACILITY

The measured outflow facility data were not normally distributed. Therefore, nonparametric tests were used for the analysis. Outflow facility was calculated using fluorophotometry and tonography at the daytime visit and tonography at the nighttime visit (Table 3). None of the study drugs had a significant effect on daytime fluorophotometric outflow facility (P = .74, by Kruskal-Wallis test). No effect was seen on tonographic outflow facility during either the daytime (P = .38, by Kruskal-Wallis test) or the nighttime (P = .52, by Kruskal-Wallis test) with any of the study drugs. The daytime to nighttime differences in outflow facility were not significant at baseline (P = .24, by Wilcoxon test) or with any study drug (P = .14-.47, by Wilcoxon test).

Table Graphic Jump LocationTable 3. Outflow Facility Measured by Fluorophotometry (Cfl) and Tonography (Cton) at Baseline and With the 3 Study Medicationsa
UVEOSCLERAL OUTFLOW

Tonographic Fu data were normally distributed, whereas fluorophotometric data were not. These variables were treated as ordinal variables, and nonparametric tests were used for comparison of means. Mean (SD) baseline daytime Fu was calculated to be −0.09 (1.40) μL/min by fluorophotometry and −0.59 (1.67) μL/min by tonography. Detailed calculations of Fu using different values of Pev and a discussion of the ordinal nature of calculated Fu have been described in a recent article.14 Mathematically calculated Fu can vary significantly depending on the Pev used for calculation34; however, the calculated changes in Fu are fairly robust and vary little irrespective of the value of the Pev used in the calculations.14 The drug-induced changes in tonographic Fu data are given in Table 4. At baseline, Fu by tonography showed a significant reduction at nighttime (by 0.61 μL/min) compared with at daytime. This difference was seen irrespective of the method used to calculate the nighttime Fu values (seated: P = .04, by Wilcoxon test; or supine: P = .03, by Wilcoxon test). Fluorophotometric calculation of Fu was not performed at nighttime. Uveoscleral outflow calculated using daytime tonography was significantly increased with latanoprost use (P = .048, by Kruskal-Wallis test with the Dunn post hoc test). The increase in fluorophotometrically calculated Fu approached significance (P = .07, by Kruskal-Wallis test). Timolol and dorzolamide did not have a significant effect on either fluorophotometric or tonographic Fu. The nighttime values for Fu were significantly lower than the daytime values in all the groups (P < .01, by Wilcoxon test).

Table Graphic Jump LocationTable 4. Change in Uveoscleral Outflow Values When Adding 2, 4, and 6 mm Hg to Episcleral Venous Pressure in the Goldmann Equationa

Glaucoma medications lower IOP by altering the variables of aqueous humor dynamics. These effects are confounded by the spontaneous 24-hour changes in normal ocular physiologic function. This study provides insights into the daytime and nighttime variations in IOP and aqueous humor dynamics in patients with ocular hypertension and investigates the interaction, whether facilitative or counteractive, between the effects of 3 IOP-lowering drugs and normal physiologic nocturnal changes in aqueous humor dynamics.

The 2-week treatment duration in this study is likely to represent the full effect of the study medications. Lack of a difference between the aqueous humor dynamics measured at 1 and 6 weeks of treatment with timolol and latanoprost has been reported previously.35 To our knowledge, a formal direct comparison of aqueous humor suppression with dorzolamide over days or weeks has not been reported. However, a consistent unchanged IOP response from 1 to 28 days36 and from 4 to 52 weeks37 has been reported previously. This finding suggests indirectly that aqueous humor dynamics after 2 weeks of dorzolamide therapy likely represent aqueous humor dynamics at any time during dorzolamide therapy.

When analyzed by paired t test, the study confirms that the mechanism of action of timolol and dorzolamide is mediated through suppression of aqueous humor production. The magnitude of the aqueous flow decrease was greater with timolol than with dorzolamide. When evaluated by ANOVA and post hoc testing, the aqueous humor suppression achieved by dorzolamide did not reach statistical significance owing to the inherent correction applied for multiple comparisons. Hence, a lack of statistical significance for aqueous humor suppression achieved by dorzolamide seen in this study may be due to the limited power to detect a significant difference rather than due to evidence against efficacy in aqueous suppression.

