Timolol in the management of secondary glaucomas

SURVEY OF OPHTHALMOLOGY

VOLUME 28 * SUPPLEMENT * DECEMBER 1983

Timolol in the Management of Secondary Glaucomas M. BRUCE SHIELDS,

M.D., AND STANLEY

D. BRAVERMAN,

M.D.

Abstract. The mechanisms

of the secondary glaucomas and the actions and side effects of antiglaucoma drugs are reviewed. Based on these observations, the advantages of timolol, as compared to other medications, in the management of secondary glaucomas are discussed. To illustrate some ofthese advantages, a study is reported in which timolol is evaluated for control of the earlv intraocular oressure elevation after routine cataract surgery. (Surv Ophthalmol 28:266-271, 1983) ’

Key words. secondary

he proper

carbonic glaucomas

medical

glaucoma

requires

particular

glaucoma

l

anhvdrase timolol

management an

for all forms

understanding

mechanism,

inhibitors

.

l

pilorarpinc

l

mas according to the gonioscopic open or closed anterior chamber

of

of the

appearance angle.

of an

as well as the

SECONDARY

side effects of the drug, or drugs, being employed. This is particularly true with regard to the secondary glaucomas, in which the mechanisms of intraocular pressure elevation are so numerous and varied. A drug that is helpful in lowering the pressure for some forms of glaucoma may actually a,ggravate the problem in other situations. This “double-edged sword” effect is especially true of miotics and epinephrine compounds. However, the acti.on and lower incidence ofocular side effects with the beta-adrenergic blocking agent, timolol maleatr, allow its use in most of the secondary glaucomas. The purpose of this paper is to provide some guidelines for the use of timolol in the management of secondary glaucomas by considering the pathogenesis of these glaucomas and the actions and side effects of antiglaucoma drugs in relation to the secondary glaucoma mechanisms. In addition, to illustrate some of these points, a study will be reported regarding the use of timolol in treating early intraocular pressure rise after cataract extraction. actions

epinephrinr

and

OPEN-ANGLE

GLAUCOMAS

In this group ofglaucomas, the anterior chamber angle structures are visible by gonioscopy, although an obstructive element is present at some point along the aqueous outflow pathway. The site of obstruction may be a membrane overlying the trabecular meshwork (pretrabecular form), alterations within the trabecular meshwork (trabecular form), or obstruction distal to the meshwork and Schlemm’s canal (posttrabecular form). Pretrabecular Form The membrane overlying the trabecular meshwork may be librovascular tissue, as in neovascular glaucoma. In other cases, the obstructive element may be an endothelial layer with a Descemet’s-like membrane, as in the iridocorneal endothelial syndrome, posterior polymorphous dystrophy, and some cases of penetrating and nonpenetrating trauma. Other conditions in which a membrane may overlie the trabecular meshwork include epithelial downgrowth, fibrous ingrowth, and some inflammatory conditions, such as Fuch’s heterochromic iridocyclitis, and luetic interstitial keratitis. In some cases, the membrane covers only a portion of the meshwork, so that the aqueous still has access to a portion of the conventional outflow system, while other eyes have complete obstruction of the mesh-

Mechanisms of the Secondary Glaucomas Ritch and Shields”’ have proposed a system for classifying the secondary glaucomas based on the mechanism of obstruction to aqueous outflow (Fig. 1). The system first divides the secondary glauco266

TIMOLOL work.

IN MANAGEMENT

Furthermore,

many

undergo

contraction

closure

of the angle,

angle-closure

OF SECONDARY

of these

with

time,

membranes

leading

converting

267

GLAUCOMAS

will

lo synechial

the
to an

mechanism.

Trabecular Form Obstruction represent trattecular

spaces,

becular aqueous ular

within

the trabecular

an accumulation

or an actual

meshwork

include

pigment

during

the trahccular sociation

cataract

(ghost

cell

\,arious

protein,

sur,yery.

Alteration and

of’ trauma.

malit)

in steroid-induced

,glaucoma

resides

in the

meshwork,

precise

tissue

trahecular change

edema

disorders

forms

is not

and

the use ofalpha-

ma)’ include

inflammatory

in WCS with

cells

folloiving

structures

with

blood

particles,

of lens zonulcs

chymotrypsin

of the tra-

that may obstruct within the trahec-

glaucomas). macrophages (hemoand melanomalytic glaucomas),

lylic, phacolytic, nroplastic cells, fragments

red

may

in the inter-

alteration

structures. Elements outflow by accumulatimg

and hemorrhagic

meshwork

of material

fully

of

in asscarring

The

abnor-

probably

also

although

the

understood.

