Goodman and Gilman Manual of Pharmacology and Therapeutics

Section IX
Special Systems Pharmacology

chapter 64
Ocular Pharmacology

The eye is a specialized sensory organ that is relatively secluded from systemic access by the blood-retinal, blood-aqueous, and blood-vitreous barriers; as a consequence, the eye exhibits some unusual pharmacodynamic and pharmacokinetic properties.

EXTRAOCULAR STRUCTURES

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 (Figure 64–1). In the orbit, connective (i.e.,Tenon’s capsule) and adipose tissues and 6 extraocular muscles support and align the eyes for vision. The retrobulbar region lies immediately behind the eye (or globe). Understanding ocular and orbital anatomy is important for safe periocular drug delivery, including subconjunctival, sub-Tenon’s, and retrobulbar injections.

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Figure 64–1 Anatomy of the globe in relationship to the orbit and eyelids. Various routes of administration of anesthesia are demonstrated by the blue needle pathways.

The external surface of the eyelids is covered by a thin layer of skin; the internal surface is lined with the palpebral portion of the conjunctiva, which is a vascularized mucous membrane continuous with the bulbar conjunctiva. At the reflection of the palpebral and bulbar conjunctivae is a space called the fornix, located superiorly and inferiorly behind the upper and lower lids, respectively. Topical medications usually are placed in the inferior fornix, also known as the inferior cul-de-sac.

The lacrimal system consists of secretory glandular and excretory ductal elements (Figure 64–2). The secretory system is composed of the main lacrimal gland, which is located in the temporal outer portion of the orbit, and accessory glands located in the conjunctiva. The lacrimal gland is innervated by the autonomic nervous system (Table 64–1 and Chapter 8). The parasympathetic innervation is clinically relevant because a patient may complain of dry eye symptoms while taking medications with anticholinergic side effects, such as tricyclic antidepressants (see Chapter 15), antihistamines (seeChapter 32), and drugs used in the management of Parkinson disease (see Chapter 22).

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Figure 64–2 Anatomy of the lacrimal system.

Table 64–1

Autonomic Pharmacology of the Eye and Related Structures

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Tears constitute a trilaminar lubrication barrier covering the conjunctiva and cornea. The anterior layer is composed primarily of lipids; the middle aqueous layer, produced by the main lacrimal gland and accessory lacrimal glands, constitutes ~98% of the tear film. Adherent to the corneal epithelium, the posterior layer is a mixture of mucins produced by goblet cells in the conjunctiva. Tears also contain nutrients, enzymes, 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 (seeFigure 64–2). With 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 epithelium; consequently, topically applied medications that pass through this nasolacrimal system have direct access to the systemic circulation.

OCULAR STRUCTURES

The eye is divided into anterior and posterior segments (Figure 64–3A). Anterior segment structures include the cornea, limbus, anterior and posterior chambers, trabecular meshwork, canal of Schlemm (Schlemm’s canal), iris, lens, zonule, and ciliary body. The posterior segment includes the vitreous, retina, choroid, sclera, and optic nerve.

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Figure 64–3 A. Anatomy of the eye. B. Enlargement of the anterior segment, revealing the cornea, angle structures, lens, and ciliary body. (Adapted with permission from Riordan-Eva P. Anatomy and embryology of the eye. In: Riordan-Eva P, Whitcher JP, eds. Vaughan & Asbury’s General Ophthalmology, 17th ed. New York: McGraw-Hill; 2008. Copyright © 2008 by The McGraw-Hill Companies, Inc. All rights reserved.)

ANTERIOR SEGMENT

Cornea and Drug Access. The cornea is a transparent and avascular tissue organized into 5 layers (Figure 64–3B). Representing an important barrier to foreign matter, including drugs, the hydrophobic epithelial layer comprises 5 to 6 cell layers. The basal epithelial cells lie on a basement membrane that is adjacent to Bowman’s membrane, a layer of collagen fibers. Constituting ~90% of the corneal thickness, the stroma, a hydrophilic layer, is organized with collagen lamellae synthesized by keratocytes. Beneath the stroma lies Descemet’s membrane, the basement membrane of the corneal endothelium. Lying most posteriorly, the endothelium is a monolayer of cells adhering to each other by tight junctions. These cells maintain corneal integrity by active transport processes and serve as a hydrophobic barrier. Hence, drug absorption across the cornea requires penetration of the trilaminar hydrophobic–hydrophilic–hydrophobic domains of the various anatomical layers.

At the periphery of the cornea and adjacent to the sclera lies a transitional zone (1-2 mm wide) called the limbus. Limbal structures include the conjunctival epithelium, which contains the corneal epithelial stem cells, Tenon’s capsule, episclera, corneoscleral stroma, canal of Schlemm, and trabecular meshwork (see Figure 64–3B). Limbal blood vessels, as well as the tears, provide important nutrients and immunological defense mechanisms for the cornea. The anterior chamber holds ~250 µL of aqueous humor. The peripheral anterior chamber angle is formed by the cornea and the iris root. The trabecular meshwork and canal of Schlemm are located just above the apex of this angle. The posterior chamber, which holds ~50 µL of aqueous humor, is defined by the boundaries of the ciliary body processes, posterior surface of the iris, and lens surface.

Aqueous Humor Dynamics and Regulation of Intraocular Pressure (IOP). Aqueous humor is secreted by the ciliary processes and flows from the posterior chamber, through the pupil, and into the anterior chamber and leaves the eye primarily by the trabecular meshwork and canal of Schlemm, thence to an episcleral venous plexus and into the systemic circulation. This conventional pathway accounts for 80-95% of aqueous humor outflow and is the main target for cholinergic drugs used in glaucoma therapy. Another outflow pathway is the uveoscleral route (i.e., fluid flows through the ciliary muscles and into the suprachoroidal space), which is the target of selective prostanoids (see “Glaucoma” and Chapter 33).

The peripheral anterior chamber angle is an important anatomical structure for differentiating 2 forms of glaucoma: open-angle glaucoma, which is by far the most common form of glaucoma in the U.S., and angle-closure glaucoma. Current medical therapy of open-angle glaucoma is aimed at decreasing aqueous humor production and/or increasing aqueous outflow. The preferred management for angle-closure glaucoma is surgical iridectomy, by either laser or incision, but short-term medical management may be necessary to reduce the acute IOP elevation and to clear the cornea prior to surgery. Long-term IOP reduction may be necessary, especially if the peripheral iris has permanently covered the trabecular meshwork.

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 change in the lens-iris relationship leads to an increase in pressure in the posterior chamber, causing the iris base to be pushed against the angle wall, thereby covering the trabecular meshwork and closing the filtration angle and markedly elevating the IOP. The result is known as an acute attack of pupillary-block angle-closure glaucoma.

Iris and Pupil. The iris is the most anterior portion of the uveal tract, which also includes the ciliary body and choroid. The anterior surface of the iris is the stroma, a loosely organized structure containing melanocytes, blood vessels, smooth muscle, and parasympathetic and sympathetic nerves. Differences in iris color reflect individual variation in the number of melanocytes located in the stroma. Individual variation may be an important consideration for ocular drug distribution due to drug-melanin binding (see “Distribution”). The posterior surface of the iris is a densely pigmented bilayer of epithelial cells. Anterior to the pigmented epithelium, the dilator smooth muscle is oriented radially and is innervated by the sympathetic nervous system (Figure 64–4), which causes mydriasis (dilation). At the pupillary margin, the sphincter smooth muscle is organized in a circular band with parasympathetic innervation, which, when stimulated, causes miosis (constriction). The use of pharmacological agents to dilate normal pupils and to evaluate the pharmacological response of the pupil is summarized in Table 64–2. Pharmacological agents are also used for the diagnostic evaluation of anisocoria (see Figure 64–5 in the 12th edition of the parent text).

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Figure 64–4 Autonomic innervation of the eye by the sympathetic (a) and parasympathetic (b) nervous systems. (Adapted with permission from Wybar KC, Kerr-Muir M. Bailliere’s Concise Medical Textbooks, Ophthalmology, 3rd ed. New York: Bailliere Tindall; 1984. Copyright © Elsevier.)

