section xv ophthalmology

8/12/2019 Section XV Ophthalmology

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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 inChapters 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

nfections, /7# !ntimicrobial !gents# Penicillins, Cephalosporins, and Other 18actam !ntibiotics,

/6# !ntimicrobial !gents# The !minoglycosides,/ !ntimicrobial !gents# Protein %ynthesis

nhibitors 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


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;ith this empirical approach to treat disease, ophthalmic therapeutics took root from remedies

discovered for systemic diseases. >or instance, silver nitratewas 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 byNeisseria gonorrhoeae. n the nineteenth century, numerous organic substanceswere 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. !tropinewas isolated and used therapeutically in the eye in (0A. n

(&7,pilocarpinewas 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 eyeoffers 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 66:. n 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 9orglobe: 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. n 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 inferiorforni2, also known as the inferior cul1de1sac.

>igure 66. !natomy of the +lobe in 'elationship to the Orbit and

@yelids.


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The lacrimal system consists of secretory glandular and e2cretory ductal elements 9>igure 66A:.

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 66:, located in the con"unctiva. The lacrimal gland is innervated by the autonomic nervous

system 9seeTable 66and 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 asantidepressants 9seeChapter )# rugs and the Treatment of Psychiatric isorders# epression and

!n2iety isorders:, antihistamines 9seeChapter A7# Bistamine, =radykinin, and Their !ntagonists:,

and drugs used in the management of ParkinsonGs disease 9seeChapter AA# Treatment of Central

$ervous %ystem egenerative isorders:. 8ocated "ust posterior to the eyelashes are meibomian

glands 9see>igure 66:, 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 66A. !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.
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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 9 i.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 66A:. ;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 660A:. !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 660. !. !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.:
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!nterior %egment

The cornea is a transparent and avascular tissue organi3ed into five layers# epithelium, =owmanGs

membrane, stroma, escemetGs membrane, and endothelium 9see>igure 660B:.

'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. Constitutingappro2imately )-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,
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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 660B:. 8imbal blood vessels, as well as the tears, provide important nutrients and

immunological defense mechanisms for the cornea. The anterior chamber holds appro2imately A7-

l 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 ntraocular 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 9seeChapter A6# 8ipid1

erived !utacoids# @icosanoids and Platelet1!ctivating >actorand 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 glaucomais aimed at decreasing aqueous

humor production andJor increasing aqueous outflow. The preferred management for angle-closure

glaucomais 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.

nterestingly, 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. n 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.

ris and Pupil

loosenessThe iris is the most anterior portion of the uveal tract, which also includes the ciliary
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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. ndividual variation may be an important consideration for ocular drug distribution due

to drug1melanin binding 9seeListribution,L below:. The posterior surface of the iris is a denselypigmented 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 66/:

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 9 i.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 66A.>igure 667provides a flowchart for the diagnostic evaluation of anisocoria.

>igure 66/. !utonomic nnervation of the @ye by the %ympathetic 9a: and

Parasympathetic 9b: %ystems.9!dapted from ;ybar and ?err uir, )(/, withpermission.:

>igure 667. !nisocoria @valuation >lowsheet.9!dapted with permission from

Thompson and Pilley, )&6.:
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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. Thislatter 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 byzonules, 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


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>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 660. ! 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 oiland a petrolatum base and are helpful in

delivering antibiotics, cycloplegic drugs, or miotic agents. %olid inserts, such as OC5%@'T P8O1A-

and P8O1/-, provide azero-orderrate 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 somepatients, 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 9seeChapter

# 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 9seeTable 660and >igure 666:.

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 66and Table 660:.

>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. ntraocular 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 666. 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.:
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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 9seeconald 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 9see8ee,

))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, especiallywhen used chronically. Possible absorption pathways of an ophthalmic drug following topical

application to the eye are shown schematically in >igure 666.

