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.

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

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

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

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

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

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

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

where data are collected relatively easily from blood samples. especially when used chronically. for comparison of to2icity. !bsorption from the nasal mucosabreak avoids so1called first1pass metabolism by the liver 9see Chapter .ynamics of .rug !bsorption. Bence. and endothelial layers.onald and %hadduck. 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. and @limination:. 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. Transcorneal and transcon"unctivalJscleral absorption are the desired routes for locali3ed ocular drug effects. .# Pharmacokinetics# The .)&&. Other factors that affect a drugGs diffusion capacity are the si3e of the molecule. . The time period between drug instillation and its appearance in the aqueous humor is defined as the lag time. animal models are studied to provide pharmacokinetic data on ophthalmic drugs. and physiology of human and rabbit ocular systems:. a drug with both hydrophilic and lipophilic properties is best suited for transcorneal absorption.5nlike clinical pharmacokinetic studies on systemic drugs. . 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. the rabbit is used for such studies 9see c. !bsorption !fter topical instillation of a drug. there is significant risk in obtaining tissue and fluid samples from the human eye.))0:. . Possible absorption pathways of an ophthalmic drug following topical application to the eye are shown schematically in >igure 66C6. Consequently. The epithelium and endothelium represent barriers for hydrophilic substancesE the stroma is a barrier for hydrophobic compounds.istribution. Commonly. ! drugGs residence time may be prolonged by changing its formulation. $asolacrimal drainage contributes to systemic absorption of topically administeredbreak ophthalmic medications. anatomy. and steric configuration. and consequently significant systemic side effects may be caused by topical medications. chemical structure. stromal.

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

Streptococcus species. and Actinomyces israelii. ben3alkonium chloride may cause a punctate keratopathy or to2ic ulcerative keratopathy 9+rant and %chuman. is an infection of the meibomian. 8ocal hygiene is the mainstay of therapyE topical antibiotics frequently are used. dacryocystitis and canalicular infections may be caused by Staphylococcus aureus. The less common causes include other infectious pathogens. varicella 3oster virus. !ppropriate selection of antibiotic and route of administration is dependent on clinical e2amination and cultureJsensitivity results.iseases in the @ye !ntibacterial !gents +eneral Considerations ! number of antibacterial antibiotics have been formulated for topical ocular use 9Table 66C/:. and the usual treatment consists of warm compresses and topical antibiotic ointment.)(7 of the !. Periocular skin infections are divided into preseptal and postseptal or orbital cellulitis.iagnostic !pplications of . enterovirus. Therapeutic and . and lacrimal e2cretory system are encountered regularly in clinical practice. sinusitis. The more common causes of con"unctivitis include viruses. ! hordeolum. in"luenzae vaccine 9!mbati et al. A---:. %pecially formulated antibiotics also may be available for serious eye infections such as corneal ulcers or keratitis and endophthalmitis. the sharp decline in the involvement of !aemophilus in"luenzae after the introduction in . The more commonly reported infectious agents are adenovirus and herpes simple2 virus.. #on$unctivitis is an inflammatory process of the con"unctiva that varies in severity from mild hyperemia to severe purulent discharge. and kinetics of individual drugs have been presented in detail in preceding chapters. and it also is usually caused by a Staphylococcus species. oral or parenteral antibiotics are administered. chlamydial species:. S. and tumors of the con"unctiva or eyelid. Neisseria species. . eyelids. Preparation of fortified solutions requires a pharmacist familiar with sterile preparation of ocular drugs. Meis. #andida species. &ic'ettsia. age of patient. and thimerosal for their antimicrobial effectiveness.g.. measles virus. co2sackievirus. for e2ample. relative immunocompromised state:. Therapeutic 5ses 6nfectious diseases of the skin. preceding trauma. con"unctiva.. The pharmacology. The typical offending bacterium is S. usually in ointment form.rugs in Ophthalmology Chemotherapy of icrobial .g.contain preservatives such as ben3alkonium chloride. 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.epending on the clinical setting 9i. 6nfectious processes of the lids include hordeolum and blepharitis.aureus. chelating agents. . or stye. contact lenses. particularly when the disease is accompanied by con"unctivitis and keratitis.aureus. followed by other viral 9e.. allergies. 6n particular. 6n infants and children. acryocystitis is an infection of the lacrimal sac. environmental irritants. structures. . Blepharitis is a common bilateral inflammatory process of the eyelids characteri3ed by irritation and burning. chlorobutanol. !aemophilus species. vaccinia1variola virus: and bacterial sources 9e. Streptococcus pneumoniae. associated systemic diseases. Mora%ella lacunata. 6n adults.e. or oll glands at the lid margins.))0:. and chemicals. immune1mediated reactions.

