A C T A O P H T H A L M O L O G I C A VOL. 57 1979

Department of Ophthalmology (Head: Torstein I . Bertelsm) llniverszty of Bergen, Bergen, Norway

TIMOLOL MALEATE IN TREATMENT OF OPEN ANGLE GLAUCOMA BY

HENRY AASVED, JOHAN H. SELAND and JON E. SLAGSVOLD

The effect of Timolol maleate on the intraocular pressure in open angle glaucoma has been examined in 37 patients, of these simple glaucoma in 26 (48 eyes), capsular glaucoma in 9 (14 eyes) and chronic secondary glaucoma in 2 patients (2 eyes). These cases constituded a group which was relatively difficult to manage. T h e average pressure reduction caused by Timolol maleate alone was about 23%. In 18 patients the intraocular pressure was adequately controlled on Timolol as the only drug and in 10 on additional drug therapy. Five patients failed on drug treatment, and the remaining four failed on one eve while the fellow eye was well regulated. Tonography indicates that the effect is caused by a reduction of the aqueous humour production. Side effects of locally applied Timolol maleate have not been observed. This drug may be the drug of choice in many instances.

Ke? zoordc: Timolol maleate - beta-adrenergic blocking agents glaucoma - simple glaucoma - capsular glaucoma.

-

open angle

Over the course of the last few years, several beta-adrenergic blocking agents have been introduced in glaucoma treatment. Both oral and local application have been proved to reduce the intraocular pressure. Such drugs have included atenolol (Brenkman 1976, Wettrell 8c Pandolfi 1977, Philips et al. 1977), propranol (Philips et al. 1967, Cote & Drance 1968, Musini et al. 1971, Vale et al. 1972, Wettrell & Pandolfi 1975, Borthne 1976), bupranolol (Krieglstein et al. 1977), pindolol Received January 18, 1979.

700

Tzmolol tn Ofim Angle Glniccoma

Bonomi 8c Steindler 1975),oxprenolol (Stilma 1976) and Timolol (Katz et al. 1976, Vareilles et al. 1977, Zimmerman & Kaufman 1977, Zimmerman et al. 1977, Nielsen 1978, Kerty & Hfirven 1978). Among these Timolol maleate seem to have some advantages over the others. Applied locally the cornea sensibility is unaltered in contrast to propranolol and bupranolol and the effect on the intraocular pressure lasts considerable longer than after application of atenolol, pindolol or oxprenolol. In addition Timolol maleate has been used systemically for several years in the treatment of arterial hypertension and angina pectoris without reports of serious side effects. For the last two years clinical trials using Timolol maleate have been initiated over large areas of the world. The intention with this paper is to report our experience with locally applied Timolol in the treatment of various types of open angle glaucoma. Of special interest is the effect on capsular glaucoma.

Material and Methods This clinical trial comprised 37 patients with open angle glaucoma, where simple glaucoma was found in 26 (48 eyes), capsular glaucoma in 9 ( I 4 eyes) and 2 patients (2 eyes) had chronic secondary glaucoma caused by chronic uveitis in one and congenital cataract treated surgically in the other. Fourteen were inpatients and 23 outpatients. The one patient with operated congenital cataract and secondary glaucoma was 30-years-old, while the age distribution of the remainder of the patients ranged from 46 to 82 years. Two patients were new cases ( 1 simple and 1 capsular glaucoma) while the others had previously received conventional antiglaucomatous drug therapy. Therapeutic procedure: Prior to the trial, all glaucoma medication was stopped. After a “wash-out period” varying from one to seven days the following examinations were performed: Ordinary ophthalmological status including perimetry, pupillometry, applanation tonometry (Goldmann tonometer), evaluation of tear production by Schirmers test and pulse and blood pressure measurements. These examinations were repeated during the control period. The aim was to establish an intraocular presure (iop) below 22 mm Hg. Initially Timolol 0.25% once a day (at night) was given. Depending on the iop level seen at the end of the ‘wash-out period’, the pressure was controlled one to seven days later. If the iop still exceded 22 mm Hg, the Timolol medication was increased to 0.5% once a day and later to 0.5% twice daily if necessary. If the iop still exceeded 22 mm 70 1