Posttrabecular Form The

main

comas pressure,

of this

examples

associated the

with

causes

ernous

fistula.

hulbar

tumors,

of’ which

cavernous and

SECONDARY

of‘secondary cornea.

outflow.

peripheral

The

within

“pushed”

the into

iris (posterior

the pcriphaqueous

be “pulled”

by contraction

(anterior

angle

meshwork

obstructing

iris may

angle the

GLAUCOMAS

glaucomas,

angle

retro-

syndrome.

to the trahecular thereby

chamber

venous

carotid-cav-

thrombosis.

Sturge-\2:eher

or peripheral

lures

include

ANGLE-CLOSURE

In this group

arc the glau-

episcleral

sinus

era1 iris is in apposition

the anterior

category

elevated

form)

by structures

into

ofstrucor may behind

hc the

form).

The

peripheral

precipitates iritis and

iris may

be pulled

into the antcrias

A third

example

of this

category

may

be

fine strands in the anterior chamundergo contraction, pulling the

of iris against

the

trabecular

meshwork.

This

category with

or subluxed

pupillary

block

lens

with

closure

may

lead

ofthe

to a

anteri-

result

htocked cases, lary quent

after

cataract

by vitreous intraocular

block

due

extraction

or an intraocular inflammation

to posterior

may synechiac

if the

pupil

lens.

In other

lead

to pupil-

with

is

suhsc-

iris bomh6.

Without Pupillary

Block

The anterior chamber angle may also be closed hy a forward shifi of the lens and iris or vitreous and

Posterior Form those cases mechanism.

Block

or chamber angle due to increased aqueous pressure within the posterior chamber. A similar mechanism may

may develop in the angle of eyes with subsequently lead to peripheral anterior

aniridia, in which ber angle evidently remnant

functional

angle by contracture of membranes discussed. In addition, inflammatory

synechiac.

With Pupillary Xn intumescent

Anterior Form or chamber previously

Fi~q. 1. :2 classilication of the secondary glaucomas hased on the mechanism of obstruction to aqueous outfbv. a. l’retrahecular open-angle form. b. ‘I’rahecular open-angle lixm. c. Posttrahecular open-anxle lbrm. d. Anterior angle-closure lixm. e. Posterior anglr-closure lixm with pupillory block. 1: Posterior angle-closure Ibrm without lxpillory block. (Reprinted Lvith permission li-om Ritch R, Shields h113: The Secondny Glnucomzs. St Louis. C:\’ Mosby. 1982)

may and

be

further

without

subdivided a pupillary

into block

iris. In some

cases,

this may

be due to displacement

of the vitreous, as with posteriorly directed aqueous in malignant (citiary block) glaucoma or the tumor

268

Surv opllthalnlol

28( Suppl) December

1983

mass of a u\.eal melanoma. In other situations, the forward shift may result from contraction of a membrane behind the lens, as in rctrolcntal fihroplasia or persistent hypcrplastic primary vitreous.

Actions and Side Effects of Antiglaucoma Drugs in Relation to Secondary Glaucoma Mechanisms MIOTICS The principal mode of‘ intraocular pressure rcduction by all the miotics is enhanced outflow facilitv. This appears to result from contraction of the ciliary musculature,” which leads to an alteration in thr trahccular meshwork, Schlemm’s canal, or both.” In order fix a miotic to he effective, therefore, aqueous must have access to a significant portion of the trahccular meshwork. In cases of secondary anglc-closure glaucoma with more than 50% of the angle closed by synechiae, miotics are usually of limited value. In fhct, it has been noted that pilocarpine decreases u\reosclcral flo\v’ and may actually cause a paradoxical rise in intraocular prcssurc in ryes that have become increasingly dependent on this mechanism of aqueous outflow.’ In the secondary open-angle glaucomas, the efficacy of a miotic is dependent upon the degree to which aqueous outllo\~ is obstructed by a membrane or an alteration in the trahecular meshwork. This question can usuall) only he answered by a trial of miotic therapy. In cases ofelexrated episcleral venous pressure, miotics are oflimited \~aluc, since the primary obstruction to outflow is beyond the trahecular meshwork and Schlemm’s canal. For that malter, all antiglaucoma medications are of minimal \.alue in the latter group of conditions, since the intraocular pressure will remain elevated in proportion to the episcleral venous pressure. However, some intraocular pressure reduction may he achieved by reducing aqueous production with carbonic anhydrase inhihitors or timolol. In addition to having limited pressure-lowering value in many forms ofsecondary glaucoma, miotics may also cause further complications in some of these conditions. The primary example of this is glaucomas associated with inflammation. In these cases, the miotic pupil may lead to the formation of posterior synechiae, which can affect the patient’s vision, as well as the physician’s visualization of the f’undus, and may also lead to iris bombi. In addition, the miotic-induced cyclotonia may lead to further discomfort in the inflamed eye. EPINEPHRINE Our understanding of- the action of epinephrine has changed considerably in recent years. It was

