Side Effects of Glaucoma Medications

SIDE EFFECTS OF GLAUCOMA MEDICATIONS

M. DETRY-MOREL*

ABSTRACT RE´SUME´ The safety profile of the different glaucoma medica- Le profil d’innocuité des différentes médications an- tions is an important issue when initiating therapy tiglaucomateuses est un paramètre déterminant au in glaucomatous patients. The decision on which moment de l’instauration d’un traitement chez tout medication to prescribe depends not only on the type patient glaucomateux. Le choix des médications dé- of glaucoma, but also on the patient’s medical his- pend non seulement du type de glaucome, mais aus- tory and needs a detailed knowledge of the poten- si des antécédents médicaux de chaque patient et tial side-effects of each medication. Medications side implique une connaissance détaillée des effets se- effects may be an important cause of non adher- condaires potentiels de chaque médication. La sur- ence for the individual patient venue d’effets secondaires liés aux médications est The properties of the drugs, the composition of the une cause potentielle importante de non observan- glaucoma eyedrops and the dynamics of ocular drug ce du patient glaucomateux à son traitement. absorption must be considered. The ocular surface Les propriétés des médications, la composition des changes induced by long-term antiglaucomatous treat- collyres et la pharmacocinétique de l’absorption des ment especially by their preservatives are a major médications oculaires sont à considérer en 1er lieu. cause of intolerance or poor tolerance to glaucoma Les modifications des tissus de surface induites par eyedrops. Moreover topically applied ophthalmic les traitements au long terme mais surtout par leur medications can attain sufficient serum levels through agent conservateur représentent une cause majeure absorption into conjunctival and nasal mucosas to d’intolérance ou de mauvaise tolérance des collyres have systemic effects and to potentially interact with administrés. En outre, les médications locales peu- other drugs. vent atteindre, via une absorption par les muqueu- Then this presentation will deal with the ocular and ses conjonctivales et nasales, des taux sériques suf- systemic side-effects which can be encountered with fisants pour induire des réactions systémiques the different classes of the currently available glau- secondaires et potentiellement interagir avec d’autres coma topical medications. médications. Recommendations than can be applied to reduce Après ce rappel général, cet article passe en revue both frequency and severity of side-effects of glau- les effets secondaires oculaires et systémiques sus- coma medications will be stressed on. Concurrently ceptibles d’être observés avec les différentes clas- patients should be fully informed not only about their ses pharmacologiques des médications actuellement disease but also the medications they used and what prescrites. side-effects they have to expect. Les recommandations et précautions à appliquer pour réduire à la fois la fréquence et la gravité des effets secondaires liés aux collyres antiglaucoma- teux sont développées. Il est indispensable que les patients soient informés non seulement sur leur ma- ladie, mais aussi sur les médications qu’ils reçoi- vent et la nature des effets secondaires auxquels ils doivent s’attendre.

zzzzzz * St Luc University Hospital, UCL, Brussels

Received: 08.12.05 Accepted: 23.01.06

Bull. Soc. belge Ophtalmol., 299, 27-40, 2006. 27 KEY WORDS INTRODUCTION Glaucoma, antiglaucoma drugs, side effects. In addition to their mechanism of action, effec- tiveness, cost and convenience, the safety of MOTS-CLES the different glaucoma medications is a major Glaucome, traitement médical, effets issue both when initiating and continuing ther- secondaires. apy in glaucomatous patients for the long term (26). Medical treatment has been proven to be an effective way of controlling glaucoma, Compli- ance is of major importance to get the full, potential protective effects against visual field defects (67). Among other considerations, tolerance of topical treatment is a crucial issue and medications side effects may be, among other barriers, an important cause of non adherence for the individual patient (26, 67). Glaucoma drug side effects are frequent but their definite frequency is probably underesti- mated (8). Based on a mail survey including a large representative French sample, J.P.Nord- mann and coworkers found that two-thirds of the questioned patients had side effects but the vision related Quality of Life (QoL) of patients with topical antiglaucomatous drug side effects was lower with poor treatment satisfaction, poor- er compliance and additional visits to their ophthalmologist (56). Side effects of glaucoma medications can be categorized in 3 groups. In addition to well- known ocular and systemic side effects, drug- drug interactions corresponding to potential interactions of glaucoma medications with other systemic drugs are the third component of this concern and beyond the scope of this re- view (33). Some preliminary general considerations are crucial to clarify the nature itself of the glaucoma drug side effects.

1. PRINCIPLES OF OCULAR THERAPEUTICS The chief advantages of topical application which is the most common route of administration are convenience, simplicity, non-invasive nature, and the patient’s ability to self administer. The properties of drugs include efficacy, potency, and therapeutic index which corresponds to the ratio comparing the efficacy of a drug to the magnitude of adverse side effects. Receptor se- lectivity, corneal penetration, protein/melanin

28 binding and pharmacokinetics are some other first time that the dry-eye condition could be important drug properties to be considered (65). caused by long-term antiglaucomatous thera- Except for the proper active ingredient, each py and especially by their preservative (13,32). topical medication contains excipients, repre- Since that time, it has been extensively de- sented by preservative, buffers, viscosity agents, monstrated that preservatives decrease the sta- vehicle and so on, to make the drug more ef- bility of the precorneal tear film through a de- fective. The pH of a formulation not only af- tergent effect on the lipid layer and a decrease fects the patient’s comfort, but also corneal of the density of goblet cells in the conjuncti- penetration and ocular absorption. Its tonicity val epithelium . According to their nature, they is impacted by the active drug, preservative and induce an allergic reaction but more frequently vehicle. Agents such as various forms of methyl- a cytotoxic reaction (10, 16, 51, 55, 77, 82). cellulose, polycarbophil and polyvinyl alcohol, These side effects are dose dependent and in- increase corneal contact time by increasing crease with the frequency of instillations. More- viscosity, bioavailability of the drug and delay- over, these changes have been demonstrated ing the phenomenon of washout. Preservatives to represent a significant risk factor for failure are added to multidose ocular medications in of filtration surgery (11). order to minimize microbial contamination and Subtle signs of ocular toxicity, such as reduced prevent from decomposition of the active drug. Break up Time, Superficial punctuate Keratitis Among preservatives, benzalkonium chloride (SPK) indicate chronic cell injury that can have (BAC) is the most frequently used and acts non- long term consequences (4). To a greater ex- specifically on cells it encounters. It is stable tent, the long term use of these agents can re- and has a long shelf life (65). sult in a form of conjunctival scarring known The large majority of topical glaucoma medi- as drug induced pemphigoid (34). In impres- cations are formulated as aqueous solutions, sion cytology specimens, C. Baudouin and co- which are easiest for patients to administer, and workers have found abnormal expression of in- generally cause the least amount of blurred vi- flammatory and allergy markers (HLA-DR an- sion upon instillation. The downside of this for- tigens and receptors to IgE CD23) in chroni- mulation is that aqueous solution quickly drains cally treated patients without clinical inflam- into the lacrimal system. Moreover, pharmaco- mation and confirmed that the toxic or immu- cinetic studies have shown that only 1% to 7% no-inflammatory effect on the ocular surface is of an instilled dose penetrates the cornea and to a large part caused by BAC (3, 4, 61, 63). that the maximal tear film concentration is These changes could probably also concern the achieved with a 20 µl drop. Any volume in ex- trabeculum structures (4). In a recent study cess of this amount simply overslows the eye dealing with the study of the inflammatory pro- or will drain in the nasolacrimal duct. file and mucin detection of conjunctival speci- Finally the flow of tears tends to decrease with mens analyzed by flow cytometry and in agree- age and to increase on irritation, as with the ment with others papers, they also concluded application of ocular medications. As a conse- that the use of long-term preserved beta-block- quence, the drug concentration in the eye as ers in glaucoma patients was associated with well as the absorption into the cornea decreas- a direct subclinical epithelial toxicity in the con- es through a dilution effect (65). junctiva comparatively with drops that did not Another major point to be stressed on concerns contain BAC (3, 4, 47). In a large retrospec- the tiveepidemiologicalstudysurvey,Pisella,Pouli- quen and Baudouin further found that symp- 2. OCULAR SURFACE CHANGES toms of foreign body sensation, dry eye sensa- INDUCED BY ANTIGLAUCOMA tion, tearing and eyelid itching as well as signs MEDICATIONS of ocular toxicity to preservatives, were signifi- cantly more common with preservatives eye- The dry-eye condition is an inflammatory dis- drops than without and that most adverse re- ease of the conjunctiva that may predispose to- actions induced by preservative glaucoma ward conjunctival hyper-reactivity to topical medication were dose-dependent and rever- drugs. Twenty years ago, it was shown for the sible after removing preservatives (62, 63).

