cyclic AMP, the usual intracellular mediator of adrenergic agonists, and may relate to Cl /HCO exchange.37

Topical administration of timolol and the other -adrenergic antagonists to one eye reduces IOP in the contralateral eye.38–40

The fact that IOP in the contralateral eye is reduced less than in the ipsilateral eye suggests a local effect in the eye rather than an effect mediated by the central nervous system or by a reduction of blood pressure. Substantial levels of timolol are found in the contralateral eye after unilateral topical administration in rabbits,41 and small but clinically significant levels are found in humans.42

Drugs in clinical use

Five different topical -blocking agents are available for clinical use in the United States: timolol, levobunolol, betaxolol, metipranolol, and carteolol. Generic ‘equivalents’ are available for timolol, levo­ bunolol, and carteolol. Timolol is available as the maleate salt and the hemihydrate salt; it is also available in various gel formulations that are suggested to prolong its time in contact with the cornea or enhance its transit into the anterior segment (potassium sorbate). The non-selective agents (all but betaxolol) appear clinically more alike than different, although there are some differences that may

be important in selected patients (Fig. 25-1).The major features of these agents are summarized in Table 25-1.

Timolol maleate

Timolol maleate (Timoptic™, Merck,West Point, Penn and generics) is a nonselective 1- and 2-adrenergic antagonist that lacks substantial intrinsic sympathomimetic activity and membrane-sta- bilizing properties (see Table 25-1). The drug is about five times more potent than is propranolol. Timolol reduces IOP in normal

and glaucomatous eyes without changing visual acuity, accommodation, or pupil size.11,38,39 On average, timolol lowers IOP by

about 5 mmHg over a 6–12 month period.43 While timolol (and the other -blockers) do a reasonable job of flattening the diurnal curve, the -blockers are less effective during the night-time hours, possibly because the secretion of aqueous is lowest during the night.44 The only effect of timolol on the pupil is a clinically insignificant decrease in the amplitude of redilation as detected by pupillogra-

phy.45 Timolol binds to melanin and is not metabolized by ocular tissues.23,46 Timolol is excreted in the urine in the form of unknown

metabolites. The ocular hypotensive effect of timolol is greater in human eyes than in animal eyes; in animals, the effect can often only be demonstrated in experimental ocular hypertensive conditions such as water loading.This is a good example of the importance of species differences in the ocular response to adrenergic drugs.

Timolol is supplied in 0.25% and 0.5% concentrations, each of which is administered every 12–24 hours.The 0.25% concentration is the top of the dose–response curve for most individuals with

lightly pigmented irides, whereas the 0.5% concentration is more effective for most patients with dark irides.39,40,47 In some patients

with light irides, the 0.5% concentration produces a longer duration of effect rather than a greater reduction in IOP.48 Timolol was thought to be equally effective in black and white patients when administered in the appropriate concentration.47 However, more

recent studies suggest that the -blockers may be less effective in those of African descent than in those of European descent.49,50

Timolol penetrates the eye rapidly; following topical administra-

tion, IOP begins to fall in 30–60 minutes, reaches a low in 2 hours, and returns to baseline in 24–48 hours.11,39 Some residual effect of

timolol on IOP may be detected for as long as 2–3 weeks, and - blockade can be detected up to 1 month after discontinuation of the drug.51 Many patients are controlled on once-daily administration of timolol52,53; however, this requires confirmation by measuring IOP 24–26 hours after the last administration of the drug.

Timolol maleate in a gel solution (Timoptic XE, Merck Inc., West Point, PA; timolol in gel-forming solution (GFS), Falcon Pharmaceuticals Ltd., Fort Worth,TX) for once-daily use has been found to prolong the contact time of timolol with the ocular surface and, therefore, theoretically, more gets into the anterior chamber, prolonging the action.54 The gel formulations have been found to be nearly equivalent to timolol maleate given twice daily.55 The two most popular gel formulations in the US appear to be equivalent in effectiveness and side effects.56 The gel formulation, because of its once-a-day dosing, theoretically reduces the systemic side effects compared with the twice-daily aqueous preparation.57 Although the gel has been compared in clinical studies to twice-daily aqueous administration, no study has compared the gel to once-daily timolol maleate solution. Studies with levobunolol and timolol hemihydrate suggest that the pressure-lowering effect

of these agents administered once daily compares favorably with once-daily administration of timolol maleate gel.58,59 A non-pre-

served timolol gel formulation has recently become available in single-dose units with equivalent effect to multidose preserved doses.60

A new formulation of timolol in potassium sorbate (timolol LA, Istalol®, Senju Pharmaceuticals, Osaka, Japan) has recently been shown in a double-masked, randomized, prospective study in the US to have equivalent IOP-lowering effect as timolol maleate 0.5% given twice daily, with a similar safety profile. It differed only in a higher rate of stinging on administration than the solution.61 The drug has been approved by the US Food and Drug Administration. Theoretically, the potassium sorbate makes the timolol more bioavailable to the tissues inside the eye through increased anterior chamber concentration, perhaps by increasing lipophilicity.62 The solution also has a lower dose of benzalkonium chloride than the standard solutions of timolol maleate.

