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Comparison of the Effect of Propranolol, Lignocaine, and Other Drugs on Normal and Raised Intraocular Pressure in Man
COMPARISON O F T H E E F F E C T O F PROPRANOLOL, LIGNOCAINE, AND O T H E R DRUGS ON NORMAL AND RAISED INTRAOCULAR P R E S S U R E IN MAN A. M U S I N I , M.D.,
B. FABBRI, M.D., M. BERGAMASCHI, P H . D . , AND V. MANDELLI, D.Sc.
Milan, Italy AND
R. G. S H A N K S ,
M.D.
Belfast, North Ireland Propranolol (Inderal), an adrenergic beta-receptor blocking agent, is reported to reduce intraocular pressure in patients with chronic simple glaucoma.1'2 The mode of ac tion of propranolol was not elucidated, but it was suggested that the effect resulted from the action of propranolol on an adrenergic mechanism responsible for either the rate of formation of aqueous humor or on the facil ity for outflow. On the other hand, it was also demonstrated that topical application of isoprenaline and adrenaline will reduce intraocular pressure in man.3"6 Conse quently, propranolol may affect intraocular pressure by actions not directly related to an effect on adrenergic receptors in the eye. In man, the systemic administration of propra nolol reduces heart rate and cardiac output and increases total peripheral resistance 7 ; as a consequence the rate of formation of aque ous humor may be reduced. To eliminate the actions of propranolol on the systemic circulation, we have studied the effect of the drug on intraocular pressure by applying it directly to the eye. In addition to its adrenergic blocking properties, propra nolol, is a potent local anesthetic.8 As this property may also affect intraocular pres sure, we have compared the effects of pro pranolol with those of lignocaine, MJ 1999 From the Ophthalmic Service of the Maggiore Hospital (Drs. Musini and Fabbri), and the Carlo Erba Institute for Therapeutic Research (Drs. Bergamaschi and Mandelli). Dr. Shanks is on leave from the Department of Therapeutics and Pharma cology, The Queen's University, Belfast, Ireland. Reprint requests to A. Musini, M.D., Ophthalmic Service, the Ospedale Maggiore, Milano, Italy.
and INPEA. The latter two drugs block ad renergic beta receptors,9 but which have no local anesthetic action. METHODS
Observations were made in 62 hospitalized patients, 31 men and 31 women, all between the ages of 30 and 80 years. The patients were divided into three groups, according to diagnostic criteria: Group 1. Normal subjects—-These were 43 patients-—(25 men and 18 women) admit ted to the ophthalmic service for conditions not affecting intraocular pressure (e.g., con junctivitis, dacryocystitis, central retinitis, strabismus, and cataract). These patients had not previously been given any drugs which might alter intraocular pressure. Group 2. Patients with chronic simple glaucoma—The 12 patients belonging to this group (six men, six women) had monocular or binocular open-angle glaucoma as judged by field loss, tonometry, gonioscopy, visual acuity, and fundus observation. Prior to their present hospitalization, all had rou tinely used drugs commonly prescribed for the treatment of glaucoma, and after admis sion, treatment with these drugs was contin ued until the danger of an acute rise of intraocular pressure had passed. A period of at least five days elapsed after drug therapy ceased before the administration of propra nolol began. Consequently, the intraocular pressures in these patients were not unduly high at the time observations were made (Table 1). In all patients in this group, the effects of the instillation of 0.9% saline was
773
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AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER, 1971
TABLE 1 E F F E C T ON INTRAOCULAR PRESSURE OF 0.9% SALINE IN PATIENTS WITH CHRONIC SIMPLE GLAUCOMA AND OF 2 % PROPRANOLOL IN NORMOTENSION, CHRONIC SIMPLE GLAUCOMA, AND ACUTE GLAUCOMA
Treatment Groups
Total No., Sex Patients
Chronic simple glaucoma
Acute glaucoma
Statistical Significance (Controls vs Treated Patients)
-60
-30
0
30
60
90
120
150
240
xmm Hg SE
24.1 ±1.8
22.9 ±1.8
22.6 ±1.6
22.3 ±1.6
22.3 ±1.6
22.1 ±1.6
22.1 ±1.6
22.3 ±1.6
22.3 ±1.6
P>0.05
6-F
x mm Hg SE
23.9 ±1.1
23.0 ±1.1
22.8 ±1.1
22.3 ±1.2
22.4 ±1.2
22.4 ±1.2
22.3 ±1.2
22.3 ±1.2
22.3 ±1.2
P>0.05
9-M
x mm Hg SE
15.5 ±0.8
15.3 ±0.9
15.3 ±0.9
13.1 ±0.8
11.2 ±0.5
9.8 ±0.3
9.4 + 0.9
± 1
11.8 ±0.7
P<0.01
9-F
x mm Hg SE
15.8 ±0.6
15.8 ±0.6
15.8 ±0.6
15.8 ±0.6
14.8 ±0.4
13.9 ±0.8
14.0 ±0.8
14.4 ±0.7
14.7 ±0.6
P<0.01
6-M
x mmHg SE
22.0 ±1.5
21.6 ±1.5
21.2 ±1.5
18.3 ±1.4
16.6 ±0.8
16.5 ±0.7
15.7 ±0.9
16.0 ±0.9
17.5 ±0.9
0.01
6-F
x mm Hg SE
23.3 ±1.1
22.3 ±1.3
22.0 ±1.4
19.5 ±1.7
18.1 ±1.7
17. ±1.7
17.6 ±1.6
18.1 ±1.5
19.5 ±1.3
0.01
7-F
£ mm Hg SE
65.5 ±8.2
65.5 ±8.2
65.5 ±8.2
65.0 ±8.4
65.0 ±8.4
65.0 ±8.4
63.2 ±8.8
63.2 ±8.8
63.9 ±8.7
P>0.05
Saline-treated controls: Chronic simple 6-M glaucoma
Propranolol-treated Normotensive
T ime (in minutes) Before and After Treatment
