Pharmacology of Ocular Beta-Adrenoceptor Antagonists
GARY D. NOVACK, IRVING H. LEOPOLD and EFRAIM DUZMAN
Table Of Contents
ROLE OF BETA-BLOCKERS IN OPHTHALMIC PRACTICE|
NONSELECTIVE BETA-BLOCKING AGENTS
NEWER BETA-ADRENOCEPTOR ANTAGONISTS
SELECTIVE BETA1 -ANTAGONISTS
SELECTIVE BETA2 -ANTAGONISTS
|ROLE OF BETA-BLOCKERS IN OPHTHALMIC PRACTICE|
|Prior to the introduction of topical ß-adrenoceptor antagonists to ophthalmology, the most commonly used topical
meditations in the treatment of glaucoma were pilocarpine and epinephrine. These
two classic medications have been used for more than 75 years. The
introduction of the ß-adrenoceptor antagonists completely changed the drug preference in glaucoma
The sites for receptor interaction of these drugs are suggested to be ß-adrenergic receptors or in the iris and ciliary body. The pharmacologic properties of these drugs are referred to as ß-adrenoceptor antagonism. In the jargon of the clinician, the drugs are called beta-blockers.
The important role the ß-blockers assumed in the treatment of glaucoma has generated a large number of animal and clinical studies designed to evaluate various aspects of these drugs. The biological principles of ocular ß-adrenergic blocking agents were reviewed by Mishima,1 and the clinical effects have been reviewed by others.2,3 The focus of the majority of the studies have been on aqueous fluid dynamics and intraocular pressure (IOP), but other functions of the eye have also been explored.
Unlike pilocarpine, the yeoman of glaucoma treatment for the last 100 years, ß-blockers generally do not contract the pupil and thus do not interfere with vision even in patients with central lens opacities.4 They also do not cause spasm of the ciliary muscle, which produces transient myopia and disturbance of accommodation.4
The animal model used most frequently for exploration of the topical ocular activity of ß-blockers has been the rabbit. This is due to the large eyes of the rabbit relative to body weight, and the ease of handling these animals. However, the cat and the monkey have also been studied. Differences among species have been legion. For example, topical ß-antagonists elicit only minimal ocular hypotension in rabbits, in contrast to their great efficacy in humans. This may be because the rabbit has a relatively low sympathetic tone, and inhibition of it by a ß-blocker has relatively little effect.5 In contrast, ß-adrenoceptor antagonists demonstrate good activity in suppressing isoproterenol-induced ocular hypotension in rabbits.6 Even though ß-blockers are clinically and physiologically important in the treatment of glaucoma, their sites and mechanisms of action in the eye are still subjects of controversy. A full picture of the role of ß-antagonists in the eye has yet to emerge.
|Propranolol is the prototype of drugs that can antagonize ß-adrenoceptors. The interaction of most ß-blockers with the receptor is competitive and reversible. The potency
of the drug in the cardiovascular system is not always indicative of the
ocular effect. For example, pindolol, one of the most potent systemic ß-blockers, requires topical ocular concentrations of 1% or greater to show
efficacy in reducing IOP.7 In some cases, pharmacokinetic characteristics such as corneal permeability
may limit their pharmacodynamic effect in the eye.|
Some of these drugs have partial agonist effects (intrinsic sympathomimetic activity; ISA)8 and some have quinidine-like actions (membrane-stabilizing property). The maximum agonist response obtainable with ß-blockers possessing ISA is lower than that seen with epinephrine and isoproterenol, although the blockers possess high affinity for the receptor site.9 The agents are most effective antagonists when circulating or local concentrations of endogenous catecholamines are relatively high. The quinidine-like effect may produce an anesthetic response in the cornea when ß-blockers are applied topically into the conjunctival sac. No correlation exists between membrane-stabilizing effect and ß -blocking activity.10,11
D-Propranolol and L-propranolol have equal local anesthetic effect but the l -isomer is up to 100 times more active in blocking adrenoceptors than the dextrorotatory.12 In contrast, the membrane-stabilizing effect is not dose dependent. The ability to antagonize ß-adrenoceptors generally resides in the levorotatory form.
