ADRENERGIC ANTAGONISTS

The introduction of topical beta-blockers in the late 1970s transformed the medical management of glaucoma. Although topical agents prior to this time effectively lowered intraocular pressure (IOP), they carried significant ocular morbidity. Practitioners often had to moderate their desire to protect the optic nerve from chronically elevated IOP by the recognition that miotics would cause blurring of the patient’s vision, and epinephrine often created an intolerably injected eye. In contrast, topically applied beta-blockers profoundly affected IOP while avoiding these side effects. Although the systemic worries of oral beta-blockers used to treat hypertension, angina, and arrhythmias were well appreciated, these side effects were initially considered unlikely to occur following eyedrops.

Over the past 20 years, topical beta-blockers have become the most widely prescribed class of glaucoma medication. Our enthusiasm for their use is tempered only by our heightened awareness that they can be systemically absorbed in amounts sufficient to cause serious pulmonary, cardiac, and perhaps metabolic effects in certain patients. These systemic adverse effects of topical beta-blockers have driven the research and development of new, topically applied classes of drugs. In clinical trials, the efficacy of these newer drugs is still compared with that of beta-blockers.

BACKGROUND

The identification of the adrenoceptors and the development of drugs to stimulate and block these membranebound proteins stand as milestones in the evolution of pharmacology. Alquist first clearly elucidated the pharmacological actions mediated by the two adrenoceptors, alpha and beta, in 1948.1 Propranolol became the first pure beta-antagonist to be used clinically, and it remains

the prototype for this class of drug.2 Although initially indicated for treating tachyarrhythmias, it has since been approved for hypertension, angina, migraine, and essential tremors. In 1967, Phillips and coworkers first reported that intravenous propranolol lowered IOP,3 and 1 year later, other investigators demonstrated that topically applied propranolol produced a similar result.4

Unfortunately, topical propranolol has membranestabilizing, or local anesthetic, effects on the eye, which prevented its clinical use.5 Another systemic beta-blocker, practolol, produced an immune-mediated oculomucocutaneous syndrome that could lead to corneal scarring and perforation6 Other beta-blockers were tried and abandoned. Finally, the nonselective beta-antagonist timolol showed no serious ocular toxicity and then became available for widespread clinical appraisal in 1978.7

It became apparent that beta-receptors consisted of at least two, and maybe three, subtypes.8 Beta1-receptors are found primarily in the heart, and their stimulation leads to an increase in heart rate and contractility. Beta2-receptors reside in a variety of tissues including the muscles of the uterus, blood vessels, and large airways. Stimulation of beta2-receptors in blood vessels and bronchi causes dilation of these structures; blockade of the receptors causes constriction. Beta3-receptors may be involved in some of the metabolic effects of adrenergic agonists and antagonists such as in the modulation of lipoproteins. To avert unwanted pulmonary beta2 blockade with nonselective agents, the relatively selective beta1 antagonist, betaxolol, was introduced commercially in 1985.9 Interestingly, betaxolol produces a significant IOPlowering effect despite the observation that 75 to 90% of the beta-receptors found in the eye (ciliary epithelium and ciliary body blood vessels) are of the beta2 subtype.10 This raises the question of how selective and nonselective beta-blockers lower IOP.

MECHANISM OF ACTION

PHARMACOLOGY

Beta-blockers lower IOP by suppressing the formation of aqueous humor.7 There is little evidence that they have any significant effect on aqueous outflow. The physiology of aqueous formation is imperfectly understood but seems to involve a combination of ultrafiltration and active secretion by the ciliary epithelium (Chapter 3). Basic research on tissues rich in beta-receptors, such as heart and bronchial smooth muscle,8 provides a detailed explanation of the cellular events involved in beta-recep- tor receptor activation and blockade.

Binding of an agonist molecule to a beta-receptor stimulates a regulatory protein (G protein) to activate adenylate cyclase. This enzyme catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP), which acts as a “second messenger” to trigger a cascade of biochemical events. In the ciliary epithelium, cAMP is believed to regulate the ion channels and enzymes involved in the secretion of aqueous humor.11 In contrast, beta-blockers cause a decrease in cAMP levels, a decrease in aqueous production, and a drop in IOP. However, the standard beta-receptor model does not entirely explain how beta-blockers affect IOP.