studied on one day (as a control) and the effects of propranolol on the following day. The treatments were given in random order. The patients in Groups 1 and 2 were ran domly picked from the whole population of the ophthalmic service. Group 3. Patients with acute glaucoma— Observations were made in seven women pa tients admitted to hospital with idiopathic or secondary acute glaucoma. All patients remained in the supine posi tion throughout periods of examination. Intraocular pressure was measured by a Schio'tz tonometer and expressed in mm Hg. With the exception of the experiments in which the effects of lignocaine and propra nolol were compared in both eyes of the same patients, local anesthesia of the cornea was produced by the instillation of 3 drops of lignocaine 10 seconds before making the first control observations. Anesthesia was maintained throughout the period of obser vation by the administration of lignocaine every 30 minutes. In all patients except those seven who had a different drug applied to each eye at the same time, an electrocardio gram was made and heart rate determined by
10.4
measurement of at least 10 R-R intervals ( R - R = interval between two subsequent R waves of the electrocardiogram). Arterial pressure was measured by auscultation using a sphygmomanometer applied to the left arm. Mean arterial pressure (mm Hg) was taken as diastolic pressure plus one-third of pulse pressure. Local anesthetic activity was mea sured on the human cornea by using the Aesthesiometer (Cochet and Bonnet, Ltd.) and expressed in conventional units. The com parison between the activities of the four compounds was made by using the Friedman rank test. Intraocular pressure, heart rate, and arterial pressure were measured every 30 minutes, and when steady values were ob tained, one of the following solutions was administered: (1) three drops of propranolol HC1 (2% solution), (2) three drops of MJ 1999 HC1 (2% solution), (3) six drops of INPEA HC1 (2% solution), or (4) three drops of sodium chloride (0.9% solution). Each solution was administered to the conjunctival sac. In order to control the influence of sex, eye laterality, and experimental times on the changes in intraocular pressure, heart rate, and arterial pressure induced by any
VOL. 72, NO. 4
775
DRUG EFFECTS ON INTRAOCULAR PRESSURE
treatment, an analysis of variance was car ried out on the data exhibited at 0, 30 and 60 minutes before treatment and 30, 60, 90, 120 and 150 minutes after treatment. RESULTS
Intraocular pressure—The averaged re sults from the three groups of patients are shown in Figure 1 and Tables 1 and 2. Control observations—The instillation of saline into the conjunctival sac did not cause any change in intraocular pressure in pa tients with chronic simple glaucoma. Normal subjects—In 18 patients (nine men, nine women) with normal intraocular pressure, propranolol eye drops produced a progressive reduction in intraocular pres sure. This was maximal 120 minutes after administration of propranolol and was highly significant (p < 0.01) when men and women patients were taken as one group. No difference in the response to propranolol instillation was observed between the right and left eyes, while a marked and highly significant difference was recorded between the two sexes (p < 0.01): the decreases in intraocular pressure was 39% for men and 19% for women (Table 1). Patients with chronic simple glaucoma— Propranolol produced a marked and signifi cant reduction in intraocular pressure (0.01 < p < 0.05) in this group which was maximal 120 minutes after treatment. The response was similar in both sexes and in right and left eyes (Table 1, Fig. 1). Patients with acute glaucoma—In patients
with monolateral acute glaucoma, the admin istration of propranolol had no effect on the intraocular pressure of the diseased eye (Ta bles 1 and 2, Figs. 1 and 2) whilst it de creased the intraocular pressure in the contralateral, normotensive eye to 73.5% of control. Heart rate and arterial pressure—The mean heart rates (beats per minute) during the control period were 8 in normal sub jects, 78 in patients with chronic simple glaucoma, and 82 in those with acute glau coma. After the administration of saline to patients with chronic simple glaucoma and of propranolol to the others, heart rate fell (Fig. 1). The decrease was maximal at 90 minutes and was highly significant (p<0.01) in all groups; this response was similar in men and women. The mean value for arterial pressure was 109 mm Hg and did not alter significantly in any of the groups of patients following the administration of either saline or propranolol. Effect of experimental drug in normal subjects—Observations were made in 14 pa tients (seven men, seven women) in whom three drops of MJ 1999 were applied to both eyes after a one-hour control period. The averaged results in these patients are given in Table 3. In both sexes the introcular pres sure fell during the control period, but no further change occurred. Effect of INPEA in normal subjects— Observations were made in 14 patients (seven men, seven women) and the averaged results are given in Table 3. The administra-
TABLE2 COMPARISON OF EFFECT OF PROPRANOLOL IN EYES WITH ACUTE GLAUCOMA AND NORMOTENSIVE FELLOW EYES IN SAME PATIENTS
T-.
•
r*
Statistical Significance
T ime (in minutes) Before and After Treatment
NO.