ß-blockers are classified as relatively selective or nonselective with respect to their actions at ß1- and ß2-adrenoceptor subtypes. Some drugs can block both ß1- and ß2-receptor activity (nonselective); others predominantly or almost exclusively block only one of the two types at low concentrations (selective; Table 1). The relative selectivity for either ß1 or ß2 is not absolute; at high doses, all ß-adrenoceptors can be antagonized (inhibited).
ß-blockers have varying degrees of protein-binding capacity and lipid solubility. Some undergo high first-pass metabolism in the liver (e.g., propranolol); some have active metabolites; and some are excreted principally by the kidney (e.g., atenolol). Pharmacologic half-life and bioavailability vary according to the physicochemical properties of the compound as well as patient variables (age, disease, interaction with other drugs, and so on).
However, differences in potency, ß-receptor subtype selectivity, metabolism, passage through the blood-brain barrier, direct effects on membranes, and degrees of intrinsic sympathomimetic activity may be the deciding factors in clinical utility.13,14 The suitability of various ß-blockers for topical ophthalmic use in the treatment of glaucoma varies in relationship to their ocular hypotensive efficacy (Table 2) and ocular and systemic safety.
* COAG, chronic open-angle glaucoma; OHT, ocular hypertension
† Duration of effect could not be calculated because more than one drop was administered.
§ Mean decreases in IOP were reported rather than mean percent decreases. Since baseline IOP values were not given, percent decreases could not be calculated. The maximum mean decreases in IOP were 11.3 mm Hg for 2% nadolol, 7.2 mm Hg for 1% pindolol, and 4.1 mm Hg for 10% practolol.
(Some of the subjects in this study had hemorrhagic or congenital glaucoma.
As of 1987, three topical ß-adrenoceptor antagonists are available for general use in the United States—timolol, betaxolol, and levobunolol. However, other ß-blockers, such as atenolol, metoprolol, nadolol, pindolol, and propranolol, are used systemically for mild and moderate hypertension, angina, and arrhythmias in doses that are known to reduce IOP. Topically applied ß-blockers can produce bradycardia and, less rarely, systemic hypotension. Some cause bronchospasms in asthmatics and patients with chronic obstructive pulmonary disease. Others produce corneal anesthesia, dry eyes, ocular irritation, and hyperemia.
The ocular ß-adrenoceptor is presumed by some to have properties that differentiate it from the cardiopulmonary, systemic ß-adrenoceptor. On the basis of biochemical and pharmacologic studies in animals and humans, appear to be ß2-adrenoceptors such as found in blood vessels and in the pulmonary system.15–21 How, then, do agents with relative ß1-adrenoceptor selectivity lower IOP? From animal studies, Chiou and colleagues concluded that the reduction of aqueous humor formation by timolol may be related to a reduction of blood flow to the ciliary body.22,23 It is also possible that agents with relative ß-andrenoceptor selectivity may be effective because the concentration required to achieve intraocular ß-blockade is much lower than the concentration present in the anterior chamber.24 The aqueous humor levels achieved in humans after topical timolol instillation are 1 μM to 2 μM.25,26
The concentration of betaxolol required for in vitro blockade of systemic ß1-adrenoceptors is 1 nM to 10 nM, and for ß2-adrenoceptors, 600 nM.27 Assuming a similar aqueous humor concentration for timolol and betaxolol, ocular ß2-blockade may still be expected to occur with a topical application of betaxolol.
Even though it is generally believed that the L-isomer is the effective agent, some 17 years ago, intravenous D-propranolol was reported effective in lowering elevated IOP in patients. However, D-propranolol was much less potent than D,L-propranolol.29 More recently, topical 1% D-timolol was reported effective in patients with elevated IOP.30 In biochemical animal studies, ocular ß-adrenoceptors had similar affinities for both L- and D-isomers.31 This is in contrast to cardiovascular ß-adrenoceptors, where L-isomers are typically 10 to 100-fold more potent than D-isomers.32 The effect of various optical isomers of befunolol on aqueous humor dynamics was investigated by Araie and Takase. They found 0.5% L-befunolol and 1.0% D,L-befunolol similar in their reduction of aqueous flow, whereas 0.5% D-befunolol was without effect.33 Rabbit studies with topical D- and L-timolol suggest a potency ratio of 1: 10, in favor of L-timolol.31 Similarly, pulmonary safety studies in human volunteers suggest a similar potency ratio for topically applied isomers of timolol.34 The importance of optical isomers in drug therapy has been emphasized by many,32,35,36 and clearly further research is needed to evaluate whether D-ß-blockers could improve the therapeutic index of glaucoma drugs.