Approximately 90% of patients respond to the initial administration of timolol. Often the response to the first few doses is a reduction in IOP of 40% or more. However, this effect diminishes over several days to a few weeks.63 This decline in efficacy has been termed the ‘short-term escape’ by Boger and co-workers63 and may relate to an increase in the number of -adrenergic receptors in the ciliary processes under the condition of prolonged-adrenergic blockade.64 Unfortunately, the response to timolol at 1 month is not predicted by the response to a single administration given in the office.65 After this initial adjustment process, most patients maintain a reduction in IOP for months to years. However, 10–20% of patients demonstrate some loss of drug effect over subsequent months.66,67 Fluorophotometric studies indicate that aqueous humor production is reduced 47% after 1 week of timolol treatment but only 25% after 1 year of treatment.68 This process has been termed the ‘long-term drift’ by Steinert and co-workers67 and may be explained by a time-dependent decrease in cellular sensitivity to adrenergic antagonists.

Timolol has become the ‘gold’ standard against which all newer glaucoma hypotensive agents are compared. It is less potent than the major prostaglandin analogs and equivalent to unoprostone, brimonidine, and the topical carbonic anhydrase inhibitors.69–73

Over the short term, timolol is more effective in reducing IOP than is pilocarpine74–76 or epinephrine.77

The ocular hypotensive effect of timolol is additive to that of the miotics63–68,74–79 and the carbonic anhydrase inhibitors (CAIs).63,80–82

It should be emphasized that timolol and the CAIs are only

somewhat additive in their effects on IOP.81,82 In one study, timolol alone reduced aqueous humor formation by 33%, acetazolamide alone reduced aqueous formation by 27%, and the combination reduced aqueous humor formation by 44%83 (i.e., the combination was more effective than either agent alone but less effective than the sum of the two drugs). On the other hand, timolol adds well to the topical carbonic anhydrase inhibitors with a decrease in aqueous humor formation and IOP with the two drugs greater than either alone.84 While timolol’s effect on reducing aqueous formation is somewhat greater than brimonidine’s (note brimonidine also improves uveoscleral outflow so only some of its effect is from reduction of aqueous flow), there is additivity of brimonidine’s effect to timolol both in reducing aqueous formation and IOP.85,86 Timolol even is additive to bunazosin, an -adrenergic antagonist.87

The question arises as to whether topical timolol reduces IOP in patients treated with systemically administered -adrenergic antagonists. The IOP response depends on the dose of the systemic agent. Topical timolol reduces IOP in patients treated with lower doses of the oral -adrenergic antagonists (e.g., propranolol, 10–80 mg/day).88 However, there is little additional reduction in IOP when topical timolol is administered to patients treated with larger doses of the systemic drugs (e.g., propranolol, 160 mg/day, or oral timolol, 20 mg/day).89 A recent study confirmed the reduced efficacy of timolol in patients taking systemic -blocking agents for hypertension, possibly because the systemic -blocker has already blocked most of the receptors and the topical agent can only block a few more.90 If the use of topical -blockers are being considered in this situation, a one-eye trial would be indicated to assess the effect of adding the topical agent, although the effectiveness in one-eye trials has been called into question especially with the use of -blocking agents as they have contralateral effects.91

Timolol (and probably all the other -adrenergic antagonists) can be affected by other drugs. For example, cimetidine, a histamine H2 antagonist causes an increase in -blockade when used concomitantly with topical timolol.92 Quinidine retards the metabolism of-blockers and thus enhances their action.93

Timolol hemihydrate

Timolol hemihydrate (Betimol®, Ciba Vision, Duluth, GA) is a recently introduced new salt of timolol. Its clinical effectiveness and side effects are similar to those of timolol maleate.94 The major advantage of this formulation seems to lie in its cost, which may be less than Timoptic but usually more than generic timolol maleate. Timolol hemihydrate is available in 0.25% and 0.5% solutions for use once or twice daily.59