60
-30
0
30
60
90
120
150
240
Treated Patients)
Acute glaucoma
7
x mm Hg SE
65.5 ±8.2
65.5 ±8.2
65.5 ±8.2
65.0 ±8.4
65.0 + 8.4
65.0 ±8.4
63.2 ±8.8
63.2 ±8.8
63.9 ±8.7
P>0.05
Normotensive
7
x m m Hg
16.3
15.9
15.9
13.4
11.9
11.7
12.2
13.3
14.5
P<0.01
AMERICAN JOURNAL OF OPHTHALMOLOGY
776
OCTOBER, 1971
100 __
90 J
100
_
Fig. 1 (Musini and associates). Effects of saline (dashed lines) and propranolol 2% eye drops (solid lines) on heart rate (top), mean arterial pressure, (center), and intraocular pressure (bottom) in patients with normal intraocular tension ( - O - ) , with chronic simple glaucoma ( - Q - ) and with acute glaucoma ( - A - ) . Variations are expressed as percent of control values.
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DRUG EFFECTS ON INTRAOCULAR PRESSURE
777
100
Fig. 2 (Musini and associates). Heart rate (top), arterial pressure (center), and intraocular pressure (bottom) responses to the instillation of propranolol 2% eye drops into the cojunctival sac of both the eyes with acute glaucoma ( - • - ) and the contralateral normotensive (-O-) eyes of the same patients. The curves are representative of the percent variations on the control values.
AMERICAN JOURNAL OF OPHTHALMOLOGY
778
OCTOBER, 1971
TABLE 3 E F F E C T OF MJ
1999 AND IN PEA
Time (in minutes) After Treatment
Total No., Sex Treatments Patients MJ 1999*
INPEAj
ON INTRAOCULAR PRESSURE OF NORMOTENSIVE PATIENTS
30
60
90
120
150
240
Statistical Significance Controls (Controls vs Treated Patients)
7-M
x mm Hg SE
12.6 + 0.8
13.2 ±0.7
13.2 ±0.8
12.9 ±0.7
12.9 ±0.7
12.9 ±0.7
13.3 ±0.9
7-F
x mm Hg SE
15.3 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
P>0.05
x mm Hg SE
12.9 ±0.7
12.2 ±0.6
12.6 ±0.7
12.6 ±0.7
12.6 ±0.7
12.3 ±0.7
12.8 ±0.8
P>0.05
x mm Hg SE
12.0 + 0.4
12.0 ±0.4
12.0 ±0.4
12.0 ±0.4
12.0 ±0.4
12.0 ±0.4
12.8 ±0.8
P>0.05
7-M 7-F
P>0.05
* Three drops of a 2 % solution. f Six drops of a 2% solution.
tion of six drops of INPEA had no effect on intraocular pressure in either sex. Local anesthetic effect on the cornea—The effects of the four drugs, propranolol, lignocaine, MJ 1999, and INPEA, were com pared in both eyes of 15 patients. Lignocaine was applied to one eye of all patients (either left or right at random) and either proprano lol, MJ 1999, or INPEA was applied to the other eye. The averaged results are given in Figure 3. In the concentrations used, MJ 1999 and INPEA had no anesthetic effect. Propranolol and lignocaine were equally ac tive and had a similar duration of action (p>0.05). Comparison of intraocular pressure effects—Observations were made in seven patients with normal intraocular pressures. Propranolol and lignocaine were applied randomly to either eye of all patients. The drugs were applied every 30 minutes for 240 minutes and intraocular pressure was mea sured 15 seconds after each administration. The averaged results are given in Table 4 and Figure 4 and show that both the drugs lowered intraocular pressure; the effect was maximal at 120 minutes and was followed by a rise in pressure. There was no significant
difference between the effect of the two drugs (Table 5). DISCUSSION
The present observations show that the topical administration of propranolol to the eye reduces intraocular pressure in patients with normotensive eyes and in those with chronic simple glaucoma. This result cannot be ascribed to propranolol-induced changes in systemic hemodynamics, as arterial pres sure was unaltered after topical application of the drug to the eyes and heart rate de creased to some extent both in control and in propranolol-treated patients. The effect is apparently not due to blockade of adrenergic beta receptors, as MJ 1999 and INPEA ad ministration had no effect on intraocular pressure. In patients with normotensive eyes both lignocaine and propranolol reduced intraocular pressure to the same extent. In all patients with normotensive eyes and in those with chronic simple glaucoma, intra ocular pressure fell during the control period during which lignocaine had been applied to the eye to enable the measurement to be made. Thus lignocaine would appear to re duce intraocular pressure in these patients
VOL. 72, NO. 4
DRUG EFFECTS ON INTRAOCULAR PRESSURE
% CORNEAL ANESTHESIA
100 _ 90
779
•
LIGNOCAINE
O
PROPRANOLOL
A
MJ 1999
□
INPEA
80 J 70 60 J 50 40 J 30 20 J 10 0 J C
T" ~i
5
1
1
1
1
1
1
1
1
10 15 20 25 30 35 40 45 50
mm.
Fig. 3 (Musini and associates). Curves representing the intensity and duration of the local anesthetic activity of lignocaiiie ( - O - ) , propranolol ( - • - ) , MJ 199 ( - □ - ) , and I N P E A ( A ) . Each point is the mean value expressed as percent of the highest level of recorded from IS healthy male subjects.