H . Aasued,J. H . SelandandJ. E . Slagtuold IOP mm Hg

70

+ =

++

capsular glaucoma

o = e n d ot washout period

= secondary glaucoma = Timolol therapy

Fig. 1. Intraocular pressure in 20 eyes (20 patients) using Timolol only. Surgical treatment of the other eye of patient No. 9 required due to failure of drug treatment. Patient No. 3 converted to pilocarpine as the only drug.

Table I . Comparison of prior therapy and Timolol

PRIOR THERAPY

I

I

I

1 .;F 1

NO, PAT. WITH I.O.P.

< 2 2 mrn Hg

TIMOLOL CONCENTRATION A N D FREQUENCY

0.25

0.5

x 1

x 1

0.5 x 2

NO. P&T. WITH I.O.P. 5 22 mm Hg 0.5

x

ONE LOCAL DRUG ( PlLO 5 , EPI 1 )

6

3

TWO LOCAL DRUGS ( PlLO + EPI )

8

4

3

1

5

2

2

0

1

20

9

6

3

2

7

2

3

1

1

2

1

LOCAL DRUGS

+

ACETAZOLAMIDE TOTAL

>

I.O.P. 22 rnm Hg O N PRIOR THERAPY A M O N G THE 20 PATIENTS

702

2

Timolol in Open Angle Glaucoma

Hg, additional therapy was given in the form of epinephrine 1 % twice daily or pilocarpine three tims daily, with the addition of acetazolamide if needed. T h e iop of the inpatients were recorded 9 and 23 h after the evening application of Timolol, while the outpatients were seen about 15 h after the evening application. Observation period :

Three patients were withdrawn from medical treatment due to insufficient response and operated on within six months of observation. The remaining 34 patients (including 3 patients operated on one eye) have been followed for 10 to 15 months (average 12 months).

Results In this report the patient and not the individual eye is presented as the treated entity. If there was any significant difference in severity of bilateral glaucoma, the figures illustrate the iop of the worst eye unless specifically commented upon. The illustrations show the iop at the last visit after 10 to 15 months of observation. T h e effect on the intraocular pressure of Timolol as the sole drug in 20 patients is illustrated in Fig. 1 and in Table I. Out of the 37 patients 18 (48.6%)had a satisfactorily regulated iop on Timolol alone. One patient (No. 3) reverted to pilocarpine as the only single drug giving IOP rnrn Hg

70

p

60

10 pat no

5

6

+ +

7

10 11

12 18 20 2 2 23 25 ' 27 30 31 33 35 36

+

+

+ + + + +

+ = capsular glaucoma o = end of washout period + + = secondary glaucoma = Tirnolol only x = conventional drug in addition to Tirnolol

Fig. 2. Intraocular pressure in 17 eyes (17 patients) o n Timolol and additional therapy. Surgical treatment of the other eye of patients Nos. 6,22, and 3 1 d u e to failure of drug treatment.

703

H. Aasued, J . H . Seland and J . E . Slagsuold

satisfactory pressure regulation. Another patient (No. 9) had good regulation of simple glaucoma in his left eye on Timolol medication for 5 months, followed by a dramatic rise in pressure refractile to any medication, and trabeculectomy was carried out. His right eye with secondary glaucoma caused by uveitis was, however, well maintained on Timolol alone as illustrated in Fig. 1 . These patients (Nos. 3 & 9) are registered in the column for iop above 22 mm Hg,in Table I. The effect of Timolol and additional therapy in 17 patients is seen in Fig. 2 . In these patients Timolol alone was not able to maintain the iop below 22 mm Hg.In two patients (Nos. 7 & 23) the iop was even higher on Timolol alone than during the wash-out period. In 10 of the patients, the iop was well regulated on Timolol and additional drugs. Drug therapy has failed in 7 patients, and in 6 of them a trabeculectomy was performed (patients Nos. 6, 12, 22, 23, 30, and 31). Three of these had satisfactory tension levels in the fellow non-operated eye using drug therapy, as illustrated in Fig. 2 (patients Nos. 6,22, and 31). Table I1 shows the comparison between the therapeutic response to the previous and to the present therapy. Out of 18 patients who could be well regulated on Timolol alone, 13 had previously used two local drugs, and another 4 had also Table I I . Comparison of prior tharapy and present medication. ~