Betaxolol

Betaxolol (Betoptic, Alcon Laboratories, Fort Worth, TX) is a relatively selective 1-adrenergic antagonist that lacks intrinsic sympathomimetic activity and membrane-stabilizing properties (see Table 25-1). It is puzzling why a 1-adrenergic antagonist

should lower IOP because the receptors in the ciliary epithelium are thought to be 2 in type.32,34 The most likely explana-

tion is that betaxolol reaches the ciliary epithelium in sufficient concentration to inhibit 2 receptors. Other possible explanations include the presence of 1 receptors in the ciliary body or a nonadrenergic effect of betaxolol on IOP.95 Betaxolol is supplied

either in a 0.5% solution or a 0.25% microsuspension for adminis­ tration every 12 hours. The drug reduces IOP95–97 by decreasing

aqueous humor formation.16 Betaxalol is effective at reducing IOP and flattening the diurnal curve.98 Although a few studies indicate that betaxolol and timolol are equipotent,99,100 most physicians believe timolol is more effective at lowering IOP.101 The latter impression is supported by experiments indicating that selective-adrenergic antagonists are less effective than are non-selective antagonists in reducing IOP in animal models of ocular hypertension.102 Clinical studies have also supported the slight superiority of timolol to betaxalol.69 Betaxalol has similar IOP-lowering efficacy to dorzolamide.103

Some clinical and animal studies suggest that tachyphylaxis is common with selective -adrenergic antagonists;7 this has not been a major problem with long-term betaxolol treatment, although it does occur to some extent. Betaxolol appears to be additive in its ocular hypotensive effect with the prostanoids, brimonidine, miotics, and the CAIs.104 Because of its relative 1 specificity, betaxolol may not block the effect of epinephrine on aqueous outflow.A few studies suggest that betaxolol and epinephrine are more additive in

their ocular hypotensive effects than are timolol or levobunolol and epinephrine.105,106

Evidence is beginning to accumulate that betaxolol may be more ‘neuroprotective’ than its more non-selective cousins despite

a weaker effect on IOP lowering. Betaxolol seems to reduce the progression of visual field defects compared with timolol107,108

and may even increase retinal sensitivity.109 Betaxolol relaxes the smooth muscle in the walls of retinal microarterioles.110 Using Doppler color imaging of retinal vessels, which is an indirect measure of blood flow, topical betaxolol seems to increase retinal blood flow.111 This appears to be particularly true in patients with normal-pressure glaucoma.112 The clinical significance of these observations remains unknown, but the implication is that some property of betaxolol other than its pressure-lowering effect may improve blood flow and/or nerve function.

Betaxolol is less likely than is timolol to induce 2-adrenergic- mediated bronchial constriction and therefore is a better choice for patients with reactive airway disease.113 It must be emphasized that the -adrenergic specificity of betaxolol is relative, and the drug can induce or exacerbate pulmonary problems in susceptible patients. Some investigators postulate that betaxolol is less likely than is timolol to produce cardiovascular and central nervous system side effects, perhaps because of decreased systemic effectiveness or more rapid metabolism.114 This impression requires further study. Betaxolol is less likely than is timolol to interfere with exercise tolerance.115 Betaxolol in solution form produces more burning and stinging on instillation than does timolol,116 whereas the microsuspension form has an ocular discomfort profile more like timolol.117

Levobetaxolol is the L-isomer of betaxolol which is a mixture of the isomers. Levobetaxolol (Betaxon™, Alcon Laboratories, Ft Worth,TX) is a more potent 1 antagonist than betaxolol or the R-isomer.118 Whether this will make a better clinical agent than betaxolol remains to be demonstrated.

Levobunolol

Levobunolol (Betagan, Allergan, Irvine, Calif ) is a non-selective

1- and 2-adrenergic antagonist that lacks intrinsic sympathomimetic activity and local anesthetic properties.119,120 The drug is

used systemically to treat hypertension, ventricular arrhythmias, and angina. Levobunolol is supplied as either a 0.25% or a 0.5% solu-

tion, which is administered every 12–24 hours.The drug appears to be similar to timolol with regard to both efficacy and safety.121–124

It has been suggested that levobunolol is more likely than timolol to control IOP with once-daily administration.125 However, the two drugs seem to have similar durations of action.126 Levobunolol

produces blepharoconjunctivitis more frequently than does timolol.127,128 The metabolites of levobunolol also appear to have

ocular hypotensive effects.

Carteolol

Carteolol (Ocupress, Otsuka America Pharmaceutical, Inc., Seattle; generics) is a non-selective, -adrenergic antagonist. It is chemically related to timolol, metipranolol, levobunolol, and betaxolol with a potency 10 times that of propranolol; it has partial intrinsic agonist properties toward both 1 and 2 adrenoreceptors but no local anesthetic activity.129 Carteolol is available as a 1% or 2% solution for use every 12 hours; the drug has a significant effect on IOP by 1 hour after administration and reaches its peak effect at about 4 hours after administration.130 Carteolol 1% appears to

produce a pressure-lowering effect similar to that of timolol 0.5% when administered every 12 hours.131,132 Carteolol seemed to

produce fewer local side effects than does timolol.126

Because of its intrinsic sympathomimetic activity, carteolol might be expected to produce fewer cardiovascular side effects, such as bradycardia and systemic hypotension, and perhaps fewer pulmonary effects. Carteolol produced less bradycardia, lowering of blood

pressure, dizziness, and headache and had less of an effect on pulmonary function studies than did topical timolol.126,133 However,

the differences are small and may be of only modest clinical significance. All of these side effects tend to occur more frequently with any of the non-selective -blocking agents in a general population and with longer-term use compared to the carefully selected patients in formal studies.