|NONSELECTIVE BETA-BLOCKING AGENTS|
Propranolol was the first ß-blocking agent to be used in clinical therapeutics and has become the standard against which other ß-blocking drugs are measured. A potent agent with membrane-stabilizing effects, but without any ISA, the synthetic drug is a standard treatment for systemic hypertension and cardiac arrhythmias. Both oral propranolol and topical propranolol lower IOP in humans.29,37–45 However, use of topical propranolol in the treatment of glaucoma is limited because of its membrane-Stabilizing effect, which results in corneal anesthesia and ocular irritation.46 The mechanism of action of propranolol by which IOP is lowered is still uncertain. Although propranolol has been reported to depress aqueous humor formation,47 it has also been credited with increasing facility of outflow.48,49 Other reports have suggested that propranolol decreases facility of out-flow.47,50
Introduced for clinical use in the United States in 1978, topical timolol maleate (Timoptic, Timoptol) has been rapidly adopted as a standard treatment for open-angle glaucoma. Timolol is also useful in many cases of secondary glaucoma, aphakic glaucoma, and ocular hypertension.51–54 Orally, timolol is 5 to 10 times more potent than propranolol and is relatively devoid of ISA and local anesthetic properties.55,56 The attraction of timolol lies in its long-term efficacy in the treatment of various types of glaucoma, the low incidence of ocular side-effects, and relatively long duration of action (12–24 hours), which allows for only once-daily or twice-daily application.
Topical ocular administration of 0.25% to 0.5% timolol maleate results in lowering of IOP in normal and glaucomatous eyes.57–63 Topical timolol is effective in reducing IOP 20% to 30% compared with pretreatment values.60,64 The maximum ocular hypotensive effect of timolol is reached with the dose range of 0.3% to 0.5%.58 Given twice daily for up to one year, timolol keeps pressures down throughout the day.65 Timolol is routinely used twice daily, although there are several re ports of its efficacy on a once-daily regimen.66,67 Oral timolol (20 mg twice daily) has also proved effective in reducing iop in patients with open-angle glaucoma.68 Topically applied timolol is not metabolized in the eye, at least in rabbits and monkeys,69 but undergoes extensive hepatic elimination once it reaches the systemic circulation.70
As noted above, the effect of timolol in animals is dissimilar to that in humans.71 The doses of timolol required to lower IOP in the cat are relatively large,71 and the ocular hypotensive action of timolol in the rabbit has been obscured by conflicting reports.60,72,73 The ocular hypotensive effect of timolol in humans is equal to or greater than that of pilocarpine,60,74–76 and is also greater than that of epinephrine.77 Timolol may be somewhat less effective than acetazolamide, according to some reports.78,79
In controlled short-term and long-term studies, 0.5% timolol does not appear significantly more effective than 0.25% timolol.80–83 Timolol can usually further reduce IOP when added to parasympathomimetic agents, as well as carbonic anhydrase inhibitors. Combined treatment with timolol and acetazolamide can reduce IOP more than with either alone.78,79 Treatment with timolol plus pilocarpine also produces a reduction of IOP greater than that with each agent alone.84
Additivity of Timolol and Adrenergic Agonists
There are conflicting reports in the literature regarding the additivity of timolol and an adrenergic agonist such as epinephrine (E) or dipivefrin (DPE). The classic systemic pharmacologist would state that timolol is a ß1 and ß2-adrenoceptor antagonist, and that E is an α1-, α2-, ß-, and adrenoceptor agonist. Therefore, only antagonism would occur at the ß-adrenoceptor. The ocular adrenoceptor might be stimulated. Because stimulation of an α -adrenoceptor by an agent such as phenylephrine was reported to have only minimal effects on aqueous humor dynamics,85 one would wonder why an ophthalmologist might combine timolol and E or DPE in the treatment of glaucoma.