Table 64–2

Effects of Pharmacological Agents on the Pupil

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Figure 64–5 Possible absorption pathways of an ophthalmic drug following topical application to the eye. Solid black arrows represent the corneal route; dashed blue arrows represent the conjunc-tival/scleral route; the black dashed arrow represents the nasolacrimal absorption pathway. (Adapted with permission from Chien D-S, et al. Curr Eye Res, 1990;9(11):1051–1059. Copyright © 1990 Informa Healthcare.)

Ciliary Body. The ciliary body serves 2 very specialized roles:

• Secretion of aqueous humor by the epithelial bilayer

• Accommodation by the ciliary muscle

The anterior portion of the ciliary body (pars plicata) comprises 70-80 ciliary processes with intricate folds. The posterior portion is the pars plana. The ciliary muscle is organized into outer longitudinal, middle radial, and inner circular layers. Coordinated contraction of this smooth muscle apparatus by the parasympathetic nervous system causes the zonule suspending the lens to relax, allowing the lens to become more convex and to shift slightly forward. This process, known as accommodation, permits focusing on near objects and may be pharmacologically blocked by muscarinic cholinergic antagonists, through the process called cycloplegia. Contraction of the ciliary muscle also puts traction on the scleral spur and hence widens the spaces within the trabecular meshwork. This latter effect accounts for at least some of the IOP-lowering effect of both directly acting and indirectly acting parasympathomimetic drugs.

Lens. The lens is suspended by zonules, specialized fibers emanating from the ciliary body. The lens is ~10 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. Aging, in addition to certain medications, such as corticosteroids, and certain diseases, such as diabetes mellitus, cause the lens to become opacified, which is termed a cataract.

POSTERIOR SEGMENT

Because of the anatomical and vascular barriers to both local and systemic access, drug delivery to the eye’s posterior pole is particularly challenging.

Sclera. The outermost coat of the eye, the sclera, covers the posterior portion of the globe. The external surface of the scleral shell is covered by an episcleral vascular coat, by Tenon’s capsule, and by the conjunctiva. The tendons of the 6 extraocular muscles insert collagen fibers into the superficial scleral. Numerous blood vessels pierce the sclera through emissaria to both supply and drain the choroid, ciliary body, optic nerve, and iris. Inside the scleral shell, a capillary network (vascular choroid) nourishes the outer retina. Between the outer retina and the capillary network lie Bruch’s membrane and the retinal pigment epithelium, whose tight junctions provide an outer barrier between the retina and the choroid. The retinal pigment epithelium serves many functions, including vitamin A metabolism, phagocytosis of the rod outer segments, and multiple transport processes.

Retina. The retina is a thin, transparent, highly organized structure of neurons, glial cells, and blood vessels; it contains the photoreceptors and the rhodopsin-based G-protein signaling system.

Vitreous. Approximately 80% of the eye’s volume is the vitreous, a clear medium containing collagen type II, hyaluronic acid, proteoglycans, glucose, ascorbic acid, amino acids, and a number of inorganic salts. Glutamate in the vitreous may have a relationship to glaucoma: ganglion cells appear to die in glaucoma via apoptosis, a process that glutamate, acting on NMDA receptors, can stimulate. Memantine, a noncompetitive NMDA receptor antagonist, is currently being investigated clinically as a treatment for glaucoma.

Optic Nerve. The optic nerve is a myelinated nerve conducting the retinal output to the CNS. It comprises:

• An intraocular portion, which is visible as the optic disk in the retina

• An intraorbital portion

• An intracanalicular portion

• An intracranial portion

The nerve is ensheathed in meninges continuous with the brain. At present, pharmacological treatment of optic neuropathies usually is based on management of the underlying disease. For example, nonarteritic ischemic optic neuropathy is best treated with intravitreal glucocorticoids, and optic neuritis with intravenous glucocorticoids. Glaucomatous optic neuropathy is medically managed by decreasing IOP.

PHARMACOKINETICS AND TOXICOLOGY OF OCULAR THERAPEUTIC AGENTS

Drug-Delivery Strategies. Properties of varying ocular routes of administration are outlined in Figure 64–1 and Table 64–3.

Table 64–3

Some Characteristics of Ocular Routes of Drug Administration

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Several 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 cul-de-sac beneath the eye lid facilitates drug absorption. Ophthalmic gels (e.g., pilocarpine 4% gel) release drugs by diffusion following erosion of soluble polymers. Ointments usually contain mineral oil and a petrolatum base and are helpful in delivering antibiotics, cycloplegic drugs, or miotic agents. Solid inserts, such as the ganciclovir intravitreal implant, provide a zero-order rate of delivery by steady-state diffusion, whereby drug is released at a more constant rate over a prolonged period of time rather than as a bolus.

PHARMACOKINETICS. The pharmacokinetic principles of absorption, distribution, metabolism, and excretion determine the time course of drug action in the eye, however, the routes of ocular drug administration, the flow of ocular fluids, and the architecture of the eye introduce other variables specific to the eye. Most ophthalmic medications are formulated to be applied topically. Drugs also may be injected by subconjunctival, sub-Tenon’s, and retrobulbar routes.

ABSORPTION. After topical instillation of a drug, the rate and extent of absorption are determined by the time the drug remains in the cul-de-sac and precorneal tear film, elimination by nasolacrimal drainage, drug binding to tear proteins, drug metabolism by tear and tissue proteins, and diffusion across the cornea and conjunctiva. A drug’s residence time may be prolonged by changing its formulation. Residence time also may be extended by blocking the egress of tears from the eye by closing the tear drainage ducts with flexible silicone (punctal) plugs. Nasolacrimal drainage contributes to systemic absorption of topically administered ophthalmic medications. Absorption from the nasal mucosa avoids first-pass metabolism by the liver; thus, topical ophthalmic medications can cause significant systemic side effects, especially when used chronically. Possible absorption pathways of an ophthalmic drug following topical application to the eye are shown schematically in Figure 64–5.

Transcorneal and transconjunctival/scleral absorption are the desired routes for localized ocular drug effects. The drug concentration gradient between the tear film and the cornea and conjunctival epithelium provides the driving force for passive diffusion across these tissues. Other factors that affect a drug’s diffusion capacity are the size of the molecule, chemical structure, and steric configuration. Transcorneal drug penetration is a differential solubility process; the cornea resembles a trilaminar “fat-water-fat” structure corresponding to the epithelial, stromal, and endothelial layers. The epithelium and endothelium represent barriers for hydrophilic substances; the stroma is a barrier for hydrophobic compounds. Hence, a drug with both hydrophilic and lipophilic properties is best suited for transcorneal absorption. Drug penetration into the eye is approximately linearly related to its concentration in the tear film. Certain disease states, such as corneal epithelial defects and corneal ulcers, may alter drug penetration. Medication absorption usually is increased when an anatomical barrier is compromised or removed.

DISTRIBUTION. Topically administered drugs may undergo systemic distribution primarily by nasal mucosal absorption and possibly by local ocular distribution by transcorneal/transconjunctival absorption. Following transcorneal absorption, the aqueous humor accumulates the drug, which then is distributed to intraocular structures and potentially to the systemic circulation via the trabecular meshwork pathway (see Figure 64–3B). Melanin binding of certain drugs is an important factor in some ocular compartments. For example, the mydriatic effect of α adrenergic–receptor agonists is slower in onset in human volunteers with darkly pigmented irides compared to those with lightly pigmented irides: drug-melanin binding is a potential reservoir for sustained drug release. Another clinically important consideration for drug-melanin binding involves the retinal pigment epithelium. In the retinal pigment epithelium, accumulation of chloroquine (see Chapter 49) causes a toxic retinal lesion known as a “bull’s-eye” maculopathy, which is associated with a decrease in visual acuity.

METABOLISM. Biotransformation of ocular drugs may be significant; a variety of enzymes, including esterases, oxidoreductases, lysosomal enzymes, peptidases, glucuronide and sulfate transferases, GSH-conjugating enzymes, COMT, MAO, and 11 β-hydroxysteroid dehydrogenase are found in the eye. The esterases have been of particular interest, permitting development of ester prodrugs for enhanced corneal permeability (e.g., dipivefrin hydrochloride is a prodrug for epinephrine, and latanoprost is a prodrug for PGF; both drugs are used for glaucoma management).

