Section XV. Ophthalmology Chapter 66.

Ocular Pharmacology

Overview This chapter focuses on specific pharmacodynamic, pharmacokinetic, and drug delivery issues relevant to ocular therapy and imparted by the unique anatomy and function of this sensory organ, introduced at the outset of this chapter. any of the pharmacological agents discussed here have been discussed in earlier chapters. !utonomic agents have several uses in ophthalmology, including diagnostic evaluation of anisocoria and myasthenia gravis, as ad"unctive therapy in laser and incisional surgeries, and in the treatment of glaucoma. These agents are discussed in detail in Chapters 6# $eurotransmission# The !utonomic and %omatic otor $ervous %ystems, &# uscarinic 'eceptor !gonists and !ntagonists, (# !nticholinesterase !gents, )# !gents !cting at the $euromuscular *unction and !utonomic +anglia, and ,-# Catecholamines, %ympathomimetic .rugs, and !drenergic 'eceptor !ntagonists. The antimicrobial agents employed for chemotherapy of orbital cellulitis, con"unctivitis, keratitis, endophthalmitis, retinitis, and uveitis also are discussed in Chapters /0# !ntimicrobial !gents# +eneral Considerations, //# !ntimicrobial !gents# %ulfonamides, Trimethoprim1%ulfametho2a3ole, 4uinolones, and !gents for 5rinary Tract 6nfections, /7# !ntimicrobial !gents# Penicillins, Cephalosporins, and Other 18actam !ntibiotics, /6# !ntimicrobial !gents# The !minoglycosides, /&# !ntimicrobial !gents# Protein %ynthesis 6nhibitors and iscellaneous !ntibacterial !gents, /(# !ntimicrobial !gents# .rugs 5sed in the Chemotherapy of Tuberculosis, Mycobacterium avium Comple2 .isease, and 8eprosy, /)# !ntimicrobial !gents# !ntifungal !gents, and 7-# !ntimicrobial !gents# !ntiviral !gents 9$onretroviral:. The vitamins and trace elements used in ad"unctive eye therapy are discussed in Chapters 60# ;ater1%oluble <itamins# The <itamin = Comple2 and !scorbic !cid and 6/# >at1 %oluble <itamins# <itamins !, ?, and @, and immunomodulatory agents important in treating vitreoretinopathy, retinitis, and uveitis are discussed in Chapter 70# 6mmunomodulators# 6mmunosuppressive !gents, Tolerogens, and 6mmunostimulants. !lso included in this chapter are the wetting agents and tear substitutes used to treat dry eye syndrome, as well as drugs and osmotic agents affecting ocular electrolyte metabolism 9see also Chapter A)# .iuretics:. The chapter concludes with a prospectus on the future of ocular therapeutics, including gene transfer, immunomodulation, molecular1 and cellular1based therapies including inhibitors of protein kinase C for diabetic retinopathy, and neuroprotection. Ocular Pharmacology# 6ntroduction Bistory 'ecords from esopotamia 9ca. 0---C/--- =.C.: reveal that mysticismDcombined with vegetable, animal, and mineral matterDwas used to treat spirits and devils causing eye disease. .uring the classical +reek era 9ca. /6-C0&7 =.C.: when Bippocrates revolutioni3ed the therapeutics of disease, several hundred remedies were described for afflictions of the eye. +alen and %usruta categori3ed eye diseases on an anatomical basis and applied medicinal as well as surgical remedies advocated by Bippocrates 9see .uke1@lder, ,)6AE !lbert and @dwards, ,))6:.

;ith this empirical approach to treat disease, ophthalmic therapeutics took root from remedies discovered for systemic diseases. >or instance, silver nitrate was used medicinally in the early seventeenth century. CredF later instituted the use of silver nitrate in newborns as prophyla2is against neonatal con"unctivitis, a potentially blinding condition, which during his time was primarily caused by Neisseria gonorrhoeae. 6n the nineteenth century, numerous organic substances were isolated from plants and introduced to treat eye diseases. The belladonna alkaloids were used as poisons, for asthmatic therapy, and for cosmetic effectE hyoscyamus and belladonna were used to treat iritis in the early ,(--s. !tropine was isolated and used therapeutically in the eye in ,(0A. 6n ,(&7, pilocarpine was isolatedE the therapeutic effect of lowering intraocular pressure was recogni3ed in ,(&&, providing the basis for a safe and effective treatment of glaucoma that is stillbreak efficacious. Overview of Ocular !natomy, Physiology, and =iochemistry The eye is a speciali3ed sensory organ that is relatively secluded from systemic access by the blood1 retinal, blood1aqueous, and blood1vitreous barriers. =ecause of this anatomical isolation, the eye offers a unique, organ1specific pharmacological laboratory to study, for e2ample, the autonomic nervous system and effects of inflammation and infectious diseases. $o other organ in the body is so readily accessible or as visible for observationE however, the eye also presents some unique opportunities as well as challenges for drug delivery 9see 'obinson, ,))0:. @2traocular %tructures The eye is protected by the eyelids and by the orbit, a bony cavity of the skull that has multiple fissures and foramina that conduct nerves, muscles, and vessels 9>igure 66C,:. 6n the orbit, connective 9i.e., TenonGs capsule: and adipose tissues and si2 e2traocular muscles support and align the eyes for vision. The area behind the eye 9or globe: is called the retrobulbar region. 5nderstanding ocular and orbital anatomy is important for safe periocular drug delivery, including subcon"unctival, sub1TenonGs, and retrobulbar in"ections. The eyelids serve several functions. >oremost, their dense sensory innervation and eyelashes protect the eye from mechanical and chemical in"uries. =linking, a coordinated movement of the orbicularis oculi, levator palpebrae, and HllerGs muscles, serves to distribute tears over the cornea and con"unctiva. 6n human beings, the average blink rate is ,7 to A- times per minute. The e2ternal surface of the eyelids is covered by a thin layer of skinE the internal surface is lined with the palpebral portion of the con"unctiva, which is a vasculari3ed mucous membrane continuous with the bulbar con"unctiva. !t the reflection of the palpebral and bulbar con"unctiva is a space called the forni2, located superiorly and inferiorly behind the upper and lower lids, respectively. Topical medications usually are placed in the inferior forni2, also known as the inferior cul1de1sac. >igure 66C,. !natomy of the +lobe in 'elationship to the Orbit and @yelids. <arious routes of administration of anesthesia are demonstrated by the blue needle pathways. 9!dapted from 'iordan1@va and Tabbara, ,))A, with permission.:

The lacrimal system consists of secretory glandular and e2cretory ductal elements 9>igure 66CA:. The secretory system is composed of the main lacrimal gland, which is located in the temporal outer portion of the orbit, and accessory glands, also known as the glands of ?rause and ;olfring 9see >igure 66C,:, located in the con"unctiva. The lacrimal gland is innervated by the autonomic nervous system 9see Table 66C, and Chapter 6# $eurotransmission# The !utonomic and %omatic otor $ervous %ystems:. The parasympathetic innervation is clinically relevant since a patient may complain of dry eye symptoms while taking medications with anticholinergic side effects, such as antidepressants 9see Chapter ,)# .rugs and the Treatment of Psychiatric .isorders# .epression and !n2iety .isorders:, antihistamines 9see Chapter A7# Bistamine, =radykinin, and Their !ntagonists:, and drugs used in the management of ParkinsonGs disease 9see Chapter AA# Treatment of Central $ervous %ystem .egenerative .isorders:. 8ocated "ust posterior to the eyelashes are meibomian glands 9see >igure 66C,:, which secrete oils that retard evaporation of the tear film. !bnormalities in gland function, as in acne rosacea and meibomitis, can greatly affect tear film stability. >igure 66CA. !natomy of the 8acrimal %ystem. 9!dapted from 'iordan1@va and Tabbara, ,))A, with permission.:

Conceptually, tears constitute a trilaminar lubrication barrier covering the con"unctiva and cornea.

The anterior layer is composed primarily of lipids secreted by the meibomian glands. The middle aqueous layer, produced by the main lacrimal gland and accessory lacrimal glands 9i.e., ?rause and ;olfring glands:, constitutes about )(I of the tear film. !dherent to the corneal epithelium, the posterior layer is a mi2ture of mucins produced by goblet cells in the con"unctiva. Tears also contain nutrients, en3ymes, and immunoglobulins to support and protect the cornea. The tear drainage system starts through small puncta located on the medial aspects of both the upper and lower eyelids 9>igure 66CA:. ;ith blinking, tears enter the puncta and continue to drain through the canaliculi, lacrimal sac, nasolacrimal duct, and then into the nose. The nose is lined by a highly vascular mucosal epitheliumE consequently, topically applied medications that pass through this nasolacrimal system have direct access to the systemic circulation. Ocular %tructures The eye is divided into anterior and posterior segments 9see >igure 66C0A:. !nterior segment structures include the cornea, limbus, anterior and posterior chambers, trabecular meshwork, %chlemmGs canal, iris, lens, 3onules, and ciliary body. The posterior segment comprises the vitreous, retina, choroid, sclera, and optic nerve. >igure 66C0. !. !natomy of the @ye. =. @nlargement of the !nterior %egment 'evealing the Cornea, !ngle %tructures, 8ens, and Ciliary =ody. 9!dapted from 'iordan1@va and Tabbara, ,))A, with permission.:

!nterior %egment The cornea is a transparent and avascular tissue organi3ed into five layers# epithelium, =owmanGs membrane, stroma, .escemetGs membrane, and endothelium 9see >igure 66C0B:. 'epresenting an important barrier to foreign matter, including drugs, the epithelial layer is composed of five to si2 layers of epithelial cells. The basal epithelial cells lie on a basement membrane that is ad"acent to =owmanGs membrane, a layer of collagen fibers. Constituting appro2imately )-I of the corneal thickness, the stroma, a hydrophilic layer, is uniquely organi3ed with collagen lamellae synthesi3ed by keratocytes. =eneath the stroma lies .escemetGs membrane,

the basement membrane of the corneal endothelium. 8ying most posteriorly, the endothelium is a monolayer of cells adhering to each other by tight "unctions. These cells maintain corneal integrity by active transport processes and serve as a hydrophobic barrier. Bence, drug absorption across the cornea necessitates penetrating the trilaminar hydrophobic1hydrophilic1hydrophobic domains of the various anatomical layers. !t the periphery of the cornea and ad"acent to the sclera lies a transitional 3one 9, to A mm wide: called the limbus. 8imbal structures include the con"unctival epithelium, which contain the stem cells, TenonGs capsule, episclera, corneoscleral stroma, %chlemmGs canal, and trabecular meshwork 9>igure 66C0B:. 8imbal blood vessels, as well as the tears, provide important nutrients and immunological defense mechanisms for the cornea. The anterior chamber holds appro2imately A7l of aqueous humor. The peripheral anterior chamber angle is formed by the cornea and the iris root. The trabecular meshwork and canal of %chlemm are located "ust above the ape2 of this angle. The posterior chamber, which holds appro2imately 7- l of aqueous humor, is defined by the boundaries of the ciliary body processes, posterior surface of the iris, and lens surface. !queous Bumor .ynamics and 'egulation of 6ntraocular Pressure !queous humor is secreted by the ciliary processes and flows from the posterior chamber, through the pupil, into the anterior chamber, and leaves the eye primarily by the trabecular meshwork and canal of %chlemm. >rom the canal of %chlemm, aqueous humor drains into an episcleral venous ple2us and into the systemic circulation. This conventional pathway accounts for (-I to )7I of aqueous humor outflow and is the main target for cholinergic drugs used in glaucoma therapy. !nother outflow pathway is the uveoscleral route 9i.e., fluid flows through the ciliary muscles and into the suprachoroidal space:, which is the target of selective prostanoids 9see Chapter A6# 8ipid1 .erived !utacoids# @icosanoids and Platelet1!ctivating >actor and later in this chapter:. The peripheral anterior chamber is an important anatomical structure for differentiating two forms of glaucoma# open1angle glaucoma, which is by far the most common form of glaucoma, and angle1 closure glaucoma. Current medical therapy of open-angle glaucoma is aimed at decreasing aqueous humor production andJor increasing aqueous outflow. The preferred management for angle-closure glaucoma is surgical iridectomy, either by laser or by incision, but short1term medical management may be necessary to reduce the acute intraocular pressure elevation and to clear the cornea prior to laser surgery. !s mentioned in other chapters, acute angle1closure glaucoma may be induced rarely in anatomically predisposed eyes by anticholinergic, sympathomimetic, and antihistaminic agents. 6nterestingly, however, individuals with those susceptible angles do not know they have them. !s far as they know, they do not have glaucoma and are not aware of a risk of angle1closure glaucoma. Ket, drug warning labels do not always specify the type of glaucoma for which this rare risk e2ists. Thus, unwarranted concern is raised among patients who have open1angle glaucoma, by far the most common form of glaucoma in the 5nited %tates, and who need not be concerned about taking these drugs. 6n any event, in anatomically susceptible eyes, anticholinergic, sympathomimetic, and antihistaminic drugs can lead to partial dilation of the pupil and a change in the vectors of force between the iris and the lens. The aqueous humor then is prevented from passing through the pupil from the posterior chamber to the anterior chamber. The result can be an increase in pressure in the posterior chamber, causing the iris base to be pushed against the angle wall, thereby closing the filtration angle and markedly elevating the intraocular pressure. 6ris and Pupil looseness,The iris is the most anterior portion of the uveal tract, which also includes the ciliary

body and choroid. The anterior surface of the iris is the stroma, a loosely organi3ed structure containing melanocytes, blood vessels, smooth muscle, and parasympathetic and sympathetic nerves. .ifferences in iris color reflect individual variation in the number of melanocytes located in the stroma. 6ndividual variation may be an important consideration for ocular drug distribution due to drug1melanin binding 9seeL.istribution,L below:. The posterior surface of the iris is a densely pigmented bilayer of epithelial cells. !nterior to the pigmented epithelium, the dilator smooth muscle is oriented radially and is innervated by the sympathetic nervous system 9see >igure 66C/: which causes mydriasis 9dilation:. !t the pupillary margin, the sphincter smooth muscle is organi3ed in a circular band with parasympathetic innervation which, when stimulated, causes miosis 9constriction:. The use of pharmacological agents to dilate normal pupils 9i.e., for clinical purposes such as e2amining the ocular fundus: and to evaluate the pharmacological response of the pupil 9e.g., unequal pupils, or anisocoria, seen in BornerGs syndrome or !dieGs pupil: is summari3ed in Table 66CA. >igure 66C7 provides a flowchart for the diagnostic evaluation of anisocoria. >igure 66C/. !utonomic 6nnervation of the @ye by the %ympathetic 9a: and Parasympathetic 9b: %ystems. 9!dapted from ;ybar and ?err uir, ,)(/, with permission.:

>igure 66C7. !nisocoria @valuation >lowsheet. 9!dapted with permission from Thompson and Pilley, ,)&6.:

Ciliary =ody The ciliary body serves two very speciali3ed roles in the eye# secretion of aqueous humor by the epithelial bilayer and accommodation by the ciliary muscle. The anterior portion of the ciliary body, called the pars plicata, is composed of &- to (- ciliary processes with intricate folds. The posterior portion is the pars plana. The ciliary muscle is organi3ed into outer longitudinal, middle radial, and inner circular layers. Coordinated contraction of this smooth muscle apparatus by the parasympathetic nervous system causes the 3onules suspending the lens to rela2, allowing the lens to become more conve2 and to shift slightly forward. This process, known as accommodation, permits focusing on near ob"ects and may be pharmacologically blocked by muscarinic cholinergic antagonists, through the process called cycloplegia. Contraction of the ciliary muscle also puts traction on the scleral spur and, hence, widens the spaces within the trabecular meshwork. This latter effect accounts for at least some of the intraocular pressure1lowering effect of both directly acting and indirectly acting parasympathomimetic drugs. 8ens The lens, a transparent biconve2 structure, is suspended by zonules, speciali3ed fibers emanating from the ciliary body. The lens is appro2imately ,- mm in diameter and is enclosed in a capsule. The bulk of the lens is composed of fibers derived from proliferating lens epithelial cells located under the anterior portion of the lens capsule. These lens fibers are continuously produced throughout life. Posterior %egment

=ecause of the anatomical and vascular barriers to both local and systemic access, drug delivery to the eyeGs posterior pole is particularly challenging. %clera The outermost coat of the eye, the sclera, covers the posterior portion of the globe. The e2ternal surface of the scleral shell is covered by an episcleral vascular coat, by TenonGs capsule, and by the con"unctiva. The tendons of the si2 e2traocular muscles insert into the superficial scleral collagen fibers. $umerous blood vessels pierce the sclera through emissaria to supply as well as drain the choroid, ciliary body, optic nerve, and iris. 6nside the scleral shell, the vascular choroid nourishes the outer retina by a capillary system in the choriocapillaris. =etween the outer retina and the choriocapillaris lies =ruchGs membrane and the retinal pigment epithelium, whose tight "unctions provide an outer barrier between the retina and the choroid. The retinal pigment epithelium serves many functions, including vitamin ! metabolism 9see Chapter 6/# >at1%oluble <itamins# <itamins !, ?, and @:, phagocytosis of the rod outer segments, and multiple transport processes. 'etina The retina is a thin, transparent, highly organi3ed structure of neurons, glial cells, and blood vessels. Of all structures within the eye, the neurosensory retina has been the most widely studied 9see .owling, ,)(&:. The unique organi3ation and biochemistry of the photoreceptors have provided a superb model for investigating signal transduction mechanisms 9see %tryer, ,)(&:. 'hodopsin has been intensely analy3ed at the level of its protein and gene structures 9see ?horana, ,))A:. The wealth of information about rhodopsin has made it an e2cellent model for the + proteinCcoupled receptors 9see Chapter A# Pharmacodynamics# echanisms of .rug !ction and the 'elationship =etween .rug Concentration and @ffect:. %uch detailed understanding holds promise for targeted therapy for some of the hereditary retinal diseases. <itreous The vitreous is a clear medium that makes up about (-I of the eyeGs volume. 6t is composed of ))I water bound with collagen type 66, hyaluronic acid, and proteoglycans. The vitreous also contains glucose, ascorbic acid, amino acids, and a number of inorganic salts 9see %ebag, ,)():. Optic $erve The optic nerve is a myelinated nerve conducting the retinal output to the central nervous system. 6t is composed of 9,: an intraocular portion, which is visible as the ,.71mm optic disk in the retinaE 9A: an intraorbital portionE 90: an intracanalicular portionE and 9/: an intracranial portion. The nerve is ensheathed in meninges continuous with the brain. !t present, pharmacological treatment of some optic neuropathies is based on management of the underlying disease. >or e2ample, optic neuritis may be treated best with intravenous methylprednisilone 9=eck et al., ,))A, ,))0:E glaucomatous optic neuropathy is medically managed by decreasing intraocular pressure. Pharmacokinetics and To2icology of Ocular Therapeutic !gents .rug .elivery %trategies