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 forhydrophilic substancesE the stroma is a barrier for hydrophobic compounds. Bence, a drug with both

hydrophilic and lipophilic properties is best suited for transcorneal absorption.
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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 coefficient9for ioni3able drugs: yield a parabolic relationship that is a useful parameter for predicting ocular

absorption. Of course, such in vitrostudies 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 thendistributed to intraocular structures as well as potentially to the systemic circulation viathe

trabecular meshwork pathway 9see>igure 660B:. 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:. n rabbits, radiolabeled atropinebinds

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 drugmelanin binding is a potential reservoir for sustained drug

release. !nother clinically important consideration for drugmelanin binding involves the retinal

pigment epithelium. n the retinal pigment epithelium, accumulation of chloroquine9seeChapter

/-# rugs 5sed in the Chemotherapy of Proto3oal nfections# 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 andcrystalline 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 9see8ee, ))A:. The esteraseshave been of particular interest because of the development of prodrugs for enhanced corneal

permeabilityE for e2ample, dipivefrinhydrochloride 9andell et al., )&(: is a prodrug for

epinephrine, and latanoprostis 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 666, 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 deliveredlocally to the eye, and the potential localto2ic 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
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contain preservatives such asben3alkonium chloride, chlorobutanol, chelating agents, and

thimerosal for their antimicrobial effectiveness. n particular, ben3alkonium chloride may cause a

punctate keratopathy or to2iculcerative 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 9 Table 66/:. The

pharmacology, structures, and kinetics of individual drugs have been presented in detail in

preceding chapters. !ppropriate selection of antibiotic and route of administrationis dependent on

clinical e2amination and cultureJsensitivity results. %pecially formulated antibiotics also may beavailable 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

nfectious 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.

acryocystitisis an infection of the lacrimal sac. n 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"luenzaeafter the introduction in )(7 of the!. in"luenzaevaccine

9!mbati et al., A---:. n adults, dacryocystitis and canalicular infections may be caused by

Staphylococcus aureus, Streptococcusspecies, #andidaspecies, andActinomyces israelii.

nfectious processes of the lids include hordeolumand 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.Blepharitisis a common bilateral inflammatory process of the eyelids characteri3ed by irritation

and burning, and it also is usually caused by a Staphylococcusspecies. 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$unctivitisis 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, varicella3oster virus, vaccinia1variola virus: and bacterial sources 9e.g.,Neisseriaspecies, Streptococcus

pneumoniae,!aemophilusspecies, S.aureus,Mora%ella lacunata, chlamydial species:.&ic'ettsia,
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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. n 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.

)ndophthalmitisis a potentially severe and devastating inflammatory, and usually infectious,

process of the intraocular tissues. ;hen the inflammatory process encompasses the entire globe, it

is calledpanophthalmitis. @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 9seePeyman and %chulman, ))/E eredith, ))/:.

n cases of endogenous seeding, parenteral antibiotics have a role in eliminating the infectious

source. n trauma or in the postoperative setting, however, the efficacy of systemic antibiotics is not

well established.

!ntiviral !gents


The various antiviral drugs currently used in ophthalmology are summari3ed in Table 6679see

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 treatmentof viral con"unctivitis caused by adenoviruses, whichusually 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 and varicella 3oster viruses. 8ess common viral

etiologies include herpes simple2 , @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 acyclovirand glucocorticoids in herpetic corneal and e2ternal eye disease has been

e2amined in the Berpetic @ye isease %tudy 9!nonymous, ))6, ))&a, ))(:. Topicalglucocorticoids are contraindicated in herpetic epithelial keratitis due to active viral replication. n

contrast, for herpetic disciform keratitis, which predominantly ispresumed to involve a cell1
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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 9oyes et al., ))/E !nonymous, ))(:.

!erpes zoster ophthalmicusis alatent reactivation of a varicella 3osterinfection in the first divisionof the trigeminal cranial nerve. %ystemic acycloviris 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 investigationaluse.