29 Indomethacin 0.1% and fluorometholone 0.1% especially dangerous because the majority of eyedrops could be effective in reducing sub- glaucomatous patients are elderly, may have clinical conjunctival inflammation before filter- multiple systemic illnesses and are taking many ing surgery (5). other medications (78). When systemically ab- Among other practical implications, these find- sorbed, many antiglaucoma medications af- ings involve that adding another medication to fect the sympathetic and parasympathetic ner- an already complex regimen is associated with vous system of patients and can cause cardio- an increase of the contact time of conjunctival vascular or respiratory toxicity. There is a con- tissues to preservatives (53). siderable variation in the degree of systemic ab- Meanwhile and except for beta-blockers, all sorption between individuals (65). Although commercially currently available antiglauco- very unfrequent, some patients can develop hy- ma eyedrops contain BAC with different dos- persensitivity and manifest systemic side ef- ages. fects to all glaucoma medications they have been prescribed whatever the concentration 3. ALLERGY TO GLAUCOMA and the frequency. MEDICATIONS By inducing discomfort and inconvenience, re- MEDICATIONS OPTIONS peated allergies represent a load to patients and AND THEIR SIDE are a factor of discouraging from compliance. EFFECTS Ocular medication allergy typically causes well known symptoms of pruritus, red eye, tearing, The currently available therapeutic options to follicular conjunctival reaction, contact derma- treat glaucoma patients include five different titis of the eyelids, occasionally chemosis or lid drug classes: the alpha-adrenergic agonists, the swelling. The patient with evidence of ocular beta-adrenergic antagonists, the parasympa- allergy on multiple medications represents a thomimetics or cholinergic agents, the carbonic particularly difficult situation to deal with. The anhydrase inhibitors, and the prostaglandin preservative toxicity has been previously dis- analogs. Whatever their pharmacological class, cussed (34, 62). Some patients develop aller- every single currently available medication has gy to the preservatives benzalkonium chloride potential ocular and/or systemic adverse ef- or EDTA in the preparation and/or also to any fects. ophthalmic preparation. Dipivefrin, brimoni- Adverse effects associated with glaucoma med- dine, apraclonidine, dorzolamide, and brinzola- ications can be of immediate onset or can oc- mide are the most frequent offending glauco- cur much later. Rechallenge allows to firmly ma medications. On the other hand, adrener- confirm the causality of the medication in the gic antagonists and miotics as well as prosta- incriminated adverse effects but is ethically im- glandin analogs cause a lower rate of ocular al- possible or in the practice only possible in a mi- lergy (39, 65). nority of the cases. Prior to 1978, only 3 classes of medications 4. SYSTEMIC ABSORPTION OF were available for the treatment of chronic glau- GLAUCOMA MEDICATIONS coma (65, 70). Among them, topical miotics were generally ef- Finally, topically ophthalmic medications can fective but, among their numerous and mostly reach sufficient levels through absorption into ocular side effects, they were, in most cases, conjunctival, nasal, oropharyngeal, and gas- poorly tolerated because of induced myopia, trointestinal mucosa to have systemic effects poor night vision, fluctuating vision, or head- and to interact with other drugs (65). In fact, ache (Table 1). topical administration to the eye has been linked Topical epinephrine or its analogs were useful, to intravenous rather than oral administration but frequently associated with rebound hyper- because a high percentage of the absorbed drug emia , allergic blepharoconjunctivitis but also avoids hepatic first-pass metabolism. The in- with tachycardia, nervousness, elevated blood duced systemic side effects and interactions are pressure (Table 2).

30 Table 1: Major ocular and systemic side effects of pa- Table 2: Summary of the most frequent side effects in- rasympathomimetics (cholinergic drugs): direct-acting (pi- duced by non-selective adrenergic agonists (dipivefrin locarpine) and indirect-acting agents (demecarium bro- 0.1%; epinephrine 0.25-2.0%). mide, ecothiophate bromide, physostigmine) OCULAR SIDE EFFECTS OCULAR SIDE EFFECTS Conjunctival rebound hyperhemia Direct and indirect-acting agents Conjunctival pigmented deposits Stinging, burning, lacrimation Allergic blepharoconjunctivitis Miosis, poor night vision Pseudomyopia (fluctuating vision) SYSTEMIC SIDE EFFECTS Browache Tachycardia Retinal detachment Arrhythmia Ciliary spasm Elevated blood pressure Increased pupillary block Increased permeability of the aqueous-blood barrier Indirect-acting agents Conjunctival thickening Table 3: Major side effects of systemic carbonic anhydra- Iris cysts se inhibitors Cataract (acetazolamide, dichlorphenamide)