Recently, a solution of carteolol 1% in alginate solution has been described; because the alginate prolongs the contact time, once-daily dosing seems reasonable. In a 2-month, masked clinical study, carteolol 1% in alginate given once daily in the morning was equivalent to carteolol 1% solution given twice daily.134 Plasma levels of carteolol are lower after prolonged use of the longacting gel formulation used once daily than in the patients using the standard solution twice daily.135

Metipranolol

Metipranolol (Optipranolol®, Bausch & Lomb, Tampa, FL) is a non-selective 1- and 2-adrenergic antagonist with a receptor selectivity similar to that of timolol and levobunolol. After several successful trials in Europe,136 a double-masked, randomized study in the United States showed that metipranolol effectively reduces IOP by suppressing aqueous outflow in ocular hypertensive eyes.137 The agent is similar in most respects to timolol in terms of effectiveness and side effects. It is available in the United States as a 0.3% solution for use twice daily.

Concern about metipranolol developed when several case

reports of granulomatous uveitis appeared in association with its use.138,139 Although uveitis had been reported with the use of other

topical -blockers, the cases involving metipranolol seemed more virulent and occurred with greater frequency. Most of the reported cases seemed to come from Great Britain, where the agent differed from the American variety not only in concentration but also in preservative, pH, and method of sterilization. A subsequent retrospective study in the United States failed to find any evidence

of uveitis associated with the 0.3% solution of metipranolol.140 However, one case report of a patient developing non-granuloma- tous anterior uveitis that reappeared after re-challenge with metipranolol appeared in the literature.141 Subsequent reports have not appeared, suggesting that this is a rare phenomenon in the US.

Metipranolol seems to have a reduced effect on exercise-induced tachycardia compared with timolol in healthy volunteers.142 Based on this study, it may be inferred that metipranolol could have fewer systemic cardiovascular side effects, although this has not been proven in a direct comparison. Metipranolol has achieved some success in the United States because it is less expensive than most of the other brand name -blocking agents.143

Other -adrenergic antagonists

Propranolol

Propranolol (Inderal, Wyeth-Ayerst Laboratory, Philadelphia) is a non-selective -adrenergic antagonist that is used widely for the treatment of a diverse group of medical conditions includ-

ing arrhythmia, angina, hypertension, and migraine. Propranolol lowers IOP when administered topically,144,145 orally,146,147 or intra-

venously.148 The drug has been shown to reduce aqueous humor formation in both monkey and human eyes.149,150 Most physicians

have abandoned propranolol as a treatment for glaucoma because its membrane-stabilizing properties produce corneal anesthesia. Patients who are treated with oral propranolol for a medical condi-

tion such as hypertension generally experience a decrease in IOP, particularly when the dose exceeds 10 mg/day.151,152

Atenolol

Atenolol (Tenormin, Zeneca Pharmaceuticals, Wilmington, DE) is a relatively selective -adrenergic antagonist that lacks intrinsic sympathomimetic activity and membrane-stabilizing properties.

The drug reduces IOP in normal and glaucomatous eyes when administered topically in a 1–4% concentration153–156 or orally in

a dose of 50 mg/day.157 There are a few reports of tachyphylaxis with atenolol treatment.149 While oral atenolol is commonly used to treat systemic hypertension, neither topical nor oral atenolol is in clinical use for glaucoma treatment at this time.

Pindolol

Pindolol is a relatively selective 1-adrenergic antagonist that has some intrinsic sympathomimetic activity but lacks local anesthetic properties. Pindolol reduces IOP when administered orally158 or topically in a 0.25–0.5% concentration.152,159

Nadolol

Nadolol is a non-selective -adrenergic antagonist that lacks intrinsic sympathomimetic activity and membrane-stabilizing properties. Nadolol is two to four times more potent than propranolol. The drug reduces IOP when administered topically in a concentration of 0.3–2%160 or orally in a dose of 20–40 mg.161 A prodrug of nadolol, diacetylnadolol, penetrates the eye more rapidly than does the parent compound and is only a little less effective than 0.5% timolol in reducing IOP.162 Like atenolol, nadolol has not yet become available for ophthalmic use in the United States.