One explanation for this apparent paradox is that α2-adrenoceptor stimulation might be responsible for some ocular hypotension. Second, the ocular adrenoceptors may have subtle differences from the systemic adrenoceptors, at least in the rabbit. Third, although timolol may act through a mechanism unrelated to ß-blockade, this is clearly not the simplest explanation (again, see above). In dynamic studies of aqueous humor, using fluorophotometry, timolol was found to reduce aqueous flow either in single or multiple instillations.86–88 Timolol is without significant effect on outflow facility, uveoscleral flow, or episcleral venous pressure.78,87,89 Thus, it is clear that timolol is an inflow drug.
Timolol may be less effective at night, when there is less endogenous E to antagonize.90 The aqueous humor dynamics of the addition of E to timolol, or vice versa, were evaluated by Schenker and co-workers in a fluorophotometric study in 16 patients.87 Ocular hypertensive patients were given timolol for one week, to which E was added, or vice versa. They found mutual additivity of E and timolol on IOP. Both decreased aqueous humor production and enhanced outflow facility were observed in the presence of both timolol and E. In a similarly designed clinical study in 16 patients, Thomas and Epstein found additivity on the ocular hypotensive effects of E and timolol.91,92 Interestingly, they found the regimen of timolol added to E more effective than E added to timolol. However, this differential effect lasted for only 4 weeks, and at 12 weeks the order of addition was not critical in efficacy. The latter study found that the enhanced outflow affects of E were affected by timolol.92
The mechanism of the ocular hypotensive and outflow-enhancing effects of E remain controversial. Topical isoproterenol, a ß1-/ß2-adrenoceptor agonist, lowered IOP in normals without affecting aqueous flow.93 This suggests that the IOP lowering of ß-adrenoceptor agonists is due to enhanced outflow.
Recently, Allen and Epstein reported that the hypotensive effect of E was greater when added to betaxolol than to timolol.94 The combination of E and timolol was equivalent to the combination of E and betaxolol. The tonographic effect of E, however, was alleviated by timolol, but not by betaxolol. The mechanism for these observations could be simply a lower potency of ß-blockade and lower efficacy of betaxolol used by itself. It also suggests that ß-adrenoceptors may be involved in the outflow effects of E. In vivo work in monkeys by Kaufman suggests a role for α1- or α2-receptors, rather than ß2-receptors, in increasing outflow.15
Some clinical studies report additivity of timolol and E84,95–97 but others do not.77,98,99 Addition of timolol to a maximal drug treatment program to control refractory glaucoma resulted in a lowering of IOP in only a minority of patients.75,100 Topical timolol produces a further reduction of IOP when given to patients already receiving oral ß-blockers for systemic hypertension.101 Thus, there is evidence for additivity of timolol and several agents, but therapy must be individualized.
Timolol is not associated with change in pupil size, pupillary reaction, accommodation, or visual acuity, and patient tolerance in most instances is excellent.102 The absence of alteration in pupil size, accommodation, or refractive error avoids many of the unpleasant and sometimes intolerable visual effects seen with many other agents (e.g., pilocarpine).
Timolol is thought to reduce IOP by suppressing aqueous humor formation in the ciliary body.87,103–105 Neufeld has postulated that timolol can act on secretion or ultrafiltration, or on both, but could not confirm an ocular vasoconstrictor action of timolol experimentally.72
Most patients with primary open-angle glaucoma respond initially to timolol. But both short-term “escape” and long-term “drift” have been reported for timolol.74,106 Short-term escape refers to an acute partial loss of therapeutic effect on IOP during the first few days of timolol treatment. A possible explanation is the finding in animal studies that the number of ß-receptors in ocular tissue increases within days of the initiation of timolol treatment.107 This suggests a decreased efficacy of timolol, due to decreased “substrate” for ß-blocker interaction. Other patients show a slow upward trend in IOP after months of therapy: long-term drift. The ocular hypotensive efficacy of timolol may decrease by up to 25% with long-term treatment.74 Calissendorff and Maren observed a greater degree of tolerance in patients with glaucoma than in patients with ocular hypertension over the course of year-long timolol treatment.108 In a large, well-controlled, two-year study of 400 patients, fewer than 10% of patients per year lost control with timolol or levobunolol as sole antiglaucoma medication.109 The apparent discrepancy between these studies and clinical anecdotal experience of tolerance might be due to difference in disease severity. Any decrease in apparent efficacy of an agent may be a true decreased efficacy or increased disease severity.
