Specific Ocular Beta Blockers

In the United States, five topical OBBs have been approved for lowering IOP. These compounds are similar, although there are some differences among the individual compounds and their activity and pharmaceutics. Figure 3.1 depicts the chemical structures of these OBBs, and table 3.1 summarizes them.

3.9.1 Nonselective Beta Blockers.

3.9.1.1 Timolol solution is available as timolol maleate 0.25% and 0.5% (Timoptic, Istalol) and as timolol hemihydrate 0.5% (Betimol). A timolol maleate gel-forming solution 0.25% and 0.5% is also available (Timoptic-XE). The timolol maleate preparations are also available as generics. Timolol maleate solution, the prototype OBB in the United States, was the first OBB approved by the FDA in 1978. As the prototype, it is discussed in greater detail than other OBBs. Many of the observations relating to timolol are relevant to the other OBBs.

The introduction of OBB drugs provided an attractive alternative to the other agents previously available. The adrenergic agonists, parasympathomimetics, and oral CAIs had adverse effect profiles that limited their tolerability. Timolol rapidly advanced to become the most commonly used first-line therapy for the treatment of elevated IOP, replaced in recent years by prostaglandin analogues.

Timolol is a nonselective beta-adrenergic antagonist. It and the other OBBs lack the membrane-stabilizing property (local anesthesia) that limited the usefulness of propranolol as an IOP-lowering medication. Timolol was demonstrated to have greater efficacy at lowering IOP than either pilocarpine or epinephrine.100,101 Ti-molol maleate has been demonstrated to lower IOP in normal, ocular hypertensive, and glaucomatous eyes.102-104

Figure 3.1. Chemical structures of beta blockers.

Timolol is available commercially at 0.25% and 0.5% concentrations in the United States. The 0.5% concentration is most commonly used; however, lower concentrations may be equally effective. (Timolol is available as 0.1% solution and gel outside the U.S.) When interpreted in the context of the knowledge we have gained about timolol, it becomes clear that early studies to establish the dose response of timolol had what we can now recognize as design flaws.

There is no clearly defined dose-response effect for reduction of IOP by timolol with concentrations ranging from 0.1% to 1.5%. A single-dose, incomplete block design study of 20 patients showed almost equivalent peak IOP reduction (no significant difference) with timolol 0.1% to 1.5% compared with fellow eyes receiving placebo or no drug. All subject received timolol at varying doses, or placebo in the study eye. The study had a somewhat complex design but is the best reported among the dose-ranging studies. There were significant IOP reductions for 24 hours with timolol at concentration of 0.25% and higher, but IOP began to increase after 8 hours with timolol 0.1% single dose. Interestingly, all concentrations maintained 25% IOP reduction or greater at 24 hours.103 Another double-blind study compared epinephrine to timolol 0.1%, 0.25%, and 0.5% twice daily in 119 glaucoma patients. Intraocular pressure measurements were performed on weeks 2, 4, 10, and 14. Timolol was superior to epinephrine, and interestingly, 68% of subjects on timolol 0.1% had an IOP below 22mm Hg.105 One of the key limitations of early studies was the lack of appreciation of the need for a run-in period; the full IOP effect is not achieved with a single dose or even with a week of therapy.

In none of the dose-ranging studies or single-dose studies is there comment on eye color. Clearly, the studies and comments are silent on the issue of the time to reach steady state with pigment binding. This may represent another fundamental error in early decisions about dosing; the 0.25% concentration may have maximal efficacy, particularly in less pigmented eyes, and lower incidence of systemic side effects.106 Despite these limitations in the early studies, clinicians in the United States most commonly prescribe timolol 0.5%.

With topical timolol maleate use, there is a contralateral effect when the drug is used in one eye. This IOP lowering in the untreated eye is believed to be due to systemic absorption of the drug.107,108

The onset of action of timolol maleate is about 30 minutes following instillation, with maximum effect after 2 hours.103 This maximal effect can persist for 12 hours following application, with measurable IOP lowering persisting for 24 hours.