>actors that affect the bioavailability of ocular drugs include pB, salt form of the drug, various structural forms of a given drug, vehicle composition, osmolality, tonicity, and viscosity. Properties of varying ocular routes of administration are outlined in Table 66C0. ! number of delivery systems have been developed for treating ocular diseases. ost ophthalmic drugs are delivered in aqueous solutions. >or compounds with limited solubility, a suspension form facilitates delivery. %everal formulations prolong the time a drug remains on the surface of the eye. These include gels, ointments, solid inserts, soft contact lenses, and collagen shields. Prolonging the time in the cul1de1 sac facilitates drug absorption. Ophthalmic gels 9e.g., pilocarpine /I gel: release drugs by diffusion following erosion of soluble polymers. The polymers used include cellulosic ethers, polyvinyl alcohol, carbopol, polyacrylamide, polymethylvinyl ether1maleic anhydride, polo2amer /-&, and puronic acid. Ointments usually contain mineral oil and a petrolatum base and are helpful in delivering antibiotics, cycloplegic drugs, or miotic agents. %olid inserts, such as OC5%@'T P68O1Aand P68O1/-, provide a zero-order rate of delivery by steady1state diffusion, whereby drug is released at a more constant rate to the precorneal tear film over a finite period of time rather than as a bolus. !lthough membrane1controlled drug delivery has advantages and is effective in some patients, the inserts have not gained widespread use, likely due to their cost and the fact that patients often have difficulty placing and retaining a solid insert in the cul1de1sac. Pharmacokinetics Classical pharmacokinetic theory based on studies of systemically administered drugs 9see Chapter ,# Pharmacokinetics# The .ynamics of .rug !bsorption, .istribution, and @limination: does not fully apply to all ophthalmic drugs 9see %choenwald, ,))0E .e%antis and Patil, ,))/:. !lthough similar principles of absorption, distribution, metabolism, and e2cretion determine the fate of drug disposition in the eye, alternative routes of drug administration, in addition to oral and intravenous routes, introduce other variables in compartmental analysis 9see Table 66C0 and >igure 66C6:. Ophthalmic medications are applied topically using a variety of formulations. .rugs also may be in"ected by subcon"unctival, sub1TenonGs, and retrobulbar routes 9see >igure 66C, and Table 66C0:. >or e2ample, anesthetic agents are administered commonly by in"ection for surgical procedures and antibiotics and glucocorticoids also may be in"ected to enhance their delivery to local tissues. 71 >luorouracil, an antimetabolite and antiproliferative agent, may be administered subcon"unctivally to retard the fibroblast proliferation related to scarring after glaucoma surgery. 6ntraocular 9i.e., intravitreal: in"ections of antibiotics are considered in instances of endophthalmitis, an intraocular infection. The sensitivities of the organisms to the antibiotic and the retinal to2icity threshold may be nearly the same for some antibioticsE hence, the antibiotic dose in"ected intravitreally must be carefully titrated. >igure 66C6. Possible !bsorption Pathways of an Ophthalmic .rug >ollowing Topical !pplication to the @ye. %olid black arrows represent the corneal routeE dashed blue arrows represent the con"unctivalJscleral routeE the black dashed line represents the nasolacrimal absorption pathway. 9!dapted from Chien et al., ,))-, with permission.:

5nlike clinical pharmacokinetic studies on systemic drugs, where data are collected relatively easily from blood samples, there is significant risk in obtaining tissue and fluid samples from the human eye. Consequently, animal models are studied to provide pharmacokinetic data on ophthalmic drugs. Commonly, the rabbit is used for such studies 9see c.onald and %hadduck, ,)&&, for comparison of to2icity, anatomy, and physiology of human and rabbit ocular systems:. !bsorption !fter topical instillation of a drug, the rate and e2tent of absorption are determined by the following# the time the drug remains in the cul1de1sac and precorneal tear film 9also known as the residence time:E elimination by nasolacrimal drainageE drug binding to tear proteinsE drug metabolism by tear and tissue proteinsE and diffusion across the cornea and con"unctiva 9see 8ee, ,))0:. ! drugGs residence time may be prolonged by changing its formulation. $asolacrimal drainage contributes to systemic absorption of topically administeredbreak ophthalmic medications. !bsorption from the nasal mucosabreak avoids so1called first1pass metabolism by the liver 9see Chapter ,# Pharmacokinetics# The .ynamics of .rug !bsorption, .istribution, and @limination:, and consequently significant systemic side effects may be caused by topical medications, especially when used chronically. Possible absorption pathways of an ophthalmic drug following topical application to the eye are shown schematically in >igure 66C6. Transcorneal and transcon"unctivalJscleral absorption are the desired routes for locali3ed ocular drug effects. The time period between drug instillation and its appearance in the aqueous humor is defined as the lag time. The drug concentration gradient between the tear film and the cornea and con"unctival epithelium provides the driving force for passive diffusion across these tissues. Other factors that affect a drugGs diffusion capacity are the si3e of the molecule, chemical structure, and steric configuration. Transcorneal drug penetration is conceptuali3ed as a differential solubility processE the cornea may be thought of as a trilamellar Lfat1water1fatL structure corresponding to the epithelial, stromal, and endothelial layers. The epithelium and endothelium represent barriers for hydrophilic substancesE the stroma is a barrier for hydrophobic compounds. Bence, a drug with both hydrophilic and lipophilic properties is best suited for transcorneal absorption.

.rug penetration into the eye is appro2imately linearly related to its concentration in the tear film. Certain disease states, such as corneal ulcers and other corneal epithelial defects or stromal keratitis, also may alter drug penetration. @2perimentally, drugs may be screened for their potential clinical utility by assessing their corneal permeability coefficients. These pharmacokinetic data combined with the drugGs octanolJwater partition coefficient 9for lipophilic drugs: or distribution coefficient 9for ioni3able drugs: yield a parabolic relationship that is a useful parameter for predicting ocular absorption. Of course, such in vitro studies do not account for other factors that affect corneal absorption, such as blink rate, dilution by tear flow, nasolacrimal drainage, drug binding to proteins and tissue, and transcon"unctival absorptionE hence, these studies have limitations in predicting ocular drug absorption in vivo. .istribution Topically administered drugs may undergo systemic distribution primarily by nasal mucosal absorption and possibly by local ocular distribution by transcornealJtranscon"unctival absorption. >ollowing transcorneal absorption, the aqueous humor accumulates the drug, which is then distributed to intraocular structures as well as potentially to the systemic circulation via the trabecular meshwork pathway 9see >igure 66C0B:. elanin binding of certain drugs is an important factor in some ocular compartments. >or e2ample, the mydriatic effect of 1adrenergic receptor agonists is slower in onset in human volunteers with darkly pigmented irides compared to those with lightly pigmented irides 9Obianwu and 'and, ,)67:. 6n rabbits, radiolabeled atropine binds significantly to melanin granules in irides of nonalbino animals 9%ala3ar et al., ,)&6:. This finding correlates with the fact that atropineGs mydriatic effect lasts longer in nonalbino rabbits than in albino rabbits, and suggests that drugCmelanin binding is a potential reservoir for sustained drug release. !nother clinically important consideration for drugCmelanin binding involves the retinal pigment epithelium. 6n the retinal pigment epithelium, accumulation of chloroquine 9see Chapter /-# .rugs 5sed in the Chemotherapy of Proto3oal 6nfections# alaria: causes a to2ic retinal lesion known as a LbullGs1eyeL maculopathy, which is associated with a decrease in visual acuity. @2traretinal manifestations of chloroquine to2icity include corneal and crystalline lens opacities and motility disturbances. etabolism @n3ymatic biotransformation of ocular drugs may be significant since local tissues in the eye e2press a variety ofen3ymes, including esterases, o2idoreductases, lysosomal en3ymes, peptidases, glucuronide and sulfate transferases, glutathione1con"ugating en3ymes, catechol1O1methyl1 transferase, monoamine o2idase, and corticosteroid 1hydro2ylase 9see 8ee, ,))A:. The esterases have been of particular interest because of the development of prodrugs for enhanced corneal permeabilityE for e2ample, dipivefrin hydrochloride 9 andell et al., ,)&(: is a prodrug for epinephrine, and latanoprost is a prodrug for prostaglandin >A 9%t"ernschant3 and 'esul, ,))A:E both drugs are used for glaucoma management. Topically applied ocular drugs are eliminated by the liver and kidney after systemic absorption. To2icology >rom the compartmental analysis given in >igure 66C6, it is apparent that all ophthalmic medications are potentially absorbed into the systemic circulation, so undesirable systemic side effects may occur. ost ophthalmic drugs are delivered locally to the eye, and the potential local to2ic effects are due to hypersensitivity reactions or to direct to2ic effects on the cornea, con"unctiva, periocular skin, and nasal mucosa. @yedrops and contact lens solutions commonly

contain preservatives such as ben3alkonium chloride, chlorobutanol, chelating agents, and thimerosal for their antimicrobial effectiveness. 6n particular, ben3alkonium chloride may cause a punctate keratopathy or to2ic ulcerative keratopathy 9+rant and %chuman, ,))0:. Therapeutic and .iagnostic !pplications of .rugs in Ophthalmology Chemotherapy of icrobial .iseases in the @ye