For adrenergic receptor blockers to have any effect at all on the eye presumes the existence of an adrenergic “tone.” Although the source of the endogenous catecholamines is unknown, they may be bloodborne as well as released from sympathetic neurons terminating in the ciliary body.12 Beta2-receptors exist in the ciliary blood vessels. Blockade of these receptors might result in unopposed alpha-receptor–mediated constriction and reduced blood delivery to the ciliary body and epithelium. This could lead to a reduction in the capillary perfusion pressure and a decrease in ultrafiltration and aqueous formation.13

Many have suggested that a simple effect on cAMP levels does not explain the receptor-mediated response to beta-blockers. Adrenergic agonists increase cAMP levels and aqueous production via a beta-receptor mechanism, but alpha-receptor stimulation should decrease aqueous inflow and enhance trabecular and uveoscleral outflow. Thus, the net effect of epinephrine will be a decrease in IOP.14 However, direct stimulators of cAMP production, such as forskolin and cholera toxin, actually lower IOP by reducing aqueous production.15 Even more difficult to reconcile is the observation that the IOP-lowering effect of timolol is the same whether the low-affinity dextroisomer or high-affinity levoisomer is used.16 A truly receptor-mediated event should show a difference in potency of several orders of magnitude between these stereoisomers.

Finally, it is unknown why a beta1-selective antagonist, such as betaxolol, should lower IOP if the receptors responsible for mediating aqueous production are of the

CHAPTER 33 ADRENERGIC ANTAGONISTS • 375

beta2 subtype. It may be as simple as recognizing that betaxolol is only relatively selective for beta1-receptors, and the high concentrations present in the eye following a drop of 0.25 or 0.5% betaxolol will also block beta2- receptors to some extent. This could also explain why the effect of betaxolol on IOP is generally less than the nonselective beta-blockers. It is also possible that neither betaxolol nor the nonselective agents lower IOP by blocking the beta-receptor receptor/cAMP mechanism. Polansky and colleagues have provided evidence that betablockers interfere with chloride conductance.17 Yu and others have reported that beta-blockers can act directly as calcium channel blockers, without involving the betareceptor receptor at all.18

EFFICACY

In the United States, there are increasing numbers of proprietary and generic beta-blocker preparations, based on five active compounds: timolol, betaxolol, levobunolol, metipranolol, and carteolol (Fig. 33–1). The peak effect depends largely on the active, or medicinal, component of the preparation. The nonmedicinal ingredients, such as salts, buffers, surfactants, and preservatives, may influence the ocular and systemic absorption, tolerability, and duration of action. Timolol maleate, the first topical beta-blocker available, remains highly popular and provides a measuring stick for the newer beta-blockers as well as medications from other classes.

Prior to timolol, medical management of chronic glaucomas consisted of direct adrenergic agonists, direct and indirect cholinergic agonists, and oral carbonic anhydrase inhibitors. Early trials demonstrated that timolol lowered IOP better than either pilocarpine19 or epinephrine.20 None of the newer beta-blockers appear to be more effective in reducing IOP than timolol. A medium-duration study showed equivalent peak effects for the alpha2 agonist apraclonidine 0.5% t.i.d. and timolol 0.5% b.i.d.,21 whereas a longer comparison between timolol 0.5% and brimonidine 0.2%, another alpha2 agonist, both dosed b.i.d., demonstrated no significant difference.22 There have been a number of clinical trials comparing the prostaglandin analog latanoprost 0.005% to timolol 0.5%. Some indicate an equal IOP-lowering efficacy,23,24 although another showed that the prostaglandin analog was slightly more effective.25 Dorzolamide, a topical carbonic anhydrase inhibitor, and betaxolol have similar efficacies26 whereas, on average, timolol lowers IOP more than dorzolamide.

Several new agents have been approved for use in glaucoma over the past several years. In general, timolols efficacy is comparable to the newer selective alpha-adrenergic agonists. On the other hand, the prostaglandin analogs usually produce greater lowering of IOP than timolol. Specific details of comparative efficacy of these compounds with timolol are discussed in Chapters 32 and 35.

376 • SECTION V MEDICAL THERAPY OF GLAUCOMA

A

B

C

D

E

FIGURE 33–1 Beta-adrenergic antagonists used for treating glaucoma. (A) Timolol. (B) Betaxolol. (C) Levobunolol.

(D) Metipranolol. (E) Carteolol.

Timolol is available in either 0.25 or 0.5% strengths. Although both concentrations produce the same peak IOP-lowering effect,27 their trough effect may differ, depending on the ocular pigmentation. It seems that melanin readily binds timolol and may become a slow release depot for the drug.28 Thus patients with dark irides may need a higher concentration of timolol than those

with less pigment to achieve the same response. This reasoning has led many clinicians to favor the higher drug concentration, except in patients with relative contraindications to the use of beta-blockers, such as mild asthma or borderline bradycardia. If beta-blockers are deemed necessary for children, the 0.25% concentration is preferable.