through its local anesthetic action. The pres ent experiments have also shown that pro pranolol is as effective as lignocaine as a local anesthetic agent on the human cornea. These results all suggest that reduction in intraocular pressure produced by proprano lol on topical application to the eye is due to its local anesthetic action. The present ex
periments do not explain the observations of Phillips and associates,1 who reported a de crease in intraocular pressure after intra venous and oral administration of proprano lol, as the local anesthetic action of proprano lol on parenteral administration has not yet been determined in man. There is also evidence from our results
AMERICAN JOURNAL OF OPHTHALMOLOGY
780
OCTOBER, 1971
TABLE 4 COMPARISON OF EFFECTS OF PROPRANOLOL AND LIGNOCAINE WHEN APPLIED CONTEMPORANEOUSLY TO FELLOW EYES
Time (in minutes) After Treatment Treatments
No. Eyes
Controls 30
60
90
120
180
240
Propranolol
7
x mm Hg SE
15.6 ±0.46
15.1 ±0.66
14.5 ±0.80
14.0 ±0.67
14.2 ±0.77
15.1 ±0.54
16.9 ±0.57
Lignocaine
7
x mm Hg SE
14.8 ±0.34
14.1 ±0.24
13.8 ±0.22
13.2 ±0.31
14.5 ±0.58
15.1 ±0.47
15.8 ±0.36
that, when topically applied, both proprano lol and lignocaine lower intraocular pressure when the iridocorneal angle is open, but not when the angle is closed, as in acute glau coma. This conclusion is further supported by the evidence that propranolol and ligno caine decrease the intraocular pressure of the normotensive eye of patients whose contralateral eye is glaucomatous. These findings suggest that the site of ac
tion of these drugs is in the chamber angle and that it involves a mechanism which can modify the resistance to outflow of the aqueous humor. T h e effect of these drugs may result from a reduction of the myogenic tone of the smooth muscle in the canal of Schlemm and in the other drainage channels, as the intra-arterial administration of pro pranolol and lignocaine reduce vascular smooth muscle tone. 11 Propranolol and ligno-
100
O
PROPRANOLOL
•
LIGNOCAINE
90-
80
c
I
30
60
—r90
— i —
120
180
240
rnin. Fig. 4 (Musini and associates). Effects of propranolol 2% (-O-) and lignocaine 2% ( - • - ) on intra ocular pressure of healthy male subjects. Variations are expressed as percent of control values.
VOL. 72, N O . 4
DRUG E F F E C T S ON INTRAOCULAR TABLE 5
RESULTS OF THREE-WAY ANALYSIS OF VARIANCE OF DATA CONCERNING PERCENT INTRAOCULAR PRESSURE CHANGES INDUCED BY LIGNOCAINE AND PROPRANOLOL CONTEMPORANEOUSLY APPLIED AT RANDOM TO EITHER EYE OF THE SAME PATIENT
Source of Variation
De S f r e e Mean „ , Squares I reedom
Drugs Patients Drugs-patients interaction Times Times-patients interaction Drugs-times interaction Residual (drugstimes-patients interaction)
F*
Statistical Signifi cance
PRESSURE
781
creasing intraocular pressure. The present results suggest that the reduction in intra ocular pressure consistently observed after topical application of propranolol to the eyes is due to the strong local anesthetic action of this drug. ACKNOWLEDGMENTS
The propranolol used in these experiments was supplied as Inderal (Imperial Chemical Industries, Ltd.) eye drops by Vister, Ltd., MJ 1999 (Sotalol) is a product of Mead Johnson, and the I N P E A was supplied as eye drops by Selvi and Co., Ltd.
1 6
2.2517 2.9273
1.09 1.41
P>0.05 P>0.05
6 5
2.0689 1.8881
5.30
P<0.01
REFERENCES 1. Phillips, C. I., Howitt G., and Rowlands D. J.: Propranolol as ocular hypotensive agent. Brit. J. Ophth. 51:222, 1967. 2. Bucci, M.G., Pecori Giraldi, J., and Missiroli, A . : La somministrazione locale di propranolo nella terapia del glaucoma. Boll. Ocul. 47:51, 1968. 3. Weeker, R., Delmarcelle, Y., and Gustin, J.: Treatment of ocular hypertension by adrenaline and diverse sympathomimetic amines. Am. J. Ophth. 40: 666, 1965. 4. Garner, L. L., Johnstone, W. W., Ballintine, E. J., and Carroll, M . E . : Effect of 2 % levo-rotari epinephrine on the intraocular pressure of the glaucomatous eye. Arch. Ophth. 62:230, 1959. 5. Prijot, F . : Contribution a l'etude cle la tonometrie et de la tonographie en ophtalmologie. Doc. Ophtal. 15 :1, 1961. 6. Becker, B., Pettit, T. H., and Gay, A. J.: Top ical epinephrine therapy of open angle glaucoma. Arch. Ophth. 66:219, 1961. 7. Shinebourne, E., Fleming, J., and Hamer, J.: Effects of beta-adrenergic blockade during exercise in hypertensive and ischaemic heart-disease. Lancet 2:1217, 1967. 8. Barrett, A. M., and Cullum, V. A . : The bio logical properties of the optical isomers of propra nolol and their effects on cardiac arrhythmias. Brit. J. Pharm. Chemother. 34:43, 1968. 9. Shanks, R. G.: The properties of beta-adren ergic blocking agents. Irish J. Med. Sci. 2:351, 1969. 10. Shanks, R. G.: The peripheral vascular effects of propranolol and related compounds. Brit. J. Pharm. Chemother. 29:204, 1967. 11. Bergamaschi, M.: Unpublished data.
30
0.3562
_
_
5
0.2908
1.37
P>0.05
30
0.2122
* F = Variances ratio (Fisher's test).
caine have also been observed to depress the myogenic activity of the isolated rabbit ileum." SUMMARY
When the mechanism underlying the hypotensive action of propranolol on intraocu lar pressure was investigated in three groups of ophthalmic patients, propranolol, applied topically, decreased intraocular pressure in the normotensive eyes and in those with openangle glaucoma, but not in eyes with acute glaucoma. Two beta-adrenoceptor blocking drugs which have no anesthetic activity, MJ 1999 and INPEA, did not alter intraocular pressure. When propranolol was applied to one eye and lignocaine to the other contempo raneously in normotensive patients, the two drugs were found to be equally potent in de
B. FABBRI, M.D., M. BERGAMASCHI, P H . D . , AND V. MANDELLI, D.Sc.
Milan, Italy AND
R. G. S H A N K S ,
M.D.
