Therapeutic Index of Pilocarpine, Carbachol, and Timolol With Nasolacrimal Occlusion T h o m J. Z i m m e r m a n , M . D . , Mordechai Sharir, M . D . , George F. N a r d i n , M . D . , and M e g Fuqua We assessed the effect of nasolacrimal occlu sion on the therapeutic index of various antiglaucoma medications in healthy volunteers and patients with glaucoma. Nasolacrimal oc clusion used with pilocarpine 2% every 12 hours gave the maximal ocular hypotensive response. Carbachol 1.5% every 12 hours with nasolacrimal occlusion gave the maximal re sponse for this drug. For timolol, nasolacrimal occlusion collapsed the dose-response curve and extended the duration of action. A final trial of carbachol added to timolol with naso lacrimal occlusion showed that timolol 0.25% and carbachol 1.5% every 12 hours gave the maximal response for this combination. Our findings suggest that most of the commercial ly used ocular hypotensive agents can achieve the same maximal effect with lower concen trations and less frequent administration (never exceeding every 12 hours) than are currently recommended should nasolacrimal occlusion be performed. Furthermore, naso lacrimal occlusion should markedly decrease the systemic absorption of topical ocular drugs and lessen the chance of systemic side effects.
A F T E R DRUG INSTILLATION, 85%
of a 50-μ1
eye-
drop is immediately lost to overflow and blink ing. 1 Much of the loss is caused by drainage through the nasolacrimal system into the pos terior nasopharynx, which has a large surface area that is lined with a highly vascularized mucosal membrane. 2 Therefore, it is not sur
prising to detect marked, and sometimes toxic blood concentrations of instilled ocular medi cations. 310 Nasolacrimal occlusion is an easy technique that can make topical ocular treatment safer and more efficacious. Nasolacrimal occlusion can improve the therapeutic index by markedly decreasing the amount of drug absorbed systemically from instillation, while increasing the drug-cornea contact time and the transcorneal movement into the eye. 9 The increase in the amount of drug absorbed by the eye might augment the effect of the drug or its duration of action, or both. This, in turn, might allow lower drug concentrations to be used less frequently, which would further increase safety. Our multiple studies assessed the importance of nasolacrimal occlusion by examining the dose response and duration of action of various topical ocular hypotensive agents with and without this technique. Portions of these stud ies were presented either orally or by a poster at the 1987 and 1988 annual meetings of the Association for Research in Vision and Oph thalmology. We used data accumulated from studies using pilocarpine, carbachol, timolol, and carbachol added to treatment with timolol. We attempted to determine whether nasolacri mal occlusion shifts the dose-response curves to the left, thereby achieving maximal drug effect by lower concentrations. Furthermore, the increased drug-cornea contact time caused by nasolacrimal occlusion might increase their duration of action.
Patients and Methods 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 Thom 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.
Dose response to pilocarpine and duration of action in patients with glaucoma—We examined six patients with glaucoma (four white, two black) by instilling 1 % pilocarpine hydrochloride in one eye and a placebo in the fellow eye in a double-masked randomly allocated fashion.
©AMERICAN JOURNAL OF OPHTHALMOLOGY 114:1-7, JULY, 1992
1
2
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
Another 15 patients with glaucoma (nine white, six black) received 2% pilocarpine hydrochloride in one eye and a placebo in the fellow eye, also by random selection. In both instances, nasolacrimal occlusion was per formed for three minutes during and immedi ately after drug instillation. Intraocular pres sures were measured at baseline and at six, eight, and 12 hours. As a control, data were gathered from another ten patients with glau coma (seven white, three black) who received 2% pilocarpine hydrochloride in one eye with out the use of nasolacrimal occlusion. For the control group, the intraocular pressures were measured at baseline and at four, eight, and ten hours after instillation. The last aspect of the study pertained to 4% pilocarpine hydrochloride. Twelve patients with glaucoma (nine white, three black) were randomly assigned to the group in which naso lacrimal occlusion was not performed, and 14 (ten white, four black) were assigned to the nasolacrimal occlusion group. All patients re ceived 4% pilocarpine hydrochloride in one eye and a placebo in the fellow eye. In all the studies, a masked observer mea sured the intraocular pressures. A two-tailed Student's i-test for paired data was used in all the statistical analyses, with a 5% level of significance.
