Glaucoma – Beta Blockers

• Betaxolol HCI 0.25%, 0.5% (Betoptic® S)
• Carteolol Hydrochloride Ophthalmic Solution USP, 1%
• Levobunolol HCI ophthalmic solution, USP 0.25%, 0.5% (Betagan®)
• Timolol maleate ophthalmic solution 0.25%, 0.5% in Ocudose dispenser  (PF)
• Timolol Maleate Ophthalmic Solution 0.5%
• Timolol maleate ophthalmic gel forming solution 0.25%, 0.5% (Timoptic-XE®)

Background

Beta-blockers (decrease inflow)

Overview

1. Decrease aqueous humor production (occurs only during the day and not during sleep)
2. Mean peak IOP lowered by 25% and the mean trough lowered by 20% (slightly less with a selective agent: betaxolol).  Approximately 21–27% reduction in IOP from baseline in most patients.
3. None of the beta-blockers should be used more than twice daily.
4. Lower concentrations are usually just as effective in most patients.
5. 10% of cases the response decreases with time (tachyphylaxis), sometimes within only a few days
6. limited supplementary effect if a topical beta-blocker is prescribed for a patient who is already on a systemic beta-blocker
7. Beta blockers should not be instilled at bedtime as this medication may cause a significant drop in blood pressure while the individual is asleep
8. The IOP-lowering effect is also believed to be less marked during sleep, as nocturnal aqueous production is normally less than half the daytime rate.
9. Contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease ; (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure ; (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.

Pharmacology:   Levobunolol hydrochloride is a noncardioselective beta-adrenoceptor blocking agent, equipotent at both beta1 and beta2 receptors. Levobunolol Hydrochloride Ophthalmic Solution has been shown to be an active agent in lowering elevated as well as normal intraocular pressure (IOP) whether or not accompanied by glaucoma. The onset of action with one drop of Levobunolol Hydrochloride Ophthalmic Solution can be detected within one hour after treatment, with maximum effect seen between 2 and 6 hours. A significant decrease in IOP can be maintained for up to 24 hours following a single dose. Long-acting beta-blocker.

Dosing: The recommended starting dose is one to two drops of Levobunolol Hydrochloride Ophthalmic Solution 0.5% in the affected eye(s) once a day. In patients with more severe or uncontrolled glaucoma, Levobunolol Hydrochloride Ophthalmic Solution 0.5% can be administered twice a day. As with any new medication, careful monitoring of patients is advised.

Side effects: In clinical trials the use of Levobunolol Hydrochloride Ophthalmic Solution has been associated with transient ocular burning and stinging in up to 1 in 3 patients, and with blepharoconjunctivitis in up to 1 in 20 patients. Decreases in heart rate and blood pressure have been reported

Efficacy: In controlled clinical studies of approximately two years duration, intraocular pressure was well-controlled in approximately 80% of subjects treated with Levobunolol Hydrochloride Ophthalmic Solution 0.5% twice a day. The mean IOP decrease from baseline was between 6.87 mm Hg and 7.81 mm Hg. No significant effects on pupil size, tear production or corneal sensitivity were observed. Levobunolol Hydrochloride Ophthalmic Solution at the concentrations tested, when applied topically, decreased heart rate and blood pressure in some patients. The IOP-lowering effect of levobunolol was well maintained over the course of these studies.

In a three-month clinical study, a single daily application of Levobunolol Hydrochloride Ophthalmic Solution 0.5% controlled the IOP of 72% of subjects achieving an overall mean decrease in IOP of 7.0 mm Hg.

Pharmacology:   Betaxolol, a cardioselective (beta-1-adrenergic) receptor blocking agent, does not have significant membrane-stabilizing (local anesthetic) activity and is devoid of intrinsic sympathomimetic action. When instilled in the eye, Betaxolol has the action of reducing elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma.

Dosing: Betaxolol Ophthalmic Solution 0.5% is a sterile, isotonic, aqueous solution of betaxolol hydrochloride, USP. Supplied as follows: 2.5 mL, 5 mL, 10 mL and 15 mL in plastic ophthalmic dropper tip bottles. BETOPTIC S Ophthalmic Suspension 0.25% is supplied as follows: 10 and 15 mL in plastic ophthalmic DROP-TAINER® dispensers

The recommended dose is one to two drops of Betaxolol Ophthalmic Solution in the affected eye(s) twice daily. In some patients, the intraocular pressure lowering responses to Betaxolol may require a few weeks to stabilize. As with any new medication, careful monitoring of patients is advised.

Side effects: In clinical trials, the most frequent adverse reaction associated with the use of BETOPTIC S Ophthalmic Suspension 0.25% has been transient ocular discomfort. The following other adverse reactions have been reported in small numbers of patients:

Ocular: blurred vision, corneal punctate keratitis, foreign body sensation, photophobia, tearing, itching, dryness of eyes, erythema, inflammation, discharge, ocular pain, decreased visual acuity and crusty lashes.

