Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

in the management of glaucoma and ocular hypertension because the former are the most effective ocular hypotensive agents available. Moreover, latanoprost has other advantages over β-blockers, including the lack of systemic side effects. Unlike β-blockers, latanoprost reduces IOP as effectively during the night as during the day. The efficacy, convenience of once-daily dosing, rare allergic reactions, ocular tolerability, and systemic safety of latanoprost have permitted this drug to take its place as firstor second-line therapy for many types of glaucoma.

Latanoprost should be dosed only once daily in the evening or at bedtime because twice-daily instillation offers less satisfactory control of IOP. Once-daily dosing offers patient convenience and improves compliance.The drug is well tolerated and provides adequate control of IOP for at least several years in patients with open-angle glaucoma or ocular hypertension. There is no evidence that long-term treatment leads to drug tolerance, with subsequent loss of IOP control. In addition to its efficacy in the treatment of primary open-angle glaucoma and ocular hypertension, latanoprost may significantly reduce IOP in patients with glaucoma associated with SturgeWeber syndrome. Latanoprost can be more effective than β-blockers in reducing IOP in patients with pigmentary glaucoma. Perhaps because of its effect on uveoscleral outflow, latanoprost can often produce a significant IOP reduction in patients with normal-tension glaucoma, but most eyes on latanoprost monotherapy may not achieve a 30% reduction of IOP. In patients with normal-tension glaucoma, latanoprost seems to be more effective at higher IOP levels. Most patients with pediatric glaucomas have little IOP reductions with latanoprost therapy, but some children, particularly older children and those with juvenile-onset open-angle glaucoma, can have a significant ocular hypertensive effect from the drug.

In addition to its efficacy when used alone as monotherapy, latanoprost can have additive effects when used in conjunction with most other ocular hypotensive medications.This additivity can be explained on the basis of the unique mechanism of action of latanoprost. Because latanoprost reduces IOP by increasing uveoscleral outflow, the drug is useful in combination with both aqueous suppressants and drugs that enhance aqueous outflow through the conventional trabecular meshwork pathway. The additive ocular hypotensive effects achieved with the combination of latanoprost and timolol are greater than when brimonidine, dorzolamide, or pilocarpine is used with timolol. The ocular hypotensive effect of latanoprost is also additive to that achieved with miotics, and pilocarpine seems to be most effective when the bedtime dose is administered 1 hour after administration of latanoprost. In addition to its effects when added to individual ocular hypotensive agents, latanoprost may provide a significant further reduction of IOP in patients already receiving maximal tolerated medical therapy and thus may be capable of delaying surgery in some patients.

Many clinicians tend to add additional medications in the management of patients who are inadequately controlled with ocular hypotensive monotherapy. Recent studies, however,have suggested that patients can be switched from timolol monotherapy to latanoprost monotherapy, which often further reduces IOP by 8% to 25%. The additional ocular hypotensive effect of switching from timolol to latanoprost can be equivalent to that of adding dorzolamide to timolol. Thus, to facilitate patient compliance and reduce medication cost, clinicians should consider switching to latanoprost monotherapy, or another prostaglandin analogue, before attempting combination drug treatment in patients whose IOP is inadequately controlled by β-blockers.

Latanoprost (Xalatan) is commercially formulated as an aqueous solution in a concentration of 0.005% preserved with 0.02% benzalkonium chloride (BAC). The recommended dosage of latanoprost is one drop daily in the evening, which permits better diurnal IOP control than does morning instillation. Refrigeration of the bottle is suggested for patients who use the medication in only one eye. Refrigeration is unnecessary for treatment of both eyes, because the bottle should be depleted within the medication’s 6-week shelf-life.

Side Effects

Reported side effects of latanoprost are listed in Box 10-2. Perhaps the most unique of these is darkening of iris color, which occurs in approximately 5% to 20% of patients and can develop as early as 4 weeks, but usually several months, after initiation of latanoprost therapy. Only mixed-colored irides have the tendency to demonstrate the increased pigmentation, in which the iris becomes uniformly darker (Figure 10-2).These irides are typically green-brown or blue/gray-brown, where the brown is distributed around the pupil. Over time, the brown pigmentation spreads peripherally, giving the iris a more uniformly darker coloration. Irides with a uniform blue, gray, green, or brown color do not appear to be susceptible. Moreover, preexisting iris freckles or nevi do not change shape or color during treatment. The change in eye color appears to be permanent after