Many investigators have debated the necessity of using any of the beta-blockers more frequently than once a day.14 Most product monographs recommend and declare FDA approval for twice-daily administration. Timolol is also available in an anionic heteropolysaccharide gellan gum, which prolongs the residence time of the drug in the tear film (Chapter 31).29 Clinical trials have shown that this product, given once a day, has an efficacy equivalent to twice-a-day timolol maleate.30,31 However, several clinical studies demonstrate that timolol maleate solutions (0.25 or 0.5%) used once every 24 hours are as efficacious as when used twice daily.27,32 Even though the serum half-life of absorbed topical beta-blockers may only be several hours (betaxolol is the longest at 12 to 20 hours28), the ocular availablity of the drug is prolonged due to the melanin binding previously noted. This depot storage phenomenon may, in part, explain the observation that at least 2 weeks is needed to entirely “wash out” the effects of timolol maleate after the drug is stopped.33

C O N T R O V E R S Y

Patients with well-controlled IOPs and early to moderate disc damage, with or without visual field defects, may be able to reduce the frequency of their beta-blocker drops from twice to once daily. Assessments 24 hours after dosing are recommended to ensure IOP control.

In most patients, beta-blockers will reduce IOP by 20 to 40%. However, this effect will diminish in some patients following either short-term or long-term use. A partial loss of effect within the first few weeks of use, known as “shortterm escape,”34 usually produces IOP levels 25% less than the pretreatment IOP. It is believed that an upregulation of beta-receptor numbers accounts for this phenomenon.35 Diminished effectiveness of beta-blockers over a longer period of months to years is known as “long-term drift.”36 A receptor, or intracellular, alteration likely underlies this effect. Clinical fluorophotometry studies have demonstrated that aqueous inflow after a year of timolol use is higher than what it was after the first week.37

Many patients use systemic beta-blockers for hypertension or heart disease. Although these oral agents can also lower IOP, this effect is usually much less than from the approved topical agents, suggesting that even high serum levels deliver only limited amounts of drug to the ciliary epithelium.

CHAPTER 33 ADRENERGIC ANTAGONISTS • 377

effects, some potentially life-threatening, can occasionally lead to discontinuance of these drugs.

OCULAR SIDE EFFECTS

Compared with their predecessors, topical beta-blockers have a very favorable ocular tolerability. However, some users do note transient stinging and burning, most commonly with betaxolol hydrochloride 0.5% solution. This has led to the development of the better-tolerated 0.25% suspension, Betoptic S.39 Metipranolol hydrochloride (Optipranolol) has also caused more burning and stinging than other beta-blockers,40 and several patients in England were reported to develop a granulomatous uveitis with an early preparation of this product.41 Carteolol hydrochloride (Occupress) may be the most comfortable beta-blocker following instillation.

Other commonly reported symptoms include blurred vision, photophobia, itching, and foreign-body sensations. Objective signs consist of superficial punctate keratitis, keratis sicca, corneal anesthesia, ptosis, and allergic blepharoconjunctivitis. As with any allergic response to topical eye medications, preservatives and ingredients other than the drug itself may be the inciting allergen. All of the beta-blocker preparations presently available in the United States use benzalkonium chloride as the preservative, except Timoptic XE (Merck) which contains benzododecinium bromide. A nonpreserved solution (Merck) is also available in unit-dose containers.

The years following the introduction of topical beta-blockers witnessed an increase in the average duration of time between diagnosis and surgery. Although this is a testament to the efficacy and generally good ocular tolerability of these drops, many surgeons also noted that the success rates for their trabeculectomies declined during this period.42 This prompted speculation that chronic beta-blocker application might cause changes in the conjunctiva that increase the tendency for scarring following filtering surgery. Histopathologic evidence later supported this contention by demonstrating that chronic topical glaucoma medications are associated with an increased cellularity (fibroblasts and lymphocytes) in the conjunctiva.43 It is currently unknown whether the major culprits are beta-blockers, cholinergic agonists, or adrenergic agonists.

