Therapeutic Index of Epinephrine and Dipivefrin With Nasolacrimal Occlusion Thorn J. Z i m m e r m a n , M.D., Mordechai Sharir, M.D., George F. Nardin, M.D., and M e g Fuqua
We assessed the effect of nasolacrimal occlusion on the therapeutic index of the adrenoreceptor agonists in healthy volunteers and patients with glaucoma. Nasolacrimal occlusion did not significantly alter the response to 2% epinephrine or to 0.1% dipivefrin in healthy subjects, suggesting that both 2% epinephrine and 0.1% dipivefrin are at the top of the doseresponse curve. When 0.5% epinephrine with nasolacrimal occlusion was tested in patients with glaucoma, effects were noticeable at four and eight hours (P < .05), but not at 12 hours. For 2% epinephrine, there was no significant difference at any measurement time. Epinephrine (1%) with and without nasolacrimal occlusion gave results similar to those of 2% epinephrine, suggesting that 1% epinephrine is also at the top of the dose-response curve. Nasolacrimal occlusion did not increase the ocular hypotensive effect of either of these concentrations. Because dipivefrin, the most widely used formulation in this class, is a prodrug of epinephrine that has a corneal penetration approximately 17 times that of epinephrine, 0.05% dipivefrin, every 12 hours, might be an adequate dosage for maximal effect. Although nasolacrimal occlusion did not alter the drug effect of 0.1% dipivefrin, preventing as much drug as possible from reaching the systemic circulation is desirable.
Accepted for publication April 28, 1992. From the Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Research Institute, Uni versity of Louisville, School of Medicine, Louisville, Kentucky. Reprint requests to Thorn J. Zimmerman, M.D., De partment of Ophthalmology and Visual Sciences, Ken tucky Lions Eye Research Institute, 301 E. Muhammad Ali Blvd., Louisville, KY 40292.
8
W E STUDIED the effect of nasolacrimal oc clusion on the therapeutic index of topical solutions of epinephrine hydrochloride and dipivefrin. Eyedrops as opposed to systemically administered medication approach organ speci ficity for the eye. However, because of sub stantial escape through the lacrimai drainage system, and absorption into the systemic circulation via the nasopharyngeal mucosa, specificity is lost to some extent. 1,2 Remarkable plasma concentrations of eye medications have been found after instillation. 310 Nasolacrimal occlusion is a technique that can make topical ocular treatment safer and more efficacious. Nasolacrimal occlusion can improve the therapeutic index by up to eight fold because of its effect on both the numerator and denominator of this fraction. Nasolacrimal occlusion markedly decreases the systemic ab sorption (denominator), while increasing ocu lar bioavailability (numerator). This maneuver allows lower drug concentrations to be used less frequently, which further increases safe ty.11 We determined the changes in the dose-re sponse curves and duration of action with and without use of nasolacrimal occlusion. Portions of these studies were presented either orally or by a poster at the 1987 and 1988 annual meet ings of the Association for Research in Vision and Ophthalmology. We analyzed data from studies with epinephrine and dipivefrin.
Patients and Methods Dose response and duration of action in healthy subjects—Twenty healthy volunteers were test ed over a two-day period with 0.5% epineph rine, 2% epinephrine, and 0.1% dipivefrin (n = 22). Each subject was treated with epinephrine or dipivefrin or a placebo over a five-week
©AMERICAN JOURNAL OF OPHTHALMOLOGY 114:8-13, JULY, 1992
Vol. 114, No. 1
Epinephrine and Dipivefrin With Nasolacrimal Occlusion
period, at 8:00 A.M. and 10:00 P.M. daily. Naso lacrimal occlusion was performed in one eye only and the intraocular pressures were mea sured at four, eight, ten, and 12 hours after instillation. Dose response and duration of action impatients with glaucoma—In our first set of doublemasked studies in which subjects were random ly assigned to treatment, the action of 0.5% epinephrine hydrochloride solution with and without nasolacrimal occlusion was compared with that of a placebo in 13 patients with glaucoma. In a second series of studies, 0.5% and 2% epinephrine solutions were instilled in both eyes of ten patients with open-angle glaucoma. During and immediately after drug instillation, nasolacrimal occlusion was performed in one eye only. Intraocular pressures were measured at baseline and at four, eight, and 12 hours. After the studies with 0.5% and 2% solutions of epinephrine, 1% epinephrine was studied in 22 patients with glaucoma. Of the two eyes treated, one eye was randomly subjected to nasolacrimal occlusion while the fellow eye served as a control. Intraocular pressures were measured at baseline and at four, eight, 12, and 24 hours. The last series of experiments with this class of medications compared 0.1% dipivefrin with and without nasolacrimal occlusion to placebo in 20 healthy subjects. The methods were al ready described. In all studies a masked observer measured the intraocular pressures. A two-tailed Student's f-test for paired data and one-way analysis of
ni i
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345-
υ Q
T [
x
2-
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6-
variance were used in all statistical analyses, with a 5% level of significance.