TOXICOLOGY. Most local toxic effects are due to hypersensitivity reactions or to direct toxic effects on the cornea, conjunctiva, periocular skin, and nasal mucosa. Eyedrops and contact lens solutions commonly contain antimicrobial preservatives such as benzalkonium chloride, chlorobutanol, chelating agents, and, rarely, thimerosal. In particular, benzalkonium chloride may cause a punctate keratopathy or toxic ulcerative keratopathy. All ophthalmic medications are potentially absorbed into the systemic circulation (Figure 64–5), so systemic side effects may occur.

OPHTHALMIC USES OF DRUGS

CHEMOTHERAPY OF MICROBIAL DISEASES IN THE EYE

ANTIBACTERIAL AGENTS. A number of antibiotics have been formulated for topical ocular use (Table 64–4).

Table 64–4

Topical Antibacterial Agents Commercially Available for Ophthalmic Use

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THERAPEUTIC USES OF OCULAR ANTIMICROBIALS. Infectious diseases of the skin, eyelids, conjunctivae, and lacrimal excretory system are encountered regularly. Periocular skin infections are divided into preseptal and postseptal or orbital cellulitis. Depending on the clinical setting (i.e., preceding trauma, sinusitis, age of patient, relative immunocompromised state), oral or parenteral antibiotics are administered.

Dacryoadenitis, an infection of the lacrimal gland, is most common in children and young adults; it may be bacterial (typically Staphylococcus aureus, Streptococcus spp.) or viral (seen in mumps, infectious mononucleosis, influenza, and herpes zoster). When bacterial infection is suspected, systemic antibiotics usually are indicated.

Dacryocystitis is an infection of the lacrimal sac. In infants and children, the disease usually is unilateral and secondary to an obstruction of the nasolacrimal duct. In adults, dacryocystitis and canalicular infections may be caused by S. aureus, Streptococcus spp., diphtheroids, Candida spp., and Actinomyces israelii. Any discharge from the lacrimal sac should be sent for smears and cultures. Systemic antibiotics typically are indicated.

Infectious processes of the lids include hordeolum and blepharitis. A hordeolum, or stye, is an infection of the meibomian, Zeis, or Moll glands at the eyelid margins. The typical offending bacterium is S. aureus, and the usual treatment consists of warm compresses and topical antibiotic (gel, drops, or ointment). Blepharitis is a common bilateral inflammatory process of the eyelids characterized by irritation and burning, usually associated with a Staphylococcus sp. Local hygiene is the mainstay of therapy; topical antibiotics frequently are used. Systemic tetracycline, doxycycline, minocycline, and erythromycin often are effective in reducing severe eyelid inflammation but must be used for weeks to months.

Conjunctivitis is an inflammatory process of the conjunctiva that varies in severity from mild hyperemia to severe purulent discharge. The more common causes of conjunctivitis include viruses, allergies, environmental irritants, contact lenses, and chemicals. The less common causes include other infectious pathogens, immune-mediated reactions, associated systemic diseases, and tumors of the conjunctiva or eyelid. The more commonly reported infectious agents are adenovirus and herpes simplex virus, followed by other viral (e.g., enterovirus, coxsackievirus, measles virus, varicella zoster virus, vaccinia variola virus) and bacterial sources (e.g., Neisseria spp., Streptococcus pneumoniae, Haemophilus spp., S. aureus, Moraxella lacunata, and chlamydial spp.). Rickettsia, fungi, and parasites, in both cyst and trophozoite form, are rare causes of conjunctivitis. Effective management is based on selection of an appropriate antibiotic for suspected bacterial pathogens. Unless an unusual causative organism is suspected, bacterial conjunctivitis is treated empirically with a broad-spectrum topical antibiotic without obtaining a culture.

Keratitis, or corneal inflammation, can occur at any level of the cornea. Numerous microbial agents have been identified as causes of infectious keratitis, including bacteria, viruses, fungi, spirochetes, and cysts and trophozoites. Severe infections with tissue loss (corneal ulcers) generally are treated more aggressively than infections without tissue loss (corneal infiltrates). Mild, small, more peripheral infections usually are not cultured, and the eyes are treated with broad-spectrum topical antibiotics. In more severe, central, or larger infections, corneal scrapings for cultures and sensitivities are performed, and the patient is immediately started on intensive hourly, around-the-clock topical antibiotic therapy. The goal of treatment is to eradicate the infection and reduce the amount of corneal scarring and the chance of corneal perforation and severe decreased vision or blindness. The initial medication selection and dosage are adjusted according to the clinical response and culture and sensitivity results.

Endophthalmitis is a potentially severe and devastating inflammatory, and usually infectious, process involving the intraocular tissues. When the inflammatory process encompasses the entire globe, it is called panophthalmitis. Endophthalmitis usually is caused by bacteria or fungi, or rarely by spirochetes. The typical case occurs during the early postoperative course (e.g., after cataract, glaucoma, cornea, or retinal surgery), following trauma, or by endogenous seeding in an immunocompromised host or intravenous drug user. Acute postoperative endophthalmitis requires a prompt vitreous tap for smears and cultures and empirical injection of intravitreal antibiotics. Immediate vitrectomy (i.e., specialized surgical removal of the vitreous) is beneficial for patients who have light perception–only vision. Vitrectomy for other causes of endophthalmitis (e.g., glaucoma bleb related, posttraumatic, or endogenous) may be beneficial. In cases of endogenous seeding, parenteral antibiotics have a role in eliminating the infectious source, but the efficacy of systemic antibiotics with trauma is not well established.

ANTIVIRAL AGENTS. Antiviral drugs used in ophthalmology are summarized in Table 64–5 (see Chapter 58 for details of these agents).

Table 64–5

Antiviral Agents for Ophthalmic Use

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THERAPEUTIC USES. The primary indications for the use of antiviral drugs in ophthalmology are viral keratitis, herpes zoster ophthalmicus, and retinitis. There currently are no antiviral agents for the treatment of viral conjunctivitis caused by adenoviruses, which usually has a self-limited course and typically is treated by symptomatic relief of irritation.

Viral keratitis, an infection of the cornea that may involve either the epithelium or stroma, is most commonly caused by herpes simplex type I and varicella zoster viruses. Less common viral etiologies include herpes simplex type II, Epstein-Barr virus, and CMV. Topical antiviral agents are indicated for the treatment of epithelial disease due to herpes simplex infection. When treating viral keratitis topically, there is a very narrow margin between the therapeutic topical antiviral activity and the toxic effect on the cornea; hence, patients must be followed very closely. Topical glucocorticoids are contraindicated in herpetic epithelial keratitis due to active viral replication. In contrast, for herpetic disciform keratitis (predominantly a cell-mediated immune reaction), topical glucocorticoids accelerate recovery. For recurrent herpetic stromal keratitis, there is clear benefit from treatment with oral acyclovir in reducing the risk of recurrence.

Herpes zoster ophthalmicus is a latent reactivation of a varicella zoster infection in the first division of the trigeminal cranial nerve. Systemic acyclovir, valacyclovir, and famciclovir are effective in reducing the severity and complications of herpes zoster ophthalmicus. Currently, there are no ophthalmic preparations of acyclovir approved by the FDA, although an ophthalmic ointment is available for investigational use.

Viral retinitis may be caused by herpes simplex virus, CMV, adenovirus, and varicella zoster virus. With highly active antiretroviral therapy (HAART; see Chapter 59), CMV retinitis does not appear to progress when specific anti-CMV therapy is discontinued, but some patients develop an immune recovery uveitis. Treatment usually involves long-term parenteral administration of antiviral drugs. Intravitreal ganciclovir has been found to be an effective alternative to systemic use. Acute retinal necrosis and progressive outer retinal necrosis, most often caused by varicella zoster virus, can be treated by various combinations of oral, intravenous, intravitreal injection of, and intravitreal implantation of antiviral medications.

