Alphaselective Agonists

The alpha-selective agonists available clinically include clonidine, apraclonidine, and brimonidine. Key differences between these agents include therapeutic index, clinical safety, penetration, level of alpha-2 selectivity, and side effects. Clonidine was the first relatively selective alpha-2 agonist available; it lowers IOP well, but its narrow therapeutic index, particularly its propensity to cause sedation and systemic hypotension, has made it unpopular in glaucoma therapy. Apraclonidine was derived from clonidine in an attempt to obtain IOP lowering without the sedation and systemic hypotension of clonidine. Apraclonidine and brimonidine remain the most widely used alpha agonists in glaucoma therapy. To date, apraclonidine is the only agent approved by the FDA that is particularly well suited for acute prophylaxis of IOP elevation following argon laser trabeculoplasty, Nd:YAG and argon laser iridotomy, Nd:YAG capsulotomy, and cataract surgery. Brimonidine is the only alpha-2 agonist approved by the FDA for the long-term therapy of glaucoma and the most alpha-2 selective.

Some brands of the alpha-selective agonists clonidine, apraclonidine, and brimonidine are listed in table 4.3.

4.4.1 Clonidine. Synthesized in the early 1960s, clonidine was the first alpha agonist used systemically and topically for glaucoma. Because of its potent vasoconstriction effect, clonidine was originally tested as a topical nasal decongestant and shaving astringent, but clinical testing revealed its narrow therapeutic index. Moreover, the side effects of systemic hypotension and sedation have limited its widespread use in ophthalmology.23 Among the three alpha agonists, clonidine is the most lipophilic, easily penetrating the corneal epithelium and endothelium and, unfortunately, the

Table 4.3 Alpha-Selective Agonists

Clonidine

Dichlorophenyl aminoimidazoline

Apraclonidine

Apraclonidine

Brimonidine tartrate

Brimonidine 0.2%

blood-brain barrier.24 Clonidine is a relatively selective alpha-2 agonist, having roughly 183 times more affinity for alpha-2 than for alpha-1 receptors. Nonetheless, clonidine causes mydriasis, an alpha-1 effect.25 Tonographic investigations failed to demonstrate an effect on aqueous outflow, leading early researchers to conclude that clonidine reduces aqueous inflow.26

Clonidine was originally noted to lower IOP following intravenous administration.27 Then, one-drop topical studies suggested that clonidine was a safe and effective ocular hypotensive agent;28 however, long-term application of topical clonidine led to the discovery of the side effect of marked systemic hypotension. The German literature contains the first documentation of the ocular hypotensive effect of intravenous27 and topical28 clonidine. IOP reduction from topical clonidine 0.125% and 0.25% was equal to that of pilocarpine and lasted 8 hours, allowing three-times-daily usage.29 These investigators found that long-term use of clonidine, even when applied topically, caused dramatic and dangerous shifts in systemic blood pressure. In half the subjects, systolic blood pressure fell 30mm Hg, and in roughly one-third of subjects, diastolic pressure fell 30mm Hg. The possible adverse effects of symptomatic hypotension, syncope, and sedation have limited the popularity of topical clonidine for glaucoma therapy.

4.4.2 Apraclonidine. The narrow therapeutic index of clonidine motivated the search for a compound that would retain clonidine's efficacy for lowering IOP but had a wider therapeutic index.

4.4.2.1 Pharmacology. Apraclonidine, a hydrophilic derivative of clonidine, achieves the substantial IOP reduction of clonidine without causing the centrally mediated side effects of systemic hypotension and drowsiness.30 Hydrophilic molecules traverse the cornea and blood-brain barrier poorly. Apraclonidine is structurally similar to clonidine, except that it has a hydrophilic amide group at the C4 position of the imidazole (benzene) ring. This modification makes apraclonidine more hydrophilic, reducing systemic absorption and blood-brain barrier penetration, but it also makes the journey across the lipid-rich barrier of the corneal epithelium and endothelium more difficult. The corneal penetration coefficient of clonidine is 21.9cm/s, nearly six times faster than apraclonidine, at 3.8cm/s.31 Given the poor penetration of apraclonidine, one group of investigators has even hypothesized that the route of ocular penetration for apraclonidine may be predominantly extracorneal.24