Results There was only a minimal difference in the intraocular pressure measurements with 0.5% epinephrine with and without nasolacrimal oc clusion in healthy volunteers (Fig. 1). Although 0.5% epinephrine without nasolacrimal occlu sion showed a statistically significant difference in intraocular pressure, decreasing from the intraocular pressure with a placebo at four and ten hours, the significant decrease in intraocu lar pressure was prolonged to at least 12 hours when nasolacrimal occlusion was added. Both 2% epinephrine with and without naso lacrimal occlusion showed significant decrease in the intraocular pressure at four, ten, and 12 hours (Fig. 2). There was no significant differ ence between these two treatments, suggesting that 2% epinephrine is at the top of the doseresponse curve. The ocular hypotensive effect of 0.1% dipivefrin with and without nasolacrimal oc clusion was compared to that of a placebo (Fig. 3). There was a significant decrease in the intraocular pressure at ten hours with and without nasolacrimal occlusion when com pared with placebo effect in healthy volunteers. There was no difference in the intraocular pres sures at any time between dipivefrin-treated eyes whether nasolacrimal occlusion was performed.
o- —■·φO
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= without nasolacrimal occlusion = with nasolacrimal occlusion -- A = Placebo
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Fig. 1 (Zimmerman and associates). The ocular hypotensive effect of 0.5% epinephrine with and without naso lacrimal occlusion vs placebo in 20 healthy subjects. Results were deter mined as mean intraocular pressure (ΙΟΡ) decrease (mm Hg) from the baseline value (±SEM). *P < .05, Stu dent's two-tailed paired f-test.
10
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
φ = without nasolacrimal occlusion Δ = with nasolacrimal occlusion
en X
O = placebo
fFig. 2 (Zimmerman and associates). The ocular hypotensive effect of 2.0% epinephrine with and without naso lacrimal occlusion vs placebo in 20 normal subjects. Results were deter mined as mean intraocular pressure (IOP) decrease (mm Hg) from the baseline value (±SEM). *P < .05, Stu dent's two-tailed paired f-test.
a m
O
Time (hr)
Further analysis of the adrenergic agents in healthy volunteers showed that there were no significant differences in intraocular pressure at any time between the eyes in which nasolacri mal occlusion was performed and the eyes in which no nasolacrimal occlusion was per formed for any concentration except for epi nephrine 0.5%. Through nasolacrimal occlu sion, there were no significant differences when comparing any concentration with another (as determined by one-way analysis of variance). When 0.5% epinephrine was tested in pa tients with glaucoma, nasolacrimal occlusion effects were noticeable, especially at four and eight hours (Fig. 4). For 2% epinephrine, there was no difference at any measurement time (Fig. 5).
I
en E E
The intermediate epinephrine concentration of 1% demonstrated a significant decrease in the intraocular pressures at all time measure ments for both eyes when compared to baseline intraocular pressures (Fig. 6). There was no difference between the group in which nasolac rimal occlusion was performed and the group in which nasolacrimal occlusion was not per formed at any time point.
Discussion The topical use of epinephrine has been asso ciated with alarming and potentially lethal side effects. Therefore, the notion that eyedrops are
9 Δ
· = without nasolacrimal occlusion Δ = with nasolacrimal occlusion
O
O = placebo
Fig. 3 (Zimmerman and associates). The ocular hypotensive effect of 0.1% dipivefrin with and without nasolacri mal occlusion vs placebo in 20 normal subjects. Results were determined as mean intraocular pressure (IOP) de crease (mm Hg) from the baseline val ue (±SEM). *P < .05, Student's twotailed paired /-test.