Efficacy: Clinical studies show that topical betaxolol ophthalmic solution reduces mean intraocular pressure 25% from baseline. In trials using 22 mmHg as a generally accepted index of intraocular pressure control, betaxolol ophthalmic solution was effective in more than 94% of the population studied, of which 73% were treated with the beta blocker alone. In controlled, double-masked studies, the magnitude and duration of the ocular hypotensive effect of ophthalmic betaxolol solution and ophthalmic timolol solution were clinically equivalent.  In controlled, double-masked studies, the magnitude and duration of the ocular hypotensive effect of Betoptic Eye Drops 0.5% and Betoptic S Eye Drops 0.25% were clinically equivalent. Betoptic S Eye Drops 0.25% were significantly more comfortable than Betoptic Eye Drops 0.5%.

Pharmacology:  Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anesthetic (membrane-stabilizing) activity. TIMOPTIC (timolol maleate ophthalmic solution), when applied topically on the eye, has the action of reducing elevated as well as normal intraocular pressure, whether or not accompanied by glaucoma. The precise mechanism of the ocular hypotensive action of TIMOPTIC (timolol maleate ophthalmic solution) is not clearly established at this time. Tonography and fluorophotometry studies in man suggest that its predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed.

Dosing: Preservative-free TIMOPTIC in OCUDOSE is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration. It is available in concentrations of 0.25 and 0.5%. 
Dosing: The usual starting dose is one drop of 0.25% Preservative-free TIMOPTIC in OCUDOSE in the affected eye(s) administered twice a day. Apply enough gentle pressure on the individual container to obtain a single drop of solution. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5% solution in the affected eye(s) administered twice a day.

Timolol Maleate Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Timolol Maleate Ophthalmic Solution in the affected eye(s) twice a day. If the clinical response is not adequate, the dosage may be changed to one drop of 0.5 percent solution in the affected eye(s) twice a day.

TIMOPTIC-XE Sterile Ophthalmic Gel Forming Solution is available in concentrations of 0.25% and 0.5%. The dose is one drop of TIMOPTIC-XE (either 0.25% or 0.5%) in the affected eye(s) once a day.

Side effects: The most frequently reported adverse experiences have been burning and stinging upon instillation (approximately one in eight patients).

Efficacy:  Timolol maleate ophthalmic solution:  In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater, Timolol Maleate Ophthalmic Solution 0.25 percent or 0.5 percent administered twice a day produced a greater reduction in intraocular pressure than 1, 2, 3, or 4 percent pilocarpine solution administered four times a day or 0.5, 1, or 2 percent epinephrine hydrochloride solution administered twice a day.

Timolol maleate ophthalmic gel forming solution 0.25%, 0.5% (Timoptic-XE®):  In controlled, double-masked, multicenter clinical studies, comparing TIMOPTIC-XE 0.25% to TIMOPTIC 0.25% and TIMOPTIC-XE 0.5% to TIMOPTIC 0.5%, TIMOPTIC-XE administered once a day was shown to be equally effective in lowering intraocular pressure as the equivalent concentration of TIMOPTIC administered twice a day. The effect of timolol in lowering intraocular pressure was evident for 24 hours with a single dose of TIMOPTIC-XE. Repeated observations over a period of six months indicate that the intraocular pressure-lowering effect of TIMOPTIC-XE was consistent.

Pharmacology:   Carteolol is a nonselective beta-adrenergic blocking agent with associated intrinsic sympathomimetic activity and without significant membrane-stabilizing activity.

Carteolol Hydrochloride reduces normal and elevated intraocular pressure (IOP) whether or not accompanied by glaucoma. The exact mechanism of the ocular hypotensive effect of beta-blockers has not been definitely demonstrated.

In general, beta-adrenergic blockers reduce cardiac output in patients in good and poor cardiovascular health. In patients with severe impairment of myocardial function, beta-blockers may inhibit the sympathetic stimulation necessary to maintain adequate cardiac function. Beta-adrenergic blockers may also increase airway resistance in the bronchi and bronchioles due to unopposed parasympathetic activity.

Dosing: The usual dose is one drop of Carteolol Hydrochloride Ophthalmic Solution 1% in the affected eye(s) twice a day.

Side effects: Ocular: Transient eye irritation, burning, tearing, conjunctival hyperemia and edema occurred in about 1 of 4 patients. Ocular symptoms including blurred and cloudy vision, photophobia, decreased night vision, and ptosis and ocular signs including blepharoconjunctivitis, abnormal corneal staining, and corneal sensitivity occurred occasionally.

Systemic: As is characteristic of nonselective adrenergic blocking agents, Carteolol may cause bradycardia and decreased blood pressure . The following systemic events have occasionally been reported with the use of Carteolol Hydrochloride Ophthalmic Solution: cardiac arrhythmia, heart palpitation, dyspnea, asthenia, headache, dizziness, insomnia, sinusitis, and taste perversion.

Efficacy: Given topically twice daily in controlled domestic clinical trials ranging from 1.5 to 3 months, Carteolol Hydrochloride produced a median percent reduction of IOP 22% to 25%. No significant effects were noted on corneal sensitivity, tear secretion, or pupil size.