A C T A O P H T H A L M O L O G I C A VOL. 5 6 1 9 7 8
Department of Ophthalmology (Head: Thore Lie Thomassen), University of Oslo, Rikshospitalet, Oslo
GLAUCOMA TREATMENT WITH TIMOLOL BY
EMlLlA KERTY and IVAR HQRVEN
Thirty-two eyes from 19 patients with either capsular glaucoma, pigmentary glaucoma o r primary open angle glaucoma were given topical timolol and followed through a 3-6 months period. Twelve eyes were previously out of control on full medication including pilocarpine, epinephrine and acetazolamide. Eight of these eyes could be adequately controlled throughout the follow-up period on topical timolol or a combination of timolol and pilocarpine, but without resorting to acetazolamide. One eye needed acetazolamide in combination with timo101, and three eyes had to be referred to surgery. Twelve eyes were adequately controlled either on pilocarpine or full medication, but could be equally well controlled on timolol alone, or timolol and pilocarpine in combination. Acetazolamide could be withheld from all of the six patients who used this drug. Eight eyes were previously untreated. They could all be adequately controlled either on timolol (5 eyes) or timolol and pilocarpine (3 eyes). The study indicates that the effect of timolol 0.5 O/o x 2 may be stronger than the combined effect of epinephrine 1 O/o x 2 and acetazolamide 500 mg a day. Topical timolol was well tolerated. No side reactions occurred and the pupillary size and reactions were not influenced by the timolol treatment.
Key words: acetazolamide - 8-adrenergic blockers - capsular glaucoma glaucoma - intraocular pressure - pigmentary glaucoma - pilocarpine ti mo1o1.
Systemic intake of 8-adrenoceptor blocking substances may reduce the intraocular pressure (IOP) (Phillips et al. 1967; Cot6 & Drance 1968; 0hrstrsm 1973; Pandolfi & 0hrstrsm 1974; Elliot et al. 1975; Borthne 1976; Wettrell 1977). Their use in glaucoma treatment is, however, restricted because a similar Received April 19, 1978.
705
Emilia Kerty and Ivar Hsrven
and sometimes even more pronounced reduction is initiated both in heart rate and systemic blood pressure, and so reduce the ocular perfusion pressure risking further glaucomatous damage (Fransois & Neetens 1970). This risk may be avoided by topical application. A t present it seems that timolol (BlocadrenD) is the drug of choice when a &blocking agent is needed for topical use. Timolol is a non-selective P-adrenergic antagonist without membrane-stabilising activity. In concentrations of 0.25 O / O and 0.5 O/O, timolol eye drops have been shown to lower the IOP in animals with a-chymotrypsininduced ocular hypertension (Vareilles et al. 1977), in normal volunteers (Katz et al. 1976) and in patients with chronic open angle glaucoma (Zimmermann & Kaufman 1977a). T h e IOP-reducing effect occurs 20-30 min after instillation and the duration of action appears to be a t least 24 h. No change occurs in accommodation, visual acuity, pupil size, tear production or systemic blood pressure (Zimmermann & Kaufman 197713; Ritch et al. 1978). A slight lowering of the heart rate (4-6 beats per min) may occur in some patients. Timolol does not change the facility of outflow (Zimmermann et al. 1977), the mechanism of action is probably through a decreased secretion of aqueous humour (Missotten & Goethals 1977). No intolerance to topical timolol has been observed (Katz et al. 1976; Ziminermann & Kaufman 1977a,b; Ritch et al. 1978). When administered together with other antiglaucoma agents, an additive effect may occur. T h e above clinical data for timolol is based on studies over days and weeks. According to Krieglstein (1978) and Leydhecker (1978) the effect of topical timolol already subsides after a few days. The need for longer follow-up periods was, therefore, pressing. In the present study patients with pigmentary glaucoma, capsular glaucoma or primary open angle glaucoma (POAG) were treated with timolol and followed through a 3-6 months period.