SYSTEMIC SIDE EFFECTS Paresthesias (2/3) Direct and indirect-acting agents Gastrointestinal symptoms and disturbances: Intestinal cramps nausea, vomiting, diarrhoea, gastralgia Diarrhea Malaise- anorexia-depression Bronchospasm Lethargy Indirect-acting agents Fatigue Cardiac irregularities Taste alteration: Tinnitus, hearing dysfunction Decreased libido Kidney stones Blood dyscrasia Oral carbonic anhydrase inhibitors such as ace- Metabolic acidosis tazolamide were also very effective but they in- Electrolytic imbalance (hypokaliemia) duced numerous and unacceptable side effects such as lethargy, malaise-anorexia-depression, Adverse reaction to sulfonamide derivatives Anaphylaxis fatigue, gastroinstestinal disturbances, hypokale- Fever rash, multiform erythema mia, and renal lithiasis. Roughly two-thirds of Stevens-Johnson syndrome patients complained of paresthesias, but that Bone-marrow depression generally improved with time. Sulfa-allergic ur- Thrombocytopenic purpura ticaria but especially Stevens-Johnson syn- Hemolytic anemia Leukopenia, pancytopenia, agranulocytosis drome, and aplastic anemia were rare but severe problems (Table 3). Since 1980, many new alternatives to treat chronic glaucoma are at the disposal of the cli- nicians. erroneous and has caused it to fall out of favour as the only first choice drug in glaucoma mana- BETA-BLOCKING AGENTS OR gement in recent years. Although the topical BETA-ADRENERGIC side effects of the beta-blocking eye drops were ANTAGONISTS relatively unfrequent, their long-term systemic adverse effects have been shown to be numer- Beta-adrenergic antagonists revolutionized the ous, sometimes severe, and, yet, frequent subtle. medical therapy of glaucoma at the end of the There are four FDA-approved non-selective and ’70’s. For the first time a topical medication one β1-adrenergic selective β-blocking agents. was available that had few visual or ocular side They induce a 20-25% IOP decrease, can be effects. Over 20 years later, beta-blockers are used once or twice daily and demonstrate a very still among the most prescribed antiglaucoma favourable ocular tolerability, a low rate of ocu- drugs all over the world and remain a first choice lar allergy, stinging, follicular conjunctivitis, and treatment. However the initial hope of a side contact dermatitis, even after many years of effect-free class of drugs has turned out to be treatment.

31 Ocular side effects (65, 70) Exacerbation of asthma and chronic obstruc- The most common ocular complaint with their tive pulmonary disease due to induced bron- use is a transient stinging and burning. chospasm are well known side effects. To a mi- Other commonly reported symptoms include nor degree for betaxolol as a selective beta- transient blurred vision, reversible myopia, for- blocker, these agents must be avoided in pa- eign body sensation, photophobia, itching, and tients with a history of reactive airway diseas- ocular irritation, as well as cystoid macular ede- es, such as asthma, emphysema, and chronic ma. bronchitis (40,43,44,78). Less well known and Objective ocular signs consist of superficial punc- moreover still controversial is the fact that, even tate keratatis, keratitis sicca, corneal hypoes- in patients with no history of asthma or ob- thesia, lid ptosis, and allergic blepharoconjunc- structive airway disease, long-term applica- tivitis due for the most part to the preserva- tion of a non selective beta-blocker can be as- tives and ingredients other than the drug itself. sociated with a reduction in pulmonary func- Iritis and uveitis had been reported with tion and even more by a subclinical increase in levobunolol hydrochloride and metipranolol, al- bronchial reactivity which may not be com- though no definitive causal relationship with pletely reversible on withdrawal of the medi- this particular molecule could been established. cation. For that reason, they theoretically had Lastly owing to their membrane stabilizing ef- to be avoided in patients who smoke. By mani- fect, patients on beta-blockers may exhibit a festing only by a nocturnal coughing in some corneal anaesthetic effect and an ability to in- unfrequent cases, this induced reduction of pul- hibit corneal epithelial cell migration. monary function can be very misleading (31,69,71). Sytemic side effects Bradycardia is another potential side effect, as It has been estimated than roughly 80% of an well as other forms of conduction defects. In eyedrop can pass through the nasal nasola- younger patients, tolerance to exercice and en- crimal duct and into the nasal mucosa and its durance may be decreased. By lowering myo- microvasculature. Eighty per cent of one 50 µl cardial contractility and cardiac output, beta- drop of a 0.5% solution contains 200 µg of ac- blockers can exacerbate congestive heart fail- tive ingredient. Considering that these eyedrops ure, although this effect is currently controver- are commonly used in both eyes once or twice sial (29,52,65,70). They can lower blood pres- a day, and that patients often squeeze more sure and are potentially associated with noc- than one drop upon instillation, the systemic turnal hypotension, which may be a risk factor implications can be dangerous (65). Subjects in progression of glaucomatous optic nerve dam- lacking of the cytochrome P 450 enzyme age (36,65,70). Moreover, they can theoreti- CYP2D6 allowing betablockers to be metabo- cally induce vasospasm by leaving alpha re- lized could have greater risk to develop system- ceptors, which mediate vasoconstriction, free ic side effects due to higher plasma concentra- to bind epinephrine that is freely circulating in tions of timolol following topical administra- the blood (65,70). tion of the drug (23). Most of the non selective betablockers have the Importantly many of systemic side effects may potential to adversely affect the plasma cho- only develop through an accumulation effect. lesterol levels, which may increase the risk of Moreover, because some side effects may be coronary artery disease (42,65,70). very mild and subtle and do not manifest until In term of psychological effects, they can cause months or years after the treatment is initiat- or worsen clinical depression after prolonged ed, a careful monitoring is needed even in pa- use (65,68,70). This is believed to result from tients who experienced no initial side effects blocking of the neurotransmitter pathways in (65,70). Some of the following side effects can the central nervous system and a decrease of be theoretically decreased with the use of gel the concentration of catecholamines and sero- forming solutions whose more viscous formu- tonine. Mood alterations, insomnia, memory lation increases corneal contact time and pen- loss, hallucinations and decreased libido could etration and decrease systemic absorption be more frequent than generally acknowledged. (22,72). Topical beta-blockers could be also a risk fac-

