A C T A O P H T H A L M O L O G I C A VOL. 5 7 1 9 7 9

DPprrrtrnPnt of Ophthnlmolog?, (Head: E . Wecterlund), Crntrnl Hmpitnl. Nykrhing FaldPr. Denmark.

TI MO LO L

in maintenance treatment of ocular hypertension and glaucoma. BY

NIELS VEST1 NIELSEN and JENS SINDBERG ERIKSEN

T h e hypotensive effect of Timolol eye drops (0.25 and 0.50%) in maintenance treatment of 64 patients with elevated intraocular pressure has heen studied. T h e patients were treated for a period of mean 13 months. In 44 patients, mostly comprising ocular hypertensives , a significant reduction in IOP (32%) could he maintained with Timolol alone (P< 0.001). In 20 patients with a high starting baseline pressure or previous mala,djustahle glaucoma it was necessary to start combined treatment. Pilocarpine, epinephrine or acetazolamide appeared to have additive pressure-lowering effect to Timolol. A significant correlation was present between pre-treatment and Timolol treated intraocular pressures. Thus a pre-treatment IOP above 25 mmHg may indicate a critically hypotensive effect helow an IOP of 20 mmHg with Timolol alone. No significant interference with visual acuity, pupillary size, blood pressure, or pulse rate was noted. Existing visual field defects in three patients were slightly aggravated and in four patients, with a pathological optic disc, visual field loss developed. In seven patients transient sensations of dry eyes and rose-hengal staining dots on the cornea developed. K P wndc: ~ Timolol maleate - hypotensive effect - combined treatment - one year result - ocular hypertension - glaucoma - side effects.

Previous reports on ocular applied timolol maleate (a P I and 82 blocking agent) have convincingly demonstrated a potent hypotensive effect on elevated intraocular pressure (Bischoff 1978; Katz et al. 1976; Kerty & Horven 1978; Kriegelstein 1978; Nielsen 1978; Radius et al. 1978; Ritch et al. 1978; Zimmerman & Kaufman 1977a,b). At the present these results have been based on short-term studies. Received March 2. 1979.

Compared to other 0-adrenergic blocking agents and o t h e r antiglaucoma drugs (pilocarpine, e p i n e p h r i n e , acetazolamide) Timolol has p r o d u c e d an e q u a l or g r e a t e r r e d u c t i o n in elevated IOP ( B o n o m i & Steindler 1975; Kriegelstein 1978; Leydecker 1977; Phillips e t al. 1978; Wetrell 1977). Moreover, Timolol has been t o l e r a t e d well in s h o r t - t e r m use. The objective of this s t u d y has been to investigate t h e pressure-lowering effect and tolerance of Timolol in m a i n t e n a n c e t r e a t m e n t of ocular hypertension and glaucoma. Further t h e additive effect of Timolol was studied, w h e n c o m b i n e d with pilocarpine, epinephrine and/or acetazolamide.

Material and Method T h e material consisted of 64 out-patients (37 females and 27 males) of various ages (mean 66 years, range 30 to 85 years). A baseline IOP > 22 mmHg without topically or systemically antiglaucoma treatment for one week was required before entering this study. In 31 patients we classified ocular hypertension and in 33 patients glaucoma (optic disc cupping and/or visual field loss). Fifty-nine patients had open angles. three narrow angle glaucoma and two spontaneously partially cured buphthalmos. Aphakic glaucoma was present in three patients. Forty-eight patients bad previously been treated with antiglaucoma drugs with a mean duration of 7.8 years (range 0.5 to 23 years). In the remaining 16 patients recent ocular hypertension or glaucoma were detected. Antiglaucoma surgery had previously been performed in IS patients. T h e main rriterias of admitting the previously treated patients to this study were either a maladjustable glaucoma or discomfort of previous treatment. Any patients with a history of intraocular inflammations or retinal detachment were excluded from this investigation. Further, patients with bradycardia ( 21 m m H g the patients were treated with Timolol 0.50’3 once or twice daily at 9 a.m. and 9 p.m. In patients, where the IOP could not be controlled on Timolol alone, we added pilocarpine 2% two or three times daily, epinephrine once or twice daily or acetazolamide 500 mg daily. Measurements of the IOP with Goldmann’s applanation tonometry were performed twice at the same time of the day on each control. During a dose adjustment period of three weeks, the IOP was controlled at least once weekly. Subsequent controls of IOP during maintenence therapy were performed on the 5th. 9th. 15th week after the onset of treatment and thereafter with a n interval of 12 weeks. In addition to pressure measurements ocular