The magnitude of the normal decrease in aqueous humor production that occurs naturally each night was twice as much as that achieved by timolol during the daytime. This explains why nocturnal reduction in aqueous flow beyond the normal decrease at night could not be achieved and why nocturnal IOP was not affected by timolol. A previous crossover study38 also found significant supine IOP lowering with latanoprost but not with timolol at night. In contrast, another crossover IOP study39 using timolol, latanoprost, and dorzolamide found significant nighttime IOP lowering with dorzolamide and latanoprost but not with timolol. A drug additivity study40 adding timolol or brinzolamide to latanoprost found additional nighttime IOP lowering with brinzolamide but not with timolol. Using timolol, brimonidine tartrate, latanoprost, and dorzolamide, one study41 found that all the medications lowered IOP at all measurement times. However, the IOP-lowering effect of timolol was found to be less during the night and that of dorzolamide was found to be less during the day. All the published studies showing a nighttime effect of topical carbonic anhydrase inhibitors used thrice-daily dosing compared with twice-daily dosing in the present study. The thrice-daily dosing of carbonic anhydrase inhibitors may lead to higher steady-state levels and nighttime IOP lowering that are not accomplished with twice-daily dosing. In clinical practice, topical carbonic anhydrase inhibitors are used at twice-daily and thrice-daily dosing. In the present study, twice-daily dosing was chosen to minimize the number of eye drops and maintain the double-masked nature of the study.

Some studies have reported nocturnal IOP lowering with timolol when used alone or as a fixed combination with either a carbonic anhydrase inhibitor42,43 or a prostaglandin analogue.44 Other studies,39,40,45 including the present one, have found a lack of an IOP-lowering effect with a β-blocker during the night.

Although no nighttime suppression of aqueous humor production was found with either timolol or dorzolamide in the present study, the drugs were different in terms of control of the 9 AM IOP, before administration of the next dose. Compared with baseline, timolol produced a significant lowering of 9 AM IOP, whereas dorzolamide did not. This likely is due to the longer half-life of timolol whereby the drug, although ineffective overnight, is available 12 hours after the last administration to have an effect on the morning IOP, likely by suppressing aqueous humor production as it starts to rise to daytime values. Such an effect was not seen with dorzolamide as it is likely eliminated before the morning surge in aqueous humor production.

Similar to the present findings, other studies38,46,47 have reported the nighttime IOP-lowering effect of prostaglandin analogues to be approximately half of the daytime effect. Based on the present study results, the IOP-lowering effect of latanoprost was mediated by its effects on Fu during the day and possibly during the night as well. Some previous studies48 also found effects of latanoprost on outflow facility. These differences may be related to the selection of participants (those with lower initial outflow facility values may show greater improvement), the duration of therapy, or both. A study22 of young Japanese adults given latanoprost or placebo twice daily for 3 days found daytime and nighttime increases in calculated Fu with latanoprost. However, unlike the present study, the Japanese study22 reported higher values of Fu at nighttime compared with daytime and a statistically significant increase in aqueous flow at night with latanoprost use compared with the contralateral control eye. The daytime and nighttime measurements were made in different participants in the Japanese study.