SYSTEMIC SIDE EFFECTS

Many patients cannot use topical beta-blockers because of systemic side effects. Approximately 80% of an eyedrop (volume 30 to 80 L) passes through the proximal nasolacrimal ducts to the nasal mucosa and its microvasculature, and is equivalent to an intravenous injection. Eighty percent of one 50 L drop of a 0.5% solution contains 200 g of active ingredient. For an infant weighing 3 or 4 kg, or a full-sized adult with labile asthma, this amount of beta-blocker could be seriously compromising. Because drops are usually instilled in both eyes twice

378 • SECTION V MEDICAL THERAPY OF GLAUCOMA

TABLE 33–2 CONTRAINDICATIONS TO BETA-BLOCKERS

Moderate to severe asthma, or other reactive airway disease Greater than first-degree heart block

Sinus bradycardia (especially in the elderly)

Left-sided heart failure

History of syncopal events

History of life-threatening depression

Brittle insulin-dependent diabetes

Dyslipoproteinemias with history of cardiovascular event

a day, and patients often squeeze more than one drop with each application, it is essential to limit systemic absorption as much as possible. Simple digital nasolacrimal occlusion, or eyelid closure, for 5 minutes can markedly reduce serum concentrations of drugs.44

Beta-receptors exist in organs throughout the body. Nontherapeutic blockade of these receptors can produce adverse pulmonary, cardiovascular, neurological/psychiatric, and metabolic side effects. Table 33–2 outlines some of the contraindications to the use of topical and systemic beta-blockers.

Beta agonists act as bronchodilators in the treatment of asthma. Beta-blockers produce the opposite effect and there are many reported cases of status asthmaticus and death resulting from topical application of these ophthalmic agents.45 The nonselective beta-blockers (timolol, levobunolol, metipranolol, and carteolol) are particularly contraindicated in people with a history of reactive airway diseases, such as asthma, emphysema, and chronic bronchitis. Carteolol, which has intrinsic sympathomimetic activity (ISA), or partial agonist properties, should theoretically be safer than the other agents in this group. However, the literature does not consistently support this assertion.46 Betaxolol is relatively specific for beta1-recep- tors and may be a safe alternative for very mild asthma, but several reports indicate that this drug can compromise breathing in patients with preexisting lung disease.47 A medical specialist should be consulted if betaxolol is required by patients with any pulmonary condition.

Beta1-receptor blockade also reduces heart rate and contractile force. This decreases cardiac output, which partially explains why these drugs lower blood pressure. Excessive reduction in blood pressure can produce cerebral hypoperfusion and syncope, whereas decreased perfusion of the heart can lead to angina, myocardial infarction, and death. Patients with compromised myocardial function can suffer congestive heart failure, heart block, or bradyarrhythmias, and exacerbation of sinus bradycardia.

In addition to decreasing cardiac output, blockade of beta2-receptors can theoretically induce vasospasm by leaving alpha-receptors, which mediate vasoconstriction, free to bind circulating norepinephrine. Blood flow to organs other than the brain is reduced with propranolol.48 This has

generated considerable discussion about the possible effects of beta-blockade on optic nerve head perfusion.49

Blood flow in the short posterior ciliary vessels and capillaries of the proximal optic nerve is extremely difficult to measure clinically, and experimental models to study the pharmacology of beta-blockers do not satisfactorily mimic the human optic disc. Many questions remain about the effects of topically applied drugs on the posterior ocular circulation. For instance, what levels of drug can be achieved in the posterior pole? And, even if beta-blockers do achieve a vasoactive concentration at the optic disc, what are the shortand long-term effects on blood flow and tissue nutrition? Other parts of the body, more readily studied than the optic nerve, show only an initial vasospasm, with no long-lasting increase in vascular resistance.50

Beta-blockers can also affect a patient’s mood. This is not surprising given that depression likely results from down-regulation of neurotransmitter pathways in the central nervous system (CNS), and all classes of antidepressants are believed to work by increasing the availability of catecholamines and serotonin at postsynaptic receptor sites. Beta-blockers may cause a depressed state51 by blocking these receptors, or exacerbate preexisting depression.52 Although depression occurs more frequently with oral beta-blockers than with eyedrops, the latter gain access to the CNS by their lipophilic nature and ready transport across the blood–brain barrier.

PEARL... Depression is common and it frequently coexists with glaucoma. Although the practitioner may attribute a patient’s mood to use of a beta-blocker, a drug holiday of 1 month should be considered before abandoning what may be a very effective IOP-low- ering treatment. Persistent depression should prompt a psychiatric consultation, both for the patient’s well-being and to determine if the beta-blocker can be restarted, along with antidepressant therapy.

Most CNS side effects have been noted with timolol. This may reflect this drug’s highly lipophilic nature, or the greater clinical exposure. Table 33–1 lists other CNS effects attributed to topical beta-blockers in case reports.53 Most of these patients were elderly and were often taking a variety of other medications with potential CNS side effects.

Adrenergic outflow and beta-receptors contribute to the symptomatic and physiological response to hypoglycemia. Blockade of the symptoms and signs of a low blood sugar level could seriously delay the physiological response to an insulin reaction. For this reason, oral beta-blockers are relatively contraindicated when treating cardiovascular disease in diabetics. Similarly, topical ophthalmic agents should be avoided in patients with brittle diabetes.