Belfast, North Ireland Propranolol (Inderal), an adrenergic beta-receptor blocking agent, is reported to reduce intraocular pressure in patients with chronic simple glaucoma.1'2 The mode of ac tion of propranolol was not elucidated, but it was suggested that the effect resulted from the action of propranolol on an adrenergic mechanism responsible for either the rate of formation of aqueous humor or on the facil ity for outflow. On the other hand, it was also demonstrated that topical application of isoprenaline and adrenaline will reduce intraocular pressure in man.3"6 Conse quently, propranolol may affect intraocular pressure by actions not directly related to an effect on adrenergic receptors in the eye. In man, the systemic administration of propra nolol reduces heart rate and cardiac output and increases total peripheral resistance 7 ; as a consequence the rate of formation of aque ous humor may be reduced. To eliminate the actions of propranolol on the systemic circulation, we have studied the effect of the drug on intraocular pressure by applying it directly to the eye. In addition to its adrenergic blocking properties, propra nolol, is a potent local anesthetic.8 As this property may also affect intraocular pres sure, we have compared the effects of pro pranolol with those of lignocaine, MJ 1999 From the Ophthalmic Service of the Maggiore Hospital (Drs. Musini and Fabbri), and the Carlo Erba Institute for Therapeutic Research (Drs. Bergamaschi and Mandelli). Dr. Shanks is on leave from the Department of Therapeutics and Pharma cology, The Queen's University, Belfast, Ireland. Reprint requests to A. Musini, M.D., Ophthalmic Service, the Ospedale Maggiore, Milano, Italy.
and INPEA. The latter two drugs block ad renergic beta receptors,9 but which have no local anesthetic action. METHODS
Observations were made in 62 hospitalized patients, 31 men and 31 women, all between the ages of 30 and 80 years. The patients were divided into three groups, according to diagnostic criteria: Group 1. Normal subjects—-These were 43 patients-—(25 men and 18 women) admit ted to the ophthalmic service for conditions not affecting intraocular pressure (e.g., con junctivitis, dacryocystitis, central retinitis, strabismus, and cataract). These patients had not previously been given any drugs which might alter intraocular pressure. Group 2. Patients with chronic simple glaucoma—The 12 patients belonging to this group (six men, six women) had monocular or binocular open-angle glaucoma as judged by field loss, tonometry, gonioscopy, visual acuity, and fundus observation. Prior to their present hospitalization, all had rou tinely used drugs commonly prescribed for the treatment of glaucoma, and after admis sion, treatment with these drugs was contin ued until the danger of an acute rise of intraocular pressure had passed. A period of at least five days elapsed after drug therapy ceased before the administration of propra nolol began. Consequently, the intraocular pressures in these patients were not unduly high at the time observations were made (Table 1). In all patients in this group, the effects of the instillation of 0.9% saline was
773
774
AMERICAN JOURNAL OF OPHTHALMOLOGY
OCTOBER, 1971
TABLE 1 E F F E C T ON INTRAOCULAR PRESSURE OF 0.9% SALINE IN PATIENTS WITH CHRONIC SIMPLE GLAUCOMA AND OF 2 % PROPRANOLOL IN NORMOTENSION, CHRONIC SIMPLE GLAUCOMA, AND ACUTE GLAUCOMA
Treatment Groups
Total No., Sex Patients
Chronic simple glaucoma
Acute glaucoma
Statistical Significance (Controls vs Treated Patients)
-60
-30
0
30
60
90
120
150
240
xmm Hg SE
24.1 ±1.8
22.9 ±1.8
22.6 ±1.6
22.3 ±1.6
22.3 ±1.6
22.1 ±1.6
22.1 ±1.6
22.3 ±1.6
22.3 ±1.6
P>0.05
6-F
x mm Hg SE
23.9 ±1.1
23.0 ±1.1
22.8 ±1.1
22.3 ±1.2
22.4 ±1.2
22.4 ±1.2
22.3 ±1.2
22.3 ±1.2
22.3 ±1.2
P>0.05
9-M
x mm Hg SE
15.5 ±0.8
15.3 ±0.9
15.3 ±0.9
13.1 ±0.8
11.2 ±0.5
9.8 ±0.3
9.4 + 0.9
± 1
11.8 ±0.7
P<0.01
9-F
x mm Hg SE
15.8 ±0.6
15.8 ±0.6
15.8 ±0.6
15.8 ±0.6
14.8 ±0.4
13.9 ±0.8
14.0 ±0.8
14.4 ±0.7
14.7 ±0.6
P<0.01
6-M
x mmHg SE
22.0 ±1.5
21.6 ±1.5
21.2 ±1.5
18.3 ±1.4
16.6 ±0.8
16.5 ±0.7
15.7 ±0.9
16.0 ±0.9
17.5 ±0.9
0.01
6-F
x mm Hg SE
23.3 ±1.1
22.3 ±1.3
22.0 ±1.4
19.5 ±1.7
18.1 ±1.7
17. ±1.7
17.6 ±1.6
18.1 ±1.5
19.5 ±1.3
0.01
7-F
£ mm Hg SE
65.5 ±8.2
65.5 ±8.2
65.5 ±8.2
65.0 ±8.4
65.0 ±8.4
65.0 ±8.4
63.2 ±8.8
63.2 ±8.8
63.9 ±8.7
P>0.05
Saline-treated controls: Chronic simple 6-M glaucoma
Propranolol-treated Normotensive
T ime (in minutes) Before and After Treatment
studied on one day (as a control) and the effects of propranolol on the following day. The treatments were given in random order. The patients in Groups 1 and 2 were ran domly picked from the whole population of the ophthalmic service. Group 3. Patients with acute glaucoma— Observations were made in seven women pa tients admitted to hospital with idiopathic or secondary acute glaucoma. All patients remained in the supine posi tion throughout periods of examination. Intraocular pressure was measured by a Schio'tz tonometer and expressed in mm Hg. With the exception of the experiments in which the effects of lignocaine and propra nolol were compared in both eyes of the same patients, local anesthesia of the cornea was produced by the instillation of 3 drops of lignocaine 10 seconds before making the first control observations. Anesthesia was maintained throughout the period of obser vation by the administration of lignocaine every 30 minutes. In all patients except those seven who had a different drug applied to each eye at the same time, an electrocardio gram was made and heart rate determined by
