Core Messages

››Beta blockers remain useful as a first line agent, although they are not as potent as prostaglandin analogs, which have largely replaced them as first line agents.

››Miotics are seldom used as first line agents because of the frequency of administration and ocular side effects; however, they are good choices where cost is an issue.

››When monotherapy fails to reach the target intraocular­ pressure (IOP) and the IOP reduction is less than 15%, a class switch should be instituted.

››When monotherapy fails to reach the target but IOP reduction is 15% or greater, a class addition should be instituted alongside the initial medication.

››Beta blockers and prostaglandin analogs may be combined with almost any topical drugs.

››There are advantages to fixed combination drugs, including a slightly greater efficacy.

preparations were approved after its introduction into the marketplace. Following its approval by the U.S. Food and Drug Administration (FDA) in 1978, it was considered the gold standard initial treatment for nearly two decades until 1996 when the first prostaglandin analog was granted approval by the FDA. Prostaglandin analogs are more potent IOP-lowering drugs than timolol and other beta blockers. However, this fact does not mean that beta blockers cannot be used as a first-line agent. This class of medication remains efficacious, tolerated, and cost effective. The following history is an illustration of this reality.

Case report: On March 2, 2006, at the Catholic University Eye Department in Santiago, Chile, a patient was diagnosed with early primary open angle glaucoma (see Fig. 24.1). Her visual acuity was 20/20 in both eyes and IOPs were 34 and 27 mmHg, respectively. The optic disc in the right eye showed an inferior notch

24.1  Should Beta Blockers Still Be Used as a First-Line Agent?

Timolol maleate was the most potent topical IOPlowering drug introduced after pilocarpine and epinephrine years ago, and a number of different beta-blocker

E. Maul

Department of Ophthalmology, School of Medicine,

Pontificia Universidad Catolica, Ave. Apoquindo 3990 Suite 708, Santiago, Chile

e-mail: emaul@med.puc.cl

Fig. 24.1  A 68-year-old woman affected by glaucoma. Intraoc­ ular pressures at diagnosis were 34 mmHg in the right eye and 27 mmHg in the left eye. Timolol 0.25% b.i.d. was initiated

Fig. 24.2 The 24–2 SITA-Standard pattern deviation of the right eye of the woman shown in Fig. 24.1, showing an early superior and nasal visual field defect

with a corresponding visual field defect (see Fig. 24.2). The optic disc and visual field in the left eye were within normal limits. After a short discussion and thorough medical history, the patient was started on timolol maleate 0.25% twice daily in both eyes. One month later, IOPs were reduced by 52.9% and 51.8%, respectively, to 16 and 13 mmHg in the right and left eyes. Therefore, topical beta blockers are still a reliable and effective therapy for elevated IOP, and they can be considered for initial medical management of glaucoma.

The following sections include facts that the eye care provider should be aware of before starting a patient on topical beta blockers.

24.1.1What is the Topical Beta Blocker Mechanism of Action?

Beta blockers antagonize b1 and b2 receptors in the ciliary body’s nonpigmented epithelium (NPE) and thereby reduce secretion of aqueous humor through an incompletely understood mechanism, which in turn lowers IOP. Action on the ciliary microvasculature may reduce the ultrafiltration component of aqueous secretion [24]. The classic view that beta blockade diminishes the concentration of cyclic adenosine monophosphate (c-AMP) within NPE cells has been questioned by a report

showing decreased aqueous inflow following an increase in NPE c-AMP [6]. An alternative speculation put forth on the mechanism of beta blockers is that they suppress adrenergic tone that continuously stimulates aqueous humor formation [11]. However, aqueous humor dynamics and IOP are known not to be affected by sympathetic denervation in postganglionic Horner’s syndrome or in sympathectomized eyes [2]. Although findings on the mechanism of action are confusing, there is little doubt that the net effect of IOP lowering is through diminished aqueous formation.

24.1.2What Magnitude of iOP Decrease is Seen with Beta Blockers?

One drop of timolol maleate 0.25% or 0.50% has its peak effect, 2 h following administration and may last for 24 h. Nonselective beta blockers (Table 24.1) lower IOP 20–30%. However, IOP reduction may be as high as 50% and last greater than 24 h in certain individuals [28]. Newer beta blockers – levobunolol, carteolol, and metipranol – have similar clinical efficacy [30]. The selective b1 blocker, betaxolol, is less effective than timolol with reported IOP reduction between 16% and 20% of baseline [12].

24.1.3How Should Beta Blockers Be initiated?