32 tor for falls in the elderly. By potentially mask- Table 4: Major side effects of Beta-adrenergic antago- ing some of the usual signs of hypoglycaemia nists Non-selective: timolol 0.1%, 0.25%, 0.50%; levobuno- and delaying the physiological response to in- lol 0.25%, 0.50%;metipranolol 0.1%, 0.3%, 0.6%). sulin, they are a relative contraindication in pa- Beta-1 selective: betaxolol 0.50%. tients with diabetes (65,70). with ISA (+): carteolol 1%, 2%. Timolol and other topical beta-blockers should OCULAR SIDE EFFECTS be avoided during pregnancy and in nursing Stinging, burning mothers, as they do cross into breast milk Transient blurred vision (65,70). Foreign body sensation, itching, hyperemia The most frequent ocular and systemic side ef- Photophobia fects induced by beta-blocking agents are sum- Epithelial keratopathy Corneal anaesthetic effect marized on table 4. SYSTEMIC SIDE EFFECTS Pulmonary system PROSTAGLANDIN ANALOGS Bronchospasm Airways obstruction Hypotensive lipids, named as eicosanoids, in- Dyspnea clude latanoprost, travoprost and bimatoprost. Coughing Due to their potent IOP lowering effect, they are currently, with beta-blockers, used as drug of Cardiovascular system choice for first-line therapy. By achieving this Bradycardia Arrhytmia effect at minimal concentrations that are or- Heart failure ders of magnitude much lower than other medi- Syncope cations, they induce relatively few systemic side Hypotension effects. However because they have not been Nocturnal hypotension Vasospasm available as long as many of the other agents, Increased plasma cholesterol levels their ultimate safety profile is relatively un- known and can justify for some authors, their Central Nervous System caution use in young patients (25,60,65). Ex- Amnesia cept for minor differences, the different com- Confusion Depression mercially available prostaglandin analogs are Headaches both comparable with respect to their ocular Impotence and systemic side effects (65,70). Insomnia Hallucinations Mood alterations Ocular side effects Risk factor for falls in the elderly? Ocular side effects include to some different de- grees hyperemia, foreign body sensation, hy- Gastrointestinal pertrichosis, increased lower eyelid pigmenta- Nausea, vomiting, diarrhea tion with darkening of the periocular skin and Diabetes ’’cernes’’, and superficial punctate keratopa- Masked hypoglycaemia in insulin dependent diabe- thy (26, 37, 57,60,65). The incidence of hy- tes mellitus peremia varies among the different studies and molecules( from 5% to 68%). It mainly occurs Beta-1 selective (betaxolol) has a better tolerance in most in the first weeks of therapy, with a progres- patients sensitive to non-selective agents. sive but non constant decrease over time. This Of some concern is the ability of these agents side class related effect may represent a cos- to cause an increase in the melanin granule metic problem to the patient, possibly leading population in the melanocytes in the iris stro- to non-or poor compliance. Allergic reactions ma, resulting in permanent hyperchromia of the occur in 1% of adult patients (35,41). iris. Iris color changes develop in 7% to ap- Increased eyelash thickness, length and num- proximately 30% of patients. Although no cel- ber appear to be related to the drug’s ability to lular proliferation or other dangerous sequelae induce growth and hypertrophy in resting fol- of this effect have been seen, long-term conse- licles (6,58). quences of prostaglandin use especially in young

33 patients still need to be evaluated. Nonhomo- should be avoided in patients with severe cor- geneous mixed color iris, i.e green-brown, or ticodependent asthma (65). Although prosta- blue-grey-brown iris are more prone to devel- glandin F2alpha is also a known vasoconstric- op permanent increased iris pigmentation with tor, no definite vasoconstrictive effect of the prostaglandin analogs (65). This effect starts prostaglandin analogs on the retinal and optic relatively early after initiation of therapy (18 to nerve head has been published yet (65). 24 weeks) but would unfrequently develop af- Side effects in children are uncommon. How- ter month 36 (1). Latanoprost has been dem- ever parents should be warned of possible sleep onstrated to be associated with the most im- disturbance, sweating, ocular hyperemia, irri- portant rate of iris pigmentation, with 16% at tation, increased iris pigmentation and lashes 12 months compared with 3% for travoprost before starting latanoprost treatment (24). and less than 2% for bimatoprost (1,65). Except for the second trimester of pregnancy, Although these associations have not been pro- latanoprost and travoprost should be avoided ven to be causal, the use of latanoprost has in pregnant women, because prostaglandins are been reported to be associated with exacerba- known to induce labor. Bimatoprost does not tion of uveitis (46) and cystoid macular edema seem to have an effect on uterine muscle in vi- in predisposed patients, i.e in pseudo- and tro, but its effects in vivo have to be further clari- aphakic patients with lens rupture capsule fied (15). (30,76,80), as well as some reports of iritis with choroidal effusion (50-66). Table 5 summarizes the ocular and systemic More significant but uncommon side effects in- side effects of prostaglandin analogs. clude reactivation of herpes simplex or herpes simplex-like keratopathy as well as development of reversible iris cyst mimicking iris melanoma (12,18) ). Whetherthetopicalapplicationofprostaglandi- nes onto the cornea reduces the central corne- Table 5: Side effects of prostaglandin derivatives and al thickness or not has to be further confirmed prostamides. (79). Relatively subtle differences exist between the OCULAR SIDE EFFECTS 3 existing prostaglandins. As previously men- Conjunctival hyperemia (5% to 68%) (transient and tioned, latanaprost has revealed to induce the usually mild) lowest rate of hyperemia but the higher rate of Burning, stinging, foreign body sensation, itching iris color changes. Hypertrichosis is more pro- Allergic reactions (1%) nounced and frequent with travoprost. Bimato- Eyelash changes (reversible) prost has less incidence of iris discoloration Increased lower eyelid pigmentation Epithelial keratopathy (about 1.5% of the patients), but a significant- Increased iris pigmentation ly higher rate of hyperemia and periocular in 7% to 30% ’’cernes’’ than any drug in this class (45). in patients with green-brown,blue/gray- brown, yellow- brown irides Cystoid macular edema in aphakes/pseudophakes Systemic adverse effects - with a posterior lens capsule rupture or Systemic side effects induced by latanoprost - in patients with known risk for macular edema and other prostaglandin analogs are unfrequent Reactivation of herpes keratitis and typically minor. They consist in migraine Anterior uveitis headaches, muscle or joint aches, through a SYSTEMIC SIDE EFFECTS probable role of prostaglandins in the media- Migraine tion of sensory (pain) perception, flu-like-symp- Muscle/joint pain toms, non ocular eczema and allergy, and up- Flu-like symptoms per respiratory signs (48,64,65). Although stud- Non-ocular eczema Upper respiratory signs: dyspnea, asthma, exacer- ies carried out in asthmatic volunteers with top- bation of asthma ical PGF2 alpha did not show any respiratory side effects, topical prostaglandins analogs Caution in corticodependent asthmatic patients!