Box 10-2 Side Effects of Latanoprost

Iris color darkening

Increased eyelid pigmentation

Hypertrichosis

Conjunctival hyperemia

Allergy

Cystoid macular edema

Anterior uveitis

Punctate corneal erosions

Corneal pseudodendrites

latanoprost treatment is discontinued. Both in vivo studies in monkeys and in vitro studies on cultured human iridial melanocytes have shown that the increased pigmentation is caused by an increase of melanin within the iridial melanocytes and is not caused by proliferation of melanocytes. In some eyes that have latanoprostinduced darkening of iris color, a relative ocular sympathetic insufficiency has been demonstrated. It may be possible that the sympathetic nervous system acts through prostaglandins to maintain iris color, and the administration of latanoprost may thus substitute for deficient sympathetic innervation to stimulate melanogenesis.

An increase in pigmentation of eyelid skin is also possible. This increased skin pigmentation can occur several months after latanoprost therapy is begun. Once the drug is discontinued, the drug-induced pigmentary changes usually subside.

PGF2a analogues, including latanoprost, bind to cell surface receptors that activate phospholipase C, initiating a variety of cellular responses, including stimulation of cell division and growth. Altered growth patterns can be induced by latanoprost and are manifested as abnormal growth of hair follicles. This phenomenon is known as hypertrichosis. The condition is evident clinically by observation of an increased number, length, thickness, curvature, or darkening of the eyelashes (Figure 10-3). Because the condition can be subtle, it is most evident in patients who receive unilateral latanoprost therapy. Evidence of hypertrichosis can be seen within several weeks after initiation of latanoprost treatment, and the condition can occur in whites, blacks, Asians, and Hispanics. It is most obvious, however, in patients who have brown or black hair. In addition to the presence of elongated or thickened eyelashes, some patients have a striking curling of the lashes, and other patients demonstrate growth of lash-like hair in areas adjacent to the normal eyelash distribution. Although hypertrichosis is benign, it can represent a cosmetic concern for some patients, especially in cases induced by unilateral latanoprost treatment.

Latanoprost can produce a mild, usually clinically insignificant, conjunctival hyperemia in approximately one-third of treated patients. This may represent a cosmetic problem for some patients, thereby leading to noncompliance with therapy. Although relatively rare, some patients develop an allergic reaction or irritation to latanoprost, necessitating discontinuation of the drug. Allergic reactions are probably more common in patients who have had previous allergic reactions and are treated with multiple glaucoma medications.

Numerous cases have been reported in which latanoprost therapy has been associated with the development of cystoid macular edema (CME). Considering the role that prostaglandins play in the pathogenesis of CME, it may be reasonable to assume that topically applied latanoprost can increase the risk of CME. However, latanoprost itself is not known to be vasoactive or to affect vascular permeability. Furthermore, pharmacokinetic studies have failed to demonstrate significant levels of latanoprost in the posterior segment of the eye after topical application. Indeed, controlled clinical studies

Figure 10-3 Eyelashes of left eye are darker and denser than those of right eye 28 weeks after latanoprost treatment was begun. (Adapted from Wand M. Latanoprost and hyperpigmentation of eyelashes. Arch Ophthalmol 1997;115: 1206–1208.)

have shown than latanoprost may enhance disruption of the blood–retinal barrier, but the increased incidence of angiographically documented CME formation in early postoperative pseudophakias is low and most likely clinically insignificant. Other studies have suggested that the BAC preservative rather than the active prostaglandin may be causative factors.

Similar to CME, a number of cases have been reported alleging an association between latanoprost therapy and the development of anterior uveitis. Although prostaglandins play an important role in the development of vascular permeability associated with uveitis, disruption of the blood–aqueous barrier associated with latanoprost can be small, transient, and sometimes reversible despite continued latanoprost therapy.

Punctate epithelial corneal erosions have occurred in patients using latanoprost. This epithelial keratopathy is sporadic and mild, and the condition may be associated more with the BAC preservative than with the latanoprost itself.

The development of latanoprost-induced corneal dendritiform epitheliopathy has been reported. These lesions resemble those of herpes simplex virus epithelial keratitis, but, in contrast to herpes simplex virus disease, the pseudodendrites associated with latanoprost promptly disappear on discontinuation of drug therapy. Coincident with discontinuation of latanoprost, patients can be treated with preservative-free artificial tears with or without topical antibiotics.