Material T h e material consists of 19 patients (32 eyes) and includes all patients who were given timolol in our clinic before January 12, 1978 with the following diagnoses: Pigmentary glaucoma. This group consists of six eyes from three male patients (Cases 4, 8, 1 7 ) . Average age was 42 (35-.51) years. In addition to elevated IOP and heavily pigmented trabecular meshworks, these patients demonstrated glaucomatous disc changes and visual field loss (Bjerrum scotoma) in one or both eyes. Case 4 was previously untreated. the other two patients complained of severe ocular discomfort
following pilocarpine instillations. 706
Glaucoma Treatment with Timolol Capsular glaucoma. This group consists of seven eyes from six patients (Cases 2, 3, 6, 10, 15, 16). There were two women and four men. Average age was 72 (60-80) years. One of the patients (Case 6 ) had capsular glaucoma in one eye, the other eye being normal. Two patients (Cases 3 and 10) had capsular glaucoma in one eye, primary open angle glaucoma in the other. Case 2 and Case 16 had haemorrhagic glaucoma with amaurosis and severe IOP elevation on one side, caused by previous capsular glaucoma. These two amaurotic eyes are not included in the study. Case 15 had capsular glaucoma in both eyes. The diagnosis of capsular glaucoma was based on elevated IOP, trabecular meshwork pigmentation and presence of pseudoexfoliative material in the anterior part of the eye including the anterior lens surface. Glaucomatous disc changes and/or visual field loss were present in five of these seven eyes. All of the patients were referred to our clinic because the IOP was out of control on heavy antiglaucomatous treatment which included acetazclamide. Primary open angle glaucoma (P0,IG). This group consists of 19 eyes from 12 patients (Cases I, 3, 5, 7, 9, 10, 1 1 , 12, 13, 14, 18, 19). There were five women and seven men with an average age of 64 (46-84) years. Case 1 had lost one eye following detachment surgery 20 years ago, Case 3 and Case 10 had POAG in one eye, capsular glaucoma in the other. Case 18 was aphakic on one side with normal IOP. The other patients had POAG in both eyes. The diagnosis was based on elevated IOP in eyes with open angles. Seven patients (12 eyes (Cases 1, 3, 5, 9, 1 1 , 12, 14) showed glaucomatous disc changes and visual field loss in one or both eyes. In five patients (7 eyes) (Cases 7, 10, 13, 18, 19) the discs and fields were normal, but the IOP was repeatedly between 27-40 mmHg. Case 7 and Case 10 demonstrated repeated IOP readings of 30 mmHg without treatment, on pilocarpine the IOP dropped to about 15 mmHg. Case 13 had used pilocarpine for several years, on treatment repeated IOP readings between 30-35 mmHg were recorded on both eyes. Case 18 demonstrated repeated IOP values between 25-30 mmHg on one side, 14-16 mmHg on the other, aphakic eye. Case 19 presented IOP values of 25 mmHg at a routine check. She was followed closely for a year without treatment, and a steady increase of IOP was noted until values of 35 mmHg and 40 mmHg were recorded in the right and left eye respectively. Six of the POAG eyes were previously untreated, while the other 13 eyes were treated with pilocarpine (5 eyes) or full medication including acetazolamide (8 eyes). Eight of these 13 eyes were inadequately controlled when timolol treatment commenced.
Methods Heart rate and systemic blood pressure we r e recorded i n t h e sitting position, the latter with th e use of a mercury sphygmomanometer. Intraocular pressure (ZOP) wa s recorded in m m H g with a G o l d ma n n appianation tonometer.
707
Emilia Kerty and Ivor Hsrven
Pupil diameter was measured in standard illumination in Goldmann’s perimeter. Schirmer’s test was performed using standardized paper strips. Tonography was performed by use of the dynamic tonometer (Hsrven 1968) which is a standardized Schistz electronic tonometer. Visual fields were recorded in Goldmann’s perimeter.
Results No major alterations were found in systemic blood pressure, pupil size or reactions, tear production or facility of outflow following timolol treatment, which confirms previous observations referred to above. A minor lowering of the heart rate was observed in some patients.
Table 1. Effect of timolol on pigmentary glaucoma eyes.
4
d
4
s
8 8 17 17
d x x 21 s x x 2 1 d x 24 s x x 24
Average:
22.5
52 50 3 0 x 2 5 x
x
x
x
x
X
x
x
39.3
22 20 18 16 12 16
20 20 14 14
14 19
17.3 16.8
x = treatment given.
708
16 18 16 16 14 18
22 22 18 16 17 19
22 22 14 18 16 20
15 17 18 16 17 22
16.3 19.0 18.7 17.5
Glaucomn Treatment with Tiinolol
In all patients, t h e timolol treatment was well tolerated without ocular discomfort o r other side-effects. I n patients treated only i n the evening, the IOP was measured both at noon a n d in the evening just before the next installation. No m a j o r differences w e r e found between these readings, indicating that the effect of one d r o p of timolol lasts at least 24 h. T h e visual fields did not change d u r i n g t h e observation period.
Pigmentary glaucoma. T h e IOP was controlled i n all eyes, although three eyes needed addition of pilocarpine (Table I). These relatively young patients sometimes h a v e severe side-effects to pilocarpine treatment, with ocular discomfort, ciliary spasm, headache a n d transient myopia.
This was especially prominent in Case 8, a man aged 54 years. He suffered attacks of urolithiasis in 1973 and 1975. His pigmentary glaucoma was diagnosed in April 1976 with an IOP of 32 mmHg and 40 mmHg in the right and left eyes respectively. The trabecular meshworks were heavily pigmented, the discs were cupped and a Bjerruin scotoma was present on the left side. Initially the IOP was controlled by epinephrine and pilocarpine eye drops with addition of pilocarpine ointment at night. However, he did not tolerate pilocarpine, which produced ocular pain, ciliary spasms and myopia rendering him unfit for work. A trabeculectomy was performed on the left eye in May 1977, and ocusert lamellas were tried on the right eye. However, in July 1977 the IOP was again elevated and he had to return to pilocarpine 2 O/o x 4 and epinephrine 1 " / o x 2 in both eyes. His ocular discomfort to pilocarpine persisted and he planned to quit work and had applied for a disability pension when the treatment was substituted with timolol 0.250/0 x 1 in both eyes. Since then his IOP has been adequately controlled. He no longer suffers ocular discomfort and he is back to full time work in his office as a shipping manager.
