Graefe's Archive
Graefe's Arch Clin Exp Ophthalmol (1991)229:50-51
lot Clinical and Experirnema!
Ophthalmology © Springer-Verlag 1991
Adrenergic and adrenolytic effects on intraocular pressure* Stephen M. Drance 1, Gordon R. Douglas 1, Kees J. Wijsman 1, and Michael Schulzer 2 1 Department of Ophthalmology and 2 Department of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, B.C. V5Z 3N9, Canada Received February 20, 1990 / Accepted May 28, 1990
Abstract. We compared the pressure-lowering effects o f timolol, pindolol, epinephrine and the mixture o f timolol and epinephrine with that o f placebo over a 12-h period. All agents reduced the pressure significantly but with varying time courses. The mixture o f timolol and epinephrine reduced the pressure significantly more than did timolol or epinephrine alone, especially at 12 h after the last administration of the drops.
Introduction The introduction o f beta-blockers has changed the pattern o f drug use for reducing intra-ocular pressure in glaucomatous eyes. These agents frequently reduce intraocular pressure markedly at the beginning of therapy, but in m a n y patients the intra-ocular pressure gradually rises later. When this occurs, we commonly combine the non-selective beta-blockers or the beta-1 selective blocker with an adrenergic agonist such as epinephrine or dipivefrin hydrochloride. Whether or not the addition of the adrenergic agonist further reduces intra-ocular pressure is a matter o f controversy. Some studies have shown a significant additive effect for the adrenergic agonist when it is used in combination with beta-blockers [3, 4], whereas other studies have not done so. In 1983 we showed [1] that at 1 h after a single topical drug instillation, a reduction in retinal light sensitivity occurred following the administration of timolol and, to a lesser degree, epinephrine, wheras pindolol showed no such change. The present study was devised to investigate the effects o f these agents and some of their combinations on visual function over a 36-h period. In this report, only the effects on intra-ocular pressure are reported.
* Supported in part by Medical Research Council grant MT-1578 Offprint requests to: S.M. Drance
Patients and methods A total of 50 glaucoma suspects with intra-ocular pressure elevations of >22 mmHg, normal optic nerve-head appearances, and full visual-field examinations were included in the study. In all, 13 patients were randomly selected for treatment with timolol; 9, for therapy with epinephrine; 8, for treatment with pindolol; 7 were assigned the combination of timolol and epinephrine; and placebo was used in 13 cases. Only one randomly selected eye of each patient was treated with the active ingredient (the other eye received placebo) from drop bottles that could not be identified by the investigators. There were a number of bottles containing identical placebo; thus, each eye of individuals randomly selected for placebo received it from a different bottle. In the group selected for the combination of timolol and epinephrine, the fellow eye received placebo from two different bottles. All patients were admitted to hospital and their intra-ocular pressures were recorded for 24 h at 6 a.m., 9 a.m., 11 a.m., 1 p.m., 3 p.m., 5 p.m., and 10 p.m., prior to the instillation of the first randomly selected medication. On the 2nd day, the randomly selected drops were instilled at 9:00 a.m, after baseline pressure recording. Intra-ocular pressures were tested again at 10:00 a.m., 11:30 a.m., and 2:00 p.m. A second medication was instilled at 9:00 p.m. that night and the intra-ocular pressure was recorded again at 9: 00 a.m., which was 24 h after the start of therapy and 12 h after the administration of the second drop of the randomly selected medication. Various visual functions were tested and the results will be reported separately. At each point in time, the intraocular pressure was compared with its baseline value and the pressure change was calculated; the percentage of pressure change was also determined. The results were analyzed for each drug by means of t-tests and the differences between drugs were evaluated by analyses of variance.