Apraclonidine retains moderate alpha-2-adrenoreceptor selectivity, having 72 times higher affinity for alpha-2 than for alpha-1 receptors.24 Nonetheless, alpha-1 receptor activation by both 0.25% and 0.5% apraclonidine and its more alpha-2-selective cousin brimonidine 0.5% is sufficient to cause notable conjunctival blanching and eyelid retraction.32,33

4.4.2.2 Mechanism of action. Apraclonidine reduces IOP by reduced aqueous production, improved trabecular outflow, and reduced episcleral venous pressure. Modern techniques to determine a drug's mechanism of action rely heavily on the understanding of aqueous physiology modeled by the Goldmann equation:

IOP = intraocular pressure

Pev = episcleral venous pressure

F = aqueous flow

U = uveoscleral outflow

Ctm = trabecular meshwork outflow facility

Each variable can be measured in humans directly or indirectly, except uveoscleral outflow, which must be calculated from the others (table 4.4).

As should be clear from the equation, conclusive statements about mechanisms of action of glaucoma medications require precise measurement of at least three of the variables in the Goldmann equation—a formidable task. In studies that track only aqueous flow changes in response to a single drop of apraclonidine 1%, limited conclusions can be drawn, because two other independent variables (episcleral venous pressure and uveoscleral outflow) may not be constant after drug instillation. Authors of two such studies cautiously state that the observed IOP drop ''could be explained'' by an observed 30% to 45% decrease in aqueous flow in otherwise-untreated ocular hypertensive patients34 and a 16% reduction in flow in glaucoma patients treated long term with timolol.35 Based on the Goldmann equation, there may be some contribution from the unmeasured episcleral pressure or uveoscleral outflow. Similarly, a randomized, placebo-controlled, unilateral trial of apraclonidine 1% found no significant change in tonographic outflow facility in treated eyes and concluded that decreased aqueous flow might be implicated.36

An elegant trial in ocular hypertensive patients challenges this theory and suggests that long-term use of apraclonidine lowers IOP through multiple mechanisms, principally by improving trabecular outflow facility.10 The authors of this study endeavored to measure three of the four independent variables of the Goldmann equation, including IOP, Pev, and Ctm. In agreement with prior work,36 apraclonidine had no effect on tonographic outflow facility. However, they did find that 1 week of unilateral apraclonidine 0.5% therapy lowered the IOP of the treated eye in ocular hypertensive patients primarily by increasing fluorophotometric outflow

Table 4.4 Techniques for Measuring Variables of Mechanism of Action

Variable

Measurement Technique

Episcleral venous pressure Aqueous flow

Trabecular meshwork outflow facility Uveoscleral outflow

Episcleral sphygmomanometry

Fluorophotometry: rate of reduction of aqueous fluorescein concentration gives rate of flow Dynamic fluorophotometry: changes in aqueous flow as intraocular pressure is lowered pharmacologically (old method: tonography) Cannot measure; must calculate from equation facility (53%) and secondarily by reducing episcleral venous pressure (10%) and decreasing aqueous flow (12%). These researchers suggest that single-drop studies are affected by pseudofacility and that fluorophotometric techniques are more accurate when measuring flow parameters in a steady state.10 Studies by Toris et al.10'11 include measuring all three measurable variables in the Goldmann equation and testing patients who used apraclonidine long term. These design points raise the likelihood that their complex conclusions will stand the test of time.

4.4.2.3 Safety. Apraclonidine enjoys the widest therapeutic index for cardiovascular and central nervous system effects of the available alpha-2 agonists' with no or minimal effect on pulse' blood pressure' or alertness at approved dosages. The hydrophilic nature of apraclonidine may limit penetration of the blood-brain barrier, thereby reducing central hypotension and sedation. However, the contralateral ocular hypotensive effects of apraclonidine' similar to those of clonidine and brimonidine, suggest that the unilateral application of apraclonidine may reduce IOP through either central effects or contralateral peripheral action or both. Application of apraclonidine causes conjunctival, oral, and nasal vasoconstriction, leading to symptoms of dry nose and mouth and to a measurable reduction in conjunctival oxygen tension. One in vitro model of retinal circulation suggests that apraclonidine may constrict retinal arterioles; however, the existing evidence in humans suggests that apraclonidine probably does not induce retinal or optic nerve vasoconstriction in vivo. The principal use-limiting side effect of apraclonidine is allergy-like papillary conjunctivitis from long-term topical use.