Capsular glaucoma. These seven eyes w e r e all out of control on full medication before timolol was started (Table 11). Following timolol treatment, acetazolamide could be discontinued i n five of t h e six patients. W i t h the addition of pilocarpine the IOP was controlled in three eyes, one patient (Case 16) was controlled o n timolol in combination with acetazolamide. Surgery had to be performed o n three eyes. Case 16 was amaurotic in one eye. On pilocarpine and epinephrine a miosis occurred, and his vision was reduced to light perception because of axial lens opacities. After timolol and acetazolamide, however, the vision remained at 20130.
Primary open angle glaucoma (POAG). Six eyes were previously untreated. Five of them were controlled o n timolol, while one eye required both pilocarpine a n d timolol (Table 111).
709
Emilia Kerty and lunr Hsruen
All of the 13 eyes previously treated with pilocarpine (5 eyes) or full medication (8 eyes) could be controlled either with timolol (7 eyes) or a combination of timolol and pilocarpine (6 eyes). Acetazolamide could be withheld from all of the six patients who used this drug (Table IV). Case 11 demonstrated a most striking effect of timolol. He started using pilocarpine 20/0 in 1965 which was later increased to 40/0. Epinephrine and acetazolamide had to be added in order to keep the IOP at a normal level. However, acetazolamide gave him gastrointestinal discomfort. Before timolol treatment was started, all medication was stopped and the IOP rose to 40 mmHg and 30 mmHg on the right and left eyes respectively. Following timolol 0.25 0:o x 1 the IOP was adequately controlled in both eyes throughout the observation period Table IV).
Table 11. Effect of timolol on capsular glaucoma eyes, previously treated with pilocarpine, epinephrine and acetazolamide.
-
'1
2 m l
j
Follow-up periods in weeks IOP (mmHg)
3
N
: a
u w
Y
W
Y
22 24 26 34 27 24 27
Average: (S-values not included) x
=
S
=
x x x x x
A
26.3
18 18 12 17 16 22 38 S 23 20 17 22 18 18
18 18 22
19 16 30 S
16 17
18 16
32 S 18 20
18 18
19 18
20 19
17.3
19.2
17.8
17.5
18.3
19.5
treatment given. - = initial concentration, later increased. surgery. A = acetazolamide instead of pilocarpine.
710
Glaucoma Treatment nlith Timolol Table 111.
Effect of timolol on primary open angle glaucoma eyes, previously untreated. -
~
Y
!
d
.
Y
X
0.I
.-2a
c 0
2
L UJ
: w"
s
5 5 12 18 19 19
d S S S
d S
2
F4
W
U -
~
2
=
32 24 27 28 35 40
treatment given.
2 .*
1
4
8
12
18
26
x
19 14 17 11 20
16 16 16 14
1s
26 17 16 17 20 20
22
16 16 16 11 20 20
14 16 16 16 20 20
18 12 16 17 19 20
16.5
19.3
17.2
16.5
17.0
17.0
a -
Average: 31.0
x
Follow-up periods in weeks IOP (mmHg)
0
2
Y
-=
19
initial concentration, later increased.
Discussion The present study does not support Krieglstein's (1978) and Leydhecker's (1978) finding that the effect of timolol subsides over a short period of time. On the contrary, the full effect of timolol was present throughout the entire observation period in all of the three glaucoma types studied. I t is well known that capsular glaucoma is more difficult to treat and has a less favourable prognosis than POAG (Tarkkanen 1965; Herven 1966). This may explain why the three eyes of the present study which could not be properly controlled with timolol and pilocarpine all belonged to the capsular glaucoma group. In the present study, nine eyes were not adequately controlled on full medication including epinephrine and acetazolamide, but showed normal IOP levels on timolol or timolol and pilocarpine. In many cases, therefore, it seems that timolol 0.5 O/O x 2 may more than compensate for the combined effect of epinephrine 1 010 x 2 and acetazolamide 500 mg a day. Taking into consideration the severe side reactions including renal calculi formation that may follow acetazolamide intake and the ocular discomfort following long-term use of 71 1
Emilia Kerty and Ivar Hvlrven
topical epinephrine, a shift to topical timolol seems reasonable and favourable. As mentioned above, no side reactions have been ascribed to short-term use of topical timolol, and the pupillary size and reactions were not influenced by the medication. This was confirmed by the present study. This is especially important in young patients and patients with lens opacities who suffer visual disturbances on pilocarpine. A shift to timolol should therefore be considered for all patients who have severe side-effects to their glaucoma medication, whether their IOP's are adequately controlled or not.
Table IV. Effect of timolol on primary open angle glaucoma eyes, previously treated.
-
* x 4 X .-B .*z 2 2 a : 2i 2: 2 0 : t . (
o . (
3
0
3
2
2JL5.Z $ 2
!-
? -
23 22 16 18 26 14 18 18 27 35 32 26 22
28 32 34 30 34 30 40 30 34
0
.-ca m
X
X
x
X
x
X
X
33 26
22.8 31.9
x
- =
4
8
12
18
26
20 12 16 16 20 18 18 18 17 20 20 27 21
22 19 16 16 16 18 18 20 18 17 17 18 20
22 18 18 18 18 18 18 18 18 18 18 16 14
20 16 18 18 20 20 18 18 16 15 22 20
19 18 17 19 18 20 16 18 14 16 17 20 19
20 18 18 20 16 18 20 19 19 17 18 18 17
18.7
18.1
17.8
18.3
17.8
18.3
2- 1 :
X
Average: treatment given.