Results In a glaucomatous population, 1% pilocar pine decreased the intraocular pressure sig-
30
H O 0 Λ A~
nificantly at six, eight, and 12 hours after instillation when nasolacrimal occlusion was performed (Fig. 1). Although the use of 1% pilocarpine with nasolacrimal occlusion showed a significant difference from baseline at 12 hours, this decrease was short of the maxi mal effect of pilocarpine seen with higher con centrations. When 2% pilocarpine was instilled in patients with glaucoma and nasolacrimal occlusion was used, a maximal decrease in the intraocular pressure of 20.1%, 18.8%, and 16.1% was noticed at six, eight, and 12 hours, respectively. Finally, the effect of 4% pilocarpine was not influenced to a great extent by the performance of nasolacrimal occlusion at any time intervals. In the nasolacrimal occlusion group, the intra ocular pressure decreased by 19.8% at six hours, by 20.0% at eight hours, and by 18.4% at 12 hours. In the group in which nasolacrimal occlusion was not performed, the intraocular pressure decrease was 21.5%, 19.1%, and 17.4% for the same time points, respectively. These results suggested that higher concentra tions of pilocarpine will not further decrease the intraocular pressure.
Discussion Early pharmacologie studies demonstrated that various concentrations of pilocarpine ( 1 % , 2%, 4%, and 8%) result in differing decreased intraocular pressures.11"14 In those studies, dura tion of action of pilocarpine ranged from six to ten hours, 1213 which established the customary
1 = 1% with nasolacrimol occlusion, (6 subjects) O = 2% without nasolacrimal occlusion, (10 subjects) ■ Φ = 2% with nasolacrimal occlusion, (16 subjects) Δ = 4% without nasolacrimal occlusion, (12 subjects) A = 4% with nasolaciimal occlusion, (14 subjects)
Fig. 1 (Zimmerman and associates). Intraocular pressure (IOP) response (mm Hg) to pilocarpine with and with out nasolacrimal occlusion in patients with glaucoma. Results were deter mined as mean (±SEM).
0_
O
15
12
Time
(hr)
Vol. 114, No. 1
Antiglaucoma Medications and Nasolacrimal Occlusion
treatment regimen of instillation every six hours. In accordance with a previous study, 15 our data suggested that pilocarpine may be instilled every 12 hours when nasolacrimal occlusion is performed (Fig. 1). At a 1% concentration, pilocarpine falls short of maximal effect at 12 hours, but it does show a marked effect at that time and may be adequate for patients with lightly pigmented irides. At a 2% concentra tion, pilocarpine yields the maximal effect at 12 hours. Four percent pilocarpine is on the top of the dose-response curve whether nasolacrimal occlusion is performed. However, the result is not markedly different from that of a 2% con centration of pilocarpine with nasolacrimal oc clusion. Of additional interest in the two 4% pilocarpine-treated groups is the decrease of the intra ocular pressure in the placebo-treated eyes. Although not a statistically significant differ ence, a trend of a greater decrease in intraocu lar pressures in eyes in which no nasolacrimal occlusion was performed was noted as com pared to the group in which nasolacrimal occlu sion was performed (5% vs 1.7% at six hours, 3.8% vs 1.7% at eight hours, and 3.8% vs 1.3% at 12 hours). This may reflect the amount of systemic absorption of pilocarpine for each group. On the basis of our data, we start pilocarpine treatment with instillation of the 2% concentra tion every 12 hours. The drops are followed immediately by three minutes of nasolacrimal occlusion. Then we adjust treatment according to the patient's response. Another reason for adopting this regimen is that compliance may be better with instillation every 12 hours than with more frequent instillation. 9
Patients and Methods Dose response to carbachol and duration of action in patients with glaucoma—Fifteen pa tients (seven white, eight black) with chronic open-angle glaucoma were treated in one eye with various concentrations (0.75%, 1.5%, and 3%) of carbachol whereas the contralateral eye received a placebo. Nasolacrimal occlusion was performed for three minutes during and imme diately after drug instillation. Intraocular pres sures were measured by applanation tonometry at baseline and at four, eight, and 12 hours after drug instillation. These studies were also de
3
signed in a single-masked fashion; the treated eye was randomly assigned to treatment, and a masked observer measured the intraocular pressures.
Results Carbachol (0.75%) was effective at four and eight hours, but not at 12 hours (Fig. 2). Carba chol at the 1.5% and 3% concentrations was maximally active at 12 hours. There was no statistically significant difference between the 1.5% and 3% carbachol solutions.