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

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

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

age. a stepped medical approach may begin with a -adrenergic receptor antagonist. 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. a $ational @ye 6nstituteCsponsored clinical trial. aims to determine whether it is best to treat patients newly diagnosed with open1angle glaucoma with filtering surgery or with medication in terms of preservation of visual function and quality of life 9 usch et al. . such as latanoprost 9N!8!T!$:. with the main goal of preventing progressive glaucomatous optic1nerve damage with minimum risk and side effects from either topical or systemic therapy. miotics should be used with caution. then systemic therapy with carbonic anhydrase inhibitors 9C!6s: is a final medication option before resorting to laser or incisional surgical treatment. the pathophysiological processes involved in glaucomatous optic nerve damage and the relationship to aqueous humor dynamics are not understood.ith these general principles in mind. There is no consensus on the best therapy for glaucoma. Of the .e. or an . and ocular status. or kidney stones. since the latter drugs can promote cataract formationE and 96: in patients who have an increased risk of retinal detachment.e. 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. those patients who have their endogenous lens:. 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. The chemical structure of latanoprost is shown below. and miotic agents.glaucomatous optic nerve damage. the Collaborative 6nitial +laucoma Treatment %tudy 9C6+T%:. .: 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. the OC5%@'T delivery system usually is preferableE 97: direct miotic agents are preferred over cholinesterase inhibitors in LphakicL patients 9i..))):. 6ronically..-adrenergic receptor agonist may be used as first1 line therapy. bradycardia and heart block: also are relative contraindications to 1adrenergic antagonists for similar reasonsE 90: history of nephrolithiasis. This study aside. %econd1 and third1line agents include topical carbonic anhydrase inhibitors. epinephrine1related drugs may be used concomitantly with a 1 adrenergic receptor antagonist. if a miotic agent is needed in a young patient.. Other patients have progressive glaucomatous optic nerve damage despite having intraocular pressures in the normal range. at present.hen there are medical contraindications to the use of 1receptor antagonists other agents. . Bowever. Currently. @pinephrineGs main intraocular pressure1lowering effect is to enhance uveoscleral outflow. a stepped medical approach depends on the patientGs health. %ome general principles prevail in patient management# 9. a prostaglandin >A prodrug. and this form of the disease is sometimes called normal1 or lo--tension glaucoma. 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. epinephrine-related drugs.

.iuretics:. Ocular and skin allergies from topical epinephrine. and treatment effects on quality of life must be recogni3ed. while effective in intraocular pressure reduction.. but sometimes they must be supplemented by systemic steroids. and nephrolithiasisE the topical C!6s may minimi3e these relatively common side effects. 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. effective in intraocular pressure reduction. #yclopentolate. 5veitis 6nflammation of the uvea. These medical strategies for managing glaucoma do help to slow the progression of this disease. and brinzolamide 9!MOPT:. @pinephrine1related compounds. To reduce side effects. or sometimes an even longer1acting antimuscarinic agent such as atropine. and medical treatment of the underlying cause 9if known: is essential in addition to the use of topical therapy. depression. The 1 adrenergic antagonists.oral preparations available 9see Chapter A)# . . an -adrenergic agonist may be used to break the synechiae by enhancing pupillary dilation. These topical C!6s do not reduce the intraocular pressure as much as do the oral agents. The use of C!6s systematically may give some patients significant problems with malaise. the best tolerated is acetazolamide in sustained1release capsules. paresthesias. %ystemic absorption of epinephrine1 related drugs can have all the side effects found with direct systemic administration. can cause a vasoconstriction1vasodilation rebound phenomenon leading to a red eye.)&(:. topical C!6s have been developedD dorzolamide hydrochloride 9T'5%OPT:. or uveitis. can produce systemic side effects readily through direct absorption in the tissues and via the nasolacrimal system. The least well tolerated are aceta3olamide tablets 98ichter et al. Beadaches can occur from the iris and ciliary body contraction. 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. yet there are potential risks from treatment1related side effects. *opical steroids usually are adequate to decrease inflammation. has both infectious and noninfectious causes. related prodrug formulations. 6f posterior synechiae have already formed. and apraclonidine are common. followed by methazolamide. fatigue. whose structures are shown below.

