BETA-ADRENERGIC BLOCKING AGENTS
FOR ELEVATED INTRAOCULAR PRESSURE

Clinical Update
     The leading cause of vision loss and irreversible blindness worldwide, glaucoma affects some 2% of those of us over the age of 40 in the United States1 and is five times as common among blacks as whites.2 Definitive diagnosis requires detection of damage to the optic nerve or blood vessels, as only about 70% of glaucoma victims demonstrate elevated intraocular pressure (IOP) or ocular hypertension. Any chronic disruption in blood flow to the optic nerve can damage it, including hypertension, hypotension, cardiovascular disease, carotid blockage, or migraine, largely accounting for the remaining 30% of normotensive (IOP between 10 and 21mmHg) glaucoma victims; but the most common treatable risk factor still seems to be elevated IOP.3 The characteristic progressive and irreversible damage to the optic nerve is usually asymptomatic until some 40% of function is lost along with significant percentages of peripheral vision, the disease often progressing without the patient’s awareness.1
     Early recognition of risk factors and appropriate intervention is necessary to prevent permanent neuronal damage and consequent visual deterioration, and reduction of IOP to within normal limits is the logical therapeutic option for most victims of primary open angle glaucoma (POAG), the most common type.4 The normal circulation of aqueous humor produced by the ciliary body in the posterior chamber, passing into the anterior chamber through the pupil, then out of the eye via the trabecular meshwork, regulates IOP. Dysregulation and ocular hypertension occur when production of aqueous humor outpaces outflow through the trabecular meshwork.5
     While surgical intervention may be necessary in some cases, especially with other causes of elevated IOP, medical management via topical medications designed to curtail aqueous production and/or enhance outflow is generally preferred and appropriate. Beta-adrenergic blocking agents, though only one of several classes of medication utilized in this role, are one means of achieving target IOP with minimal inconvenience and side effects.6
     As with any therapeutic option, efficacy, tolerability, concomitant disease, drug interactions, convenience, and cost must all be considered, and the generic beta-adrenergic blocking agents compare favorably in all aspects of the problem. Compliance with ocular regimens depends on perceived efficacy, dosing frequency, side effects, comorbid ocular and systemic conditions, number of medications, and cost of therapy. Cost comparisons are often complicated by variances in measured and labeled bottle volumes, drop volumes, and loss due to overflow and blinking.2

Pharmacology
     While improvement in capillary perfusion in tissues supplying the optic nerve may be a more realistic measure of medication efficacy, reduction in IOP is more readily measured, and the two are thought to be closely related. Since production of aqueous humor and outflow from the anterior chamber are both under sympathetic regulation, medications that alter sympathetic activity locally in the eye are logical therapeutic tools. Beta blockers tend to lower IOP primarily by decreasing production of aqueous humor by the ciliary body, but they also tend to increase aqueous outflow to varying degrees.2
     The direct-acting sympathomimetics, once the mainstay of glaucoma therapy, have been supplanted by the beta-adrenergic blocking agents as first-line therapies of choice over the past twenty years for several reasons. The beta blockers generally cause fewer and less-bothersome side effects, providing comparable efficacy while not appreciably affecting visual acuity; and frequency of administration can be a significant concern.6
     Systemic absorption of topically applied medications can be a significant source of adverse effects, particularly in patients on other medications with which they interact, like antihypertensives and antiarrhythmics. Medications administered to the eye pass rapidly through the nasolacrimal duct to the highly vascularized nasal mucosa, where they enter the systemic circulation, circumventing first-pass hepatic metabolism.6
     Beta-adrenergic blockers have been associated with asthma exacerbation, status asthmaticus, exacerbated congestive heart failure, heart block, and even sudden death. They can block the typical symptoms of hypoglycemia, so they should be used with caution in patients with diabetes; and ocular administration has also been reported to cause dysthymia and frank depression observed with oral administration. Impotence, another recognized side effect of topically applied beta blockers may discourage compliance and frank discussion.2

