Effects of some ophthalmic medications on pupil size: a literature review

CAN J OPHTHALMOL—VOL. 44, NO. 2, 2009 193

Effects of some ophthalmic medications on pupil size: a literature reviewElena S. Novitskaya,* PhD; Simon J. Dean,† FRANZCO; Jonathan E. Moore,*‡ FRCOphth, PhD; Tara C.B. Moore,* PhD; Sonali Nagendran,§ MBChB; Anant Sharma,|| FRCOphth

Ophthalmological pharmacology is a rapidly expanding field aimed at achieving the safest and most effective treatment results. Physicians must be aware of the side-effect profiles, both beneficial and harmful, of medications currently used. This review highlights the available data on the effect of some ophthalmic medications on pupil size; it was limited to all reports or studies describing topical ophthalmic agents not originally designed or indicated to alter pupil diameter. This awareness will protect patients from unwanted drug-induced side effects and will improve clinical management and patient care.

La pharmacologie ophtalmologique est un champ qui prend rapidement de l’expansion, son but étant d’obtenir les traitements les plus sûrs et les plus efficaces. Les médecins doivent être avertis des effets secondaires, bienfaisants et nocifs, des médicaments couramment utilisés. Cette revue souligne les données disponibles sur les effets de certains médicaments ophtalmiques sur le diamètre pupillaire; elle se limite aux compte-rendus ou études portant sur les agents ophtalmiques topiques dont la conception ou l’indication originale n’avait pas pour but d’altérer le diamètre de la pupille. Cette information protégera les patients des effets secondaires non souhaités des médicaments et amélior-era la prise en charge clinique et le soin des patients.

The importance of pupil size is becoming more widely recognized in different areas of modern ophthalmol-

ogy. Evaluation of the size and motility of the pupil is vital in cataract and refractive surgery outcome. The pupil is a dynamic structure effected by numerous factors, includ-ing pupillary hippus, emotional status, and systemic and topical ophthalmic medications. However, even slight changes in pupil size can correlate with considerable dif-ferences in contrast sensitivity and visual acuity. There are many varieties of eye drops that can notably modify pupil diameter, and they are mainly used as miotics and my-driatics. We are well aware of the effects of most of these medications, and routinely use them for diagnostic and treatment purposes, aimed mostly at change of pupil size. Among the different pharmacological groups of drops ap-plied to achieve other effects (such as lowering intraocular pressure), there are quite a few medications that can in-duce or prevent miosis or mydriasis. By providing a review of literature on the data available on the effects of some ophthalmic medications that are not commonly used to alter pupil size, this article may contribute to our under-standing of patients’ tolerability of drops and the effects of the combined use of different medications.

METHODS

Articles assessed for this review were identified by an electronic search of PubMed and MEDLINE and by sub-sequent review of the reference section of each of these databases. Fifty relevant articles relating to the effects of dif-ferent drops on pupil size were identified, including original publications, reviews, and animal studies.

RESULTS

AntibioticsFluoroquinolones are a wide group of antibiotics used

for ocular infection. Side effects of the 2 new ophthalmic solutions of the fourth-generation fluoroquinolones, gati-floxacin 0.3% and moxifloxacin 0.5%, were compared in a double-masked design study.1 The authors found a signifi-cant reduction in pupil size in eyes that received moxiflox-acin, from 5.65 to 5.05 mm (p = 0.004).

There are few data available on the impact of other groups of antibiotics on pupil size. A case of mydriasis and paresthesia from local gentamicin sulphate was reported by Awan2 in 1985.

From *the University of Ulster, Coleraine, Northern Ireland, U.K.; †Auckland Hospital, Auckland, New Zealand; ‡Belfast Health and Social Care Trust, Belfast, Northern Ireland, U.K.; §Addenbrooke’s Hospital, Cambridge, U.K.; and ||Moorfield Eye Hospital, Bedford, U.K.