Several cases have been reported in which herpes simplex virus keratitis developed after initiation of latanoprost therapy. Although these cases are anecdotal, it is known that prostaglandins may play a crucial role in mediating inflammatory events that could incite herpetic infection.

Latanoprost appears to be devoid of any systemic side effects. In contrast to β-blockers, latanoprost has no significant effects on the cardiovascular system or pulmonary system.

Contraindications

Latanoprost may be relatively contraindicated in patients with a history of uveitis or prior incisional ocular surgery. Likewise, the drug may be contraindicated in patients who have had previous episodes of herpes simplex virus keratitis. Latanoprost should be used cautiously after cataract surgery in patients who have risk factors favoring the development of CME.These include a history of CME, epiretinal membrane formation, vitreous loss during cataract surgery, history of macular edema associated with branch retinal vein occlusion, history of anterior uveitis, and diabetes mellitus. It is also wise to advise patients that unilateral treatment can result in heterochromia or hypertrichosis that may become cosmetically objectionable. Unlike β-blockers, latanoprost is not contraindicated in patients with concomitant bronchial asthma because the drug is not

associated with bronchoconstriction or deterioration of asthma.

Travoprost (Travatan)

Pharmacology

Travoprost is a PGF2a analogue used for treatment of patients with open-angle glaucoma or ocular hypertension. Its mechanism of action is similar to that of latanoprost. When instilled topically into the human eye, travoprost, a prodrug, is converted by corneal esterases into travoprost acid, which exerts its biologic activity at the FP receptor on the ciliary muscle.The result is enhanced uveoscleral outflow. Clinical studies indicate that the 0.004% solution provides the maximum ocular hypotensive effect with an acceptable safety profile. Travoprost 0.004% provides excellent diurnal IOP control throughout a 24-hour period, reducing IOP from 6.8 to 8.3 mm Hg over the diurnal IOP cycle. Both morning and evening dosing regimens produce significant IOP reductions 24 hours after dosing, and morning and evening dosing schedules appear to be equally effective. As has been shown with latanoprost, twice-daily dosing of travoprost does not appear to have greater ocular hypotensive efficacy compared with once-daily dosing.

Clinical Uses

Travoprost is indicated for the treatment of elevated IOP in patients with open-angle glaucoma and ocular hypertension.The drug is formulated as an aqueous solution in a concentration of 0.004% preserved with 0.015% BAC. The recommended dosage is one drop daily in the evening.

Both in vitro and in vivo studies of corneal epithelial cells have demonstrated the potential for toxicity to BAC. The implication is that chronic use of BAC-containing glaucoma medications has the potential to cause or exacerbate ocular surface disease.This research has led to the development of a BAC-free prostaglandin analogue for the treatment of glaucoma. Travoprost (Travatan Z) is formulated with a unique ionic buffered compound consisting of zinc, sorbitol, and borate (sofZia), which has the preservative and antimicrobial properties of BAC but without its associated toxic effects.

A 3-month study demonstrated identical IOP lowering efficacy between travoprost 0.004% with and without BAC in patients with open-angle glaucoma or ocular hypertension. In a double-masked multicenter study, patients were randomized to either travoprost 0.004% with BAC or travoprost 0.004% without BAC dosed oncedaily in the evening. Mean IOP reductions ranged from 7.3 to 8.5 mm Hg for travoprost 0.004% without BAC and from 7.4 to 8.4 mm Hg for travoprost 0.004% with BAC. Adverse events were comparable between the two treatment groups. In one study conjunctival hyperemia occurred in slightly fewer patients treated with travoprost 0.004% without BAC than in patients treated with

144 CHAPTER 10 Ocular Hypotensive Drugs

travoprost 0.004% with BAC.The difference in hyperemia might suggest that in some patients BAC may be contributing to the hyperemic response.

Side Effects

Safety assessments in travoprost studies have included evaluation of visual acuity, pupil diameter, iris color, anterior chamber flare, conjunctival hyperemia, pulse, blood pressure, blood chemistry profiles, and urinalysis values. The observed adverse events have generally been mild to moderate and have resolved without treatment. Most of the side effects seen with latanoprost can occur with travoprost treatment. Conjunctival hyperemia induced by travoprost is clinically insignificant but generally more than that observed with latanoprost.