Apraclonidine has little impact on human cardiovascular physiology when compared to clonidine. Examination of the safety of dosages approved by the FDA reveals little or no cardiovascular side effects of apraclonidine. In one double-masked, crossover study, normal female volunteers experienced no significant effects on blood pressure or exercise-induced tachycardia with either the 0.5% or the 0.25% apraclonidine concentration. By contrast, there was significant depression of heart rate in a group treated with timolol 0.5% who underwent treadmill testing.9 In an uncontrolled, open-label investigation, a small, clinically insignificant reduction in diastolic blood pressure of 5 mm Hg was reported in normal volunteers using apraclonidine 0.5% or 1% twice daily for 1 month.37

The evidence suggests that apraclonidine does not cause sedation. While 10% of patients in the uncontrolled dose-response study complained of lethargy,7 two prospective, placebo-controlled studies found no association between any dose of apraclonidine and fatigue in healthy volunteers9 or glaucoma patients16 using apraclonidine. These studies, however, had small enrollment and did not perform a rigorous symptom review with a validated survey instrument.

The most common acute symptom caused by apraclonidine is dosage-dependent dry nose or mouth, which affects 5% of subjects using 0.25% apraclonidine, 20% of those using 0.5% apraclonidine, and 57% of those using 1% apraclonidine.7,36 Overall, these nasopharyngeal symptoms are mild and seem to diminish with time. Other detectable acute signs include transient eyelid retraction and subtle con-junctival blanching. Minimal mydriasis was measured, <0.5mm in 45% of patients after treatment. The mydriasis is a sufficiently small effect that investigators have reported apraclonidine safe in patients with narrow-angle configuration. One case report has even described the use of apraclonidine to abort an attack of narrowangle glaucoma.38

The known vasoactivity of alpha agonists has prompted evaluation of the vascular effects of ocular hypotensive agents on the optic nerve in glaucoma patients. Investigations described below suggest that topical apraclonidine therapy causes an acute reduction in blood flow in the anterior segment of the human eye,39 but no vasoconstriction of the optic nerve or peripapillary retina has been identified in vivo. Unfortunately, optic nerve blood flow is difficult to measure directly in humans, and the vascular responses to alpha agonists can vary according to species, tissue, and even location within a given vascular bed,40 making extrapolation from animal data uncertain.

Animal and human studies suggest that apraclonidine constricts anterior segment vasculature in rabbits and humans. Vascular casting studies of rabbit eyes show that treatment with apraclonidine causes constriction of the precapillary sphincters in the ciliary body,41 but not of the anterior optic nerve vasculature.42 In humans, apraclonidine causes a marked and prolonged reduction of conjunctival oxygen tension, lasting up to 5 hours.39 Thus, apraclonidine would be a poor choice in patients with known ocular ischemic syndrome or advanced diabetic eye disease.

In certain animal models, apraclonidine can affect the retinal vasculature, but these effects have not been demonstrated in vivo. Human retinal xenografts in the cheek pouch of the newborn hamster offer a model for retinal vascular response to drugs. One such report found that, among the alpha agonists, clonidine induced the most retinal vasoconstriction, and brimonidine the least, with apraclonidine falling in between. Applied directly to the retina, apraclonidine produced a modest amount (15.9%) of retinal vascular constriction, after the lowest concentration (10-11 M), to a maximal 28% at the highest concentration (10-5 M). This in vitro finding is not supported by existing human studies: Doppler ultrasonography studies suggest that apraclonidine does not constrict retinal arterial or central ophthalmic artery flow.43,44 Similarly, scanning laser Doppler flowmeter examinations in healthy human volunteers suggest that unilateral apraclonidine 0.5% does not reduce tissue perfusion in the neural rim or peripapillary retina of the treated eye compared to the contralateral eye.45 Unfortunately, in these studies, investigators sought to demonstrate differences between the two eyes of an individual subject after unilateral application of apraclonidine. The known contralateral effects of apraclonidine would have minimized the apparent magnitude of a vasoactive effect in the treated eye. This raises the possibility that a small but deleterious effect on optic nerve or retinal blood flow due to apraclonidine may have been missed because of the study design.