34 ALPHA-ADRENERGIC AGONISTS Ocular and systemic side effects of brimonidine are summarized on table 6. In this class, apraclonidine (Iopidinet 0.50%, 1%, Alcon) is a relatively non selective alpha- adrenergic agent. Its high rate of tachyphylax- Table 6: Side effects of alpha-2 selective adrenergic ago- is and its high incidence of allergy have made nists (apraclonidine 0.5-1%, brimonidine). it less useful for long-term therapy (33,65, 83). OCULAR SIDE EFFECTS Brimonidine is a selective alpha-2 adrenergic Rebound hyperemia agonist which has about the same efficiency Lid elevation than topical beta-blockers. It works by both in- Pupil dilatation (for apraclonidine) creasing uveoscleral outflow and by decreas- Allergy (up to 26% for brimonidine, up to 36% for ing aqueous formation (17,33,65). apraclonidine) Uveitis ± allergic conjunctivitis ± IOP increase Ocular side effects related to this molecule in- (brimonidine) clude the typical rebound hyperaemia of adrenergic agonists along with conjunctival follicle SYSTEMIC SIDE EFFECTS formation (17,65). Allergy has been reported Dry mouth Headaches in 4 to 26% of patients (17,20,21). An his- Fatigue tory of eyedrop allergy and of reduction of the Drowsiness tear film production could be more frequently Dizziness associated with the development of a brimoni- Decrease in systolic blood pressure dine induced ocular allergy (49,57). That brimonidine should be considered as a possible cause of drug-induced uveitis with or without TOPICAL CARBONIC concurrent allergic conjunctivitis is less known ANHYDRASE INHIBITORS (IAC) (7). It has been also suggested that the delayed development of a follicular conjunctivitis Although dorzolamide and brinzolamide are could be frequently associated with a loss of slightly less efficacious in lowering IOP than IOP control and recommended that patients on their oral counterparts, their systemic side ef- brimonidine eyedrops should be instructed to fects are greatly decreased (65, 73). report promptly to their ophthalmologist the onset of redness of their eyes so that their glau- Ocular side effects coma treatment could be adjusted (81). Dorzolamide is known to induce stinging and The frequency of systemic side effects induced burning upon instillation in more than one-third by brimonidine varies in adult series from 20% of patients because of its low pH (at 5.8), but to 50% and could be more frequent in elderly also ocular dryness, superficial punctate kerati- patients (20,21). These include dry mouth in tis and blurred vision. However pain symptoms nearly one-third of patients. Headaches, fa- become generally fewer following chronic dos- tigue, dizziness, drowsiness (which can be both ing and are generally characterized as mild. attributed to the drug’s lipophilicity and induced Brinzolamide in suspension allows buffering to hypotension) have been reported to various de- a more neutral pH, which increases patient com- grees and represent potentially significant prob- fort but with a white deposit or debris on the lems (20,21). Somnolence could interfere with eyelids (33,65,75). driving or professional activities. Except for young For both drugs, allergic reactions may be seen, children, cardiovascular and pulmonary side ef- most related with sulfamide-allergy. Because fects are rare in adults (83). topical IAC inhibit carbonic anhydrase which Brimonidine should be avoided in newborns, is required for the pumping action of the cor- young infants and children with juvenile glau- neal endothelium, corneal decompensation may coma younger than 12 years, because of some occur in patients with already compromised en- reports of apneic spells and cyanosis, hypo- dothelium and pre-existing corneal edema (65). thermia, hypotony related to Central Nervous Induced myopia, prolonged hypotony follow- System depression due to the immaturity of the ing filtering surgery, choroidal detachment and blood-brain barrier (9,25). angle-closure glaucoma due to a forward rota-

35 tion of the ciliary body, have been reported in Table 7: Side effects of topical carbonic anhydrase inhi- some rare cases (26,33,65). bitors (brinzolamide 1%, dorzolamide 2%). OCULAR SIDE EFFECTS Systemic side effects Burning A percentage of the medication is absorbed and Stinging binds to erythrocytes. A metallic, bitter or dis- Dryness Superficial punctate keratitis torted taste, especially with carbonated bever- Blurred vision ages, are noticed by approximately 25% of the Tearing patients. This rarely precludes chronic therapy Allergy (sulfonamide derivatives) and is generally easily decreased with digital Corneal decompensation punctal occlusion. Myopia, prolonged hypotony, Choroidal detachment, angle closure glaucoma Rarely, transient gastrointestinal symptoms are seen. Headaches, dizziness and sometimes de- SYSTEMIC SIDE EFFECTS pression have been reported with topical IAC. Bitter taste (25%) Rare cases of nephrolithiasis have been report- Gastrointestinal disorders Headaches ed, although a causal relationship has not firm- Dizziness ly established with any of topical IAC. Depression Caution is advised when used in patients with Fatigue sulfa allergy which must be systematically Urticaria, pruritus searched for on initiation of therapy. Serious side effects are rare and a causal relationship has not been firmly established for any between presented side effects, especially sys- of these. Aplastic anemia and Stevens-Johnson temic side effects, and the instilled drug (14). syndrome remain a theoretical risk as with any Therefore we have to be aware of the potential sulfamide-derived drug, even with topically ACI ocular and systemic side effects of the differ- agents, although these have been never de- ent available medications, although they are scribed until now. In return, excessive fatigue less frequent with new meds such as prosta- and especially sensation of weakness of the in- glandins. Patients must be informed on their ferior limbs are probably more frequent than disease, the medications they use and what usually recognized and must be periodically side effects they have to expect. Without being searched for (19,26,33,65). suggested, they will be questioned during each Ocular and systemic side effects of topical ACI visit about potential side effects. are summarized on table 7. The goal of glaucoma treatment should be ob- tained with the least possible side effects, the COMBINATION PRODUCTS least possible dosing frequency and the lowest patient cost (26,33,65). Carteopilt, Cosoptt, Normoglaucont and Xa- Systemic levels of glaucoma medication can be lacomt represent the four currently commer- reduced by using lower frequency (daily vs twice cially available combination products. orthricedaily)andlowerconcentrationsofmedi- As fixed combinations, there is theoretically less cation (i.e timolol 0.25% versus 0.50%). chance of washout effect, fewer long-term oc- Punctal occlusion and lacrimal sac compres- ular side effects because of fewer preserva- sion can further reduce absorption. Practically tives than when using concomitant therapy. many patients neglect, will not be able to do However the contraindications and adverse re- or forget this recommendation. Removing ex- actions are similar to those of each individual cess fluid from lid margins combined with sim- agent (1,2,38,59,74). ple eyelid closure during at least one minute which will increase ocular contact time and de- CONCLUSIONS crease systemic absorption of topical medications, can work just about as well (27,65). Drug side effects are frequent and can have a All current systemic and ocular medications major impact on glaucoma management. Very should be noted to plan appropriate therapy often, patients do not establish a relationship and to avoid potential adverse effects, dupli-