PRESENT THERAPY NO. PAT. WITH I . O . P . < 2 2 m m Hg

PRIOR THERAPY

TIMOLOL

O N E LOCAL D R U G ( P l L O 7, EPI 1 )

8

TWO LOCAL DRUGS ( P l L O + EPI )

TIMOLOL

TIMOLOL

EPINEPHR.

PlLO

+

+

NO. PAT-. WITH I . 0 . P 5 2 2 rnm Hg I N ONE OR BOTH EYES t

ACETAZOL.

5

2

8

LOCAL DRUGS

+

ACETAZ OLAM IDE

17

ACETAZOLAMIDE

1

4

1

1

37

18

3

1

6

9

I . O . P . > 2 2 m m Hg ON PRIOR THERAPY 16 A M O N G THE 37 PATIENTS

6

2

0

2

6

TOTAL

704

7

Tiniolol In Open Angle Glaucoma Caps QI IOP m m HQ 50

E K 1902

40 30 23

10

3ate

Fzg. 3 .

Pressure curve from a patient showing a relative slowly developing insensitivity to Timolol reverting to normal level when converted to pilocarpine.

received acetazolamide. Among the 18 patients who had previously used acetazolamide, six had no need for this drug while on the present therapy. On prior therapy 34 patients had to use piolocarpine 3 times a day and/or acetazolamide. Half of these patients were well regulated on Timolol alone with application one (14 patients) o r two (3 patients) times a day. Among the 9 patients with iop above 22 mm Hg, drug treatment failed on one eye in 4 patients, while the glaucoma in the fellow eye was well regulated. Out of 16 patients, who with previous medication had iop above 22 mm Hg, 10 patients were well regulated by the new treatment and 6 of these with Timolol alone. T h e average reduction of iop in the total group was about 23% with standard deviation 16.4. T h e effect of Timolol maleate could be registered already 9, respectively 15 h. after the first application. Some patients, however, subsequently developed relative insensitivity to the drug, requiring a stronger solution of Timolol or the addition of conventional drugs. Such relative insensitivity was already oberved in one patient during the first week of treatment and in another case during the first 5 to 6 months (Fig 3 ) . Tonography has shown almost no change in the facility of outflow, not even when the iop dropped from 46 to 16 mm Hg from one day to the next.

The effect of Timolol on different types of glaucoma

In Figs. 1 & 2 it is shown that only one of the 9 patients with capsular glaucoma could be maintained on Timolol as the sole drug, while 17 of the 26 patients with simple glaucoma required Timolol medication alone. Surgical treatment had to be performed in 4 patients with capsular glaucoma (patients Nos. 6, 2 3 , 30, and 31), while trabeculectomy was performed in only 2 patients with simple glaucoma (patients Nos. 12 & 22). 705 4i

H A n r i d , J H Srlundnnd J E Slng\idd

T h e average reduction of the iop on medical treatment was approximately 10% in 14 eyes with capsular glaucoma and approximately 26% in 48 eyes with simple glaucoma. T h e two patients with chronic secondary glaucoma (patients Nos. 9 & 33) had satisfactory pressure levels on the new regimen, and one of these required only Timolol to maintain this. Both these patients had previously needed maximal treatment, and one of them was even then not adequately controlled.