Studies of aqueous flow have demonstrated that timolol reduces aqueous production below baseline levels when taken in the morning but does not reduce it below baseline levels following an evening dose.109 There is a normal physiologic decrease in aqueous flow at night, and timolol did not reduce flow below this level. Recent sleep laboratory data have further suggested a lack of nocturnal efficacy of timolol. When IOP is measured in habitual position (upright during daytime and supine at night), timolol dosed once daily in the morning lowered daytime IOP below baseline values but did not lower nocturnal IOP below the baseline.110

The prolonged duration of action and the lack of effect on aqueous flow with dosing at night and the sleep laboratory data have raised questions about the dosing frequency of OBBs. Although the labeled indication for the drug specifies twice-daily dosing, clinical studies and practical experience have demonstrated that once-daily administration may be effective and, in fact, preferable.111-113

In some patients, the efficacy of timolol maleate may decrease over time. It has been hypothesized that the decrease may be due to the response of beta receptors to constant exposure to an antagonist. Initially, most patients have a substantial re duction in IOP in response to timolol maleate, but after several weeks IOP response may lessen. This phenomenon is called short-term escape. It has been suggested that, in response to the beta-receptor antagonism, there is drug-induced up-regulation of beta receptors in the target tissue.

Over a longer time period of months to years, some patients who were initially well controlled by timolol maleate evidenced reduced IOP control. This effect, termed long-term drift, does not occur in all patients. Following a several-week drug holiday, earlier levels of IOP lowering can be restored. One might also wonder if this is an acquired lack of efficacy or poor adherence and a lack of using the eye drops.

The effects of timolol may persist for weeks after discontinuation of the drug. Some IOP lowering may persist for up to 2 weeks, and aqueous flow may be affected for up to 6 weeks. For clinical studies, 4 weeks is accepted as a "washout" for timolol maleate.

Timolol has been demonstrated to be additive to most other IOP medications. As mentioned above, newer IOP-lowering agents have been studied in comparison to timolol and were often studied as an adjunct to timolol. This is not because of any particular advantage of timolol over other nonselective beta blockers. Because of its widespread acceptance, timolol became a benchmark to which new IOP-lowering therapies are compared. It would be reasonable to expect that additivity of other nonselective beta blockers would be similar (see section 3.7).

Timolol maleate is available in gel-forming solutions. The first of these (Timoptic-XE) is formulated in gellan gum. This vehicle forms a gel when it comes in contact with cations in tear film. It has been proposed that this would increase bioavail-ability and decrease systemic absorption.

In clinical trials, the IOP-lowering effect of once-daily Timoptic-XE was compared to that of twice-daily timolol maleate solution and found to be similar.53 No large trials are available comparing Timoptic-XE once daily with timolol maleate solution once daily. Timoptic-XE has as its preservative benzododecinium bromide rather than BAK, which is found in other beta blocker preparations. This may be useful for a patient with sensitivity to BAK. A generic equivalent to the gel-forming solution is available. Timolol in xantham gum gel-forming solution (Timolol GFS) was approved by the FDA as an A-B equivalent.

As mentioned above, the once-daily administration of timolol in gel-forming solution should decrease the amount available for systemic absorption through naso-lacrimal drainage and thus decrease adverse effects. In a small crossover study comparing Timoptic-XE 0.5% once daily to timolol maleate 0.5% solution twice daily, plasma levels of timolol were lower in patients receiving once-daily gel-forming so-lution.114 It is not clear if this result is due to the gel or the less frequent dosing.

Timolol hemihydrate (Betimol) is a timolol solution available as 0.25% and 0.5% in which hemihydrate has been substituted for the maleate anion. Timolol hemihydrate is similar to timolol maleate in IOP-lowering effect and is expected to have a similar adverse effect profile.115

Timolol maleate 0.5% has been formulated with potassium sorbate (Istalol), with a claim to enhance bioavailability and with a lower concentration of BAK. This formulation administered once daily in the morning was compared with timolol maleate 0.5% solution administered twice daily, with 290 patients completing the

12-month study. At none of the visits did the 95% confidence intervals for between-treatment comparisons exceed 1.5 mm Hg, and at most of the visits, these intervals did not exceed 1.0mm Hg.116 Istalol is the only timolol maleate solution compared with twice-daily dosing of the original formulation and received an indication for once-daily dosing. No studies are available that compare once-daily with twice-daily dosing of the original formulation of timolol maleate.

3.9.1.2 Carteolol hydrochloride 1% (Ocupress) is a nonselective beta blocker approved in 1992 for use in the United States. The branded product is no longer marketed in the United States. Generic carteolol is available.

Carteolol differs from the other nonselective OBBs by having ISA. This means that, while acting as a competitive antagonist, carteolol binds to the adrenergic receptor and results in partial agonist activity. This effect appears to be due to a metabolite that is also a potent IOP-lowering agent. An OBB with ISA offers the theoretical advantage of causing less frequent or less severe adverse effects of beta blockade. Such benefits have not been clearly established in clinical practice.