No controlled investigation of an adrenergic agent suggests that these drugs cause vision loss. However, the concern that decreased blood flow might compromise vision led one group46 to review the charts of apraclonidine users. Unfortunately, they did not include a control group or measure vision or blood flow in a validated fashion. This retrospective case series did find that 7% (14 of 185) patients lost two to four lines of vision over a mean of 7 weeks. Then, in a small subset of patients, the investigators measured the blood velocity within the short posterior ciliary arteries with color Doppler ultrasound. This technique is unable to determine flow without simultaneous measurement of the vessel diameter in question. Despite the lack of a control group to support the association or a validated technique for measuring blood flow, the researchers speculate that the vision loss might be due to reductions in perfusion of short posterior ciliary arteries. They qualify their conclusion by stating that ''color Doppler as an estimate of optic nerve blood flow has not been established with certainty.'' No controlled investigation has suggested that apra-clonidine, brimonidine, or clonidine promotes vision loss.

As with epinephrine and propine, the principal clinical side effect of apraclonidine 1% is a delayed allergy-like reaction, with prominent follicular conjunctivitis and periocular dermatitis in up to 48% of patients after a mean of 4.6 months.47 The incidence of this reaction appears to be dose and time dependent. A 90-day, prospective, randomized trial yielded allergy rates of 9% (apraclonidine 0.25%) and 36% (apraclonidine 0.50%) versus none in the timolol 0.5% group.48 Another 90-day trial found 13.8% incidence of allergy with apraclonidine 0.5% and 20.3% rate with apraclonidine 1%.49 Other investigators report similar data.46,50

The cause of this delayed allergy-like reaction is unknown and may be either an increased susceptibility to external allergens or bioactivation and antigen formation of a specific part of the adrenergic molecule itself. Because epinephrine shrinks trabecular epithelial cells in vitro, Butler et al.47 have hypothesized that adrenergi-cally induced cell shrinkage may stress intercellular junctions, enabling the penetration of exogenous environmental allergens. Recent biochemical investigations suggest that apraclonidine allergy may be caused by oxidation of a hydroquinone-like subunit, which it shares chemically with its cousin epinephrine, but not with clonidine or brimonidine. This subunit is readily oxidized and may conjugate with thiol groups in ocular tissues, creating a potentially sensitizing hapten.51 This theory requires further substantiation.

4.4.2.4 Indications. Apraclonidine indications include prophylaxis of acute IOP rise after ophthalmic anterior segment laser procedures:

4.4.2.4.1 Argon laser trabeculoplasty. Ironically, argon laser trabeculoplasty (ALT) was pioneered initially in part as a means of causing increased IOP and a novel primate model of open-angle glaucoma.52 Thus, even after Wise and Witter53 successfully demonstrated the IOP-lowering effect of lower energy ALT, the potential danger of IOP elevation following laser treatment remained.54 And indeed, IOP elevations of at least 10mm Hg were found in one-third of patients following 360c ALT.55 The Glaucoma Laser Trial, a prospective, randomized, controlled trial, showed that treating half the trabecular meshwork led to some IOP rise in 54% of those treated. In 14% of the subjects, IOP rose 6 to 10mm Hg, and in 7%, IOP rose 10mm Hg above baseline.56

Several dramatic cases warn about the potential damage of post-ALT IOP spikes.55 In an early randomized, double-masked study55 comparing ALT of half versus the entire trabecular meshwork, investigators reported that one of the patients with exfoliative glaucoma and severe glaucomatous atrophy developed acute postlaser IOP elevation to a maximum of 62mm Hg. This spike resulted in obliteration of the central island of vision and acuity loss within 24 hours. A similar case was reported in a series of 334 eyes with advanced glaucoma treated with ALT. In this study, one 83-year-old-man with phakic primary open-angle glaucoma who had a small central island lost vision after an ALT-induced IOP rise to 42 mm Hg, 3 days after ALT.57

While dramatic, the frequency of this type of dangerous field loss from a postlaser IOP spike in the average glaucoma patient is hard to gauge. These cases represent 2.5% of patients treated in the first study and 0.33% in the latter study. Because both cases noted above involved patients with end-stage glaucomatous optic neuropathy and only central islands of vision remaining, it is unclear whether the danger can be generalized to patients with mild or moderate glaucoma. Unfortunately, in the Glaucoma Laser Trial,58 visual field results were not stratified by postlaser IOP response. Thus, it is not possible to evaluate whether those early glaucoma patients who participated in the Glaucoma Laser Trial and who had documented postlaser IOP rise suffered more rapid progression of visual field loss than did those whose IOP was not elevated transiently after the procedure.