Timolol has been used systemically in humans in the United States for many years for the treatment of hypertension, angina, and other cardiovascular disorders.110 Topically applied timolol is tolerated relatively well.3,111
Lin and associates112 followed 145 patients for 24 months and found no significant adverse clinical reactions attributable to timolol in any patient. This is substantially different from other studies and anecdotal clinical experience. Zimmerman and colleagues3 reported adverse reactions in 23% of patients in a study lasting 14 months and designed to track adverse effects.
The most frequently reported ocular side-effects are mild bunting and stinging when the drug is applied. Allergic blepharoconjunctivitis, conjunctival hyperemia, superficial punctate keratitis, and blurred vision can also occur.3,113 Allergy to topical ß-blockers, as evidenced by blepharoconjunctivitis, occurs in some patients after long-term use of timolol. Similar reactions have also been reported to occur after nadolol,114 levobunolol,115 and metoprolol.116 Cross-reactivity among ß-blockers is not complete,116 suggesting that hypersensitivity is related to chemical structure, not to conformation of ß-blockers per se. Thus, as more topical ß-blockers become available for general use, patients developing intolerance to one ß-blocker may be switched to an alternate one. Decreased tear production in glaucoma patients was also reported but was not deemed dangerous unless the eye had abnormally low lacrimal secretion.117 In patients with normal tear secretion, timolol decreased tear break-up time, but this did not occur with all beta-blockers.118 Slowing of the heart rate is a common systemic finding in clinical studies with topical timolol.64,74,119 Bradycardia, other cardiac arrhythmias, and syncope can also occur. Timolol may exacerbate preexisting asthmatic conditions113,120 and also cause impotence and decreased libido. Headaches, fatigue, dizziness, weakness, anxiety, hallucinations, and depression are central nervous system (CNS) complaints reported with timolol use.3,54,113
The issue of compliance is frequently discussed,121 especially in the use of topical glaucoma drugs.122 In a study using compliance monitors, compliance of four-times-daily pilocarpine123–127 and twice-daily timolol128 is about 75% of total dose. However, extended periods without meditation were found. Several studies report increased efficacy when adding or switching a new ß-blocker for timolol.129,130 However, one must be concerned that an improved compliance with drug regimen occurs at the time the patient gets involved in a clinical trial. This improvement may partially explain the improved therapeutic effect.129,131 In a progressive disease, it is difficult to separate the worsening of disease from a diminution in efficacy of the medications.
Glaucoma is a disease characterized by progressive loss of visual field over many years. Efficacy of a new ß-blocker is generally assessed by its ocular hypotensive effects, since decreasing iop is assumed to prevent visual field loss. IOP has the advantage of being a single-dimensional, “objective” measurement. It also is acutely responsive in that it may be changed by a new treatment within hours.
True efficacy of any glaucoma treatment demands the long-term preservation of visual fields. In contrast to E,132,133 few data exist on the long-term effect of timolol on visual fields. In a preliminary report after 2 years of study, Palmer and coworkers reported timolol treatment in 27 ocular hypertensives more effective than no treatment in 32 patients.134 In a 2-year evaluation of levobunolol and timolol in 400 patients, no significant field progression was reported with either drug.109 In two recent abstracts, Crick and colleagues and Sponsel and associates, have reported long-term (up to 4 years) treatment with timolol more effective in preservation of visual field than pilocarpine, although both had similar effects on IOP.135,136 Also in a recent abstract, Alexander and co-workers reported timolol to be more effective than E on iop or visual field parameters, or both, over a 1- to 2-year treatment period.137 Flammer and associates138 evaluated timolol and pindolol in a 6-month study using automated perimetry. They found a 0.5-dB (2%) improvement with pindolol and a similar worsening with timolol.138 One must use caution in comparing various studies because the study populations may not be similar with respect to visual field status at entry.