107 1

examinations inchided visual acuity, visual field. pupillary diameter, slitlamp examination including break-up time (BUT) of the tear film and rose bengal vital staining, corneal sensitivitv, Schirmer test and ophthalmoscopy. Blood pressure and pulse rate were regularly (ontrolled and suhjective adverse symptoms, if present, were recorded.

Statistical analyses T h e hypotensive effect of Timolol was estimated by means of Wilcoxon's signed rank test (two sample tests). A correlation hetween pre-treatment baseline pressures and Timolol treated pressures was ewluated hv family regression.

Results lntraocular pressure In 44 patients the IOP was controlled with Timolol alone and in 20 patients combined treatment was instituted. Regarding the duration of therapy, five subjects had been treated for 6-9 months, seven subjects for 9-12 months, 37 subjects for 12-15 months and 15 subjects for 15-18 months. In the group of 44 patients treated with Timolol alone, a significant reduction in the IOP (P< 0.01) could be maintained (Fig. 1). The IOP was reduced with mean 32% after one year of treatment. This group (mean age 6 3 years, range 33-76

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53

vears) consisted of 16 patients with glaucoma and 28 ocular hypertensives. Thus, 90% (28/31) of the ocular hypertensives contrary to 48% (I6/33) of the patients with glaucoma were controlled on Timolol alone. N o diminuation of the initial pressure-lowering effect of Timolol on maintenance therapy was noted in these 44 patients (P > 0.10). In 20 subjects it was necessary to combine Timolol with pilocarpine, epinephrine or acetazolamide (Table I). After 1 to 3 weeks of treatment with Timolol 16 patients entered the combined therapy, one patient after 15 weeks and 3 patients after 39 weeks. This group characteristically comprised patients with glaucoma (85%). previously malad justable glaucoma, high baseline pressures (mean 34.6 mmHg, range 23-60 mrpHg) and patients of a high age (mean 71.8 years, range 58-85 vears). T h e mean reduction in IOP with Timolol alone was 11.7 mmHg (33.8%) and after onset of combined maintenance therapy 14.6 mmHg (41.9%)(Table I). In Fig. 2a predictive estimate of the hypotensive response of Timolol compared with baseline pressure before treatment has been attempted. It appears that a starting baseline pressure above 25 mmHg may indicate a critical pressure-lowering effect of Timolol alone, when a Timolol treated IOP below 20 mmHg is desirable. Antiglaucoma surgery had to be performed in two patients after 20 and 24 weeks on treatment with Timolol. In a patient with unmanageable narrow angle glaucoma. trabeculectomy was performed, and cyclodialysis was performed in a patient with an aphakic glaucoma. T h e latter continued treatment with Timolol. Visual field

Glaucomatous visual field loss was present in 24 patients before treatment with Timolol was instituted. After one year on treatment with Timolol a further four patients with an abnormal optic developed a visual field lesion and a slight aggravation of existing visual field defects in three patients. Visual acuity

T h e pre-treatment distance vision was mean 0.80 (range 1 .0 to 0 . 1 ) . N o significant changes in visual acuity (P > 0.10) were disclosed after 12 months of treatment (mean 0.76, range 1.0-0.01). In nine patients with cataract a slight reduction of visual acuity was noted. One patient was operated for cataract. In general, patients previously treated with miotics obtained a better distance vision on Timolol treatment, whereas near vision was disturbed with their former correction. Side-effects and adverse reactions

Timolol did not induce changes o n pupillary diameter or retina. N o interference with blood pressure or pulse rate was recorded Investigations of corneal sensitivity.