Q_
O
σ CD
υ cu Q
Time (hr)
Vol. 114, No. 1
Epinephrine and Dipivefrin With Nasolacrimal Occlusion
11
without nasolocrimal occlusion
X
with nasolacrimal occlusion
Fig. 4 (Zimmerman and associates). The ocular hypotensive effect of 0.5% epinephrine with and without naso lacrimal occlusion in ten patients with glaucoma. Results were determined as mean intraocular pressure decrease (mm Hg) from the baseline value (±SEM). *P < .05, Student's twotailed paired f-test.
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Time (hr)
harmless is debatable. Research has focused on increasing the therapeutic index of the ocular medications. Once a topical medication gains access to the circulation, the potential for side effects cannot be altered to any substantial degree, because they are dependent on the inherent properties of the drug and several host factors. Nasolacrimal occlusion increases the drug concentration available to the eye and marked ly decreases systemic absorption. 11 We hypothe sized that nasolacrimal occlusion can increase drug absorption in the eye by preventing the drug from escaping via overflow access into the systemic circulation. The minimal drug concen tration and frequency of instillation that is still effective and, therefore, safer than the currently
cs
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26
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used conventional treatment regimens were de termined. The studies with the sympathomimetic agents in a normal population failed to demon strate any difference in the dose-response curves or the duration of action between 0.5% epinephrine and 2% epinephrine if nasolacri mal occlusion was used (Figs. 1 and 2). In the same setting, dipivefrin with and without naso lacrimal occlusion (Fig. 3) and 0.5% epineph rine without nasolacrimal occlusion (Fig. 1) fell short of the other treatments. In our patients with glaucoma, nasolacrimal occlusion increased the magnitude of the ocular hypotensive effect of 0.5% epinephrine at four and eight hours (Fig. 4, P < .05). Epinephrine (0.5%) with nasolacrimal occlusion was statisti
nasolacrimal occlusion ° -- ο = without with nasolacrima occlusion
··-- - - · = 1
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1
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Fig. 5 (Zimmerman and associates). The ocular hypotensive effect of 2.0% epinephrine with and without naso lacrimal occlusion in ten patients with glaucoma. Results were determined as mean intraocular pressure decrease (mm Hg) from the baseline value (±SEM). *P < .05, Student's twotailed paired f-test.
12
I
E E
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
- Ο = without nosolacrimol occlusion ♦ = with nasolacrimal occlusion
Fig. 6 (Zimmerman and associates). The ocular hypotensive effect of 1.0% epinephrine with and without naso lacrimal occlusion in 22 patients with glaucoma. Results were determined as mean intraocular pressure decrease (mm Hg) from the baseline value (±SEM). *P < .05, Student's twotailed paired i-test.
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Time (hr) cally different from placebo at 12 hours (Fig. 1, P < .05). Epinephrine (1%) with and without nasolacrimal occlusion (Fig. 6) gave results sim ilar to those of 2% epinephrine (Fig. 5), sug gesting that both of these concentrations are at the top of the dose-response curve. Nasolacri mal occlusion did not change the pharmacolog ie effect of either of these concentrations. Fur thermore, 1% epinephrine with or without nasolacrimal occlusion was significantly differ ent than placebo at 24 hours (P < .05, Fig. 6). Adrenoreceptor agonists have been gradually disappearing from the antiglaucoma armamen tarium. Most patients do not respond favorably to treatment with these agents. The medication most used in this class is dipivefrin. Being a prodrug of epinephrine with a corneal penetra tion approximately 17 times that of epineph rine, treatment with 0.05% dipivefrin every 12 hours might be adequate for maximal effect. Although nasolacrimal occlusion did not alter the drug effect of 0.1% dipivefrin, it is impor tant to prevent systemic absorption of these agents as much as possible because of their potentially lethal side effects. There is never a situation in which a systemic plasma concentra tion is desirable after the instillation of a topi cal ocular medication. Because of the potential ly lethal side effects, nasolacrimal occlusion should be performed when eyedrops are dis pensed, whether for glaucoma or for any other indication. All of our studies demonstrated that use of nasolacrimal occlusion achieves maximal drug effect with half the concentrations com monly prescribed. Furthermore, the frequency of instillation can be reduced (that is, from four
times a day and three times a day to twice a day, and from twice a day to once daily). These alterations change markedly the therapeutic index (therapeutic index = desired effect/side effect) of the medication. ACKNOWLEDGMENT
The following glaucoma fellows gathered data for this manuscript at the University of Louisville during the years 1986 through 1990: Thomas K. Mundorf, M.D., Kenyon Kendall, D.O., Harvey DuBiner, M.D., David K. Linn, M.D., Richard B. Patchett, M.D., Umar M. Dukar, M.D., William H. Lee, M.D., and Robert E. Price, M.D.