!ntibacterial !gents +eneral Considerations ! number of antibacterial antibiotics have been formulated for topical ocular use 9Table 66C/:. The pharmacology, structures, and kinetics of individual drugs have been presented in detail in preceding chapters. !ppropriate selection of antibiotic and route of administration is dependent on clinical e2amination and cultureJsensitivity results. %pecially formulated antibiotics also may be available for serious eye infections such as corneal ulcers or keratitis and endophthalmitis. Preparation of fortified solutions requires a pharmacist familiar with sterile preparation of ocular drugs. Therapeutic 5ses 6nfectious diseases of the skin, eyelids, con"unctiva, and lacrimal e2cretory system are encountered regularly in clinical practice. Periocular skin infections are divided into preseptal and postseptal or orbital cellulitis. .epending on the clinical setting 9i.e., preceding trauma, sinusitis, age of patient, relative immunocompromised state:, oral or parenteral antibiotics are administered. acryocystitis is an infection of the lacrimal sac. 6n infants and children, the disease usually is unilateral and secondary to an obstruction of the nasolacrimal duct. The physician should be aware of the changing microbiological spectrum for orbital cellulitis, for e2ample, the sharp decline in the involvement of !aemophilus in"luenzae after the introduction in ,)(7 of the !. in"luenzae vaccine 9!mbati et al., A---:. 6n adults, dacryocystitis and canalicular infections may be caused by Staphylococcus aureus, Streptococcus species, #andida species, and Actinomyces israelii. 6nfectious processes of the lids include hordeolum and blepharitis. ! hordeolum, or stye, is an infection of the meibomian, Meis, or oll glands at the lid margins. The typical offending bacterium is S.aureus, and the usual treatment consists of warm compresses and topical antibiotic ointment. Blepharitis is a common bilateral inflammatory process of the eyelids characteri3ed by irritation and burning, and it also is usually caused by a Staphylococcus species. 8ocal hygiene is the mainstay of therapyE topical antibiotics frequently are used, usually in ointment form, particularly when the disease is accompanied by con"unctivitis and keratitis. #on$unctivitis is an inflammatory process of the con"unctiva that varies in severity from mild hyperemia to severe purulent discharge. The more common causes of con"unctivitis include viruses, allergies, environmental irritants, contact lenses, and chemicals. The less common causes include other infectious pathogens, immune1mediated reactions, associated systemic diseases, and tumors of the con"unctiva or eyelid. The more commonly reported infectious agents are adenovirus and herpes simple2 virus, followed by other viral 9e.g., enterovirus, co2sackievirus, measles virus, varicella 3oster virus, vaccinia1variola virus: and bacterial sources 9e.g., Neisseria species, Streptococcus pneumoniae, !aemophilus species, S.aureus, Mora%ella lacunata, chlamydial species:. &ic'ettsia,

fungi, and parasites, in both cyst and tropho3oite form, are rare causes of con"unctivitis. @ffective management is based on selection of an appropriate antibiotic for suspected bacterial pathogens. 5nless an unusual causative organism is suspected, bacterial con"unctivitis is treated empirically without obtaining a culture. (eratitis, or corneal ulcer, may occur at any level of the cornea, e.g., epithelium, subepithelium, stroma, or endothelium. $umerous microbial agents have been isolated, including bacteria, viruses, fungi, spirochetes, and cysts and tropho3oites. 6n aggressive forms of bacterial keratitis, immediate empirical and intensive antibiotic therapy is essential to prevent blindness from corneal perforation and secondary corneal scarring. 'esults of culture and sensitivity tests should guide the final drug of choice. )ndophthalmitis is a potentially severe and devastating inflammatory, and usually infectious, process of the intraocular tissues. ;hen the inflammatory process encompasses the entire globe, it is called panophthalmitis. @ndophthalmitis usually is caused by bacteria, by fungi, or rarely by spirochetes. The typical case occurs during the early postoperative course 9e.g., after cataract, glaucoma, cornea, or retinal surgery:, following trauma, or by endogenous seeding in the immunocompromised host or intravenous drug user. Prompt therapy usually includes vitrectomy 9i.e., speciali3ed surgical removal of the vitreous: and empirical intravitreal antibiotics to treat suspected bacterial or fungal microorganisms 9see Peyman and %chulman, ,))/E eredith, ,))/:. 6n cases of endogenous seeding, parenteral antibiotics have a role in eliminating the infectious source. 6n trauma or in the postoperative setting, however, the efficacy of systemic antibiotics is not well established. !ntiviral !gents +eneral Considerations The various antiviral drugs currently used in ophthalmology are summari3ed in Table 66C7 9see Chapter 7-# !ntimicrobial !gents# !ntiviral !gents 9$onretroviral: for additional details about these agents:. Therapeutic 5ses The primary indications for the use of antiviral drugs in ophthalmology are viral keratitis 9?aufman, A---:, herpes 3oster ophthalmicus 98iesegang, ,)))E Chern and argolis, ,))(:, and retinitis 9Cassou2 et al., ,)))E Koser et al., ,))0:. There are currently no antiviral agents for the treatment of viral con"unctivitis caused by adenoviruses, which usually has a self1limited course and typically is treated by symptomatic relief of irritation. Viral 'eratitis, an infection of the cornea that may involve either the epithelium or stroma, is most commonly caused by herpes simple2 type 6 and varicella 3oster viruses. 8ess common viral etiologies include herpes simple2 66, @pstein1=arr virus, and cytomegalovirus. Topical antiviral agents are indicated for the treatment of epithelial disease due to herpes simple2 infection. ;hen treating viral keratitis topically, there is a very narrow margin between the therapeutic topical antiviral activity and the to2ic effect on the corneaE hence, patients must be followed very closely. The role of oral acyclovir and glucocorticoids in herpetic corneal and e2ternal eye disease has been e2amined in the Berpetic @ye .isease %tudy 9!nonymous, ,))6, ,))&a, ,))(:. Topical glucocorticoids are contraindicated in herpetic epithelial keratitis due to active viral replication. 6n contrast, for herpetic disciform keratitis, which predominantly is presumed to involve a cell1

mediated immune reaction, topical glucocorticoids accelerate recovery 9;ilhelmus et al., ,))/:. >or recurrent herpetic stromal keratitis, there is clear benefit from treatment with oral acyclovir in reducing the risk of recurrence 9 oyes et al., ,))/E !nonymous, ,))(:. !erpes zoster ophthalmicus is a latent reactivation of a varicella 3oster infection in the first division of the trigeminal cranial nerve. %ystemic acyclovir is effective in reducing the severity and complications of herpes 3oster ophthalmicus 9Cobo et al., ,)(6:. Currently, there are no ophthalmic preparations of acyclovir approved by the 5nited %tates >ood and .rug !dministration 9>.!:, although an ophthalmic ointment is available for investigational use. Viral retinitis may be caused by herpes simple2 virus, cytomegalovirus 9C <:, adenovirus, and varicella 3oster virus. ;ith the highly active antiretroviral therapy 9B!!'TE see Chapter 7,# !ntiretroviral !gents# !ntiretroviral !gents:, C < retinitis does not appear to progress when specific anti1C < therapy is discontinued, but some patients develop an immune recovery uveitis 9*acobson et al., A---E ;hitcup, A---:. Treatment usually involves long1term parenteral administration of antiviral drugs. 6ntravitreal administration of ganciclovir has been found to be an effective alternative to the systemic route 9%anborn et al., ,))A:. !ntifungal !gents +eneral Considerations The only currently available ophthalmic antifungal preparation is a polyene, natamycin 9$!T!CK$:, which has the following structure# Other antifungal agents may be specially preparedbreak for topical, subcon"unctival, or intravitreal routes of administration 9see Table 66C6:. The pharmacology andbreak structures of available antifungal agents are given inbreak Chapter /)# !ntimicrobial !gents# !ntifungal !gents. Therapeutic 5ses !s with systemic fungal infections, the incidence of ophthalmic fungal infections has risen with the growing number of immunocompromised hosts. Ophthalmic indications for antifungal medications include fungal keratitis, scleritis, endophthalmitis, mucormycosis, and canaliculitis 9see =ehlau and =aker, ,))/:. .rug selection is based on identifying the pathogenic fungi and, if available, sensitivity data. !ntiproto3oal !gents +eneral Considerations Parasitic infections involving the eye usually manifest themselves as a form of uveitis, an inflammatory process of either the anterior or posterior segments, and less commonly as con"unctivitis, keratitis, and retinitis. Therapeutic 5ses 6n the 5nited %tates, the most commonly encountered proto3oal infections include Acanthamoeba and *o%oplasma gondii. 6n contact1lens wearers who develop keratitis, physicians should be highly suspicious of the presence of Acanthamoeba 9 cCulley et al., A---:. Treatment usually consists of