Discussion Carbachol is usually instilled every eight hours. It is most frequently prescribed at its highest available concentration of 3 % . In our studies, 1.5% carbachol was still maxi mally active for 12 hours in the patients with open-angle glaucoma (Fig. 2). Therefore, carba chol, when used with nasolacrimal occlusion, should also be considered a twice-a-day dosage drug. Therapy should be initiated by instilling the 1.5% solution every 12 hours. Concentra tions and frequency of instillation should then be adjusted according to the patient's response.
Patients and Methods Dose response to timolol maleate and duration of action in normotensive subjects—Initially, 13 normotensive white patients received 0.25% timolol maleate in one eye and a placebo in the fellow eye, followed immediately by nasolacri mal occlusion. Intraocular pressures were mea sured at baseline and at two, four, eight, and 24 hours after instillation. In a second group (nine patients) the trial was repeated in the same manner, but without performing nasolacrimal occlusion. Data were gathered and assessed in the same masked fashion as already described. Dose response and duration of action in patients with glaucoma—Nineteen patients with chronic open-angle glaucoma received 0.25% timolol maleate in one eye and a placebo in the fellow eye by random allocation. Nasolacrimal occlu sion was performed immediately for three min utes. Intraocular pressures were measured at
o—-o
· · - • Δ —- Δ
= 0.75% with nasolacrimal occlusion, (15 subjects) = 1.5% with nasolacrimal occlusion, (13 subjects) = 3.0% with nasolacrimal occlusion, (13 subjects)
o
01 X
--....
E
Ï
y^
·
Q."
o
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
4
3-
J *
-
\ I '■■-.
y/
*
*
Δ-...
i ~~ - - ^ " - -*Δ -
,
Δ J
Fig. 2 (Zimmerman and associates). Decrease in intraocular pressure (IOP) (mm Hg) using carbachol with naso lacrimal occlusion in a population with glaucoma. Results were deter mined as mean (±SEM). *P < .05, two-tailed Student's f-test for paired data.
1 fi-
1
1
1
12 Time
(hr)
baseline and at 24 hours. A second group of 19 patients with glaucoma received 0.5% timolol maleate in one eye and a placebo in the fellow eye, again using nasolacrimal occlusion, with intraocular pressure measurements at baseline and at 24 hours. Carbachol added to preexisting topical timolol treatment in patients with glaucoma—This study was performed to establish the dose response and duration of action of carbachol when added to preexisting treatment with timolol eyedrops. We hypothesized that the instillation of carba chol, five minutes after timolol instillation, would provide maximal effect at lower concen trations and a less frequent dose schedule than previously recommended. We further hypothe sized that because of timolol's effect on the corneal epithelium, the positive-charged amine carbachol (which normally crosses the corneal epithelium with difficulty) might enter the eye in greater amounts. Carbachol in the commercially available strengths of 0.75%, 1.5%, and 3% was instilled in one eye of patients with glaucoma who were already using 0.25% or 0.5% timolol maleate in both eyes. Nasolacrimal occlusion was per formed for three minutes and the intraocular pressures were measured at baseline and at four, eight, and 12 hours by a masked observer.
Results In the group of normotensive subjects treated with timolol maleate, a reduction of intraocular
pressure of at least 15% was maintained at 24 hours in 12 of the 13 subjects (92%) in whom nasolacrimal occlusion was performed, where as a reduction of 15% was maintained at 24 hours in only five of the subjects (55%) in whom no nasolacrimal occlusion was per formed. The mean decrease from baseline in traocular pressures at 24 hours was 2.8 mm Hg (-18.4%) in the nasolacrimal occlusion group and only 1.0 mm Hg (-7.3%) in the group in which no nasolacrimal occlusion was per formed (P < .05, Fig. 3). At 24 hours in the patients with glaucoma, there was no difference between the ocular hypotensive effect of 0.25% timolol and 0.5% timolol when nasolacrimal occlusion was used (18.1% vs 17.7% decrease from baseline intraocular pressure, respectiveiy). The instillation of 0.75% carbachol in eyes pretreated with 0.25% timolol was not impres sive at any time point and may be attributed to a low baseline intraocular pressure of 17 mm Hg. When higher concentrations of carbachol (1.5% and 3%) were instilled five minutes after 0.25% or 0.5% timolol treatment, the ocular hypoten sive effect was significant at all time intervals, including 12 hours for the 0.25% timolol/1.5% carbachol combination (Fig. 4).