References 1. Patton, T. F., and Francoeur, M.: Ocular bioavailability and systemic loss of topically applied ophthalmic drugs. Am. J. Ophthalmol. 85:225, 1978. 2. Proetz, A. W.: Essays on the Applied Physiology of the Nose, ed. 2. St. Louis, Annals Publishing Co., 1953, p. 326. 3. Wei, C.-P., Anderson, J. A., and Leopold I. H.: Ocular absorption and metabolism of topically ap plied epinephrine and a dipivalyl ester of epineph rine. Invest. Ophthalmol. Vis. Sci. 17:315, 1978. 4. Ballin, N., Becker, B., and Goldman, M. L.: Sys temic effects of epinephrine applied topically to the eye. Invest Ophthalmol. Vis. Sci. 5:125, 1966. 5. Fraunfelder, F. T.: Interim report. National reg istry of possible drug-induced ocular side-effects. Ophthalmology 87:87, 1980.
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Epinephrine and Dipivefrin With Nasolacrimal Occlusion
6. Becker, B., and Morton, W. R.: Topical epineph rine in glaucoma suspects. Am. J. Ophthalmol. 62:272, 1966. 7. Fraunfelder, F. T., and Scandi, A. F.: Possible adverse effects from ocular 10% phenylephrine. Am. J. Ophthalmol. 85:447, 1978. 8. Anderson, J. A.: Systemic absorption of topical ocularly applied epinephrine and dipivefrin. Arch. Ophthalmol. 98:350, 1980. 9. Lansche, R. K.: Systemic reactions to topical
13
epinephrine and phenylephrine. Am. J. Ophthalmol. 61:95, 1966. 10. McReynolds, W. U., Havener, W. H., and Hen derson, J. W.: Hazards of the use of sympathomimetic drugs in ophthalmology. Arch. Ophthalmol. 56:176, 1956. 11. Zimmerman, T. J., Kooner, K. S., Kandarakis, A. S., and Ziegler, L. P.: Improving the therapeutic index of topically applied ocular drugs. Arch. Oph thalmol. 102:551, 1984.
OPHTHALMIC MINIATURE
Perplexity came to her from the beast. " W h a t is this dark? What is this light? We do not understand. Your father and the boy, Calvin, have asked this, too. They say that it is night now on our planet, and that they cannot see. They have told us that our atmosphere is what they call opaque, so that the stars are not visible, and then they were surprised that we know stars, that we know their music and the m o v e m e n t s of their dance far better t h a n beings like you w h o spend h o u r s studying t h e m t h r o u g h w h a t you call telescopes. We do not u n d e r s t a n d what this m e a n s , to see." "Well, it's what things look l i k e , " Meg said helplessly. "We do not know what things look like, as you say," the beast said. "We know what things are like. It must be a very limiting thing, this seeing." " O h , n o ! " Meg cried. "It's—it's the most wonderful thing in the world!" " W h a t a strange world yours must b e ! " the beast said, " t h a t such a peculiar-seeming thing should be of such importance. Try to tell me, what is this thing called light that you are able to do so little w i t h o u t ? " "Well, we can't see without it," Meg said, realizing that she was completely u n a b l e to explain vision a n d light and dark. How can you explain sight on a world where n o one has ever seen a n d where there is n o need of eyes?" Madeleine L'Engle, A Wrinkle in Time New York, Bantam Doubleday Dell Publishing, 1962, p. 181
We assessed the effect of nasolacrimal occlusion on the therapeutic index of the adrenoreceptor agonists in healthy volunteers and patients with glaucoma. Nasolacrimal occlusion did not significantly alter the response to 2% epinephrine or to 0.1% dipivefrin in healthy subjects, suggesting that both 2% epinephrine and 0.1% dipivefrin are at the top of the doseresponse curve. When 0.5% epinephrine with nasolacrimal occlusion was tested in patients with glaucoma, effects were noticeable at four and eight hours (P < .05), but not at 12 hours. For 2% epinephrine, there was no significant difference at any measurement time. Epinephrine (1%) with and without nasolacrimal occlusion gave results similar to those of 2% epinephrine, suggesting that 1% epinephrine is also at the top of the dose-response curve. Nasolacrimal occlusion did not increase the ocular hypotensive effect of either of these concentrations. Because dipivefrin, the most widely used formulation in this class, is a prodrug of epinephrine that has a corneal penetration approximately 17 times that of epinephrine, 0.05% dipivefrin, every 12 hours, might be an adequate dosage for maximal effect. Although nasolacrimal occlusion did not alter the drug effect of 0.1% dipivefrin, preventing as much drug as possible from reaching the systemic circulation is desirable.