10.4
measurement of at least 10 R-R intervals ( R - R = interval between two subsequent R waves of the electrocardiogram). Arterial pressure was measured by auscultation using a sphygmomanometer applied to the left arm. Mean arterial pressure (mm Hg) was taken as diastolic pressure plus one-third of pulse pressure. Local anesthetic activity was mea sured on the human cornea by using the Aesthesiometer (Cochet and Bonnet, Ltd.) and expressed in conventional units. The com parison between the activities of the four compounds was made by using the Friedman rank test. Intraocular pressure, heart rate, and arterial pressure were measured every 30 minutes, and when steady values were ob tained, one of the following solutions was administered: (1) three drops of propranolol HC1 (2% solution), (2) three drops of MJ 1999 HC1 (2% solution), (3) six drops of INPEA HC1 (2% solution), or (4) three drops of sodium chloride (0.9% solution). Each solution was administered to the conjunctival sac. In order to control the influence of sex, eye laterality, and experimental times on the changes in intraocular pressure, heart rate, and arterial pressure induced by any
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DRUG EFFECTS ON INTRAOCULAR PRESSURE
treatment, an analysis of variance was car ried out on the data exhibited at 0, 30 and 60 minutes before treatment and 30, 60, 90, 120 and 150 minutes after treatment. RESULTS
Intraocular pressure—The averaged re sults from the three groups of patients are shown in Figure 1 and Tables 1 and 2. Control observations—The instillation of saline into the conjunctival sac did not cause any change in intraocular pressure in pa tients with chronic simple glaucoma. Normal subjects—In 18 patients (nine men, nine women) with normal intraocular pressure, propranolol eye drops produced a progressive reduction in intraocular pres sure. This was maximal 120 minutes after administration of propranolol and was highly significant (p < 0.01) when men and women patients were taken as one group. No difference in the response to propranolol instillation was observed between the right and left eyes, while a marked and highly significant difference was recorded between the two sexes (p < 0.01): the decreases in intraocular pressure was 39% for men and 19% for women (Table 1). Patients with chronic simple glaucoma— Propranolol produced a marked and signifi cant reduction in intraocular pressure (0.01 < p < 0.05) in this group which was maximal 120 minutes after treatment. The response was similar in both sexes and in right and left eyes (Table 1, Fig. 1). Patients with acute glaucoma—In patients
with monolateral acute glaucoma, the admin istration of propranolol had no effect on the intraocular pressure of the diseased eye (Ta bles 1 and 2, Figs. 1 and 2) whilst it de creased the intraocular pressure in the contralateral, normotensive eye to 73.5% of control. Heart rate and arterial pressure—The mean heart rates (beats per minute) during the control period were 8 in normal sub jects, 78 in patients with chronic simple glaucoma, and 82 in those with acute glau coma. After the administration of saline to patients with chronic simple glaucoma and of propranolol to the others, heart rate fell (Fig. 1). The decrease was maximal at 90 minutes and was highly significant (p<0.01) in all groups; this response was similar in men and women. The mean value for arterial pressure was 109 mm Hg and did not alter significantly in any of the groups of patients following the administration of either saline or propranolol. Effect of experimental drug in normal subjects—Observations were made in 14 pa tients (seven men, seven women) in whom three drops of MJ 1999 were applied to both eyes after a one-hour control period. The averaged results in these patients are given in Table 3. In both sexes the introcular pres sure fell during the control period, but no further change occurred. Effect of INPEA in normal subjects— Observations were made in 14 patients (seven men, seven women) and the averaged results are given in Table 3. The administra-
TABLE2 COMPARISON OF EFFECT OF PROPRANOLOL IN EYES WITH ACUTE GLAUCOMA AND NORMOTENSIVE FELLOW EYES IN SAME PATIENTS
T-.
•
r*
Statistical Significance
T ime (in minutes) Before and After Treatment
NO.
60
-30
0
30
60
90
120
150
240
Treated Patients)
Acute glaucoma
7
x mm Hg SE
65.5 ±8.2
65.5 ±8.2
65.5 ±8.2
65.0 ±8.4
65.0 + 8.4
65.0 ±8.4
63.2 ±8.8
63.2 ±8.8
63.9 ±8.7
P>0.05
Normotensive
7
x m m Hg
16.3
15.9
15.9
13.4
11.9
11.7
12.2
13.3
14.5
P<0.01
AMERICAN JOURNAL OF OPHTHALMOLOGY
776
OCTOBER, 1971
100 __
90 J
100
_
Fig. 1 (Musini and associates). Effects of saline (dashed lines) and propranolol 2% eye drops (solid lines) on heart rate (top), mean arterial pressure, (center), and intraocular pressure (bottom) in patients with normal intraocular tension ( - O - ) , with chronic simple glaucoma ( - Q - ) and with acute glaucoma ( - A - ) . Variations are expressed as percent of control values.