The effect of acute ocular hypotensive therapy on visual field performance has been investigated by several researchers. Holmin and Krakau evaluated the acute effects of timolol and vehicle in a crossover study of 15 glaucomatous patients using the COMPETER.139 Following placebo instillation, visual field performance decreased by 7.8 P-units, compared with a decrease of 12.3 P-units with timolol. In a similar study, Drance and Flammer evaluated the acute effects of timolol and vehicle in 28 eyes of glaucoma suspects using a special OCTOPUS central 30°-threshold, automated-perimetric test.140 They found a decrease in retinal sensitivity with timolol (0.7-dB decrease) in contrast to 0.1-dB decrease with vehicle. That ß-blockers may have direct or reflexive actions on vasculature has lead some researchers to correlate this with vasopathology in glaucoma patients.141 Interestingly, topical timolol increases choroidal blood flow in cats,142 retinal blood flow in normal humans,143 and has no effect in rabbits.
On the average, the plasma level of timolol after topical application of 0.5% timolol is approximately 1 ng/ml.144–147 The ß-blocker plasma level after 0.5% levobunolol is reported to be less than this (0.21 ng/ml);148 after arotinolol 0.5%, similar or slightly higher (2.9 ng/ml);149 and after befunolol 1% significantly higher (40 ng/ml).150 Betaxolol may have very low blood levels after topical instillation.151 Plasma levels of topical timolol can be higher in newborns (up to 20 ng/ml)146 and lower when punctal occlusion or eyelid closure is utilized after instillation (0.4 ng/ml).147 One can assume that such absorption-limiting techniques would result in lower systemic absorption of other topical ß-blockers as well.
Topically instilled ß-blockers lower IOP not only in the treated eye, but also in the fellow eye up to 30% to 40% of the ipsilateral response, as has been reported for timolol,152 levobunolol153 carteolol,154 bupranolol,155 and metoprolol.156 In rabbits, the level of timolol in aqueous humor contralateral to treatment, 19.5 μg/ml, although less than ipsilateral, 328 μg/ml,26 is more than that required for adenylate cyclase inhibition, 0.8 μg/ ml.16 This study indicates that when treating one eye of a rabbit with 0.5% timolol, sufficient timolol is delivered to the contralateral eye to have a direct effect. Shin reports on the clinical utility of monocular ß-blocker treatment in seven patients.
|NEWER BETA-ADRENOCEPTOR ANTAGONISTS|
|Since the introduction of timolol, many new topically administered ß-blockers
have been evaluated for the treatment of glaucoma. As timolol
has become the standard, the objective of most of the research has
been to compare efficacy and ocular and systemic safety of these new
agents to timolol. To the practicing ophthalmologist with many years
of experience with timolol, some reticence may be appropriate prior to
utilizing one of the newer agents with less clinical exposure. However, the
quality and size of the clinical studies in which equivalency of
the new agent has been compared to timolol vary greatly. As has been
pointed out elsewhere in a review of clinical studies on new agents by
one of us,2 only a few of the published efficacy studies on newer agents are of sufficient
size to prove similar efficacy to timolol on a long-term basis.|
Betaxolol,158 levobunolol,88 carteolol,159 and metipranolol160 have also been reported to decrease aqueous humor production. Similar to timolol, levobunolol has been reported to have no effect on uveoscleral flow, outflow facility, or episcleral venous pressure.88 Carteolol has no effect on total outflow facility.161 Whether all new beta-blockers are similar to timolol in solely affecting aqueous humor production must be determined through research using both fluorophotometry and outflow measurements.162,163
Levobunolol, an analogue of propranolol, is 45 times more potent than propranolol when given orally, and about sixfold higher in potency when given intravenously. This may be related to the activity of its metabolite.164 Levobunolol does not exhibit intrinsic sympathomimetic activity or significant local anesthetic effects, and is equipotent at ß1- and ß2-adrenoceptor sites.165 The pharmacology of levobunolol was recently reviewed.165 Levobunolol can reduce IOP 30% to 44% for longer than 12 hours.114,166 Additionally, the major ocular and systemic metabolite of levobunolol, dihydrolevobunolol, has a plasma half-life of 7 hours.167,168 Dihydrolevobunolol has been reported to be similar in ß-blocker potency and efficacy in several systems. Given intravenously to dogs, dihydrolevobunolol is equipotent and equieffective to levobunolol in blockade of isoproterenol-induced tachycardia.164 In vitro, dihydrolevobunolol is similar tin potency to levobunolol in competition for ß-blocker sites in rat lung.27 Ocularly, dihydrolevobunolol is an effective antagonist of isoproterenol-induced ocular hypotension in rabbits.169 In human iris ciliary body tissue, the affinity of the ß-adrenoceptor for dihydrolevobunolol and levobunolol is 6.7 nM and 3.9 nM, respectively, which is similar to that for timolol.21 As with timolol, levobunolol is well tolerated by patients. Given twice daily, levobunolol is as effective as timolol for long-term use, and it does not reduce pupil size or significantly reduce tear production or corneal sensitivity.78,109 Tolerance does not appear to develop to the drug.109 In one report, both levobunolol and timolol were reported effective when given once daily, with levobunolol slightly more efficacious.170 In humans, orally administered levobunolol has successfully been used to treat systemic hypertension, cardiac arrhythmias, and angina.