Originally received May 8, 2008Accepted for publication Aug. 28, 2008Published online Feb. 27, 2009

Correspondence to Elena Novitskaya, PhD, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, U.K.; [email protected]

This article has been peer-reviewed. Cet article a été évalué par les pairs.

Can J Ophthalmol 2009;44:193–7doi:10.3129/i09-003

Effects of ophthalmic medications on pupil size—Novitskaya et al.

194 CAN J OPHTHALMOL—VOL. 44, NO. 2, 2009

Antiglaucoma drugsThe effect of antiglaucoma drugs on pupil size is very im-

portant, especially in angle-closure glaucoma, where miosis is often necessary. In the recent literature, there are a lot of data regarding the side-effect profiles of many antiglaucoma drugs, including influence on the pupil. We did not include pilocarpine hydrochloride in the review because it is a well-known miotic agent.

Antiglaucoma drugs with miotic effect

Brimonidine tartrateThere are several reports of the effect of the alpha-2

adrenergic agonist brimonidine tartrate on pupil size.3–9 It has been demonstrated that brimonidine tartrate 0.15% produces a significant miotic effect under all 3 illuminance conditions (scotopic, mesopic, and photopic). McDonald et al.6 found that brimonidine tartrate effectively decreased scotopic pupil diameter but did not significantly change photopic pupil size. The authors claim that this effect of brimonidine tartrate may benefit postoperative refractive patients who report night-vision difficulties, such as halos, related to a large pupil. A study that aimed to compare the influence on pupil size of brimonidine tartrate versus dapip-razole hydrochloride, which is commonly used to reverse the effects of mydriatics, demonstrated a slightly stronger effect of brimonidine tartrate.10

Thymoxamine hydrochlorideThymoxamine hydrochloride is a selective alpha-adrener-

gic blocking agent that has been advocated for treatment of angle-closure glaucoma.11–13 The chemistry and pharma-cology of thymoxamine are known in detail. It produces alpha-adrenergic blockage by competitive antagonism and constricts the pupil, producing an average miotic effect of 2.2 mm in normal eyes, and 1.5 mm in eyes with open-angle glaucoma.13,14 It is also speculated that this agent may help to distinguish open-angle glaucoma from narrow-angle and angle-closure glaucoma.13,14

Antiglaucoma drugs with mydriatic effect

Apraclonidine hydrochlorideApraclonidine hydrochloride, a direct-acting cholinergic

(alpha-2 adrenergic) agonist, was developed to lower intra-ocular pressure and minimize the systemic side effects associated with the use of its parent drug, clonidine hydro-chloride. This medication is also used in the investigation of Horner syndrome. Many researchers have demonstrated that apraclonidine hydrochloride 1.0% tends to have a pupil-dilating effect.15–17 A randomized study evaluating the effects of unilateral therapy with topical 1% apraclonidine hydro-chloride in normal volunteers demonstrated significant mydriasis following application of apraclonidine (p < 0.05 after 1 hour, p < 0.01 after 5 hours, and p < 0.005 after 7 hours).16 A comparative study of the efficacy and side effects

of clonidine and apraclonidine hydrochloride in normal and ocular hypertensive volunteers found eyelid retraction, conjunctival blanching, and mydriasis in eyes treated with apraclonidine hydrochloride, and no changes in either pupil diameter or intrapalpebral fissure width with clonidine.18

Antiglaucoma drugs with little or no effect on pupil size

Beta-blockersAlthough many studies have proved that timolol maleate

has no statistically significant effect on pupil size,19–21 some in-vestigators have reported a slight reduction in pupil diameter, which may suggest the presence of inhibitory beta receptors on the sphincter papillae.19,22,23 Curiously, animal experi-ments in glaucomatous dogs, comparing the effects of topical administration of timolol maleate, dorzolamide hydrochlor-ide, and a combination of dorzolamide and timolol, demon-strated that timolol maleate significantly decreased pupil size (−1.42 + 0.4 mm, no level of significance was cited).24