For the purpose of calculating Fu using the Goldmann equation, investigators have used measured,12,49 standard,35 and multiple21 values of assumed Pev. In addition to using the measured value, we provide offsets of 2, 4, and 6 mm Hg (Table 4). It was assumed that in all the participants, the true hydrostatic pressure downstream from the trabecular meshwork is offset from the measured Pev by a similar amount in all participants and is not altered by any of the study drugs. Participants taking latanoprost had a statistically significant increase in daytime Fu regardless of how it was calculated. Therefore, the daytime IOP-lowering effects of latanoprost can be explained by improvements in Fu. With tonographic outflow facility in the calculation, Fu increased by 0.9 μL/min. The spontaneous nighttime physiologic reduction in Fu (by tonography) was approximately 0.6 μL/min. The mean nighttime change in Fu (by tonography) with latanoprost was approximately 0.3 μL/min, which did not reach statistical significance. The numerical concordance of the previously mentioned data from this study may suggest that the potential maximal increase in Fu during the day may be partially negated by the spontaneous decrease in Fu at night. According to the Goldmann equation, a change in Fu of 0.3 μL/min adequately explains an IOP change of 1.5 mm Hg, assuming no change in any other variables of aqueous humor dynamics. The present data showed a mean nighttime lowering of habitual IOP by 2.2 mm Hg and that of seated IOP by 2.3 mm Hg. To fully explain a 2.2-mm Hg decrease in IOP, a 0.44–μL/min increase in Fu would be needed. The change in Fu at night in this study was slightly lower than this value. This study was not sufficiently powered to detect a statistically significant difference of this magnitude. A study designed to detect a difference of 0.3 μL/min with the baseline means and standard deviations seen in this study at a power of 80% would require a sample size greater than 200. Since neither the aqueous flow nor the outflow facility changed with latanoprost use at nighttime, an increase in Fu is the most likely explanation for the significant IOP decrease at night with latanoprost.

Nocturnal measurements made in this study required awakening the volunteers several times during the night to collect the data. This is likely a significant departure from the participants' normal nocturnal schedule and has the potential to affect the measurements thus obtained.50 However, this disturbance was unavoidable owing to the limitations of the currently available techniques. Our understanding of aqueous humor dynamics at night will improve when new methods become available that can make all measurements under the closed eyelid of the sleeping individual.

In conclusion, significant nocturnal physiologic changes in aqueous humor dynamics affect the efficacy of commonly used glaucoma drugs. Newer drugs are still needed that can control IOP better at night. Drugs that could facilitate nocturnal aqueous humor suppression would reduce nocturnal IOP, but this mechanism of action is not desirable because aqueous humor and its flow serve important physiologic functions. Drugs that could improve outflow facility or negate the spontaneous reduction in Fu during the night can be potential candidates for IOP lowering at night. Future studies are necessary to better understand the mediating pathways for nocturnal changes and potentially use these for more efficient IOP lowering and control of glaucoma.

Correspondence: Carol B. Toris, PhD, Department of Ophthalmology and Visual Sciences, University of Nebraska Medical Center, 985840 Nebraska Medical Center, Omaha, NE 68198-5840 (ctoris@unmc.edu).

Submitted for Publication: August 1, 2011; final revision received November 1, 2011; accepted November 22, 2011.

Published Online: February 13, 2012. doi:10.1001/archophthalmol.2011.2573

Financial Disclosure: None reported.

Funding/Support: This study was supported by Research to Prevent Blindness and by an unrestricted grant from Pfizer (Dr Toris).

Additional Contributions: Carl B. Camras, MD, was involved in the initial design of the study and provided support, ideas, and mentorship.