36 cation of therapy, and adverse drug interac- flammation following chronic application of an- tions (33,65). tiglaucomatous drugs. Graefes’Arch Clin Exp Obtaining a history of allergies and systemic Ophthalmol 2002; 240:929-935. and ocular medication intolerances will guide (6) BEARDEN W., ANDERSON R. − Trichiasis as- glaucoma medications choice and avoid the sociated with prostaglandin analog use. Ophthal possibility of placing the patient on a medica- Plast Reconstr Surg 2004;20: 320-322. tion to which he or she is allergic or have had (7) BECKER H.I., WALTON R.C., DIAMANT J.I., ZEGANS M.E. − Anterior uveitis and concur- a previous intolerance or adverse event (80). rent allergic conjunctivitis associated with long- Major concerns deal with the preservatives con- term use of topical 0.2% brimonidine tartrate. tained within topical eye drop preparations. For Arch Ophthalmol 2004; 122: 1063-1066. patients at risk for ocular surface damage and (8) BHATT R., WHITTAKER K.W., APPASWAMY toimprovethelong-termlocaltoleranceofmedi- S., DESAI A., FITT A., SANDRAMOULI S. − cations, it is recommended to choose medica- Prospective survey of adverse reactions to to- tions with either low levels of BAC or alterna- pical antiglaucoma medications in a hospital tive preservative or preservative-free solutions population. Eye 2004; 19: 392-395. (54). Monodoses of free preservatives are cur- (9) BOWMAN R.J.C., COPE J., NISCHAL K.K. − rently available for some beta-blockers. Unfor- Ocular and systemic side effects of brimonidi- tunately, they are relatively expensive and still ne 0.2% eye drops (Alphagant) in children. non reimbursed to the patient for some of them. Eye 2004; 18:24-26. Whenever adjunctive therapy is needed, it is (10) BRANDT J.D., WITTPENN J.R., KATZ L.J., STEINMANN W.N., SPAETH G.L. − Conjunc- important to consider the use of preservative- tival impression cytology in patients with glau- free preparations/delivery systems and/or fixed coma using long-term topical medications. Am combinations. Anyway we must encourage Phar- J Ophthalmol 1993; 112:297-301. maceutics and Public Health Services to devel- (11) BROADWAY D.C., GRIERSON I., O’BRIEN C., op alternative free-preservative drugs for each HITCHINGS R.A. − Adverse effects of topical pharmacologic class. antiglaucoma medication. II. The outcome of Finally we also have a role in mentioning some filtration surgery. Arch Ophthalmol 1994; unusual adverse effects to the manufacturer of 112:1446-1454. the medication (28). (12) BROWNING D.J., PERKINS S.L., LARK K.K. − Iris cyst secondary to latanoprost mimicking REFERENCES iris melanoma. Am J Ophthalmol 2003; 135:419-421 (1) ALM A., SCHOENFELDER J., McDERMOTT J. (13) BURNSTEIN N.L. − Preservatives cytotoxic − A 5-year, multicenter, open-label, safety stu- threshold for benzalkonium chloride and chlor- dy of adjunctive latanoprost therapy for glau- hexidine digluconate in cat and rabbit corneas. coma. Arch Ophthalmol. 2004;122:957-965. Invest Ophthalmol Vis Sci. 1980; 19: 308- (2) ATTANASIO A., BAGLIO S., QUATRANA M., 313. BARTORELLI L. − Accelerated idioventricular (14) CARREIRO M., VALLAT D., VIDAL M., MAR- rhythm associated to ophthalmic timolol/dor- GARIT-COLL N., SAILLER L., GASTON F.G., zolamide solution. Intern J Cardiol OLLIER S., ARLET P. − Malaise with sweating 2004;95:343-345. induced by eyedrop. A case of iatrogenic pa- (3) BAUDOUIN C., GARCHER C., HAOUAT N., thology caused by diagnostic error. Presse Med BRON A., GASTAUD P. − Expression of inflam- 2003; 8; 32:406-407. matory membrane markers by conjunctival cells (15) CHEN J. Senior J., MARSCHALL K. − Studies in chronically treated patients with glaucoma. using isolated uterine and other preparations Ophthalmology 1994;101:454-460. show bimatoprost and prostanoid PF agonists (4) BAUDOUIN C., PISELLA P.J.,FILLACIER K. − have different activity profiles. Br J Pharma- Ocular surface inflammatory changes induced col. 2005; 144:493-501. by topical antiglaucoma drugs. Ophthalmo- (16) CVENKEL B. − Ocular surface changes indu- logy 1999; 106:556-563. ced by topical antiglaucomatous monothera- (5) BAUDOUIN C., NORDMANN J.P., DENIS P., py. Ophthalmologica 2002; 216:175-179. CREUZOT-GARCHER C., ALLAIRE C., TRIN- (17) DAVID R. − Brimonidine (Alphagant): a clini- QUAND C. − Efficacy of indomethacin 0.1% cal profile four years after launch. Eur J Oph- and fluorometholone 0.1% on conjunctival in- thalmol 2001; 11 (Suppl 2): S72-S77.