Viral retinitismay be caused by herpes simple2 virus, cytomegalovirus 9C


16/30

a combination topical antibiotic, such aspolymy%in Bsul"ate, bacitracinzinc, and neomycinsul"ate

9e.g.,$@O%PO'$:, and sometimes an imidazole9e.g., clotrimazole, miconazole, or 'etoconazole:. n

the 5nited ?ingdom, the aromatic diamidines 9i.e.,propamine isethionatein bothtopical aqueous

and ointment forms, ='O8@$@: have been used successfully to treatthis relatively resistant

infectious keratitis 9Bargrave et al., ))):. !nother treatment forAcanthamoebais the cationicantiseptic agentpolyhe%amethylene biguanide, although this is not an >!1approved antiproto3oal

agent 98indquist, ))(:.

*o%oplasmosismay 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"adiazineand clindamycin+9/:

clindamycin+and 97: trimethoprim,sul"ametho%azolewith or without clindamycin9see@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 9seee>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 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 inophthalmology as well as the responses 9i.e., mydriasis

and cycloplegia: to muscarinic cholinergic antagonists are summari3ed in Table 66&.

Therapeutic 5ses

!utonomic drugs are used e2tensively for diagnostic and surgical purposes and for the treatment of

glaucoma, uveitis, and strabismus.

+laucoma

n 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 9seeTielsch, ))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. Thesepatients 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
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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-tensionglaucoma. 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 nstitutesponsored

clinical trial, the Collaborative nitial +laucoma Treatment %tudy 9C+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 9usch 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 fromsystemic absorption viathe 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%@'Tdelivery 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 agonistmay 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. ronically, epinephrine1related drugs may be used concomitantly with a 1

adrenergic receptor antagonist. @pinephrineGs main intraocular pressure1lowering effect isto

enhance uveoscleral outflow, but it also may alter trabecular meshwork function and ciliary body

blood flow. f combined topical therapy fails to achieve the target intraocular pressure or fails tohalt glaucomatous optic nerve damage, then systemic therapy with carbonic anhydrase inhibitors

9C!s: is a final medication option before resorting to laser or incisional surgical treatment. Of the
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oral preparations available 9seeChapter A)# iuretics:, the best tolerated is acetazolamidein

sustained1release capsules, followed by methazolamide. The least well tolerated are aceta3olamide

tablets 98ichter et al., )&(:. Toreduce side effects, topical C!s have been developedD

dorzolamidehydrochloride9T'5%OPT:, and brinzolamide9!MOPT:, whose structures are shown

below. These topical C!s 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 wanesbetween 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 apraclonidineare 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 viathe nasolacrimal system. The use of

C!s systematically may give some patients significant problems with malaise, fatigue, depression,

paresthesias, and nephrolithiasisE the topical C!s 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 onquality of life must be recogni3ed.

5veitis

nflammation 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.

f posterior synechiae have already formed, an -adrenergic agonistmay be used to break the

synechiae by enhancing pupillary dilation. *opical steroidsusually are adequate to decreaseinflammation, but sometimes they must be supplemented by systemic steroids.
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%trabismus

%trabismus, or ocular misalignment, has numerous causes and may occur at any age. n children,

strabismus may lead to amblyopia9reduced vision:. $onsurgical efforts to treat amblyopia include

occlusion therapy, orthoptics, optical devices, and pharmacological agents. The eyes of childrenwith hyperopia, or farsightedness, must accommodate to focus distant images. n some cases, the

synkinetic accommodative1convergence response leads to e2cessive convergence and a manifest

esotropia9turned1in eye:. This deviated eye does not develop normal visual acuity and is therefore

amblyopic. n this setting, atropine9I: 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.)chothiophateiodidealso 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 echothiophatecauses 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 9seeTable 66&:.

ntraoperatively, there are circumstances when miosis is preferred, and two cholinergic agonists are

available for intraocular use, acetylcholineand carbachol. Patients with myasthenia gravis may first

present to an ophthalmologist with complaints of double vision 9diplopia: or lid droop 9ptosis:E the

edrophoniumtestis helpful in diagnosing thesepatients 9seeChapter (# !nticholinesterase !gents:.