NADOLOL, OXPRENOLOL, PINDOLOL, BUPRANOLOL, CARTEOLOL, AND METIPRANOLOL
Nadolol (Corgard), used clinically to treat angina and hypertension, is a nonselective ß-blocker with no local anesthetic properties and a ß-blocking potency equivalent to propranolol. However, its markedly fewer direct myocardial depressant effects are clinically appealing. The unique pharmacologic aspect of nadolol is that it is not metabolized; it is primarily excreted unchanged by the kidney.171 Nadolol significantly reduced IOP in glaucomatous patients.172–175 The reduction was maximal at 4 hours and endured 6 to 24 hours. Blood pressure, pulse rate, and pupil diameter were not significantly affected. However, with long-term use, nadolol appears to be a less effective ocular hypotensive agent than timolol.175 Diacetyl nadolol, a lipophilic prodrug analog able to penetrate the corneal epithelium ten times better than nadolol, has been tested. A 2% preparation was able to decrease IOP to an extent comparable to 0.5% timolol during the first 8 hours following topical administration.114,176 Oxprenolol has an intrinsic sympathomimetic activity and a membrane-stabilizing effect. Administration of a 1% solution in glaucomatous eyes produced a maximum drop in ocular pressure of 28%. The decrease was most pronounced at the second and third hours, and a complete recovery occurred 6 to 12 hours later.43 Although the drug was well tolerated, a transient and slight hyperemia and some miosis were reported. Oxprenolol does not trigger tachycardia, the limiting side-effect of isoproterenol. Topical oxprenolol also can apparently lead to corneal epitheliopathy.177
Pindolol has a slight intrinsic adrenergic activity but no local anesthetic action at clinically useful levels. It has only one-third the antiarrhythmic property of propranolol.7 Instilled into the conjunctival sac of normal and glaucomatous eyes, the drug produced a significant drop in IOP.7 With prolonged treatment, an increase in facility of outflow apparently appeared. No effect on either pupil motility or corneal sensitivity was detectable. Smith and co-workers178 reported that pindolol lowered IOP in both treated and untreated eyes with only minimal reduction in resting pupil diameter and light reflex response. The authors reported a decrease in resting heart rate and a reduction in exercise tachycardia after topical administration. Pindolol 0.25% administered topically twice daily to eyes of patients with open-angle glaucoma was able to control IOP as effectively as timolol 0.5% twice daily.149
Bupranolol is available for general use in Germany. It is chemically related to propranolol, with a stronger potency to block ß-receptor sites.118 Topical application of a 0.5% solution significantly lowered IOP in glaucomatous eyes.118 The maximum effect (68%) occurred within 4 hours and lasted longer than 24 hours. No significant effect on outflow facility, blood pressure, or tear flow was detectable. However, bupranolol produced local anesthesia in the eye, and tachyphylaxis could be a problem.118
Carteolol has relatively strong intrinsic sympathomimetic activity. It displays a feeble local anesthetic effect and causes dose-dependent changes in cardiac function.179 Kitazawa and colleagues154,180 reported a maximum 23% drop in IOP in human glaucomatous eyes that lasted for 8 hours. Heart rate is affected with this drug. Carteolol has been reported to be less discomforting than timolol.181
Metipranolol, a ß1-/ß2-adrenoceptor antagonist,182 has been used extensively in Europe. The proceedings of a symposium on its ophthalmic use have been published.183 Metipranolol appears similar to timolol or levobunolol in efficacy studies of up to 3 months' treatment.184–186 However, ocular comfort appears to be a concern with this drug.185,187 Levomoprolol, of similar pharmacology, has been reported effective in glaucoma patients.188