0
2
.w
=
cy X
X
0
.g
M
Follow-up periods in weeks IOP (mmHg)
.. m
X
X
initial concentration, later increased.
= Mintacol instead of epinephrine.
712
17
Glancoma Treatment with Timolol
In the present study combined pilocarpine a n d timolol treatment was followed by a larger decrease i n IOP than administration of either drug alone, indicating an additive effect. Zimmermann & Kaufman (197713) described a dose relationship f o r timolol in concentrations of 0.1 O / O , 0.25 O / O a n d 0.5 O / O . Increasing the concentration to 1 0 / 0 did not cause further reduction of the IOP. To some extent the present data confirm these results. In 12 eyes the timolol dose had to be increased from 0.25 O / O x 1 to 0.5 O / O x 2 before maximal effect was obtained (Table 11, 111, IV). It should be stressed t h a t the effect of timolol over a period of years has not yet been evaluated. All patients receiving topical timolol should therefore be followed closely f o r possible side-effects and reduced response. So far, topical timolol seems to be a very promising approach f o r treatment of various types of glaucoma.
Acknowledgment Timolol used in the present study was kindly provided by Merck Sharp SC Dohme.
References Borthne A. (1976) The treatment of glaucoma with propranolol (InderalB). A clinical trial. ( A c t a ophthal. (Kbh.) .54, 291-300. Cot6 G. & Drance S. M. (1968) The effect of propranolol on human intraocular pressure. Canad. 1.Ofihthal. 3, 207-212. Elliot M. J., Cullen P. M. & Phillips C. I. (1975) Ocular hypotensive effect of atenolo1 (‘renormin ICI). A new beta-adrenergic blocker. Brit. /. Ophthal. 59, 296-300. Fransois J. & Neetens A. (1970) The deterioration of the visual field in glaucoma and the blood pressure. Docum. opltthal. 28, 70-132. Hsrven I. (1966) Exfoliation syndrome. Incidence and prognosis of glaucoma capsulare in Massachusetts. Arch. Ophthnl. (Chicago) 76, 505-51 1. Hsrven I. (1968) Dynamic tonometry. I. T h e dynamic tonometer. Acta ofihthal. (Kbh.) 46, 1213-1221. Katz I. M., Hubbard W. A,, Getson A. J. & Gould A L. (1976) Intraocular pressure decrease in normal volunteers following timolol ophthalmic solution. Invest. Ophthal. 15, 489-492. Krieglstein (1978) Die Wirkung von Beta-Blockern auf den Augeninnendruck. Klin. Mbl. Augenheilk. 172, 123. Leydhecker W . (1978) Sympathikomimetika und Sympathikolytika in der Glaucomtherapie. Klin. Mbl. Angenheilk. 172, 123. Missotten L. & Goethals M. (1977) Timolol reduces the standing potential of the eye. Ophthal. Res 9, 321-323. Pandolfi M. & 0hrstrsm A. (1974) Treatment of ocular hypertension with oral betaadrenergic blocking agents. Acta ophthal. (Kbh.) 52, 464-467.
i13 Act3 uphthal. 56, 5
46
Emilia Kerty and Iuar H m v e n Phillips C. I., Howitt G. & Rowlands D. J. (1967) Propranolol as ocular hypotensive agent. Brit. J . Ophthal. 51, 222-226. Ritch K., Hargett N. A. & Podos S. M. (1978) The effect of 1.5 O / o timolol maleate on intraocular pressure. Acta ophthal. (Kbh.) 56, 6-10. Tarkkanen A. (1965) Treatment of chronic open angle glaucoma associated with pseudoexfoliation. Acta ophthal. (Kbh.) 43, 514-523. Vareilles P., Silvertone D., Plazonnet B., Le Douarec J. C., Sears M. L. & Stone C. A. (1977) Comparison of the effects of timolol and other adrenergic agents on intraocular pressure in the rabbit. Invest. Ophthal. 16, 987--996. Wettrell K. (1977) Beta-adrenoceptor antagonism and intraocular pressure. A clinical study on propranolol, practolol and atenolol. Acta ophthal. (Kbh.) Suppl. 34, p. 51. Zimmermann T . J. & Kaufman H. E. (1977a) Timolol. A ,p-adrenergic blocking agent for the treatment of glaucoma. Arch. ophthal. (Chicago) 95, 601-604. Zimmermann T . J. & Kaufman H. E. (197713) Timolol. Dose response and duration of action. Arch. Ophthal. (Chicago) 95, 605-60. Zimmermann T. J., Harbin R., Pett M. & Kaufman H. E. (1977) Timolol and facility of outflow. Invest. Ophthal. 16, 623-624. Ohrstrclm A. (1973) Clinical experience with propranolol in the treatment of glaucoma. Acta ophthal. (Kbh.) 51, 639-614.
Author’s address: Dr. Emilia Kerty, M. D., Eye Department, Rikshospitalet, Oslo 1, Norway.