Timolol Maleate Ophthalmic HydroGel
     In terms of efficacy, side effects, and cost, timolol maleate has become the standard against which other therapeutic options are measured, and it is often considered the first-line agent of choice; but systemic side effects may limit its use. It is generally more effective at reducing IOP than betaxolol and is often considered the logical choice when cardiopulmonary effects are not an issue. The solution is normally dosed twice daily, but the newer gel formulation provides comparable efficacy, reducing IOP some 30% on average with once-daily administration with comparable side effects.7
     Blurred vision is a common observation with the gel formulation, but it is generally a short-lived side effect that endures for only a few minutes after administration. The single daily dose and generally favorable side effect profile make it a logical first choice for many patients with elevated IOP, especially since its generic availability has significantly lowered the cost of therapy; but it is often a superb choice in conjunction with other therapeutic options in patients that fail to respond to a single agent.7

Betaxolol Ophthalmic Suspension 0.25%
     Betaxolol is a cardioselective beta blocker, affecting primarily beta-1 receptors, though beta-2 effects may be seen with higher doses.6 Potential cardiopulmonary side effects are significantly less than with timolol solution; and its suspension formulation containing 0.25% betaxolol rather than the solution’s 0.5% further helps to reduce any systemic side effects. Thus, it may be a better choice for the ocular hypertension patient with concomitant potential for one or a combination of congestive heart failure, hypotension, asthma, and blood glucose dysregulation. Since the number of glaucoma patients increases along with age and various other comorbid conditions, this can be a significant advantage over other less beta-2-selective agents 7
     Some studies indicate that betaxolol may also preserve visual field more effectively in many patients, a phenomenon that may be related to observations that it actually improves microcirculation in some cases, effectively improving tissue perfusion and offering some measure of neuroprotection for the optic nerve head (ONH), a phenomenon not observed with timolol. 8

Outlook
     Topically-applied ocular medications are more site specific than oral medications, generally providing superior efficacy with more favorable systemic side effect and drug interaction profiles, in spite of some significant systemic absorption; so they are preferred in the treatment of glaucoma. Conjunctival and localized allergic reactions are relatively more common with topical agents, but severe reactions are more rare with them. The beta-adrenergic blocking agents have distinguished themselves as reliable first-line agents in glaucoma treatment and valuable adjuncts in multi-medication regimens when a single agent produces insufficient improvement in IOP.

References
1. Glaucoma Guidelines: A Way to Improve Care? Available at: http://www.medscape.com/adis/DTP/2000/v15.n01/dtp1501.03/dtp1501.03-01.html. Accessed December 15, 2000.

2. Lewis P, Phillips T, Sassani J. Topical Therapies for Glaucoma: What Family Physicians Need to Know. American Family Physician. Available at: http://www.aafp.org/afp/990401ap/1871.html. Accessed December 15, 2000.

3. Current Glaucoma Treatment Modalities. Available at: http://www.wroa.com/glaucoma.html. Accessed December 15, 2000.

4. Glaucoma. All About Vision. Available at: http://www.allaboutvision.com/conditions/glaucoma.htm. Accessed December 15, 2000.

5. Glaucoma. Eye Facts. Available at: http://www.uic.edu/com/eye/patients/eyefacts/glaucoma.htm. Accessed December 15, 2000.

6. Beta-adrenergic blocking agents. Agents for Glaucoma. Drug Facts and Comparisons. Electronic Edition, December, 2000.

7. Ardjomand B, Feigl M. Eckhardt M. Efficacy of Timolol Hydrogel 0.1% In Patients With Open Angle Glaucoma. Available at: http://www.dog.org/1999/e-abstract99/389.html

8. Groh M, Michelson G, Harazny J, Groh M, and Koschinsky K. Effect of Topical Glaucoma-Medication On Retinal and Optic Nerve Head Blood Flow. Available at: http://www.dog.org/1998/e-abstract98/217.html