Discussion Early studies of the dose response and dura tion of action of timolol maleate demonstrated maximal effect at a concentration of 0.5% in-
Vol. 114, No. 1
O O φ — Φ
Antiglaucoma Medications and Nasolacrimal Occlusion
5
= 0.25SÌ without nasolacrimal occlusion, (9 subjects) = 0.25X with nasolacrimal occlusion, (13 subjects)
normotensive volunteers
-O
X
E
Fig. 3 (Zimmerman and associates). Decrease in intraocular pressure (IOP) (mm Hg) by using timolol with and without nasolacrimal occlusion in normotensive volunteers. Results were determined as decrease from baseline value. *P < .05, two-tailed Student's f-test for unpaired data.
CL
o
O IA O
A F T E R DRUG INSTILLATION, 85%
of a 50-μ1
eye-
drop is immediately lost to overflow and blink ing. 1 Much of the loss is caused by drainage through the nasolacrimal system into the pos terior nasopharynx, which has a large surface area that is lined with a highly vascularized mucosal membrane. 2 Therefore, it is not sur
prising to detect marked, and sometimes toxic blood concentrations of instilled ocular medi cations. 310 Nasolacrimal occlusion is an easy technique that can make topical ocular treatment safer and more efficacious. Nasolacrimal occlusion can improve the therapeutic index by markedly decreasing the amount of drug absorbed systemically from instillation, while increasing the drug-cornea contact time and the transcorneal movement into the eye. 9 The increase in the amount of drug absorbed by the eye might augment the effect of the drug or its duration of action, or both. This, in turn, might allow lower drug concentrations to be used less frequently, which would further increase safety. Our multiple studies assessed the importance of nasolacrimal occlusion by examining the dose response and duration of action of various topical ocular hypotensive agents with and without this technique. Portions of these stud ies were presented either orally or by a poster at the 1987 and 1988 annual meetings of the Association for Research in Vision and Oph thalmology. We used data accumulated from studies using pilocarpine, carbachol, timolol, and carbachol added to treatment with timolol. We attempted to determine whether nasolacri mal occlusion shifts the dose-response curves to the left, thereby achieving maximal drug effect by lower concentrations. Furthermore, the increased drug-cornea contact time caused by nasolacrimal occlusion might increase their duration of action.
Patients and Methods 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 Thom 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.
Dose response to pilocarpine and duration of action in patients with glaucoma—We examined six patients with glaucoma (four white, two black) by instilling 1 % pilocarpine hydrochloride in one eye and a placebo in the fellow eye in a double-masked randomly allocated fashion.
©AMERICAN JOURNAL OF OPHTHALMOLOGY 114:1-7, JULY, 1992
1
2
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
Another 15 patients with glaucoma (nine white, six black) received 2% pilocarpine hydrochloride in one eye and a placebo in the fellow eye, also by random selection. In both instances, nasolacrimal occlusion was per formed for three minutes during and immedi ately after drug instillation. Intraocular pres sures were measured at baseline and at six, eight, and 12 hours. As a control, data were gathered from another ten patients with glau coma (seven white, three black) who received 2% pilocarpine hydrochloride in one eye with out the use of nasolacrimal occlusion. For the control group, the intraocular pressures were measured at baseline and at four, eight, and ten hours after instillation. The last aspect of the study pertained to 4% pilocarpine hydrochloride. Twelve patients with glaucoma (nine white, three black) were randomly assigned to the group in which naso lacrimal occlusion was not performed, and 14 (ten white, four black) were assigned to the nasolacrimal occlusion group. All patients re ceived 4% pilocarpine hydrochloride in one eye and a placebo in the fellow eye. In all the studies, a masked observer mea sured the intraocular pressures. A two-tailed Student's i-test for paired data was used in all the statistical analyses, with a 5% level of significance.
Results In a glaucomatous population, 1% pilocar pine decreased the intraocular pressure sig-
30
H O 0 Λ A~
nificantly at six, eight, and 12 hours after instillation when nasolacrimal occlusion was performed (Fig. 1). Although the use of 1% pilocarpine with nasolacrimal occlusion showed a significant difference from baseline at 12 hours, this decrease was short of the maxi mal effect of pilocarpine seen with higher con centrations. When 2% pilocarpine was instilled in patients with glaucoma and nasolacrimal occlusion was used, a maximal decrease in the intraocular pressure of 20.1%, 18.8%, and 16.1% was noticed at six, eight, and 12 hours, respectively. Finally, the effect of 4% pilocarpine was not influenced to a great extent by the performance of nasolacrimal occlusion at any time intervals. In the nasolacrimal occlusion group, the intra ocular pressure decreased by 19.8% at six hours, by 20.0% at eight hours, and by 18.4% at 12 hours. In the group in which nasolacrimal occlusion was not performed, the intraocular pressure decrease was 21.5%, 19.1%, and 17.4% for the same time points, respectively. These results suggested that higher concentra tions of pilocarpine will not further decrease the intraocular pressure.