ANTIFUNGAL AGENTS

The only currently available topical ophthalmic antifungal preparation is a polyene, natamycin (NATACYN). Other antifungal agents may be extemporaneously compounded for topical, subconjunctival, or intravitreal routes of administration (Table 64–6see also Chapter 57).

Table 64–6

Antifungal Agents for Ophthalmic Use

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THERAPEUTIC USES. As with systemic fungal infections, the incidence of ophthalmic fungal infections has risen with the growing number of immunocompromised hosts. Ophthalmic indications for antifungal medications include fungal keratitis, scleritis, endophthalmitis, mucormycosis, and canaliculitis. Risk factors for fungal keratitis include trauma, chronic ocular surface disease, contact lens wear, and immunosuppression (including topical steroid use). When fungal infection is suspected, samples of the affected tissues are obtained for smears, cultures, and sensitivities, and this information is used to guide drug selection.

ANTIPROTOZOAL AGENTS

Parasitic infections involving the eye usually manifest themselves as a form of uveitis, an inflammatory process of either the anterior or posterior segments and, less commonly, as conjunctivitis, keratitis, and retinitis.

THERAPEUTIC USES. In the U.S., the most commonly encountered protozoal infections include Acanthamoeba and Toxoplasma gondii. In contact lens wearers who develop keratitis, physicians should be highly suspicious of the presence of Acanthamoeba. Risk factors for Acanthamoeba keratitis include poor contact lens hygiene, wearing contact lenses in a pool or hot tub, and ocular trauma. Treatment usually consists of a combination of topical agents. The aromatic diamidines (i.e., propamidine isethionate in both topical aqueous and ointment forms [BROLENE, NOT AVAILABLE IN U.S.]) have been used successfully to treat this relatively resistant infectious keratitis. The cationic antiseptic agent polyhexamethylene biguanide (PHMB) also is used in drop form for Acanthamoeba keratitis. Topical chlorhexidine can be used as an alternative to PHMB. Oral imidazoles (e.g., itraconazole, fluconazole, ketoconazole, voriconazole) often are used in addition to the topical medications. Resolution ofAcanthamoeba keratitis often requires many months of treatment.

Treatment of toxoplasmosis is indicated when inflammatory lesions encroach upon the macula and threaten central visual acuity. Several regimens have been recommended with concurrent use of systemic steroids: (1) pyrimethamine, sulfadiazine, and folinic acid (leucovorin); (2) pyrimethamine, sulfadiazine, clindamycin, and folinic acid; (3) sulfadiazine and clindamycin; (4) clindamycin; (5) trimethoprim-sulfamethoxazole ± clindamycin. Other protozoal infections (e.g., giardiasis, leishmaniasis, malaria) and helminths are less common eye pathogens in the U.S. Systemic pharmacological management as well as vitrectomy may be indicated for selected parasitic infections.

AUTONOMIC AGENTS

THERAPEUTIC USES. Autonomic drugs are used extensively for diagnostic and surgical purposes and for the treatment of glaucoma, uveitis, and strabismus. The autonomic agents used in ophthalmology and the responses (i.e., mydriasis, cycloplegia) to muscarinic cholinergic antagonists are summarized in Table 64–7.

Table 64–7

Autonomic Drugs for Ophthalmic Use

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Glaucoma. Glaucoma is characterized by progressive optic nerve cupping and visual field loss. Risk factors include increased IOP, positive family history of glaucoma, African American heritage, and possibly myopia and hypertension. Reducing IOP can delay glaucomatous nerve or field damage. Although markedly elevated IOPs (e.g., >30 mm Hg) usually will lead to optic nerve damage, the optic nerves in certain patients (ocular hypertensives) apparently can tolerate IOPs in the mid- to high 20s. Other patients have progressive glaucomatous optic nerve damage despite having IOPs in the normal range, and this form of the disease sometimes is called normal- or low-tension glaucoma. A reduction of IOP by 30% reduces disease progression from ~35-10%, even for normal-tension glaucoma patients. At present the pathophysiological processes involved in glaucomatous optic nerve damage and the relationship to aqueous humor dynamics are not understood. Current pharmacotherapies are targeted at decreasing the production of aqueous humor at the ciliary body and increasing outflow through the trabecular meshwork and uveoscleral pathways. There is no consensus on the best IOP-lowering technique for glaucoma therapy.

A stepped medical approach depends on the patient’s health, age, and ocular status, with knowledge of systemic effects and contraindications for all medications. A stepped medical approach may begin with a topical prostaglandin (PG) analog. Due to their once-daily dosing, low incidence of systemic side effects, and potent IOP-lowering effect, PG analogs have largely replaced β adrenergic–receptor antagonists as first-line medical therapy for glaucoma. The PG analogs consist of latanoprost (XALATAN), travoprost (TRAVATAN, TRAVATAN Z), bimatoprost (LUMIGAN, LATISSE), and tafluprost (ZIOPTAN). PGF reduces IOP but has intolerable local side effects. Modifications to the chemical structure of PGF have produced analogs with a more acceptable side-effect profile. The mechanism by which this occurs is unclear. PGF and its analogs (prodrugs that are hydrolyzed to PGF) bind to FP receptors that link to Gq11 and then to the PLC–IP3–Ca2+ pathway. This pathway is active in isolated human ciliary muscle cells. Other cells in the eye also may express FP receptors. Theories of IOP lowering by PGF range from altered ciliary muscle tension to effects on trabecular meshwork cells to release of matrix metalloproteinases and digestion of extracellular matrix materials that may impede outflow tracts.

The β receptor antagonists now are the next most common topical medical treatment. Nonselective β blockers bind to both β1 and β2 receptors and include timolol, levobunolol, metipranolol, and carteolol. The β1-selective antagonist, betaxolol, is available for ophthalmic use but is less efficacious than the nonselective β blockers because the β receptors of the eye are largely of the β2 subtype. However, betaxolol is less likely to cause breathing difficulty due to blockade of pulmonary β2 receptors. In the eye, the targeted tissues are the ciliary body epithelium and blood vessels, where β2 receptors account for 75-90% of the total population. How β blockade leads to decreased aqueous production and reduced IOP is uncertain. Production of aqueous humor seems to be activated by a β receptor–mediated cyclic AMP–PKA pathway; β blockade blunts adrenergic activation of this pathway. Another hypothesis is that β blockers decrease ocular blood flow, which decreases the ultrafiltration responsible for aqueous production.

When there are medical contraindications to the use of PG analogs or β receptor antagonists, other agents, such as an α2 adrenergic receptor agonist or topical carbonic anhydrase inhibitor (CAI), may be used as first-line therapy. The α2 adrenergic agonists appear to decrease IOP by reducing aqueous humor production and by enhancing both conventional (via an α2 receptor mechanism) and uveoscleral outflow (perhaps via PG production) from the eye. Although effective, epinephrine is poorly tolerated, principally due to localized irritation and hyperemia. Dipivefrin is an epinephrine prodrug that is converted into epinephrine by esterases in the cornea; it is much better tolerated but is still prone to cause epinephrine-like side effects. The α2 adrenergic agonist and clonidine derivative, apraclonidine (IOPIDINE), is a relatively selective α2 adrenergic agonist that is highly ionized at physiological pH and does not cross the blood-brain barrier, and is thus relatively free of the CNS effects of clonidine. Brimonidine (ALPHAGAN, others) also is a selective α2 adrenergic agonist but is lipophilic, enabling easy corneal penetration. Both apraclonidine and brimonidine reduce aqueous production and may enhance some uveoscleral outflow. Both appear to bind to pre- and postsynaptic α2 receptors. By binding to the presynaptic receptors, the drugs reduce the amount of neurotransmitter release from sympathetic nerve stimulation and thereby lower IOP. By binding to postsynaptic α2 receptors, these drugs stimulate the Gi pathway, reducing cellular cyclic AMP production, thereby reducing aqueous humor production.

The development of a topical CAI was prompted by the poor side-effect profile of oral CAIs. Dorzolamide (TRUSOPT, others) and brinzolamide (AZOPT) both work by inhibiting carbonic anhydrase (isoform II), which is found in the ciliary body epithelium. This reduces the formation of bicarbonate ions, which reduces fluid transport and, thus, IOP.