37 (18) DEAI T., FUKUDA M., HIBINO T., HIGAKI S., (30) FURUICHI M., CHIBA T., KEITETSU A., KOGU- HAYASHI K., SHIMOMURA Y. − Herpes sim- RE S., IIJIMA H., TSUKAHARA S., KASHIWA- plex virus genome quantification in two pa- GI K. − Cystoid macular edema associated with tients who developed herpetic epithelial kera- topical latanoprost in glaucomatous eyes with titis during treatment with antiglaucoma me- a normally functioning blood-ocular barrier. J dications. Cornea 2004; 23:125-128. Glaucoma 2001; 10:233-236. (19) DETRY-MOREL M. , DE HOSTE F. − Traite- (31) GANDOLFI S.A., CHETTA A., CIMINO L., MORA ment des glaucomes par les inhibiteurs de P., SANGERMANI C., TARDINI M.G. − Bron- l’anhydrase carbonique en collyre: expérience chial reactivity in healthy individuals under- rétrospective à moyen terme du dorzolamide. going long-term topical treatment with β-bloc- Bull Soc belge Ophtalmol 1998; 267 :157- kers. Arch Ophthalmol 2005; 123:35-38. 166. (32) GASSET A.R., ISHII Y., KAUFMAN H.E. − Cy- (20) DETRY-MOREL M., DUTRIEUX C. − Traite- totoxicity of ophthalmic preservatives. Am J ment des glaucomes par la brimonidine (Al- Ophthalmol 1974; 78:98-105. phaganr 0,2%r). J Fr Ophtalmol 2000; 23, (33) GERBER S.L., CANTOR L.B. − Systemic side 8:763-768. effects and interactions of glaucoma medica- (21) DETRY-MOREL M., C. DUTRIEUX L. − Corres- tions. In: “Clinical Guide to Glaucoma mana- pondance à propose de l’article “Traitement des gement” Eds Higginbotham E.J., Lee D.A. But- glaucomes par la brimonidine” DETRY-MO- terworth and Heinemann Elsevier Inc. 2004; REL M., DUTRIEUX C. J. Fr Ophtalmol 2001; 8:123-145. 24, 7:748-749 (34) GIBRAN S.K. − Unilateral drug-induced ocu- (22) DICKSTEIN K., HAPNES R., AARSLAND T. − lar pseudopemphigoid. Eye 2004; 18:1270. Comparison of aqueous and Gellan ophthal- (35) GUENOUN J.M., BAUDOUIN C., RAT P.,PAU- mic timolol with placebo on the 24-hour heart LY A., WARNET J.M., BRIGNOLLE-BAUDOUIN rate response in patients on treatment for glau- F. − In vitro study of inflammatory potential and coma. Am J Ophthalmol 2001; 132:626-631. toxicity profile of lanatonoprost, travoprost, and (23) EDEKI T.I. He H., WOOD A.J. − Pharmacoge- bimatoprost in conjunctival-derived epithelial netic explanation for excessive beta-blockade cells. IOVS 2005; 46: 2444-2450. follwing timolol eye drops. Potential for oral- (36) HAYREHS.S− Effectofnocturnalbloodpressu- ophthalmic drug interaction. J Am Med Assoc re reduction on retrobulbar hemodynamics in 1995; 274:1611-1613. glaucoma. Graefes Arch Clin Exp Ophthalmol (24) ENYEDI L.B., FREEDMAN S.F. − Latanoprost 2002; 240: 867-868. for the treatment of pediatric glaucoma. Surv (37) HERNDON L.W., WILLIAMS R.D., WAND M., Ophthalmol 2002; 47 (Supl 1) S129-S132. ASRANI S. − Increased periocular pigmenta- (25) ENYEDI L.B., FREEDMAN S.F. − Safety and ef- tion with ocular hypotensive lipid use in Afri- ficacy of brimonidine in children with glauco- can Americans. Am J Ophthalmol. 2003; ma. J AAPOS 2001; 5:281-284. 135:713-715. (26) EUROPEAN GLAUCOMA SOCIETY. − Termino- (38) HIGGINBOTHAM E.J., DIESTELHORST M., logy and Guidelines for Glaucoma (European PFEIFFER N., ROULAND J.F., ALM A. − The Guidelines). Glaucoma Society. 2nd ed. Savo- efficacy and safety of unfixed and fixed com- na, Italy: Editrice DOGMA, 2003; 3: 3-26. binations of latanoprost and other antiglauco- (27) FRAUNFELDER F.T., MEYER S.M. − Systemic ma medications. Surv Ophthalmol side effects from ophthalmic timolol and their 2002;47(Suppl 1):S133-S140. prevention. J Ocul Pharmacol 1987; 3:177- (39) HOLDINESS M.R. Contact dermatitis to topi- 184. cal drugs from glaucoma. Am J Contact Der- (28) FRAUNFELDER F.W., FRAUFELDER F.T. − Ad- mat. 2001; 12:217-219. verse ocular drug reactions recently identified (40) HUERTA C., GARCIA RODRIGUEZ L.A., MOL- by the National Registry of drug-induced ocu- LER C.S., ARELLANO F.M. − The risk of ob- lar side effects. Ophthalmology 2004; structive airways disease in a glaucoma popu- 111:1275-1279. lation. Pharmacoepidemiol. Drug Saf. 2001; (29) FRISHMAN W.H., KOWALSKI M., NAGNUR 10:157-163. S., WARSHAFSKI S., SICA D. − Cardiovascu- (41) JERSTAD K.M., WARSHAW E. − Allergic con- lar considerations in using topical, oral, and in- tact dermatitis to latanoprost. Am J Contact travenous drugs for the treatment of glauco- Derm 2002; 13:29-41. ma and ocular hypertension: focus on beta- (42) KHAMAR M.B., BHATT N., PATEL K. − Se- adrenergic blockade. Heart Dis. 2001; 3:386- rum lipid profile and timolol gel. J Indian Med 397. Assoc. 2002; 100: 620-621.

38 (43) KIRWAN J.F., NIGHTINGALE J.A., WORMALD (56) NORDMANN J.P., AUZANNEAU N., RICARD R. β Blockers for glaucoma and excess risk of S., BERDEAUX G. − Vision related quality of airways obstructive based cohort study. BMJ life and topical glaucoma treatment side ef- 2002; 325:1396-1397. fects. Health and Quality of Life Outcomes (44) KIRWAN J.F., NIGHTINGALE J.A., BUNCE C., 2003; 1:1-9. WORMALD R. − Do selective topical β anta- (57) OSBORNE S.A. MONTGOMERI D.M.I, MOR- gonists for glaucoma have respiratory side ef- RIS D., McKAY I.C. − Alphagan allergy may in- fects? Br J Ophthalmol 2004; 88:196-198. crease the propensity for multiple eye-drop al- (45) KONSTAS A.G., KATSIMBRIS J.M., LALLOS N. lergy. Eye 2005; 19:129-137. BOUKARAS G.P., JENKIS J.N., STEWART W.C. (58) O’TOOLE L., CAHILL M., O’BRIEN C. − Eyelid − Latanoprost 0.005% versus bimatoprost hypertrichosis associated with latanoprost is 0.03% in primary open-angle glaucoma pa- reversible. Eur J Ophthalmol 2001; 11:377- tients. Ophthalmology 2005; 112:262-266. 379. (46) KUMARASAMY M. DESAI S.P. − Anterior uvei- (59) PAJIC B.; Conductors of the Swiss COSOPT tis associated with travoprost. BMJ 2004; Survery (CSCS). Experience with COSOPT, the 329:205. fixed combination of timolol and dorzolamide, (47) KUPPENS E.V., DE JONG C.A., STOLWIJK T.R. gained in Swiss ophthalmologists’s offices. Curr − Effects of timolol with and without preser- Med Res Opin 2003;19:95-101. vative on the basal tear turnover in glaucoma. (60) PERRY C.M., McGAVIN J.K., CULY C.R., IB- Br J Ophthalmol 1995; 79:339-342. BOTSON T. − Latanoprost: an update of its use (48) LEE Y.C. − Abdominal cramp as an adverse ef- in glaucoma and ocular hypertension. Drugs fect to travoprost. Am J Ophthalmol. 2005; Aging 2003; 20:597-560. 139:202-203. (61) PISELLA P.J.,FILLACIER K., ELENA P.P. − Com- (49) MANNI G., CENTOFANTI M., SACCHETTI M., parison of the effects of preserved and unpre- ODDONE F., BONINI S., PARRAVANO M., BUC- served formulations of timolol on the ocular CI M.G. − Demographic and clinical factors as- surface of albino rabbits. Ophthalmic Res. sociated with development of brimonidine tar- 2000; 32:3-8. trate 0.2%-indiced ocular allergy. J Glaucoma (62) PISELLA P.J., POULIQUEN .P, BAUDOUIN C. 2004; 13:163-167. − Prevalence of ocular symptoms and signs (50) MARQUES PEREIRA M.L., KATZ L.J. − Cho- with preserved and preservative-free glauco- roidal detachment after the use of topical la- ma medication. Br J Ophthalmol 2002; tanoprost. Am J Ophthalmol 2001; 132:928- 86:418-423. 929. (63) PISELLA P.J., LALA E., PARIER V., BRIGNO- (51) MIETZ H., NIESEN U., KRIEGELSTEIN G.K. − LE F., BAUDOUIN C. − Effect of preservatives The effects of preservatives and antiglaucoma- on the conjunctiva: a comparative study of be- tous medications on histopathology of the con- ta-blocker eye drops with and without preser- junctiva. Graefes Arch Clin Exp Ophthalmol vatives in glaucoma patients. J Fr Ophtalmol 1994; 232:561-565. 2003; 26:675-679. (52) MINISH T., HERD A. − Symptomatic bradycar- (64) RAJAN M.S., SYAM P., LIU C. − Systemic side dia secondary to interaction between topical ti- effects of topical latanoprost. Eye 2003; molol maleate, verapamil, and flecainide: a 17:442-444. case report. J Emerg Med. 2002; 22:247- (65) ROCKWOOD J.E. − Medical Management of 249. Glaucoma. In: “Clinical Guide to Glaucoma (53) NEELAKANTAN A., VAISHNAV H.D, LYER S.A., management”. In Higginbotham E.J., Lee D.A. SHERWOODS M.B. − Is addition of a third or Butterworth and Heinemann Elsevier Inc. 2004; fourth antiglaucoma medication effective? J 7:107-122. Glaucoma 2004; 13:130-136. (66) SAKAI H., SAKIMA N., NAKAMURA Y., HAYA- (54) NETLAND P.A., MICHAEL M., ROSNER S.A., BAWA K., SAWAGUCHI S. − Ciliochoroidal ef- KATZMAN B., MACY J.I. − Brimonidine Purite fusion induced by topical latanoprost in a pa- and bimatoprost compared with timolol and la- tient with Sturge-Weber syndrome. Jpn J Oph- tanoprost in patients with glaucoma and ocu- thalmol 2002; 46:553-555. lar hypertension. Adv Ther. 2003; 20:20-30. (67) SCHWARTZ G.F. − Compliance and persisten- (55) NOECKER R.J., HERRYGERS L.A., ANWARUD- cy in glaucoma follow-up treatment. Curr Opin DIN R. − Corneal and conjunctival changes Ophthalmol, 2005; 16:114-21. caused by commonly used glaucoma medica- (68) SCHWEITZER I., MAGUIRE K., TUCKWELL V. tions. Cornea 2004; 23:490-496. − Antiglaucoma medication and clinical de-