|SELECTIVE BETA1 -ANTAGONISTS|
ATENOLOL, BETAXOLOL, AND METOPROLOL
Atenolol, a ß2 -blocker with no sympathomimetic or membrane-stabilizing activity, is currently used clinically for the treatment of mild to moderate systemic hypertension. Topical ocular application of atenolol as 1%, 2%, and 4% drops reduced IOP in patients with ocular hypertension.187–191 However, atenolol's ocular effect is relatively short-lived: four to six times daily instillation may be necessary for a 24-hour control of IOP.192 In this regard, its ocular duration of action is shorter than its oral, antihypertensive action, where once-daily oral therapy is the standard. A single oral 50-mg dose of atenolol decreases IOP in patients with ocular hypertension, open-angle glaucoma, and chronic angle-closure glaucoma.193 However, long-term drift and short-term escape have been reported for atenolol.194–196 Atenolol was ineffective in lowering IOP in cats.71
Betaxolol, which has no sympathomimetic or membrane-stabilizing activity, reduced IOP in glaucomatous eyes when applied topically in 0.25% to 0.5% solution.197–199 In several studies betaxolol has been reported similar to timolol in efficacy,200–202 although others report it to be less effective.203 The reduction in IOP was submaximal in eyes treated with a 0.125% solution.204 The major appeal of betaxolol to the ophthalmologist is its relative lack of systemic ß2-adrenergic blockade. In several controlled pulmonary safety studies,205,206 betaxolol has been reported to be indistinguishable from placebo in its effects on pulmonary function, in contrast to timolol. However, reports of adverse pulmonary effects in clinical use of betaxolol suggest its selectivity on ß1-adrenoceptors is not absolute.207
Metoprolol, a relatively selective ß1-antagonist that possesses no partial ß-receptor agonist activity or membrane-stabilizing properties, is used clinically to treat mild to moderate systemic hypertension. Topically administered metoprolol can effectively reduce IOP.156,173,208–213 Patients with ocular hypertension or glaucoma treated with 3% metoprolol for 4 months were able to maintain IOPs between 23% and 30% below pretreatment values.208 Metoprolol has been reported to be comparable to pilocarpine (2%–4%)214 and timolol (0.5%)211–213 in reducing IOP. However, other studies have found metoprolol to be less effective than timolol in reducing IOP.208,209 Oral metoprolol has also been shown to be capable of reducing IOP.208,209 Topical metoprolol has been reported to cause allergic reactions.116
Practolol, although effective in reducing IOP,215 is not used clinically because of its serious side-effects. These side-effects led to the removal of practolol as a therapy for systemic hypertension. An oculomucocutaneous syndrome occurred in a small percentage (less than 5%) of patients treated with practolol.216–218 The reaction can include painful dry eye with subconjunctival fibrosis, conjunctival shrinkage, and in some instances corneal opacification and ulceration. Other symptoms are psoriasiform skin rash, conduction deafness, and a polyserositis that may involve the peritoneum, pleura, or pericardium and may lead to intestinal obstruction secondary to sclerosing peritonitis. Of importance is the fact that this reaction to practolol is not elicited by other ß-blockers. Patients in whom skin and conjunctival changes developed with practolol were able to take oxprenolol or propranolol without recurrence of these adverse effects.218
|SELECTIVE BETA2 -ANTAGONISTS|
|Two relatively selective ß2 -antagonists, H 35/25 and IPS 339, lowered IOP in cats71 and rabbits,17 respectively. Because the predominant ß-receptor in the ciliary body is of the ß2-subtype, evaluations of the clinical efficacy of such agents would be quite interesting.|
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