Any of these 4 drug classes can be used as additive second- or third-line therapy. In fact, the β receptor antagonist timolol has been combined with the CAI dorzolamide in a single medication (COSOPT, others) and with the α2 adrenergic agonist brimonidine (COMBIGAN). Such combinations reduce the number of drops needed and may improve compliance.

Topical miotic agents are less commonly used today because of their numerous side effects and inconvenient dosing. Miotics lower IOP by causing muscarinic-induced contraction of the ciliary muscle, which facilitates aqueous outflow. They do not affect aqueous production. Pilocarpine and carbachol are cholinomimetics that stimulate muscarinic receptors. Echothiophate (PHOSPHOLINE IODIDE) is an organophosphate inhibitor of acetylcholinesterase; it is relatively stable in aqueous solution and, by virtue of its quaternary ammonium structure, is positively charged and poorly absorbed. If combined topical therapy fails to achieve the target IOP or fails to halt glaucomatous optic nerve damage, then systemic therapy with CAI is a final medication option before resorting to laser or incisional surgical treatment. The best-tolerated oral preparation is acetazolamide in sustained-release capsules (see Chapter 25), followed by methazolamide. The least well tolerated are acetazolamide tablets.

TOXICITY OF ANTI-GLAUCOMA AGENTS. 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 waxes and wanes between doses. Headaches can occur from the iris and ciliary body contraction. α2 Agonists, effective in IOP reduction, can cause a vasoconstriction–vasodilation rebound phenomenon leading to a red eye. Ocular and skin allergies from topical epinephrine, related prodrug formulations, apraclonidine, and brimonidine are common. Brimonidine is less likely to cause ocular allergy and therefore is more commonly used. These agents can cause CNS depression and apnea in neonates and are contraindicated in children <2 years of age. Systemic absorption of α2 agonists and β adrenergic antagonists can induce all the side effects of systemic administration. The use of CAIs systemically may give some patients significant problems with malaise, fatigue, depression, paresthesias, and nephrolithiasis; the topical CAIs may minimize these relatively common side effects.

Uveitis. Inflammation of the uvea, or uveitis, has both infectious and non-infectious causes, and medical treatment of the underlying cause (if known), in addition to the use of topical therapy, is essential. Cyclopentolate (CYCLOGYL, others), tropicamide (MYDRIACYL), or sometimes even longer-acting antimuscarinic agents such as atropine, scopolamine (ISOPTO HYOSCINE), and homatropine frequently are 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.

If posterior synechiae already have formed, an α adrenergic agonist may be used to break the synechiae by enhancing pupillary dilation. A solution of scopolamine 0.3% in combination with 10% phenylephrine (MUROCOLL-2) is available for this purpose. Two others, 1% hydroxyamphetamine hydrobromide combined with 0.25% tropicamide (PAREMYD) and 1% phenylephrine in combination with 0.2% cyclopentolate (CYCLOMYDRIL), are indicated only for induction of mydriasis. Topical steroids usually are adequate to decrease inflammation, but sometimes they must be supplemented with systemic steroids.

StrabismusStrabismus, or ocular misalignment, has numerous causes and may occur at any age. Besides causing diplopia (double vision), strabismus in children may lead to amblyopia (reduced vision). Nonsurgical efforts to treat amblyopia include occlusion therapy, orthoptics, optical devices, and pharmacological agents.

An eye with hyperopia, or farsightedness, must constantly accommodate to focus on distant images. In some hyperopic children, the synkinetic accommodative-convergence response leads to excessive convergence and a manifest esotropia (turned-in eye). The brain rejects diplopia and suppresses the image from the deviated eye. If proper vision is not restored by ~7 years of age, the brain never learns to process visual information from that eye. The result is that the eye appears structurally normal but does not develop normal visual acuity and is therefore amblyopic. This is a fairly common cause of visual disability. In this setting, atropine (1%) instilled in the preferred seeing eye produces cycloplegia and the inability of this eye to accommodate, thus forcing the child to use the amblyopic eye. Echothiophate iodide also has been used in the setting of accommodative strabismus. Accommodation drives the near reflex, the triad of miosis, accommodation, and convergence. An irreversible cholinesterase inhibitor such as echothiophate causes miosis and an accommodative change in the shape of the lens; hence, the accommodative drive to initiate the near reflex is reduced, and less convergence will occur.

Surgery and Diagnostic Purposes. For certain surgical procedures and for clinical funduscopic examination, it is desirable to maximize the view of the retina and lens. Muscarinic cholinergic antagonists and sympathomimetic agents frequently are used singly or in combination for this purpose (see Table 64–7). Intraoperatively, there are circumstances in which miosis is preferred, and 2 cholinergic agonists are available for intraocular use, acetylcholine (MIOCHOL-E) and carbachol. Patients with myasthenia gravis may first present to an ophthalmologist with complaints of double vision (diplopia) or lid droop (ptosis); the edrophonium test is helpful in diagnosing these patients (see Chapter 10). For surgical visualization of the lens, trypan blue (VISIONBLUE) is marketed to facilitate visualization of the lens and for staining during surgical vitrectomy procedures to guide the excision of tissue (MEMBRANEBLUE).

ANTI-INFLAMMATORY, IMMUNOMODULATORY, AND ANTIMITOTIC DRUGS

GLUCOCORTICOIDS. Glucocorticoids have an important role in managing ocular inflammatory diseases; their chemistry and pharmacology are described in Chapter 42.

Therapeutic Uses. The glucocorticoids formulated for topical administration to the eye are dexamethasone (DEXASOL, others), prednisolone (PRED FORTE, others), fluorometholone (FML, others), loteprednol (ALREX, LOTEMAX), rimexolone (VEXOL), and difluprednate (DUREZOL). Because of their anti-inflammatory effects, topical corticosteroids are used in managing significant ocular allergy, anterior uveitis, external eye inflammatory diseases associated with some infections and ocular cicatricial pemphigoid, and postoperative inflammation following refractive, corneal, and intraocular surgery. After glaucoma filtering surgery, topical steroids can delay the wound-healing process by decreasing fibroblast infiltration, thereby reducing potential scarring of the surgical site. Steroids commonly are given systemically and by sub-Tenon’s capsule injection to manage posterior uveitis. Intravitreal injection of steroids is used to treat age-related macular degeneration (ARMD), diabetic retinopathy, and cystoid macular edema. Two intravitreal triamcinolone formulations, TRIVARIS and TRIESENCE, are approved for ocular inflammatory conditions unresponsive to topical corticosteroids and visualization during vitrectomy, respectively. Parenteral steroids followed by tapering oral doses is the preferred treatment for optic neuritis. An ophthalmic implant of fluocinolone (RETISERT) is marketed for the treatment of chronic, non-infectious uveitis.

Toxicity of Steroids. Ocular complications include the development of posterior subcapsular cataracts, secondary infections, and secondary open-angle glaucoma. There is a significant increase in the risk for developing secondary glaucoma when there is a positive family history of glaucoma. In the absence of a family history of open-angle glaucoma, only ~5% of normal individuals respond to topical or long-term systemic steroids with a marked increase in IOP. With a positive family history, however, moderate to marked steroid-induced IOP elevations may occur in up to 90% of patients. Newer topical steroids, so-called “soft steroids” (e.g., loteprednol), have been developed that reduce, but do not eliminate, the risk of elevated IOP.

Nonsteroidal Anti-Inflammatory Agents. Pharmacological properties of nonsteroidal anti-inflammatory drugs (NSAIDs) are presented in Chapter 34.

Therapeutic Uses. Five topical NSAIDs approved for ocular use: flurbiprofen (OCUFEN, others), ketorolac (ACULAR, others), diclofenac (VOLTAREN, others), bromfenac (XIBROM), and nepafenac (NEVANAC). Flurbiprofen is used to counter unwanted intraoperative miosis during cataract surgery. Ketorolac is given for seasonal allergic conjunctivitis. Diclofenac is used for postoperative inflammation. Both ketorolac and diclofenac are effective in treating cystoid macular edema occurring after cataract surgery and in controlling pain after corneal refractive surgery. Bromfenac and nepafenac are indicated for treating postoperative pain and inflammation after cataract surgery. Topical and systemic NSAIDs occasionally have been associated with sterile corneal melts and perforations, especially in older patients with ocular surface disease, such as dry eye syndrome.