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

$onsteroidal !ntiinflammatory !gents +eneral Considerations $onsteroidal drug therapy for inflammation is discussed in Chapter A&# !nalgesic1!ntipyretic and !ntiinflammatory !gents and .s: are now being applied to the treatment of ocular disease. Therapeutic 5ses Currently. however. there are four topical $%!6. There is a significant increase in potential risk for developing secondary glaucoma when there is a positive family history of glaucoma.s approved for ocular use# diclo"enac 9<O8T!'@$:.))&:. Typically. and supro"en 9P'O>@$!8:.1receptor antagonists. .iclofenac is used for postoperative inflammation. .)60a. moderate to marked steroid1induced intraocular pressure elevations may be seen in up to )-I of patients. These include the development of posterior subcapsular cataracts and secondary infections 9see Chapter 6-# !drenocorticotropic BormoneE !drenocortical %teroids and Their %ynthetic !nalogsE 6nhibitors of the %ynthesis and !ctions of !drenocortical Bormones: and secondary open1angle glaucoma 9=ecker and ills. The nonsteroidal antiinflammatory drugs 9$%!6.))&b: have been found to be effective in treating cystoid macular edema occurring after cataract surgery. a phenylalkanoic acid. steroid1induced elevation of intraocular pressure is reversible once administration of the steroid ceases. . . but there is evidence that the /0#1A gene may be involved 9%tone et al. =oth ketorolac 9. a vasoconstrictor. "lurbipro"en 9OC5>@$:. .)))a: and diclofenac 9!nonymous. .corticosteroids.)60b:. . and suprofen. ?etorolac is given for seasonal allergic con"unctivitis. and Their !ntagonists: and antazoline. both B.rugs @mployed in the Treatment of +out. are formulated in combination with naphazoline.. are shown below# >lurbiprofen and suprofen are used to counter unwanted intraoperative miosis during cataract surgery. !ntihistamines and ast1Cell %tabili3ers 2heniramine 9see Chapter A7# Bistamine. . . =radykinin. 'etorolac 9!C58!':. a pyrrolo1pyrolle derivative. 6f there is no family history of open1angle glaucoma.eis3 et al. for .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. The pathophysiology of steroid1induced glaucoma is not fully understood..ith a positive family history.)60E !rmaly. only about 7I of normal individuals respond to topical or long1term systemic steroids with a marked increase in intraocular pressure.

relief of allergic con"unctivitis.))AE +reenfield. such as vernal con"unctivitis. !lthough the use of mitomycin C for both pterygium and glaucoma filtration surgeries augments the success of these surgical procedures. itomycin C is used intraoperatively as a single subcon"unctival application at the trabeculectomy site 9Chen. since mitomycin C is e2tremely to2ic to intraocular structures. . another mast1cell1stabili3ing agent.))):. and 'etoti"en "umarate 9M!.)(0:. and 'eiterGs syndromeDrequire systemic immunosuppression 9see Chapter 70# 6mmunomodulators# 6mmunosuppressive !gents. . 1odo%amide tromethamine 9!8O 6.egenerGs granulomatosis. also are available for ophthalmic use. 71 >luorouracil may be used intraoperatively andJor during the postoperative course and is delivered subcon"unctivally 9 >luorouracil >iltering %urgery %tudy +roup. #romolyn sodium 9C'O8O :.rugs 5sed in the Treatment of !sthma:.. eticulous care is used to avoid intraocular penetration.@:. and 6mmunostimulants:. both 71fluorouracil and mitomycin C improve the success of filtration surgery by limiting the postoperative wound1healing process. olopatadine hydrochloride 9P!T!$O8:. Tolerogens. which prevents the release of histamine and other autacoids from mast cells 9see Chapter A(# . . 6n cornea surgery.6TO':. . .)():. and pemirolast 9!8! !%T:. 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. a fibrovascular membrane that can grow onto the cornea 9%ugar. mitomycin C has been used topically after e2cision of pterygium. . has found limited use in treating con"unctivitis that is thought to be allergen1mediated. The chemical structure of anta3oline is# $ewer topical antihistamines include emedastine di"umarate 9@ !.rugs and =iological !gents 5sed in Ophthalmic %urgery .))A:. Therapeutic 5ses 6n glaucoma surgery. rheumatoid arthritis. . Certain systemic diseases with serious vision1threatening ocular manifestationsDbreak such as =ehOetGs disease.))(E Bardten and %amuelson. levocabastine hydrochloride 986<O%T6$:. caution is advocated in light of the potentially serious delayed ocular complications 9'ubinfeld et al. .6$@:. a mast1cell stabili3er that also has other antiinflammatory effects.