Accepted for publication April 28, 1992. From the Department of Ophthalmology and Visual Sciences, Kentucky Lions Eye Research Institute, Uni versity of Louisville, School of Medicine, Louisville, Kentucky. Reprint requests to Thorn J. Zimmerman, M.D., De partment of Ophthalmology and Visual Sciences, Ken tucky Lions Eye Research Institute, 301 E. Muhammad Ali Blvd., Louisville, KY 40292.
8
W E STUDIED the effect of nasolacrimal oc clusion on the therapeutic index of topical solutions of epinephrine hydrochloride and dipivefrin. Eyedrops as opposed to systemically administered medication approach organ speci ficity for the eye. However, because of sub stantial escape through the lacrimai drainage system, and absorption into the systemic circulation via the nasopharyngeal mucosa, specificity is lost to some extent. 1,2 Remarkable plasma concentrations of eye medications have been found after instillation. 310 Nasolacrimal occlusion is a technique that can make topical ocular treatment safer and more efficacious. Nasolacrimal occlusion can improve the therapeutic index by up to eight fold because of its effect on both the numerator and denominator of this fraction. Nasolacrimal occlusion markedly decreases the systemic ab sorption (denominator), while increasing ocu lar bioavailability (numerator). This maneuver allows lower drug concentrations to be used less frequently, which further increases safe ty.11 We determined the changes in the dose-re sponse curves and duration of action with and without use of nasolacrimal occlusion. Portions of these studies were presented either orally or by a poster at the 1987 and 1988 annual meet ings of the Association for Research in Vision and Ophthalmology. We analyzed data from studies with epinephrine and dipivefrin.
Patients and Methods Dose response and duration of action in healthy subjects—Twenty healthy volunteers were test ed over a two-day period with 0.5% epineph rine, 2% epinephrine, and 0.1% dipivefrin (n = 22). Each subject was treated with epinephrine or dipivefrin or a placebo over a five-week
©AMERICAN JOURNAL OF OPHTHALMOLOGY 114:8-13, JULY, 1992
Vol. 114, No. 1
Epinephrine and Dipivefrin With Nasolacrimal Occlusion
period, at 8:00 A.M. and 10:00 P.M. daily. Naso lacrimal occlusion was performed in one eye only and the intraocular pressures were mea sured at four, eight, ten, and 12 hours after instillation. Dose response and duration of action impatients with glaucoma—In our first set of doublemasked studies in which subjects were random ly assigned to treatment, the action of 0.5% epinephrine hydrochloride solution with and without nasolacrimal occlusion was compared with that of a placebo in 13 patients with glaucoma. In a second series of studies, 0.5% and 2% epinephrine solutions were instilled in both eyes of ten patients with open-angle glaucoma. During and immediately after drug instillation, nasolacrimal occlusion was performed in one eye only. Intraocular pressures were measured at baseline and at four, eight, and 12 hours. After the studies with 0.5% and 2% solutions of epinephrine, 1% epinephrine was studied in 22 patients with glaucoma. Of the two eyes treated, one eye was randomly subjected to nasolacrimal occlusion while the fellow eye served as a control. Intraocular pressures were measured at baseline and at four, eight, 12, and 24 hours. The last series of experiments with this class of medications compared 0.1% dipivefrin with and without nasolacrimal occlusion to placebo in 20 healthy subjects. The methods were al ready described. In all studies a masked observer measured the intraocular pressures. A two-tailed Student's f-test for paired data and one-way analysis of
ni i
o
CD
o
o
345-
υ Q
T [
x
2-
E
6-
variance were used in all statistical analyses, with a 5% level of significance.