Contraindications

The contraindications to travoprost are the same as for latanoprost.

Bimatoprost (Lumigan)

Pharmacology

Bimatoprost is generally considered to be part of the prostaglandin family of ocular hypotensive analogues. Studies sponsored by the manufacturer, however, imply that bimatoprost differs sufficiently in both structure and function from other prostaglandin compounds to warrant a new class of ocular hypotensive agents, called prostamides. Prostamides are members of the fatty acid amide family. Bimatoprost is a synthetic analogue that mimics the actions of prostamides, effectively reducing IOP. Controversy exists over this drug’s mechanism of action. Early studies suggested that bimatoprost works at novel prostamide-sensitive receptors. Pharmacokinetic studies indicated that bimatoprost does not act through any known prostanoid receptor,including the FP receptor. More recent studies, however, indicate that bimatoprost, like latanoprost and travoprost, does exhibit properties of a prodrug and has weak activity at the FP receptor.

Tonographic facility of outflow has been shown to increase by 35% in bimatoprost-treated eyes relative to placebo-treated eyes. This result suggests that bimatoprost increases outflow through the trabecular-mesh- work outflow pathway. From the changes in the measured parameters (IOP, aqueous inflow, and facility of outflow), the drug was calculated to cause a 50% increase in uveoscleral outflow. Thus, the ocular hypotensive action of bimatoprost is believed to be due to a dual mechanism of increasing aqueous outflow through both the pressure-sensitive (trabecular) and pressure-insensi- tive (uveoscleral) pathways.

Clinical Uses

Bimatoprost is formulated as a 0.03% solution in citrate/phosphate buffer, pH range 6.8 to 7.8.The concentration of preservative (BAC) is low (0.005%) and thus

may be tolerated by some BAC-sensitive patients. The drug is indicated as primary therapy for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension. Recommended dosage is one drop once daily in the evening.

Bimatoprost dosed once daily provides lower mean IOP than does timolol used twice daily. The mean IOP is consistently 2 to 3 mm Hg lower in patients receiving bimatoprost compared with timolol. During the 6-month pivotal clinical studies, the mean IOP reduction from baseline at 10 AM was 8.1 mm Hg (33%) with bimatoprost used once daily versus 5.6 mm Hg (23%) with timolol 0.5% twice daily. Of the bimatoprosttreated patients, 45% achieved IOP reductions of at least 35% from baseline compared with 21% of timolol-treated patients.

A 12-week, randomized, multicenter study was conducted to compare the ocular hypotensive efficacy and safety of latanoprost 0.005%, travoprost 0.004%, and bimatoprost 0.03% in patients with open-angle glaucoma or ocular hypertension. Medication was dosed once daily in the evening. At the end of 12 weeks each prostaglandin analogue was comparable in its ability to reduce IOP (Figure 10-4). However, fewer patients treated with latanoprost reported ocular adverse events, and those treated with bimatoprost encountered greater conjunctival hyperemia. In other head-to-head comparison studies bimatoprost has been shown to have a slightly greater ocular hypotensive effects that either latanoprost or travoprost.

Side Effects

Similar to latanoprost and travoprost, bimatoprost has been reported to cause changes to pigmented tissues. These reports include pigmentation of the iris and periorbital tissue (eyelid). These changes may be permanent. The long-term effects on the melanocytes and the consequences of potential injury to the melanocytes and/or deposition of pigment granules to other areas of the eye are unknown.

Conjunctival hyperemia is the most frequent side effect associated with bimatoprost therapy and generally occurs more often than in patients treated with travoprost or latanoprost. Most occurrences, however, are mild. For most patients the hyperemia occurs within 6 weeks of initiating treatment. However, hyperemia can be seen as early as within 24 hours for some patients. The severity of hyperemia often diminishes over time and is not associated with ocular surface or intraocular inflammation. The only other frequent side effect (reported in more than 10% of patients) is eye pruritus.

Systemic adverse events reported in approximately 10% of patients are infections (primarily colds and upper respiratory tract infections). Systemic adverse events reported in approximately 1% to 5% of patients include headaches, asthenia, and hirsutism.

Contraindications

The contraindications to bimatoprost are the same as for latanoprost.