a combination topical antibiotic, such as polymy%in B sul"ate, bacitracin zinc, and neomycin sul"ate 9e.g., $@O%PO'6$:, and sometimes an imidazole 9e.g., clotrimazole, miconazole, or 'etoconazole:. 6n the 5nited ?ingdom, the aromatic diamidines 9i.e., propamine isethionate in both topical aqueous and ointment forms, ='O8@$@: have been used successfully to treat this relatively resistant infectious keratitis 9Bargrave et al., ,))):. !nother treatment for Acanthamoeba is the cationic antiseptic agent polyhe%amethylene biguanide, although this is not an >.!1approved antiproto3oal agent 98indquist, ,))(:. *o%oplasmosis may present as a posterior 9e.g., focal retinochoroiditis, papillitis, vitritis, or retinitis: or occasionally as an anterior uveitis. Treatment is indicated when inflammatory lesions encroach upon the macula and threaten central visual acuity. %everal regimens have been recommended with concurrent use of systemic steroids# 9,: pyrimethamine, sul"adiazine, and "olinic acid+ 9A: pyrimethamine, sul"adiazine, clindamycin, and "olinic acid+ 90: sul"adiazine and clindamycin+ 9/: clindamycin+ and 97: trimethoprim,sul"ametho%azole with or without clindamycin 9see @ngstrom et al., ,)),E Opremcak et al., ,))A:. Other proto3oal infections 9e.g., giardiasis, leishmaniasis, and malaria: and helminths are less common eye pathogens in the 5nited %tates 9see .e>reitas and .unkel, ,))/:. %ystemic pharmacological management as well as vitrectomy may be indicated for selected parasitic infections. 5se of !utonomic !gents in the @ye +eneral Considerations +eneral autonomic pharmacology has been discussed e2tensively in Chapters 6# $eurotransmission# The !utonomic and %omatic otor $ervous %ystems, &# uscarinic 'eceptor !gonists and !ntagonists, (# !nticholinesterase !gents, )# !gents !cting at the $euromuscular *unction and !utonomic +anglia, and ,-# Catecholamines, %ympathomimetic .rugs, and !drenergic 'eceptor !ntagonists. The autonomic agents used in ophthalmology as well as the responses 9i.e., mydriasis and cycloplegia: to muscarinic cholinergic antagonists are summari3ed in Table 66C&. Therapeutic 5ses !utonomic drugs are used e2tensively for diagnostic and surgical purposes and for the treatment of glaucoma, uveitis, and strabismus. +laucoma 6n the 5nited %tates, glaucoma is the leading cause of blindness in !frican !mericans and the third leading cause in Caucasians. Characteri3ed by progressive optic nerve cupping and visual field loss, glaucoma is responsible for visual impairment of (-,--- !mericans, and at least A million to 0 million have the disease 9see Tielsch, ,))0:. 'isk factors associated with glaucomatous nerve damage include increased intraocular pressure, positive family history of glaucoma, !frican1 !merican heritage, myopia, and hypertension. The production and regulation of aqueous humor have been discussed in an earlier section of this chapter. !lthough particularly elevated intraocular pressures 9e.g., greater than 0- mm Bg: usually will lead to optic nerve damage, certain patientsG optic nerves appear to be able to tolerate intraocular pressures in the mid1to1high twenties. These patients are referred to as ocular hypertensives+ a prospective, multicenter study is being conducted to determine whether or not early medical treatment to lower intraocular pressure will prevent

glaucomatous optic nerve damage. Other patients have progressive glaucomatous optic nerve damage despite having intraocular pressures in the normal range, and this form of the disease is sometimes called normal1 or lo--tension glaucoma. Bowever, at present, the pathophysiological processes involved in glaucomatous optic nerve damage and the relationship to aqueous humor dynamics are not understood. Current medical therapies are targeted to decrease the production of aqueous humor at the ciliary body and to increase outflow through the trabecular meshwork and uveoscleral pathways. There is no consensus on the best therapy for glaucoma. Currently, a $ational @ye 6nstituteCsponsored clinical trial, the Collaborative 6nitial +laucoma Treatment %tudy 9C6+T%:, aims to determine whether it is best to treat patients newly diagnosed with open1angle glaucoma with filtering surgery or with medication in terms of preservation of visual function and quality of life 9 usch et al., ,))):. This study aside, a stepped medical approach depends on the patientGs health, age, and ocular status. %ome general principles prevail in patient management# 9,: asthma and chronic obstructive pulmonary emphysema having a bronchospastic component are relative contraindications to the use of topical 1adrenergic receptor antagonists because of the risk of significant side effects from systemic absorption via the nasolacrimal systemE 9A: some cardiac dysrhythmias 9i.e., bradycardia and heart block: also are relative contraindications to 1adrenergic antagonists for similar reasonsE 90: history of nephrolithiasis, or kidney stones, is sometimes a contraindication for carbonic anhydrase inhibitorsE 9/: young patients usually are intolerant of miotic therapy secondary to visual blurring from induced myopiaE therefore, if a miotic agent is needed in a young patient, the OC5%@'T delivery system usually is preferableE 97: direct miotic agents are preferred over cholinesterase inhibitors in LphakicL patients 9i.e., those patients who have their endogenous lens:, since the latter drugs can promote cataract formationE and 96: in patients who have an increased risk of retinal detachment, miotics should be used with caution, since they have been implicated in promoting retinal tears in susceptible individualsE such tears are thought to be due to altered forces at the vitreous base produced by ciliary body contraction induced by the drug. ;ith these general principles in mind, a stepped medical approach may begin with a -adrenergic receptor antagonist, with the main goal of preventing progressive glaucomatous optic1nerve damage with minimum risk and side effects from either topical or systemic therapy. ;hen there are medical contraindications to the use of 1receptor antagonists other agents, such as latanoprost 9N!8!T!$:, a prostaglandin >A prodrug, or an .-adrenergic receptor agonist may be used as first1 line therapy. The chemical structure of latanoprost is shown below.

%econd1 and third1line agents include topical carbonic anhydrase inhibitors, epinephrine-related drugs, and miotic agents. 6ronically, epinephrine1related drugs may be used concomitantly with a 1 adrenergic receptor antagonist. @pinephrineGs main intraocular pressure1lowering effect is to enhance uveoscleral outflow, but it also may alter trabecular meshwork function and ciliary body blood flow. 6f combined topical therapy fails to achieve the target intraocular pressure or fails to halt glaucomatous optic nerve damage, then systemic therapy with carbonic anhydrase inhibitors 9C!6s: is a final medication option before resorting to laser or incisional surgical treatment. Of the

oral preparations available 9see Chapter A)# .iuretics:, the best tolerated is acetazolamide in sustained1release capsules, followed by methazolamide. The least well tolerated are aceta3olamide tablets 98ichter et al., ,)&(:. To reduce side effects, topical C!6s have been developedD dorzolamide hydrochloride 9T'5%OPT:, and brinzolamide 9!MOPT:, whose structures are shown below. These topical C!6s do not reduce the intraocular pressure as much as do the oral agents.

To2icity of !gents in Treatment of +laucoma Ciliary body spasm is a muscarinic cholinergic effect that can lead to induced myopia and a changing refraction due to iris and ciliary body contraction as the drug effect wa2es and wanes between doses. Beadaches can occur from the iris and ciliary body contraction. @pinephrine1related compounds, effective in intraocular pressure reduction, can cause a vasoconstriction1vasodilation rebound phenomenon leading to a red eye. Ocular and skin allergies from topical epinephrine, related prodrug formulations, and apraclonidine are common. %ystemic absorption of epinephrine1 related drugs can have all the side effects found with direct systemic administration. The 1 adrenergic antagonists, while effective in intraocular pressure reduction, can produce systemic side effects readily through direct absorption in the tissues and via the nasolacrimal system. The use of C!6s systematically may give some patients significant problems with malaise, fatigue, depression, paresthesias, and nephrolithiasisE the topical C!6s may minimi3e these relatively common side effects. These medical strategies for managing glaucoma do help to slow the progression of this disease, yet there are potential risks from treatment1related side effects, and treatment effects on quality of life must be recogni3ed. 5veitis 6nflammation of the uvea, or uveitis, has both infectious and noninfectious causes, and medical treatment of the underlying cause 9if known: is essential in addition to the use of topical therapy. #yclopentolate, or sometimes an even longer1acting antimuscarinic agent such as atropine, frequently is used to prevent posterior synechia formation between the lens and iris margin and to relieve ciliary muscle spasm that is responsible for much of the pain associated with anterior uveitis. 6f posterior synechiae have already formed, an -adrenergic agonist may be used to break the synechiae by enhancing pupillary dilation. *opical steroids usually are adequate to decrease inflammation, but sometimes they must be supplemented by systemic steroids.

%trabismus %trabismus, or ocular misalignment, has numerous causes and may occur at any age. 6n children, strabismus may lead to amblyopia 9reduced vision:. $onsurgical efforts to treat amblyopia include occlusion therapy, orthoptics, optical devices, and pharmacological agents. The eyes of children with hyperopia, or farsightedness, must accommodate to focus distant images. 6n some cases, the synkinetic accommodative1convergence response leads to e2cessive convergence and a manifest esotropia 9turned1in eye:. This deviated eye does not develop normal visual acuity and is therefore amblyopic. 6n this setting, atropine 9,I: instilled in the preferred seeing eye every five days produces cycloplegia and the inability of this eye to accommodate, thus forcing the child to use the amblyopic eye. )chothiophate iodide also has been used in the setting of accommodative strabismus. !ccommodation drives the near refle2, the triad of miosis, accommodation, and convergence. ! reversible cholinesterase inhibitor such as echothiophate causes miosis and an accommodative change in the shape of the lensE hence, the accommodative drive to initiate the near refle2 is reduced, and less convergence will occur. %urgery and .iagnostic Purposes >or certain surgical procedures and for clinical funduscopic e2amination, it is desirable to ma2imi3e the view of the retina and lens. uscarinic cholinergic antagonists and A1adrenergic agonists frequently are used singly or in combination for this purpose 9see Table 66C&:. 6ntraoperatively, there are circumstances when miosis is preferred, and two cholinergic agonists are available for intraocular use, acetylcholine and carbachol. Patients with myasthenia gravis may first present to an ophthalmologist with complaints of double vision 9diplopia: or lid droop 9ptosis:E the edrophonium test is helpful in diagnosing these patients 9see Chapter (# !nticholinesterase !gents:. 5se of 6mmunomodulatory .rugs for Ophthalmic Therapy +lucocorticoids +lucocorticoids have an important role in managing ocular inflammatory diseasesE their chemistry and pharmacology are described in Chapter 6-# !drenocorticotropic BormoneE !drenocortical %teroids and Their %ynthetic !nalogsE 6nhibitors of the %ynthesis and !ctions of !drenocortical Bormones. Therapeutic 5ses =ecause of their antiinflammatory effect, topical corticosteroids are used in managing anterior uveitis, e2ternal eye inflammatory diseases associated with some infections and ocular cicatricial pemphigoid, and postoperative inflammation following intraocular surgery. !fter glaucoma filtering surgery, topical steroids are particularly valuable in delaying the wound1healing process by decreasing fibroblast infiltration, which reduces the potential scarring of the surgical site. %teroids are commonly given systemically and by sub1TenonGs capsule in"ection to manage posterior uveitis. Parenteral steroids followed by tapering oral doses are the preferred treatment for optic neuritis 9?aufman et al., A---E Trobe et al., ,))):. To2icity of %teroids @2tensive discussion has been directed to the to2ic effects to the eyes of topical and systemic