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Reiss GR, Lee DA, Topper JE, Brubaker RF. Aqueous humor flow during sleep.  Invest Ophthalmol Vis Sci. 1984;25(6):776-778
PubMed
Schenker HI, Yablonski ME, Podos SM, Linder L. Fluorophotometric study of epinephrine and timolol in human subjects.  Arch Ophthalmol. 1981;99(7):1212-1216
PubMed   |  Link to Article
Dailey RA, Brubaker RF, Bourne WM. The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human subjects.  Am J Ophthalmol. 1982;93(2):232-237
PubMed
Brubaker RF, Nagataki S, Bourne WM. Effect of chronically administered timolol on aqueous humor flow in patients with glaucoma.  Ophthalmology. 1982;89(3):280-283
PubMed
Yamazaki Y, Miyamoto S, Sawa M. Effect of MK-507 on aqueous humor dynamics in normal human eyes.  Jpn J Ophthalmol. 1994;38(1):92-96
PubMed
Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2 α analog, on aqueous humor dynamics in human eyes.  Ophthalmology. 1993;100(9):1297-1304
PubMed
Lim KS, Nau CB, O'Byrne MM,  et al.  Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects: a crossover study.  Ophthalmology. 2008;115(5):790-795.e4
PubMed  |  Link to Article   |  Link to Article
Mishima HK, Kiuchi Y, Takamatsu M, Rácz P, Bito LZ. Circadian intraocular pressure management with latanoprost: diurnal and nocturnal intraocular pressure reduction and increased uveoscleral outflow.  Surv Ophthalmol. 1997;41:(suppl 2)  S139-S144
PubMed   |  Link to Article
McCannel CA, Heinrich SR, Brubaker RF. Acetazolamide but not timolol lowers aqueous humor flow in sleeping humans.  Graefes Arch Clin Exp Ophthalmol. 1992;230(6):518-520
PubMed   |  Link to Article
Koskela T, Brubaker RF. Apraclonidine and timolol: combined effects in previously untreated normal subjects.  Arch Ophthalmol. 1991;109(6):804-806
PubMed   |  Link to Article
Stamper RL, Lieberman MF, Drake MV. Becker-Schaffer's Diagnosis and Therapy of the Glaucomas. St Louis, MO: Mosby; 1999:101-113
Yablonski ME, Zimmerman TJ, Waltman SR, Becker B. A fluorophotometric study of the effect of topical timolol on aqueous humor dynamics.  Exp Eye Res. 1978;27(2):135-142
PubMed   |  Link to Article
Zeimer RC, Gieser DK, Wilensky JT, Noth JM, Mori MM, Odunukwe EE. A practical venomanometer: measurement of episcleral venous pressure and assessment of the normal range.  Arch Ophthalmol. 1983;101(9):1447-1449
PubMed   |  Link to Article
Toris CB, Zhan GL, Yablonski ME, Camras CB. Effects on aqueous flow of dorzolamide combined with either timolol or acetazolamide.  J Glaucoma. 2004;13(3):210-215
PubMed   |  Link to Article
Wang RF, Serle JB, Podos SM, Sugrue MF. MK-507 (L-671,152), a topically active carbonic anhydrase inhibitor, reduces aqueous humor production in monkeys.  Arch Ophthalmol. 1991;109(9):1297-1299
PubMed   |  Link to Article
Toris CB, Yablonski ME, Wang YL, Hayashi M. Prostaglandin A2 increases uveoscleral outflow and trabecular outflow facility in the cat.  Exp Eye Res. 1995;61(6):649-657
PubMed   |  Link to Article
Eisenlohr JE, Langham ME, Maumenee AE. Manometric studies of the pressure-volume relationship in living and enucleated eyes of individual human subjects.  Br J Ophthalmol. 1962;46(9):536-548
PubMed   |  Link to Article
Blondeau P, Tétrault JP, Papamarkakis C. Diurnal variation of episcleral venous pressure in healthy patients: a pilot study.  J Glaucoma. 2001;10(1):18-24
PubMed   |  Link to Article
Sultan M, Blondeau P. Episcleral venous pressure in younger and older subjects in the sitting and supine positions.  J Glaucoma. 2003;12(4):370-373
PubMed   |  Link to Article
Brubaker RF. Measurement of uveoscleral outflow in humans.  J Glaucoma. 2001;10(5):(suppl 1)  S45-S48
PubMed   |  Link to Article
Johnson TV, Fan S, Zhan G, Camras CB, Toris CB. Efficacy and mechanisms of intraocular pressure reduction with latanoprost and timolol in participants with ocular hypertension: a comparison of 1 and 6 weeks of treatment.  J Glaucoma. 2010;19(6):356-364