The dramatic IOP reduction observed after initiation of timolol, for example, can be long lasting in many patients. However, in up to 20% of cases, the initial IOP reduction can be lost within 2–3 weeks. This has been called “short term escape,” and most likely reflects an

Table 24.1 Available beta-blocker agents

Nonselective beta blockers

Timolol preparations: Timolol maleate 0.25 and 0.50%; Preservative free timolol 0.25 and 0.50%; Timolol maleate gel-forming solution 0.5%; Timolol hemihydrate 0.25 and 0.50%

Levobunolol hydrochloride 0.25 and 0.50% Carteolol hydrochloride 1%

Metipranolol hydrochloride 0.3%

Selective beta-1 blocker

Betaxolol hydrochloride suspension 0.25%

upregulation in the number of ocular beta receptors after initial complete blockade [4, 30]. For this reason, it is recommended to wait at least 4 weeks following initiation of therapy before assessing IOP effect.

There are two approaches to follow when initiating beta-blocker treatment. Generally, the lowest concentration (0.25% vs. 0.5%) and lowest frequency (once daily vs. twice daily) necessary should be used to avoid excess drug absorption and to minimize adverse effects. One option is to prescribe one drop in the morning, and, if the target IOP is not maintained throughout the day, a second drop can be added in a 12-h regimen. If once-daily administration is sufficient, the daily drop should be used in the morning. It has been shown that timolol has little effect in sleeping patients because at night aqueous secretion is less than half that seen during daytime hours [23]. Another option is to start with a twice-daily regimen. After pressure levels off, if the target pressure has been reached, the patient can be instructed to change administration to one drop in the morning for 4 weeks prior to the next visit. This will help determining whether once-daily administration is sufficient to reach the therapeutic goal; otherwise the twice-daily regimen can be reinitiated.

Beta-blocker treatment can maintain control of IOP for years. However, in some patients IOP control may be lost after many years of therapy, or even within 3 months [4]. This phenomenon is called “long term drift” and may be the result of drug tolerance or progression of the trabecular meshwork outflow problems. In a 10-year follow-up of timolol-treated patients, 35% needed additional therapy, laser, or surgery because of loss of control with timolol monotherapy [15].

24.1.4What Are the Differences Between Individual Beta Blockers?

Selective b1 blockers are less potent at reducing IOP than their nonselective counterparts, which can make them less attractive in patients who need a bigger IOP reduction. The advantage of selective b1 blockers is that they have less effect on the b2 receptors found predominantly in the pulmonary system, making­ them more tolerable in patients with the potential for bronchospasm. Among nonselective beta blockers there are no differences in terms of IOP lowering efficacy. Carteolol has intrinsic a2 agonist sympathomimetic activity that does not interfere

with the therapeutic benefits of its beta-blocker action [2]. Patients under treatment with systemic beta blockers may experience a reduced effect of topical administration and increased side effects [14].

24.1.5  What Are the Side Effects

of Beta Blockers?

There are ocular, cardiovascular, pulmonary, metabolic, and central nervous system side effects. In general, beta blockers are well tolerated when applied topically; however, there are reports of ocular discomfort due to burning, hyperemia, toxic keratopathy, punctate keratopathy, periocular contact dermatitis, and dry eye [2]. Chronic administration of benzalkonium chloride used as preservative in most beta-blocker solutions may play a role in ocular toxicity. Use of preservative free timolol may help identify preservative as the source of local side effects. Timolol is available as a solution and in a gel-forming preparation. Gel-forming preparations allow longer permanence on the ocular surface for a sustained effect, and the once-daily administration can lead to fewer side effects. Gel-forming solution is also less likely to reach the nasolacrimal duct, lessening the potential for systemic side effects [29]. Gel-forming timolol solutions may cause transient blurring, allergic conjunctivitis, and frosting of the lid margins and eyelashes. Metipranolol as manufactured in the United Kingdom was associated with granulomatous uveitis [11].

Systemic side effects. Beta blockers are absorbed via the nasolacrimal system by the nasal and oral mucosa, thus bypassing the first pass effect in the liver [10]. Direct access to the blood stream explains many systemic side effects and contralateral IOP lowering. Systemic side effects must be thoroughly searched for by a careful medical history since patients often overlook their eye drops as a potential cause of systemic symptoms. The majority of patients will not experience systemic adverse effects with topical beta-blocker use, but some patients can be exquisitely sensitive.

Cardiovascular side effects. b1 receptor blockade lowers blood pressure and heart rate, which can cause severe bradycardia, especially in patients with advanced age or underlying medical conditions, such as greater than first degree heart block (a contraindication for the use of beta blockers). They also cause decrease myocardial contractility, which is a relative