7 14
Department of Ophthalmology (Head: Thore Lie Thomassen), University of Oslo, Rikshospitalet, Oslo
GLAUCOMA TREATMENT WITH TIMOLOL BY
EMlLlA KERTY and IVAR HQRVEN
Thirty-two eyes from 19 patients with either capsular glaucoma, pigmentary glaucoma o r primary open angle glaucoma were given topical timolol and followed through a 3-6 months period. Twelve eyes were previously out of control on full medication including pilocarpine, epinephrine and acetazolamide. Eight of these eyes could be adequately controlled throughout the follow-up period on topical timolol or a combination of timolol and pilocarpine, but without resorting to acetazolamide. One eye needed acetazolamide in combination with timo101, and three eyes had to be referred to surgery. Twelve eyes were adequately controlled either on pilocarpine or full medication, but could be equally well controlled on timolol alone, or timolol and pilocarpine in combination. Acetazolamide could be withheld from all of the six patients who used this drug. Eight eyes were previously untreated. They could all be adequately controlled either on timolol (5 eyes) or timolol and pilocarpine (3 eyes). The study indicates that the effect of timolol 0.5 O/o x 2 may be stronger than the combined effect of epinephrine 1 O/o x 2 and acetazolamide 500 mg a day. Topical timolol was well tolerated. No side reactions occurred and the pupillary size and reactions were not influenced by the timolol treatment.
Key words: acetazolamide - 8-adrenergic blockers - capsular glaucoma glaucoma - intraocular pressure - pigmentary glaucoma - pilocarpine ti mo1o1.
Systemic intake of 8-adrenoceptor blocking substances may reduce the intraocular pressure (IOP) (Phillips et al. 1967; Cot6 & Drance 1968; 0hrstrsm 1973; Pandolfi & 0hrstrsm 1974; Elliot et al. 1975; Borthne 1976; Wettrell 1977). Their use in glaucoma treatment is, however, restricted because a similar Received April 19, 1978.
705
Emilia Kerty and Ivar Hsrven
and sometimes even more pronounced reduction is initiated both in heart rate and systemic blood pressure, and so reduce the ocular perfusion pressure risking further glaucomatous damage (Fransois & Neetens 1970). This risk may be avoided by topical application. A t present it seems that timolol (BlocadrenD) is the drug of choice when a &blocking agent is needed for topical use. Timolol is a non-selective P-adrenergic antagonist without membrane-stabilising activity. In concentrations of 0.25 O / O and 0.5 O/O, timolol eye drops have been shown to lower the IOP in animals with a-chymotrypsininduced ocular hypertension (Vareilles et al. 1977), in normal volunteers (Katz et al. 1976) and in patients with chronic open angle glaucoma (Zimmermann & Kaufman 1977a). T h e IOP-reducing effect occurs 20-30 min after instillation and the duration of action appears to be a t least 24 h. No change occurs in accommodation, visual acuity, pupil size, tear production or systemic blood pressure (Zimmermann & Kaufman 197713; Ritch et al. 1978). A slight lowering of the heart rate (4-6 beats per min) may occur in some patients. Timolol does not change the facility of outflow (Zimmermann et al. 1977), the mechanism of action is probably through a decreased secretion of aqueous humour (Missotten & Goethals 1977). No intolerance to topical timolol has been observed (Katz et al. 1976; Ziminermann & Kaufman 1977a,b; Ritch et al. 1978). When administered together with other antiglaucoma agents, an additive effect may occur. T h e above clinical data for timolol is based on studies over days and weeks. According to Krieglstein (1978) and Leydhecker (1978) the effect of topical timolol already subsides after a few days. The need for longer follow-up periods was, therefore, pressing. In the present study patients with pigmentary glaucoma, capsular glaucoma or primary open angle glaucoma (POAG) were treated with timolol and followed through a 3-6 months period.