PubMed   |  Link to Article
Wilkerson M, Cyrlin M, Lippa EA,  et al.  Four-week safety and efficacy study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor.  Arch Ophthalmol. 1993;111(10):1343-1350
PubMed   |  Link to Article
MK-507 Clinical Study Group.  Long-term glaucoma treatment with MK-507, dorzolamide, a topical carbonic anhydrase inhibitor.  J Glaucoma. 1995;4(1):6-10
PubMed
Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure.  Am J Ophthalmol. 2004;138(3):389-395
PubMed   |  Link to Article
Orzalesi N, Rossetti L, Invernizzi T, Bottoli A, Autelitano A. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension.  Invest Ophthalmol Vis Sci. 2000;41(9):2566-2573
PubMed
Liu JH, Medeiros FA, Slight JR, Weinreb RN. Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy.  Ophthalmology. 2009;116(3):449-454
PubMed   |  Link to Article
Quaranta L, Gandolfo F, Turano R,  et al.  Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma.  Invest Ophthalmol Vis Sci. 2006;47(7):2917-2923
PubMed   |  Link to Article
Quaranta L, Miglior S, Floriani I, Pizzolante T, Konstas AG. Effects of the timolol-dorzolamide fixed combination and latanoprost on circadian diastolic ocular perfusion pressure in glaucoma.  Invest Ophthalmol Vis Sci. 2008;49(10):4226-4231
PubMed   |  Link to Article
Orzalesi N, Rossetti L, Bottoli A, Fumagalli E, Fogagnolo P. The effect of latanoprost, brimonidine, and a fixed combination of timolol and dorzolamide on circadian intraocular pressure in patients with glaucoma or ocular hypertension.  Arch Ophthalmol. 2003;121(4):453-457
PubMed   |  Link to Article
Konstas AG, Holló G, Mikropoulos D,  et al.  Twenty-four-hour intraocular pressure control with bimatoprost and the bimatoprost/timolol fixed combination administered in the morning, or evening in exfoliative glaucoma.  Br J Ophthalmol. 2010;94(2):209-213
PubMed   |  Link to Article
Nakamoto K, Yasuda N. Effect of carteolol hydrochloride on 24-hour variation of intraocular pressure in normal-tension glaucoma.  Jpn J Ophthalmol. 2010;54(2):140-143
PubMed   |  Link to Article
Orzalesi N, Rossetti L, Bottoli A, Fogagnolo P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension.  Ophthalmology. 2006;113(2):239-246
PubMed   |  Link to Article
Sit AJ, Weinreb RN, Crowston JG, Kripke DF, Liu JH. Sustained effect of travoprost on diurnal and nocturnal intraocular pressure.  Am J Ophthalmol. 2006;141(6):1131-1133
PubMed   |  Link to Article
Toris CB, Gabelt BT, Kaufman PL. Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction.  Surv Ophthalmol. 2008;53:(suppl 1)  S107-S120
PubMed   |  Link to Article
Toris CB, Tafoya ME, Camras CB, Yablonski ME. Effects of apraclonidine on aqueous humor dynamics in human eyes.  Ophthalmology. 1995;102(3):456-461
PubMed
Liu JH, Weinreb RN. Monitoring intraocular pressure for 24 h.  Br J Ophthalmol. 2011;95(5):599-600
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Schedule of study visits.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Seated (A) and habitual (B) intraocular pressure (IOP) at baseline and when taking each of the 3 study drugs. Error bars represent 1 SEM. The asterisks indicate statistically significant IOP changes from baseline. The x-axis is discontinuous between the daytime and nighttime data.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Daytime and nighttime aqueous flow in participants with ocular hypertension at baseline and after 2 weeks of treatment with latanoprost, timolol maleate, or dorzolamide hydrochloride. Using analysis of variance, P = .006 for daytime and P = .96 for nighttime. During the day, the difference between baseline and timolol treatment was statistically significant. Daytime changes in aqueous flow with dorzolamide were significant (P = .03 by paired t test). Error bars represent 1 SEM.