Discussion Early pharmacologie studies demonstrated that various concentrations of pilocarpine ( 1 % , 2%, 4%, and 8%) result in differing decreased intraocular pressures.11"14 In those studies, dura tion of action of pilocarpine ranged from six to ten hours, 1213 which established the customary
1 = 1% with nasolacrimol occlusion, (6 subjects) O = 2% without nasolacrimal occlusion, (10 subjects) ■ Φ = 2% with nasolacrimal occlusion, (16 subjects) Δ = 4% without nasolacrimal occlusion, (12 subjects) A = 4% with nasolaciimal occlusion, (14 subjects)
Fig. 1 (Zimmerman and associates). Intraocular pressure (IOP) response (mm Hg) to pilocarpine with and with out nasolacrimal occlusion in patients with glaucoma. Results were deter mined as mean (±SEM).
0_
O
15
12
Time
(hr)
Vol. 114, No. 1
Antiglaucoma Medications and Nasolacrimal Occlusion
treatment regimen of instillation every six hours. In accordance with a previous study, 15 our data suggested that pilocarpine may be instilled every 12 hours when nasolacrimal occlusion is performed (Fig. 1). At a 1% concentration, pilocarpine falls short of maximal effect at 12 hours, but it does show a marked effect at that time and may be adequate for patients with lightly pigmented irides. At a 2% concentra tion, pilocarpine yields the maximal effect at 12 hours. Four percent pilocarpine is on the top of the dose-response curve whether nasolacrimal occlusion is performed. However, the result is not markedly different from that of a 2% con centration of pilocarpine with nasolacrimal oc clusion. Of additional interest in the two 4% pilocarpine-treated groups is the decrease of the intra ocular pressure in the placebo-treated eyes. Although not a statistically significant differ ence, a trend of a greater decrease in intraocu lar pressures in eyes in which no nasolacrimal occlusion was performed was noted as com pared to the group in which nasolacrimal occlu sion was performed (5% vs 1.7% at six hours, 3.8% vs 1.7% at eight hours, and 3.8% vs 1.3% at 12 hours). This may reflect the amount of systemic absorption of pilocarpine for each group. On the basis of our data, we start pilocarpine treatment with instillation of the 2% concentra tion every 12 hours. The drops are followed immediately by three minutes of nasolacrimal occlusion. Then we adjust treatment according to the patient's response. Another reason for adopting this regimen is that compliance may be better with instillation every 12 hours than with more frequent instillation. 9
Patients and Methods Dose response to carbachol and duration of action in patients with glaucoma—Fifteen pa tients (seven white, eight black) with chronic open-angle glaucoma were treated in one eye with various concentrations (0.75%, 1.5%, and 3%) of carbachol whereas the contralateral eye received a placebo. Nasolacrimal occlusion was performed for three minutes during and imme diately after drug instillation. Intraocular pres sures were measured by applanation tonometry at baseline and at four, eight, and 12 hours after drug instillation. These studies were also de
3
signed in a single-masked fashion; the treated eye was randomly assigned to treatment, and a masked observer measured the intraocular pressures.
Results Carbachol (0.75%) was effective at four and eight hours, but not at 12 hours (Fig. 2). Carba chol at the 1.5% and 3% concentrations was maximally active at 12 hours. There was no statistically significant difference between the 1.5% and 3% carbachol solutions.
Discussion Carbachol is usually instilled every eight hours. It is most frequently prescribed at its highest available concentration of 3 % . In our studies, 1.5% carbachol was still maxi mally active for 12 hours in the patients with open-angle glaucoma (Fig. 2). Therefore, carba chol, when used with nasolacrimal occlusion, should also be considered a twice-a-day dosage drug. Therapy should be initiated by instilling the 1.5% solution every 12 hours. Concentra tions and frequency of instillation should then be adjusted according to the patient's response.