1074

B U T and rose-bengal vital staining have benn reported in a previous paper (Nielsen & Eriksen 1979). In 10 patients a mild smarting sensation occurred in relation to installation of Timolol. Four patients complained of headache for 2 to 3 h following installation. Seven patients developed transitory dry eyes and innoxious functional and morphological changes (Nielsen & Eriksen 1979). In none of these patients was treatment with Timolol discontinued. After six months of treatment an exudative maculopathy of the left eye occurred in a 70-years male patient with excessive myopia. Visual acuity was severely detenoriated a large central scotoma was disclosed. Discontinuance from the study

Four patients were withdrawn from Timolol treatment. A 70-years-old male patient died from heart failure and pneumonia after 9 months. In two patients surgery, trabeculectomy (24 weeks) and cataract extraction (36 weeks), was performed and further hypotensive treatment was superfluous. The fourth patient did not want to be controlled regularly on Timolol after eight months of treatment.

Discussion T h e present study demonstrates a powerful and prolonged ocular hypotensive effect of topically used Timolol. Thus, Timolol seems to be useful in maintenance treatment of elevated IOP. Kriegelstein (1978) and Leydecker (1977) have proclaimed that the hypotensive response of Timolol declines after a short time of treatment (tachyphylaxis) just as is noted with atenolol (Brenkman 1978; Wetrell 1977). We did not disclose any significant diminuation of pressure-lowering effect in the present material after mean 13 months of treatment. However, in three cases we noted a subsidence of the hypotensive effect or an aggravation of glaucoma after 39 weeks of treatment. It should be emphasized that the Occurrence of tachyphylaxis may be difficult to assess in clinical studies. After a dose adjustment period, we were able to distinguish two groups of patients with regard to pressure lowering responses of Timolol. In general, Timolol proved to have the best effect in the group with a majority of ocular hypertensives, whereas combined therapy chiefly had to be instituted in cases with previously hard manageable glaucomas and high intraocular pressures. In this study as in previous investigations (Bischoff 1978; Kerty & Horven 1978; Nielsen 1978; Radius et al. 1978) pilocarpine, epinephrine and acetazolamide proved to have an additive effect to Timolol, also when used in maintenance treatment. I075

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Taking the total material into consideration, a significant correlation was observed between the pre-treatment IOP and the IOP obtained by Timolol (Fig. 2). Thus, from this relationship it may be possible to predict the level of a Timolol treated IOP from a known pre-treatment IOP and to estimate, whether combined treatment should be expected. Brenkman (1978) has noted an inadequate hypotensive effect of atenolol, when pre-treatment IOP exceeded 25 mmHg. The pressure-lowering response of Timolol alone in the present study may be dubious above pre-treatment IOP of 28 mmHg. Generally, Timolol was tolerated well. The dry eyes manifestations were transitory and did not require discontinuance of Timolol therapy (Nielsen & Eriksen 1979). Timolol did not significantly interfere with visual acuity. In some of our cases a worsening of existing cataract occurred after one year with Timolol treatment. This may obviously appear without hypotensive treatment. However, Timolol seemingly reduces the aqueous formation (Chiou & Zimmerman 1975; Yablonski et al. 1978; Zimmerman et al. 1978). Prolonged Timolol induced reduction of aqueous secretion, and possible changes of aqueous composition may hypothetically interfere with the metabolism of the lens. Treatment with acetazolamide has not induced cataract (Reich 1953). Smith et al. (1979) have described a reduction of resting and exercise heart rate during topical treatment with pindolol. We have not as other investigators (Bischoff (1978; Kerty & Horven 1978; Kriegelstein 1978; Radius et al. 1978; Ritch et al. 1978; Zimmerman & Kaufman 1977a.b) noted any significant influence of Timolol on blood pressure and pulse rate. At the present, Timolol seems to be a useful drug in the future treatment of elevated intraocular pressure.