Carteolol lowers IOP within 1 hour of administration, with peak effect at 4 hours. Significant IOP lowering persists for 12 hours.117,118 Carteolol appears to be as effective as other nonselective OBBs.119,120

The side effects associated with carteolol can be expected to be similar to those of other OBBs, although the intrinsic sympathomimetic activity (ISA) of carteolol may confer some advantages. As noted above, in some studies, the effect on heart rate and lipid profile with carteolol was more favorable than that with timolol. However, in stark contrast with other beta blockers, those with ISA in fact are not favored systemically because the ISA component results in a significant reduction in the survival advantage that beta blockers as a class have in patients with a history of myocardial infarction.121

3.9.1.3 Levobunolol hydrochloride (Betagan) is a nonselective OBB derived from propranolol. It was approved for use in the United States in 1985. The commercial preparation is formulated in 0.25% and 0.5% concentrations and contains only the levo-isomer. Generic preparations are available.

As with other OBBs, levobunolol decreases IOP in normal subjects and in those with elevated IOP. The IOP-lowering effect begins within 1 hour of administration and reaches peak in 2 to 6 hours.122 A significant effect can be maintained for 24 hours.112,123,124 A metabolite of levobunolol, dihydrobunolol, possesses beta-blocking activity and may account for the sustained effect. As noted above, levo-bunolol is indicated for once-daily or twice-daily dosing.

In short-term studies, levobunolol twice daily was equivalent to other OBBs in IOP-lowering ability.125-127 However, in a 3-month, double-masked trial comparing once-daily levobunolol 0.5% and 1% with once-daily timolol 0.5%, the levobu-nolol groups had a significantly greater mean reduction in IOP than did the timolol group (7 and 6.5mm Hg vs 4.5mm Hg). It is interesting to note that 72% (18 of 25) of the levobunolol 0.5% group and 64% (16 of 25) of the timolol 0.5% group were considered to have satisfactory IOP control on the once-daily regimen.112 Additivity and adverse effects with levobunolol are similar to those of other nonselective OBBs.

3.9.1.4 Metipranolol 0.3% (Optipranolol) is a nonselective beta blocker approved in 1991 for use in the United States. It is available only as a generic preparation.

The IOP-lowering effect of metipranolol is similar to that of other nonselective OBBs.19,128 Onset of action is within 30 minutes of administration, with peak effect at 2 hours. A detectable IOP effect can last for 24 hours.129 Like levobunolol, metipranolol has an active metabolite that may contribute to prolonged action.

Additivity and adverse effects of metipranolol are similar to those of other non-selective OBBs. As mentioned in section 3.6.1, there may be an association between metipranolol and granulomatous uveitis.

3.9.2 Selective Beta Blockers

3.9.2.1 Betaxolol hydrochloride is a relatively selective beta-1-adrenergic antagonist. It was initially introduced as a 0.5% solution (Betoptic) and approved for use in the United States in 1985. A new vehicle was introduced in 1991, consisting of betaxolol 0.25% in a suspension of resin-coated beads designed to allow a gradual release of drug. It is marketed under the trade name Betoptic S (suspension). The commercial product is a racemic mixture of the dextro- and levo-isomers. It is available as a 0.25% suspension. (The 0.5% solution is no longer marketed in the U.S.) In clinical trials, betaxolol was effective at lowering iop.130-133 In most studies, it lowers IOP slightly less than timolol or other nonselective beta block-ers.17,134,135,136 The betaxolol 0.25% suspension has the same IOP-lowering effect as the 0.5% solution, and it seems to cause less ocular irritation.20

In an intriguing study, the long-term effects on visual fields in patients taking betaxolol were compared with those in patients taking timolol. Even though the IOP was higher in the betaxolol group, the visual fields were judged slightly better.137,138 Similar results were found in another study.139 These small studies have not been verified with larger, prospective studies.

Betaxolol may possess other interesting properties. There is some evidence that it possesses calcium channel blocker properties.140,141 Preliminary limited evidence raised the possibility that the drug may also have neuroprotective effects under certain conditions.142-145 The significance of these observations to human glaucoma, if any, remains to be established.

Betaxolol is highly lipid soluble and has a large volume of distribution. It binds well to plasma proteins. This may explain in part the lower incidence of CNS side effects with betaxolol than with timolol.40,41

3.9.3 Combination Drugs. Timolol has been tested as a component of several fixed-combination products, which are discussed in chapter 7.

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