Results The mean pressure reductions for each drug and combination o f drugs at 1, 2.5, 5 and 12 h are shown graphically in Fig. 1 and are given quantitatively with the corresponding standard deviations in Table 1. Analysis o f variance on the pressure reductions induced by the five d r u g s and drug combinations at 1 h showed a highly significant ( P = 0 . 0 0 1 4 ) difference a m o n g the means. Multiple comparisons using D u n c a n ' s method showed that the effects o f timolol, pindolol and the combination of timolol and epinephrine were not
51 Table 1. Means and standard deviations of reductions in intra-ocular pressure from baseline values (in mmHg) for each drug and drug combination at 1, 2.5, 5 and 12 h Drug
Time (h)
Placebo Timolol Epinephrine Pindolol Timolol + epinephrine
+5
1
2.5
5
12
0.31 ± 2.59 4.19 ± 4.15 1.22 ± 3.06 4.56 ± 1.86 5.57 ± 2.92
0.54 ± 1.93 5.58 ± 3.86 2.33 ± 2.30 2.06 ± 1.88 7.71 ± 2.77
1.00 ± 3.04 5.65 ± 2.99 2.33 ± 2.66 2.19 ± 2.31 6.57 ± 3.27
- 1.46 ± 3.31 4.42 ± 4.22 3.44 ± 1.90 1.19 ± 3.88 8.43 ± 4.57
Discussion
1st drop O • [3 • A
Rise
-
Placebo (13) Timolol (13) Epinephrine (9) Pindolol (8) Timolol + Epinephrine (7)
0 -'1-
0-
o
-5
Fall _
-10
" NS
I
I
I
I
I
I
I
0
1
2
3
4
5
12
Hours After Instillation of Drops
Fig. 1. The pressure reduction produced by placebo, timolol, epinephrine, pindolol and the mixture of timolol and epinephrine. The statistically non-significant (NS) differences as compared with placebo values are indicated by asterisks. The greater pressure reduction at the end of 12 h produced by the mixture of timolol and epinephrine was statistically significantly different from the reductions caused by either timolol or epinephrine alone
statistically distinguishable but were all statistically greater than those of either epinephrine or the placebo. There was no statistical difference between the effects of epinephrine and those of the placebo. At 2.5 h, the changes induced by timolol and timolol plus epinephrine were not distinguishable from one another but were statistically larger ( P < 0.0001) than those caused by either epinephrine, pindolol or the placebo. The effects of the last three were again statistically indistinguishable from one another. At 5 h, the statistical order of the effects (P=0.0002) was the same as that observed at 2.5 h. Finally, at 12 h, timolol plus epinephrine had a statistically larger effect (P < 0.0001) than did either timolol, epinephrine, pindolol or the placebo alone. The changes induced by timolol and epinephrine alone were not statistically different but were statistically larger ( P < 0.0001) than those caused by the placebo.
The present study confirms that the combination of timolol and epinephrine reduces pressure more effectively than does either timolol or epinephrine alone. In the small sample studied, the difference was not statistically significant at up to 5 h after the instillation of the medication but became so at 12 h. This may explain some of the conflicting results reported in the literature, which may be attributable to the varying protocols used. The studies that reported a difference [3, 4] between changes induced by a beta-blocker and those caused by a combination of beta-blockers and an adrenergic agonist included pressure readings taken approximately 12 h after the last topical instillations. In the other studies [2, 5], the pressure reduction was measured only up to 3 or 4 h after the instillation of medication. In the present study, pindolol had a pressure-lowering effect similar to that of timolol but of much shorter duration, whereas the effects of epinephrine alone in reducing pressure were considerably smaller. The addition of an adrenergic agonist to a beta-blocker in the management of intra-ocular pressure should therefore be evaluated individually in every patient and may be particularly useful for pressure control over a longer period of time, such as 12 h after the previous instillation. It appears to be timely to study over a more prolonged period the effects of both beta-blockers and a combination of beta-blockers with adrenergic agonists as measured at 12 h after the instillation of the last dose. Such studies are now being undertaken. References I. Flammer J, Drance SM (1983) The effect of a number of glaucoma medications on the differential light threshold. In: Proceedings of the 5th International Visual Field Symposium. Junk, The Hague, pp 145-158 2. Keats EU, Stone RA (1981) Safety and effectiveness of concomitant administration of dipivefrin and timolol maleate. Am J Ophthalmol 91 : 243-248 3. Ohstrom A, Kattstrom O (1981) Interaction of timolol and adrenaline. Br J Ophthalmol 65: 53-55 4. Parrow KA, Young JH, Shin DH, Shi D-X, McCarty B (1989) Is it worthwhile to add dipivefrin CHL 0.1% to topical BI-, B2-blocker therapy? Ophthalmology 96:1338-1342 5. Thomas JV, Epstein DL (1981) TimoloI and epinephrine in primary open angle glaucoma: transient additive effect. Arch Ophthalmol 99 : 91-95
Graefe's Arch Clin Exp Ophthalmol (1991)229:50-51
lot Clinical and Experirnema!