PROSTAGLANDIN COMBINATION COMPOUNDS

It is recognized that many patients treated for glaucoma require a second concomitant medication to lower IOP. The appeal of a combination product stems from the belief that adherence to complex multiple medical regimens is improved with simplified dosing schedules. The two most common ocular hypotensive medications are in the prostaglandin and β-blocker classes. Several combination products are presently available worldwide that combine various prostaglandin analogues with a nonselective β-blocker.These products include a combination of latanoprost or travoprost with timolol. Studies have demonstrated comparable efficacy and in the case of the travoprost–timolol combination, a favorable IOP reduction between the combination product and the separate compounds administered concomitantly. At the present time, neither combination product is available in the United States.

b-ADRENERGIC ANTAGONISTS

The potential ocular hypotensive effects of β-adrenoceptor antagonists (β-blockers) were first evaluated in the 1970s. This section highlights five agents currently marketed in the United States: timolol, levobunolol, betaxolol, metipranolol, and carteolol (Table 10-1).

Timolol

Pharmacology

Timolol is a noncardioselective β-blocker without intrinsic sympathomimetic activity (ISA). Antagonism of the β2-adrenoceptor at the ciliary body is primarily responsible for the ocular hypotensive efficacy of timolol.

Given topically to individuals with elevated IOP, timolol induces a significant and long-lasting ocular hypotension. Mean decreases in IOP are approximately 25%, and the maximal efficacy of 0.25% and 0.5% timolol is similar. The ocular hypotensive activity of timolol is greater than that of pilocarpine and topical carbonic anhydrase inhibitors (CAIs).

Early in the development of timolol, some reports indicated the relatively rapid development of tolerance to the drug’s ocular hypotensive effects, referred to as “escape.” The IOP is lower early in the course of therapy than with chronic treatment. The IOP results, however, are similar with chronic use of either 0.5% timolol or 0.25% timolol. In addition, the fellow untreated eye may show a decrease in IOP, which most likely results from a consensual (contralateral) effect. Contralateral effects resulting from systemic drug absorption can be significant.

A long-term “drift” or drug tolerance has also been described.This observation may also result from changes in disease state or noncompliance in certain patients rather than as tolerance to timolol per se. Nevertheless, less than half the eyes initially treated with timolol or other β-blockers can be expected to be treated with the original medication after 5 years. The remainder of eyes generally requires either additional medication

or surgery. As a class, prostaglandin analogues are associated with better long-term efficacy and compliance (treatment adherence) than are β-blockers (Figure 10-5).

In patients with open-angle glaucoma or ocular hypertension, the ocular hypotensive efficacy of timolol is approximately 7 mm Hg, or a 26% reduction.Timolol used twice daily provides a consistent ocular hypotensive effect throughout the day. Because the IOP is reduced for at least 12 hours during chronic therapy, the instillation of

a second drop provides little additional lowering of IOP. Timolol continues to exert significant ocular hypotensive effects for up to 2 weeks once therapy is discontinued. Longer “washout”periods may be needed in patients with dark irides.

Once-daily therapy with timolol appears to be an effective treatment regimen. The ocular hypotensive effect of once-daily 0.25% or 0.5% timolol ranges from 17% to 28%, which overlaps with that of twice-daily timolol.

Habitual IOP (mmHg)

Aqueous flow shows a diurnal variation, and the ability of timolol to reduce IOP is greatest during the day (Figure 10-6).

Serendipitously, most of the chronic studies of oncedaily instillation of timolol selected a morning instillation. Because timolol decreases aqueous flow with daytime but not with nighttime instillation and compliance may be greater with a morning rather than evening dose, morning instillation is probably the better time for oncedaily use. However, the precise timing of the daytime dose may not be critical in achieving maximal efficacy.

Little evidence exists for a greater ocular hypotensive effect of 0.5% timolol than for 0.25% timolol with chronic use. Although the response of individual patients may vary, long-term controlled clinical trials suggest that 0.25% and 0.5% timolol are equally effective.

As demonstrated with fluorophotometry, timolol acts predominantly by decreasing the production of aqueous humor and does not significantly alter facility of outflow. Most studies support the view that both short-term and long-term administration of timolol do not alter optic nerve head circulation or produce retrobulbar hemodynamic changes. The ocular hypotensive effect of timolol is additive to most other therapies, including outflow agents (e.g., pilocarpine) and inflow agents (e.g., dorzolamide, brinzolamide, apraclonidine, and brimonidine). When added to latanoprost, timolol and most other β-blockers further reduce IOP approximately 2 mm Hg. This reduction is less than that attained by topical CAIs such as dorzolamide (Table 10-2).