Systemic beta-blockers can affect lipid metabolism. Similarly, topical timolol can increase serum levels of triglycerides and decrease high-density lipoproteins (HDL) in normal volunteers.54 Systemic beta-blockers are not recommended in patients with a history of dyslipopro- teinemia-related cardiac events. Although carteolol apparently has the least effect on HDLs of the compounds presently available in the United States,55 the clinical significance of this finding is unknown.

CURRENT FORMULATIONS

BETAXOLOL HYDROCHLORIDE

This lipophilic, selective beta1-blocker was originally formulated for its cardioselective properties to minimize the risk of bronchospasm. Until recently, betaxolol was available both as Betoptic, which is no longer available, and Betoptic S (Alcon, Fort Worth, TX), a suspension for increased comfort.

Patients with ocular hypertension and glaucoma experienced 20 to 30% lowering of IOP with Betoptic56,57 and a similar effect with the 0.25% concentration, Betoptic S.39 Neither betaxolol preparation appears to lower IOP as much as timolol, with most studies showing about a 2 mm Hg difference. Despite this, some published evidence shows a better preservation, and even improvement, of visual fields with betaxolol as compared with timolol,58 which some investigators attribute to a beneficial effect on optic disc blood flow. Adding betaxolol does not augment IOP reduction in patients already receiving a topical nonselective beta-blocker.59 However, betaxolol can produce an additive effect if combined with pilocarpine,60 carbonic anhydrase inhibitors,60 epinephrine,59 or dipivefrin.61

CARTEOLOL HYDROCHLORIDE

Carteolol (Ocupress), a relatively hydrophilic, nonselective betablocker solution, seems to lower IOP as well as timolol in patients with open-angle glaucoma,62 and reduces IOP by 14 to 38% in healthy volunteers with normal IOP.63 Few reports elaborate on its additivity to other classes of glaucoma medications, but it appears generally comparable to the other nonselective beta-blockers in this regard. Currently, no studies address its long-term effect on visual fields in patients with glaucoma.

LEVOBUNOLOL HYDROCHLORIDE

Used twice daily, levobunolol (Betagan), a lipophilic, nonselective beta-blocker solution, and timolol provide equally effective long-term IOP control.64 In selected patients, once-daily administration of levobunolol 0.25% may adequately control IOP for 24 hours.65 The prolonged action of this agent probably results from its binding and slow release from ocular melanin, combined with its metabolism to dihydrobunolol, which also has beta-

CHAPTER 33 ADRENERGIC ANTAGONISTS • 379

blocking activity. Levobunolol is as additive to pilocarpine as timolol66 and is minimally additive to dipivefrin, similar to other nonselective beta-blockers.67

METIPRANOLOL

Experience in Britain and mainland Europe with this nonselective, lipophilic beta-blocker solution demonstrated a similar IOP-lowering efficacy to timolol40 and levobunolol.68 The prolonged duration of action of metipranolol is optipranolol attributed to a beta-block- ing metabolite, des-acetyl metipranolol. Most consider its additivity to the other classes of glaucoma medications as similar to timolol and levobunolol.

TIMOLOL MALEATE

This lipophilic, nonselective beta-blocker solution is available in three preparations from the original manufacturer, as well as several recently introduced generic preparations. Aside from Timolol solution, Timolol is available in occudose, a preservative-free formulation. Timolol also is formulated with gellan gum (Gelrite), a surface-activated gel, to prolong ocular contact and improve penetration. This preparation (Timoptic XE) used once daily has the same IOP-lowering efficacy as twice-daily Timoptic solution.30,31 Patients will notice blurring that usually lasts for several minutes after instillation.

TIMOLOL HEMIHYDRATE

The safety and efficacy of timolol hemihydrate 0.5%, a lipophilic, nonselective beta-blocker solution, is comparable to timolol maleate 0.5%.69

GENERIC PREPARATION

An increasing number of generic beta-blocker preparations have appeared on the market. Provided that the active ingredients are the same, these products should produce similar peak effects on IOP. However, the duration of action and tolerability (ocular and systemic) of these new products may differ depending on their nonmedicinal constituents.

COMBINATION PREPARATIONS CONTAINING

BETA-BLOCKERS

A combination preparation of timolol maleate 0.5% and dorzolamide 2% (Cosopt) is now available. One large study shows that Cosopt b.i.d. is comparable to the concomitant use of dorzolamide 2% t.i.d. and timolol 0.5% b.i.d.70 Expected local and systemic side effects should be a composite of both classes of drug.