SHIELDS,

BRAVERMAN

once felt that epinephrine reduced intraocular pressure primarily hy reduction of aqueous production. For this reason, epinephrine \vas often used to treat those forms ofsecondary glaucoma in which miotics \vere not f‘elt to hc efrective due to mechanical ohstruction of the trahecular mrshwork. More recent studies, howrver, ha\~e shown that epinephrine reduces the intraocular pressure primarily by increasing aqueous outtlow,‘” and fluorophotometric studies suggest that epinephrine may actually increase production.” The actual mechanism by which epinephrine increases outflow f.acility is not fully understood, and further study of this is needed before the precise value of epinephrine in treating various secondary glaucomas can he determined. The ocular side efyects of epinephrine limit its usefulness in certain forms of secondary glaucoma. I\‘hrn the anterior chamber has become shallow, the mydriatric cfI’ect of epinephrine may cause pupillar); block and angle closure glaucoma. In addition. epinephrine should he used with caution in aphakic eyes, due to the risk of cystoid macular edema.” CARBONIC

ANHYDRASE

INHIBITORS

Alan); of the problems noted above for miotics and rpinephrine compounds can he avoided hy the use of carbonic anhydrase inhibitors. Since these drugs lower the intraocular pressure by reducing aqueous production, their action is independent of alterations in thr anterior chamber angle. Furthermore, they have no effect on the pupil or ciliary muscle and, therefore, can he used without risk of ocular side effects in most forms of secondary glaucoma. However, the well known systemic side effects of this class of drugs significantly limits their usefulness. TIMOLOL This drug has the same advantages as the carhonic anhydrase inhihitors in the management of secondary glaucomas, hut has the additional advantage of less frequent systemic side effects. Tonographic’l.” and fluorophotometric?“” studies have shown that the principal intraocular pressure lowering mechanism of timolol is reduced aqueous production. For this reason its action on the intraocular pressure is independent of alterations in the anterior chamber angle. Furthermore, it has no effect on the pupil”’ or ciliary musculature and, therefore, can he used in eyes that are inflamed or have shallow anterior chamber angles. There has also been no report of cystoid macular edema in eyes treated with timo101. For the reasons noted above, timolol may he used to lower the intraocular pressure in most forms of

TIMOLOL

IN MANAGEMENT

OF SECONDARY

secondary glaucoma with a low risk of additional ocular complications. It may also he used with carbonic anhydrase inhibitors, since the two ha\pe a partially additilrc elltct on intraocular pressure. The main limiting f‘actor of‘timolol, however, is the systemic side cfrects, which have been \vell documented in numerous publications,‘,“.“‘.” and these must be caref‘ully considered in each patient befbrc prescribing the drug.