Sidp-PffPctT: Two of the patients showed at one visit a pulse rate below 60 per min, but had no subjective symptoms and the frequency was easily increased by light excercise. No influence on blood pressure was recorded. During treatment with Timolol as the only drug, the pupillary diameter has been about the same size as during the “wash-out period”, and the pupillarv reactions have been normal. We have seen no changes in the conjunctiva, cornea, lens or retina. No progressions in optic nerve damage have been observed. We have not recorded any lowering of the tear production as judged by the Schirmer test.

Discussion This study supports the earlier reports that Timolol maleate has a marked pressure reducing effect when applied locally to open angle glaucoma. The mode of action seems to be a lowering of aqueous humour production with no alteration in the outflow facility. This agrees with earlier observations (Zimmerman et al. 1977). The present study is an open study not randomized, and comprises a relatively large proportion of glaucomas difficult to treat. Thus 14 patients have been admitted to the department, and 11 patients had glaucoma of such a severity that surgery was considered the only alternative. It is worth noting that 5 of these 11 were satisfactorily regulated on the new medical therapy, while the remaining 6 had to undergo surgical treatment. Among the 37 patients 18 were maintained satisfactorily on Timolol alone, while the remainder needed the addition of conventional drugs (13 patients) or surgery (6 patients). T h e effect of Timolol is seen by a decrease of the iop the day after the first application. The relative insensitivity to the drug seen in some patients is probably explained by an initial dramatic drop of aqueous production with a later stabilization at a higher level. O u r study indicates that capsular glaucoma responds less well to Timolol than do the simple glaucomas, as 65% of the patients with simple glaucoma required Timolol as the only form of treatment compared to 1 1% of the capsular glaucomas. 706

Timolol in Open Angle Glaucoma

Amongst the 16 patients with iop exceeding 22 mm Hg on previous treatment, 3 had capsular glaucoma, and all these had iop exceeding 22 mm Hg at least in one eye also on present medication. This confirms the earlier observation that capsular glaucoma is a more difficult type of glaucoma to treat than simple glaucoma (Aasved 1971; Kerti 8c Horven 1978). Applied locally, Timolol maleate has a prolonged effect. Out of the 18 patients maintained on Timolol as the only drug, 15 needed only one application a day. As the interval between application and iop registration was 15 h for the outpatients and up to 23 h for the inpatients, this study supports earlier investigations that the effect of Timolol lasts longer than 24 h. (Zimmerman et al. 1977). This study also confirms the absence of side-effects using this drug. This has been spontaneously expressed by many patients who en,joy better sight and night vision as the niiosis of earlier treatment have disappeared. The reduction of applications t o 1-2 times a day must also be of great benefit. In this investigation the pressure reducing effect of Timolol in most cases has been almost unchanged during the period of observation. If the pressure reducing effect of Timolol maleate proves to be a lasting one over several years of treatment without any serious side-effects this might well represent the beginning of a new era in the treatment of open angle glaucoma. O u r present experience indicates that Timolol maleate in many instances will be the drug of choice.

Acknowledgment Timolol maleate (Blocadre@) used in the present study was kindly provided by Merck Sharp & Dohme.

References Aasved H. (1971) T h e frequency of optic nerve damage and surgical treatment in chronic simple glaucoma and capsular glaucoma. Acts ophthrtl. (Khh.) 4 9 , 589-1500. Bonomi L. &- Steindler P. (197.5) Effect of pindonol on intraocular pressure. Brit.,J. Ophthnl. 59,301-303. Rorthne A . (1976) T h e treatment of glaucoma with propranolol (InderaP). A clinical trial, Actn ophthal. (Khh.) 54, 29 1-300. Brenkman R. F. (1976) Ocular hypotensive effect of atenolo144 eye drops in glaucoma. In: Docum. Ophthal. Proc. Ser., vol 12, pp. 85-94, &eve E. L., ed., Symposium mrdicnl thrrnpif.s in glcirccomn, Arn.ctrrrklm 1976. Dr. W. Junk. the Hague 1977. Cote G . 8c Drance S. (1968) T h e effect of propranolol on human intraocular pressure. Ccmnrl. J . Ophthnl. 3, 207-2 12.