TimPilo (timolol maleate 0.5% and pilocarpine 2 or 4%) is now available as a twice-daily combination therapy

380 • SECTION V MEDICAL THERAPY OF GLAUCOMA

in Canada and several European countries, its active ingredients mixed with an alkaline buffer to prolong the action of the pilocarpine. As with other combination strategies, the individual drugs will influence the tolerability of this product.

A fixed combination of 0.005% latanoprost and 0.5% Timolol maleate has been compared to each of the drugs separately in glaucoma and ocular hypertensive patients. The fixed combination, admistered once daily, was well tolerated and as effective in lowering IOP as either of the component drugs used separately.71

REFERENCES

1.Ahlquist RP. A study of the adrenotropic receptors. Am J Physiol 1948;153:586.

2.Black JW, Stephenson JS. Pharmacology of a new beta-adrenergic receptor blocking compound. Lancet 1962;2:311.

3.Phillips CI, Howitt G, Rowlands DJ. Propranolol as ocular hypotensive agent. Br J Ophthalmol 1967; 51:222.

4.Bucci MG, Missiroli A, Pecori Giraldi J, Virno M. Local administration of propranolol in the treatment of glaucoma. Boll Oculist 1968;47:51.

5.Musini A, Fabbri B, Bergamaschi M, Mandelli V, Shanks RG. Comparison of the effect of propranolol, lignocaine, and other drugs on normal and raised intraocular pressure in man. Am J Ophthalmol 1971;72:773.

6.Rahi AHS, Chapman CM, Barner A, Wright P. Pathology of practolol-induced ocular toxicity. Br J Ophthalmol 1976;60:312.

7.Yablonski ME, Zimmerman TJ, Waltman SR, Becker B. A fluorophotometric study of the effect of topical timolol on aqueous humor dynamics. Exp Eye Res 1978;27:135.

8.Lefkowitz RJ, Hoffman BB, Taylor P. Neurohumoral transmission: the autonomic and somatic motor nervous systems. In: Goodman LS, Gilman AG, Gilman A, eds. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. New York: Pergamon; 1990.

9.Feghali JG, Kaufman PL. Decreased intraocular pressure in the hypertensive human eye with betax-

olol, beta1-adrenergic antagonist. Am J Ophthalmol 1985;100:777.

10.Nathanson JA. Human ciliary process adrenergic receptor: pharmacological characterization. Invest Ophthalmol Vis Sci 1981;21:798.

11.Caprioli J. The ciliary epithelia and aqueous humor. In: Moses RA, Hart WH Jr, eds. Adler’s Physiology of the Eye: Clinical Application. St Louis: Mosby; 1987.

12.Sears ML, et al. A mechanism for the control of aqueous humor formation. In: Drance SM, Neufeld A,

eds. Applied Pharmacology in the Medical Treatment of Glaucoma. New York: Grune & Stratton; 1984.

13.Watanabe K, Chiou GCY. Mechanism of action of timolol to lower intraocular pressure in rabbits.

Ophthalmic Res 1983;15:160.

14.Epstein DL. Medications used in chronic glaucoma therapy—adrenergic agents: blockers and agonists. In: Epstein DL, Schuman J, Allingham R, eds. Chandler and Grant’s Glaucoma. Baltimore: Williams & Wilkins; 1997.

15.Caprioli J, Sears M, Bausher L, Gregory D, Mead A. Forskolin lowers intraocular pressure by reducing aqueous inflow. Invest Ophthalmol Vis Sci 1984; 25:268.

16.Keates EV, Stone R. The effect of d-timolol on intraocular pressure in patients with ocular hypertension. Am J Ophthalmol 1984;98:73.

17.Polansky JR, Cherskey BD, Alvarado JA. Update on-adrenergic drug therapy. In: Drance SM, Van Buskirk EM, Neufeld AH, eds. Pharmacology of Glaucoma. Baltimore: Williams & Wilkins; 1992.

18.Yu D-Y, et al. Effect of beta-blockers and Ca2+ entry blockers on ocular vessels. In: Drance SM, ed. Vascular Risk Factors and Neuroprotection in Glaucoma: Update 1996. Amsterdam: Kugler; 1997.

19.Boger WP III, Steinert RF, Puliafito CA, PavanLangston D. Clinical trial comparing timolol ophthalmic solution to pilocarpine in open-angle glaucoma. Am J Ophthalmol 1978;86:8.

20.Sonntag JR, Brindley GO, Shields MB, Arafat NI, Phelps CD. Timolol and epinephrine: comparison of efficacy and side effects. Arch Ophthalmol 1979; 97:273.

21.Najasubramanian S, et al. Comparison of apraclonidine and timolol in chronic open angle glaucoma: a three-month study. Ophthalmology 1993; 100:1318.