A Study of Timolol in Treating Early Intraocular Pressure Elevation after Cataract Extraction To illustrate the ad\.antages of timolol in the management of one form of secondary glaucoma, the fi)llowing study is reported. INTRAOCULAR PRESSURE ELEVATION AFTER CATARACT SURGERY Intraocular pressure elevation during the postoperative period has become a fi+equent complication of‘ routine cataract surgery. It is usually transient and not associated with serious sequelae, although related problems, such as pain and wound leak, ma) occur. Furthermore, in eyes with preexisting glaucoma. e\.en the transient pressure rise may cause f‘urthcr optic nerve damage. hleasures to control the intraocular pressure during the early postoperati\.c period are needed to minimize thesr complications. The prrcise alteration in the anterior chamber angle that leads to obstruction of‘aqueous outflow in the early postoperative period after cataract surger) is not fully understood. Possible mechanisms include inflammation, edema along the corncoscleral incision.” and the dispersion of zonular fragments associated with the use of‘alpha-chymotrypsin.’ As previously discussed, miotics may not he fully efl‘ecti\fr in lowering the intraocular pressure when such alterations are present in the aqueous outflow system, and this has been supported in one study with pilocarpine.’ Furthermore, miosis is not desirable in the inflamed eye. The prolonged use of epinephrinc may also present a hazard in the aphakic eye, with regard to the possibility of cystoid macular edema. For these reasons, the early pressure rise after cataract surgery has been managed in the past with carbonic anhydrase inhibitors in spite of their numerous systemic side effects and conflicting reports regarding their efficacy in this specific clinical situation.“.‘.” With the introduction of timolol, a drug is now available which oilers the ocular advantages of the carbonic anhydrase inhibitors, but with a significantly lower incidence of systemic side effects. For this reason, the following study was designed to explore the efficacy of a low, daily dose of timolol as

GLAUCOMAS proph!,lasis against the early pressure tine cataract surgery. MATERIALS

rise after rou-

AND METHODS

Thirty consecutive eyes (28 patients) were studied in a prospective, randomized, double-masked comparison between timolol maleatc and the vehiclc oftimolol. Each patient underwent routine intracapsular cataract extraction hv one of the authors (R1.B.S.) using one surgical technique. The patients included those with chronic open angle glaucoma as we11 as nonglaucomatous indi\,iduals, but no paticnt had undergone previous surgery. nor did any patient ha1.c combined glaucoma surgery at the time of the cataract procedure. The operative procedure in all cases included a fornix-based conjunctival flap, a 180” superior corneoscleral incision, and closure of‘ the wound with seven 10-O nylon suturrs. Alpha-ch?,motrypsin was used in the non-glaucomatous eyes. but not in those with preexisting glaucoma. Two peripheral iridectomies or a sector iridectomy was used in each case. All lenses were extracted with a cryoprobe, using the sliding technique. By random allocation, each patient recei\.ed either 0.25% timolol or the vehicle of timolol beginnin,q on the morning of- the first postoperative day and continuing on a daily basis for ten days. Allocation of the study drug was performed independent11 for thr two groups with and without preexisting glaucoma. The identity of the study drug was masked to both examiner and patient. Each patient also received an antibiotic-steroid ointment, twice dail!,. and 1“/o tropicamide each e\,ening. The intraocular pressure was measured, and the eye was examined by slitlamp biomicroscopy daily for the first four postoperative days and on the tenth day. If, at any time during the study, the intraocular pressure exceeded 30 mm Hg or was felt to be too high for the state of glaucomatous optic atrophy, the study drug was identified, and the treatment was changed. For patients receiving timolol, the dose was increased to 0.5% timolol, twice daily. Patients receiving a placebo were started on twice daily 0.25% timolol and this dose was increased to 0.5% if necessary. When further pressure reduction was desired in patients receiving 0.5% timolol twice daily, acetazolamide 500 mg was added to the regimen. RESULTS Fifteen patients received timolol as the unknown study drug, and fifteen received the placebo. There was no significant difrerence between these two groups with regard to age, race, or sex. Table 1 summarizes the intraocular pressure course of these

270

Surv Ophthalmol

28(Suppl)

December

SHIELDS,

1983 TABLE

Results

of Timolol

Placebo

9

6

IOP controlled with 0.25% timolol daily IOP controlled with 0.5% timolol BID

6 (66%)

I

1

3

2

2

two groups during the study. Significant intraocular pressure elevations, in excess of 30 mm Hg, occurred in patients who were normotensive before the surgery, as well as those with preexisting glaucoma, although the incidence of this complication was significantly higher in the latter group (p < .02). The intraocular pressure course for those patients receiving timolol 0.25% once daily was not statistically significantly better than those receiving a placebo. However, in the 16 eyes with postoperative pressures in excess of 30 mm Hg, the twice daily use of timolol 0.25% or 0.5% effectively controlled the intraocular pressure in ten cases (62%). No ocular or systemic side effects were encountered, which could be attributed to the study drugs.