Results There was only a minimal difference in the intraocular pressure measurements with 0.5% epinephrine with and without nasolacrimal oc clusion in healthy volunteers (Fig. 1). Although 0.5% epinephrine without nasolacrimal occlu sion showed a statistically significant difference in intraocular pressure, decreasing from the intraocular pressure with a placebo at four and ten hours, the significant decrease in intraocu lar pressure was prolonged to at least 12 hours when nasolacrimal occlusion was added. Both 2% epinephrine with and without naso lacrimal occlusion showed significant decrease in the intraocular pressure at four, ten, and 12 hours (Fig. 2). There was no significant differ ence between these two treatments, suggesting that 2% epinephrine is at the top of the doseresponse curve. The ocular hypotensive effect of 0.1% dipivefrin with and without nasolacrimal oc clusion was compared to that of a placebo (Fig. 3). There was a significant decrease in the intraocular pressure at ten hours with and without nasolacrimal occlusion when com pared with placebo effect in healthy volunteers. There was no difference in the intraocular pres sures at any time between dipivefrin-treated eyes whether nasolacrimal occlusion was performed.
o- —■·φO
1 -,
1 -■
9
\
·-
= without nasolacrimal occlusion = with nasolacrimal occlusion -- A = Placebo
^ \
-Δ
T .----4-- ' "A" 1
\
x
8-
„_—1
*
j
1
o
' 1 *
1 *
1
h-
" '1 ·' * —1
12 Time (hr)
Fig. 1 (Zimmerman and associates). The ocular hypotensive effect of 0.5% epinephrine with and without naso lacrimal occlusion vs placebo in 20 healthy subjects. Results were deter mined as mean intraocular pressure (ΙΟΡ) decrease (mm Hg) from the baseline value (±SEM). *P < .05, Stu dent's two-tailed paired f-test.
10
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
φ = without nasolacrimal occlusion Δ = with nasolacrimal occlusion
en X
O = placebo
fFig. 2 (Zimmerman and associates). The ocular hypotensive effect of 2.0% epinephrine with and without naso lacrimal occlusion vs placebo in 20 normal subjects. Results were deter mined as mean intraocular pressure (IOP) decrease (mm Hg) from the baseline value (±SEM). *P < .05, Stu dent's two-tailed paired f-test.
a m
O
Time (hr)
Further analysis of the adrenergic agents in healthy volunteers showed that there were no significant differences in intraocular pressure at any time between the eyes in which nasolacri mal occlusion was performed and the eyes in which no nasolacrimal occlusion was per formed for any concentration except for epi nephrine 0.5%. Through nasolacrimal occlu sion, there were no significant differences when comparing any concentration with another (as determined by one-way analysis of variance). When 0.5% epinephrine was tested in pa tients with glaucoma, nasolacrimal occlusion effects were noticeable, especially at four and eight hours (Fig. 4). For 2% epinephrine, there was no difference at any measurement time (Fig. 5).
I
en E E
The intermediate epinephrine concentration of 1% demonstrated a significant decrease in the intraocular pressures at all time measure ments for both eyes when compared to baseline intraocular pressures (Fig. 6). There was no difference between the group in which nasolac rimal occlusion was performed and the group in which nasolacrimal occlusion was not per formed at any time point.
Discussion The topical use of epinephrine has been asso ciated with alarming and potentially lethal side effects. Therefore, the notion that eyedrops are
9 Δ
· = without nasolacrimal occlusion Δ = with nasolacrimal occlusion
O
O = placebo
Fig. 3 (Zimmerman and associates). The ocular hypotensive effect of 0.1% dipivefrin with and without nasolacri mal occlusion vs placebo in 20 normal subjects. Results were determined as mean intraocular pressure (IOP) de crease (mm Hg) from the baseline val ue (±SEM). *P < .05, Student's twotailed paired /-test.