The rationale for prophylaxis of post-ALT IOP spikes is as follows: At least 30% of axons in the optic nerve are irrevocably damaged in glaucoma patients before the first appearance of visual field defects.59 And because the purpose of ALT is the reduction of IOP, any perioperative IOP elevation could be dangerous to the survival of retinal ganglion cell axons, even if immediate field loss is not apparent.

Robin et al.60 found that apraclonidine 1% used perioperatively reduced the incidence of any IOP rise after ALT from 59% to 21%. More important, the percentage of eyes having a rise of 10mm Hg fell from 18% to 0%. One randomized, multiple-treatment-arm study61 compared the prophylactic efficacy of perioperative apraclonidine with pilocarpine 4%, timolol maleate 0.5%, dipivefrin 0.1%, and acetazolamide to reduce postoperative ocular hypertensive reactions following ALT. Apraclonidine proved superior to all of the other drugs, reducing IOP elevations above 5mmHg to 3% compared with 32% to 39% for all other tested medications. This finding was not entirely surprising, however, because apraclonidine was the only drop not used long term in any of the patients enrolled in the study. More than 90% of patients were already taking beta blockers long term: 72% to 86% epinephrine, 54% to 80% pilocarpine, and 16% to 25% carbonic anhydrase inhibitors. It may be that, if a drug is already in a patient's ciliary body from a morning application, use of the same drug may offer little additional benefit, unless sufficient time has elapsed for the drug to wash out. A subsequent study has shown that the long-term use of apraclonidine may reduce its efficacy in the prophylaxis of acute IOP elevation following ALT.62 The investigators found that, among those patients naive to apraclonidine, only 3% experienced an IOP elevation of 5mmHg at 1 hour post-ALT. By contrast, those subjects who were long-term apraclonidine users at the time of ALT were four times more likely to experience an IOP elevation of at least 5 mm Hg at 1 hour after ALT. One trial compared the effect of using apraclonidine and pilocarpine together to the effect of using each agent alone.63 The combination of apraclonidine and pilocarpine in patients naive to both appears slightly more effective than either drug alone. It appears that one drop of apraclo-nidine 1%, whether given 15 minutes or 60 minutes before ALT or just after ALT, is as effective as two drops in preventing IOP elevation.64,65

The FDA has approved the 1% concentration of apraclonidine for the prevention of postlaser IOP elevation, but the 0.5% apraclonidine solution has undergone limited testing, as well. One center has demonstrated equal efficacy between 0.5% and 1% apraclonidine when it is used both before and after ALT.66 Another group found no difference between 0.5% and 1% apraclonidine when used just after ALT. This study, however, did not monitor IOP after 2 hours.67

The enhanced safety afforded by apraclonidine with ALT has enabled 360c treatment with apraclonidine 1% to be performed as safely as 180c ALT treatment without apraclonidine.68 Apraclonidine's potency has led some clinicians to abandon the 24-hour postlaser IOP check.69 While the case for apraclonidine's role in the prophylaxis of ALT-related IOP rise is well documented, the ultimate benefit to the average patient's visual field progression is uncertain. No prospective data are available on the benefit of prophylaxis, with clinical end points such as effect on visual acuity, visual field, color vision, vascular occlusions, progressive optic neuropathy, and glaucoma. The relatively low rate of documented field loss due to acute IOP rise after ALT55,57 (between 0% and 2.5%) would make the numbers required to study in a prospective clinical trial rather large.

4.4.2.4.2 Argon or Nd:YAG laser iridotomy. The rationale for apraclonidine prophylaxis of laser iridotomy is similar to that for ALT. Roughly one-third of patients undergoing either argon or Nd:YAG laser iridotomy experience a marked IOP rise of 10mm Hg or more.70 Two drops of apraclonidine 1% have been proven to be highly effective in the prevention of IOP elevation following either argon or Nd:YAG laser iridotomy in white71 and Hispanic American patients.72