Material T h e material consists of 19 patients (32 eyes) and includes all patients who were given timolol in our clinic before January 12, 1978 with the following diagnoses: Pigmentary glaucoma. This group consists of six eyes from three male patients (Cases 4, 8, 1 7 ) . Average age was 42 (35-.51) years. In addition to elevated IOP and heavily pigmented trabecular meshworks, these patients demonstrated glaucomatous disc changes and visual field loss (Bjerrum scotoma) in one or both eyes. Case 4 was previously untreated. the other two patients complained of severe ocular discomfort
following pilocarpine instillations. 706
Glaucoma Treatment with Timolol Capsular glaucoma. This group consists of seven eyes from six patients (Cases 2, 3, 6, 10, 15, 16). There were two women and four men. Average age was 72 (60-80) years. One of the patients (Case 6 ) had capsular glaucoma in one eye, the other eye being normal. Two patients (Cases 3 and 10) had capsular glaucoma in one eye, primary open angle glaucoma in the other. Case 2 and Case 16 had haemorrhagic glaucoma with amaurosis and severe IOP elevation on one side, caused by previous capsular glaucoma. These two amaurotic eyes are not included in the study. Case 15 had capsular glaucoma in both eyes. The diagnosis of capsular glaucoma was based on elevated IOP, trabecular meshwork pigmentation and presence of pseudoexfoliative material in the anterior part of the eye including the anterior lens surface. Glaucomatous disc changes and/or visual field loss were present in five of these seven eyes. All of the patients were referred to our clinic because the IOP was out of control on heavy antiglaucomatous treatment which included acetazclamide. Primary open angle glaucoma (P0,IG). This group consists of 19 eyes from 12 patients (Cases I, 3, 5, 7, 9, 10, 1 1 , 12, 13, 14, 18, 19). There were five women and seven men with an average age of 64 (46-84) years. Case 1 had lost one eye following detachment surgery 20 years ago, Case 3 and Case 10 had POAG in one eye, capsular glaucoma in the other. Case 18 was aphakic on one side with normal IOP. The other patients had POAG in both eyes. The diagnosis was based on elevated IOP in eyes with open angles. Seven patients (12 eyes (Cases 1, 3, 5, 9, 1 1 , 12, 14) showed glaucomatous disc changes and visual field loss in one or both eyes. In five patients (7 eyes) (Cases 7, 10, 13, 18, 19) the discs and fields were normal, but the IOP was repeatedly between 27-40 mmHg. Case 7 and Case 10 demonstrated repeated IOP readings of 30 mmHg without treatment, on pilocarpine the IOP dropped to about 15 mmHg. Case 13 had used pilocarpine for several years, on treatment repeated IOP readings between 30-35 mmHg were recorded on both eyes. Case 18 demonstrated repeated IOP values between 25-30 mmHg on one side, 14-16 mmHg on the other, aphakic eye. Case 19 presented IOP values of 25 mmHg at a routine check. She was followed closely for a year without treatment, and a steady increase of IOP was noted until values of 35 mmHg and 40 mmHg were recorded in the right and left eye respectively. Six of the POAG eyes were previously untreated, while the other 13 eyes were treated with pilocarpine (5 eyes) or full medication including acetazolamide (8 eyes). Eight of these 13 eyes were inadequately controlled when timolol treatment commenced.
Methods Heart rate and systemic blood pressure we r e recorded i n t h e sitting position, the latter with th e use of a mercury sphygmomanometer. Intraocular pressure (ZOP) wa s recorded in m m H g with a G o l d ma n n appianation tonometer.
707
Emilia Kerty and Ivor Hsrven
Pupil diameter was measured in standard illumination in Goldmann’s perimeter. Schirmer’s test was performed using standardized paper strips. Tonography was performed by use of the dynamic tonometer (Hsrven 1968) which is a standardized Schistz electronic tonometer. Visual fields were recorded in Goldmann’s perimeter.
Results No major alterations were found in systemic blood pressure, pupil size or reactions, tear production or facility of outflow following timolol treatment, which confirms previous observations referred to above. A minor lowering of the heart rate was observed in some patients.
Table 1. Effect of timolol on pigmentary glaucoma eyes.
4
d
4
s
8 8 17 17
d x x 21 s x x 2 1 d x 24 s x x 24
Average:
22.5
52 50 3 0 x 2 5 x
x
x
x
x
X
x
x
39.3
22 20 18 16 12 16
20 20 14 14
14 19
17.3 16.8
x = treatment given.
708
16 18 16 16 14 18
22 22 18 16 17 19
22 22 14 18 16 20
15 17 18 16 17 22
16.3 19.0 18.7 17.5
Glaucomn Treatment with Tiinolol
In all patients, t h e timolol treatment was well tolerated without ocular discomfort o r other side-effects. I n patients treated only i n the evening, the IOP was measured both at noon a n d in the evening just before the next installation. No m a j o r differences w e r e found between these readings, indicating that the effect of one d r o p of timolol lasts at least 24 h. T h e visual fields did not change d u r i n g t h e observation period.
Pigmentary glaucoma. T h e IOP was controlled i n all eyes, although three eyes needed addition of pilocarpine (Table I). These relatively young patients sometimes h a v e severe side-effects to pilocarpine treatment, with ocular discomfort, ciliary spasm, headache a n d transient myopia.
This was especially prominent in Case 8, a man aged 54 years. He suffered attacks of urolithiasis in 1973 and 1975. His pigmentary glaucoma was diagnosed in April 1976 with an IOP of 32 mmHg and 40 mmHg in the right and left eyes respectively. The trabecular meshworks were heavily pigmented, the discs were cupped and a Bjerruin scotoma was present on the left side. Initially the IOP was controlled by epinephrine and pilocarpine eye drops with addition of pilocarpine ointment at night. However, he did not tolerate pilocarpine, which produced ocular pain, ciliary spasms and myopia rendering him unfit for work. A trabeculectomy was performed on the left eye in May 1977, and ocusert lamellas were tried on the right eye. However, in July 1977 the IOP was again elevated and he had to return to pilocarpine 2 O/o x 4 and epinephrine 1 " / o x 2 in both eyes. His ocular discomfort to pilocarpine persisted and he planned to quit work and had applied for a disability pension when the treatment was substituted with timolol 0.250/0 x 1 in both eyes. Since then his IOP has been adequately controlled. He no longer suffers ocular discomfort and he is back to full time work in his office as a shipping manager.