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DRUG EFFECTS ON INTRAOCULAR PRESSURE
777
100
Fig. 2 (Musini and associates). Heart rate (top), arterial pressure (center), and intraocular pressure (bottom) responses to the instillation of propranolol 2% eye drops into the cojunctival sac of both the eyes with acute glaucoma ( - • - ) and the contralateral normotensive (-O-) eyes of the same patients. The curves are representative of the percent variations on the control values.
AMERICAN JOURNAL OF OPHTHALMOLOGY
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OCTOBER, 1971
TABLE 3 E F F E C T OF MJ
1999 AND IN PEA
Time (in minutes) After Treatment
Total No., Sex Treatments Patients MJ 1999*
INPEAj
ON INTRAOCULAR PRESSURE OF NORMOTENSIVE PATIENTS
30
60
90
120
150
240
Statistical Significance Controls (Controls vs Treated Patients)
7-M
x mm Hg SE
12.6 + 0.8
13.2 ±0.7
13.2 ±0.8
12.9 ±0.7
12.9 ±0.7
12.9 ±0.7
13.3 ±0.9
7-F
x mm Hg SE
15.3 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
15.4 ±0.6
P>0.05
x mm Hg SE
12.9 ±0.7
12.2 ±0.6
12.6 ±0.7
12.6 ±0.7
12.6 ±0.7
12.3 ±0.7
12.8 ±0.8
P>0.05
x mm Hg SE
12.0 + 0.4
12.0 ±0.4
12.0 ±0.4
12.0 ±0.4
12.0 ±0.4
12.0 ±0.4
12.8 ±0.8
P>0.05
7-M 7-F
P>0.05
* Three drops of a 2 % solution. f Six drops of a 2% solution.
tion of six drops of INPEA had no effect on intraocular pressure in either sex. Local anesthetic effect on the cornea—The effects of the four drugs, propranolol, lignocaine, MJ 1999, and INPEA, were com pared in both eyes of 15 patients. Lignocaine was applied to one eye of all patients (either left or right at random) and either proprano lol, MJ 1999, or INPEA was applied to the other eye. The averaged results are given in Figure 3. In the concentrations used, MJ 1999 and INPEA had no anesthetic effect. Propranolol and lignocaine were equally ac tive and had a similar duration of action (p>0.05). Comparison of intraocular pressure effects—Observations were made in seven patients with normal intraocular pressures. Propranolol and lignocaine were applied randomly to either eye of all patients. The drugs were applied every 30 minutes for 240 minutes and intraocular pressure was mea sured 15 seconds after each administration. The averaged results are given in Table 4 and Figure 4 and show that both the drugs lowered intraocular pressure; the effect was maximal at 120 minutes and was followed by a rise in pressure. There was no significant
difference between the effect of the two drugs (Table 5). DISCUSSION
The present observations show that the topical administration of propranolol to the eye reduces intraocular pressure in patients with normotensive eyes and in those with chronic simple glaucoma. This result cannot be ascribed to propranolol-induced changes in systemic hemodynamics, as arterial pres sure was unaltered after topical application of the drug to the eyes and heart rate de creased to some extent both in control and in propranolol-treated patients. The effect is apparently not due to blockade of adrenergic beta receptors, as MJ 1999 and INPEA ad ministration had no effect on intraocular pressure. In patients with normotensive eyes both lignocaine and propranolol reduced intraocular pressure to the same extent. In all patients with normotensive eyes and in those with chronic simple glaucoma, intra ocular pressure fell during the control period during which lignocaine had been applied to the eye to enable the measurement to be made. Thus lignocaine would appear to re duce intraocular pressure in these patients
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DRUG EFFECTS ON INTRAOCULAR PRESSURE
% CORNEAL ANESTHESIA
100 _ 90
779
•
LIGNOCAINE
O
PROPRANOLOL
A
MJ 1999
□
INPEA
80 J 70 60 J 50 40 J 30 20 J 10 0 J C
T" ~i
5
1
1
1
1
1
1
1
1
10 15 20 25 30 35 40 45 50
mm.
Fig. 3 (Musini and associates). Curves representing the intensity and duration of the local anesthetic activity of lignocaiiie ( - O - ) , propranolol ( - • - ) , MJ 199 ( - □ - ) , and I N P E A ( A ) . Each point is the mean value expressed as percent of the highest level of recorded from IS healthy male subjects.