ANTIHISTAMINES AND MAST-CELL STABILIZERS

Pheniramine (see Chapter 32) and antazoline, both H1 receptor antagonists, are formulated in combination with naphazoline, a vasoconstrictor, for relief of allergic conjunctivitis; emedastine difumarate (EMADINE) also is used. Cromolyn sodium (CROLOM, others) has found limited use in treating conjunctivitis that is thought to be allergen mediated, such as vernal conjunctivitis. Lodoxamide tromethamine (ALOMIDE) and pemirolast (ALAMAST), mast-cell stabilizers, also are available for ophthalmic use. Nedocromil (ALOCRIL) also is primarily a mast-cell stabilizer with some antihistamine properties. Olopatadine hydrochloride (PATANOL, PATADAY), ketotifen fumarate (ZADITOR, ALAWAY), bepotastine (BEPREVE), and azelastine (OPTIVAR) are H1 antagonists with mast cell–stabilizing properties. Epinastine (ELESTAT) antagonizes H1 and H2 receptors and exhibits mast cell–stabilizing activity.

IMMUNOSUPPRESSANTS

Topical cyclosporine (cyclosporin A; RESTASIS) is approved for the treatment of chronic dry eye associated with inflammation. Use of cyclosporine is associated with decreased inflammatory markers in the lacrimal gland, increased tear production, and improved vision and comfort. Interferon a-2b is used in the treatment of conjunctival papilloma and certain conjunctival tumors.

ANTIMITOTIC AGENTS. In glaucoma surgery, the anti-neoplastic agents fluorouracil and mitomycin (MUTAMYCIN) (see Chapter 61) improve the success of filtration surgery by limiting the postoperative wound-healing process.

Therapeutic Uses. Mitomycin is used intraoperatively as a single subconjunctival application at the trabeculectomy site. Fluorouracil may be used intraoperatively at the trabeculectomy site and/or subconjunctivally during the postoperative course. Both agents work by limiting the healing process; sometimes this can result in thin, ischemic, avascular tissue that is prone to breakdown. The resultant leaks can cause hypotony (low IOP) and increase the risk of infection. In corneal surgery, mitomycin has been used topically. Mitomycin can be used to reduce the risk of scarring after procedures to remove corneal opacities and prophylactically to prevent corneal scarring after photorefractive and phototherapeutic keratectomy. Mitomycin also is used to treat certain conjunctival and corneal tumors. Caution is advocated when using mitomycin in light of the potentially serious delayed ocular complications.

Intraocular methotrexate (see Chapter 61) is used to treat uveitis and uveitic cystoid macular edema. It also has been used to treat the uncommon complication of lymphoma in the vitreous, an inaccessible compartment for most anti-neoplastic drugs.

AGENTS USED IN OPHTHALMIC SURGERY

Presurgical Antiseptics. Povidone iodine (BETADINE) is formulated as a 5% sterile ophthalmic solution for use prior to surgery to prep periocular skin and irrigate ocular surfaces, including the cornea, conjunctiva, and palpebral fornices. Following irrigation, the exposed tissues are flushed with sterile saline. Hypersensitivity to iodine is a contraindication.

Viscoelastic Substances. Such agents assist in ocular surgery by maintaining spaces, moving tissue, and protecting surfaces. These substances are prepared from hyaluronate (HEALON, others), chondroitin sulfate (VISCOAT), or hydroxypropylmethylcellulose and share the following important physical characteristics: viscosity, shear flow, elasticity, cohesiveness, and coatability. Complications associated with viscoelastic substances are related to transient elevation of IOP after surgery.

Ophthalmic Glue. Cyanoacrylate tissue adhesive (ISODONT, DERMABOND, HISTOACRYL), while not FDA-approved for the eye, is widely used in the management of corneal ulcerations and perforations. Fibrinogen glue (TISSEEL, EVICEL) is increasingly being used on the ocular surface to secure tissue such as conjunctiva, amniotic membrane, and lamellar corneal grafts.

Anterior Segment Gases. Sulfur hexafluoride (SF6) and perfluoropropane gases are used as vitreous substitutes during retinal surgery. They are used in non-expansile concentrations to treat Descemet’s detachments, typically after cataract surgery. These detachments can cause mild to severe corneal edema. The gas is injected into the anterior chamber to push Descemet’s membrane up against the stroma, where ideally it reattaches and clears the corneal edema.

Vitreous Substitutes (Table 64–8). Several compounds, including gases, perfluorocarbon liquids, and silicone oils are available. Their primary use is reattachment of the retina following vitrectomy and membrane-peeling procedures for complicated proliferative vitreoretinopathy and traction retinal detachments. The use of expansile gases carries the risk of complications from elevated IOP, subretinal gas, corneal edema, and cataract formation. The gases are absorbed over a period of days (for air) to 2 months (for perfluoropropane).

Table 64–8

Vitreous Substitutes

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The liquid perfluorocarbons (specific gravity, 1.76-1.94) are denser than vitreous and are helpful in flattening the retina when vitreous is present. Silicone oil (polydimethylsiloxanes; ADATOSIL 5000) is used for long-term tamponade of the retina. Complications from silicone oil use include glaucoma, cataract formation, corneal edema, corneal band keratopathy, and retinal toxicity.

Surgical Hemostasis and Thrombolytic Agents. Hemostasis has an important role in most surgical procedures and usually is achieved by temperature-mediated coagulation. Intravitreal administration of thrombin can assist in controlling intraocular hemorrhage during vitrectomy. When used intraocularly, a potentially significant inflammatory response may occur that can be minimized by thorough irrigation after hemostasis is achieved.

Recombinant tissue plasminogen activator (t-PA; alteplase) (see Chapter 30) has been used during intraocular surgeries to assist evacuation of a hyphema, subretinal clot, or nonclearing vitreous hemorrhage. Alteplase also has been administered subconjunctivally and intracamerally (i.e., controlled intraocular administration into the anterior segment) to lyse blood clots obstructing a glaucoma filtration site. The main complication related to the use of t-PA is bleeding.

Botulinum Toxin Type A in the Treatment of Strabismus, Blepharospasm, and Related Disorders. Botulinum toxin type A is FDA-approved for the treatment of strabismus and blepharospasm associated with dystonia, facial wrinkles (glabellar lines), axillary hyperhidrosis, and spasmodic torticollis (cervical dystonia). Two botulinum toxin type A preparations are marketed in the U.S.: onabotulinumtoxin A (BOTOX, BOTOX COSMETIC) and abobotulinumtoxinA (DYSPORT). By preventing acetylcholine release at the neuromuscular junction, botulinum toxin A usually causes a temporary paralysis of the locally injected muscles. Complications related to this toxin include double vision (diplopia) and lid droop (ptosis) and, rarely, potentially life-threatening distant spread of toxin effect from the injection site (hours to weeks after administration).

Agents Used to Treat Blind and Painful Eye. Retrobulbar injection of either absolute or 95% ethanol may provide relief from chronic pain associated with a blind and painful eye. Retrobulbar chlorpromazine also has been used. This treatment is preceded by administration of local anesthesia. Local infiltration of the ciliary nerves provides symptomatic relief from pain, but other nerve fibers may be damaged, causing paralysis of the extraocular muscles, including those in the eyelids, or neuroparalytic keratitis. The sensory fibers of the ciliary nerves may regenerate, and repeated injections sometimes are needed to control pain.

OCULAR SIDE EFFECTS OF SYSTEMIC AGENTS

Certain systemic drugs have ocular side effects. These can range from mild and inconsequential to severe and vision threatening. Examples are listed in the following sections.

Glaucoma. The anti-seizure drug topiramate (TOPAMAX, others) reportedly causes choroidal effusions leading to angle-closure glaucoma.