corticosteroids. These include the development of posterior subcapsular cataracts and secondary infections 9see Chapter 6-# !drenocorticotropic BormoneE !drenocortical %teroids and Their %ynthetic !nalogsE 6nhibitors of the %ynthesis and !ctions of !drenocortical Bormones: and secondary open1angle glaucoma 9=ecker and ills, ,)60E !rmaly, ,)60a, ,)60b:. There is a significant increase in potential risk for developing secondary glaucoma when there is a positive family history of glaucoma. 6f there is no family history of open1angle glaucoma, only about 7I of normal individuals respond to topical or long1term systemic steroids with a marked increase in intraocular pressure. ;ith a positive family history, however, moderate to marked steroid1induced intraocular pressure elevations may be seen in up to )-I of patients. The pathophysiology of steroid1induced glaucoma is not fully understood, but there is evidence that the /0#1A gene may be involved 9%tone et al., ,))&:. Typically, steroid1induced elevation of intraocular pressure is reversible once administration of the steroid ceases. $onsteroidal !ntiinflammatory !gents +eneral Considerations $onsteroidal drug therapy for inflammation is discussed in Chapter A&# !nalgesic1!ntipyretic and !ntiinflammatory !gents and .rugs @mployed in the Treatment of +out. The nonsteroidal antiinflammatory drugs 9$%!6.s: are now being applied to the treatment of ocular disease. Therapeutic 5ses Currently, there are four topical $%!6.s approved for ocular use# diclo"enac 9<O8T!'@$:, "lurbipro"en 9OC5>@$:, 'etorolac 9!C58!':, and supro"en 9P'O>@$!8:. .iclofenac and flurbiprofen are discussed in Chapter A&# !nalgesic1!ntipyretic and !ntiinflammatory !gents and .rugs @mployed in the Treatment of +outE the chemical structures of ketorolac, a pyrrolo1pyrolle derivative, and suprofen, a phenylalkanoic acid, are shown below#

>lurbiprofen and suprofen are used to counter unwanted intraoperative miosis during cataract surgery. ?etorolac is given for seasonal allergic con"unctivitis. .iclofenac is used for postoperative inflammation. =oth ketorolac 9;eis3 et al., ,)))a: and diclofenac 9!nonymous, ,))&b: have been found to be effective in treating cystoid macular edema occurring after cataract surgery. !ntihistamines and ast1Cell %tabili3ers

2heniramine 9see Chapter A7# Bistamine, =radykinin, and Their !ntagonists: and antazoline, both B,1receptor antagonists, are formulated in combination with naphazoline, a vasoconstrictor, for

relief of allergic con"unctivitis. The chemical structure of anta3oline is#

$ewer topical antihistamines include emedastine di"umarate 9@ !.6$@:, olopatadine hydrochloride 9P!T!$O8:, levocabastine hydrochloride 986<O%T6$:, and 'etoti"en "umarate 9M!.6TO':. #romolyn sodium 9C'O8O :, which prevents the release of histamine and other autacoids from mast cells 9see Chapter A(# .rugs 5sed in the Treatment of !sthma:, has found limited use in treating con"unctivitis that is thought to be allergen1mediated, such as vernal con"unctivitis. 1odo%amide tromethamine 9!8O 6.@:, another mast1cell1stabili3ing agent, and pemirolast 9!8! !%T:, a mast1cell stabili3er that also has other antiinflammatory effects, also are available for ophthalmic use. 6mmunosuppressive and !ntimitotic !gents +eneral Considerations The principal application of immunosuppressive and antimitotic agents to ophthalmology relates to the use of 3-"luorouracil and mitomycin # in corneal and glaucoma surgeries. Certain systemic diseases with serious vision1threatening ocular manifestationsDbreak such as =ehOetGs disease, ;egenerGs granulomatosis, rheumatoid arthritis, and 'eiterGs syndromeDrequire systemic immunosuppression 9see Chapter 70# 6mmunomodulators# 6mmunosuppressive !gents, Tolerogens, and 6mmunostimulants:. Therapeutic 5ses 6n glaucoma surgery, both 71fluorouracil and mitomycin C improve the success of filtration surgery by limiting the postoperative wound1healing process. itomycin C is used intraoperatively as a single subcon"unctival application at the trabeculectomy site 9Chen, ,)(0:. eticulous care is used to avoid intraocular penetration, since mitomycin C is e2tremely to2ic to intraocular structures. 71 >luorouracil may be used intraoperatively andJor during the postoperative course and is delivered subcon"unctivally 9 >luorouracil >iltering %urgery %tudy +roup, ,)():. 6n cornea surgery, mitomycin C has been used topically after e2cision of pterygium, a fibrovascular membrane that can grow onto the cornea 9%ugar, ,))A:. !lthough the use of mitomycin C for both pterygium and glaucoma filtration surgeries augments the success of these surgical procedures, caution is advocated in light of the potentially serious delayed ocular complications 9'ubinfeld et al., ,))AE +reenfield, ,))(E Bardten and %amuelson, ,))):. .rugs and =iological !gents 5sed in Ophthalmic %urgery

!d"uncts in !nterior %egment %urgery !yaluronidase depolymeri3es hyaluronic acid, a mucopolysaccharide, in interstitial tissue spaces. This en3yme often is used to enhance local anesthesia 9e.g., in retrobulbar optic nerve block:. There are no direct complications due to the use of this drug. Bowever, improperly placed retrobulbar in"ections of anesthetic can perforate the globe or penetrate the optic nerve and can lead to C$% depression secondary to diffusion into the optic nerve sheath. Viscoelastic substances assist in ocular surgery by maintaining spaces, moving tissue, and protecting surfaces 9see 8iesegang, ,))-E +oa and =enfield, ,))/:. These substances are prepared from hyaluronate, chondroitin sulfate, or hydro2ypropylmethylcellulose and share the following important physical characteristics# viscosity, shear flow, elasticity, cohesiveness, and coatability. They are used almost e2clusively in anterior segment surgery. Complications associated with viscoelastic substances are related to transient elevation of intraocular pressure after the surgical procedure. Corneal =and ?eratopathy @thylenediaminetetraacetic acid 9@.T!: is a chelating agent that can be used to remove a band keratopathy 9i.e., a calcium deposit at the level of =owmanGs membrane on the cornea:. <itreous %ubstitutes The primary use of vitreous substitutes is reattachment of the retina following vitrectomy and membrane1peeling procedures for complicated proliferative vitreoretinopathy and traction retinal detachments 9see Peyman and %chulman, ,))/E Chang, ,))/:. %everal compounds may be selected, including gases, per"luorocarbon li4uids, and silicone oil 9see Table 66C(:. ;ith the e2ception of air, the gases e2pand because of interaction with systemic o2ygen, carbon dio2ide, and nitrogen, and this property makes them desirable to temporarily tamponade areas of the retina. Bowever, use of these e2pansile gases carries the risk of complications from elevated intraocular pressure, subretinal gas, corneal edema, and cataract formation. The gases are absorbed over a time period of from days 9for air: to as long as two months 9for perfluoropropane:. The liquid perfluorocarbons have specific gravities between ,.&6 and ,.)/ and are helpful in flattening the retina when vitreous is present, because the perfluorocarbons are denser than vitreous. !lso, in the event of a lens becoming dislocated into the vitreous, a perfluorocarbon liquid in"ection posteriorly will float the lens anteriorly, leading to easier surgical retrieval. This liquid potentially is to2ic if it remains in chronic contact with the retina. %ilicone oil has had e2tensive use both in @urope and in the 5nited %tates for long1term tamponade of the retina 9see Peyman and %chulman, ,))/E Parel and <illain, ,))/:. Complications from silicone oil use include glaucoma, cataract formation, corneal edema, corneal band keratopathy, and retinal to2icity. %urgical Bemostasis and Thrombolytic !gents !n important component of most surgical procedures, hemostasis, usually is achieved by temperature1mediated coagulation. 6n selective intraocular surgeries, thrombin has a valuable role in hemostasis. 6ntravitreal administration of thrombin sometimes is helpful in controlling intraocular hemorrhage during vitrectomy. ;hen used intraocularly, a potentially significant inflammatory