Discussion Although a low, daily dose of timolol did not appear to significantly alter the early intraocular pressure course after cataract extraction in the present study, twice daily use of the drug did control more than half of the cases with elevated intraocular pressure. While the numbers in this study may be too small to be clinically meaningful, they are generally consistent with other similar studies that have supported the value of timolol during the early postcataract period. g,1b.‘8Each of these reports illustrate the unique advantage of timolol over other antiglaucoma agents in the management of this form of secondary glaucoma. Timolol has also been evaluated in patients with elevated intraocular pressures after penetrating keratoplasty. In one study, the drug was found to control postkeratoplasty secondary angle-closure glauit was not effective in a series of coma,14 although aphakic keratoplasties.17 In theory, timolol should be of value in virtually all forms of secondary glaucoma, based on our cur-

Group

N ormotensive Pre-operatively

Pre-existing Glaucoma

No. of eyes

Additional medication reauired

1

Therakv After C’atnmd Extrnction

Timolol Group Normotensive Pre-operatively

BRAVERMAN

No. of eyes IOP controlled without active drugs IOP controlled with 0.25-0.5% timolol BID Additional medication reauired

Pre-existing Glaucoma

II

3

6 (55%)

I

4

2

1

1

rent understanding of the pressure-lowering mechanism and the low incidence of ocular side effects. Wilson and coworkers” have lent support to this concept in a study of glaucomas with varied etiologies, including early postsurgical, aphakia, neovascular, pigmentary, exfoliation syndrome, traumatic, inflammatory, and aniridia. They found that timol01 lowered the intraocular pressure in almost every diagnostic category. However, the number of cases in each group was small and there was marked variability within each category of glaucoma. As these authors suggest, a therapeutic trial for each patient is the best approach to the use of timolol for any type of glaucoma, and further study is needed to confirm the benefit of this drug for each specific form of secondary glaucoma. Furthermore, we must remain alert to the known systemic hazards of timol01,‘.“.‘~‘,~~ as well as the potential ocular and systemic side effects that may become apparent as our understanding of this drug continues to expand. Acknowledgments James E. Arena, B.S., prepared the study drugs, and Max A. Woodbury, Ph.D. performed the statistical analysis ofthe data in this study.

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TIMOLOL IN MANAGEMENT

OF SECONDARY

drux-induced side effects. Ophthalmolqgv 87:87-90, 1980 I, 1,~ M’R, Abraham S: Effects of pilocarpinc on the morphology of the human outflow apparatus. Rr J Ophthnfmol 62.302-313, 1978 Haiman LIG, Phelps CD: Prophylactic rimolol for the prevcntion of high intraocular pressure aftw cataract extraction. A randomized prosprrtivr. double-blind study. Ophthaimolyq &‘?:233-238. 198 1 ,Johnson SH. Bruhakcr RF. ‘l‘rautman*JC: Absence of an effcrt oftimolol on the pupil. Inuert Ophthalmol I’isSccr 17:924-926. 1978 Kaufman PI., Barany EH: Loss of acute pilocarpinr effect on outflow facility following suqiral disinsertion and retrodisplaccmcnt of the ciliary musclr from the scleral spur in the cynomolgus monkey. Inzwrl Ophthnlmol 15:793-807, 1976 Kirsch RE, Lcvinr 0, Singer,JA: Further studies on thr ridgr at the internal edge of the cataract incision. Trans Am Acnd Ophthalmol Otolaygol 83.224-23 I. 1977 Kolker AE, Becker B: Epinrphrine macutopathy. .4x/2 Ophthnlmol 7X.552-562. t 968 I,ass,JH. Pavan-Langston 1): ‘l‘imolol therapy in secondary angle-closure glaucoma post penetrating kcratoplasty. Ophthaimolqr %:5lL59, 1979 McMahon CD. Sharer RN, Hoskins HD,Jr, HctheringronJ.Jr: Advcrsc effects experienced by patients taking timolol. Am ./

8. Gricrson

9.

10. 11.

12.

13. 14.

15.

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GLAUCOMAS

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SA. Galin MA: 7‘hc effect of timolol on cataract and intraocular pressure. Am J Ophthalmol 80: 1017~

extraction 1019, 1979 17. Olson R,J. Kaufman HE, Zimmerman ‘rJ: Effects oftimolol and daranidr on rlevatrd intraocular pressure after aphakic krrato-

Reprint rcqursrs should hr addressed to 1~1.Bruce Shields, M.D., Dukr University Eyr Crntrr, Box 3802, Durham. N.C. 27710.