148 CHAPTER 10 Ocular Hypotensive Drugs

Clinical Uses

Along with prostaglandin analogues, timolol is among the most effective ocular hypotensive agents in patients with primary open-angle glaucoma and ocular hypertension. In clinical practice timolol has been widely accepted, largely as a result of its significant ocular hypotensive efficacy, a duration of action that requires only onceor twice-daily instillation, and a relative lack of untoward ocular symptoms. In addition to its utility in the treatment of primary open-angle glaucoma and ocular hypertension, timolol is effective in the treatment of many secondary glaucomas. Timolol is also effective for the prophylactic treatment of elevations in IOP after laser iridotomy, posterior capsulotomy, and cataract surgery.

When topical timolol is administered to patients already receiving oral β-blocking agents for the treatment of systemic hypertension, a further reduction of IOP may occur. Ocular hypotensive efficacy, however, is generally reduced in patients treated with systemic β-blockers, and systemic safety can be adversely impacted. Ocular hypotensive agents other than β-blockers may be a more appropriate first-line therapy for patients who concurrently take a systemic β-blocker.

Timolol is supplied as a 0.25% and 0.5% sterile ophthalmic solution of the maleate salt (see Table 10-1). The drug is also available as a 0.25% and 0.5% hemihydrate salt (Betimol), which has an ocular hypotensive efficacy and safety profile clinically equivalent to that of the maleate salt. A formulation of timolol in a Gelrite vehicle (Timoptic XE) is also available. A single daily instillation of this formulation in the morning has an ocular hypotensive effect comparable with that of timolol solution used every 12 hours. Timolol (Istalol) is also formulated in potassium sorbate (0.47%), which increases the lipophilicity and allows for higher anterior chamber concentrations. Istalol solution is dosed once daily and is reported to have 45% less systemic levels compared to other timolol solutions dosed twice daily and therefore may exhibit reduced cardiovascular effects. Burning and stinging was 38% in the Istalol group versus 23% in the timolol control group. Multiuse containers of timolol solution are preserved with BAC 0.01% or benzododecinium bromide 0.012% (Timoptic XE), and a unit-of-use nonpreserved product is available (Ocudose). The ocular hypotensive effect of the nonpreserved formulation is the same as that of the preserved formulation. Timolol is approved for either onceor twice-daily use.

Side Effects

Ocular Effects. Timolol may cause some adverse ocular effects (Box 10-3). A local allergic reaction can occur.This allergic reaction manifests as a blepharoconjunctivitis, with erythema and edema of the lids. The reaction can occur as early as the first month of therapy. Management may include changing to another β-blocker or other class of drug.

Box 10-3 Adverse Events Possibly Assoicated

With Topical Ophthalmic β-Blockers

Cardiovascular

Bradycardia

Conduction arrhythmias

Hypotension

Raynaud’s phenomenon

Fluid retention

Pulmonary

Bronchoconstriction/bronchospasm

Asthma

Dyspnea

Central nervous system

Amnesia

Depression

Confusion

Headache

Migraine prophylaxis

Impotence

Insomnia

Myasthenia gravis

Gastrointestinal

Diarrhea

Nausea

Dermatologic

Alopecia

Nail pigmentation

Urticaria

Lichen planus

Other systemic effects

Hypoglycemia

Ocular effects

Allergic blepharoconjunctivitis

Dry eye/decreased tear breakup time

Corneal anesthesia

Macular edema (aphakics)

Macular hemorrhage/retinal detachment

Uveitis

Cataract progression

Adapted from Novack GD, Leopold IH. The toxicity of topical ophthalmic β-blockers. J Toxicol Cut Ocular Toxicol 1987; 6:283–297.

The ability of β-blockers to stabilize membrane excitability has been exploited therapeutically in the treatment of selected cardiac arrhythmias. However, when these agents are given topically, such a property can induce corneal anesthesia. Significant decreases in corneal sensitivity

have been reported in some patients. Timolol, however, ranks low among β-blockers in its corneal anesthetic effects, and corneal sensitivity is not a major clinical problem with timolol. In some patients, timolol can induce superficial punctate keratitis. If this condition becomes chronic and is not treated, it could lead to additional epitheliopathy and possible corneal epithelial erosions. Topical timolol may reduce tear breakup time, elicit some dry eye symptoms, or decrease tear flow. None of the commonly used β-blockers, including timolol, appears to inhibit corneal epithelial wound healing.When timolol is administered in a gel-forming vehicle, it may induce a momentary visual disturbance, but the visual dysfunction does not preclude use during the patient’s waking hours.