response may occur, but this reaction can be minimi3ed by thorough irrigation after hemostasis is achieved. This coagulation factor also may be applied topically via soaked sponges to e2posed con"unctiva and sclera where hemostasis may be a challenge due to the rich vascular supply. .epending on the intraocular location of a clot, there may be significant problems relating to intraocular pressure, retinal degeneration, and persistent poor vision. *issue plasminogen activator 9t1P!: 9see Chapter 77# !nticoagulant, Thrombolytic, and !ntiplatelet .rugs: has been used during intraocular surgeries to assist evacuation of a hyphema 9blood in the anterior chamber:, subretinal clot, or nonclearing vitreous hemorrhage. t1P! also has been administered subcon"unctivally and intracamerally 9i.e., controlled intraocular administration into the anterior segment: to lyse blood clots obstructing a glaucoma filtration site 9Orti3 et al., ,)((:. The main complication related to the use of t1P! is bleeding. =otulinum To2in Type a in the Treatment of %trabismus, =lepharospasm, and 'elated .isorders Botulinum to%in type A 9=OTON: has been used to treat strabismus, blepharospasm, eigeGs syndrome, spasmodic torticollis hemifacial spasm, and facial wrinkles 9Tsui, ,))6E Price et al., ,))&E see also Chapter )# !gents !cting at the $euromuscular *unction and !utonomic +anglia:. =y preventing acetylcholine release at the neuromuscular "unction, botulinum to2in ! usually causes a temporary paralysis of the locally in"ected muscles. The variability in duration of paralysis may be related to the rate of developing antibodies to the to2in, upregulation of nicotinic cholinergic postsynaptic receptors, and aberrant regeneration of motor nerve fibers at the neuromuscular "unction. Complications related to this to2in include double vision 9diplopia: and lid droop 9ptosis:. =lind and Painful @ye 'etrobulbar in"ection of either absolute or )7I alcohol may provide relief from chronic pain associated with a blind and painful eye. This treatment is preceded by administration of local anesthesia. 8ocal infiltration of the ciliary nerves provides symptomatic relief from pain, but other nerve fibers may be damaged, causing paralysis of the e2traocular muscles, including those in the eyelids, or neuroparalytic keratitis. The sensory fibers of the ciliary nerves may regenerate, and repeated in"ections are sometimes needed to control pain. !gents 5sed to !ssist in Ocular .iagnosis ! number of agents are used in an ocular e2amination 9e.g., mydriatic agents and topical anesthetics, and dyes to evaluate corneal surface integrity:, to facilitate intraocular surgery 9e.g., mydriatic and miotic agents, topical and local anesthetics:, and to help in making a diagnosis in cases of anisocoria 9see >igure 66C7: and retinal abnormalities 9e.g., intravenous contrast agents:. The autonomic agents have been discussed earlier. The diagnostic and therapeutic uses of topical and intravenous dyes and of topical anesthetics are discussed below. !nterior %egment and @2ternal .iagnostic 5ses @piphora 9or tearing: and surface problems of the cornea and con"unctiva are commonly encountered e2ternal ocular disorders. The dyes "luorescein and rose bengal are used in evaluating these problems. !vailable both as a AI alkaline solution and as an impregnated paper strip, fluorescein reveals epithelial defects of the cornea and con"unctiva and aqueous humor leakage that may occur after trauma or ocular surgery. 6n the setting of epiphora, fluorescein is used to help

determine the patency of the nasolacrimal system. 6n addition, this dye is used as part of the procedure of applanation tonometry 9intraocular pressure measurement: and to assist in determining the proper fit of rigid and semirigid contact lenses. 'ose bengal, which also is available as a solution and as saturated paper strips, stains devitali3ed tissue on the cornea and con"unctiva. %uch a staining pattern is valuable in assessing e2posed areas that are the possible consequence of any of the following# corneal keratitis from herpes simple2E a neuromuscular disorder, such as =ellGs palsyE an anatomical problem resulting from +ravesG eye disease or a burn to the eyelid causing skin contracturesE or a physiological problem relating to decreased tear production. Posterior %egment .iagnostic and Therapeutic 5ses The integrity of the bloodCretinal and retinal pigment epithelial barriers may be e2amined directly by retinal angiography using intravenous administration of either "luorescein sodium or indocyanine green, whose structures are shown below. Of the agents used in assisting the making of a diagnosis, the intravenous dyes are among the most to2ic. These agents commonly cause nausea, but they also may precipitate a serious allergic reaction in susceptible individuals.

Vertepor"in 9<6%5.K$@: was approved by the >.! in A--- for photodynamic therapy of the e2udative form of age1related macular degeneration with classic choroidal neovascular membranes 9>ine et al., A---E !nonymous ,))):. The >.! is e2pected to broaden its approval to include treatment of classic choroidal neovasculari3ation caused by conditions such as pathological myopia and ocular histoplasmosis syndrome. The chemical structure of verteporfin, which is a mi2ture of two regioisomers 96 and 66:, is shown below#

<erteporfin is administered intravenously, and once it reaches the choroidal circulation, the drug is light1activated by a nonthermal laser source. .epending on the si3e of the neovascular membrane and concerns of occult membranes and recurrence, multiple photodynamic treatments may be necessary. !ctivation of the drug in the presence of o2ygen generates free radicals, which cause vessel damage and subsequent platelet activation, thrombosis, and occlusion of choroidal neovasculari3ation. The half1life of the drug is five to si2 hours. 6t is eliminated predominantly in the fecesE less than -.-,I of the drug is recovered in the urine. The potential side effects include headache, in"ection site reactions, and visual disturbances. The drug causes temporary photosensiti3ation, and patients must avoid e2posure of skin or eyes to direct sunlight or bright indoor lights for 7 days after receiving it. 5se of !nesthetics in Ophthalmic Procedures Topical anesthetic agents used clinically in ophthalmology include cocaine5 proparacaine, and tetracaine 9see Chapter ,7# 8ocal !nesthetics:. Proparacaine and tetracaine are used topically to perform tonometry, to remove foreign bodies on the con"unctiva and cornea, and to manipulate the nasolacrimal canalicular system. Tetracaine is used topically to anestheti3e the ocular surface for refractive surgery using either the e2imer laser or placement of intrastromal corneal rings. Cocaine may be used intranasally in combination with topical anesthesia for cannulating the nasolacrimal system. 8ocal anesthetics, commonly lidocaine and bupivacaine, are used for both infiltration and retrobulbar block anesthesia for surgery 9see Chapter ,7# 8ocal !nesthetics for chemical structures and pharmacology:. Potential complications and risks relate to allergic reactions, globe perforation, and vascular and subdural in"ections. =oth preservative1free lidocaine 9,I:, which is introduced into the anterior chamber, andJor lidocaine "elly 9AI:, which is placed on the ocular surface during preoperative patient preparation, are used for cataract surgery performed under topical anesthesia. +eneral anesthetics and sedation are important ad"uncts for patient care for surgery and e2amination of the eye. ost inhalation agents and central nervous system depressants are associated with a reduction in intraocular pressure. The e2ception appears to be ketamine, which has been associated with an elevation in intraocular pressure. 6n the setting of a patient with a ruptured globe, the anesthesia should be selected carefully to avoid agents that depolari3e the e2traocular muscles, which may result in e2pulsion of intraocular contents.

Other !gents for Ophthalmic Therapy <itamins and Trace @lements +eneral Considerations The chemistry, nutritional deficiencies, and human requirements for the water1soluble 9see Chapter 60# ;ater1%oluble <itamins# The <itamin = Comple2 and !scorbic !cid: and fat1soluble 9see Chapter 6/# >at1%oluble <itamins# <itamins !, ?, and @: vitamins are discussed elsewhere in this edition. Table 66C) summari3es the current understanding of vitamins related to eye function and disease. Therapeutic 5ses 6n the setting of nutritional deficiency, %erophthalmia, a progressive disease characteri3ed by nyctalopia 9night blindness:, %erosis 9dryness:, and 'eratomalacia 9corneal thinning: which may lead to perforation, may be reversed with vitamin ! therapy 9;BOJ5$6C@>J6<!++ Task >orce, ,)((:. Bowever, rapid, irreversible blindness ensues once the cornea perforates. <itamin ! also is thought to be involved in epithelial differentiation and may have some role in corneal epithelial wound healing. Currently, there is no evidence to support using topical vitamin ! for keratocon"unctivitis sicca in the absence of a nutritional deficiency. The potential therapeutic roles of vitamins ! and @ in retinitis pigmentosa have been e2amined, and the current recommendation is to supplement with ,7,--- 65 of vitamin ! palmitate daily under the supervision of an ophthalmologist and to avoid high1dose vitamin @ 9%andberg et al., ,))6E =erson et al., ,))0:. !nother characteristic nutritional deficiency that has ocular manifestations is alcoholJtobacco amblyopia, which typically appears as temporal optic atrophy with corresponding decreased vision and characteristic visual field defects 9see 8essell, ,))/:. This optic neuropathy often is irreversible. +yrate atrophy is an autosomal recessive, retinal degeneration caused by deficient mitochondrial ornithine aminotransferase. 6t is characteri3ed by hyperornithinemia, nyctalopia, and progressive chorioretinal atrophy accompanied by progressive loss of visual field. 6t appears that supplemental pyrido2ine or vitamin =6 may have a role in managing this inborn error of metabolism 9;eleber and ?ennaway, ,)(,:. uch attention has been given to the use of antio2idants, particularly vitamins C and @ and trace elements, to prevent cataract formation 9see Chylak, ,))/: and to protect the retina from the proposed o2idative damage induced by ultraviolet light 9see @gan and %eddon, ,))/E ;est et al., ,))/:. 6t is hypothesi3ed that o2idative pathways generate free radicals, which may have a role in the pathogenesis of macular degeneration and cataract formation. 6nterestingly, the concentration of ascorbic acid in the aqueous humor is A7 times greater than that in plasma in human beings 9.e =erardinis et al., ,)67:. The biochemical and physiological roles of vitamin C have not been adequately e2plained by any studies to date, but this striking observation certainly leads to speculation about a possible protective effect against ultraviolet radiation. ! recent case1control study has demonstrated that elevated plasma homocysteine is a risk factor for central retinal vein occlusion, a multifactorial disease that can cause poor vision 9<ine, A---:. Currently recommended for reducing the risk of atherothrombotic vascular disease related to hyperhomocysteinemia 9i.e., a plasma homocysteine level greater than ,, : is a daily