39 pression. Austr and New Zealand J of Psych. used to treat obstructive lung disease, conges- 2001; 35:569-571. tive heart failure and depression among users (69) SNAPE J.P.,WALDOCK A. − Spirometry for pa- of topical beta blockers:estimates from three tients prescribed topical beta-blockers. Nurs Veterans Affairs Medical Centers. Pharmaco- Stand. 2000; 15:35-38. epidemiol Drug Saf. 2001;10:511-516. (70) STAMPER R.L., WIGGINTON S.A., HIGGIN- (79) VIESTENZ A., MARTUS P., SCHLOTZER- BOTHAM E.J. − Primary drug treatment for SCHREHARDT U., LANGENBUCHER A., MAR- Glaucoma: beta-blockers versus other medi- DIN C.Y. − Impact of prostaglandin-F(2alpha)- cations. Surv Ophthalmol 2002; 47:63-73. analogues and carbonic anhydrase inhibitors (71) STEWART W.C., DAY D.G., HOLMES K.T.,STE- on central corneal thickness − a cross sectio- WART J.A. − Effect of timolol 0.5% gel and so- nal study on 403 eyes. Klin Monatsbl Augen- lution on pulmonary function in older glauco- heilkd 2004; 221: 753-756. ma patients. J Glaucoma 2001;10:227-232. (80) WAND M., GAUDIO A.R., SHIELDS M.B. − La- (72) STEWART W.C., SHARPE E.D., STEWART tanoprost and cystoid macular edema in high- J.A., HOTT C.E. The safety and efficacy of ti- risk aphakic or pseudophakic eyes. J Cataract molol 0.5% in xanthan gum versus timolol gel Refract Surg 2001; 27:1397-1401. forming solution 0.5%. Curr Eye Res (81) WATTS P., HAWKSWORTH N. − Delayed hy- 2002;24:387-391. persensitivity to brimonidine tartrate 0.2% as- (73) STEWART W.C., HALPER L.K., JOHNSON- sociated with high intraocular pressure. Eye PRATT L., POLIS A., HARTENBAUM D. Tolera- 2002; 16:132-135. bility and efficacy of dorzolamide versus ace- (82) YALVAC I.S., GEDIKOGLU G., KARAGOZ Y. − tazolamide added to timolol. J Ocul Pharma- Effects of antiglaucoma drugs on ocular surfa- col Ther 2002;18:211-220 ce. Acta Ophthalmol Scand 1995; 73:246- (74) STEWART W.C., STEWART J.A., DAY D.G., 248. SHARPE E.D., JENKINS J.N. Efficacy and sa- (83) YUKSEL N., KARABAS L., ALTINTAS O., YIL- fety of the latanoprost timolol maleate fixed DIRIM Y., CAGLAR Y. − A comparison of the combination vs concomitant brimonidine and short-term hypotensive effects and side effects latanoprost therapy. Eye 2004;18:990-995. of unilateral brimonidine and apraclonidine in (75) STEWART W.C., DAY D.G., STEWART J.A., patients with elevated intraocular pressure. HOLMES K.T., JENKIS J.N. Short-term ocular Ophthalmologica 2002; 216:45-49. tolerability of dorzolamide 2% and brinzolamide 1% vs placebo in primary open-angle This manuscript has been presented during glaucoma and ocular hypertension subjects. Eye 2004;18:905-910. the meeting of the Belgian Glaucoma Society (76) TOKUNAGA T., KASHIWAGI K., SAITO J., KO- on 23.11.2005 (OB 2005) BAYASHI K., KOBORI Y., ABE K., TSUKAHA- RA S. A case of cystoid macular edema associated with latanoprost ophthalmic solution. zzzzzz Jpn J Ophthalmol 2002;46:659-659. (77) TURACLI E., BUDAK K., KAUR A. The effects Correpondence and reprints: Prof. M. DETRY-MOREL of long-term glaucoma medication on conjunc- St Luc University Hospital tival impression cytology. Int Ophthalmol Department of Ophthalmology 1997;21:27-33. Avenue Hippocrate, 10 (78) VALUCK R.J., PERLMAN J.I., ANDERSON C. B-1200 Brussels WORTMAN G.I. Co-prescribing of medications e-mail: [email protected]