4.4.2.4.3 Nd:YAG laser capsulotomy. The rationale for prophylaxis of IOP elevation after Nd:YAG laser capsulotomy is also similar to the rationale for prophylaxis after ALT. Numerous reports documenting IOP elevation in up to 59% of glauco-matous eyes undergoing Nd:YAG capsulotomy, combined with case reports of acute visual compromise in glaucoma patients after Nd:YAG laser capsulotomy, have generated understandable fears of this common phenomenon. Mechanisms of vision loss after Nd:YAG capsulotomy in one case included IOP-induced acute corneal edema and compromised chorioretinal perfusion, causing transient vision loss to light perception only.73 In another case, a transient central retinal artery occlusion occurred, with transient loss of light perception.74 In a third patient, with preexisting field loss from primary open-angle glaucoma, Nd:YAG capsulotomy resulted in a prolonged (4- to 5-day) IOP elevation, peaking at 72mm Hg. This patient developed progressive, permanent glaucomatous field loss just 4 weeks later.75

In pseudophakic eyes undergoing Nd:YAG laser capsulotomy, IOP increases to a maximum 31% higher than pretreatment levels, 41% having a rise of 5 mm Hg and 16% having a rise of 10mm Hg or greater. Eyes of glaucoma patients undergo rises that are higher and longer lasting than do nonglaucomatous eyes, with 59% 5mm Hg higher and 26% 10mm Hg higher.76 One multicentered, double-masked, placebo-controlled trial77 found that apraclonidine 1% used 1 hour before and immediately after capsulotomy eliminated nearly all "clinically significant'' IOP rise up to 3 hours. A cohort study using historical controls found that IOP rises exceeding 10mm Hg were cut from 26% to 4% in glaucomatous eyes pretreated with apraclonidine.76

One investigation observed similar efficacy of apraclonidine 0.5% and 1% in the prophylaxis of IOP elevation after Nd:YAG laser capsulotomy, but IOP was monitored only 2 hours after the procedure.67 Earlier dose-response data suggest a shorter duration of action for apraclonidine 0.5% versus the 1% concentration (8 hours vs. 12 hours, respectively). Thus, it is unlikely that the efficacy is truly equivalent over 24 hours.7 One case report78 warns of the limited protection that a single application of apraclonidine 1% affords. It points out that singledrop perioperative apraclonidine therapy may be insufficient to prevent marked IOP rise 24 to 48 hours following Nd:YAG capsulotomy, particularly when pigment is "polished" off the intraocular lens face. Therefore, while perioperative application of apraclonidine 1% has dramatically reduced the risk surrounding Nd:YAG laser capsulotomy, close follow-up is advised for patients undergoing secondary membrane discission or pigment "polishing," given the risk of late IOP rise.

Apraclonidine has been investigated in the treatment of ocular hypertension, as an adjunct to short- and long-term timolol use, as a surgery-sparing agent in patients with primary open-angle glaucoma failing maximum tolerable medical therapy, and in angle-closure glaucoma attacks.

1. Single-drop studies include one prospective, placebo-controlled trial of apraclonidine 0.5% and 1% in untreated ocular hypertensive patients that showed an acute 20% reduction in IOP compared to placebo within 2 hours and lasting up to 12 hours.37 In a 1-week dose-response study of ocular hypertensive patients,7 a 27% maximal IOP reduction was achieved compared to placebo, with either 0.25% or 0.5% apraclonidine at 2 to 5 hours. The peak hypotensive response with either concentration was equal in amplitude, but the duration of the response to apra-clonidine 0.5% was longer than that of apraclonidine 0.25%. Longer term therapy with apraclonidine showed similar efficacy. A prospective comparison of apraclo-nidine or timolol in ocular hypertensive patients and mild glaucoma patients who completed 90 days of therapy showed that both groups achieved a similar IOP reduction of roughly 20% in the morning after a bedtime dose and again 20% reduction compared to baseline 8 hours after a morning dose. A rapid diminution of efficacy, or tachyphylaxis, was observed in only one patient (2%) treated with apraclonidine, and poor compliance was suspected.48

2. Several well-controlled studies have confirmed an additive IOP-lowering effect when apraclonidine is added to the regimen of open-angle glaucoma patients who use timolol long term. Morrison and Robin16 demonstrated that a single drop of apraclonidine 1%, but not dipivefrin, given to patients with mild glaucoma treated long term with timolol resulted in an additional 15% to 18% reduction in IOP compared to placebo. A similar study demonstrated an average IOP reduction of 16.5% in the first 3 hours after a single drop of apraclonidine 1% was added to one eye of ocular hypertensive patients and early glaucoma patients treated long-term with either levobunolol 0.5% or timolol maleate 0.5%.79 The authors suggest at least three-times-daily apraclonidine dosing in timolol users, because the additional effect lasted under 12 hours. A 3-month dose-response study of apraclonidine added to long-term timolol use in patients with mild glaucoma found equal efficacy of the 0.5% and 1% apraclonidine concentrations.49