multivitamin supplement containing /-- g of folic acid 9Omenn et al., ,))(:. ;etting !gents and Tear %ubstitutes +eneral Considerations The current management of dry eyes usually includes instilling artificial tears and ophthalmic lubricants. 6n general, tear substitutes are hypotonic or isotonic solutions composed of electrolytes, surfactants, preservatives, and some viscosity1increasing agent that prolongs the residence time in the cul1de1sac and precorneal tear film. Common viscosity agents include cellulose polymers 9e.g., carbo%ymethylcellulose, hydro%yethyl cellulose, hydro%ypropyl cellulose, hydro%ypropyl methylcellulose, and methylcellulose:, polyvinyl alcohol, polyethylene glycol, mineral oil, glycerin, and de%tran. The tear substitutes are available as preservative1containing or preservative1free preparations. %ome tear formulations also are combined with a vasoconstrictor, such as napha3oline, phenylephrine, or tetrahydro3oline. 6n other countries, hyaluronic acid is sometimes used as a viscous agentE however, this en3yme has not been approved for use in the 5nited %tates. The lubricating ointments are composed of a mi2ture of white petrolatum, mineral oil, liquid or alcohol lanolin, and sometimes a preservative. These highly viscous formulations cause considerable blurring of vision, and consequently they are used primarily at bedtime or in very severe dry eye conditions. %uch aqueous and ointment formulations are only fair substitutes for the precorneal tear film, which is truly a poorly understood Llipid, aqueous, and mucinL trilaminar barrier 9see above:. To date, no study has demonstrated the clinical efficacy of treating dry eyes with tear substitutes. Consequently, the >.! has restricted the use of tear substitute components to nonprescription products. <arious doses of cyclosporine ophthalmic emulsion have been tested in phase A and 0 clinical trials as treatment of moderate to severe dry eye syndrome 9%all et al., A---E %tevenson et al., A---:. This drug appears to improve both ob"ective and sub"ective signs of dry eye disease, but it is not approved currently for use in the treatment of this condition. Therapeutic 5ses any local eye conditions and systemic diseases may affect the precorneal tear film. 8ocal eye disease, such as blepharitis, ocular rosacea, ocular pemphigoid, chemical burns, or corneal dystrophies, may alter the ocular surface and change the tear composition. !ppropriate treatment of the symptomatic dry eye includes treating the accompanying disease and possibly the addition of tear substitutes. There are also a number of systemic conditions that may manifest themselves with symptomatic dry eyes, including %"PgrenGs syndrome, rheumatoid arthritis, vitamin ! deficiency, %tevensC*ohnson syndrome, and trachoma. Treating the systemic disease may not eliminate the symptomatic dry eye complaintsE chronic therapy with tear substitutes or surgical occlusion of the lacrimal drainage system may be indicated. Osmotic !gents and .rugs !ffecting Carbonic !nhydrase +eneral Considerations The main osmotic drugs for ocular use include glycerin, isosorbide, mannitol 9see Chapter A)# .iuretics:, and hypertonic saline. ;ith the availability of these agents, the use of urea for management of acutely elevated intraocular pressure is nearly obsolete. Oral carbonic anhydrase

inhibitors are a valuable ad"unct to topical agents used to treat glaucoma. The pharmacology of this class of diuretic 9i.e., aceta3olamide and metha3olamide: is discussed in detail in Chapter A)# .iuretics, and their use in glaucoma was discussed earlier in this chapter. Carbonic anhydrase inhibitors also are used to treat pseudotumor cerebri in the setting of headache management, as well as to treat optic neuropathy associated with elevated intracranial pressure. Therapeutic 5ses Ophthalmologists occasionally use glycerin, isosorbide, and mannitol for short1term management of acute rises in intraocular pressure. Occasionally, these agents are used intraoperatively to dehydrate the vitreous prior to anterior segment surgical procedures. any patients with acute glaucoma do not tolerate oral medications because of nausea. Therefore, intravenous administration of mannitol andJor aceta3olamide may be preferred over oral administration of glycerin or isosorbide. These agents should be used with caution in patients with congestive heart failure or renal failure. 6n diabetic patients, isosorbide is preferred over glycerin because the latter compound is metaboli3ed rapidly to glucose. Corneal edema is a clinical sign of corneal endothelial dysfunction, and topical osmotic agents may effectively dehydrate the cornea. 6dentifying the cause of corneal edema will guide therapy, and topical osmotic agents, such as hypertonic saline, may tempori3e the need for surgical intervention in the form of a corneal transplant. %odium chloride is available in either aqueous or ointment formulations. Topical glycerin also is availableE however, because it causes pain upon contact with the cornea and con"unctiva, the use of topical glycerin is limited to urgent evaluation of filtration1 angle structures. 6n general, when corneal edema occurs secondary to acute glaucoma, the use of an oral osmotic agent to help reduce intraocular pressure is preferred to topical glycerin, which simply clears the cornea temporarily. 'educing the intraocular pressure will help clear the cornea more permanently to allow both a view of the filtration angle by gonioscopy and a clear view of the iris as required to perform laser iridotomy. Prospectus !dvances in ocular pharmacology will develop as a result of new insights into basic cellular, genetic, and physiological processes of specific tissues of the eye. >uture directions in ocular pharmacology include immunomodulation for dry eyes and uveitisE molecular1 and cellular1based therapy for corneal surface disease and inherited retinal dystrophiesE and neuroprotection for glaucoma. 6mmunomodulation ! better understanding of the pathogenesis of immunologically based eye diseases, such as dry eye syndrome, uveitis, and corneal melting syndromes, which are "ust a few e2amples of chronic and potentially intractable eye disorders, should lead to improved nobreak therapeutic interventions. %pecifically for dry eye syndrome, ma"or advances soon will lead to the use of new approaches for management of keratocon"unctivitis sicca rather than simplistic, polymer1based artificial tear replacement and punctal occlusion of the canaliculi 9>igure 66CA:. !ndrogen deficiency, lymphocytic inflammatory mediators, dysfunctional regulation of mucin gene e2pression, and other growth factors and hormones have all been implicated in the pathogenesis of dry eye syndrome 98emp, ,))):. !mong potential treatments for dry eye syndrome, immunomodulation with a topical emulsion of cyclosporine 9'@%T!%6%: is being evaluated in clinical trials 9%tevenson et al., A---:.

>or uveitis, novel immunomodulation therapies are in clinical trials 9;hitcup and $ussenblatt, ,))&:. Oral administration of retinal antigens has been used to treat ocular inflammation without a statistically significant impact on recurrence of ocular inflammation or cessation of conventional immunosuppressive therapy 9$ussenblatt et al., ,))&:. ! recent nonrandomi3ed, open1label, pilot study holds promise for the use of a humani3ed, anti1681A1receptor monoclonal antibody 9daclizumab, see Chapter 70# 6mmunomodulators# 6mmunosuppressive !gents, Tolerogens, and 6mmunostimulants: in preventing intraocular inflammation while patients are not receiving conventional immunosuppressive therapy 9$ussenblatt et al., ,))):. >urther clinical trials and basic research should lead to the development of such novel therapeutic strategies for treating ocular inflammatory diseases by an approach more selective than general immunosuppression. olecular1 and Cellular1=ased Therapy any biochemical and genetic defects have been identified in inherited retinal and retinal1pigment epithelial degenerations 9%harma and @hinger, ,))):. any treatments have been proposed, such as various neurotrophins and growth factors 9>rasson et al., ,)))E 8a<ail et al., ,))(:, vitamin ! 9seeL<itamins and Trace @lements,L above:, '$! antisense therapy with ribo3ymes 9Crooke, ,))):, and cell1based therapies including retinal pigment epithelial 9;eis3 et al., ,))) b: and retinal transplantation 9 ohand1%aid et al., A---:. !nother potential approach to the treatment of eye disease is the use of protein 'inase-# inhibitors to prevent the neovasculari3ation associated with diabetic retinopathy 9%eo et al., ,))):. 6t is proposed that vascular complications of diabetes are caused in part by vascular endothelial growth factorCmediated activation of protein kinase1C beta 9!iello et al., ,))&:. Clinical trials are under way to evaluate the effect of selective protein kinase1C inhibitors administered orally to prevent the complications of diabetic retinopathy 9*irousek et al., ,))6:. $europrotection The issue of neuroprotection in relation to glaucoma involves balancing factors that promote life versus death of the retinal ganglion cells. Potential therapeutic targets include trophic factors, e2citoto2ins and their associated signaling pathways, ischemia, free radicals, neuroimmunomodulatory factors, and blood flow in the optic disk 98evin, ,))):. There is e2perimental evidence to support nonintraocular pressure1lowering mechanisms in rodent models of chronic ocular hypertension 9$eufeld et al., ,))): and optic1nerve crush in"uries 9Koles et al., ,))):. The e2perimental end points can be observed histologically by ganglion cell counts and a2on counts, but functional correlates are not yet possible in these rodent models, and the relevance to the clinical setting is yet to be determined. !n additional challenge in developing neuroprotective agents for glaucoma involves the design of clinical drug trials in which the end point of progressive optic disk cupping and correlation with visual function changes take many years. 6n contrast, the surrogate end point of intraocular pressure1lowering is achieved quicklyE LpeakL and LtroughL effects of drugs that lower the pressure can be determined within hours and their adverse events and efficacy assessed over several months. @2panded research in this area should lead to new insights into mechanisms and pathways leading to glaucomatous optic neuropathy. 6n addition to the aforementioned prospects for ocular pharmacology, efforts to develop novel strategies for drug delivery are e2pected, given the limitations in access to the filtration angle, retina, and optic nerve. >or further discussion of disturbances of vision and ocular movement, see Chapter A7 in !arrison6s

2rinciples o" 1nternal Medicine, ,6th ed.,

c+raw1Bill, $ew Kork, A--7.