Capsular glaucoma. These seven eyes w e r e all out of control on full medication before timolol was started (Table 11). Following timolol treatment, acetazolamide could be discontinued i n five of t h e six patients. W i t h the addition of pilocarpine the IOP was controlled in three eyes, one patient (Case 16) was controlled o n timolol in combination with acetazolamide. Surgery had to be performed o n three eyes. Case 16 was amaurotic in one eye. On pilocarpine and epinephrine a miosis occurred, and his vision was reduced to light perception because of axial lens opacities. After timolol and acetazolamide, however, the vision remained at 20130.
Primary open angle glaucoma (POAG). Six eyes were previously untreated. Five of them were controlled o n timolol, while one eye required both pilocarpine a n d timolol (Table 111).
709
Emilia Kerty and lunr Hsruen
All of the 13 eyes previously treated with pilocarpine (5 eyes) or full medication (8 eyes) could be controlled either with timolol (7 eyes) or a combination of timolol and pilocarpine (6 eyes). Acetazolamide could be withheld from all of the six patients who used this drug (Table IV). Case 11 demonstrated a most striking effect of timolol. He started using pilocarpine 20/0 in 1965 which was later increased to 40/0. Epinephrine and acetazolamide had to be added in order to keep the IOP at a normal level. However, acetazolamide gave him gastrointestinal discomfort. Before timolol treatment was started, all medication was stopped and the IOP rose to 40 mmHg and 30 mmHg on the right and left eyes respectively. Following timolol 0.25 0:o x 1 the IOP was adequately controlled in both eyes throughout the observation period Table IV).
Table 11. Effect of timolol on capsular glaucoma eyes, previously treated with pilocarpine, epinephrine and acetazolamide.
-
'1
2 m l
j
Follow-up periods in weeks IOP (mmHg)
3
N
: a
u w
Y
W
Y
22 24 26 34 27 24 27
Average: (S-values not included) x
=
S
=
x x x x x
A
26.3
18 18 12 17 16 22 38 S 23 20 17 22 18 18
18 18 22
19 16 30 S
16 17
18 16
32 S 18 20
18 18
19 18
20 19
17.3
19.2
17.8
17.5
18.3
19.5
treatment given. - = initial concentration, later increased. surgery. A = acetazolamide instead of pilocarpine.
710
Glaucoma Treatment nlith Timolol Table 111.
Effect of timolol on primary open angle glaucoma eyes, previously untreated. -
~
Y
!
d
.
Y
X
0.I
.-2a
c 0
2
L UJ
: w"
s
5 5 12 18 19 19
d S S S
d S
2
F4
W
U -
~
2
=
32 24 27 28 35 40
treatment given.
2 .*
1
4
8
12
18
26
x
19 14 17 11 20
16 16 16 14
1s
26 17 16 17 20 20
22
16 16 16 11 20 20
14 16 16 16 20 20
18 12 16 17 19 20
16.5
19.3
17.2
16.5
17.0
17.0
a -
Average: 31.0
x
Follow-up periods in weeks IOP (mmHg)
0
2
Y
-=
19
initial concentration, later increased.
Discussion The present study does not support Krieglstein's (1978) and Leydhecker's (1978) finding that the effect of timolol subsides over a short period of time. On the contrary, the full effect of timolol was present throughout the entire observation period in all of the three glaucoma types studied. I t is well known that capsular glaucoma is more difficult to treat and has a less favourable prognosis than POAG (Tarkkanen 1965; Herven 1966). This may explain why the three eyes of the present study which could not be properly controlled with timolol and pilocarpine all belonged to the capsular glaucoma group. In the present study, nine eyes were not adequately controlled on full medication including epinephrine and acetazolamide, but showed normal IOP levels on timolol or timolol and pilocarpine. In many cases, therefore, it seems that timolol 0.5 O/O x 2 may more than compensate for the combined effect of epinephrine 1 010 x 2 and acetazolamide 500 mg a day. Taking into consideration the severe side reactions including renal calculi formation that may follow acetazolamide intake and the ocular discomfort following long-term use of 71 1
Emilia Kerty and Ivar Hvlrven
topical epinephrine, a shift to topical timolol seems reasonable and favourable. As mentioned above, no side reactions have been ascribed to short-term use of topical timolol, and the pupillary size and reactions were not influenced by the medication. This was confirmed by the present study. This is especially important in young patients and patients with lens opacities who suffer visual disturbances on pilocarpine. A shift to timolol should therefore be considered for all patients who have severe side-effects to their glaucoma medication, whether their IOP's are adequately controlled or not.
Table IV. Effect of timolol on primary open angle glaucoma eyes, previously treated.
-
* x 4 X .-B .*z 2 2 a : 2i 2: 2 0 : t . (
o . (
3
0
3
2
2JL5.Z $ 2
!-
? -
23 22 16 18 26 14 18 18 27 35 32 26 22
28 32 34 30 34 30 40 30 34
0
.-ca m
X
X
x
X
x
X
X
33 26
22.8 31.9
x
- =
4
8
12
18
26
20 12 16 16 20 18 18 18 17 20 20 27 21
22 19 16 16 16 18 18 20 18 17 17 18 20
22 18 18 18 18 18 18 18 18 18 18 16 14
20 16 18 18 20 20 18 18 16 15 22 20
19 18 17 19 18 20 16 18 14 16 17 20 19
20 18 18 20 16 18 20 19 19 17 18 18 17
18.7
18.1
17.8
18.3
17.8
18.3
2- 1 :
X
Average: treatment given.