3. Apraclonidine can also be used to lower IOP in patients failing maximum medical therapy.50 Apraclonidine 0.5% three times daily added to one eye of patients with advanced glaucoma failing maximum medical therapy prevented or delayed by half the need for filtering surgery, compared to placebo alone. Of 174 patients randomized to apraclonidine or placebo, 60% of apraclonidine-treated patients, compared to 32% of placebo-treated patients, maintained adequate IOP control throughout the study and avoided surgery. Better responses were seen in patients with primary open-angle glaucoma not concurrently treated with beta blockers or carbonic anhydrase inhibitors. Since most patients requiring multiple agents for IOP control are usually taking brimonidine, the addition of apraclonidine is usually restricted to patients unable to tolerate such therapy.

4.4.3 Brimonidine. Initially investigated for the treatment of systemic hypertension, brimonidine is the latest alpha agonist to be approved by the FDA for the treatment of glaucoma and prophylaxis of laser-related IOP elevation. Despite similarities between apraclonidine and brimonidine, studies have shown limited cross-allergy, indicating that a reaction to one does not predict an allergy to the other.80-82

4.4.3.1 Pharmacology. In animal models, brimonidine is a highly alpha-2-selective agonist.83 In the rabbit model, brimonidine is 7- to 12-fold more alpha-2 selective than clonidine and 23- to 32-fold more alpha-2 selective than apraclonidine. While initial studies with the first approved formulation of brominidine 0.5% had a fairly high rate of alpha-1-adrenergic side effects, such as conjunctival blanching and eyelid retraction,84 more recent studies of the lower concentration 0.2% bromini-dine show a substantially improved side effect profile.85-88 The newer formulation with Purite as the preservative agents and 0.15% brimonidine has been shown to be well tolerated and as effective in IOP lowering.89 A lower concentration of brimonidine 0.1% has also been recently approved by the FDA as equally effective.

Brimonidine is less lipophilic than clonidine but more so than apraclonidine. Penetration of the cornea (and presumably the blood-brain barrier) is also intermediate between clonidine and apraclonidine.24 While sedation and systemic hypotension were more common with 0.5% brimonidine, newer formulations have been better tolerated. 88,89

4.4.3.2 Mechanism of action. Brimonidine reduces IOP in ocular hypertensive patients by reducing aqueous flow (20%) and possibly by increasing uveoscleral out-flow.90 Apraclonidine reduces aqueous flow and episcleral venous pressure but does not appear to improve uveoscleral outflow.10,11 A central mechanism may account for part of the IOP reduction from brimonidine 0.2%, because a single-eye treatment trial for 1 week caused a statistically significant reduction of 1.2mm Hg in the fellow eye.11

4.4.3.3 Efficacy. In the preclinical trial, a multicentered, double-masked, month-long, placebo-controlled trial32 tested the efficacy of 0.08%, 0.2%, and 0.5% bri-monidine in ocular hypertensive patients and patients with early glaucoma. All three concentrations reduced IOP throughout the month. A dose-dependent peak reduction of IOP of 16.1%, 22.4%, and 30.1%, respectively, was present in the first treatment week. At later time points, the dose effect was less direct, and the 0.2% brimonidine was as effective as the 0.5% brimonidine (and more effective at some averaged points). Over the later dates in the study, the reduction in IOP was in the 15.5% to 18.3% range. This is similar to the reduction in potency from 20% to 14% that was observed after 1 week of apraclonidine therapy.7 Brimonidine's peak effect occurs at about 2 hours and, with the 0.2% and 0.5% concentrations, maintains significant albeit reduced effectiveness (14.5% and 12.0% reductions) after 8 hours. Several long-term studies have demonstrated IOP reductions comparable to timolol 0.5% with use of 0.2% brimonidine, with a mean peak reduction in IOP of 5.2 to 6.3mm Hg (timolol) and 5.9 to 7.0mm Hg (brimonidine), and similar side effect profiles, except for more reduction of heart rate in the timolol group.86