22.Schuman JS. Clinical experience with brimonidine 0.2% and timolol 0.5% in glaucoma and ocular hypertension. Surv Ophthalmol 1996;41:S27.

23.Alm A, Stjernschantz J, Scandinavian Latanoprost Study Group. Effects on intraocular pressure and side effects of 0.005% latanoprost once daily, evening or morning: a comparison with timolol. Ophthalmology 1995;102:1743.

24.Watson P, Stjernschantz J, UK Latanaprost Study Group. A six-month randomized double-masked study comparing latanoprost to timolol in openangle glaucoma and ocular hypertension. Ophthalmology 1996;103:126.

25.Camras CB, USA Latanoprost Study Group. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma. Ophthalmology 1996;103:1916.

26.Strahlman E, Tipping R, Vogel R, and the International Dorzolamide Study Group. A double-masked,

randomized 1-year study comparing dorzolamide, timolol and betoptic. Arch Ophthalmol 1995;113:1009.

27.Letchinger SL, Frohlichstein D, Glieser DK. Can the concentration of timolol or the frequency of its administration be reduced? Ophthalmology 1993; 100:1259.

28.Juzych MS, Zimmerman TJ. Beta-blockers. In: Zimmerman TJ, ed. Textbook of Ocular Pharmacology. Philadelphia: Lippincott-Raven; 1997.

29.Greaves JL, Wilson CG, Rozier A, Grove J, Plazonnet B. Scintigraphic assessment of an ophthalmic gelling vehicle in man and rabbit. Curr Eye Res 1990;9:415.

30.Timoptic-XE Study Group. Multiclinic, doublemasked study of 0.5% Timoptic-XE once daily versus 0.5% Timoptic twice daily. Ophthalmology 1993;S100:111.

31.Lawrence J, et al. A double-masked, placebocontrolled evaluation of timolol in gel vehicle. J Glaucoma 1993;2:177.

32.Soll DB. Evaluation of timolol in chronic open angle glaucoma: once a day vs twice a week. Arch Ophthalmol 1990;98:2178.

33.Schlect LP, Brubaker RF. The effect of withdrawal of timolol in chronically treated glaucoma patients.

Ophthalmology 1988;95:1215.

34.Boger WI. Short-term “escape” and long-term “drift.” The dissipation effects of the beta-adrener- gic blocking agents. Surv Ophthalmol 1983;28:235.

35.Neufeld AH, Zawistowski KA, Page ED, Bromberg BB. Influences on the density of beta-adrenergic receptors in the cornea and iris–ciliary body of the rabbit. Invest Ophthalmol Vis Sci 1978;17:1069.

36.Steinert RF, Thomas JV, Boger WP. Long-term drift and continued efficacy after multiyear timolol therapy. Arch Ophthalmol 1981;99:100.

37.Brubaker RF, Nagataki S, Bourne WM. Effect of chronically administered timolol on aqueous humor flow in patients with glaucoma. Ophthalmology 1982; 89:280.

38.Zimmerman TJ, Kass MA, Yablonski ME, Becker B. Timolol maleate: efficacy and safety. Arch Ophthalmol 1979;97:656.

39.Weinreb RN, Caldwell DR, Goode SM, et al. A dou- ble-masked three-month comparison between 0.25% betaxolol suspension and 0.5% betaxolol ophthalmic solution. Am J Ophthalmol 1990;110:189.

40.Mills KB, Wright G. A blind randomized cross-over trial comparing metipranolol 0.3% with timolol 0.25% in open-angle glaucoma: a pilot study. Br J Ophthalmol 1986;70:39.

41.Akingbehin T, Villada JR. Metipranolol-associated granulomatous anterior uveitis. Br J Ophthalmol 1991;75:519.

42.Watson PG. When to operate in open-angle glaucoma. Eye 1987;1:51.

CHAPTER 33 ADRENERGIC ANTAGONISTS • 381

43.Broadway DC, Grierson I, O’Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication, II: the outcome of filtration surgery. Arch Ophthalmol 1994;112:1446.

44.Zimmerman TJ, Kooner KS, Kandarakis AS, Ziegler LP. Improving the therapeutic index of topically applied ocular drugs. Arch Ophthalmol 1984;102: 551.

45.Van Buskirk EM, Fraunfelder FT. Ocular betablockers and systemic effects. Am J Ophthalmol 1984; 98:623.

46.Hugues FC, Le Jeunne C, Munera Y. Systemic effects of topical antiglaucomatous drugs. Glaucoma 1992; 14:100.

47.Harris LS, Greenstein SH, Bloom AF. Respiratory difficulties with betaxolol. Am J Ophthalmol 1986; 101:274.