0
2
.w
=
cy X
X
0
.g
M
Follow-up periods in weeks IOP (mmHg)
.. m
X
X
initial concentration, later increased.
= Mintacol instead of epinephrine.
712
17
Glancoma Treatment with Timolol
In the present study combined pilocarpine a n d timolol treatment was followed by a larger decrease i n IOP than administration of either drug alone, indicating an additive effect. Zimmermann & Kaufman (197713) described a dose relationship f o r timolol in concentrations of 0.1 O / O , 0.25 O / O a n d 0.5 O / O . Increasing the concentration to 1 0 / 0 did not cause further reduction of the IOP. To some extent the present data confirm these results. In 12 eyes the timolol dose had to be increased from 0.25 O / O x 1 to 0.5 O / O x 2 before maximal effect was obtained (Table 11, 111, IV). It should be stressed t h a t the effect of timolol over a period of years has not yet been evaluated. All patients receiving topical timolol should therefore be followed closely f o r possible side-effects and reduced response. So far, topical timolol seems to be a very promising approach f o r treatment of various types of glaucoma.
Acknowledgment Timolol used in the present study was kindly provided by Merck Sharp SC Dohme.
References Borthne A. (1976) The treatment of glaucoma with propranolol (InderalB). A clinical trial. ( A c t a ophthal. (Kbh.) .54, 291-300. Cot6 G. & Drance S. M. (1968) The effect of propranolol on human intraocular pressure. Canad. 1.Ofihthal. 3, 207-212. Elliot M. J., Cullen P. M. & Phillips C. I. (1975) Ocular hypotensive effect of atenolo1 (‘renormin ICI). A new beta-adrenergic blocker. Brit. /. Ophthal. 59, 296-300. Fransois J. & Neetens A. (1970) The deterioration of the visual field in glaucoma and the blood pressure. Docum. opltthal. 28, 70-132. Hsrven I. (1966) Exfoliation syndrome. Incidence and prognosis of glaucoma capsulare in Massachusetts. Arch. Ophthnl. (Chicago) 76, 505-51 1. Hsrven I. (1968) Dynamic tonometry. I. T h e dynamic tonometer. Acta ofihthal. (Kbh.) 46, 1213-1221. Katz I. M., Hubbard W. A,, Getson A. J. & Gould A L. (1976) Intraocular pressure decrease in normal volunteers following timolol ophthalmic solution. Invest. Ophthal. 15, 489-492. Krieglstein (1978) Die Wirkung von Beta-Blockern auf den Augeninnendruck. Klin. Mbl. Augenheilk. 172, 123. Leydhecker W . (1978) Sympathikomimetika und Sympathikolytika in der Glaucomtherapie. Klin. Mbl. Angenheilk. 172, 123. Missotten L. & Goethals M. (1977) Timolol reduces the standing potential of the eye. Ophthal. Res 9, 321-323. Pandolfi M. & 0hrstrsm A. (1974) Treatment of ocular hypertension with oral betaadrenergic blocking agents. Acta ophthal. (Kbh.) 52, 464-467.
i13 Act3 uphthal. 56, 5
46
Emilia Kerty and Iuar H m v e n Phillips C. I., Howitt G. & Rowlands D. J. (1967) Propranolol as ocular hypotensive agent. Brit. J . Ophthal. 51, 222-226. Ritch K., Hargett N. A. & Podos S. M. (1978) The effect of 1.5 O / o timolol maleate on intraocular pressure. Acta ophthal. (Kbh.) 56, 6-10. Tarkkanen A. (1965) Treatment of chronic open angle glaucoma associated with pseudoexfoliation. Acta ophthal. (Kbh.) 43, 514-523. Vareilles P., Silvertone D., Plazonnet B., Le Douarec J. C., Sears M. L. & Stone C. A. (1977) Comparison of the effects of timolol and other adrenergic agents on intraocular pressure in the rabbit. Invest. Ophthal. 16, 987--996. Wettrell K. (1977) Beta-adrenoceptor antagonism and intraocular pressure. A clinical study on propranolol, practolol and atenolol. Acta ophthal. (Kbh.) Suppl. 34, p. 51. Zimmermann T . J. & Kaufman H. E. (1977a) Timolol. A ,p-adrenergic blocking agent for the treatment of glaucoma. Arch. ophthal. (Chicago) 95, 601-604. Zimmermann T . J. & Kaufman H. E. (197713) Timolol. Dose response and duration of action. Arch. Ophthal. (Chicago) 95, 605-60. Zimmermann T. J., Harbin R., Pett M. & Kaufman H. E. (1977) Timolol and facility of outflow. Invest. Ophthal. 16, 623-624. Ohrstrclm A. (1973) Clinical experience with propranolol in the treatment of glaucoma. Acta ophthal. (Kbh.) 51, 639-614.
Author’s address: Dr. Emilia Kerty, M. D., Eye Department, Rikshospitalet, Oslo 1, Norway.
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