Retina. Numerous drugs have toxic side effects on the retina. The anti-arthritis and antimalarial medicines hydroxychloroquine (PLAQUENIL, others) and chloroquine can cause a central retinal toxicity by an unknown mechanism. With normal dosages, toxicity does not appear until ~6 years after the drug is started. Stopping the drug will not reverse the damage but will prevent further toxicity. Tamoxifen can cause a crystalline maculopathy. The antiseizure drug vigabatrin (SABRIL) causes progressive and permanent bilateral concentric visual field constriction in a high percentage of patients.

Optic Nerve. The PDE5 inhibitors, sildenafil (VIAGRA, REVATIO), vardenafil (LEVITRA), and tadalafil (CIALIS, ADCIRCA), inhibit PDE5 in the corpus cavernosum to help achieve and maintain penile erection. The drugs also mildly inhibit PDE6, which controls the levels of cyclic GMP in the retina, causing a bluish haze or light sensitivity. Multiple medications can cause a toxic optic neuropathy characterized by gradually progressive bilateral central scotomas and vision loss, including ethambutol, chloramphenicol, and rifampin. Systemic or ocular steroids can cause elevated IOP and glaucoma. If the steroids cannot be stopped, glaucoma medications, and even filtering surgery, often are required.

Anterior Segment. Steroids have been implicated in cataract formation. Rifabutin, if used in conjunction with clarithromycin or fluconazole for treatment of Mycobacterium avium complex (MAC) opportunistic infections in human immunodeficiency virus (HIV)-positive persons, is associated with an iridocyclitis and even hypopyon. This will resolve with steroids or by stopping the medication.

Ocular Surface. Isotretinoin (ACCUTANE, others) has a drying effect on mucous membranes and is associated with dry eye and meibomian gland dysfunction.

Cornea Coryanghiva and Eyelids. The cornea, conjunctiva, and eyelids can be affected by systemic medications. One of the most common drug deposits found in the cornea is from the cardiac medication amiodarone. It deposits in the inferior and central cornea in a whorl-like pattern termed cornea verticillata, appearing as fine tan or brown pigment in the epithelium. The deposits seldom affect vision and are rarely a cause to discontinue the medication. The deposits disappear slowly when the medication is stopped. Other medications, including indomethacin, atovaquone, chloroquine, and hydroxychloroquine, can cause a similar pattern. The phenothiazines, including chlorpromazine and thioridazine, can cause brown pigmentary deposits in the cornea, conjunctiva, and eyelids. They typically do not affect vision. The ocular deposits generally persist after discontinuation of the medication and can even worsen. Tetracyclines can cause a yellow discoloration of the light-exposed conjunctiva. Systemic minocycline can induce a blue-gray scleral pigmentation that is most prominent in the interpalpebral zone.

AGENTS USED TO ASSIST IN OCULAR DIAGNOSIS

A number of agents are used in an ocular examination (e.g., mydriatic agents, topical anesthetics, dyes to evaluate corneal surface integrity), to facilitate intraocular surgery (e.g., mydriatic and miotic agents, topical and local anesthetics), and to help in making a diagnosis in cases of anisocoria and retinal abnormalities (e.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.

Anterior Segment and External Diagnostic Uses. Epiphora (excessive tearing) and surface problems of the cornea and conjunctiva are commonly encountered external ocular disorders. The dyes fluorescein, rose bengal, and lissamine green are used in evaluating these problems. Fluorescein (available as a 2% alkaline solution, 10% and 25% solutions for injection, and an impregnated paper strip) reveals epithelial defects of the cornea and conjunctiva and aqueous humor leakage that may occur after trauma or ocular surgery. In the setting of epiphora, fluorescein is used to determine the patency of the nasolacrimal system. In addition, this dye is used in applanation tonometry (IOP measurement) and to assist in determining the proper fit of rigid and semirigid contact lenses. Fluorescein in combination with proparacaine or benoxinate is available for procedures in which a disclosing agent is needed in conjunction with a topical anesthetic. Fluorexon (FLUORESOFT), a high-molecular-weight fluorescent solution, is used when fluorescein is contraindicated (as when soft contact lenses are in place). Rose bengal and lissamine green (available as saturated paper strips) stain devitalized tissue on the cornea and conjunctiva.

Posterior Segment Diagnostic Uses. The integrity of the blood-retinal and retinal pigment epithelial barriers may be examined directly by retinal angiography using intravenous administration of eitherfluorescein sodium or indocyanine green. These agents commonly cause nausea and may precipitate serious allergic reactions in susceptible individuals.

TREATMENT OF RETINAL NEOVASCULARIZATION AND MACULAR DEGENERATION

Verteporfin (VISUDYNE) is approved for photodynamic therapy of the exudative form of ARMD with predominantly classic choroidal neovascular membranes. Verteporfin also is used in the treatment of predominantly classic choroidal neovascularization caused by conditions such as pathological myopia and presumed ocular histoplasmosis syndrome. Verteporfin is administered intravenously; once it reaches the choroidal circulation, the drug is light activated by a nonthermal laser source. Activation of the drug in the presence of oxygen generates free radicals, which cause vessel damage and subsequent platelet activation, thrombosis, and occlusion of choroidal neovascularization. The t1/2 of the drug is 5-6 h; it is eliminated predominantly in the feces. Potential side effects include headache, injection-site reactions, and visual disturbances. The drug causes temporary photosensitization; patients must avoid exposure of the skin or eyes to direct sunlight or bright indoor lights for 5 days after receiving it.

Pegaptanib (MACUGEN), a selective vascular endothelial growth factor (VEGF) antagonist, is approved for neovascular (wet) ARMD. VEGF165 induces angiogenesis and increases vascular permeability and inflammation, which actions likely contribute to the progression of the neovascular (wet) form of ARMD, a leading cause of blindness. Pegaptanib inhibits VEGF165 binding to VEGF receptors. Pegaptanib (0.3 mg) is administered once every 6 weeks by intravitreous injection into the eye to be treated. Following the injection, patients should be monitored for elevation in IOP and for endophthalmitis. Rare cases of anaphylaxis/anaphylactoid reactions have been reported.

Eylea (AFLIBERCEPT) is a recombinant fusion protein, consisting of portions of human VEGF receptors 1 and 2, that acts as a soluble decoy receptor for VEGF-A. It is approved for neovascular (wet) form of ARMD. Aflibercept (2 mg) is administered once every 4 weeks by intravitreous injection into the eye for 12 weeks followed by 2 mg once every 8 weeks. Serious side effect may include eye pain or redness, swelling, vision problems, photosensitivity, headaches, sudden numbness on one side of the body, confusion, and problems with speech and balance. The drug is contraindicated in patients who have an active eye inflection active ocular inflammation.

Bevacizumab (AVASTIN) is a monoclonal murine antibody that targets VEGF-A and thereby inhibits vascular proliferation and tumor growth (see Chapter 62).

Ranibizumab (LUCENTIS) is a variant of bevacizumab that has had the Fab domain affinity matured. Both drugs are delivered by intravitreal injection and often are used on a weekly or monthly basis for maintenance therapy. Both have been associated with the risk of cerebral vascular accidents.

ANESTHETICS IN OPHTHALMIC PROCEDURES

Topical anesthetic agents used clinically in ophthalmology include proparacaine and tetracaine drops, lidocaine gel (see Chapter 20), and intranasal cocaine.

Cocaine may be used intranasally in combination with topical anesthesia for cannulating the nasolacrimal system. Lidocaine and bupivacaine are used for infiltration and retrobulbar block anesthesia for surgery. Potential complications and risks relate to allergic reactions, globe perforation, hemorrhage, and vascular and subdural injections. Both preservative-free lidocaine (1%), which is introduced into the anterior chamber, and lidocaine jelly (2%), which is placed on the ocular surface during preoperative patient preparation, are used for cataract surgery performed under topical anesthesia. Most inhalational agents and CNS depressants are associated with a reduction in IOP. An exception is ketamine, which has been associated with an elevation in IOP. In the setting of a patient with a ruptured globe, the anesthesia should be selected carefully to avoid agents that depolarize the extraocular muscles, which may result in expulsion of intraocular contents.