through its local anesthetic action. The pres ent experiments have also shown that pro pranolol is as effective as lignocaine as a local anesthetic agent on the human cornea. These results all suggest that reduction in intraocular pressure produced by proprano lol on topical application to the eye is due to its local anesthetic action. The present ex
periments do not explain the observations of Phillips and associates,1 who reported a de crease in intraocular pressure after intra venous and oral administration of proprano lol, as the local anesthetic action of proprano lol on parenteral administration has not yet been determined in man. There is also evidence from our results
AMERICAN JOURNAL OF OPHTHALMOLOGY
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OCTOBER, 1971
TABLE 4 COMPARISON OF EFFECTS OF PROPRANOLOL AND LIGNOCAINE WHEN APPLIED CONTEMPORANEOUSLY TO FELLOW EYES
Time (in minutes) After Treatment Treatments
No. Eyes
Controls 30
60
90
120
180
240
Propranolol
7
x mm Hg SE
15.6 ±0.46
15.1 ±0.66
14.5 ±0.80
14.0 ±0.67
14.2 ±0.77
15.1 ±0.54
16.9 ±0.57
Lignocaine
7
x mm Hg SE
14.8 ±0.34
14.1 ±0.24
13.8 ±0.22
13.2 ±0.31
14.5 ±0.58
15.1 ±0.47
15.8 ±0.36
that, when topically applied, both proprano lol and lignocaine lower intraocular pressure when the iridocorneal angle is open, but not when the angle is closed, as in acute glau coma. This conclusion is further supported by the evidence that propranolol and ligno caine decrease the intraocular pressure of the normotensive eye of patients whose contralateral eye is glaucomatous. These findings suggest that the site of ac
tion of these drugs is in the chamber angle and that it involves a mechanism which can modify the resistance to outflow of the aqueous humor. T h e effect of these drugs may result from a reduction of the myogenic tone of the smooth muscle in the canal of Schlemm and in the other drainage channels, as the intra-arterial administration of pro pranolol and lignocaine reduce vascular smooth muscle tone. 11 Propranolol and ligno-
100
O
PROPRANOLOL
•
LIGNOCAINE
90-
80
c
I
30
60
—r90
— i —
120
180
240
rnin. Fig. 4 (Musini and associates). Effects of propranolol 2% (-O-) and lignocaine 2% ( - • - ) on intra ocular pressure of healthy male subjects. Variations are expressed as percent of control values.
VOL. 72, N O . 4
DRUG E F F E C T S ON INTRAOCULAR TABLE 5
RESULTS OF THREE-WAY ANALYSIS OF VARIANCE OF DATA CONCERNING PERCENT INTRAOCULAR PRESSURE CHANGES INDUCED BY LIGNOCAINE AND PROPRANOLOL CONTEMPORANEOUSLY APPLIED AT RANDOM TO EITHER EYE OF THE SAME PATIENT
Source of Variation
De S f r e e Mean „ , Squares I reedom
Drugs Patients Drugs-patients interaction Times Times-patients interaction Drugs-times interaction Residual (drugstimes-patients interaction)
F*
Statistical Signifi cance
PRESSURE
781
creasing intraocular pressure. The present results suggest that the reduction in intra ocular pressure consistently observed after topical application of propranolol to the eyes is due to the strong local anesthetic action of this drug. ACKNOWLEDGMENTS
The propranolol used in these experiments was supplied as Inderal (Imperial Chemical Industries, Ltd.) eye drops by Vister, Ltd., MJ 1999 (Sotalol) is a product of Mead Johnson, and the I N P E A was supplied as eye drops by Selvi and Co., Ltd.
1 6
2.2517 2.9273
1.09 1.41
P>0.05 P>0.05
6 5
2.0689 1.8881
5.30
P<0.01
REFERENCES 1. Phillips, C. I., Howitt G., and Rowlands D. J.: Propranolol as ocular hypotensive agent. Brit. J. Ophth. 51:222, 1967. 2. Bucci, M.G., Pecori Giraldi, J., and Missiroli, A . : La somministrazione locale di propranolo nella terapia del glaucoma. Boll. Ocul. 47:51, 1968. 3. Weeker, R., Delmarcelle, Y., and Gustin, J.: Treatment of ocular hypertension by adrenaline and diverse sympathomimetic amines. Am. J. Ophth. 40: 666, 1965. 4. Garner, L. L., Johnstone, W. W., Ballintine, E. J., and Carroll, M . E . : Effect of 2 % levo-rotari epinephrine on the intraocular pressure of the glaucomatous eye. Arch. Ophth. 62:230, 1959. 5. Prijot, F . : Contribution a l'etude cle la tonometrie et de la tonographie en ophtalmologie. Doc. Ophtal. 15 :1, 1961. 6. Becker, B., Pettit, T. H., and Gay, A. J.: Top ical epinephrine therapy of open angle glaucoma. Arch. Ophth. 66:219, 1961. 7. Shinebourne, E., Fleming, J., and Hamer, J.: Effects of beta-adrenergic blockade during exercise in hypertensive and ischaemic heart-disease. Lancet 2:1217, 1967. 8. Barrett, A. M., and Cullum, V. A . : The bio logical properties of the optical isomers of propra nolol and their effects on cardiac arrhythmias. Brit. J. Pharm. Chemother. 34:43, 1968. 9. Shanks, R. G.: The properties of beta-adren ergic blocking agents. Irish J. Med. Sci. 2:351, 1969. 10. Shanks, R. G.: The peripheral vascular effects of propranolol and related compounds. Brit. J. Pharm. Chemother. 29:204, 1967. 11. Bergamaschi, M.: Unpublished data.
30
0.3562
_
_
5
0.2908
1.37
P>0.05
30
0.2122
* F = Variances ratio (Fisher's test).
caine have also been observed to depress the myogenic activity of the isolated rabbit ileum." SUMMARY
When the mechanism underlying the hypotensive action of propranolol on intraocu lar pressure was investigated in three groups of ophthalmic patients, propranolol, applied topically, decreased intraocular pressure in the normotensive eyes and in those with openangle glaucoma, but not in eyes with acute glaucoma. Two beta-adrenoceptor blocking drugs which have no anesthetic activity, MJ 1999 and INPEA, did not alter intraocular pressure. When propranolol was applied to one eye and lignocaine to the other contempo raneously in normotensive patients, the two drugs were found to be equally potent in de