Tables

Table Graphic Jump LocationTable 1. Study Schedule and Proceduresa
Table Graphic Jump LocationTable 2. CCT, ACV, Pev, and BP at Baseline and After Treatment With 3 Study Medicationsa
Table Graphic Jump LocationTable 3. Outflow Facility Measured by Fluorophotometry (Cfl) and Tonography (Cton) at Baseline and With the 3 Study Medicationsa
Table Graphic Jump LocationTable 4. Change in Uveoscleral Outflow Values When Adding 2, 4, and 6 mm Hg to Episcleral Venous Pressure in the Goldmann Equationa

References

AGIS Investigators.  The Advanced Glaucoma Intervention Study (AGIS), 12: baseline risk factors for sustained loss of visual field and visual acuity in patients with advanced glaucoma.  Am J Ophthalmol. 2002;134(4):499-512
PubMed   |  Link to Article
Gordon MO, Beiser JA, Brandt JD,  et al.  The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary open-angle glaucoma.  Arch Ophthalmol. 2002;120(6):714-720
PubMed   |  Link to Article
AGIS Investigators.  The Advanced Glaucoma Intervention Study (AGIS), 7: the relationship between control of intraocular pressure and visual field deterioration.  Am J Ophthalmol. 2000;130(4):429-440
PubMed   |  Link to Article
Glaucoma Laser Trial Research Group.  The Glaucoma Laser Trial (GLT) and glaucoma laser trial follow-up study, 7: results.  Am J Ophthalmol. 1995;120(6):718-731
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Glaucoma Laser Trial Research Group.  The Glaucoma Laser Trial (GLT), 2: results of argon laser trabeculoplasty versus topical medicines.  Ophthalmology. 1990;97(11):1403-1413
PubMed
Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M.Early Manifest Glaucoma Trial Group.  Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial.  Arch Ophthalmol. 2002;120(10):1268-1279
PubMed
Maus TL, Larsson LI, McLaren JW, Brubaker RF. Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans.  Arch Ophthalmol. 1997;115(1):45-49
PubMed   |  Link to Article
Zimmerman TJ, Boger WP III. The β-adrenergic blocking agents and the treatment of glaucoma.  Surv Ophthalmol. 1979;23(6):347-362
PubMed   |  Link to Article
Alm A. Prostaglandin derivates as ocular hypotensive agents.  Prog Retin Eye Res. 1998;17(3):291-312
PubMed   |  Link to Article
Camras CB. Mechanism of the prostaglandin-induced reduction of intraocular pressure in humans.  Adv Prostaglandin Thromboxane Leukot Res. 1995;23:519-525
PubMed
Toris CB, Camras CB, Yablonski ME. Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients.  Am J Ophthalmol. 1999;128(1):8-14
PubMed   |  Link to Article
Toris CB, Gleason ML, Camras CB, Yablonski ME. Effects of brimonidine on aqueous humor dynamics in human eyes.  Arch Ophthalmol. 1995;113(12):1514-1517
PubMed   |  Link to Article
Liu H, Fan S, Gulati V,  et al.  Aqueous humor dynamics during the day and night in healthy mature volunteers.  Arch Ophthalmol. 2011;129(3):269-275
PubMed   |  Link to Article
Fan S, Hejkal JJ, Gulati V, Galata S, Camras CB, Toris CB. Aqueous humor dynamics during the day and night in volunteers with ocular hypertension.  Arch Ophthalmol. 2011;129(9):1162-1166
PubMed   |  Link to Article
Reiss GR, Lee DA, Topper JE, Brubaker RF. Aqueous humor flow during sleep.  Invest Ophthalmol Vis Sci. 1984;25(6):776-778
PubMed
Schenker HI, Yablonski ME, Podos SM, Linder L. Fluorophotometric study of epinephrine and timolol in human subjects.  Arch Ophthalmol. 1981;99(7):1212-1216