Systemic Effects. When timolol is given by the topical route, the possibility of systemic β-blockade must be considered (see Box 10-3).Within the first few hours after topical instillation of 0.5% timolol solution, the mean drug plasma level is approximately 1 ng/ml.This level can be as high as 20 ng/ml in newborns and can be reduced in adults with nasolacrimal occlusion or simple eyelid closure. Use of timolol in gel-forming solution can substantially lower plasma drug levels. Because the administration of topical timolol results in mean drug plasma levels less than 5 ng/ml, it is somewhat puzzling that bradycardia is a frequently associated side effect of topical timolol. However, it appears that even with systemic administration, plasma levels of beta-blocking agents are not always indicative of systemic beta-blockade. Ocularly instilled medications also may reach the heart directly, via nasolacrimal and pharyngeal absorption, without the potential for inactivation by hepatic metabolism or dilution in total body plasma.

The presence of pharmacologically effective plasma levels of timolol after topical instillation dictates that the clinician considers the risk of systemic beta-blockade when administering any β-blocker for glaucoma. Antagonism of β-adrenoceptors can result in bradycardia, systemic hypotension, congestive heart failure, heart block, bronchospasm, diarrhea, and amnesia. β-Adrenergic antagonists of both subtypes may adversely affect memory. All these adverse effects have occurred with topical timolol therapy. In some cases these adverse events have been serious, life threatening, and even fatal. Systemic adverse events may be more frequent in elderly persons, because these patients have a greater propensity for coexisting systemic conditions and, as a result of flaccid lids, have the propensity for greater storage of instilled drug volumes in the lower cul-de-sac.

Mean resting heart rate may decrease 3 to 10 beats per minute (bpm) during use of timolol. Other cardiovascular effects include palpitations, systemic hypotension, and syncope. Similar to oral β-blockers, topical timolol may reduce exercise-induced tachycardia. This decrease may be a problem not only in patients with compromised cardiovascular status, but also in patients who normally

TIME (min)

Figure 10-7 Mean change in forced expiratory volume in 1 second (FEV1) after instillation of timolol, betaxolol, or placebo (vehicle). Timolol induced a significant decrease in airflow, whereas betaxolol produced values no different from those for the placebo. (Reprinted with permission from Am J Ophthalmol 1984;97:86–92. Copyright by the Ophthalmic Publishing Company.)

engage in strenuous exercise. Timolol in Gelrite vehicle, however, and timolol hemihydrate, dosed once daily, may have less effect on heart rate, probably because of reduced systemic absorption.

Timolol use can bring on wheezing, dyspnea, bronchospasm, and other signs and symptoms of decreased respiratory function. Acute bronchospasm can occur in previously asymptomatic asthmatic patients after the topical use of timolol.Timolol elicits an average decrease of 25% in forced expiratory volume (FEV1) in patients with chronic obstructive pulmonary disease (COPD) (Figure 10-7).

Topical β-blockers have been associated with adverse central nervous system (CNS) effects, including depression, emotional lability, and sexual dysfunction. Complaints of lethargy, lightheadedness, weakness, fatigue, mental depression, dissociative behavior, and memory loss are most common. The onset of symptoms varies from a few days to months after initiation of therapy. In most cases these symptoms are mild and transient. In certain patients, however, timolol must be discontinued.

Timolol may also elicit dermatologic signs and symptoms that include rashes, alopecia, urticaria, and discoloration of nails. Other systemic effects reported after topical timolol treatment include myasthenia gravis and retroperitoneal fibrosis. When treating a nursing mother, clinicians should also be aware that topically applied timolol may be excreted in breast milk.

Topical timolol may alter the plasma lipid profile.Timolol maleate adversely affects the high-density lipoprotein cholesterol levels in older white, black, and Japanese patients.There is no evidence, however, that chronic use of topical timolol increases the risk of coronary artery disease.

Contraindications

Timolol is contraindicated in patients with bronchial asthma, a history of bronchial asthma, or severe COPD.