Ophthalmology © Springer-Verlag 1991
Adrenergic and adrenolytic effects on intraocular pressure* Stephen M. Drance 1, Gordon R. Douglas 1, Kees J. Wijsman 1, and Michael Schulzer 2 1 Department of Ophthalmology and 2 Department of Medicine, University of British Columbia, 2550 Willow Street, Vancouver, B.C. V5Z 3N9, Canada Received February 20, 1990 / Accepted May 28, 1990
Abstract. We compared the pressure-lowering effects o f timolol, pindolol, epinephrine and the mixture o f timolol and epinephrine with that o f placebo over a 12-h period. All agents reduced the pressure significantly but with varying time courses. The mixture o f timolol and epinephrine reduced the pressure significantly more than did timolol or epinephrine alone, especially at 12 h after the last administration of the drops.
Introduction The introduction o f beta-blockers has changed the pattern o f drug use for reducing intra-ocular pressure in glaucomatous eyes. These agents frequently reduce intraocular pressure markedly at the beginning of therapy, but in m a n y patients the intra-ocular pressure gradually rises later. When this occurs, we commonly combine the non-selective beta-blockers or the beta-1 selective blocker with an adrenergic agonist such as epinephrine or dipivefrin hydrochloride. Whether or not the addition of the adrenergic agonist further reduces intra-ocular pressure is a matter o f controversy. Some studies have shown a significant additive effect for the adrenergic agonist when it is used in combination with beta-blockers [3, 4], whereas other studies have not done so. In 1983 we showed [1] that at 1 h after a single topical drug instillation, a reduction in retinal light sensitivity occurred following the administration of timolol and, to a lesser degree, epinephrine, wheras pindolol showed no such change. The present study was devised to investigate the effects o f these agents and some of their combinations on visual function over a 36-h period. In this report, only the effects on intra-ocular pressure are reported.
* Supported in part by Medical Research Council grant MT-1578 Offprint requests to: S.M. Drance
Patients and methods A total of 50 glaucoma suspects with intra-ocular pressure elevations of >22 mmHg, normal optic nerve-head appearances, and full visual-field examinations were included in the study. In all, 13 patients were randomly selected for treatment with timolol; 9, for therapy with epinephrine; 8, for treatment with pindolol; 7 were assigned the combination of timolol and epinephrine; and placebo was used in 13 cases. Only one randomly selected eye of each patient was treated with the active ingredient (the other eye received placebo) from drop bottles that could not be identified by the investigators. There were a number of bottles containing identical placebo; thus, each eye of individuals randomly selected for placebo received it from a different bottle. In the group selected for the combination of timolol and epinephrine, the fellow eye received placebo from two different bottles. All patients were admitted to hospital and their intra-ocular pressures were recorded for 24 h at 6 a.m., 9 a.m., 11 a.m., 1 p.m., 3 p.m., 5 p.m., and 10 p.m., prior to the instillation of the first randomly selected medication. On the 2nd day, the randomly selected drops were instilled at 9:00 a.m, after baseline pressure recording. Intra-ocular pressures were tested again at 10:00 a.m., 11:30 a.m., and 2:00 p.m. A second medication was instilled at 9:00 p.m. that night and the intra-ocular pressure was recorded again at 9: 00 a.m., which was 24 h after the start of therapy and 12 h after the administration of the second drop of the randomly selected medication. Various visual functions were tested and the results will be reported separately. At each point in time, the intraocular pressure was compared with its baseline value and the pressure change was calculated; the percentage of pressure change was also determined. The results were analyzed for each drug by means of t-tests and the differences between drugs were evaluated by analyses of variance.