A selective beta-blocker, betaxolol hydrochloride, had no effect on pupil size in several double-masked randomized studies in patients with glaucoma (no p value was cited).20,25 In a series of controlled clinical studies, no difference in pu-pil size was observed following application of levobunolol hydrochloride.26,27

Carbonic anhydrase inhibitorsCarbonic anhydrase inhibitors are routinely used for

reduction of intraocular pressure. A comparative ocular tolerance study undertaken with the topical carbonic an-hydrase inhibitor MK-927 and its S-enantiomer MK-417 (sezolamide) in 20 healthy volunteers revealed no changes in pupil size or central vision.28

Experiments undertaken in veterinary ophthalmology with topical administration of brinzolamide in healthy cats and dorzolamide hydrochloride in glaucomatous dogs also did not find alterations of pupil size.24,29 There are no published data available on the measurement of pupil size before and after application of dorzolamide hydrochloride and brinzolamide hydrochloride in humans.

Prostaglandin analoguesProstaglandin analogues represent a class of very effective

ocular hypotensive agents. Their safety and side-effect pro-file are well reported in the literature.30,31

In a clinical evaluation of unoprostone isopropyl in the ad-junctive treatment of primary open-angle glaucoma, inves-tigators did not observe any influence on pupil diameter.32

Marchini et al.33 assessed the effect of latanoprost on ocu-lar anterior segment geometry, and did not detect pupillary alterations.

In numerous clinical trials with travoprost, side effects regarding the pupil were not reported.

Topical corticosteroidsThere are few data on the possible effect of steroids on



pupil size. Armaly34 applied topical dexamethasone-21-phosphate and administered subconjunctival methylpred-nisolone acetate in monkeys, but did not demonstrate a change in pupil diameter. However, pupillary dilatation fol-lowing topical application of corticosteroids was observed in some patients after 2 weeks of therapy, and was reversible by stopping the medication.34 Newsome et al. 35 investigat-ed pupil size and interpalpebral fissure following the use of dexamethasone with vehicle and dexamethasone in normal saline, in monkeys. The results showed that dexamethasone with vehicle, and vehicle alone, produced relative pupillary dilatation and ptosis, but dexamethasone in saline did not.35 The authors suggested the mydriasis and ptosis appeared to be caused by a myopathic effect of the vehicle.

Topical anestheticsOphthalmologists frequently use lidocaine hydrochlor-

ide (lignocaine), benoxinate hydrochloride, amethocaine hydrochloride (tetracaine), proparacaine hydrochloride, and other medications of this class as topical anesthetic agents. Local anaesthetic medications inhibit the rate of corneal epithelial cell migration by disrupting cytoplasmic action in filaments and destroying superficial corneal epithelial microvilli.36 This phenomenon potentiates the mydriasis induced by routinely used mydriatics. It has been shown that dilation of the pupil is considerably greater if a topical anesthetic is applied before the mydriatic.36–38 Benoxinate, proparacaine, and tetracaine produced approximately equal degrees of enhancement of the mydriasis.37,38 Ghose et al.38 demonstrated that in the eyes pretreated with ligno-caine, pupillary diameter increased by 3.62 (SD 0.75) mm (p = 0.000), significantly more than in the placebo group. The median time to achieve a 6 mm pupil size was signifi-cantly shorter in the group with lignocaine (p = 0.005). In-vestigators claimed that this remarkable phenomenon could find use with many other important topical medications.

Intracameral lidocaine hydrochloride is also commonly used to produce pupillary dilatation in cases of mild intra-operative miosis, which presumably occurs secondary to a greater effect upon the sphincter papillae.39–41 Whether the adjunctive dilatation noted with the use of topical anesthet-ics is also related to this effect, in addition to the enhanced penetration of other dilators, is unknown.

