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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. $umerous microbial agents have been isolated, including bacteria, viruses,
fungi, spirochetes, and cysts and tropho3oites. n aggressive forms of bacterial keratitis, immediate
empirical and intensive antibiotic therapy is essential to prevent blindness from corneal perforation
and secondary corneal scarring. 'esults of culture and sensitivity tests should guide the final drug of
choice.
)ndophthalmitisis a potentially severe and devastating inflammatory, and usually infectious,
process of the intraocular tissues. ;hen the inflammatory process encompasses the entire globe, it
is calledpanophthalmitis. @ndophthalmitis usually is caused by bacteria, by fungi, or rarely by
spirochetes. The typical case occurs during the early postoperative course 9e.g., after cataract,glaucoma, cornea, or retinal surgery:, following trauma, or by endogenous seeding in the
immunocompromised host or intravenous drug user. Prompt therapy usually includes vitrectomy
9i.e., speciali3ed surgical removal of the vitreous: and empirical intravitreal antibiotics to treat
suspected bacterial or fungal microorganisms 9seePeyman and %chulman, ))/E eredith, ))/:.
n cases of endogenous seeding, parenteral antibiotics have a role in eliminating the infectious
source. n trauma or in the postoperative setting, however, the efficacy of systemic antibiotics is not
well established.
!ntiviral !gents
+eneral Considerations
The various antiviral drugs currently used in ophthalmology are summari3ed in Table 6679see
Chapter 7-# !ntimicrobial !gents# !ntiviral !gents 9$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
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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 Considerations
+eneral autonomic pharmacology has been discussed e2tensively in Chapters 6# $eurotransmission#
The !utonomic and %omatic otor $ervous %ystems, uscarinic 'eceptor !gonists and
!ntagonists, (# !nticholinesterase !gents, )# !gents !cting at the $euromuscular *unction and
!utonomic +anglia, and -# Catecholamines, %ympathomimetic rugs, and !drenergic 'eceptor
!ntagonists. The autonomic agents used 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
+eneral Considerations
$onsteroidal drug therapy for inflammation is discussed in Chapter A !nalgesic1!ntipyretic and
!ntiinflammatory !gents and rugs @mployed in the Treatment of +out. The nonsteroidal
antiinflammatory drugs 9$%!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
+eneral Considerations
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.