Q_
O
σ CD
υ cu Q
Time (hr)
Vol. 114, No. 1
Epinephrine and Dipivefrin With Nasolacrimal Occlusion
11
without nasolocrimal occlusion
X
with nasolacrimal occlusion
Fig. 4 (Zimmerman and associates). The ocular hypotensive effect of 0.5% epinephrine with and without naso lacrimal occlusion in ten patients with glaucoma. Results were determined as mean intraocular pressure decrease (mm Hg) from the baseline value (±SEM). *P < .05, Student's twotailed paired f-test.
in Q_
Z5 O O D
C
o
0)
Time (hr)
harmless is debatable. Research has focused on increasing the therapeutic index of the ocular medications. Once a topical medication gains access to the circulation, the potential for side effects cannot be altered to any substantial degree, because they are dependent on the inherent properties of the drug and several host factors. Nasolacrimal occlusion increases the drug concentration available to the eye and marked ly decreases systemic absorption. 11 We hypothe sized that nasolacrimal occlusion can increase drug absorption in the eye by preventing the drug from escaping via overflow access into the systemic circulation. The minimal drug concen tration and frequency of instillation that is still effective and, therefore, safer than the currently
cs
I E E Zi
ω C/ì
26
1Γ
244 ττ .
"*. j
used conventional treatment regimens were de termined. The studies with the sympathomimetic agents in a normal population failed to demon strate any difference in the dose-response curves or the duration of action between 0.5% epinephrine and 2% epinephrine if nasolacri mal occlusion was used (Figs. 1 and 2). In the same setting, dipivefrin with and without naso lacrimal occlusion (Fig. 3) and 0.5% epineph rine without nasolacrimal occlusion (Fig. 1) fell short of the other treatments. In our patients with glaucoma, nasolacrimal occlusion increased the magnitude of the ocular hypotensive effect of 0.5% epinephrine at four and eight hours (Fig. 4, P < .05). Epinephrine (0.5%) with nasolacrimal occlusion was statisti
nasolacrimal occlusion ° -- ο = without with nasolacrima occlusion
··-- - - · = 1
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1
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1 Ϊ
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Fig. 5 (Zimmerman and associates). The ocular hypotensive effect of 2.0% epinephrine with and without naso lacrimal occlusion in ten patients with glaucoma. Results were determined as mean intraocular pressure decrease (mm Hg) from the baseline value (±SEM). *P < .05, Student's twotailed paired f-test.
12
I
E E
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
- Ο = without nosolacrimol occlusion ♦ = with nasolacrimal occlusion
Fig. 6 (Zimmerman and associates). The ocular hypotensive effect of 1.0% epinephrine with and without naso lacrimal occlusion in 22 patients with glaucoma. Results were determined as mean intraocular pressure decrease (mm Hg) from the baseline value (±SEM). *P < .05, Student's twotailed paired i-test.
Ζ!
υ ο ο
C
σ
CD
Time (hr) cally different from placebo at 12 hours (Fig. 1, P < .05). Epinephrine (1%) with and without nasolacrimal occlusion (Fig. 6) gave results sim ilar to those of 2% epinephrine (Fig. 5), sug gesting that both of these concentrations are at the top of the dose-response curve. Nasolacri mal occlusion did not change the pharmacolog ie effect of either of these concentrations. Fur thermore, 1% epinephrine with or without nasolacrimal occlusion was significantly differ ent than placebo at 24 hours (P < .05, Fig. 6). Adrenoreceptor agonists have been gradually disappearing from the antiglaucoma armamen tarium. Most patients do not respond favorably to treatment with these agents. The medication most used in this class is dipivefrin. Being a prodrug of epinephrine with a corneal penetra tion approximately 17 times that of epineph rine, treatment with 0.05% dipivefrin every 12 hours might be adequate for maximal effect. Although nasolacrimal occlusion did not alter the drug effect of 0.1% dipivefrin, it is impor tant to prevent systemic absorption of these agents as much as possible because of their potentially lethal side effects. There is never a situation in which a systemic plasma concentra tion is desirable after the instillation of a topi cal ocular medication. Because of the potential ly lethal side effects, nasolacrimal occlusion should be performed when eyedrops are dis pensed, whether for glaucoma or for any other indication. All of our studies demonstrated that use of nasolacrimal occlusion achieves maximal drug effect with half the concentrations com monly prescribed. Furthermore, the frequency of instillation can be reduced (that is, from four
times a day and three times a day to twice a day, and from twice a day to once daily). These alterations change markedly the therapeutic index (therapeutic index = desired effect/side effect) of the medication. ACKNOWLEDGMENT
The following glaucoma fellows gathered data for this manuscript at the University of Louisville during the years 1986 through 1990: Thomas K. Mundorf, M.D., Kenyon Kendall, D.O., Harvey DuBiner, M.D., David K. Linn, M.D., Richard B. Patchett, M.D., Umar M. Dukar, M.D., William H. Lee, M.D., and Robert E. Price, M.D.