150 CHAPTER 10 Ocular Hypotensive Drugs

Box 10-4 Contraindications to Topical

Ophthalmic β-Blockers

Bronchial asthma

History of bronchial asthma

Severe chronic obstructive pulmonary disease Bradycardia

Severe heart block Overt cardiac failure Children and infants

It is also contraindicated in patients with bradycardia (pulse rate less than 60 bpm), severe heart block, overt cardiac failure, and hypersensitivity to any of its components (Box 10-4).

More broadly, timolol therapy should be considered with caution in patients with any significant sign, symptom, or history for which systemic beta-blockade would be medically unwise.This includes disorders of cardiovascular or respiratory origin (e.g., asthma, chronic bronchitis, and emphysema) as well as many other conditions. Spirometric evaluation after institution of timolol therapy may help to identify patients in whom bronchospasm develops after commencement of therapy. In general, however, patients with asthma and other obstructive pulmonary diseases should avoid this drug. Sympathetic stimulation may be essential to support the circulation in individuals with diminished myocardial contractility, and its inhibition by β-adrenoceptor antagonists may precipitate more severe cardiac failure.

As may occur with topical timolol, β-adrenoceptor blockade may mask the signs and symptoms of thyrotoxicosis or acute hypoglycemia. Thus, timolol should be used with caution in patients prone to such disorders, including diabetes.

Using two topical β-blockers simultaneously has no potential for added ocular hypotensive efficacy, and such a combination can only increase the possibility of an untoward event. Because timolol in children and infants may result in a relative systemic overdose, its use in these patients should be avoided.

Careful patient histories and examinations are critical before using this drug. For many patients, the eye care specialist should contact the patient’s internist or primary care physician regarding the use of topical timolol or any other topical β-blocker. Although this warning is most important for chronic use, some of the reports of serious adverse reactions to timolol involve a single drop of medication.

Levobunolol

Pharmacology

Its metabolic fate, however, differs from that of timolol. Levobunolol is metabolized to dihydrobunolol, a compound with equipotent beta-blocking effects both systemically and ocularly. The potency of levobunolol at the ocular β2-adrenoceptor is similar to that of timolol.

When given topically to individuals with elevated IOP, levobunolol induces a long-lasting ocular hypotension. The mean reduction in IOP with twice-daily 0.5% and 1% levobunolol is equivalent to that of timolol. As with timolol, the predominant mechanism of levobunolol’s ocular hypotensive action is a decrease in the production of aqueous humor, with no significant effect on facility of outflow.

Clinical Uses

Levobunolol is used for the chronic treatment of elevated IOP in ocular hypertension and open-angle glaucoma. Also like timolol, levobunolol is effective for prophylactic treatment of elevations in IOP after cataract surgery and anterior segment laser procedures.

Levobunolol is supplied as a 0.25% and 0.5% sterile ophthalmic solution of the levo-isomer of the hydrochloride salt.The formulation contains a viscosity agent, 1.4% polyvinyl alcohol, and is preserved with BAC 0.004% (see Table 10-1).

Once-daily therapy with levobunolol can be an effective ocular hypotensive regimen. The hypotensive effect of once-daily 0.25% or 0.5% levobunolol is similar to that for twice-daily dosing.The 0.25% and 0.5% concentrations used twice daily are also equally effective. Thus, as with timolol, consideration may be given to using the lower concentration once daily.

Side Effects

Ocular Effects. Because levobunolol has the same pharmacologic activity as timolol, it has the propensity for the same untoward ocular effects as timolol. The ocular comfort of levobunolol is similar to that of timolol. Corneal anesthesia is not a significant problem with levobunolol, nor does it seem to elicit dry eye symptoms or mydriasis. Although allergic blepharoconjunctivitis can occur with levobunolol, it may also be tolerated in patients in whom timolol elicits an allergic reaction.

Systemic Effects. Because levobunolol is a potent and effective β1 and β2 blocker, it shares with timolol the same potential for systemic beta-blockade. Mean resting heart rate may decrease 3 to 10 bpm during use of levobunolol, and some reduction in blood pressure may occur.Topical ocular dosing with levobunolol results in plasma levels of approximately 1 ng/ml. As with timolol, 0.5% levobunolol reduces maximal exercise-induced heart rate by approximately 9 bpm.

Contraindications

Similar to timolol, levobunolol is a noncardioselective β- blocker without significant local anesthetic activity or ISA.

The contraindications for levobunolol are the same as those for timolol. Levobunolol is contraindicated in