VITAMIN A

Vitamin deficiencies can alter eye function, especially a deficiency of vitamin A (Table 64–9). In vision, the functional form of vitamin A is retinal; its deficiency interferes with vision in dim light, contributing to a condition known as night blindness (nyctalopia).

Table 64–9

Ophthalmic Effects of Selected Vitamin Defciencies and Zinc Deficiency

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Chemistry and TerminologyRetinoid refers to the chemical entity retinol and other closely related naturally occurring derivatives. Retinoids, which exert most of their effects by binding to specific nuclear receptors and modulating gene expression, also include structurally related synthetic analogs that need not have retinol-like (vitamin A) activity. The purified plant pigment carotene (provitamin A) is a protean source of vitamin A. β-Carotene is the most active carotenoid found in plants. The structural formulas for β-carotene and the vitamin A family of retinoids are shown in Figure 64–6. Retinoic acid analogs used clinically are discussed in detail in Chapter 65.

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Figure 64–6 β-carotene and some members of the vitamin A family of retinoids.

RETINAL AND THE VISUAL CYCLE

Photoreception is accomplished by 2 types of specialized retinal cells, termed rods and cones. Rods are especially sensitive to light of low intensity; cones act as receptors of high-intensity light and are responsible for color vision. The chromophore of both rods and cones is 11-cis-retinal. The holoreceptor in rods is termed rhodopsin—a combination of the protein opsin and 11-cis-retinal attached as a prosthetic group. The 3 different types of cone cells (red, green, and blue) contain individual, related photoreceptor proteins and respond optimally to light of different wavelengths. Figure 64–7 summarizes the signaling pathway initiated by absorption of a photon by 11-cis-retinal in rods.

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Figure 64–7 A pharmacologist’s view of photoreceptor signaling. The system is an example of GPCR signaling. The basal state (DARK) is represented by the shaded area to the left. The signal, a photon, activates the receptor, rhodopsin, resulting in the isomerization of 11-cis-retinal to all-trans-retinal and initiating the LIGHT reactions (on the right side of the figure). The main characteristics of the DARK and LIGHT states are summarized in the boxes at the bottom of each section. The guanylyl cyclase activity is constitutively active and enhanced by Ca2+. Mostly Na+ and some Ca2+ enter via the CNG channels, contributing to depolarization. The Na+/Ca2+ exchanger (NCX), Na+/K+ ATPase, and K+ currents are active and contribute to hyperpolarization. PDE5 inhibitors such as sildenafil also inhibit PDE6, causing a bluish cast to vision. αt, the α sub-unit of transducin; CNG, cyclic nucleotide gated.

VITAMIN A DEFICIENCY AND VISION. Humans deficient in vitamin A lose their ability for dark adaptation. Rod vision is affected more than cone vision. Upon depletion of retinol from liver and blood, usually at plasma concentrations of retinol of <0.2 mg/L (0.70 µM), the concentrations of retinol and rhodopsin in the retina fall. Unless the deficiency is overcome, opsin, lacking the stabilizing effect of retinal, decays, and anatomical deterioration of the rod outer segment occurs.

Vitamin A and Epithelial Structures. In the presence of retinol or retinoic acid, basal epithelial cells are stimulated to produce mucus. Excessive concentrations of the retinoids lead to the production of a thick layer of mucin, the inhibition of keratinization, and the display of goblet cells. In the absence of vitamin A, goblet mucous cells disappear and are replaced by basal cells that have been stimulated to proliferate. These undermine and replace the original epithelium with a stratified, keratinizing epithelium. The suppression of normal secretions leads to irritation and infection. Reversal of these changes is achieved by the administration of retinol, retinoic acid, or other retinoids. When this process happens in the cornea, severe hyperkeratinization (xerophthalmia) may lead to permanent blindness. Common causes of vitamin A deficiency include malnutrition and bariatric surgery.

Retinoic acid influences gene expression by combining with nuclear receptors (see Figures 3–12 and 6–8). There are 2 families of retinoid receptors: the retinoic acid receptors (RARs), and the retinoid X receptors (RXRs). The endogenous RXR ligand is 9-cis-retinoic acid.

Therapeutic Uses. Nutritional vitamin A deficiency causes xerophthalmia, a progressive disease characterized by nyctalopia (night blindness), xerosis (dryness), and keratomalacia (corneal thinning), which may lead to corneal perforation. Vitamin A therapy can reverse xerophthalmia; however, rapid, irreversible blindness ensues once the cornea perforates. Vitamin A also is involved in epithelial differentiation and may have a role in corneal epithelial wound healing. The current recommendation for retinitis pigmentosa is to administer 15,000 IU of vitamin A palmitate daily under the supervision of an ophthalmologist and to avoid high-dose vitamin E. Clinical studies suggest a reduction in the risk of progression of some types of ARMD by high doses of vitamins C (500 mg), E (400 IU), β-carotene (15 mg), cupric oxide (2 mg), and zinc (80 mg).

WETTING AGENTS AND TEAR SUBSTITUTES

The current management of dry eyes usually includes instilling artificial tears and ophthalmic lubricants. In general, tear substitutes are hypotonic or isotonic solutions composed of electrolytes, surfactants, preservatives, and some viscosity-increasing agent that prolongs the residence time in the cul-de-sac and precorneal tear film.

Common viscosity agents include cellulose polymers, polyvinyl alcohol, polyethylene glycol, polysorbate, mineral oil, glycerin, and dextran. The tear substitutes are available as preservative-containing or preservative-free preparations. The viscosity of the tear substitute depends on its exact formulation and can range from watery to gel like. Some tear formulations also are combined with a vasoconstrictor, such as naphazoline, phenylephrine, or tetrahydrozoline. Tyloxapol (ENUCLENE) is marketed as an over-the-counter ophthalmic preparation used to facilitate the wearing comfort of artificial eyes. The lubricating ointments are composed of a mixture 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, in critically ill patients, or in very severe dry eye conditions. A hydroxypropyl cellulose ophthalmic insert (LACRISERT) that is placed in the inferior cul-de-sac and dissolves during the day is available to treat dry eyes.

Therapeutic Uses. Local eye disease, such as blepharitis, ocular rosacea, ocular pemphigoid, chemical burns, or corneal dystrophies, may alter the ocular surface and change the tear composition. Appropriate treatment of the symptomatic dry eye includes treating the accompanying disease and possibly the addition of tear substitutes, punctal plugs (see “Absorption”), or ophthalmic cyclosporine (see “Immunosuppressants”). There also are a number of systemic conditions that may manifest themselves with symptomatic dry eyes, including Sjögren syndrome, rheumatoid arthritis, vitamin A deficiency, Stevens-Johnson syndrome, and trachoma. Treating the systemic disease may not eliminate the symptomatic dry eye complaints; chronic therapy with tear substitutes, ophthalmic cyclosporine, insertion of punctal plugs, placement of dissolvable collagen implants, or surgical occlusion of the lacrimal drainage system may be indicated. Ophthalmic cyclosporine (RESTASIS) can be used to increase tear production in patients with ocular inflammation associated with keratoconjunctivitis sicca.

OSMOTIC AGENTS

The main osmotic drugs for ocular use are glycerin, mannitol, and hypertonic saline. Glycerin and mannitol are used for short-term management of acute rises in IOP. Sporadically, these agents are used intraoperatively to dehydrate the vitreous prior to anterior segment surgical procedures. Many patients with acute glaucoma do not tolerate oral medications because of nausea; therefore, intravenous administration of mannitol and/or acetazolamide may be preferred over oral administration of glycerin. These agents should be used with caution in patients with congestive heart failure or renal failure.

Corneal edema is a clinical sign of corneal endothelial dysfunction, and topical osmotic agents may effectively dehydrate the cornea. Sodium chloride is available in either aqueous or ointment formulations. Topical glycerin also is available; however, because it causes pain on contact with the cornea and conjunctiva, its use is limited to urgent evaluation of filtration-angle structures. In general, when corneal edema occurs secondary to acute glaucoma, the use of an oral osmotic agent to help reduce IOP is preferred over topical glycerin, which simply clears the cornea temporarily. Reducing the IOP 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.