48.Nies AS, Evans GH, Shand DG. Regional hemodynamic effects of beta-adrenergic blockade with propranolol in the unanesthetized primate. Am Heart J 1973;85:97.

49.Drance SM , ed. Vascular Risk Factors and Neuroprotection in Glaucoma: Update 1996. Amsterdam: Kugler; 1997.

50.Mimran A, Ducailar G. Systemic and regional haemodynamic profile of diuretics and alphaand beta-blockers: a review comparing acute and chronic effects. Drugs 1988;35:60.

51.McMahon CD, Shaffer RN, Hoskins HD Jr. Hetherington J Jr. Adverse effects experienced by patients taking timolol. Am J Ophthalmol 1979;88:736.

52.Duch S, Duch C, Pasto L, Ferrer P. Changes in depressive status associated with topical beta-block- ers. Int Ophthalmol 1992;16:331.

53.Fraunfelder, FT. Sexual dysfunction secondary to topical ophthalmic timolol. JAMA 1985;253:3092.

54.Coleman AL, Diehl DL, Jampel HD, Bachorik PS, Quigley HA. Topical timolol decreases plasma highdensity lipoprotein cholesterol level. Arch Ophthalmol 1990;108:1260.

55.Freedman SF, et al. Effects of ocular carteolol and timolol on plasma high-density lipoproteins cholesterol level. Am J Ophthalmol 1994;116:600.

56.Berry DP, Van Buskirk EM, Shields MB. Betaxolol and timolol: a comparison of efficacy and side effects. Arch Ophthalmol 1984;102:42.

57.Stewart RH, Kimbrough RL, Ward RL. Betaxolol vs timolol: a six-month double blind comparison. Arch Ophthalmol 1986;104:46.

58.Messmer C, Flammer J, Stumpfig D. Influence of betaxolol and timolol on the visual fields of patients with glaucoma. Am J Ophthalmol 1991; 112:678.

59.Allen RC, Epstein DL. Additive effects of epinephrine to betaxolol and timolol, in primary open-angle glaucoma. Arch Ophthalmol 1986;104:1178.

382 • SECTION V MEDICAL THERAPY OF GLAUCOMA

60.Smith JP, Weeks RH, Newland EF, Ward RL. Betaxolol and acetazolamide: combined ocular hypotensive effect. Arch Ophthalmol 1984;102:1794.

61.Weinreb RN, Ritch R, Kushner FH. Effect of adding betaxolol to dipivefrin therapy. Am J Ophthalmol 1986;101:196.

62.Stewart WC, Shields MB, Allen RC, et al. A 3- month comparison of 1% and 2% carteolol and 0.5% timolol in open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 1991;229:258.

63.Negishi C, Kanai A, Nakajima A, et al. Ocular effects of beta-blocking agent carteolol on healthy volunteers and glaucoma patients. Jpn J Ophthalmol 1981; 25:464.

64.The Levobunolol Study Group. Levobunolol: a fouryear study of efficacy and safety in glaucoma treatment. Ophthalmology 1989;96:642.

65.Silverstone D, Zimmerman T, Choplin N, et al. Evaluation of once-daily levobunolol 0.25% and timolol 0.25% therapy for increased intraocular pressure. Am J Ophthalmol 1991;112:56.

66.David R, Ober M, Masi R, et al. Treatment of elevated intraocular pressure with concurrent lev-

obunolol and pilocarpine. Can J Ophthalmol 1987; 22:208.

67.Allen R, et al. Efficacy and safety of levobunolol compared with timolol in combination with dipivefrin in glaucoma. Invest Ophthalmol Vis Sci 1986;27:181.

68.Kriegelstein GK, Novack GD, Voepel E, et al. Levobunolol and metipranolol: comparative ocular hypotensive efficacy, safety, and comfort. Br J Ophthalmol 1987;71:250.

69.Mundorf TK, Cate EA, Sine CS, Otero DW, Stewart JA, Stewart WC. The safety and efficacy of switching timolol maleate 0.5% solution to timolol hemihydrate 0.5% solution given twice daily. J Ocul Pharmacol Ther 1998;14:129.

70.Strohmaier K, Snyder E, DuBiner H, Adamsons I, the Dorzolamide-Timolol Study Group. The efficacy and safety of the dorzolamide-timolol combination versus the concomitant administration of its components. Ophthalmology 1998;105:1936.

71.Higginbotham EJ, Feldman R, Stiles M, Dubiner H. Latanoprost and timolol combination therapy vs. monotherapy: one-year randomized trial. Arch Ophthalmol 2002;120:915.