707 Ii

H . Anrued,J . H . Seland and J . E . Slagsi~old Katz I. M.. Hubbard W. A , , Getson A . J. & Could A . L.. (1976) Intraocular pressure decrease in normal volunteet-s following Timolol ophthalmic solutions. In71nt.Ophthnl. 15, 4 8 9 4 9 2 , Kei-tv E. & Hiirven I. (1978) Glaucoma treatment with Timolol. Actn ophthnl. (Khh.) 56, 705-714. Kriegelstein G. K . , Sold-Darseff .J. & Leydhecker U’.V. (1977) T h e intraocular pressure response of glaucomatous eyes to topical applied bupranolol. Alhrrrht 71. Grcwf~tArch. Klin. e u p . Ophfliril.202, 8 1-86. Musini A , , Fabhri R., Bet-gamaschy M. & Mandelli V. (1971) Comparion of the effect of propi-anolol, lignocaine, and other drugs on normal and raised intraocular pressure in man. Ainrr.,]. Ophtliril. 72, 773-78 1. Nielsen N. V . (1978) Timolol. Hypotensive effect, used alone and in cornhination for treatment of increased intraocular pressure. Actcr ophthrrl. (Khh.) 56, 504-509. Phillips C . I., Howitt G. & Rowlands D. J . (1967) Propranolol as ocular hypotensive agent. Rut.,]. Ophthnl. 51. 222-226. Phillips C. I . , Gore S. M.. McDonald M. ,J. & Cullen P. M. (1977) Atenolol eye drops in glaucoma: A double masked controled study. Brit.,]. Ophthnl. 6 1 , 349-353. Stilma J . S. (1976) Use of oxprenolol eve drops in glaucoma patients. I n : Docurn. Opthal. Proc. Ser., vol 12, pp. 95-97. Greve E. L., ed., S?mposiitm on mrciical thrrnpit.7 in gloncoma, Ainztrrdnm 1976, Dr. W. Junk, the Hague 1977. Vale J . , Gibbs A . C. C. & Phillips C . I. (1972) Topical propranolol & ocular tension in the human. Rr.it.,]. Oplithril. 56, 770-775. \7. aieilles - ’ P., Silverstone D., Plazonnot R., I’Douared, Searse M . L,. & Stone C. A. (1977) Comparison of the effects of Timolol and adrenergic agents on intraocular pressure in rabbit. 17i7mt. ophthnl. & Viznnl Sci. 16, 987-996. U’ettrell K . & Pandolfi M. (1975) Effect of oral administration of various beta-blocking agents on the intraocular pressure in healthy volunteers. Exp. A. Rrc. 21.45 1 4 5 6 . Wettrell K. & Pandolfi M. (1977) Effect of topical atenolol on intraocular pressure. Brit. ,I. Ophthril. 61. 334-338. Zirnmermann T. 1. & Kaufmann H. E. (1977a) Timolol. Beta-adrenergic blocking agent for the treatment of glaucoma. Arch. ophthnl. 95, 6 0 1 4 0 4 . Zimmermann T. .J. & Kaufmann H. E. (1977b) Timolol. Dose response and duration of action. Arrh. oplithril. 95, 605-607. Zimmermann T . ,J., Harbin R., Pett M. & Kaufmann H. E. (1977) Timolol and facility of outflow. In7wt. ophthnl. & Visirrc/Scz. 95, 623-624.

A i t tho r 5 ’ ritltln~c Department of Ophthalmology, N-5016 Haukeland sykehus, Bergen, Norway

708

Timolol maleate in treatment of open angle glaucoma.

A C T A O P H T H A L M O L O G I C A VOL. 57 1979 Department of Ophthalmology (Head: Torstein I . Bertelsm) llniverszty of Bergen, Bergen, Norway T...
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