Results The mean pressure reductions for each drug and combination o f drugs at 1, 2.5, 5 and 12 h are shown graphically in Fig. 1 and are given quantitatively with the corresponding standard deviations in Table 1. Analysis o f variance on the pressure reductions induced by the five d r u g s and drug combinations at 1 h showed a highly significant ( P = 0 . 0 0 1 4 ) difference a m o n g the means. Multiple comparisons using D u n c a n ' s method showed that the effects o f timolol, pindolol and the combination of timolol and epinephrine were not
51 Table 1. Means and standard deviations of reductions in intra-ocular pressure from baseline values (in mmHg) for each drug and drug combination at 1, 2.5, 5 and 12 h Drug
Time (h)
Placebo Timolol Epinephrine Pindolol Timolol + epinephrine
+5
1
2.5
5
12
0.31 ± 2.59 4.19 ± 4.15 1.22 ± 3.06 4.56 ± 1.86 5.57 ± 2.92
0.54 ± 1.93 5.58 ± 3.86 2.33 ± 2.30 2.06 ± 1.88 7.71 ± 2.77
1.00 ± 3.04 5.65 ± 2.99 2.33 ± 2.66 2.19 ± 2.31 6.57 ± 3.27
- 1.46 ± 3.31 4.42 ± 4.22 3.44 ± 1.90 1.19 ± 3.88 8.43 ± 4.57
Discussion
1st drop O • [3 • A
Rise
-
Placebo (13) Timolol (13) Epinephrine (9) Pindolol (8) Timolol + Epinephrine (7)
0 -'1-
0-
o
-5
Fall _
-10
" NS
I
I
I
I
I
I
I
0
1
2
3
4
5
12
Hours After Instillation of Drops
Fig. 1. The pressure reduction produced by placebo, timolol, epinephrine, pindolol and the mixture of timolol and epinephrine. The statistically non-significant (NS) differences as compared with placebo values are indicated by asterisks. The greater pressure reduction at the end of 12 h produced by the mixture of timolol and epinephrine was statistically significantly different from the reductions caused by either timolol or epinephrine alone
statistically distinguishable but were all statistically greater than those of either epinephrine or the placebo. There was no statistical difference between the effects of epinephrine and those of the placebo. At 2.5 h, the changes induced by timolol and timolol plus epinephrine were not distinguishable from one another but were statistically larger ( P < 0.0001) than those caused by either epinephrine, pindolol or the placebo. The effects of the last three were again statistically indistinguishable from one another. At 5 h, the statistical order of the effects (P=0.0002) was the same as that observed at 2.5 h. Finally, at 12 h, timolol plus epinephrine had a statistically larger effect (P < 0.0001) than did either timolol, epinephrine, pindolol or the placebo alone. The changes induced by timolol and epinephrine alone were not statistically different but were statistically larger ( P < 0.0001) than those caused by the placebo.
The present study confirms that the combination of timolol and epinephrine reduces pressure more effectively than does either timolol or epinephrine alone. In the small sample studied, the difference was not statistically significant at up to 5 h after the instillation of the medication but became so at 12 h. This may explain some of the conflicting results reported in the literature, which may be attributable to the varying protocols used. The studies that reported a difference [3, 4] between changes induced by a beta-blocker and those caused by a combination of beta-blockers and an adrenergic agonist included pressure readings taken approximately 12 h after the last topical instillations. In the other studies [2, 5], the pressure reduction was measured only up to 3 or 4 h after the instillation of medication. In the present study, pindolol had a pressure-lowering effect similar to that of timolol but of much shorter duration, whereas the effects of epinephrine alone in reducing pressure were considerably smaller. The addition of an adrenergic agonist to a beta-blocker in the management of intra-ocular pressure should therefore be evaluated individually in every patient and may be particularly useful for pressure control over a longer period of time, such as 12 h after the previous instillation. It appears to be timely to study over a more prolonged period the effects of both beta-blockers and a combination of beta-blockers with adrenergic agonists as measured at 12 h after the instillation of the last dose. Such studies are now being undertaken. References I. Flammer J, Drance SM (1983) The effect of a number of glaucoma medications on the differential light threshold. In: Proceedings of the 5th International Visual Field Symposium. Junk, The Hague, pp 145-158 2. Keats EU, Stone RA (1981) Safety and effectiveness of concomitant administration of dipivefrin and timolol maleate. Am J Ophthalmol 91 : 243-248 3. Ohstrom A, Kattstrom O (1981) Interaction of timolol and adrenaline. Br J Ophthalmol 65: 53-55 4. Parrow KA, Young JH, Shin DH, Shi D-X, McCarty B (1989) Is it worthwhile to add dipivefrin CHL 0.1% to topical BI-, B2-blocker therapy? Ophthalmology 96:1338-1342 5. Thomas JV, Epstein DL (1981) TimoloI and epinephrine in primary open angle glaucoma: transient additive effect. Arch Ophthalmol 99 : 91-95