Brimonidine is also effective when added to other glaucoma mediations. When used as adjunctive therapy, a large retrospective study showed a 32.2% decrease in IOP by the addition of brimonidine to latanoprost and a 15.5% decrease in IOP when added to a beta blocker.91 A direct comparison study with 24-hour diurnal measurements showed a 10.1% decrease in diurnal IOP when 0.15% brimonidine was added to latanoprost (which was equivalent to 2% dorzolamide in this study).92 In another study of brimonidine added to combination timolol-dorzolamide treatment, more than 70% of the patients had a greater than 15% IOP reduction (the treatment goal in the study). This was equivalent to latanoprost added to fixed timolol-dorzolamide.93 Another study compared a combination of brimonidine and latanoprost to timolol and dorzolamide and showed a decrease of 34.7% and 33.9% in two different arms of the study (which was greater than the timolol-dorzolamide reduction of 25.3% and 26.3%).94

4.4.3.4 Safety. As noted above, because the side effect profile of 0.5% brimonidine was less than ideal, lower concentration preparations are the only ones currently available in the United States and have a markedly reduced side effect profile.85,86 Like apraclonidine, low-dose brimonidine 0.2% did not blunt exercise-induced tachycardia.95

A 1-year study85 evaluated the safety and efficacy of long-term use of brimonidine 0.2% twice daily compared to timolol 0.5%. As with apraclonidine 0.25%, dry mouth and allergy were among the most common side effects in brimonidine-treated patients. Allergic blepharitis or conjunctivitis occurred in 9.6% of brimonidine-treated patients but in none of the timolol-treated patients. This is similar to the rate of allergy reported from low-dose apraclonidine 0.25% (9%) but less frequent than that found with the more common regimen for apraclonidine 0.5% (36%).48 Fatigue and drowsiness were found to occur with similar frequency in the timolol and brimonidine groups. These long-term studies show allergy rates of 9%; dry mouth, 33%; fatigue, 19.9% (comparable to timolol at 17.9%); and hyperemia, 30.2%.89

Several studies have shown that patients that have had allergic reactions to apraclonidine could be safely treated with brimonidine, presumably due to the differences in chemical structure between the two molecules.80-82

4.4.3.5 Indications. Brimonidine indications include prophylaxis of postlaser IOP elevation (approved originally for 0.5%) and treatment of glaucoma and ocular hypertension (approved for 0.2%).

4.4.3.5.1 Postlaser IOP rise. Several placebo-controlled clinical trials of brimonidine have documented the efficacy of brimonidine 0.5% in the prevention of IOP elevation. Two peer-reviewed trials demonstrated that a single drop of brimonidine 0.5% given either 30 to 45 minutes before or just after ALT was effective in reducing the incidence of postlaser IOP elevation of 10mm Hg from 23% among the placebo group to 2% or less in any brimonidine-treated patient. Table 4.5 shows the number of patients with IOP elevation of 5 and 10 mm Hg or greater following ALT when brimonidine 0.5% was used prophylactically before ALT, after ALT, and both before and after ALT.84

More recently, brimonidine 0.2% and 0.15% was compared to apraclonidine 0.5% and 1% for controlling IOP rise after anterior segment laser surgery and was found to be equally effective.96,97 The unavailable 0.5% formulation is now not used for preventing IOP rise after laser procedures, but the 0.2% formulation (and others) is sometimes substituted for apraclonidine in allergic patients.

4.4.3.5.2 Glaucoma and ocular hypertension. Brimonidine may be used as primary or secondary treatment for open-angle glaucoma or ocular hypertension. Several long-term studies have demonstrated that brimonidine 0.2% has comparable peak IOP lowering, although slightly less trough IOP lowering, than timolol 0.5%. Both were equally effective at preventing visual field loss or visual acuity loss.85,86 Since initial studies showed some decrease in effect over a 1-month study, the longer term data showing continued effectiveness is important.88,98 Brimonidine is additive to timolol (4.4mm Hg additional reduction), significantly better than dorzolamide 2% added to timolol.99

4.4.3.6 Neuroprotection. Medical or surgical reduction of IOP reduction is established as an effective treatment for open-angle glaucoma. Although investigational at this time, there is interest in the use of neuroprotective strategies for treatment of glaucoma. Ideally, treatments that directly prevent the loss of retinal ganglion cells

Table 4.5 Incidence of Intraocular Pressure Rise After Argon Laser Trabeculoplasty With Brimonidine 0.5%

Frequency of Administration

Number of Subjects IOP >5mm Hg IOP >10mmHg

Before ALT (n = 62)

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