5se of mmunomodulatory 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 nhibitors 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
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corticosteroids. These include the development of posterior subcapsular cataracts and secondary

infections 9seeChapter 6-# !drenocorticotropic BormoneE !drenocortical %teroids and Their

%ynthetic !nalogsE nhibitors 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 positivefamily history of glaucoma. f there is no family history of open1angle glaucoma, only about 7I of

normal individuals respond to topical or long1term systemic steroids with amarked 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#1Agene may be

involved 9%tone et al., ))&:. Typically, steroid1induced elevation of intraocular pressure is

reversible once administration of the steroid ceases.

$onsteroidal !ntiinflammatory !gents


$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$%!s: are now being applied to the treatment of ocular disease.

Therapeutic 5ses

Currently, there are four topical $%!s approved for ocular use# diclo"enac9@$!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#

>lurbiprofenand suprofen are used to counter unwanted intraoperative miosis during cataract

surgery. ?etorolacis given for seasonal allergic con"unctivitis. iclofenacis 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

2heniramine9seeChapter A7# Bistamine, =radykinin, and Their !ntagonists: and antazoline, both

B1receptor antagonists, are formulated in combination with naphazoline, a vasoconstrictor, for
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relief of allergic con"unctivitis. The chemical structure of anta3oline is#

$ewer topical antihistamines include emedastinedi"umarate9@!$@:, olopatadine

hydrochloride9P!T!$O8:, levocabastinehydrochloride98luorouracil >iltering %urgery %tudy +roup, )():.

n cornea surgery, mitomycinC 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
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!d"uncts in !nterior %egment %urgery

!yaluronidasedepolymeri3es 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 retrobulbarin"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.

Viscoelasticsubstances assist in ocular surgery by maintaining spaces, moving tissue, and

protecting surfaces 9see8iesegang, ))-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:.


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response may occur, but this reaction can be minimi3ed by thorough irrigation after hemostasis is

achieved. This coagulation factor also may be applied topically viasoaked 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 tointraocular pressure, retinal degeneration, and persistent poor vision. *issue plasminogen activator

9t1P!: 9seeChapter 77# !nticoagulant, Thrombolytic, and !ntiplatelet rugs: has been used during

intraocular surgeries to assist evacuation of a hyphema9blood 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 A9=OTON: has been used to treat strabismus, blepharospasm, eigeGssyndrome, spasmodic torticollis hemifacial spasm, and facial wrinkles 9Tsui, ))6E Price et al.,

))&Esee alsoChapter )# !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 topicalanesthetics, 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 667: 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"luoresceinand rose bengalare 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. n the setting of epiphora, fluorescein is used to help
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determine the patency of the nasolacrimal system. n addition, this dye is used as part of the

procedure of applanation tonometry9intraocular 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 devitali3edtissue 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 bloodretinal and retinal pigment epithelial barriers may be e2amined directly

by retinal angiography using intravenous administration of either"luoresceinsodiumor

indocyanine green, whose structures are shown below. Of the agents used in assisting the making ofa 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"in9! in A--- for photodynamic therapy of thee2udative 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 9 and :, is shown below#
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Other !gents for Ophthalmic Therapy


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multivitamin supplement containing /-- g of folic acid9Omenn et al., ))(:.

;etting !gents and Tear %ubstitutes


The current management of dry eyes usually includes instilling artificial tearsand ophthalmic

lubricants. n 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. n other countries,hyaluronic acidis 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 9seeabove:. 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.


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inhibitors are a valuable ad"unct to topical agents used to treat glaucoma. The pharmacology of this

class of diuretic 9i.e., aceta3olamideand 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 mannitolfor 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 aceta3olamidemay 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. n

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. dentifying 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 chlorideis available in either aqueous or ointment

formulations. Topical glycerinalso 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. n 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.

mmunomodulation

! 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 66A:. !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 topicalemulsion of cyclosporine9'@%T!%%: is being evaluated in clinical trials 9%tevenson et al., A---:.
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>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, anti181A1receptor monoclonal antibody9daclizumab,seeChapter 70# mmunomodulators# mmunosuppressive !gents, Tolerogens, and

mmunostimulants: 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


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

section xv ophthalmology

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