Acknowledgement

References Bischoff P. (1978) Erfahrungen mit Timolol in d e r Glaucomtherapie. Klin. Mhl. Atigmhrilk. 173,202-207. Bonomi L. & Steindler P. (1975) Effect of pindolol on intraocular pressure. Brit. J . Ophthal. 5 9 . 3 0 1-303. Brenkman R. F. (1978) Long-term hypotensive effect of atenolol 4 % eyedrops. Brit. J. Ophthal. 62, 287-29 1. Chiou C. Y. & Zimmerman T . J. ( I 975) Ocular hypotensive effects of autonomic drugs. IniiP.rt. Ophthal. 14,41f3-417. Katz 1. M., Hubbard W. A,, Getson A. .J. & Cmuld A. I.. (1976) Intraocular pressure decrease in normal volunteers following Timolol ophthalmic solution. Inrvrt. Ophthal. I5,48%492. Kerty E. & Horven I. (1978) Glaucoma treatment with Timolol. Act0 ophthnl. (Khh.) 56, 705-714. Kriegelstein G. K. (1978) Die Wierkung von Beta-Blockern auf den Augeninnendruck. Klin. Mhl. Augenheilk. 172, 6 7 7 4 8 5 . Kriegelstein G. K. (1978) Die Wirkung von Metoprololtartrat auf den Augendruck. Klin. Mhl. AugenhPilk. 173,632-637. Leydecker W. ( 1977) Sympathikomimetika und Sympathikolytika in d e r Glaucomtherapie. Klin. Mbl. Augenheilk. 171, 538-546. Nielsen N. V. (1978) Timolol. Hypotensive effect used alone and in combination for treatment of increased intraocular pressure. Acta ophthal. (Khh.)56.504-509. Nielsen N. V. & Eriksen J. S. (1979) Timolol. Transitory manifestations of dry eyes in long-term treatment. Actu ophthal. (Khh.) in press. Phillips C. I.. Gore S. M. & Gunn P. M. (1978) Atenolol versus adrenaline eye drops and an evaluation o f these two combined. Brit.]. Ophthal. 62, 296-301. Radius R. L., Gary R. D., Pollack I. P. & Langham M. E. (1978) Timolol. A new drug for management of chronic simple glaucoma. Arch. Ophthal. (Chicago) 96, 1003-1008. Reich T . (1953) Anhydrase activity of bovine lenses. Amer.J. Ophthal. 36,500. Ritch R., Hargett N. A. & Podos S. M. (1978) T h e effect of 1.5% Timolol malleate on intraocular pressure. Artu ophthal. (Khh.) 56,6-I0. Smith S. E., Smith S. A., Reynolds F. & Whitmarsch V. B. (1979) Ocular and cardiovascular effects of local a n d systemic pindolol. Brit.]. Ophthal. 63, 63-66. Wetrell K. ( 1977) Beta-adrenoceptor antagonism and intraocular pressure. A clinical study o n propranolol, practolol and atenolol. Acta ophthal. (Kbh.)Suppl. 134. Yablonski M. E., Zimmerman T. J., Waltman S. R. & Becker B. (1978) A fluorophotometric study of the effect of topical Timolol o n aqueous humor dynamics. ARVO ab.rtract.r 122. Zimmerman T. .J. & Kaufman H. E. (1977a) Timolol. A B-adrenergic blocking agent for the treatment of glaucoma. Arch. Ophthal. (Chicago) 95,601-604. Zimmerman T . J. & Kaufman H. E. (1977b) Timolol. Dose response and duration of action. Arch. Ophthal. (Chicago) 9 5 , 6 0 5 4 0 7 . Zimmerman T . J., Harbin R., Pett M. & Kaufman H. E. (1977) Timolol and facility of outflow. 1nve.rt. Ophthal. 16,623-624. Author’,$arldrm:

Niels Vesti Nielsen, M.D., Department of Ophthalmology, Central Hospital, DK-4800 Nykebing Falster. G =nmark.