References 1. Patton, T. F., and Francoeur, M.: Ocular bioavailability and systemic loss of topically applied ophthalmic drugs. Am. J. Ophthalmol. 85:225, 1978. 2. Proetz, A. W.: Essays on the Applied Physiology of the Nose, ed. 2. St. Louis, Annals Publishing Co., 1953, p. 326. 3. Wei, C.-P., Anderson, J. A., and Leopold I. H.: Ocular absorption and metabolism of topically ap plied epinephrine and a dipivalyl ester of epineph rine. Invest. Ophthalmol. Vis. Sci. 17:315, 1978. 4. Ballin, N., Becker, B., and Goldman, M. L.: Sys temic effects of epinephrine applied topically to the eye. Invest Ophthalmol. Vis. Sci. 5:125, 1966. 5. Fraunfelder, F. T.: Interim report. National reg istry of possible drug-induced ocular side-effects. Ophthalmology 87:87, 1980.
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Epinephrine and Dipivefrin With Nasolacrimal Occlusion
6. Becker, B., and Morton, W. R.: Topical epineph rine in glaucoma suspects. Am. J. Ophthalmol. 62:272, 1966. 7. Fraunfelder, F. T., and Scandi, A. F.: Possible adverse effects from ocular 10% phenylephrine. Am. J. Ophthalmol. 85:447, 1978. 8. Anderson, J. A.: Systemic absorption of topical ocularly applied epinephrine and dipivefrin. Arch. Ophthalmol. 98:350, 1980. 9. Lansche, R. K.: Systemic reactions to topical
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epinephrine and phenylephrine. Am. J. Ophthalmol. 61:95, 1966. 10. McReynolds, W. U., Havener, W. H., and Hen derson, J. W.: Hazards of the use of sympathomimetic drugs in ophthalmology. Arch. Ophthalmol. 56:176, 1956. 11. Zimmerman, T. J., Kooner, K. S., Kandarakis, A. S., and Ziegler, L. P.: Improving the therapeutic index of topically applied ocular drugs. Arch. Oph thalmol. 102:551, 1984.
OPHTHALMIC MINIATURE
Perplexity came to her from the beast. " W h a t is this dark? What is this light? We do not understand. Your father and the boy, Calvin, have asked this, too. They say that it is night now on our planet, and that they cannot see. They have told us that our atmosphere is what they call opaque, so that the stars are not visible, and then they were surprised that we know stars, that we know their music and the m o v e m e n t s of their dance far better t h a n beings like you w h o spend h o u r s studying t h e m t h r o u g h w h a t you call telescopes. We do not u n d e r s t a n d what this m e a n s , to see." "Well, it's what things look l i k e , " Meg said helplessly. "We do not know what things look like, as you say," the beast said. "We know what things are like. It must be a very limiting thing, this seeing." " O h , n o ! " Meg cried. "It's—it's the most wonderful thing in the world!" " W h a t a strange world yours must b e ! " the beast said, " t h a t such a peculiar-seeming thing should be of such importance. Try to tell me, what is this thing called light that you are able to do so little w i t h o u t ? " "Well, we can't see without it," Meg said, realizing that she was completely u n a b l e to explain vision a n d light and dark. How can you explain sight on a world where n o one has ever seen a n d where there is n o need of eyes?" Madeleine L'Engle, A Wrinkle in Time New York, Bantam Doubleday Dell Publishing, 1962, p. 181