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

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

! in A--.. which is a mi2ture of two regioisomers 96 and 66:. 'ose bengal. Of the agents used in assisting the making of a diagnosis. the intravenous dyes are among the most to2ic. The >. 6n addition. is shown below# . 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.! is e2pected to broaden its approval to include treatment of classic choroidal neovasculari3ation caused by conditions such as pathological myopia and ocular histoplasmosis syndrome. %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.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.determine the patency of the nasolacrimal system. stains devitali3ed tissue on the cornea and con"unctiva. but they also may precipitate a serious allergic reaction in susceptible individuals. whose structures are shown below. 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. Vertepor"in 9<6%5. A---E !nonymous .))):.for photodynamic therapy of the e2udative form of age1related macular degeneration with classic choroidal neovascular membranes 9>ine et al. These agents commonly cause nausea. Posterior %egment .K$@: was approved by the >. which also is available as a solution and as saturated paper strips. The chemical structure of verteporfin.

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

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

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

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

see Chapter A7 in !arrison6s .))):. such as various neurotrophins and growth factors 9>rasson et al... There is e2perimental evidence to support nonintraocular pressure1lowering mechanisms in rodent models of chronic ocular hypertension 9$eufeld et al.))&:. '$! antisense therapy with ribo3ymes 9Crooke. . Tolerogens.))):.. >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. .))):. $europrotection The issue of neuroprotection in relation to glaucoma involves balancing factors that promote life versus death of the retinal ganglion cells. free radicals. Oral administration of retinal antigens has been used to treat ocular inflammation without a statistically significant impact on recurrence of ocular inflammation or cessation of conventional immunosuppressive therapy 9$ussenblatt et al.))):. . The e2perimental end points can be observed histologically by ganglion cell counts and a2on counts.. olecular1 and Cellular1=ased Therapy any biochemical and genetic defects have been identified in inherited retinal and retinal1pigment epithelial degenerations 9%harma and @hinger.))&:. and 6mmunostimulants: in preventing intraocular inflammation while patients are not receiving conventional immunosuppressive therapy 9$ussenblatt et al.))) b: and retinal transplantation 9 ohand1%aid et al. e2citoto2ins and their associated signaling pathways. . and blood flow in the optic disk 98evin..eis3 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. see Chapter 70# 6mmunomodulators# 6mmunosuppressive !gents. novel immunomodulation therapies are in clinical trials 9. efforts to develop novel strategies for drug delivery are e2pected. A---:. ischemia. 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. 6n addition to the aforementioned prospects for ocular pharmacology. . and optic nerve. but functional correlates are not yet possible in these rodent models.))(:.. !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.))&:.)))E 8a<ail et al. . >or further discussion of disturbances of vision and ocular movement.))6:. open1label.))):. ! recent nonrandomi3ed..))):. !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. given the limitations in access to the filtration angle.hitcup and $ussenblatt..))): and optic1nerve crush in"uries 9Koles et al. . retina. .>or uveitis. . neuroimmunomodulatory factors. @2panded research in this area should lead to new insights into mechanisms and pathways leading to glaucomatous optic neuropathy. any treatments have been proposed. 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. 6n contrast.L above:. Potential therapeutic targets include trophic factors. ... vitamin ! 9seeL<itamins and Trace @lements. pilot study holds promise for the use of a humani3ed. and cell1based therapies including retinal pigment epithelial 9. . . anti1681A1receptor monoclonal antibody 9daclizumab. and the relevance to the clinical setting is yet to be determined..

. A--7. .2rinciples o" 1nternal Medicine. $ew Kork.6th ed. . c+raw1Bill.

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