MorphineThe effect of general administration of opioids such as

morphine hydrochloride on pupil size is well known. Fan-ciullacci et al.42 showed that local application of 4% mor-phine hydrochloride eye drops administered to 1 eye caused a miosis limited to that eye. The authors also demonstrated that topical use of morphine hydrochloride after installation of 0.5% homatropine hydrobromide reduces mydriasis.42

SympathomimeticsTwo studies were carried out in volunteers without any

abnormal ocular conditions to assess the effects and safety

of an ophthalmic preparation of oxymetazoline hydrochlor-ide (0.025%) used to reduce conjunctival congestion. In 1 study, where oxymetazoline was compared with placebo and phenylephrine hydrochloride, the results of infrared electronic pupillography demonstrated that oxymetazoline in therapeutic doses had no effect on pupil size or near-point recession.43

Nonsteroidal anti-inflammatory drugsTopical nonsteroidal anti-inflammatory drugs are widely

used in ophthalmological practice. This group of medica-tions does not have a direct effect on pupil size but prevents surgically induced miosis. Extensive data are available on the effect of diclofenac sodium, indomethacin, and flurbi-profen sodium on pupil diameter during and after cataract surgery.44–47 The studies have shown that these drops can significantly prevent surgically induced miosis. Interest-ingly, diclofenac sodium is 50% more effective than indo-methacin in maintaining intraoperative mydriasis.44

A study aimed at assessing the miotic effect induced by cryotherapy, and the ability of diclofenac sodium to over-come such an effect, was conducted on 18 rabbits by al-Salem et al.48 A highly statistical difference was observed in the reduction of the miotic effect of cryotherapy in those eyes treated with diclofenac sodium.

Hydroxypropyl methylcellulose and sodium hyaluronate

Hydroxypropyl methylcellulose and sodium hyaluronate are nonpyrogenic viscoelastic solutions used in anterior seg-ment surgery. Many clinical series have noted no significant difference in terms of postoperative complications in eyes operated on using methylcellulose and sodium hyaluronate. However, Tan and Humphry49 reported fixed and semidi-lated pupils in 9 (16.7%) of 54 patients following extraca-psular cataract extraction (first observed 2 days to 6 weeks postoperatively), which was neither reactive to light nor ac-commodation. Additionally, 15 of the 54 had a partially reactive pupil. In the group of patients in whom sodium hyaluronate was used, none of the 48 patients had a non-reactive pupil, and only 9 had a partially reactive pupil. A prospective randomized clinical trial was set up to compare the effect of these 2 medications on pupil size and reactivity following use in cataract surgery during phacoemulsifica-tion.50 This study observed a nonreactive pupil in 2% and a partially reactive pupil in 4% of the eyes of the methylcellu-lose group, and no nonreactive pupils following the use of sodium hyaluronate. The authors concluded that the visco-elastic solutions have a similar effect on the pupil following their use in cataract surgery.50

Most publications investigating the side effects of visco-elastics demonstrated that retention of viscoelastic material may induce a significant rise in intraocular pressure after surgery.51–54 The same mechanism may cause postoperative alteration of pupil size. In addition, incomplete removal of viscoelastic allows it to act as a vehicle for other medica-


196 CAN J OPHTHALMOL—VOL. 44, NO. 2, 2009

tion that may dilate the pupil. Increased miotic effect was demonstrated in animal experiments using a combination of pilocarpine and sodium hyaluronate; however, the same mechanism may reinforce the effect of mydriatics used in cataract surgery.55

CONCLUSIONS

Ophthalmological pharmacology is a rapidly expanding field, with many drugs being utilized for properties and ef-fects for which they were not originally designed or indi-cated. Because of this, physicians must be aware of the side-effect profiles, both beneficial and harmful, including the possibility of alteration of pupil size. This awareness will protect patients from unwanted drug-induced side effects, but more importantly, will allow the judicious use of agents to improve clinical management and patient care.

The authors have no proprietary or commercial interest in any materials discussed in this article.

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Keywords: pupil, miosis, mydriasis, anaesthetic drops, antibiotic drops, side effects

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Effects of some ophthalmic medications on pupil size: a literature review