PubMed   |  Link to Article
Dailey RA, Brubaker RF, Bourne WM. The effects of timolol maleate and acetazolamide on the rate of aqueous formation in normal human subjects.  Am J Ophthalmol. 1982;93(2):232-237
PubMed
Brubaker RF, Nagataki S, Bourne WM. Effect of chronically administered timolol on aqueous humor flow in patients with glaucoma.  Ophthalmology. 1982;89(3):280-283
PubMed
Yamazaki Y, Miyamoto S, Sawa M. Effect of MK-507 on aqueous humor dynamics in normal human eyes.  Jpn J Ophthalmol. 1994;38(1):92-96
PubMed
Toris CB, Camras CB, Yablonski ME. Effects of PhXA41, a new prostaglandin F2 α analog, on aqueous humor dynamics in human eyes.  Ophthalmology. 1993;100(9):1297-1304
PubMed
Lim KS, Nau CB, O'Byrne MM,  et al.  Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects: a crossover study.  Ophthalmology. 2008;115(5):790-795.e4
PubMed  |  Link to Article   |  Link to Article
Mishima HK, Kiuchi Y, Takamatsu M, Rácz P, Bito LZ. Circadian intraocular pressure management with latanoprost: diurnal and nocturnal intraocular pressure reduction and increased uveoscleral outflow.  Surv Ophthalmol. 1997;41:(suppl 2)  S139-S144
PubMed   |  Link to Article
McCannel CA, Heinrich SR, Brubaker RF. Acetazolamide but not timolol lowers aqueous humor flow in sleeping humans.  Graefes Arch Clin Exp Ophthalmol. 1992;230(6):518-520
PubMed   |  Link to Article
Koskela T, Brubaker RF. Apraclonidine and timolol: combined effects in previously untreated normal subjects.  Arch Ophthalmol. 1991;109(6):804-806
PubMed   |  Link to Article
Stamper RL, Lieberman MF, Drake MV. Becker-Schaffer's Diagnosis and Therapy of the Glaucomas. St Louis, MO: Mosby; 1999:101-113
Yablonski ME, Zimmerman TJ, Waltman SR, Becker B. A fluorophotometric study of the effect of topical timolol on aqueous humor dynamics.  Exp Eye Res. 1978;27(2):135-142
PubMed   |  Link to Article
Zeimer RC, Gieser DK, Wilensky JT, Noth JM, Mori MM, Odunukwe EE. A practical venomanometer: measurement of episcleral venous pressure and assessment of the normal range.  Arch Ophthalmol. 1983;101(9):1447-1449
PubMed   |  Link to Article
Toris CB, Zhan GL, Yablonski ME, Camras CB. Effects on aqueous flow of dorzolamide combined with either timolol or acetazolamide.  J Glaucoma. 2004;13(3):210-215
PubMed   |  Link to Article
Wang RF, Serle JB, Podos SM, Sugrue MF. MK-507 (L-671,152), a topically active carbonic anhydrase inhibitor, reduces aqueous humor production in monkeys.  Arch Ophthalmol. 1991;109(9):1297-1299
PubMed   |  Link to Article
Toris CB, Yablonski ME, Wang YL, Hayashi M. Prostaglandin A2 increases uveoscleral outflow and trabecular outflow facility in the cat.  Exp Eye Res. 1995;61(6):649-657
PubMed   |  Link to Article
Eisenlohr JE, Langham ME, Maumenee AE. Manometric studies of the pressure-volume relationship in living and enucleated eyes of individual human subjects.  Br J Ophthalmol. 1962;46(9):536-548
PubMed   |  Link to Article
Blondeau P, Tétrault JP, Papamarkakis C. Diurnal variation of episcleral venous pressure in healthy patients: a pilot study.  J Glaucoma. 2001;10(1):18-24
PubMed   |  Link to Article
Sultan M, Blondeau P. Episcleral venous pressure in younger and older subjects in the sitting and supine positions.  J Glaucoma. 2003;12(4):370-373
PubMed   |  Link to Article
Brubaker RF. Measurement of uveoscleral outflow in humans.  J Glaucoma. 2001;10(5):(suppl 1)  S45-S48
PubMed   |  Link to Article