Patients and Methods Dose response to timolol maleate and duration of action in normotensive subjects—Initially, 13 normotensive white patients received 0.25% timolol maleate in one eye and a placebo in the fellow eye, followed immediately by nasolacri mal occlusion. Intraocular pressures were mea sured at baseline and at two, four, eight, and 24 hours after instillation. In a second group (nine patients) the trial was repeated in the same manner, but without performing nasolacrimal occlusion. Data were gathered and assessed in the same masked fashion as already described. Dose response and duration of action in patients with glaucoma—Nineteen patients with chronic open-angle glaucoma received 0.25% timolol maleate in one eye and a placebo in the fellow eye by random allocation. Nasolacrimal occlu sion was performed immediately for three min utes. Intraocular pressures were measured at
o—-o
· · - • Δ —- Δ
= 0.75% with nasolacrimal occlusion, (15 subjects) = 1.5% with nasolacrimal occlusion, (13 subjects) = 3.0% with nasolacrimal occlusion, (13 subjects)
o
01 X
--....
E
Ï
y^
·
Q."
o
July, 1992
AMERICAN JOURNAL OF OPHTHALMOLOGY
4
3-
J *
-
\ I '■■-.
y/
*
*
Δ-...
i ~~ - - ^ " - -*Δ -
,
Δ J
Fig. 2 (Zimmerman and associates). Decrease in intraocular pressure (IOP) (mm Hg) using carbachol with naso lacrimal occlusion in a population with glaucoma. Results were deter mined as mean (±SEM). *P < .05, two-tailed Student's f-test for paired data.
1 fi-
1
1
1
12 Time
(hr)
baseline and at 24 hours. A second group of 19 patients with glaucoma received 0.5% timolol maleate in one eye and a placebo in the fellow eye, again using nasolacrimal occlusion, with intraocular pressure measurements at baseline and at 24 hours. Carbachol added to preexisting topical timolol treatment in patients with glaucoma—This study was performed to establish the dose response and duration of action of carbachol when added to preexisting treatment with timolol eyedrops. We hypothesized that the instillation of carba chol, five minutes after timolol instillation, would provide maximal effect at lower concen trations and a less frequent dose schedule than previously recommended. We further hypothe sized that because of timolol's effect on the corneal epithelium, the positive-charged amine carbachol (which normally crosses the corneal epithelium with difficulty) might enter the eye in greater amounts. Carbachol in the commercially available strengths of 0.75%, 1.5%, and 3% was instilled in one eye of patients with glaucoma who were already using 0.25% or 0.5% timolol maleate in both eyes. Nasolacrimal occlusion was per formed for three minutes and the intraocular pressures were measured at baseline and at four, eight, and 12 hours by a masked observer.
Results In the group of normotensive subjects treated with timolol maleate, a reduction of intraocular
pressure of at least 15% was maintained at 24 hours in 12 of the 13 subjects (92%) in whom nasolacrimal occlusion was performed, where as a reduction of 15% was maintained at 24 hours in only five of the subjects (55%) in whom no nasolacrimal occlusion was per formed. The mean decrease from baseline in traocular pressures at 24 hours was 2.8 mm Hg (-18.4%) in the nasolacrimal occlusion group and only 1.0 mm Hg (-7.3%) in the group in which no nasolacrimal occlusion was per formed (P < .05, Fig. 3). At 24 hours in the patients with glaucoma, there was no difference between the ocular hypotensive effect of 0.25% timolol and 0.5% timolol when nasolacrimal occlusion was used (18.1% vs 17.7% decrease from baseline intraocular pressure, respectiveiy). The instillation of 0.75% carbachol in eyes pretreated with 0.25% timolol was not impres sive at any time point and may be attributed to a low baseline intraocular pressure of 17 mm Hg. When higher concentrations of carbachol (1.5% and 3%) were instilled five minutes after 0.25% or 0.5% timolol treatment, the ocular hypoten sive effect was significant at all time intervals, including 12 hours for the 0.25% timolol/1.5% carbachol combination (Fig. 4).
Discussion Early studies of the dose response and dura tion of action of timolol maleate demonstrated maximal effect at a concentration of 0.5% in-
Vol. 114, No. 1
O O φ — Φ
Antiglaucoma Medications and Nasolacrimal Occlusion
5
= 0.25SÌ without nasolacrimal occlusion, (9 subjects) = 0.25X with nasolacrimal occlusion, (13 subjects)
normotensive volunteers
-O
X
E
Fig. 3 (Zimmerman and associates). Decrease in intraocular pressure (IOP) (mm Hg) by using timolol with and without nasolacrimal occlusion in normotensive volunteers. Results were determined as decrease from baseline value. *P < .05, two-tailed Student's f-test for unpaired data.
CL
o
O IA O
