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MANAGING OPEN ANGLE GLAUCOMA

SECOND-LINE OR ADJUNCTIVE TREATMENT OPTIONS
Beta-adrenoceptor blocking agents
The beta-adrenoceptor blocking agents, or beta-blockers, have been work-horses in glaucoma management for de-
cades. While IOP-lowering is significant (~27%, range 19 to 29%) with once-daily or twice-daily dosing, their use
as a first-line therapy has been essentially usurped by the prostaglandin analogue medications due to their potency
for reducing IOP and their relative lack of systemic adverse effects. 331,332 The primary mechanism of action for the
beta-blockers is decreased aqueous production. They are broadly categorized as either non-selective where both
beta-1 and beta-2 receptors are targeted (timolol 0.25% and 0.5%, levobunolol 0.25% and 0.5%) or cardio-selective
where beta-1 receptors are preferentially targeted (betaxolol 0.5% solution and 0.25% suspension). While the non-
selective agents may be dosed once per day, betaxolol is generally dosed twice. As the production of aqueous is
physiologically reduced at night, it follows that morning instillation is recommended when only once per day dos-
ing is prescribed. Unlike the prostaglandin analogues, most of the expected lowering of IOP will occur within 2
weeks with timolol. The systemic adverse effects of the beta-blockers are well known and include exacerbation of
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pulmonary conditions such as asthma and chronic obstructive pulmonary disease, precipitation of heart block, and
fatigue and impotence. Local adverse effects include stinging, decreased corneal sensation.

The beta-blocker timolol is considered the gold standard in this class. As such, 0.5% timolol can be found in fixed
combination with each of the three main prostaglandin analogues, the alpha-adrenoceptor agonist brimonidine,
and both carbonic anhydrase inhibitors (CAIs) dorzolamide and brinzolamide. A preservative-free formulation of
timolol is also available.

Despite providing slightly less IOP reduction, betaxolol may preserve visual field as well or better than timolol. 334

Alpha-adrenoceptor agonists (∞2)
The selective (∞2) alpha-adrenoceptor agonist agents, or alpha-agonists, have also been in use for many years. IOP-
lowering is initially significant (20 to 30%) but may drop to lower levels over time (~17% reduction). Brimonidine
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0.2% administered three times per day is considered to be approximately equivalent to timolol 0.5% used twice per
day. The mechanism of action for the alpha-agonists is both decreased aqueous production and increased outflow
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through the uveoscleral pathway. While apraclonidine (0.5%, 1.0% unit dose) was first produced as a selective
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alpha-agonist, it soon fell out of favour for the treatment of open angle glaucoma due to high rates of tachyphylaxis
and ocular allergy. However, it is very effective at preventing post-operative IOP spikes. Brimonidine (0.2%, 0.15%
and 0.1% in US only) is a much more selective agent than apraclonidine and has a lower rate of tachyphylaxis and
allergy. The onset of action of the alpha-agonists is quick at 1 hour and peak at 2 to 3 hours, with trough at 10 to
14 hours. This is the reason that dosing is three times per day if used as a single drug therapy; however, evidence
suggests that brimonidine can be successfully reduced to twice per day when used as adjunctive therapy. The sys-
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temic adverse effects of the alpha-agonists are relatively uncommon but include fatigue or drowsiness, dry mouth
and headache. Caution should be taken with patients with severe cardiovascular disease, orthostatic hypotension
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and Raynaud syndrome. This agent is also contraindicated in children due to significant central nervous system ef-
fects including excessive sleepiness and lethargy: these effects have been reported after even a single drop of 0.2%
brimonidine in infants. Local adverse effects include hyperemia, allergy (in as many as one in four patients), burn-
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ing on instillation, dryness, visual disturbance, tearing and eyelid edema.
While a number of the requirements to determine if a drug is neuroprotective have been satisfied by research into
the use of brimonidine, and some studies have suggested better visual field preservation with brimonidine than
timolol, to date no conclusive evidence supporting neuroprotection has been provided in human glaucoma.
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Brimonidine is available in FC with both timolol 0.5% and brinzolamide 1.0%.

Carbonic anhydrase inhibitors (CAIs)
The agents that inhibit carbonic anhydrase include dorzolamide (2.0%) and brinzolamide (1.0%). Due to IOP-low-
ering that is significantly inferior to that of the prostaglandin analogues or beta-blockers, the CAIs are generally
used as adjunctive treatments. However, like the alpha-agonists, if prescribed on their own they should be admin-
istered three times per day, while as add-on therapy they can be administered twice. Generally, morning and
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mid-afternoon are considered reasonable dosing times when added to a prostaglandin analogue dosed at bedtime.

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