Johnson TV, Fan S, Zhan G, Camras CB, Toris CB. Efficacy and mechanisms of intraocular pressure reduction with latanoprost and timolol in participants with ocular hypertension: a comparison of 1 and 6 weeks of treatment.  J Glaucoma. 2010;19(6):356-364
PubMed   |  Link to Article
Wilkerson M, Cyrlin M, Lippa EA,  et al.  Four-week safety and efficacy study of dorzolamide, a novel, active topical carbonic anhydrase inhibitor.  Arch Ophthalmol. 1993;111(10):1343-1350
PubMed   |  Link to Article
MK-507 Clinical Study Group.  Long-term glaucoma treatment with MK-507, dorzolamide, a topical carbonic anhydrase inhibitor.  J Glaucoma. 1995;4(1):6-10
PubMed
Liu JH, Kripke DF, Weinreb RN. Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure.  Am J Ophthalmol. 2004;138(3):389-395
PubMed   |  Link to Article
Orzalesi N, Rossetti L, Invernizzi T, Bottoli A, Autelitano A. Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension.  Invest Ophthalmol Vis Sci. 2000;41(9):2566-2573
PubMed
Liu JH, Medeiros FA, Slight JR, Weinreb RN. Comparing diurnal and nocturnal effects of brinzolamide and timolol on intraocular pressure in patients receiving latanoprost monotherapy.  Ophthalmology. 2009;116(3):449-454
PubMed   |  Link to Article
Quaranta L, Gandolfo F, Turano R,  et al.  Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma.  Invest Ophthalmol Vis Sci. 2006;47(7):2917-2923
PubMed   |  Link to Article
Quaranta L, Miglior S, Floriani I, Pizzolante T, Konstas AG. Effects of the timolol-dorzolamide fixed combination and latanoprost on circadian diastolic ocular perfusion pressure in glaucoma.  Invest Ophthalmol Vis Sci. 2008;49(10):4226-4231
PubMed   |  Link to Article
Orzalesi N, Rossetti L, Bottoli A, Fumagalli E, Fogagnolo P. The effect of latanoprost, brimonidine, and a fixed combination of timolol and dorzolamide on circadian intraocular pressure in patients with glaucoma or ocular hypertension.  Arch Ophthalmol. 2003;121(4):453-457
PubMed   |  Link to Article
Konstas AG, Holló G, Mikropoulos D,  et al.  Twenty-four-hour intraocular pressure control with bimatoprost and the bimatoprost/timolol fixed combination administered in the morning, or evening in exfoliative glaucoma.  Br J Ophthalmol. 2010;94(2):209-213
PubMed   |  Link to Article
Nakamoto K, Yasuda N. Effect of carteolol hydrochloride on 24-hour variation of intraocular pressure in normal-tension glaucoma.  Jpn J Ophthalmol. 2010;54(2):140-143
PubMed   |  Link to Article
Orzalesi N, Rossetti L, Bottoli A, Fogagnolo P. Comparison of the effects of latanoprost, travoprost, and bimatoprost on circadian intraocular pressure in patients with glaucoma or ocular hypertension.  Ophthalmology. 2006;113(2):239-246
PubMed   |  Link to Article
Sit AJ, Weinreb RN, Crowston JG, Kripke DF, Liu JH. Sustained effect of travoprost on diurnal and nocturnal intraocular pressure.  Am J Ophthalmol. 2006;141(6):1131-1133
PubMed   |  Link to Article
Toris CB, Gabelt BT, Kaufman PL. Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction.  Surv Ophthalmol. 2008;53:(suppl 1)  S107-S120
PubMed   |  Link to Article
Toris CB, Tafoya ME, Camras CB, Yablonski ME. Effects of apraclonidine on aqueous humor dynamics in human eyes.  Ophthalmology. 1995;102(3):456-461
PubMed
Liu JH, Weinreb RN. Monitoring intraocular pressure for 24 h.  Br J Ophthalmol. 2011;95(5):599-600
PubMed   |  Link to Article

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